Unique IL-13Rα2-based HIV-1 vaccine strategy to enhance mucosal immunity, CD8(+) T-cell avidity and protective immunity.

We have established that mucosal immunization can generate high-avidity human immunodeficiency virus (HIV)- specific CD8þ T cells compared with systemic immunization, and interleukin (IL)-13 is detrimental to the functional avidity of these T cells. We have now constructed two unique recombinant HIV-1 vaccines that co-express soluble or membrane-bound forms of the IL-13 receptor a2 (IL-13Ra2), which can ‘‘transiently’’ block IL-13 activity at the vaccination site causing wild-type animals to behave similar to an IL-13 KO animal. Following intranasal/intramuscular prime-boost immunization, these IL-13Ra2-adjuvanted vaccines have shown to induce (i) enhanced HIV-specific CD8þ Tcells with higher functional avidity, with broader cytokine/chemokine profiles and greater protective immunity using a surrogate mucosal HIV-1 challenge, and also (ii) excellent multifunctional mucosal CD8þ T-cell responses, in the lung, genito-rectal nodes (GN), and Peyer’s patch (PP). Data revealed that intranasal delivery of these IL-13Ra2-adjuvanted HIV vaccines recruited large numbers of unique antigen-presenting cell subsets to the lung mucosae, ultimately promoting the induction of high-avidity CD8þ Tcells. We believe our novel IL-13R cytokine trap vaccine strategy offers great promise for not only HIV-1, but also as a platform technology against range of chronic infections that require strong sustained high-avidity mucosal/systemic immunity for protection.

Progression of cardiovascular and endocrine dysfunction in a rabbit model of obesity

In rabbits, mean arterial pressure (MAP) increases in response to fat feeding, but does not increase further with progressive weight gain. We documented the progression of adiposity and the alterations in endocrine/cardiovascular function in response to fat feeding in rabbits, to determine whether stabilization of MAP after 3 weeks could be explained by stabilization of neurohormonal factors. Rabbits were fed a control diet or high-fat diet for 9 weeks (n¼23). Fat feeding progressively increased body mass and adiposity. Heart rate (HR) was elevated by week 3 (15±3%) but changed little thereafter. The effects of fat feeding on MAP were dependent on baseline MAP and peaked at 3 weeks. From baseline, MAP p80mmHg, MAP had increased by 8.1±1.3, 4.7±1.7 and 5.6±1.2mmHg, respectively, 3, 6 and 9 weeks after commencing the high-fat diet, but by only 2.6±1.5, 3.0±1.7 and 3.9±1.4mmHg, respectively, in control rabbits. Fat feeding did not increase MAP from a baseline 480mmHg. Plasma concentrations of leptin and insulin increased during the first 3–6 weeks of fat feeding and then stabilized (increasing by 111±17% and 731±302% by week 9, respectively), coinciding with the pattern of changes in MAP and HR. Plasma total cholesterol, triglycerides, renin activity, aldosterone and atrial natriuretic peptide were not significantly altered by fat feeding. Given that the changes in plasma leptin and insulin mirrored the changes in MAP and HR, leptin and insulin may be important factors in the development of hypertensionand tachycardia in the rabbit model of obesity.

Salt loading in canola oil fed SHRSP rats induces endothelial dysfunction

This study aimed to determine if 50 days of canola oil intake in the absence or presence of salt loading affects: (1) antioxidant and oxidative stress markers, (2) aortic mRNA of NADPH oxidase (NOX) subunits and superoxide dismutase (SOD) isoforms and (3) endothelial function in SHRSP rats. SHRSP rats were fed a diet containing 10 wt/wt% soybean oil or 10 wt/wt% canola oil, and given tap water or water containing 1% NaCl for 50 days. Without salt, canola oil significantly increased RBC SOD, plasma cholesterol and triglycerides, aortic p22phox, NOX2 and CuZn-SOD mRNA, and decreased RBC glutathione peroxidase activity. With salt, canola oil reduced RBC SOD and catalase activity, LDL-C, and p22phox mRNA compared with canola oil alone, whereas plasma malondialdehyde (MDA) was reduced and RBC MDA and LDL-C were higher. With salt, the canola oil group had significantly reduced endothelium-dependent vasodilating responses to ACh and contractile responses to norepinephrine compared with the canola oil group without salt and to the WKY rats. These results indicate that ingestion of canola oil increases O2 - generation, and that canola oil ingestion in combination with salt leads to endothelial dysfunction in the SHRSP model.

