Showing papers by "Philimon Gona published in 2005"

Prevalence of elevated cholesterol and associated risk factors among perinatally HIV-infected children (4-19 years old) in Pediatric AIDS Clinical Trials Group 219C.

Abstract: Background: HIV protease inhibitors (PIs) are known to disturb lipid metabolism in adults, leading to hypercholesterolemia. A number of cross-sectional studies have also reported this phenomenon in perinatally HIV-infected children but differ greatly with respect to prevalence and/or methodology. Methods: The Pediatric AIDS Clinical Trials Group 219C (PACTG 219C) is a prospective cohort study designed to examine long-term outcomes in children born to HIV-infected women. The outcome of interest in this analysis was total cholesterol, and patients were classified as hypercholesterolemic if their total cholesterol was above the 95th percentile of US Third National Health and Nutrition Survey (NHANES III) standards for gender, race/ethnicity, and age. We hypothesized that hypercholesterolemia would be more common among older children receiving PI therapy who demonstrated excellent adherence and might be associated with hypertension and obesity. Information regarding treatment, adherence, and laboratory values was obtained using the date closest to the cholesterol measurement. Crude and adjusted effect measures were estimated using exposure odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) from univariate and multivariate logistic regression models. Results: Among 1812 HIV-infected participants between 4 and 19 years of age, 229 children had hypercholesterolemia (prevalence = 13.0%, 95% CI: 11.1-14.3) compared with 9 of 187 HIV-uninfected children (prevalence = 4.8%, 95% CI: 2.2-8.8). After adjusting for confounders, current PI use (OR = 5.3, 95% CI: 3.1-9.2), age from 4 to <6 years (OR = 2.9, 95% Cl: 1.7-4.9), HIV-1 RNA <400 copies/mL (OR = 2.3, 95% CI: 1.7-3.2), self-report of no missed doses in the past 3 days (OR = 2.2, 95% CI: 1.3-3.8), white race (OR = 2.2, 95% CI: 1.4-3.3), age from 6 to <12 years (OR = 1.9, 95% CI: 1.3-2.9), Hispanic ethnicity (OR = 1.8, 95% CI: 1.2-2.5), and current nonnucleoside reverse transcriptase inhibitor use (OR = 1.7, 95% CI: 1.2-2.3) were independently associated with the presence of hypercholesterolemia among the HIV-infected children. There was a positive association with elevated systolic blood pressure in univariate but not multivariate analysis, and no association was present with body mass index. Conclusions: Among the HIV-infected children, the overall prevalence of hypercholesterolemia was 13.0% and the strongest associated risk factor for hypercholesterolemia was current use of a PI in the antiretroviral regimen. Continued follow-up is needed to assess the long-term effects of hypercholesterolemia in children.

Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Alters Mitochondrial Membrane Lipids

Abstract: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been shown to have selective antitumor activity. TRAIL induces ubiquitous pathways of cell death in which caspase activation is mediated either directly or via the release of apoptogenic factors from mitochondria; however, the precise components of the mitochondrial signaling pathway have not been well defined. Notably, mitochondria constitute an important target in overcoming resistance to TRAIL in many types of tumors. Bid is considered to be fundamental in engaging mitochondria during death receptor–mediated apoptosis, but this action is dependent on mitochondrial lipids. Here, we report that TRAIL signaling induces an alteration in mitochondrial membrane lipids, particularly cardiolipin. This occurs independently of caspase activation and primes mitochondrial membranes to the proapoptotic action of Bid. We unveil a link between TRAIL signaling and alteration of membrane lipid homeostasis that occurs in parallel to apical caspase activation but does not take over the mode of cell death because of the concurrent activation of caspase-8. In particular, TRAIL-induced alteration of mitochondrial lipids follows an imbalance in the cellular homeostasis of phosphatidylcholine, which results in an elevation in diacylglycerol (DAG). Elevated DAG in turn activates the δ isoform of phospholipid-dependent serine/threonine protein kinase C, which then accelerates the cleavage of caspase-8. We also show that preservation of phosphatidylcholine homeostasis by inhibition of lipid-degrading enzymes almost completely impedes the activation of pro-caspase-9 while scarcely changing the activation of caspase-8.