Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose

AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic β-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic β-cell function

Baker Center Journal of Applied Public Policy - Vol. IV, No.II

This special edition includes articles from speakers at a 2010 conference - Howard H. Baker, Jr: A Life in Public Service and a special addendum including photographs and cartoons from Sen. Baker\u27s career

Amino Acid Metabolic Origin as an Evolutionary Influence on Protein Sequence in Yeast

The metabolic cycle of Saccharomyces cerevisiae consists of alternating oxidative (respiration) and reductive (glycolysis) energy-yielding reactions. The intracellular concentrations of amino acid precursors generated by these reactions oscillate accordingly, attaining maximal concentration during the middle of their respective yeast metabolic cycle phases. Typically, the amino acids themselves are most abundant at the end of their precursor’s phase. We show that this metabolic cycling has likely biased the amino acid composition of proteins across the S. cerevisiae genome. In particular, we observed that the metabolic source of amino acids is the single most important source of variation in the amino acid compositions of functionally related proteins and that this signal appears only in (facultative) organisms using both oxidative and reductive metabolism. Periodically expressed proteins are enriched for amino acids generated in the preceding phase of the metabolic cycle. Proteins expressed during the oxidative phase contain more glycolysis-derived amino acids, whereas proteins expressed during the reductive phase contain more respiration-derived amino acids. Rare amino acids (e.g., tryptophan) are greatly overrepresented or underrepresented, relative to the proteomic average, in periodically expressed proteins, whereas common amino acids vary by a few percent. Genome-wide, we infer that 20,000 to 60,000 residues have been modified by this previously unappreciated pressure. This trend is strongest in ancient proteins, suggesting that oscillating endogenous amino acid availability exerted genome-wide selective pressure on protein sequences across evolutionary time

A Cohort Study of Serum Bilirubin Levels and Incident Non-Alcoholic Fatty Liver Disease in Middle Aged Korean Workers

BACKGROUND: Serum bilirubin may have potent antioxidant and cytoprotective effects. Serum bilirubin levels are inversely associated with several cardiovascular and metabolic endpoints, but their association with nonalcoholic fatty liver disease (NAFLD) has not been investigated except for a single cross-sectional study in a pediatric population. We assessed the prospective association between serum bilirubin concentrations (total, direct, and indirect) and the risk for NAFLD. METHODS AND FINDINGS: We performed a cohort study in 5,900 Korean men, 30 to 59 years of age, with no evidence of liver disease and no major risk factors for liver disease at baseline. Study participants were followed in annual or biennial health examinations between 2002 and 2009. The presence of fatty liver was determined at each visit by ultrasonography. We observed 1,938 incident cases of NAFLD during 28,101.8 person-years of follow-up. Increasing levels of serum direct bilirubin were progressively associated with a decreasing incidence of NAFLD. In age-adjusted models, the hazard ratio for NAFLD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.61 (95% CI 0.54-0.68). The association persisted after adjusting for multiple metabolic parameters (hazard ratio comparing the highest to the lowest quartile 0.86, 95% CI 0.76-0.98; P trend = 0.039). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of NAFLD. CONCLUSIONS: In this large prospective study, higher serum direct bilirubin levels were significantly associated with a lower risk of developing NAFLD, even adjusting for a variety of metabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for NAFLD risk

P300 amplitude is insensitive to working memory load in schizophrenia

<p>Abstract</p> <p>Background</p> <p>Working memory (WM) tasks usually elicit a P300 ERP component, whose amplitude decreases with increasing WM load. So far, this effect has not been studied in schizophrenics (SZs), a group that is considered to have an aberrant brain connectivity and impairments in WM capacity. The aim of this study was to determine the dependency of the P300 component on WM load in a sample of SZ subjects.</p> <p>Methods</p> <p>We recorded 26 subjects (13 SZ patients and their matched controls) with an 80-channel electroencephalogram. Subjects performed an N-back task, a WM paradigm that manipulates the number of items to be stored in memory.</p> <p>Results</p> <p>In healthy subjects, P300 amplitude was highest in the low WM load condition, and lowest in both the attentional control condition and the high WM load condition. In contrast, SZs evidenced low P300 amplitude in all conditions. A significant between group difference in P300 amplitude was evidenced only at the low WM load condition (1 -back), being smaller in SZs.</p> <p>Conclusions</p> <p>SZ subjects display a lower than normal P300 amplitude, which does not vary as a function of memory load. These results are consistent with a general impairment in WM capacity in these patients.</p

Guidelines on acute gastroenteritis in children: a critical appraisal of their quality and applicability in primary care