Light-intensity physical activity and cardiometabolic biomarkers in US adolescents

Skeletal muscle fat metabolism after exercise in humans: influence of fat availability

The mechanisms facilitating increased skeletal muscle fat oxidation following prolonged, strenuous exercise remain poorly defined. The aim of this study was to examine the influence of plasma free fatty acid (FFA) availability on intramuscular malonyl-CoA concentration and the regulation of whole-body fat metabolism during a 6-h postexercise recovery period. Eight endurance-trained men performed three trials, consisting of 1.5 h high-intensity and exhaustive exercise, followed by infusion of saline, saline + nicotinic acid (NA; low FFA), or Intralipid and heparin [high FFA (HFA)]. Muscle biopsies were obtained at the end of exercise (0 h) and at 3 and 6 h in recovery. Ingestion of NA suppressed the postexercise plasma FFA concentration throughout recovery (P < 0.01), except at 4 h. The alteration of the availability of plasma FFA during recovery induced a significant increase in whole-body fat oxidation during the 6-h period for HFA (52.2 ± 4.8 g) relative to NA (38.4 ± 3.1 g; P < 0.05); however, this response was unrelated to changes in skeletal muscle malonyl-CoA and acetyl-CoA carboxylase (ACC)β phosphorylation, suggesting mechanisms other than phosphorylation-mediated changes in ACC activity may have a role in regulating fat metabolism in human skeletal muscle during postexercise recovery. Despite marked changes in plasma FFA availability, no significant changes in intramuscular triglyceride concentrations were detected. These data suggest that the regulation of postexercise skeletal muscle fat oxidation in humans involves factors other than the 5′AMP-activated protein kinase-ACCβ-malonyl-CoA signaling pathway, although malonyl-CoA-mediated regulation cannot be excluded completely in the acute recovery period.

Improvements in insulin resistance with exercise training: a lipocentric approach

Traditional views on the metabolic derangements underlying insulin resistance and Type 2 diabetes have been largely “glucocentric” in nature, focusing on the hyperglycemic and/or hyperinsulinemic states that result from impaired glucose tolerance. But in addition to glucose intolerance, there is a coordinated breakdown in lipid dynamics in individuals with insulin resistance, manifested by elevated levels of circulating free fatty acids, diminished rates of lipid oxidation, and excess lipid accumulation in skeletal muscle and/or liver. This review examines the premise that an oversupply and/or accumulation of lipid directly inhibits insulin action on glucose metabolism via changes at the level of substrate competition, enzyme regulation, intracellular signaling, and/or gene transcription. If a breakdown in lipid dynamics is causal in the development of insulin resistance (rather than a coincidental feature resulting from it), it should be possible to demonstrate that interventions that improve lipid homeostasis cause reciprocal changes in insulin sensitivity. Accordingly, the efficacy of aerobic endurance training in human subjects in mediating the association between deranged lipid metabolism and insulin resistance will be examined. It will be demonstrated that aerobic exercise training is a potent and effective primary intervention strategy in the prevention and treatment of individuals with insulin resistance.

