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Why do we make hasty decisions for short-term gain? Rapid decision-making with limited accumulation of evidence and delay discounting are forms of decisional impulsivity. The subthalamic nucleus is implicated in inhibitory function but its role in decisional impulsivity is less well-understood. Here we assess decisional impulsivity in subjects with obsessive compulsive disorder who have undergone deep brain stimulation of the limbic and associative subthalamic nucleus. We show that stimulation of the subthalamic nucleus is causally implicated in increasing decisional impulsivity with less accumulation of evidence during probabilistic uncertainty and in enhancing delay discounting. Subthalamic stimulation shifts evidence accumulation in subjects with obsessive-compulsive disorder towards a functional less cautious style closer to that of healthy controls emphasizing its adaptive nature. Thus, subjects with obsessive compulsive disorder on subthalamic stimulation may be less likely to check for evidence (e.g. checking that the stove is on) with no difference in subjective confidence (or doubt). In a separate study, we replicate in humans (154 healthy controls) using resting state functional connectivity, tracing studies conducted in non-human primates dissociating limbic, associative and motor frontal hyper-direct connectivity with anterior and posterior subregions of the subthalamic nucleus. We show lateralization of functional connectivity of bilateral ventral striatum to right anterior ventromedial subthalamic nucleus consistent with previous observations of lateralization of emotionally evoked activity to right ventral subthalamic nucleus. We use a multi-echo sequence with independent components analysis, which has been shown to have enhanced signal-to-noise ratio, thus optimizing visualization of small subcortical structures. These findings in healthy controls converge with the effective contacts in obsessive compulsive disorder patients localized within the anterior and ventral subthalamic nucleus. We further show that evidence accumulation is associated with anterior associative-limbic subthalamic nucleus and right dorsolateral prefrontal functional connectivity in healthy controls, a region implicated in decision-making under uncertainty. Together, our findings highlight specificity of the anterior associative-limbic subthalamic nucleus in decisional impulsivity. Given increasing interest in the potential for subthalamic stimulation in psychiatric disorders and the neuropsychiatric symptoms of Parkinson's disease, these findings have clinical implications for behavioural symptoms and cognitive effects as a function of localization of subthalamic stimulation. [ABSTRACT FROM AUTHOR]

Aims: Several pacing modalities across multiple manufacturers have been introduced to minimize unnecessary right ventricular pacing. We conducted a meta-analysis to assess whether ventricular pacing reduction modalities (VPRM) influence hard clinical outcomes in comparison to standard dual-chamber pacing (DDD).Methods and Results: An electronic search was performed using Cochrane Central Register, PubMed, Embase, and Scopus. Only randomized controlled trials (RCT) were included in this analysis. Outcomes of interest included: frequency of ventricular pacing (VP), incident persistent/permanent atrial fibrillation (PerAF), all-cause hospitalization and all-cause mortality. Odds ratios (OR) were reported for dichotomous variables. Seven RCTs involving 4119 adult patients were identified. Ventricular pacing reduction modalities were employed in 2069 patients: (MVP, Medtronic Inc.) in 1423 and (SafeR, Sorin CRM, Clamart) in 646 patients. Baseline demographics and clinical characteristics were similar between VPRM and DDD groups. The mean follow-up period was 2.5 ± 0.9 years. Ventricular pacing reduction modalities showed uniform reduction in VP in comparison to DDD groups among all individual studies. The incidence of PerAF was similar between both groups {8 vs. 10%, OR 0.84 [95% confidence interval (CI) 0.57; 1.24], P = 0.38}. Ventricular pacing reduction modalities showed no significant differences in comparison to DDD for all-cause hospitalization or all-cause mortality [9 vs. 11%, OR 0.82 (95% CI 0.65; 1.03), P= 0.09; 6 vs. 6%, OR 0.97 (95% CI 0.74; 1.28), P = 0.84, respectively].Conclusion: Novel VPRM measures effectively reduce VP in comparison to standard DDD. When actively programmed, VPRM did not improve clinical outcomes and were not superior to standard DDD programming in reducing incidence of PerAF, all-cause hospitalization, or all-cause mortality. [ABSTRACT FROM AUTHOR]

Background:  We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.Methods:  Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH).Results:  All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic.Conclusions:  SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.Clinical Trials Registration:  NCT01705990. [ABSTRACT FROM AUTHOR]

Aims: Electrophysiological simulations may help to investigate causes and possible treatments of ventricular conduction disturbances. Most electrophysiological models do not take into account that the heart moves during the cardiac cycle. We used an electro-mechanical model to study the effect of mechanical deformation on the results of electrophysiological simulations.Methods and Results: Pseudo-electrocardiogram (ECG) were generated from the propagation of electrical signals in tissue slabs undergoing active mechanical deformation. We used the mono-domain equation for electrophysiology with the Bueno-Orovio ionic model and a fully incompressible Guccione-Costa hyperelastic law for the mechanics with the Nash-Panfilov model for the active force. We compared a purely electrophysiological approach (PE) with mono-directional (MD) and bi-directional (BD) electromechanical coupling strategies. The numerical experiments showed that BD and PE simulations led to different S- and T-waves. Mono-directional simulations generally approximated the BD ones, unless fibres were oriented along one short axis of the slab. When present, notching in the QRS-complex was larger in MD than in BD simulations.Conclusions: Tissue deformation has to be taken into account when estimating the S- and T-wave of the ECG in electrophysiological simulations. [ABSTRACT FROM AUTHOR]

Background. Chronic inflammatory and peripheral neuropathic pain (PNP) is a major health problem for which effective drug treatment is lacking. The pathophysiology of these debilitating conditions is incompletely understood, but nerve growth factor (NGF) is believed to play a major role. NGFantagonism has previously been shown to prevent pain hypersensitivity in rodent models of acute inflammatory pain and PNP, but most of those animal studies did not address the more clinically relevant issue of whether NGF-antagonism provides relief of established chronic pain behavior. Therefore, the aim of this study was to investigate whether blocking NGF actions with a humanized anti-NGF monoclonal antibody (PG110) would reverse/ attenuate established pain hypersensitivity in rat models of chronic/persistent inflammatory pain and PNP. Methods. The complete Freund's adjuvant (CFA) rat model of persistent inflammatory pain, and the L5 spinal nerve axotomy (SNA) model of PNP, were used in the present study. The effect of a single intravenous injection (10, 30, and 300 μg/kg) of an anti-NGF antibody PG110 on heat and mechanical hypersensitivity was assessed 5 and 7 days after CFA and SNA, respectively. Results. Compared to vehicle treated group, PG110 dose dependently attenuated established heat and mechanical hypersensitivity induced by CFA, but not that induced by SNA. The anti-allodynic and anti-hyperalgesic effects of PG110 in the CFA model were similar to those of the positive control naproxen (30mg/kg, i.v.). Conclusion. These findings suggest that therapies that target NGF or its receptors may be effective for treatment of persistent/chronic inflammatory pain, but probably not PNP. [ABSTRACT FROM AUTHOR]

Study Question: In comparison to in vivo development, how do different conditions of in vitro culture ('one step' versus 'sequential medium') impact DNA methylation and hydroxymethylation in preimplantation embryos?Summary Answer: Using rabbit as a model, we show that DNA methylation and hydroxymethylation are both affected by in vitro culture of preimplantation embryos and the effect observed depends on the culture medium used.What Is Known Already: Correct regulation of DNA methylation is essential for embryonic development and DNA hydroxymethylation appears more and more to be a key player. Modifications of the environment of early embryos are known to have long term effects on adult phenotypes and health; these probably rely on epigenetic alterations.Study Design Size, Duration: The study design we used is both cross sectional (control versus treatment) and longitudinal (time-course). Each individual in vivo experiment used embryos flushed from the donor at the 2-, 4-, 8-, 16- or morula stage. Each stage was analyzed in at least two independent experiments. Each individual in vitro experiment used embryos flushed from donors at the 1-cell stage (19 h post-coïtum) which were then cultured in parallel in the two tested media until the 2-, 4-, 8- 16-cell or morula stages. Each stage was analyzed in at least three independent experiments. In both the in vivo and in vitro experiments, 4-cell stage embryos were always included as an internal reference.Participants/materials, Setting, Methods: Immunofluorescence with antibodies specific for 5-methylcytosine (5meC) and 5-hydroxymethylcytosine (5hmeC) was used to quantify DNA methylation and hydroxymethylation levels in preimplantation embryos. We assessed the expression of DNA methyltransferases (DNMT), of ten eleven translocation (TET) dioxigenases and of two endogenous retroviral sequences (ERV) using RT-qPCR, since the expression of endogenous retroviral sequences is known to be regulated by DNA methylation. Three repeats were first done for all stages; then three additional repetitions were performed for those stages showing differences or tendencies toward differences between the different conditions in the first round of quantification.Main Results and the Role Of Chance: The kinetics of DNA methylation and hydroxymethylation were modified in in vitro cultured embryos, and the observed differences depended on the type of medium used. These differences were statistically significant. In addition, the expression of TET1 and TET2 was significantly reduced in post-embryonic genome activation (EGA) embryos after in vitro culture in both tested conditions. Finally, the expression of two retroviral sequences was analyzed and found to be significantly affected by in vitro culture.Limitations Reasons For Caution: Our study remains mostly descriptive as no direct link can be established between the epigenetic changes observed and the expression changes in both effectors and targets of the studied epigenetic modifications. The results we obtained suggest that gene expression could be affected on a large scale, but this remains to be confirmed.Wider Implications Of the Findings: Our results are in agreement with the literature, showing that DNA methylation is sensitive to in vitro culture. As we observed an effect of both tested culture conditions on the tested epigenetic marks and on gene expression, we cannot conclude which medium is potentially closest to in vivo conditions. However, as the observed effects are different, additional studies may provide more information and potential recommendations for the use of culture media in assisted reproductive technology.Study Funding/competing Interests: This work was supported by an 'AMP diagnostic prénatal et diagnostic génétique' 2012 grant from the French Agence de la Biomédecine. This study was performed within the framework of ANR LABEX 'REVIVE' (ANR-10-LABX-73). Authors are members of RGB-Net (TD 1101) and Epiconcept (FA 1201) COST actions. The authors declare that there is no competing interest. [ABSTRACT FROM AUTHOR]

