Hypertriglyceridemic waist: a simple clinical phenotype associated with coronary artery disease in women

The aim of the present study was to compare the ability of the hypertriglyceridemic waist phenotype and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) clinical criteria to predict coronary artery disease (CAD) risk in a sample of women. We studied 254 women among whom the presence/absence of CAD was assessed by angiography. The hypertriglyceridemic waist phenotype was defined as having both a high waist circumference (≥85 cm) and increased fasting triglyceride levels (≥1.5 mmol/L), whereas the presence of at least 3 of the 5 NCEP-ATP III criteria was used as the "reference" screening approach to identify women with the features of the metabolic syndrome. Women with hypertriglyceridemic waist were characterized by higher adiposity indices as well as by a more disturbed fasting metabolic risk profile compared with women without this phenotype. Similar differences were observed when comparing the metabolic profile of women with vs without at least 3 of the NCEP-ATP III clinical criteria. Moreover, differences in the Framingham risk score were essentially similar when women were considered at low or high risk by either hypertriglyceridemic waist or by NCEP-ATP III clinical criteria (P < .0001). Finally, both clinical phenotypes were predictive of CAD (hypertriglyceridemic waist: relative odds ratio, 2.1; 95% confidence interval, 1.1-3.8; P = .02; NCEP-ATP III clinical criteria: relative odds ratio, 2.5; 95% confidence interval, 1.4-4.6; P < .003). These results suggest that hypertriglyceridemic waist is a simple screening tool to identify women with clustering metabolic abnormalities and at increased CAD risk.     

A score to estimate 30-day mortality after intensive care admission after cardiac surgery

Objective

Several risk-scoring systems have been developed to predict surgical mortality and complications in cardiac surgical patients, but none of the current systems include factors related to the intraoperative period. The purpose of this study was to develop a score that incorporates both preoperative and intraoperative factors so that it could be used for patients admitted to a cardiac surgical intensive care unit (ICU) immediately after surgery.

Anti-Hepatitis C Virus Activity and Toxicity of Type III Phosphatidylinositol-4-Kinase Beta Inhibitors

Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.     

Mechanism of action of and mechanism of reduced susceptibility to the novel anti-Clostridium difficile compound LFF571

LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.     

Take the challenge: strategies to improve support for parents of chronically ill children

Parents of children with chronic illnesses experience tremendous burden when caring for their children at home. There are many challenges that are present throughout the course of chronic illnesses. To provide better care to the family caring for an ill child at home, clinicians must understand the experiences family members go through on a daily basis. The purpose of this article is to help clinicians better understand these parental experiences; by increasing clinicians' awareness, strategies can then be used, which will improve the outcome for the child, parents, and siblings.     

Antibiotic optimization and chemical structure stabilization of thiomuracin a

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of 1 included removing the C2-C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to 1. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of 2, a structurally simplified and chemically stable analogue of 1 which retained potent antibiotic activity.     

Visceral adiposity and endothelial lipase

CONTEXT: Overexpression of endothelial lipase (EL) has been shown to reduce plasma high-density lipoprotein cholesterol levels in animal models. However, the extent to which EL contributes to modulate the deteriorated high-density lipoprotein profile observed in obesity in humans is less clear. OBJECTIVES: The objectives of this study were to investigate the association between levels of obesity and visceral adiposity in particular and plasma EL concentrations. METHODS: Postheparin plasma EL concentrations were measured by ELISA and visceral adiposity by computed tomography in a sample of 80 sedentary men in good health. EL mRNA levels in abdominal sc and omental adipose tissues obtained during abdominal hysterectomies were measured in another sample of 14 women. RESULTS: Plasma EL levels were positively correlated with body mass index (R = 0.46, P < 0.0001), visceral adipose tissue accumulation (R = 0.44, P < 0.0001), and a proatherogenic lipid profile including increased plasma cholesterol and triglycerides. However, EL mRNA levels were similar in sc and omental AT and were 10,000-fold lower than lipoprotein lipase mRNA levels in those tissues. CONCLUSIONS: Increased visceral adiposity is significantly correlated with elevated plasma EL levels, but this association is unlikely to be causal and may reflect other common metabolic alterations.