PGC-1α and PGC-1β increase CrT expression and creatine uptake in myotubes via ERRα

Intramuscular creatine plays a crucial role in maintaining skeletal muscle energy homeostasis, and its entry into the cell is dependent upon the sodium chloride dependent Creatine Transporter (CrT; Slc6a8). CrT activity is regulated by a number of factors including extra- and intracellular creatine concentrations, hormones, changes in sodium concentration, and kinase activity, however very little is known about the regulation of CrT gene expression. The present study aimed to investigate how Creatine Transporter (CrT) gene expression is regulated in skeletal muscle. Within the first intron of the CrT gene, we identified a conserved sequence that includes the motif recognized by the Estrogen-related receptor α (ERRα), also known as an Estrogen-related receptor response element (ERRE). Additional ERREs confirming to the known consensus sequence were also identified in the region upstream of the promoter. When partnered with peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1β), ERRα induces the expression of many genes important for cellular bioenergetics. We therefore hypothesized that PGC-1 and ERRα could also regulate CrT gene expression and creatine uptake in skeletal muscle. Here we show that adenoviral overexpression of PGC-1α or PGC-1β in L6 myotubes increased CrT mRNA (2.1 and 1.7-fold, P<0.0125) and creatine uptake (1.8 and 1.6-fold, P<0.0125), and this effect was inhibited with co-expression of shRNA for ERRα. Overexpression of a constitutively active ERRα (VP16-ERRα) increased CrT mRNA approximately 8-fold (P<0.05), resulting in a 2.2-fold (P<0.05) increase in creatine uptake. Lastly, chromatin immunoprecipitation assays revealed that PGC-1α and ERRα directly interact with the CrT gene and increase CrT gene expression.

Distilled technical cashew nut shell liquid (DT-CNSL) as an effective biofuel and additive to stabilize triglyceride biofuels in diesel

We report distilled technical cashew nut shell liquid (DT-CNSL) as a non-transesterified biofuel and also as an additive to convert triglycerides to biofuel, without the need for the formation of methyl esters. DT-CNSL blends of diesel obey physico-chemical parameters of diesel. DT-CNSL offers stability to blends of straight vegetable oil (SVO) and tallow oil in diesel. Fluorescence studies using charge transfer probes show that the blend of DT-CNSL, triglycerides and diesel is a uniform solution, and fluorescence behavior is similar to that of diesel. The economics for the cultivation of cashew (Anacardium occidentale), its industrial use and rich carbon sink properties indicate that DT-CNSL could complement or replace traditional biodiesel crops like Jatropha and improve income for farmers. © 2014 Elsevier Ltd.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies

Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.

Pharmacological management of aggression and violence.

The pharmacological management of violence and aggression is a common and substantial clinical dilemma in the emergency psychiatric situation. A literature search was conducted through PubMed and using the Cochrane Library. This was followed by a manual search of selected literature. Randomised controlled trials were sought that specifically addressed the acute situation, rather than the ongoing management of chronic conditions. There was a paucity of well-controlled data and insufficient evidence to support the use of many agents in emergency situations. Many studies had considerable limitations making comparison difficult. Efficacy data for a range of treatment options exists, including the use of classical and atypical anti-psychotic agents, benzodiazepines and combination therapies. Clinical risk, tolerability and environmental factors need to form part of a careful and considered judgement in the choice of treatment. Safety, tolerability and the potential for a positive experience are major considerations, thus paving the way for long term compliance.

The effect of known cardiovascular risk factors on carotid-femoral pulse wave velocity in school-aged children: a population based twin study

Childhood cardiovascular risk factors affect vascular function long before overt cardiovascular disease. Twin studies provide a unique opportunity to examine the influence of shared genetic and environmental influences on childhood cardiovascular function. We examined the relationship between birth parameters, markers of adiposity, insulin resistance, lipid profile and blood pressure and carotid-femoral pulse wave velocity (PWV), a validated non-invasive measure of arterial stiffness in a healthy cohort of school-aged twin children. PWV was performed on a population-based birth cohort of 147 twin pairs aged 7-11 years. Fasting blood samples, blood pressure and adiposity measures were collected concurrently. Mixed linear regression models were used to account for twin clustering, within- and between-twin pair associations. There were positive associations between both markers of higher adiposity, insulin resistance, elevated triglycerides and PWV, which remained significant after accounting for twin birth-set clustering. There was a positive association between both diastolic and mean arterial blood pressure and PWV in within-pair analysis in dizygotic, but not monozygotic twins, indicating genetic differences evident in dizygotic not monozygotic twins may affect these associations. Increased blood pressure, triglycerides and other metabolic markers are associated with increased PWV in school-aged twins. These results support both the genetic and environmental contribution to higher PWV, as a marker of arterial stiffness, and reiterate the importance of preventing metabolic syndrome from childhood.