Background:  Bacterial vaginosis (BV) is characterized by low abundance of Lactobacillus species, high pH, and immune cell infiltration and has been associated with an increased risk of human papillomavirus (HPV) infection. We molecularly assessed the cervicovaginal microbiota over time in human immunodeficiency virus (HIV)-infected and HIV-uninfected women to more comprehensively study the HPV-microbiota relationship, controlling for immune status.Methods:  16S ribosomal RNA gene amplicon pyrosequencing and HPV DNA testing were conducted annually in serial cervicovaginal lavage specimens obtained over 8-10 years from African American women from Chicago, of whom 22 were HIV uninfected, 22 were HIV infected with a stable CD4+ T-cell count of > 500 cells/mm3, and 20 were HIV infected with progressive immunosuppression. Vaginal pH was serially measured.Results:  The relative abundances of Lactobacillus crispatus and other Lactobacillus species were inversely associated with vaginal pH (all P < .001). High (vs low) L. crispatus relative abundance was associated with decreased HPV detection (odds ratio, 0.48; 95% confidence interval, .24-.96; Ptrend = .03) after adjustment for repeated observation and multiple covariates, including pH and study group. However, there were no associations between HPV and the relative abundance of Lactobacillus species as a group, nor with Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii individually.Conclusions:  L. crispatus may have a beneficial effect on the burden of HPV in both HIV-infected and HIV-uninfected women (independent of pH). [ABSTRACT FROM AUTHOR]

Objectives: Carbapenemase-resistant bacteria are increasingly spreading worldwide causing public concern due to their ability to elude antimicrobial treatment. Early identification of these bacteria is therefore of high importance. Here, we describe the development of a simple and robust protocol for the detection of carbapenemase activity in clinical isolates of Enterobacteriaceae, suitable for routine and clinical applications.Methods: The final protocol involves cellular lysis and enzyme extraction from a defined amount of bacterial cells followed by the addition of a benchmark drug (e.g. the carbapenem antibiotic imipenem or ertapenem). Carbapenem inactivation is mediated by enzymatic hydrolysis (cleavage) of the β-lactam common structural motif, which can be detected using MALDI-TOF MS.Results: A total of 260 strains were studied (208 carbapenemase producers and 52 non-carbapenemase producers) resulting in 100% sensitivity and 100% specificity for the KPC, NDM and OXA-48-like PCR-confirmed positive isolates using imipenem as benchmark. Differences between the benchmark (indicator) antibiotics imipenem and ertapenem, buffer constituents and sample preparation methods have been investigated. Carbapenemase activity was further characterized by performing specific inhibitor experiments. Intraday and interday reproducibility (coefficient of variation) of the observed hydrolysis results were 15% and 30%, respectively. A comparative study of our extraction method and a recently published method using whole bacterial cells is presented and differences are discussed.Conclusions: Using this method, an existing carbapenemase activity can be directly read from the mass spectrum as a ratio of hydrolysed product and substrate, setting an important step towards routine application in clinical laboratories. [ABSTRACT FROM AUTHOR]

Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures. [ABSTRACT FROM AUTHOR]

Aims: We investigated the applicability of the Ventricular Capture Control (VCC) and Atrial Capture Control (ACC) algorithms for automatic management of cardiac stimulation featured by Biotronik pacemakers in a broad, unselected population of pacemaker recipients.Methods and Results: Ventricular Capture Control and Atrial Capture Control were programmed to work at a maximum adapted output voltage as 4.8 V in consecutive recipients of Biotronik pacemakers. Ambulatory threshold measurements were made 1 and 12 months after pacemaker implant/replacement in all possible pacing/sensing configurations, and were compared with manual measurements. Among 542 patients aged 80 (73-85) years, 382 had a pacemaker implant and 160 a pacemaker replacement. Ventricular Capture Control could work at long term in 97% of patients irrespectively of pacing indication, lead type, and lead service life, performance being superior with discordant pacing/sensing configurations. Atrial Capture Control could work in 93% of patients at 4.8 V maximum adapted voltage and at any pulse width, regardless of pacing indication, lead type, and service life. At 12-month follow-up, a ventricular threshold increase ≥1.5 V had occurred in 4.4% of patients uneventfully owing to VCC functioning. Projected pacemaker longevity at 1 month was strongly correlated with the 12-month estimate, and exceeded 13 years in >60% of patients.Conclusion: These algorithms for automatic management of pacing output ensure patient safety in the event of a huge increase of pacing threshold, while enabling maximization of battery longevity. Their applicability is quite broad in an unselected pacemaker population irrespectively of lead choice and service of life. [ABSTRACT FROM AUTHOR]

Introduction: Adequate evaluation of novel tobacco products must include investigation of consumers' psychological response to such products. Traditionally, subjective scales of product liking have been used to assess consumer acceptability of tobacco products. However, subjective scales may miss cognitive changes that can only be captured by direct neurophysiological assessment. The present investigation explored the viability of using electroencephalography (EEG), in combination with traditional subjective measures, to assess consumer acceptability of five smokeless tobacco products. Given previous work linking product liking to arousal/attentional (executive function) enhancement, we focused on EEG measures of attention/arousal to objectively characterize cognitive changes associated with tobacco product use.Methods: During five separate laboratory visits, smokeless tobacco users used Verve discs, Ariva dissolvables, Skoal snuff, Camel snus, or Nicorette lozenges. The N2 and P3b event-related potential components elicited by an oddball task were used to index attentional changes before/after product usage. Additionally, resting state alpha band EEG activity was analyzed before/after product usage to index cortical arousal.Results: Although analyses of the subjective results provided limited inference, analyses of the electrophysiological measures, particularly the alpha suppression measure, revealed robust differences between products. Skoal elicited significantly enhanced alpha suppression compared to all four other products tested. Additionally, alpha suppression was found to correlate positively with subjective measures of satisfaction and psychological reward, but was unrelated to perceived aversion.Conclusions: The present results provide evidence that electrophysiological measures can yield important insights into consumer acceptability of novel tobacco products and are a valuable complement to subjective measures.Implications: This study is the first to employ a combination of electrophysiological measures and traditional subjective assays in order to assess the consumer acceptability of smokeless tobacco products. The results highlight the importance of adopting a multidimensional/multi-method approach to studying the consumer acceptability of tobacco products. [ABSTRACT FROM AUTHOR]

Introduction: Nicotine dependence and smoking frequency are critical factors for smoking cessation. The aims of this study are (1) to determine if nicotine dependence Fagerström Test for Nicotine Dependence (FTND) scores are associated with urinary levels of nicotine metabolites, (2) to assess the relationship of hydroxycotinine/cotinine ratio with FTND score and cigarettes smoked per day (CPD), and (3) to identify significant predictors of cigarettes per day among biomarker concentrations and individual FTND items.Methods: Urine samples and questionnaire data of 239 daily smokers were obtained. Nicotine, cotinine and hydroxycotinine urinary levels were determined by UPLC MS/MS.Multiple linear regression models were developed to explore the relationship between nicotine, cotinine, hydroxycotinine levels and separate FTND scores (for all six items).Results: We found significant correlations between the different urinary biomarker concentrations, and the FTND score. The time before the first cigarette after waking (TTFC) was significantly associated with the nicotine, cotinine and hydroxycotinine concentrations. No association was found between the ratio of hydroxycotinine to cotinine and either the FTND or the CPD. A model including four FTND questions, sex, age, and the cotinine concentration, accounted for 45% of the variance of CPD.Conclusions: There are significant relationships between urinary levels of nicotine, cotinine, and hydroxycotinine and the FTND score. Especially the FTND question about TTFC is relevant for explaining the biomarker concentrations. CPD (below 15) was significantly explained by four FTND dependence items and urinary cotinine levels in a regression model.Implications: We investigated associations between urinary levels of nicotine, cotinine, and hydroxycotinine in daily smokers and the FTND scores for nicotine dependence. We did not find association between the hydroxycotinine/cotinine ratio and CPD. We developed a model that explains the cigarettes smoked daily (CPD) in a group of light smokers by combining FTND items, urinary cotinine levels, sex, and age. Our results might be of importance for clinical use or future studies on larger smoking populations. [ABSTRACT FROM AUTHOR]

Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders.The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face. [ABSTRACT FROM AUTHOR]

With aging, there is a decline in cardiac function accompanying increasing risk of arrhythmias. These effects are likely to be mechanistically associated with age-associated changes in calcium regulation within cardiac myocytes. Previous studies suggest that lifelong exercise can potentially reduce age-associated changes in the heart. Although exercise itself is associated with changes in cardiac function, little is known about the interactions of aging and exercise with respect to myocyte calcium regulation. To investigate this, adult (12 months) and old (24 months) C57/Bl6 mice were trained using moderate-intensity treadmill running. In response to 10 weeks' training, comparable cardiac hypertrophic responses were observed, although aging independently associated with additional cardiac hypertrophy. Old animals also showed increased L- and T-type calcium channels, the sodium-calcium exchange, sarcoendoplasmic reticulum calcium ATPase, and collagen (by 50%, 92%, 66%, 88%, and 113% respectively). Short-term exercise training increased D-type and T-type calcium channels in old animals only, whereas an increase in sodium-calcium exchange was seen only in adult animals. Long-term (12 months) training generally opposed the effects of aging. Significant hypertrophy remained in long-term trained old animals, but levels of sarcoendoplasmic reticulum calcium ATPase, sodium-calcium exchange, and collagen were not significantly different from those found in the adult trained animals. [ABSTRACT FROM AUTHOR]

Background: Decreased cortical excitability has been proposed as a potential mechanism underlying task failure during sustained muscular contractions, and cortical excitability may decrease with old age. We tested the hypothesis that transcranial direct current stimulation, which has been reported to raise cortical excitability, would prolong the time to task failure during a sustained muscular contraction in older adults.Methods: Thirteen older adults (68.3±2.0 years; eight women and five men) performed isometric, elbow flexions to failure while receiving sham or anodal transcranial direct current stimulation. Order of stimulation was randomized, and the subjects and investigators were blinded to condition. Time to task failure was measured alongside selected psychological indices of perceived exertion and affect.Results: Anodal transcranial direct current stimulation prolonged mean time to task failure by approximately 15% (16.9±2.2 vs 14.7±1.8 minutes) and slowed the rate of increase in rating of perceived exertion (0.29±0.03 vs 0.31±0.03) relative to the sham condition.Conclusions: These preliminary findings suggest that anodal transcranial direct current stimulation enhances time to task failure of a sustained, submaximal contraction in older adults by potentially increasing cortical excitability and/or influencing the perception of exertion. These results raise the question of whether interventions that acutely increase cortical excitability could enhance physical function and/or exercise-induced adaptations in older adults. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a common and severe neurodegenerative disorder. Human telomeres are fundamental for the maintenance of genomic stability and play prominent roles in both cellular senescence and organismal aging. Regulation of telomere length (TL) is the result of the complex interplay between environmental and genetic factors. Alterations in TL are increasingly being studied as a possible risk factor for AD, and published studies on TL in AD show discrepant results, highlighting the need for a meta-analysis.Methods: In the current study, we carried out a meta-analysis of published studies of TL in AD patients and healthy controls. PubMed, Web of Science and Google Scholar databases (from inception to September 2015) were used to identify relevant articles reporting TL in humans with AD, from which we retrieved data such as sample size, experimental methods, and mean TL for cases and controls. A random-effects model was used for meta-analytical procedures.Results: The meta-analysis included 13 primary studies and demonstrated a significant difference in TL between 860 AD patients and 2,022 controls, with a standardized mean difference of -0.984 (confidence interval: -1.433 to -0.535; p value: <.001).Conclusions: Our results show a consistent evidence of shorter telomeres in AD patients and highlight the importance of the analysis of epigenomic markers associated with neurodegeneration and with the risk for common and severe neurological diseases, such as AD. [ABSTRACT FROM AUTHOR]

Background: The "motoric cognitive risk" (MCR) syndrome is a newly reported predementia syndrome combining cognitive complaint and slow gait speed. We hypothesized that individuals with MCR syndrome would have lower brain volumes compared with non-MCR individuals. This study aims (i) to compare the cognitive profile of nondemented older community-dwellers with and without MCR syndrome and (ii) to examine association of global and regional brain volumes with MCR syndrome.Methods: A total of 171 individuals (28 MCR and 143 non-MCR) were included in this cross-sectional study. Total white matter abnormalities, total white matter, total cortical and subcortical gray matters, hippocampus, motor cortex, premotor cortex, and prefrontal cortex were examined. Brain volumes were quantified from a three-dimensional T1-weighted magnetic resonance imaging using semi-automated software. Age, gender, education level, number of drugs taken daily, use of psychoactive drugs, and cognitive profile were also measured.Results: The distribution of cognitively healthy individuals and those with mild cognitive impairment was not different in participants with and without MCR. Multiple logistic regression models showed that smaller volumes of total gray matter (p = .016), total cortical gray matter (p = .010), premotor cortex (p = .018), prefrontal cortex (p = .026), and dorsolateral segment of prefrontal cortex (p = .032) were associated with MCR status. The premotor cortex presented the highest mean difference for brain regional volume between MCR and non-MCR participants (p = .03).Conclusions: The findings revealed similar cognitive profile in MCR and non-MCR participants, and MCR-related smaller global and regional gray matter volumes involving premotor and prefrontal cortices, suggesting that the MCR syndrome may predict cortical neurodegenerative dementia more than subcortical dementia. [ABSTRACT FROM AUTHOR]

Objective: Better Nights/Better Days, a distance intervention for insomnia in school-aged children (with and without attention-deficit/hyperactivity disorder [ADHD]), was evaluated to determine its effectiveness on children's sleep and psychosocial functioning.Methods: A single center, parallel group design randomized controlled trial (stratified on ADHD diagnosis) was conducted. Parents were randomized to intervention (n = 31) or waitlist control (n = 30), and completed questionnaires administered over the phone at baseline, postintervention (2 months), and follow-up (6 months). Actigraphy was also collected. The intervention consisted of a five-session manual and weekly telephone coach support.Results: The intervention group demonstrated a significant reduction in sleep problems and improved psychosocial functioning at postintervention and follow-up. Actigraphy results indicated improved sleep onset, but not sleep duration. Children with and without ADHD responded in a similar manner to this intervention. Parents provided high satisfaction ratings.Conclusions: This intervention holds promise as an accessible, sustainable, and effective program to address insomnia in school-aged children. [ABSTRACT FROM AUTHOR]

Objectives: The treatment of skin infections caused by Staphylococcus aureus is limited by acquired antibiotic resistance and poor drug delivery into pathogen and host cells. Here, we investigated the antibacterial activities of six topically used antimicrobials and a cationic polymer, polyhexamethylene biguanide (PHMB), against intracellular MSSA strain RN4420 and MRSA strains EMRSA-15 and USA 300.Methods: The MICs of antimicrobials were determined for MSSA and MRSA strains, and the bactericidal activities of nadifloxacin and PHMB against intracellular MRSA were determined using infected keratinocytes. Fluorescein-tagged PHMB (PHMB-FITC) was used to study PHMB uptake, co-localization with intracellular EMRSA-15 and retention in keratinocytes. The mechanism(s) of PHMB uptake into keratinocytes were studied using a dynamin inhibitor, dynasore.Results: Gentamicin, nadifloxacin and PHMB showed the lowest MICs for MRSA. Nadifloxacin at 10 mg/L killed 80% of intracellular EMRSA-15, but was not effective against USA 300. PHMB at 4 mg/L killed almost 100% of intracellular EMRSA-15 and USA 300. PHMB entered keratinocytes, co-localized with intracellular EMRSA-15 and was retained by the cells for over 5 h. PHMB uptake and its intracellular antibacterial activities were inhibited by the dynamin inhibitor, dynasore.Conclusions: PHMB kills intracellular MRSA via direct interaction with pathogens inside keratinocytes and host cell entry is dynamin dependent. [ABSTRACT FROM AUTHOR]

Objectives: The resistance development, cross-resistance to other NNRTIs and the impact of resistance on viral replicative fitness were studied for the new and potent NNRTI UAMC01398.Methods: Resistance was selected by dose escalation and by single high-dose selection against a comprehensive panel of NNRTIs used as therapeutics and NNRTIs under investigation for pre-exposure prophylaxis of sexual HIV transmission. A panel of 27 site-directed mutants with single mutations or combinations of mutations involved in reverse transcriptase (RT) inhibitor-mediated resistance was developed and used to confirm resistance to UAMC01398. Cross-resistance to other NNRTIs was assessed, as well as susceptibility of UAMC01398-resistant HIV to diarylpyrimidine-resistant viruses. Finally, the impact of UAMC01398 resistance on HIV replicative fitness was studied.Results: We showed that UAMC01398 has potent activity against dapivirine-resistant HIV, that at least four mutations in the RT are required in concert for resistance and that the resistance profile is similar to rilpivirine, both genotypically and phenotypically. Resistance development to UAMC01398 is associated with a severe fitness cost.Conclusions: These data, together with the enhanced safety profile and good solubility in aqueous gels, make UAMC01398 an excellent candidate for HIV topical prevention. [ABSTRACT FROM AUTHOR]

