Pharmacological inhibition of LIM kinase pathway impairs platelets functionality and facilitates thrombolysis.

Actin is highly abundant in platelets, and its function is dependent on its structure. Actin filaments (F-actin) are dynamic structures involved in many cellular processes including platelet shape changes and adhesion. The actin cytoskeleton is tightly regulated by actin-binding proteins, which include members of the actin depolymerising factor (ADF)/cofilin family.

Influence of anterior midcingulate cortex on drinking behavior during thirst and following satiation.

In humans, activity in the anterior midcingulate cortex (aMCC) is associated with both subjective thirst and swallowing. This region is therefore likely to play a prominent role in the regulation of drinking in response to dehydration. Using functional MRI, we investigated this possibility during a period of "drinking behavior" represented by a conjunction of preswallow and swallowing events.

Endogenous central amygdala mu-opioid receptor signaling promotes sodium appetite in mice.

Due to the importance of dietary sodium and its paucity within many inland environments, terrestrial animals have evolved an instinctive sodium appetite that is commensurate with sodium deficiency. Despite a well-established role for central opioid signaling in sodium appetite, the endogenous influence of specific opioid receptor subtypes within distinct brain regions remains to be elucidated. Using selective pharmacological antagonists of opioid receptor subtypes, we reveal that endogenous mu-opioid receptor (MOR) signaling strongly drives sodium appetite in sodium-depleted mice, whereas a role for kappa (KOR) and delta (DOR) opioid receptor signaling was not detected, at least in sodium-depleted mice.

Overdrinking, swallowing inhibition, and regional brain responses prior to swallowing.

In humans, drinking replenishes fluid loss and satiates the sensation of thirst that accompanies dehydration. Typically, the volume of water drunk in response to thirst matches the deficit. Exactly how this accurate metering is achieved is unknown; recent evidence implicates swallowing inhibition as a potential factor.

Meta-Analysis of Association Between Mediastinal Radiotherapy and Long-Term Heart Failure.

This investigation sought to identify and quantify any increased risk of long-term heart failure (HF) after thoracic radiotherapy (RT) for cancer and identify any population covariates that corresponded with increased risk. Electronic databases were systematically searched for studies reporting relative risk, odds ratio, and hazard ratio (HR) for symptomatic HF more than 5 years after RT administration. Clinical characteristics, study design, univariable effect sizes, and associated 95% CIs were extracted.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes.

Challenging the dogma of mitochondrial reactive oxygen species overproduction in diabetic kidney disease.

The paradigm that high glucose drives overproduction of superoxide from mitochondria as a unifying theory to explain end organ damage in diabetes complications has been tightly held for more than a decade. With the recent development of techniques and probes to measure the production of distinct reactive oxygen species (ROS) in vivo, this widely held dogma is now being challenged with the emerging view that specific ROS moieties are essential for the function of specific intracellular signaling pathways and represent normal mitochondrial function. This review will provide a balanced overview of the dual nature of ROS, detailing current evidence for ROS overproduction in diabetic kidney disease, with a focus on cell types and sources of ROS.

Improvements in life expectancy among Australians due to reductions in smoking: Results from a risk percentiles approach.

Background: Tobacco smoking is a major burden on the Australian population in terms of health, social and economic costs. Because of this, in 2008, all Australian Governments agreed to set targets to reduce prevalence of smoking to 10 % by 2018 and subsequently introduced several very strong anti-smoking measures. On this backdrop, we estimated in 2012-13 the impact of several scenarios related to reduction of smoking prevalence to 10 % across the entire Australian population and for below specific ages, on improving life expectancy.

Reducing Sitting Time After Stroke: A Phase II Safety and Feasibility Randomized Controlled Trial.

Objective: To test the safety, feasibility, and effectiveness of reducing sitting time in stroke survivors.

Design: Randomized controlled trial with attention-matched controls and blinded assessments.

Setting: Community.

Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection.

Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro.

DPP IV inhibitor suppresses STZ-induced islets injury dependent on activation of the IGFR/Akt/mTOR signaling pathways by GLP-1 in monkeys.

Background: To evaluate the protective effect of the DPP IV inhibitor in STZ-induced islet injury and to identify the molecular events that protect islet against apoptosis.

Methods: 4 diabetic monkeys were treated with streptozotocin (70 mg/kg) in the presence or absence of the DPP IV inhibitor (Sitagliptin), continuing administered for 4 weeks after STZ. The monkeys were evaluated by plasma DPP IV activity, serum active GLP-1 response, blood glucose, insulin and C-P levels, the insulin resistance index (HOMA-IR), and the expression of insulin, caspase-3, IGF receptor (IGFR), p-Akt and p-mTOR in pancreas islets tissues.

Compensatory regulation of HDAC5 in muscle maintains metabolic adaptive responses and metabolism in response to energetic stress.

Some gene deletions or mutations have little effect on metabolism and metabolic adaptation because of redundancy and/or compensation in metabolic pathways. The mechanisms for redundancy and/or compensation in metabolic adaptation in mammalian cells are unidentified. Here, we show that in mouse muscle and myogenic cells, compensatory regulation of the histone deacetylase (HDAC5) transcriptional repressor maintains metabolic integrity.