Factors influencing insulin resistance in relation to atherogenicity in mood disorders, the metabolic syndrome and tobacco use disorder

OBJECTIVE: This study examines the effects of malondialdehyde (MDA) and uric acid on insulin resistance and atherogenicity in subjects with and without mood disorders, the metabolic syndrome (MetS) and tobacco use disorder (TUD). METHODS: We included 314 subjects with depression and bipolar depression, with and without the MetS and TUD and computed insulin resistance using the updated homeostasis model assessment (HOMA2IR) and atherogenicity using the atherogenic index of plasma (AIP), that is log10 (triglycerides/high density lipoprotein (HDL) cholesterol. RESULTS: HOMA2IR is correlated with body mass index (BMI) and uric acid levels, but not with mood disorders and TUD, while the AIP is positively associated with BMI, mood disorders, TUD, uric acid, MDA and male sex. Uric acid is positively associated with insulin and triglycerides and negatively with HDL cholesterol. MDA is positively associated with triglyceride levels. Comorbid mood disorders and TUD further increase AIP but not insulin resistance. Glucose is positively associated with increasing age, male gender and BMI. DISCUSSION: The results show that mood disorders, TUD and BMI together with elevated levels of uric acid and MDA independently contribute to increased atherogenic potential, while BMI and uric acid are risk factors for insulin resistance. The findings show that mood disorders and TUD are closely related to an increased atherogenic potential but not to insulin resistance or the MetS. Increased uric acid is a highly significant risk factor for insulin resistance and increased atherogenic potential. MDA, a marker of lipid peroxidation, further contributes to different aspects of the atherogenic potential. Mood disorders and TUD increase triglyceride levels, lower HDL cholesterol and are strongly associated with the atherogenic, but not insulin resistance, component of the MetS.

The metabolic syndrome and cancer: is the metabolic syndrome useful for predicting cancer risk above and beyond its individual components?

AIMS: The metabolic syndrome (MetS) is a risk factor for cancer. However, it is not known if the MetS confers a greater cancer risk than the sum of its individual components, which components drive the association, or if the MetS predicts future cancer risk. MATERIALS AND METHODS: We linked 20,648 participants from the Australian and New Zealand Diabetes and Cancer Collaboration with complete data on the MetS to national cancer registries and used Cox proportional hazards models to estimate associations of the MetS, the number of positive MetS components, and each of the five MetS components separately with the risk for overall, colorectal, prostate and breast cancer. Hazard ratios (HR) and 95% confidence intervals (95%CI) are reported. We assessed predictive ability of the MetS using Harrell's c-statistic. RESULTS: The MetS was inversely associated with prostate cancer (HR 0.85; 95% CI 0.72-0.99). We found no evidence of an association between the MetS overall, colorectal and breast cancers. For those with five positive MetS components the HR was 1.12 (1.02-1.48) and 2.07 (1.26-3.39) for overall, and colorectal cancer, respectively, compared with those with zero positive MetS components. Greater waist circumference (WC) (1.38; 1.13-1.70) and elevated blood pressure (1.29; 1.01-1.64) were associated with colorectal cancer. Elevated WC and triglycerides were (inversely) associated with prostate cancer. MetS models were only poor to moderate discriminators for all cancer outcomes. CONCLUSIONS: We show that the MetS is (inversely) associated with prostate cancer, but is not associated with overall, colorectal or breast cancer. Although, persons with five positive components of the MetS are at a 1.2 and 2.1 increased risk for overall and colorectal cancer, respectively, and these associations appear to be driven, largely, by elevated WC and BP. We also demonstrate that the MetS is only a moderate discriminator of cancer risk.

