Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: A randomized clinical trial

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistanceThis is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38)

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Technological capabilities and global–local interactions: the electronics industry in two Mexican regions

The evolutionary approach to technical change considers technological capability building as the outcome of interactions among individuals, firms, and organizations within a socio-economic and institutional framework in a geographically defined space. This paper aims to study technological capabilities by combining the analysis of both micro and meso levels, emphasizing the role of global–local interactions. It addresses the following research question: what are the main determinants of advanced technological capabilities of firms and regions in an FDI-dominated manufacturing sector? We study the case of the electronics industry in two regions of Mexico. The methodology allows accounting for process and product-centered capabilities in the case of the firms, and for components, attributes, and relationships in the regions

THP-1 and MDM macrophages release pro-inflammatory cytokines after exposure to CS.

<p>Concentrations of TNF-α and IL-1β were measured by ELISA in culture supernatant from CS-exposed and unexposed THP-1 (A and B) and MDM (C and D) macrophages infected with Mtb. Bars indicate mean ± SD from eight independent experiments. ****P≤0.0001, **P<0.01, *P<0.05 ANOVA and Dunnett’s post-hoc test compared to unexposed macrophages.</p

CS limits macrophage ability to control intracellular bacterial growth.

<p>THP-1 (A) and MDM (B) macrophages were exposed to CS at concentrations of 1, 5 and 10 μg/ml for 24 h and then infected with Mtb-H37Rv (MOI 1). On day 4 post-infection, CFU were enumerated. Bars indicate mean ± SD from five independent experiments. *P<0.05, **P<0.01. ANOVA and Dunnett’s post-hoc test compared to unexposed macrophages. </p

Proposed model for immunological damage in Mtb-H37Rv-infected macrophages pre-exposed to CS.

<p>In normal conditions, TLR2 activation in a dose-dependent manner leads to cytokine production in the macrophages. 2) Macrophages exposed to CS have increased ASK1 and JNK1 levels (perhaps as signals of cellular stress), but decreased expression of TLR2 and levels of the anti-apoptotic molecules Bcl-2 and Mcl-1; under these conditions, the macrophage is more susceptible to cell death. 3) Where the macrophages pre-exposed to CS are infected with Mtb-H37Rv, there is an increased secretion of pro-apoptotic cytokines (TNF-α and IL-1β). When macrophages are exposed to CS, they become more susceptible to cell death, if they are also infected with M.tb, pro-inflammatory cytokines are secreted and necrosis is established, favoring the release of viable intracellular bacilli.</p

CS increased ASK1 and JNK1 expression in exposed macrophages.

<p>THP-1 macrophages were exposed to CS at concentrations of 1, 5 and 10 μg/ml for 24 h and infected with Mtb. Relative units of ASK-1 (A), P-p38 (B), JNK1 (D) and JNK2 (D) are shown; band densities in the Western Blots were normalized against GAPDH. One of the five independent Western Blots for ASK1, P-p38, JNK1 and JNK2 (C, F) is shown. Total protein was determined using GAPDH as a loading control. Bars indicate mean ± SD. *P<0.05, **P<0.01. ANOVA and Dunnett’s post-hoc test compared to unexposed macrophages.</p