Phospholipase Cbeta1b associates with a Shank3 complex at the cardiac sarcolemma.

Activation of the heterotrimeric G protein Gq causes cardiomyocyte hypertrophy in vivo and in cell models. Our previous studies have shown that responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because only this PLCβ subtype localizes at the cardiac sarcolemma. In the current study, we investigated the proteins involved in targeting PLCβ1b to the sarcolemma in neonatal rat cardiomyocytes.

Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy.

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE-/-) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE-/- mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide.

Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab study.

Epidemiological studies often rely on self-reported cardiovascular disease (CVD) information, but this may be inaccurate. We investigated the accuracy of self-reported CVD (myocardial infarction, stroke, coronary artery bypass surgery and coronary artery angioplasty) during the follow up of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Self-reported CVD events, including the date of the event and hospital admission details, were collected with an interviewer-administered questionnaire.

A prospective study of glycemia, body size, insulin resistance and the risk of hypertension in Mauritius.

Objective: To estimate the associations between new-onset hypertension and glycemia, insulin resistance, and overall and regional adiposity in a prospective study conducted in Mauritius.

Research Design And Methods: Three thousand five hundred and eighty-one adults without hypertension, pregnancy, or known diabetes at baseline (1987) were followed for incident hypertension in 1992 and 1998, (systolic blood pressure > or =140 mmHg or diastolic blood pressure > or =90 mmHg or antihypertensive medication treatment). Other measurements included fasting plasma glucose and 2-h plasma glucose after a 75-g oral glucose load, fasting insulin, BMI, waist circumference, smoking, alcohol use, exercise, and demographic information.

Sleep-disordered breathing and type 2 diabetes: a report from the International Diabetes Federation Taskforce on Epidemiology and Prevention.

Sleep-disordered breathing (SDB) has been associated with insulin resistance and glucose intolerance, and is frequently found in people with type 2 diabetes. SDB not only causes poor sleep quality and daytime sleepiness, but has clinical consequences, including hypertension and increased risk of cardiovascular disease. In addition to supporting the need for further research into the links between SDB and diabetes, the International Diabetes Federation Taskforce on Epidemiology and Prevention strongly recommends that health professionals working in both type 2 diabetes and SDB adopt clinical practices to ensure that a patient presenting with one condition is considered for the other.

Longitudinal association of glucose metabolism with retinopathy: results from the Australian Diabetes Obesity and Lifestyle (AusDiab) study.

Objective: We determined the longitudinal association of glucose metabolism with retinopathy in a sample of the Australian population.

Research Design And Methods: The Australian Diabetes Obesity and Lifestyle (AusDiab) study is a national, longitudinal study of adults aged > or =25 years from 42 randomly selected areas of Australia. Retinopathy was assessed at baseline in 1999-2000 and 5 years later in 2004-2005 in participants identified as having diabetes (based on self-report and oral glucose tolerance test) and impaired glucose metabolism and in a random sample with normal glucose tolerance.

Differences in height explain gender differences in the response to the oral glucose tolerance test- the AusDiab study.

Aim: To determine the extent of gender-related differences in the prevalence of glucose intolerance for the Australian population and whether body size may explain such differences.

Methods: Cross-sectional data were collected from a national cohort of 11 247 Australians aged > or = 25 years. Glucose tolerance status was assessed according to both fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) levels following a 75-g oral glucose tolerance test (OGTT).

The metabolic syndrome as a tool for predicting future diabetes: the AusDiab study.

Objective: To compare the ability of the metabolic syndrome (MetS), a diabetes prediction model (DPM), a noninvasive risk questionnaire and individual glucose measurements to predict future diabetes.

Design: Five-year longitudinal cohort study. Tools tested included MetS definitions [World Health Organization, International Diabetes Federation, ATPIII and European Group for the study of Insulin Resistance (EGIR)], the FINnish Diabetes RIsk SCore risk questionnaire, the DPM, fasting and 2-h post load plasma glucose.

Epidemiology of childhood type 2 diabetes and obesity.

Over the last decade, it has become apparent that type 2 diabetes extends not only into the young adult population but is also found in adolescents and even, occasionally, in children. The limited data that are currently available present a rather uncertain picture, with a rather wide range of prevalences and incidences of type 2 diabetes in children and adolescents. Not surprisingly, the majority of the cases, and the highest prevalences, have been found among ethnic groups known to be at high risk of adult type 2 diabetes.

Two-hour glucose predicts the development of hypertension over 5 years: the AusDiab study.

Elevated 2-h plasma glucose concentration (2hPG) from an oral glucose tolerance (OGTT) test more strongly predicts risk of subsequent cardiovascular disease than fasting plasma glucose (FPG), but the association between these glucose measurements and hypertension risk is less clear. We examined the association between 2hPG, FPG and risk of hypertension. We conducted a prospective observational study (The Australian Diabetes, Obesity and Lifestyle Study-AusDiab) among 4413 Australian residents who attended a baseline (1999-2000) and follow-up (2004-2005) examinations.

Selenoprotein S1: a novel inflammatory gene.

Selenoprotein S1 (SEPS1), a novel gene involved in the stress response of endoplasmic reticulum and inflammation control. Recent results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines, suggesting SEPS1 may play a major role in the mediation of inflammation in IDDM and some other immunological disorders.