Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons.

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes

PPARgamma activity in subcutaneous abdominal fat tissue and fat mass gain during short-term overfeeding

Objective: As the peroxisome proliferator-activated receptor (PPAR) plays a central role in fat mass regulation, we investigated whether initial subcutaneous PPAR activity is related to fat mass generation during overfeeding. Subjects: Fourteen healthy female subjects (age 254 years, BMI 22.12.3 kg/m2). Design and measurements: Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Fasting blood samples were analyzed for leptin, insulin and glucose. Fasting subcutaneous abdominal fat biopsies were obtained for analysis of PPAR1, PPAR2, aP2 and UCP2 mRNAs. Results: Initial PPAR1 and 2, aP2 and UCP2 mRNAs were not related to fat gain (P>0.12). However, PPAR1, PPAR2 and aP2 mRNA changes were positively related to changes in plasma leptin (

Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status

Background: A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. Methods: The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Results: Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Conclusions: Most people with chronic physical health problems have medium or high levels of PMH. The variables that adversely affect PMH are old age, polypharmacy and frequent consumption of analgesics. The type of health problem does not influence the levels of PMH. Much more extensive studies with samples without chronic pathology are now required in order to be able to draw more robust conclusions

Case-based reported mortality associated with laboratory-confirmed influenza A(H1N1) 2009 virus infection in the Netherlands: the 2009-2010 pandemic season versus the 2010-2011 influenza season

<p>Abstract</p> <p>Background</p> <p>In contrast to seasonal influenza epidemics, where the majority of deaths occur amongst elderly, a considerable part of the 2009 pandemic influenza related deaths concerned relatively young people. In the Netherlands, all deaths associated with laboratory-confirmed influenza A(H1N1) 2009 virus infection had to be notified, both during the 2009-2010 pandemic season and the 2010-2011 influenza season. To assess whether and to what extent pandemic mortality patterns were reverting back to seasonal patterns, a retrospective analyses of all notified fatal cases associated with laboratory-confirmed influenza A(H1N1) 2009 virus infection was performed.</p> <p>Methods</p> <p>The notification database, including detailed information about the clinical characteristics of all notified deaths, was used to perform a comprehensive analysis of all deceased patients with a laboratory-confirmed influenza A(H1N1) 2009 virus infection. Characteristics of the fatalities with respect to age and underlying medical conditions were analysed, comparing the 2009-2010 pandemic and the 2010-2011 influenza season.</p> <p>Results</p> <p>A total of 65 fatalities with a laboratory-confirmed influenza A(H1N1) 2009 virus infection were notified in 2009-2010 and 38 in 2010-2011. During the pandemic season, the population mortality rates peaked in persons aged 0-15 and 55-64 years. In the 2010-2011 influenza season, peaks in mortality were seen in persons aged 0-15 and 75-84 years. During the 2010-2011 influenza season, the height of first peak was lower compared to that during the pandemic season. Underlying immunological disorders were more common in the pandemic season compared to the 2010-2011 season (p = 0.02), and cardiovascular disorders were more common in the 2010-2011 season (p = 0.005).</p> <p>Conclusions</p> <p>The mortality pattern in the 2010-2011 influenza season still resembled the 2009-2010 pandemic season with a peak in relatively young age groups, but concurrently a clear shift toward seasonal patterns was seen, with a peak in mortality in the elderly, i.e. ≥ 75 years of age.</p

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference

An algorithm for classifying tumors based on genomic aberrations and selecting representative tumor models