Objectives: Biofilm-associated implant infections represent a serious public health problem. Covalent immobilization of antimicrobial agents on titanium (Ti), thereby inhibiting biofilm formation of microbial pathogens, is a solution to this problem.Methods: Vancomycin (VAN) and caspofungin (CAS) were covalently bound on Ti substrates using an improved processing technique adapted to large-scale coating of implants. Resistance of the VAN-coated Ti (VAN-Ti) and CAS-coated Ti (CAS-Ti) substrates against in vitro biofilm formation of the bacterium Staphylococcus aureus and the fungal pathogen Candida albicans was determined by plate counting and visualized by confocal laser scanning microscopy. The efficacy of the coated Ti substrates was also tested in vivo using an adapted biomaterial-associated murine infection model in which control-Ti, VAN-Ti or CAS-Ti substrates were implanted subcutaneously and subsequently challenged with the respective pathogens. The osseointegration potential of VAN-Ti and CAS-Ti was examined in vitro using human bone marrow-derived stromal cells, and for VAN-Ti also in a rat osseointegration model.Results: In vitro biofilm formation of S. aureus and C. albicans on VAN-Ti and CAS-Ti substrates, respectively, was significantly reduced compared with biofilm formation on control-Ti. In vivo, we observed over 99.9% reduction in biofilm formation of S. aureus on VAN-Ti substrates and 89% reduction in biofilm formation of C. albicans on CAS-Ti substrates, compared with control-Ti substrates. The coated substrates supported osseointegration in vitro and in vivo.Conclusions: These data demonstrate the clinical potential of covalently bound VAN and CAS on Ti to reduce microbial biofilm formation without jeopardizing osseointegration. [ABSTRACT FROM AUTHOR]

Introduction: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers.Methods: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits.Results: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL.Conclusions: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases. [ABSTRACT FROM AUTHOR]

Study Question: Does investigation of metabolic perturbations in endometrial tissue of women with dormant genital tuberculosis (GTB) during the window of implantation (WOI) assist in improving the understanding of endometrial receptivity?Summary Answer: In dormant GTB cases significant alterations in endometrial tissue metabolites occur, largely related to energy metabolism and amino acid biosynthesis in dormant GTB cases.What Is Known Already: As an intracellular pathogen, Mycobacterium tuberculosis strongly influences the metabolism of host cells causing metabolic dysregulation. It is also accepted that dormant GTB impairs the receptive status of the endometrium. Global metabolic profiling is useful for an understanding of disease progression and distinguishing between diseased and non-diseased groups.Study Design, Size, Duration: Endometrial tissue samples were collected from patients reporting at the tertiary infertility care center during the period September 2011-March 2013. Women having tested positive for GTB were considered as the study group (n = 24). Normal healthy women undergoing sterilization (n = 26) and unexplained infertile women with repeated IVF failure (n = 21) volunteered to participate as controls.Participants/materials, Setting, Methods: Endometrial tissue samples were collected 6-10 days after confirmation of ovulation. PCR and BACTEC-460 culture were used for diagnosing GTB. Proton nuclear magnetic resonance (1H NMR) spectra of tissue were recorded using a 700 MHz Bruker Avance AV III spectrometer. Following phase and baseline correction of all NMR spectra by Bruker Topspin 2.1 software, spectral peak alignment of the data was performed. Multivariate analysis was applied to all spectra and individual metabolites identified and multiple correlation analysis was performed.Main Results and the Role Of Chance: Leucine, isoleucine, acetate, lactate, glutamate, glutamine, methionine, lysine, creatine, glycogen, glycine, proline and choline were found to be significantly increased (P < 0.05) in endometrial tissue of women with dormant GTB compared with unexplained infertile women with repeated implantation failure. Valine, citrate, succinate and aspartate were also observed to be significantly up-regulated (P < 0.01). Furthermore, a significant decrease in glucose (P < 0.05), threonine (P < 0.05), tyrosine (P < 0.01) and phenylalanine (P < 0.0001) was observed in women with dormant GTB. Pearson's correlation analysis between the expression of various endometrial receptivity markers and metabolites showed a significant negative correlation (-0.236 to -0.545, P < 0.05). Also, the metabolites were positively correlated with endometrial receptivity markers (0.207 to 0.618, P < 0.05).Limitations, Reasons For Caution: It is often difficult to diagnose dormant GTB because it tends to exist without any clinical signs or symptoms. In addition, the diagnosis of GTB by culture remains a challenge due to low detection rates and its paucibacillary nature. Testing for prostate-specific antigen or the Y chromosome in order to account for the possible influences of recent exposure to semen on endometrial metabolism would be important.Wider Implications Of the Findings: The metabolic changes associated with the dormant tubercle infection are of potential relevance to clinicians for the treatment of dormant GTB-related infertility.Study Funding/competing Interests: Government of India, Indian Council of Medical Research. There are no conflicts of interest. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation has shown promise to improve recovery in patients with post-stroke aphasia, but previous studies have only assessed stimulation effects on impairment parameters, and evidence for long-term maintenance of transcranial direct current stimulation effects from randomized, controlled trials is lacking. Moreover, due to the variability of lesions and functional language network reorganization after stroke, recent studies have used advanced functional imaging or current modelling to determine optimal stimulation sites in individual patients. However, such approaches are expensive, time consuming and may not be feasible outside of specialized research centres, which complicates incorporation of transcranial direct current stimulation in day-to-day clinical practice. Stimulation of an ancillary system that is functionally connected to the residual language network, namely the primary motor system, would be more easily applicable, but effectiveness of such an approach has not been explored systematically. We conducted a randomized, parallel group, sham-controlled, double-blind clinical trial and 26 patients with chronic aphasia received a highly intensive naming therapy over 2 weeks (8 days, 2 × 1.5 h/day). Concurrently, anodal-transcranial direct current stimulation was administered to the left primary motor cortex twice daily at the beginning of each training session. Naming ability for trained items (n = 60 pictures that could not be named during repeated baseline assessments), transfer to untrained items (n = 284 pictures) and generalization to everyday communication were assessed immediately post-intervention and 6 months later. Naming ability for trained items was significantly improved immediately after the end of the intervention in both the anodal (Cohen's d = 3.67) and sham-transcranial direct current stimulation groups (d = 2.10), with a trend for larger gains in the anodal-transcranial direct current stimulation group (d = 0.71). Treatment effects for trained items were significantly better maintained in the anodal-transcranial direct current stimulation group 6 months later (d = 1.19). Transfer to untrained items was significantly larger in the anodal-transcranial direct current stimulation group after the training (d = 1.49) and during the 6 month follow-up assessment (d = 3.12). Transfer effects were only maintained in the anodal-transcranial direct current stimulation group. Functional communication was significantly more improved in the anodal-transcranial direct current stimulation group at both time points compared to patients treated with sham-transcranial direct current stimulation (d = 0.75-0.99). Our results provide the first evidence from a randomized, controlled trial that transcranial direct current stimulation can improve both function and activity-related outcomes in chronic aphasia, with medium to large effect sizes, and that these effects are maintained over extended periods of time. These effects were achieved with an easy-to-implement and thus clinically feasible motor-cortex montage that may represent a promising 'backdoor' approach to improve language recovery after stroke. [ABSTRACT FROM AUTHOR]

Background: Liver disease is common during human immunodeficiency virus (HIV) infection, but valid serum fibrosis markers are lacking. We hypothesize that HIV monoinfection and HIV/hepatitis C virus (HCV) coinfection is associated with an enhanced liver fibrosis (ELF) score higher than that for uninfected controls and examine whether this association is affected by factors other than liver injury.Methods: The association of HIV and HIV/HCV coinfection with the ELF score was evaluated using multivariable regression after controlling for transient elastography-measured liver stiffness and traditional and HIV-related factors in a cross-sectional analysis of 297 women.Results: HIV/HCV-coinfected and HIV-monoinfected women had higher median ELF scores than controls (9.6, 8.5, and 8.2, respectively). After adjustment for demographic, behavioral, and metabolic factors and for inflammatory markers, HIV/HCV coinfection remained associated with a 9% higher ELF score (95% confidence interval [CI], 5%-13%), while the association of HIV monoinfection was substantially attenuated (1% higher ELF score; 95% CI, -2% to 4%). After further adjustment for liver stiffness, HIV/HCV coinfection remained associated with 6% higher levels (95% CI, 3%-10%). In HIV/HCV-coinfected and HIV-monoinfected women, higher liver stiffness values were associated with higher ELF scores, as were older age and a nadir CD4(+) T-cell count of <200 cells/mm(3).Conclusions: Our findings suggest that the ELF score can be used to assess liver fibrosis severity in HIV-infected women. However, higher ELF scores may reflect extrahepatic fibrosis in HIV-infected patients with a history of severe immunosuppression or advanced age. [ABSTRACT FROM AUTHOR]

