Insulin sparing action of Adenovirus 36 and its E4orf1 protein

Additional drugs are required to effectively manage diabetes and its complications. Recent studies have revealed protective effects of Ad36, a human adenovirus, and its E4orf1 protein on glucose disposal, which may be creatively harnessed to develop novel anti-diabetic agents. Experimental Ad36 infection improves hyperglycemia in animal models and natural Ad36 infection in humans is associated with better glycemic control. Available data indicate distinctive advantages for a drug that may mimic the action of Ad36 / E4orf1. The key features of such a potential drug include the ability to increase glucose uptake by adipose tissue and skeletal muscle, to reduce hepatic glucose output independent of proximal insulin signaling, and to up-regulate adiponectin and its hepatic action. The effect of Ad36/E4orf1 on hepatocyte metabolism suggests a role for treating hepatic steatosis. Despite these potential advantages, considerable research is required before such a drug is developed. The in vivo efficacy and safety of E4orf1 in improving hyperglycemia remain unknown, and an appropriate drug delivery system is required. Nonetheless, Ad36 E4orf1 offers a research opportunity to develop a new anti-diabetic agent with multiple potential advantages and conceptually advances the use of a rather unconventional source, microbial proteins, for anti-diabetic drug development.     

Ready-to-eat cereal products as meal replacements for weight loss

OBJECTIVE: To test the effectiveness of three commercially available partial meal replacement products on weight-loss outcomes. METHODS: In a randomized controlled clinical trial, 164 eligible overweight and obese adults (ages 18-65 years; body mass index >/=25 kg/m(2)) were randomly assigned to a Control group (CN) or to one of three intervention groups, including 'Cereal Substitution plus Nutrient Bar' (CB), 'Cereal and Waffle Substitution plus Nutrient Bar' (CWB), and 'Cereal Substitution, no Nutrient Bar' (CR). RESULTS: Compared with the CN group, the CB, CWB, and CR groups evidenced significantly greater reductions in weight, body mass index, waist, hip, and thigh measurements, and the CB and CR groups evidenced significantly greater reductions in percentage body fat. Despite strong adherence (88%) and retention (80%), the groups did not differ in cardiovascular risk profile, mood, or satiety. CONCLUSIONS: A variety of ready-to-eat cereal products may be safely and effectively used as meal replacements in weight-loss programs.     

Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey

Background  

Studies show that tuberculosis notification declines with increasing altitude. This can be due to declining incidence or declining case detection. In Vietnam notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in Vietnam in general (69/100,000 population). In order to clarify whether this is explained by low incidence or low case detection, we aimed to assess the prevalence of new smear-positive tuberculosis among adults with prolonged cough in three mountainous provinces in central Vietnam.     

Primary ventricular fibrillation complicating acute myocardial infarction

A controversy exists about whether or not primary ventricular fibrillation in patients with acute myocardial infarction is always preceded by premonitory cardiac arrhythmias. The monitoring system in the Toronto General Hospital Coronary Unit yields a permanent record of every heartbeat and provides a unique opportunity to answer this question. Of 851 patients with proved myocardial infarction, primary ventricular fibrillation developed in 20; 12 of these had frequent ventricular arrhythmias before ventricular fibrillation. In 5 patients, ventricular fibrillation occurred without any warning arrhythmia and the remaining 3 patients had only rare ventricular premature beats.     