Breaking up of prolonged sitting over three days sustains, but does not enhance, lowering of postprandial plasma glucose and insulin in overweight and obese adults

To compare the cumulative (3-day) effect of prolonged sitting on metabolic responses during a mixed meal tolerance test (MTT), with sitting that is regularly interrupted with brief bouts of light-intensity walking. Overweight/obese adults (n=19) were recruited for a randomized, 3-day, outpatient, cross-over trial involving: (1) 7-h days of uninterrupted sitting (SIT); and (2) 7-h days of sitting with light-intensity activity breaks [BREAKS; 2-min of treadmill walking (3.2 km/h) every 20 min (total: 17 breaks/day)]. On days 1 and 3, participants underwent a MTT (75 g of carbohydrate, 50 g of fat) and the incremental area under the curve (iAUC) was calculated from hourly blood samples. Generalized estimating equation (GEE) models were adjusted for gender, body mass index (BMI), energy intake, treatment order and pre-prandial values to determine effects of time, condition and time × condition. The glucose iAUC was 1.3 ± 0.5 and 1.5 ± 0.5 mmol·h·l(-1) (mean differences ± S.E.M.) higher in SIT compared with BREAKS on days 1 and 3 respectively (condition effect: P=0.001), with no effect of time (P=0.48) or time × condition (P=0.8). The insulin iAUC was also higher on both days in SIT (day 1: ∆151 ± 73, day 3: ∆91 ± 73 pmol·h·l(-1), P=0.01), with no effect of time (P=0.52) or time × condition (P=0.71). There was no between-treatment difference in triglycerides (triacylglycerols) iAUC. There were significant between-condition effects but no temporal change in metabolic responses to MTT, indicating that breaking up of sitting over 3 days sustains, but does not enhance, the lowering of postprandial glucose and insulin.

Cholinesterase Research Outreach Project (CROP): measuring cholinesterase activity and pesticide use in an agricultural community

BACKGROUND: Australian farmers and their workers are exposed to a wide variety of pesticides. Organophosphate (OP) insecticides are a widely used class of pesticide used for animal husbandry practices (Naphthalophos for sheep dipping, jetting and drench), crop production for pest control (Dimethoate) and in public health (Maldison for head lice). Acute poisonings with this class of insecticide are reported among agricultural workers and children around the globe, due to the inhibition of acetylcholinesterase (AChE). Less is known about chronic exposures. Regular monitoring of erythrocyte AChE will enable farmers to identify potential exposure to organophosphate insecticides and take action to reduce exposures and improve their health and safety practices. This study aims to assess and improve the integration of AChE monitoring into routine point of care health clinics, and provide farming and non-farming people with a link between their AChE activity and their household chemical and agrichemical use. METHODS/DESIGN: The research will target individuals who work on mixed farming enterprises and routinely using OPs (n = 50) and non-farmers (n = 30). Baseline data are collected regarding demographic, health conditions and behaviours, Kessler 10 (K10) scores, chemical use and personal protection. Baseline anthropometric measures include height, weight, hip and waist circumference, body fat analysis and, biochemical analysis of fasted total serum cholesterol, triglycerides, low-density cholesterol (LDL), high-density cholesterol (HDL) and blood glucose. Analysis of erythrocyte cholinesterase (EAChE) activity is also conducted using a finger prick test. Testing of EAChE is then repeated in all participants every 3 weeks for a maximum of three times over a period 10 weeks. Participants are provided with full feedback and counselling about their EAChE activity after each reading and a detailed summary provided to all participants at the completion of the study. Data will be analysed using repeated measures within a general linear model. DISCUSSION: This work will provide an evidence base and recommendations for the integration of EAChE monitoring into Australian rural health clinics, leading to research which will further quantify pesticide exposure both on the farm and in the home, highlighting the importance of sustaining and providing a safe work and home environment for farming communities. TRIAL REGISTRATION: ACTRN12613001256763.