<p>Abstract</p> <p>Background</p> <p>Reasons for poor guideline adherence in acute gastroenteritis (AGE) in children in high-income countries are unclear, but may be due to inconsistency between guideline recommendations, lack of evidence, and lack of generalizability of the recommendations to general practice. The aim of this study was to assess the quality of international guidelines on AGE in children and investigate the generalizability of the recommendations to general practice.</p> <p>Methods</p> <p>Guidelines were retrieved from websites of professional medical organisations and websites of institutes involved in guideline development. In addition, a systematic search of the literature was performed. Articles were selected if they were a guideline, consensus statement or care protocol.</p> <p>Results</p> <p>Eight guidelines met the inclusion criteria, the quality of the guidelines varied. 242 recommendations on diagnosis and management were found, of which 138 (57%) were based on evidence.</p> <p>There is a large variety in the classification of symptoms to different categories of dehydration. No signs are generalizable to general practice.</p> <p>It is consistently recommended to use hypo-osmolar ORS, however, the recommendations on ORS-dosage are not evidence based and are inconsistent. One of 14 evidence based recommendations on therapy of AGE is based on outpatient research and is therefore generalizable to general practice.</p> <p>Conclusions</p> <p>The present study shows considerable variation in the quality of guidelines on AGE in children, as well as inconsistencies between the recommendations. It remains unclear how to asses the extent of dehydration and determine the preferred treatment or referral of a young child with AGE presenting in general practice.</p

Genetic Basis of Hidden Phenotypic Variation Revealed by Increased Translational Readthrough in Yeast

Eukaryotic release factors 1 and 3, encoded by SUP45 and SUP35, respectively, in Saccharomyces cerevisiae, are required for translation termination. Recent studies have shown that, besides these two key factors, several genetic and epigenetic mechanisms modulate the efficiency of translation termination. These mechanisms, through modifying translation termination fidelity, were shown to affect various cellular processes, such as mRNA degradation, and in some cases could confer a beneficial phenotype to the cell. The most studied example of such a mechanism is [PSI+], the prion conformation of Sup35p, which can have pleiotropic effects on growth that vary among different yeast strains. However, genetic loci underlying such readthrough-dependent, background-specific phenotypes have yet to be identified. Here, we used sup35C653R, a partial loss-of-function allele of the SUP35 previously shown to increase readthrough of stop codons and recapitulate some [PSI+]-dependent phenotypes, to study the genetic basis of phenotypes revealed by increased translational readthrough in two divergent yeast strains: BY4724 (a laboratory strain) and RM11_1a (a wine strain). We first identified growth conditions in which increased readthrough of stop codons by sup35C653R resulted in different growth responses between these two strains. We then used a recently developed linkage mapping technique, extreme QTL mapping (X-QTL), to identify readthrough-dependent loci for the observed growth differences. We further showed that variation in SKY1, an SR protein kinase, underlies a readthrough-dependent locus observed for growth on diamide and hydrogen peroxide. We found that the allelic state of SKY1 interacts with readthrough level and the genetic background to determine growth rate in these two conditions

Mining for genotype-phenotype relations in Saccharomyces using partial least squares

<p>Abstract</p> <p>Background</p> <p>Multivariate approaches are important due to their versatility and applications in many fields as it provides decisive advantages over univariate analysis in many ways. Genome wide association studies are rapidly emerging, but approaches in hand pay less attention to multivariate relation between genotype and phenotype. We introduce a methodology based on a BLAST approach for extracting information from genomic sequences and Soft- Thresholding Partial Least Squares (ST-PLS) for mapping genotype-phenotype relations.</p> <p>Results</p> <p>Applying this methodology to an extensive data set for the model yeast <it>Saccharomyces cerevisiae</it>, we found that the relationship between genotype-phenotype involves surprisingly few genes in the sense that an overwhelmingly large fraction of the phenotypic variation can be explained by variation in less than 1% of the full gene reference set containing 5791 genes. These phenotype influencing genes were evolving 20% faster than non-influential genes and were unevenly distributed over cellular functions, with strong enrichments in functions such as cellular respiration and transposition. These genes were also enriched with known paralogs, stop codon variations and copy number variations, suggesting that such molecular adjustments have had a disproportionate influence on <it>Saccharomyces </it>yeasts recent adaptation to environmental changes in its ecological niche.</p> <p>Conclusions</p> <p>BLAST and PLS based multivariate approach derived results that adhere to the known yeast phylogeny and gene ontology and thus verify that the methodology extracts a set of fast evolving genes that capture the phylogeny of the yeast strains. The approach is worth pursuing, and future investigations should be made to improve the computations of genotype signals as well as variable selection procedure within the PLS framework.</p

Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL

Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1

Screen or not to screen for peripheral arterial disease: Guidance from a decision model

__Abstract__ Background: Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. Methods. A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. Results: For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Ye