Dihydrotestosterone decreases tumor necrosis factor-(alpha) and lipopolysaccharide-induced inflammatory response in human endothelial cells

Context: An increasing body of evidence suggests that testosterone may exert beneficial effects on the development of atherosclerosis. It was suggested that testosterone may act after conversion into estradiol and activation of the estrogen receptors; however, a direct role of androgens on the vascular wall has been proposed. Objective: We investigated the effects of dihydrotestosterone on the proinflammatory response observed in human endothelial cells. Design: Human endothelial cells isolated from umbilical cords were incubated with lipopolysaccharide or TNF(alpha) in the presence or absence of dihydrotestosterone (DHT). mRNA and cellular proteins were processed for gene expression studies, and transient transfection experiments were performed to investigate molecular mechanisms involved in the effects observed. Setting: These studies took place at the Department of Pharmacological Sciences, University of Milan, Milan, Italy. Results: Lipopolysaccharide and TNF(alpha) induced VCAM-1 and ICAM-1 mRNA and protein expression, as detected by real-time quantitative PCR, fluorescence-activated cell sorting, and confocal microscopy, but this effect was inhibited when cells were incubated with DHT. In addition, DHT inhibited mRNA expression of IL-6, MCP-1, CD40, TLR4, PAI-1, and Cox-2 and the release of cytokines and chemokines such as GRO, granulocyte-macrophage colony-stimulating factor, and TNF. The DHT effect was counteracted by bicalutamide, an antagonist of the androgen receptor. Furthermore, when cells were cotransfected with a Cox-2 promoter or a 3X-NF-(kappa)B luciferase reporter vector and a plasmid expressing the human androgen receptor, DHT treatment inhibited the increase of the luciferase activity observed with TNF(alpha). Conclusion: DHT could positively regulate endothelial function through the control of the inflammatory response mediated by nuclear factor-(kappa)B in endothelial cell

Safety and efficacy of mipomersen in patients with heterozygous familial hypercholesterolemia

BACKGROUND AND AIMS: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular disease risk. Despite multiple LDL-C-lowering therapies, many HeFH patients do not reach LDL-C targets. Mipomersen, an antisense oligonucleotide against apolipoprotein B (apoB), might further lower LDL-C in HeFH patients. We assessed the efficacy and safety of two mipomersen dosing regimens in HeFH patients and explored whether thrice-weekly dosing improves the benefit-risk profile. METHODS: In this double-blind trial, HeFH patients (LDL-C >160\u202fmg/dL) on maximal tolerated LDL-lowering therapy were randomized to mipomersen 200\u202fmg once weekly (n\u202f=\u202f104), mipomersen 70\u202fmg thrice weekly (n\u202f=\u202f102), or placebo in matching frequency (n\u202f=\u202f103) for 60 weeks. Main outcomes were LDL-C, apoB, and lipoprotein(a) levels after 60 weeks of treatment. RESULTS: Mipomersen 200\u202fmg once weekly and mipomersen 70\u202fmg thrice weekly significantly lowered LDL-C compared with placebo by 21.0% and 18.8%, respectively, and apoB by 22.1% and 21.7% (all p\u202f<\u202f0.001). Lipoprotein(a) was significantly lowered by 27.7% (p\u202f<\u202f0.001) with thrice-weekly dosing. Injection-site reactions and flu-like symptoms led to discontinuation in 21.2% (200\u202fmg), 17.6% (70\u202fmg), and 5.8% (placebo) of participants. Alanine transaminase was elevated ( 653 7 upper limit of normal at least once) in 21.2%, 21.6%, and 1.0% of subjects, respectively. CONCLUSIONS: Mipomersen 200\u202fmg once weekly and 70\u202fmg thrice weekly are effective in lowering apoB-containing lipoproteins in HeFH patients. This is counterbalanced by limited tolerability and increased hepatic transaminase levels in about 21% of patients. The thrice-weekly dosing regimen was associated with lower frequency of flu-like symptoms, which might help avert discontinuation in some patients, but otherwise had no major benefits

Non-linear homogenization of polymer composites with porous inclusions

We homogenize the mechanical properties of a two-phase polymer composite, made of a polyurethane matrix containing porous spherical silicone-based inclusions, and designed to be used for wave control as a local resonant insulator. First we consider a homogenized energy for the spherical inclusions, an expression obtained by an explicit method. Then, we couple inclusions and matrix by means of the second-order tangent method. Direct finite element simulations allow some comparisons with available experiments

Effect of a long-term oral l-arginine supplementation on glucose metabolism : a randomized, double-blind, placebo-controlled trial

Aim: This study assessed the efficacy of long-term l-arginine (l-arg) therapy in preventing or delaying type 2 diabetes mellitus. Methods: A mono-centre, randomized, double-blind, parallel-group, placebo-controlled, phase III trial (l-arg trial) was conducted on 144 individuals affected by impaired glucose tolerance (IGT) and metabolic syndrome (MS). l-Arg/placebo was administered (6.4 g/day) on a background structured lifestyle intervention for 18 months plus a 12-month extended follow-up period after study drug termination. Fasting glucose levels and glucose tolerance after oral glucose tolerance test were evaluated throughout the study. Results: After 18 months, l-arg as compared with placebo did not reduce the cumulative incidence of diabetes [21.4 and 20.8%, respectively, hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.58-1.86] while the cumulative probability to become normal glucose tolerant (NGT) increased (42.4 and 22.1%, respectively, HR, 2.60; 95% CI, 1.51-4.46, p < 0.001). The higher cumulative probability to become of NGT was maintained during the extended period in subjects previously treated with l-arg (HR, 3.21; 95% CI, 1.87-5.51; p < 0.001). At the end of the extended period, the cumulative incidence of diabetes in subjects previously treated with l-arg was reduced as compared with placebo (27.2 and 47.1%, respectively, HR, 0.42; 95% CI, 0.24-0.75, p < 0.05). During both periods, l-arg significantly improved insulin sensitivity and \u3b2-cell function. Conclusion: Among persons with IGT and MS, the supplementation of l-arg for 18 months does not significantly reduce the incidence of diabetes but does significantly increase regression to NGT. \ua9 2012 Blackwell Publishing Ltd

Optimizing Cholesterol Treatment in Patients with Muscle Complaints

Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms