PLIN5 deletion remodels intracellular lipid composition and causes insulin resistance in muscle

Defective control of lipid metabolism leading to lipotoxicity causes insulin resistance in skeletal muscle, a major factor leading to diabetes. Here, we demonstrate that perilipin (PLIN) 5 is required to couple intramyocellular triacylglycerol lipolysis with the metabolic demand for fatty acids. PLIN5 ablation depleted triacylglycerol stores but increased sphingolipids including ceramide, hydroxylceramides and sphingomyelin. We generated perilipin 5 (Plin5)-/- mice to determine the functional significance of PLIN5 in metabolic control and insulin action. Loss of PLIN5 had no effect on body weight, feeding or adiposity but increased whole-body carbohydrate oxidation. Plin5-/- mice developed skeletal muscle insulin resistance, which was associated with ceramide accumulation. Liver insulin sensitivity was improved in Plin5-/- mice, indicating tissue-specific effects of PLIN5 on insulin action. We conclude that PLIN5 plays a critical role in coordinating skeletal muscle triacylglycerol metabolism, which impacts sphingolipid metabolism, and is requisite for the maintenance of skeletal muscle insulin action. © 2014 The Authors

Group Incentives and Rational Voting

Our model describes competition between groups driven by the choices of self-interested voters within groups. Within a Poisson voting environment, parties observe aggregate support from groups and can allocate prizes or punishments to them. In a tournament style analysis, the model characterizes how contingent allocation of prizes based on relative levels of support affects equilibrium voting behavior. In addition to standard notions of pivotality, voters influence the distribution of prizes across groups. Such prize pivotality supports positive voter turnout even in non-competitive electoral settings. The analysis shows that competition for a prize awarded to the most supportive group is only stable when two groups actively support a party. However, competition among groups to avoid punishment is stable in environments with any number of groups. We conclude by examining implications for endogenous group formation and how politicians structure the allocation of rewards and punishments.Comment: 34 pages, 1 figur

Age-Related Changes in the Epithelial and Stromal Compartments of the Mammary Gland in Normocalcemic Mice Lacking the Vitamin D3 Receptor

The vitamin D3 receptor (VDR) serves as a negative growth regulator during mammary gland development via suppression of branching morphogenesis during puberty and modulation of differentiation and apoptosis during pregnancy, lactation and involution. To assess the role of the VDR in the aging mammary gland, we utilized 12, 14, and 16 month old VDR knockout (KO) and wild type (WT) mice for assessment of integrity of the epithelial and stromal compartments, steroid hormone levels and signaling pathways. Our data indicate that VDR ablation is associated with ductal ectasia of the primary mammary ducts, loss of secondary and tertiary ductal branches and atrophy of the mammary fat pad. In association with loss of the white adipose tissue compartment, smooth muscle actin staining is increased in glands from VDR KO mice, suggesting a change in the stromal microenviroment. Activation of caspase-3 and increased Bax expression in mammary tissue of VDR KO mice suggests that enhanced apoptosis may contribute to loss of ductal branching. These morphological changes in the glands of VDR KO mice are associated with ovarian failure and reduced serum 17β-estradiol. VDR KO mice also exhibit progressive loss of adipose tissue stores, hypoleptinemia and increased metabolic rate with age. These developmental studies indicate that, under normocalcemic conditions, loss of VDR signaling is associated with age-related estrogen deficiency, disruption of epithelial ductal branching, abnormal energy expenditure and atrophy of the mammary adipose compartment

In Situ Ambient Pressure X-ray Photoelectron Spectroscopy Studies of Lithium-Oxygen Redox Reactions

The lack of fundamental understanding of the oxygen reduction and oxygen evolution in nonaqueous electrolytes significantly hinders the development of rechargeable lithium-air batteries. Here we employ a solid-state Li4+xTi5O12/LiPON/LixV2O5 cell and examine in situ the chemistry of Li-O2 reaction products on LixV2O5 as a function of applied voltage under ultra high vacuum (UHV) and at 500 mtorr of oxygen pressure using ambient pressure X-ray photoelectron spectroscopy (APXPS). Under UHV, lithium intercalated into LixV2O5 while molecular oxygen was reduced to form lithium peroxide on LixV2O5 in the presence of oxygen upon discharge. Interestingly, the oxidation of Li2O2 began at much lower overpotentials (~240 mV) than the charge overpotentials of conventional Li-O2 cells with aprotic electrolytes (~1000 mV). Our study provides the first evidence of reversible lithium peroxide formation and decomposition in situ on an oxide surface using a solid-state cell, and new insights into the reaction mechanism of Li-O2 chemistry.National Science Foundation (U.S.) (Materials Research Science and Engineering Center (MRSEC) Program, Award DMR-0819762)United States. Dept. of Energy (Assistant Secretary for Energy Efficiency and Renewable Energy, Office of FreedomCAR and Vehicle Technologies of the U. S. Department of Energy under contract no. DE-AC03-76SF00098)Lawrence Berkeley National LaboratoryUnited States. Dept. of Energy (Office of Basic Energy Sciences, Materials Sciences and Engineering

A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity

Variability and Predictors of Urinary Bisphenol A Concentrations during Pregnancy

BackgroundPrenatal bisphenol A (BPA) exposure may be associated with developmental toxicity, but few studies have examined the variability and predictors of urinary BPA concentrations during pregnancy.ObjectiveOur goal was to estimate the variability and predictors of serial urinary BPA concentrations taken during pregnancy.MethodsWe measured BPA concentrations during pregnancy and at birth in three spot urine samples from 389 women. We calculated the intraclass correlation coefficient (ICC) to assess BPA variability and estimated associations between log10-transformed urinary BPA concentrations and demographic, occupational, dietary, and environmental factors, using mixed models.ResultsGeometric mean (GM) creatinine-standardized concentrations (micrograms per gram) were 1.7 (16 weeks), 2.0 (26 weeks), and 2.0 (birth). Creatinine-standardized BPA concentrations exhibited low reproducibility (ICC = 0.11). By occupation, cashiers had the highest BPA concentrations (GM: 2.8 μg/g). Consuming canned vegetables at least once a day was associated with higher BPA concentrations (GM = 2.3 μg/g) compared with those consuming no canned vegetables (GM = 1.6 μg/g). BPA concentrations did not vary by consumption of fresh fruits and vegetables, canned fruit, or store-bought fresh and frozen fish. Urinary high-molecular-weight phthalate and serum tobacco smoke metabolite concentrations were positively associated with BPA concentrations.ConclusionsThese results suggest numerous sources of BPA exposure during pregnancy. Etiological studies may need to measure urinary BPA concentrations more than once during pregnancy and adjust for phthalates and tobacco smoke exposures

The prevalence and functional impact of musculoskeletal conditions amongst clients of a primary health care facility in an under-resourced area of Cape Town

BACKGROUND:The extent of disease burden of musculoskeletal conditions (MSC) not due to injury has not been well determined in sub-Saharan Africa. The 1999 Global Burden of Disease study estimated the prevalence of osteoarthritis and rheumatoid arthritis to be 150/100,000 compared to 1,500/100,000 in Europe. The objective of the study was to determine the prevalence of MSC and the functional implications in a sample of people attending community health centres in Cape Town, South Africa. METHODS: A cross-sectional, descriptive study was conducted in clinics in two resource poor communities. Phase I consisted of screening and those who screened positive for peripheral or spinal joint pain went on to complete Phase II, which included the Stanford Health Assessment Questionnaire. RESULTS: 1005 people were screened in Phase I. Of these, 362 (36%) reported MSC not due to injury in the past three months. Those with MSC had higher rates of co-morbidities in every category than those without. The mean Disability Index for those with MSC was mild to moderate and moderate to severe in those over 55 years. CONCLUSIONS: Although the sample may not be representative of the general community, the prevalence is considerably greater than those reported elsewhere even when the population of the catchment area is used as a denominator, (367/100 000). The common presentation of MSC with co-morbid diabetes and hypertension requires holistic management by appropriately trained health care practitioners. Any new determination of burden of disease due to MSC should recognise that these disorders may be more prevalent in developing countries than previously estimated

Hand-held echocardiography: added value in clinical cardiological assessment

BACKGROUND: The ultrasonic industry has recently produced echocardiographic Hand Held Devices (miniaturized, compact and battery-equipped echocardiographic systems). Their potential usefulness has been successfully assessed in a wide range of clinical conditions. The aim of the study was to verify if the routine use of a basic model of echocardiographic Hand Held Device (HHD) could be an important diagnostic tool during outpatient cardiologic consulting or in non-cardiologic hospital sections. METHODS: 87 consecutive patients were included in this study; they underwent routine physical examination, resting ECG and echocardiographic evaluation using a basic model of HHD performed by trained echocardiographists; the cardiologist, whenever possible, formulated a diagnosis. The percentage of subjects in whom the findings were judged reasonably adequate for final diagnostic and therapeutic conclusions was used to quantify the "conclusiveness" of HHD evaluation. Successively, all patients underwent a second echocardiographic evaluation, by an examiner with similar echocardiographic experience, performed using a Standard Echo Device (SED). The agreement between the first and the second echocardiographic exam was also assessed. RESULTS: Mean examination time was 6.7 ± 1.5 min. using HHD vs. 13.6 ± 2.4 min. using SED. The echocardiographic examination performed using HHD was considered satisfactory in 74/87 patients (85.1% conclusiveness). Among the 74 patients for whom the examination was conclusive, the diagnosis was concordant with that obtained with the SED examination in 62 cases (83.8% agreement). CONCLUSION: HHD may generally allow a reliable cardiologic basic evaluation of outpatient or subjects admitted to non-cardiologic sections, more specifically in particular subgroups of patients, with a gain in terms of time, shortening patient waiting lists and reducing healthy costs

Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa: a cross-sectional study

Background Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy. Methods A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. Results The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7) for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load), and 33.8 (95% CI 6.4 – 178.9) for those that were HC2 positive with a HPV viral load > 181.1 RLU. Conclusion Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for the increasing numbers of women accessing ARV therapy so that the benefits of ARVs are not partially offset by an excess risk in cervical cancer

Interventional radiography and mortality risks in U.S. radiologic technologists

With the exponential increase in minimally invasive fluoroscopically guided interventional radiologic procedures, concern has increased about the health effects on staff and patients of radiation exposure from these procedures. There has been no systematic epidemiologic investigation to quantify serious disease risks or mortality. To quantify all-cause, circulatory system disease and cancer mortality risks in U.S. radiologic technologists who work with interventional radiographic procedures, we evaluated mortality risks in a nationwide cohort of 88,766 U.S. radiologic technologists (77% female) who completed a self-administered questionnaire during 1994–998 and were followed through 31 December 2003. We obtained information on work experience, types of procedures (including fluoroscopically guided interventional procedures), and protective measures plus medical, family cancer history, lifestyle, and reproductive information. Cox proportional hazards regression models were used to compute relative risks (RRs) with 95% confidence intervals (CIs). Between completion of the questionnaire and the end of follow-up, there were 3,581 deaths, including 1,209 from malignancies and 979 from circulatory system diseases. Compared to radiologic technologists who never or rarely performed or assisted with fluoroscopically guided interventional procedures, all-cause mortality risks were not increased among those working on such procedures daily. Similarly, there was no increased risk of mortality resulting from all circulatory system diseases combined, all cancers combined, or female breast cancer among technologists who daily performed or assisted with fluoroscopically guided interventional procedures. Based on small numbers of deaths (n=151), there were non-significant excesses (40%–0%) in mortality from cerebrovascular disease among technologists ever working with these procedures. The absence of significantly elevated mortality risks in radiologic technologists reporting the highest frequency of interventional radiography procedures must be interpreted cautiously in light of the small number of deaths during the relatively short follow-up. The present study cannot rule out increased risks of cerebrovascular disease, specific cancers, and diseases with low case-fatality rates or a long latency period preceding death