<p>Abstract</p> <p>Background</p> <p>Cancer is a heterogeneous disease caused by genomic aberrations and characterized by significant variability in clinical outcomes and response to therapies. Several subtypes of common cancers have been identified based on alterations of individual cancer genes, such as HER2, EGFR, and others. However, cancer is a complex disease driven by the interaction of multiple genes, so the copy number status of individual genes is not sufficient to define cancer subtypes and predict responses to treatments. A classification based on genome-wide copy number patterns would be better suited for this purpose.</p> <p>Method</p> <p>To develop a more comprehensive cancer taxonomy based on genome-wide patterns of copy number abnormalities, we designed an unsupervised classification algorithm that identifies genomic subgroups of tumors. This algorithm is based on a modified genomic Non-negative Matrix Factorization (gNMF) algorithm and includes several additional components, namely a pilot hierarchical clustering procedure to determine the number of clusters, a multiple random initiation scheme, a new stop criterion for the core gNMF, as well as a 10-fold cross-validation stability test for quality assessment.</p> <p>Result</p> <p>We applied our algorithm to identify genomic subgroups of three major cancer types: non-small cell lung carcinoma (NSCLC), colorectal cancer (CRC), and malignant melanoma. High-density SNP array datasets for patient tumors and established cell lines were used to define genomic subclasses of the diseases and identify cell lines representative of each genomic subtype. The algorithm was compared with several traditional clustering methods and showed improved performance. To validate our genomic taxonomy of NSCLC, we correlated the genomic classification with disease outcomes. Overall survival time and time to recurrence were shown to differ significantly between the genomic subtypes.</p> <p>Conclusions</p> <p>We developed an algorithm for cancer classification based on genome-wide patterns of copy number aberrations and demonstrated its superiority to existing clustering methods. The algorithm was applied to define genomic subgroups of three cancer types and identify cell lines representative of these subgroups. Our data enabled the assembly of representative cell line panels for testing drug candidates.</p

Temporal resolution of protein–protein interactions in the live-cell plasma membrane

We have recently devised a method to quantify interactions between a membrane protein (“bait”) and a fluorophore-labeled protein (“prey”) directly in the live-cell plasma membrane (Schwarzenbacher et al. Nature Methods 5:1053–1060 2008). The idea is to seed cells on surfaces containing micro-patterned antibodies against the exoplasmic domain of the bait, and monitor the co-patterning of the fluorescent prey via fluorescence microscopy. Here, we characterized the time course of bait and prey micropattern formation upon seeding the cells onto the micro-biochip. Patterns were formed immediately after contact of the cells with the surface. Cells were able to migrate over the chip surface without affecting the micropattern contrast, which remained constant over hours. On single cells, bait contrast may be subject to fluctuations, indicating that the bait can be released from and recaptured on the micropatterns. We conclude that interaction studies can be performed at any time-point ranging from 5 min to several hours post seeding. Monitoring interactions with time opens up the possibility for new assays, which are briefly sketched in the discussion section

Parent proxy-report of their children's health-related quality of life: an analysis of 13,878 parents' reliability and validity across age subgroups using the PedsQL™ 4.0 Generic Core Scales

BACKGROUND: Health-related quality of life (HRQOL) measurement has emerged as an important health outcome in clinical trials, clinical practice improvement strategies, and healthcare services research and evaluation. While pediatric patient self-report should be considered the standard for measuring perceived HRQOL, there are circumstances when children are too young, too cognitively impaired, too ill or fatigued to complete a HRQOL instrument, and reliable and valid parent proxy-report instruments are needed in such cases. Further, it is typically parents' perceptions of their children's HRQOL that influences healthcare utilization. Data from the PedsQL™ Database(SM )were utilized to test the reliability and validity of parent proxy-report at the individual age subgroup level for ages 2–16 years as recommended by recent FDA guidelines. METHODS: The sample analyzed represents parent proxy-report age data on 13,878 children ages 2 to 16 years from the PedsQL™ 4.0 Generic Core Scales Database(SM). Parents were recruited from general pediatric clinics, subspecialty clinics, and hospitals in which their children were being seen for well-child checks, mild acute illness, or chronic illness care (n = 3,718, 26.8%), and from a State Children's Health Insurance Program (SCHIP) in California (n = 10,160, 73.2%). RESULTS: The percentage of missing item responses for the parent proxy-report sample as a whole was 2.1%, supporting feasibility. The majority of the parent proxy-report scales across the age subgroups exceeded the minimum internal consistency reliability standard of 0.70 required for group comparisons, while the Total Scale Scores across the age subgroups approached or exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores. Construct validity was demonstrated utilizing the known groups approach. For each PedsQL™ scale and summary score, across age subgroups, healthy children demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition, with most effect sizes in the medium to large effect size range. CONCLUSION: The results demonstrate the feasibility, reliability, and validity of parent proxy-report at the individual age subgroup for ages 2–16 years. These analyses are consistent with recent FDA guidelines which require instrument development and validation testing for children and adolescents within fairly narrow age groupings and which determine the lower age limit at which reliable and valid responses across age categories are achievable. Even as pediatric patient self-report is advocated, there remains a fundamental role for parent proxy-report in pediatric clinical trials and health services research