Role of adenoviruses in obesity

Five human adenovirus subtypes, Ad5, Ad9, Ad31, Ad36, and Ad37, and a non‐human adenovirus, SMAM1, are linked to increased adiposity in vitro or in vivo. Experimental infection with Ad5, Ad36, and Ad37 produced excess adiposity or weight gain in animals. Ad9 and Ad31 increase fat storage in tissue culture but are not associated with animal or human obesity. Ad36 is the most extensively studied adipogenic adenovirus and is correlated with some measure of overweight/obesity in humans from multiple countries. The correlation is strongest and most consistent in children, but some studies have been negative in both children and adults. About 30% of overweight/obese children and adults and about 15–20% of lean individuals have Ad36 antibodies in epidemiologic studies. The mechanisms of action of Ad36 are due to the early gene 4, open reading frame 1 (E4‐ORF1). Blocking E4‐ORF1 with siRNA prevents the effects of Ad36, and transfection of lentivirus with E4‐ORF1 reproduces the Ad36 effects. Increased adiposity is caused by stimulation of at least three pathways by Ad36. Cell membrane glucose receptors are increased via the Ras pathway, leading to increased intracellular glucose. Fatty acid synthase is increased, which converts the glucose to fatty acids. Finally, peroxisome proliferator‐activated receptor‐γ is increased, resulting in differentiation of adult stem cells into adipocytes. Conclusions: several adenoviruses increase adiposity in animals and are associated with obesity in humans. There are critical gaps in the literature needing further investigation including evaluation of other adenovirus subtypes and better research designs to improve the strength of causal inferences. Copyright © 2015 John Wiley & Sons, Ltd.     

Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis

BackgroundCalcification and inflammation are key pathological processes in aortic stenosis and atherosclerosis. Using combined positron emission tomography and computed tomography (PET/CT), we sought to investigate their contribution to disease progression in aortic stenosis and to help identify vulnerable atherosclerotic plaque.MethodsIn the first part of the study patients with calcific aortic valve disease stenosis were prospectively compared with age-matched and sex-matched controls with normal valves. Aortic valve severity was determined at baseline and 1 year by echocardiography and CT calcium scoring. Calcification and inflammation in the valve were assessed by sodium 18-fluoride (NaF) and 18-fluorodeoxyglucose (FDG) uptake with PET. In the second part of the study NaF and FDG activity was assessed in the coronary arteries both in patients with stable coronary disease and in patients after myocardial infarction.Findings101 patients with aortic stenosis were compared with 20 controls. Tracer activity (target to background ratio [TBR]) was higher in patients with aortic stenosis than in controls (mean NaF 2·87 [SD 0·82] vs 1·55 [0·17], FDG 1·58 [0·21] vs 1·30 [0·13]; both p<0·01). NaF uptake displayed a progressive rise with valve severity (r²=0·540) with a more modest increase observed for FDG (r²=0·218). Baseline NaF correlated closely with alkaline phosphatase staining on immunohistochemistry (r²=0·79) and was a better predictor of disease progression at 1 year (r²=0·44, n=20) than was FDG (r²=0·02) or baseline calcium score (r²=0·36, current best predictor). Increased NaF activity was observed in 45 (42%) of 106 patients with stable coronary atherosclerosis and was localised to individual coronary plaques. These patients had higher rates of previous major adverse cardiovascular events (p=0·016) and higher Framingham risk scores (p=0·011) than did patients without increased uptake. In patients after myocardial infarction (n=15) intense NaF activity was observed at the site of the culprit lesion, with increased uptake compared with the maximum uptake elsewhere in the coronary arteries (TBR median 1·56 [IQR 1·49–1·82] vs 1·23 [1·15–1·48], p=0·02).InterpretationIn the valve, NaF holds promise in predicting aortic stenosis progression. In the coronary arteries it identifies culprit plaque post myocardial infarction and stable patients at elevated cardiac risk.FundingBritish Heart Foundation.     

GSK1562590, a slowly dissociating urotensin-II receptor antagonist, exhibits prolonged pharmacodynamic activity ex vivo

BACKGROUND AND PURPOSE

Recently identified antagonists of the urotensin–II (U-II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U-II due to poor potency and limited selectivity and/or intrinsic activity.

EXPERIMENTAL APPROACH

The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.

KEY RESULTS

GSK1440115 (pK_i= 7.34–8.64 across species) and GSK1562590 (pK_i= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100-fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA₂= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pK_b= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pK_b= 8.87–8.93). Likewise, GSK1562590 inhibited the hU-II-induced systemic pressor response in anaesthetized cats at a dose 10-fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU-II-induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.

CONCLUSIONS AND IMPLICATIONS

Whereas both GSK1440115 and GSK1562590 represent high-affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U-II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.