Aims: Data on longer right to left ventricular activation delay (RV-LV AD) predicting clinical outcome after cardiac resynchronization therapy (CRT) by left bundle branch block (LBBB) are limited. We aimed to evaluate the impact of RV-LV AD on N-terminal pro-B-type natriuretic peptide (NT-proBNP), ejection fraction (EF), and clinical outcome in patients implanted with CRT, stratified by LBBB at baseline.Methods and Results: Heart failure (HF) patients undergoing CRT implantation with EF ≤ 35% and QRS ≥ 120 ms were evaluated based on their RV-LV AD at implantation. Baseline and 6-month clinical parameters, EF, and NT-proBNP values were assessed. The primary endpoint was HF or death, the secondary endpoint was all-cause mortality. A total of 125 patients with CRT were studied, 62% had LBBB. During the median follow-up of 2.2 years, 44 (35%) patients had HF/death, 36 (29%) patients died. Patients with RV-LV AD ≥ 86 ms (lower quartile) had significantly lower risk of HF/death [hazard ratio (HR): 0.44; 95% confidence interval (95% CI): 0.23-0.82; P = 0.001] and all-cause mortality (HR: 0.48; 95% CI: 0.23-1.00; P = 0.05), compared with those with RV-LV AD < 86 ms. Patients with RV-LV AD ≥ 86 ms and LBBB showed the greatest improvement in EF (28-36%; P<0.001), NT-proBNP (2771-1216 ng/mL; P < 0.001), and they had better HF-free survival (HR: 0.23, 95% CI: 0.11-0.49, P < 0.001) and overall survival (HR: 0.35, 95% CI: 0.16-0.75; P = 0.007). There was no difference in outcome by RV-LV AD in non-LBBB patients.Conclusion: Left bundle branch block patients with longer RV-LV activation delay at CRT implantation had greater improvement in NT-proBNP, EF, and significantly better clinical outcome. [ABSTRACT FROM AUTHOR]

Study Question: Are maternal urinary phenol concentrations associated with cord steroid hormone levels and anogenital distance (AGD) in male newborns?Summary Answer: High maternal urinary Bisphenol A (BPA) levels are associated with decreases in cord testosterone levels and the ratio of testosterone to estradiol in male newborns, but there was no significant association with AGD.What Is Known Already: Early life exposure to phenolic endocrine disrupting compounds (EDCs) is known to disrupt hormonal activities and affect reproductive development in males. However, studies on the health effects of prenatal human exposure are scarce.Study Design, Size, Duration: This was a cross-sectional study to investigate the association between maternal phenolic exposure and cord sex steroid hormones and AGD in male newborns. We recruited 100 mother-infant pairs from each of two hospitals, one in a polluted town (Guiyu) and the other in a cleaner town (Haojiang), from September 2010 to September 2011.Participants/materials, Setting, Methods: One hundred and seventy eight maternal urine samples and 137 cord blood samples were available for quantification, thus 137 complete records entered into the final analysis. Of them, 77 pairs were from Guiyu, and 60 were from Haojiang. The chemical concentrations were determined by solid phase extraction and gas chromatography-mass spectrometry (SPE-GC-MS), and cord sex hormones were detected by radioimmunoassay (RIA). Neonatal anthropometric parameters including AGD were measured.Main Results and the Role Of Chance: Log2-transformed maternal urinary BPA concentration was negatively correlated with testosterone level and the ratio of testosterone to estradiol (T/E2) in male fetal cord blood after adjustment for potential confounders in linear regression models (βadjusted = -31.09 (95% CI, -53.07 to -9.11) and βadjusted = -0.08 (95% CI, -0.13 to -0.01), respectively). Moreover, compared with the lowest quartile group of BPA level, the highest group showed a significant decrease in testosterone level and T/E2 (βadjusted = -179.84 (95% CI, -333.45 to -26.24) and βadjusted = -0.37 (95% CI, -0.81 to 0.07), respectively). No significant associations between AGD or anogenital index (AGI, [AGI = AGD/birthweight (mm/kg)]) and phenolic EDCs or cord hormone levels were found.Limitations, Reasons For Caution: Results in the present study should be interpreted with caution because of its cross-sectional nature, small sample size and sampling time.Wider Implications Of the Findings: Testosterone plays an important role in sex differentiation and normal development of the fetus and newborn, and the balance between testosterone and estradiol is thought an important mediator of prostate disease. Therefore, our findings may have important implications for human reproductive health.Study Funding/competing Interests: This work was supported by the National Natural Science Foundation of China (21377077) and Guangdong University Project for International Cooperation and Innovation Platform (2013gjhz0007). The authors declare they have no actual or potential competing financial interests. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is highly prevalent at ages 80 and above. The association of physical functioning (PF), a key to an optimal aging trajectory, with CVD and specific CVD diagnosis in women who survive to age 80 and above has not been described previously and has important public health significance given our aging population.Methods: Women's Health Initiative participants aged 80 years or older at the time of self-reporting PF (RAND SF-36) were studied in relationship to CVD diagnosis, whether present at study baseline (1993-1998) or diagnosed during follow-up through 2012. Cross-sectional analyses utilized demographic, medical, lifestyle, and psycho-social questionnaire data from baseline or updated at the time of self-reported PF.Results: Among 27,145 older Women's Health Initiative participants, 22.0% (N = 5,959) had been diagnosed with CVD, specifically: 11.3% (N = 3,071) with coronary heart disease; 4.7% (N = 1,279), stroke; 5.2% (N = 1,397), venous thromboembolism; 2.7% (N = 737), peripheral arterial disease; and 2.7% (N = 725), congestive heart failure. PF scores (mean ± SE) were significantly (p < .0001) higher without CVD (60.0 ± 26.9), compared with any CVD (47.9 ± 27.3), and for each specific CVD diagnosis: coronary heart disease (48.8 ± 27.1); stroke (44.8 ± 27.9); venous thromboembolism (48.9 ± 27.4); peripheral arterial disease (41.9 ± 2.2); and congestive heart failure (38.8 ± 26.1). Regardless of CVD diagnosis, higher PF was associated with: younger age at the time of PF assessment; lower body mass index; higher recreational physical activity; better self-reported general health; fewer hip fractures after age 55; no history of arthritis; and no recent use of non-steroidal anti-inflammatory drugs.Conclusions: Older women with any CVD, and particularly women with congestive heart failure or peripheral arterial disease, reported significantly lower PF compared to women with no CVD. Regardless of CVD diagnosis, higher PF was strongly associated with a more active lifestyle and lower body mass index, suggesting potential intervention targets for more optimal aging. [ABSTRACT FROM AUTHOR]

Aims: Right ventricular pacing adversely affects left atrial (LA) structure and function that may trigger atrial fibrillation (AF). This study compares the occurrence of persistent/permanent AF during long-term Hisian area (HA), right ventricular septal (RVS), and right ventricular apex (RVA) pacing in patients with complete/advanced atrioventricular block (AVB).Methods and Results: We collected retrospective data from 477 consecutive patients who underwent pacemaker implantation for complete/advanced AVB. Ventricular pacing leads were located in the HA, RVS, and RVA in 148, 140, and 189 patients, respectively. The occurrence of persistent/permanent AF was observed in 114 (23.9%) patients (follow-up 58.5 ± 26.5 months). Hisian area groups presented a lower rate of AF occurrence (16.9%) compared with RVS and RVA groups (25.7 and 28.0%, respectively), P = 0.049. Cox's proportional hazard model was used to estimate HR. The risk of persistent/permanent AF was significantly lower in the patients paced from HA compared with those paced from RVA, HR = 0.28 (95% CI 0.16-0.48, P = 0.0001). The RVS and RVA pacing groups showed a similar AF risk: HR 1.04 (95% CI 0.66-1.64, P = 0.856). Other independent predictors of persistent/permanent AF occurrence included previous (before device implantation) paroxysmal AF (HR = 4.08; 95% CI 3.15-7.31, P = 0.0001), LA diameter, and age, whereas baseline bundle-branch block was associated with a lower risk of AF occurrence (HR = 0.56; 95% CI 0.35-0.81, P = 0.003).Conclusions: HA pacing compared with RVA or RVS pacing seems to be associated with a lower risk of persistent/permanent AF occurrence. The risk of persistent/permanent AF was similar in the RVA vs. RVS groups. [ABSTRACT FROM AUTHOR]

Several studies have analyzed the potential of T regulatory cells (Treg cells) as biomarkers of acute rejection (AR). The aim of the present multicenter study was to correlate the percentage of peripheral Treg cells in liver graft recipients drawn at baseline up to 12 months after transplantation with the presence of AR. The percentage of central memory (cm) Treg cells (CD4+CD25highCD45RO+CD62L+) was monitored at pre-transplant and at 1 and 2 weeks, and 1, 2, 3 and 6 months and 1 year posttransplantation. The same validation standard operating procedures were used in all participating centers. Fifteen patients developed AR (23.4%). Hepatitis C virus recurrence was observed in 16 recipients, who displayed low peripheral blood cmTreg levels compared with patients who did not. A steady increase of cmTregs was observed during the first month after transplantation with statistically significant differences between AR and non-AR patients. The high frequency of memory Treg cells allowed us to monitor rejection episodes during the first month post-transplantation. On the basis of these data, we developed a prediction model for assessing risk of AR that can provide clinicians with useful information for managing patients individually and customizing immunosuppressive therapies. [ABSTRACT FROM AUTHOR]

Study Question: Is the survival of donor oocytes with the CryotopSC device superior to the survival with the closed CBSvit device?Summary Answer: The CryotopSC device and the CBSvit device showed similar survival rates.What Is Known Already: Health authorities are cautious about possible cross contamination during liquid nitrogen storage or handling when working with open vitrification devices. At present, the use of open devices is still allowed since little information is available on the efficiency of closed devices.Study Design, Size, Duration: A prospective randomized sibling oocyte study was performed in the Centre for Reproductive Medicine (UZBrussel) between January 2014 and July 2015. The survival after warming and the embryological outcome of donor oocytes vitrified using two devices was compared: the CBSvit device (closed vitrification and closed storage) and the CryotopSC device (open vitrification and closed storage). A difference of 10% was defined to prove the superiority of the CryotopSC device. In total, 250 warmed oocytes were needed in each arm.Participants/materials, Setting, Methods: Oocytes from 48 donors were included in the study: 253 vitrified with the CBSvit device and 257 with the CryotopSC device. Equal numbers of oocytes from both devices and originated from the same donor cycle were allocated to each of 78 recipients, in order to exclude donor and recipient (male factor) effects.Main Results and the Role Of Chance: There were no differences found between the CBSvit and the CryotopSC in terms of survival after warming (93.7 versus 89.9%) or fertilization per injected oocyte (74.3 versus 81.4%). The degeneration rate after ICSI was significantly higher for the CBSvit device: 11.4 versus 6.1% (P = 0.041). A significantly higher number of zygotes in the CryotopSC group finished their first mitosis 25-27 h post-injection (34.1 versus 52.1%, P = 0.001). On Day 3, the overall embryo quality distribution did not vary between groups, but a significantly higher cell number was obtained in the CryotopSC device: 6.8 ± 2.8 versus 7.6 ± 2.8 (P = 0.01). The utilization rate per mature oocyte, per surviving oocyte or per fertilized oocyte did not differ. The embryos with the highest quality were selected for transfer on Day 3. The clinical pregnancy rate per transfer cycle was 36.5%.Limitations, Reasons For Caution: The results of this study should not be extrapolated to other female groups, since oocytes from young fertile donors were used in this study.Wider Implications Of the Findings: In many countries, the use of open devices is still allowed due to the limited reports on the efficiency of closed devices. Knowing the caution of health authorities about the use of open devices, there is an urgent need for efficiency studies with closed devices. The results obtained in the current study shows the efficiency of a safe closed vitrification device, leaving behind any concern about possible cross contamination during handling or storage.Study Funding/competing Interests: No funding was obtained. The authors have no conflict of interest to declare.Trial Registration Number: NCT01952184.Trial Registration Date: 24 September 2013.Date Of First Patient's Enrolment: 23 January 2014. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C virus (HCV) infection is a global health problem, resulting in liver failure, hepatocellular carcinoma, and liver-related death. Natural killer (NK) cells are innate immune cells, and their activity is known to correlate to viral treatment response of HCV. In this study, we investigate the immune effects of viral load decline with direct-acting antivirals (DAAs) in blood.Methods: Twelve patients with chronic HCV were treated with asunaprevir and daclatasvir, and peripheral blood was analyzed at various time points during therapy.Results: In line with previous studies, we confirmed restoration of HCV-specific T-cell frequency upon viral load decline. In addition, we show that serum interferon (IFN)-γ inducible-protein 10, interleukin (IL)-12p40, and IL-18 levels decreased early after start of therapy. Surface expression of activation receptors NKp30, NKp46, and inhibitory receptor NKG2A on blood NK cells reduced during therapy. In addition, the expression of TRAIL on NK cells was reduced during IFN-free therapy, suggesting a decrease in TRAIL-mediated killing by NK cells.Conclusions: We show that viral load decline as a consequence of treatment with novel DAAs in chronic HCV patients reduces serum levels of NK cell-stimulating cytokines and causes correction of the altered NK cell phenotype observed in chronic HCV patients.Clinical Trials Registration: NCT02282709. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to analyse whether there is an association between reduced susceptibility to biocides in Acinetobacter baumannii and (i) antimicrobial resistance (co-resistance), (ii) prevalent (epidemic) clones, (iii) changes in the fitness or (iv) expression of genes related to efflux pumps and porins.Methods: Susceptibility to biocides and antimicrobials was determined in 49 clonally unrelated isolates of A. baumannii. Biological cost, in terms of mean generation time, was determined by spectrophotometry. Quantitative real-time RT-PCR was used to determine the relative expression of genes encoding several efflux pumps and porins.Results: Reduced susceptibility to chlorhexidine digluconate, benzalkonium chloride and Irgasan(®) was associated with resistance to aminoglycosides, tetracycline and ciprofloxacin (P < 0.05). The MICs of carbapenems, aminoglycosides, doxycycline and ciprofloxacin for isolate Ab70 (epidemic clone) exposed to these biocides increased by ≥2 dilutions. Reduced susceptibility to Orsan(®) was more frequent among prevalent clones than non-prevalent clones (P < 0.05). Mean generation times for Ab70 before and after exposure to benzalkonium chloride were 57.8 and 78.1 min, respectively (P = 0.02). Relative expression of abeS and adeB was increased in Ab46 and Ab70 after exposure to chlorhexidine digluconate, but was decreased for ompA and carO after exposure to Irgasan(®).Conclusions: Reduced susceptibility to biocides is associated with co-resistance to carbapenems, aminoglycosides, tetracycline and ciprofloxacin. Reduced susceptibility to Orsan(®) may be a marker of prevalent clones. Acquisition of reduced susceptibility to benzalkonium chloride has a biological cost. Exposure to biocides affects the relative expression of genes related to some efflux pump genes (increased expression) or porins (reduced expression). [ABSTRACT FROM AUTHOR]

Aims: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts.Method and Results: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference.Conclusion: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening. [ABSTRACT FROM AUTHOR]

Objectives: Widespread antimony resistance in the Indian subcontinent has enforced a therapy shift in visceral leishmaniasis treatment primarily towards miltefosine and secondarily also towards paromomycin. In vitro selection of miltefosine resistance in Leishmania donovani turned out to be quite challenging. Although no increase in IC50 was detected in the standard intracellular amastigote susceptibility assay, promastigote back-transformation remained positive at high miltefosine concentrations, suggesting a more 'resistant' phenotype. This observation was explored in a large set of Nepalese clinical isolates from miltefosine cure and relapse patients to assess its predictive value for patient treatment outcome.Methods: The predictive value of the promastigote back-transformation for treatment outcome of a set of Nepalese L. donovani field isolates (n = 17) derived from miltefosine cure and relapse patients was compared with the standard susceptibility assays on promastigotes and intracellular amastigotes.Results: In-depth phenotypic analysis of the clinical isolates revealed no correlation between the different susceptibility assays, nor any clear link to the actual treatment outcome. In addition, the clinical isolates proved to be phenotypically heterogeneous, as reflected by the large variation in drug susceptibility among the established clones.Conclusions: This in vitro laboratory study shows that miltefosine treatment outcome is not necessarily exclusively linked with the susceptibility profile of pre-treatment isolates, as determined in standard susceptibility assays. The true nature of miltefosine treatment failures still remains ill defined. [ABSTRACT FROM AUTHOR]

Lepidosirenidae is a clade of freshwater lungfishes that include the extant South American Lepidosiren paradoxa Fitzinger, 1837 and African species of the genus Protopterus. These genera have been geographically separated since the break-up of Gondwana in the Early Cretaceous, but they display similar biology and morphology. Species were distinguished by a combination of features such as head-to-body ratios, the number of pairs of ribs, and the presence of external gills, but no discrete skeletal characters were identified, and no comparative studies including all extant species have been published. I used computed tomography ( CT), X-ray photography, and specimens from museum collections to describe the skeletal morphology of all species of lepidosirenid in a comparative context. I digitally disarticulated the bones in each specimen to compile a comparative atlas of the cranial and pectoral elements of all extant lungfishes, which has the potential to increase the correct identifications of specimens in museum collections. The morphology of the frontoparietal, parasphenoid, supraorbital, and suboperculum differ between species. I used those characters, along with molecular sequence data from the ribosomal RNA gene 16 S, to run combined morphological and molecular phylogenetic analyses. Lepidosirenidae is monophyletic in all analyses, but the interrelationships of the species of Protopterus vary with the different sources of character data. © 2015 The Linnean Society of London [ABSTRACT FROM AUTHOR]

Background. The ulnar nerve upper limb neurodynamic test (ULNT3) uses upper limb positioning to investigate symptoms arising from the ulnar nerve. It is proposed to selectively increase tension of the nerve; however, this property of the test is not well established. Objective. The aim of this study was to determine the upper limb position that results in: (1) the greatest tension of the ulnar nerve and (2) the greatest difference in tension between the ulnar nerve and the other 2 major nerves of the upper limb: median and radial. Design. This was an observational cadaver study. Methods. Tension (in newtons) of the ulnar, median, and radial nerves was measured simultaneously using 3 buckle force transducers in 5 upper limb positions in 10 embalmed human cadavers (N=20 limbs). Repeated-measures analysis of variance (ANOVA) with Bonferroni post hoc tests determined differences in tension among nerves and among limb positions. Results. The addition of shoulder horizontal abduction (H.Abd; 12.62 N; 95% confidence interval [95% Cl] = 10.76, 14.47) and combined shoulder abduction and internal rotation (H.Abd + IR; 11.86 N; 95% CI=9.96, 13-77) to ULNT3 (scapular depression, shoulder abduction and external rotation, elbow flexion, forearm pro nation, and wrist and finger extension) produced significantly greater ulnar nerve tension compared with the ULNT3 alone (8.71 N; 95% CI=7.25, 10.17). The ULNT3+H.Abd test demonstrated the greatest difference in tension among nerves (mean difference between ulnar and median nerves= 11.87 N; 95% CI=9.80, 13.92; mean difference between ulnar and radial nerves=8.47 N; 95% CI=6.4l, 10.53). Limitations. These results pertain only to the biomechanical plausibility of the ulnar nerve neurodynamic test and do not account for other factors that may affect the clinical application of this test. Conclusions. The ULNT3 +H.Abd is a biomechanically plausible test for detecting peripheral neuropathic pain related to the ulnar nerve. In situations where the shoulder complex will not tolerate the combination of shoulder external rotation in abduction, performing upper limb neurodynamic tests with internal rotation instead of external rotation is a biomechanically plausible alternative. [ABSTRACT FROM AUTHOR]

Introduction: Lengthy storage times and associated storage lesion can result in reduced red blood cell (RBC) efficacy, particularly dangerous for massively transfused patients. Today's inventory management makes storage times the de-facto metric of blood quality. However, RBC units' quality may vary because of time-independent factors. Mechanical fragility (MF) of RBC, reflecting sub-lethal cell damage, can potentially provide a more physiologically relevant predictor of cell's performance "in vivo."Methods: Mechanical stress was applied using a bead mill (50 Hz) over durations varying from 0.5 to 60 minutes, or using ultrasound (40 W) with durations from 0.1 to 120 seconds. MF profiles were described in terms of percentage hemolysis following stresses of specified durations.Results: RBC MF declined significantly in the presence of albumin, with albumin protecting membrane against damage from elevated temperature or from methyl-β-cyclodextrin or diamide. MF profiles allowed detection of sub-lethal membrane damage caused by elevated temperature, to a greater extent than was reflected by autohemolysis. Different types of profiles for RBC damage were associated with MF changes at different stress intensities and potentially stress types.Conclusions: These findings indicate that MF profiles can provide a powerful and versatile tool for investigation of RBC, as well as a potential metric of RBC quality. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has been shown to modulate subjective craving ratings in drug dependents by modification of cortical excitability in dorsolateral prefrontal cortex (DLPFC). Given the mechanism of craving in methamphetamine (meth) users, we aimed to test whether tDCS of DLPFC could also alter self-reported craving in abstinent meth users while being exposed to meth cues. In this double-blinded, crossover, sham-controlled study, thirty two right-handed abstinent male meth users were recruited. We applied 20 rain 'anodal' tDCS (2 mA) or 'sham' tDCS over right DLPFC in a random sequence while subjects performed a computerized cue-induced craving task (CICT) starting after 10 min of stimulation. Immediate craving was assessed before the stimulation, after 10 min of tDCS, and after tDCS termination by visual analog scale (VAS) of 0 to 100. Anodal tDCS of rDLPFC altered craving ratings significantly. We found a significant reduction of craving at rest in real tDCS relative to the sham condition (p=0.016) after 10min of stimulation. On the other hand, cue-induced VAS craving was rated significantly higher in the real condition in comparison with sham stimulation (p=0.012). Our findings showed a state dependent effect of tDCS: while active prefrontal tDCS acutely reduced craving at rest in the abstinent meth users, it increased craving during meth-related cue exposure. These findings reflect the important role of the prefrontal cortex in both cue saliency evaluation and urge to meth consumption. [ABSTRACT FROM AUTHOR]

The purpose of the current study was to find novel rheumatoid arthritis ( RA)-specific gene expression by simultaneously comparing the expression profiles of the synovial tissues from patients with RA, osteoarthritis ( OA) and ankylosing spondylitis ( AS). The Illumina Human HT-12 v4 Expression Bead Chip was used to investigate the global gene expression profiles in synovial tissues from RA ( n = 12), OA ( n = 14) and AS ( n = 7) patients. By comparing the profiles in synovial tissues from RA, OA and AS, we identified the CD38, ankyrin repeat domain 38 ( ANKRD38), E2F transcription factor 2 ( E2 F2), craniofacial development protein 1 ( CFDP1), cluster of differentiation ( CD)7, interferon-stimulated exonuclease gene 20 kDa ( ISG20) and interleukin-2 receptor gamma ( IL)-2 RG genes as differentially expressed gene expression in RA synovial tissues. The increased expression of CD38, E2 F2 and IL-2 RG, as revealed using real-time polymerase chain reaction ( PCR) with synovial tissues from RA ( n = 30), OA ( n = 26) and AS patients ( n = 20), was in agreement with the microarray data. Immunohistochemistry revealed significant CD38 expression and E2 F2 in synovial membranes from RA patients ( n = 5). The CD38+ cells had high a percentage in the RA patients' blood ( n = 103) and in the CD3+ and CD56+ subsets. The CD38+ cell percentage was correlated significantly with RF level ( P = 0·026) in RA patients. The IL-1α and IL-β levels were depressed significantly in the culture medium of RA synovial fibroblast cells ( n = 5) following treatment with siRNAs targeting the E2 F2 or CD38 genes. This study suggests that the uniquely increased expression of CD38 and E2 F2 in RA synovial tissues contribute to the immunoactivation of the disease. [ABSTRACT FROM AUTHOR]

The study investigated the possibility to transform normal young Norway spruce (Picea abies (L.) Karst) forests to develop more heterogeneous stand structures, aiming for multi-layered forest in the long run. On three sites in central and south Sweden, 60 per cent of stand basal area was removed by thinning mainly medium-sized trees and leaving the smallest and the largest trees. Over the next 50 years, future stand development was simulated using a single-tree growth model. Simulations were run with and without ingrowth. An additional ingrowth scenario after soil preparation was tested. Basal area was kept between 10 and 20 m2 ha−1 during simulations. Projected stem wood production for the next 50 years was one-third lower compared with conventional thinning regimes. After 50 years, a multi-layered forest structure was indicated for the boreal sites in central Sweden, but not for the site in south Sweden. [ABSTRACT FROM PUBLISHER]

The article presents a study on Hemerocallis fulva (H. fulva) conducted to analyze the microRNA (miRNA) gene expression profile of Hemerocallis fulva species at low temperature. Topics include comparative analysis of RNA sequences under normal and low temperatures, similarity between monocotyledons and dicotyledons, and use of a computational algorithm for homology-independent discovery of viroids. The results show that miRNA can improve the resistance of H. fulva to low temperature.

The adult CNS has limited potential for functional recovery after structural lesions. Lindau et al. report that a blocking antibody to the neurite-growth inhibitory protein Nogo-A improved functional recovery in a rat sensorimotor cortex stroke model. The functional recovery was accompanied by increased corticospinal innervation from the contralateral cortex.Adult Long Evans rats received a photothrombotic stroke that destroyed >90% of the sensorimotor cortex unilaterally; they were subsequently treated intrathecally for 2 weeks with a function blocking antibody against the neurite growth inhibitory central nervous system protein Nogo-A. Fine motor control of skilled forelimb grasping improved to 65% of intact baseline performance in the anti-Nogo-A treated rats, whereas control antibody treated animals recovered to only 20% of baseline scores. Bilateral retrograde tract tracing with two different tracers from the intact and the denervated side of the cervical spinal cord, at different time points post-lesion, indicated that the intact corticospinal tract had extensively sprouted across the midline into the denervated spinal hemicord. The original axonal arbours of corticospinal tract fibres that had recrossed the midline were subsequently withdrawn, leading to a complete side-switch in the projection of a subpopulation of contralesional corticospinal tract axons. Anterograde tracing from the contralesional cortex showed a 2–3-fold increase of midline crossing fibres and additionally a massive sprouting of the pre-existing ipsilateral ventral corticospinal tract fibres throughout the entire cervical enlargement of the anti-Nogo-A antibody-treated rats compared to the control group. The laminar distribution pattern of the ipsilaterally projecting corticospinal tract fibres was similar to that in the intact spinal cord. These plastic changes were paralleled by a somatotopic reorganization of the contralesional motor cortex where the formation of an ipsilaterally projecting forelimb area was observed. Intracortical microstimulation of the contralesional motor cortex revealed that low threshold currents evoked ipsilateral movements and electromyography responses at frequent cortical sites in the anti-Nogo-A, but not in the control antibody-treated animals. Subsequent transection of the spared corticospinal tract in chronically recovered animals, treated with anti-Nogo-A, led to a reappearance of the initial lesion deficit observed after the stroke lesion. These results demonstrate a somatotopic side switch anatomically and functionally in the projection of adult corticospinal neurons, induced by the destruction of one sensorimotor cortex and the neutralization of the CNS growth inhibitory protein Nogo-A. [ABSTRACT FROM AUTHOR]

A simple hemispherical phantom has been designed and prepared for the EURADOS intercomparison exercise on 241Am activity determination in the skull (2011–13). The phantom consists of three parts that substitute bone and soft tissues. 241Am is deposited on the surfaces of the bone-substituting part. The design and assumed composition of phantom parts are discussed. A preparation of the voxel representation of the phantom is described. The spectrum of a real measurement of the physical phantom agrees well with the simulation. The physical phantom, and its voxel representation, is provided to the participants of the intercomparison exercise. [ABSTRACT FROM AUTHOR]

Previous work on Daphnia found that phosphoglucose isomerase (Pgi) homozygotes produced a more thermally stable form of the enzyme compared with heterozygotes. We found a positive relationship between temperature and homozygote frequency in a cooling reservoir with strong thermal gradients. Laboratory experiments revealed that heterozygotes had lower thermal tolerance. Integrating existing information about biochemical properties of Pgi, and data from thermal tolerance assays helped explain the population genetic consequences of temperature shifts in this lake. [ABSTRACT FROM PUBLISHER]

Objectives: The main purpose of this study was to determine the accuracy of cone beam CT (CBCT) in measuring the trabecular bone microstructure, in comparison with micro-CT. The subobjective was to examine to what extent bone quality assessment is influenced by X-ray tube current and voltage settings as well as soft tissue surrounding the bone. Methods: Eight human mandibular bone samples were scanned using three different clinical exposure protocol within water (W1-3) and without water (NW1-3) by a high-resolution (80 µm) CBCT machine (3D Accuitomo 170®; Morita, Kyoto, Japan). Subsequently, the samples underwent micro-CT scanning (SkyScan 1174®; SkyScan, Antwerp, Belgium). After image acquisition, similar volumes of interest of the trabecular structures captured with CBCT and micro-CT were aligned with each other. Segmentation was then performed, and the morphometric parameters were quantified within the volumes of interest by CTAn software (CTAnalyser®; SkyScan, Antwerp, Belgium). Descriptive statistical analyses and multiple comparisons between all protocols were applied in R software. Results: High positive Pearson's correlation coefficients were observed between CBCT and micro-CT protocols for all tested morphometric indices except for trabecular thickness. No significant differences were observed between all exposure protocols except for trabecular separation. When examining the soft-tissue effect on trabecular bone structures, no significant differences between NW (1-3) and W (1-3) protocols were observed for all variables. Conclusions: The present study demonstrated the potential of high-resolution CBCT imaging for in vivo applications of quantitative bone morphometry and bone quality assessment. However, the overestimation of morphometric parameters and acquisition settings in CBCT must be taken into account. [ABSTRACT FROM AUTHOR]

Background. Although not well understood, foot kinematics are changed with hallux valgus. Objective. The purpose of this study was to examine tarsal kinematics in women with hallux valgus deformity. Design. A prospective, cross-sectional design was used. Methods. Twenty women with (n=10) and without (n=10) deformity participated. Data were acquired with the use of a magnetic resonance scanner. Participants were posed standing to simulate gait, with images reconstructed into virtual bone datasets. Measures taken described foot posture (hallux angle, intermetatarsal angle, arch angle). With the use of additional computer processes, the image sequence was then registered across gait conditions to compute relative tarsal position angles, first-ray angles, and helical axis parameters decomposed into X, Y, and Z components. An analysis of variance model compared kinematics between groups and across conditions. Multiple regression analysis assessed the relationship of arch angle, navicular position, and inclination of the first-ray axis. Results. Both the hallux and intermetatarsal angles were larger with deformity; arch angle was not different between groups. The calcaneus was everted by ≥6.6 degrees, and the first ray adducted (F=44.17) by ≥9.3 degrees across conditions with deformity. There was an interaction (F=5.06) for the first-ray axis. Follow-up comparisons detected increased inclination of the first-ray axis over middle stance compared with late stance in the group with deformity. Limitations. Gait was simulated, kinetics were not measured, and sample size was small. Conclusions. There were group differences. Eversion of the calcaneus and adduction of the first ray were increased, and the first-ray axis was inclined 24 degrees over middle stance in women with deformity compared with 6 degrees in control participants. Results may identify risk factors of hallux valgus and inform nonoperative treatment (orthoses, exercise) strategies. [ABSTRACT FROM AUTHOR]

The human microbiome is a complex biological system with numerous interacting components across multiple organizational levels. The assembly, ecology and dynamics of the microbiome and its contribution to the development, physiology and nutrition of the host are clearly affected not only by the set of genes or species in the microbiome but also by the way these genes are linked across numerous pathways and by the interactions between the various species. To date, however, most studies of the human microbiome have focused on characterizing the composition of the microbiome and on comparative analyses, whereas significantly less effort has been directed at elucidating, characterizing and modeling these interactions and on studying the microbiome as a complex, interconnected and cohesive system. Here, specifically, I highlight the pressing need for the development of predictive system-level models and for a system-level understanding of the microbiome, and discuss potential computational frameworks for metagenomic-based modeling of the microbiome at the cellular, ecological and supra-organismal level. I review some preliminary attempts at constructing such models and examine the challenges and hurdles that such modeling efforts face. I also discuss possible future applications and research avenues that such metagenomic systems biology and predictive system-level models may facilitate. [ABSTRACT FROM PUBLISHER]

Significant interspecies differences exist between human and rodent with respect to absorption, distribution, and excretion of bisphenol A (BPA) and its primary metabolite, BPA-glucuronide (BPA-G). ATP-Binding Cassette (ABC) transporter enzymes play important roles in these physiological processes, and their enzyme localization (apical vs. basolateral) in the plasma membrane allows for different cellular efflux pathways. In this study, we utilized an ATPase assay to evaluate BPA and BPA-G as potential substrates for the human and rat ABC transporters: P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs), and breast cancer- resistant protein (BCRP). Based on high ATPase activity, BPA is likely a substrate for rat mdr1b but not for human MDR1 or rat mdr1a. Results indicate that BPA is a potential substrate for rat mrp2 and human MRP2, BCRP, and MRP3. The metabolite BPAG demonstrated the highest apparent substrate binding affinity for rat mrp2 and human MRP3 but appeared to be a nonsubstrate or potential inhibitor for human MRP2, MDR1, and BCRP and for rat mdr1a, mdr1b, and bcrp. Analysis of ABC transporter amino acid sequences revealed key differences in putative binding site composition that may explain substrate specificity. Collectively, these results suggest that in both rat and human, apical transporters efflux BPA into the bile and/or intestinal lumen. BPA-G would follow a similar pathway in rat; however, in human, due to the basolateral location of MRP3, BPA-G would likely enter systemic and portal blood supplies. These differences between human and rodent ABC transporters may have significant implications for interspecies extrapolation used in risk assessment. [ABSTRACT FROM AUTHOR]

Amylases from the midgut gland of wild Farfantepenaeus subtilis (Pérez-Farfante, 1967) and Litopenaeus schmitti (Burkenroad, 1936), and farmed Litopenaeus vannamei (Boone, 1931) were characterized through studies on the effect of inhibitor and metallic ions, optimal pH and temperature, thermal stability and zymograms. The substrate zymogram revealed nine, eight, ten and seven amylolytic bands from F. subtilis, L. schmitti, adults and juveniles L. vannainei, respectively. Total amylolytic activity in the farmed shrimp was three times as high as that of the wild specimens. Amylases from all species exhibited residual activity above 85% at alkaline pH (7.0-8.0), with optimal temperature between 40 and 50°C. None of the enzymes from the species were thermally stable at temperatures above 55°C. Aipha-amylase activity in F. subtilis and L. schmitti was totally inhibited by Type I inhibitor at 50 and 100 μg.mL-1, while enzymes from adult and juvenile L. vannamei retained 43.5 ± 1.98 and 22.5 ± 0.65% of their activity, respectively, at these same concentrations. Ca2+ increased amylase activity in all species only at a concentration of 1 mM, inhibiting activity at 5 and 10 mM. All other ions employed (Cd2+, Zn2+, Hg2+, Cu2+ and A13+) strongly inhibited amylase activity, regardless of the concentration used. [ABSTRACT FROM AUTHOR]