Slow Acceptance of Universal Antiretroviral Therapy (ART) Among Mothers Enrolled in IMPAACT PROMISE Studies Across the Globe.

The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the "Treat All" strategy.

The relationship of respiratory and cardiovascular hospital admissions to the southern California wildfires of 2003.

OBJECTIVE: There is limited information on the public health impact of wildfires. The relationship of cardiorespiratory hospital admissions (n = 40 856) to wildfire-related particulate matter (PM(2.5)) during catastrophic wildfires in southern California in October 2003 was evaluated. METHODS: Zip code level PM(2.5) concentrations were estimated using spatial interpolations from measured PM(2.5), light extinction, meteorological conditions, and smoke information from MODIS satellite images at 250 m resolution. Generalised estimating equations for Poisson data were used to assess the relationship between daily admissions and PM(2.5), adjusted for weather, fungal spores (associated with asthma), weekend, zip code-level population and sociodemographics. RESULTS: Associations of 2-day average PM(2.5) with respiratory admissions were stronger during than before or after the fires. Average increases of 70 microg/m(3) PM(2.5) during heavy smoke conditions compared with PM(2.5) in the pre-wildfire period were associated with 34% increases in asthma admissions. The strongest wildfire-related PM(2.5) associations were for people ages 65-99 years (10.1% increase per 10 microg/m(3) PM(2.5), 95% CI 3.0% to 17.8%) and ages 0-4 years (8.3%, 95% CI 2.2% to 14.9%) followed by ages 20-64 years (4.1%, 95% CI -0.5% to 9.0%). There were no PM(2.5)-asthma associations in children ages 5-18 years, although their admission rates significantly increased after the fires. Per 10 microg/m(3) wildfire-related PM(2.5), acute bronchitis admissions across all ages increased by 9.6% (95% CI 1.8% to 17.9%), chronic obstructive pulmonary disease admissions for ages 20-64 years by 6.9% (95% CI 0.9% to 13.1%), and pneumonia admissions for ages 5-18 years by 6.4% (95% CI -1.0% to 14.2%). Acute bronchitis and pneumonia admissions also increased after the fires. There was limited evidence of a small impact of wildfire-related PM(2.5) on cardiovascular admissions. CONCLUSIONS: Wildfire-related PM(2.5) led to increased respiratory hospital admissions, especially asthma, suggesting that better preventive measures are required to reduce morbidity among vulnerable populations.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing.

The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).

Effects of endotoxin on expression of VLA integrins by human bronchoalveolar lavage macrophages.

Endotoxin (lipopolysaccharide, LPS) is known to induce inflammatory responses, such as monocyte/macrophage adherence, migration, and accumulation. Recruitment and accumulation of macrophages during infection and inflammation are regulated by integrin-mediated cell-extracellular matrix interactions. In the present report, we studied the effects of LPS on the expression of VLA-5 (alpha 5 beta 1), VLA-3 (alpha 3 beta 1), and VLA-2 (alpha 2 beta 1) integrins and fibronectin (FN) by human alveolar macrophages in an attempt to understand the mechanism by which LPS regulates macrophage adhesion to matrix proteins. Bronchoalveolar lavage macrophages were treated with varying concentrations of Escherichia coli LPS for different times and evaluated for expression of the integrins and FN by immunofluorescence, immunoelectron microscopy, autoradiography, and radioimmunoassay. Immunofluorescent and immunoelectron microscopic observations showed that VLA integrins were constitutively expressed on the cell surface and concentrated on the microvilli and pseudopodia of the macrophages. The effects of LPS on expression of the integrins were dose and time related. VLA-5 expression was increased after 30 min of stimulation by LPS, suggesting that LPS may induce rapid secretion of the integrin. However, incubations with LPS longer than 30 min decreased VLA-5 expression in a dose-dependent pattern. LPS also caused dose-related decreases in the expression of VLA-3 and VLA-2 integrins and increases of intracellular FN 24 h after stimulation. The results suggest that a prolonged exposure to LPS may impede VLA integrin-mediated migration and result in local accumulation of macrophages in the lung.

Differential effects of transforming growth factor-beta 1 on lipopolysaccharide induction of endothelial adhesion molecules.

In this report, we studied the effects of transforming growth factor (TGF)-beta 1 on lipopolysaccharide (LPS)-induced expression of endothelial cell (EC) adhesion molecules. Confluent human umbilical cord vein EC cultures were stimulated with Escherichia coli LPS and TGF-beta 1, alone or in combination for various times and evaluated for expression of ICAM-1, E-selectin, and VCAM-1 by immunofluorescence and radioimmunoassay. Effects of LPS and/or TGF-beta 1 on cell growth were also studied by 3H-thymidine incorporation. Both LPS and TGF-beta 1 alone stimulated EC expression of the adhesion molecules in a dose-dependent manner. The effects of TGF-beta 1 on LPS induction of the adhesion molecules varied with LPS concentration and treatment time, mode, and duration. Pretreatment with TGF-beta 1 for 24 h greatly augmented LPS induction of ICAM-1 and VCAM-1 expression, but decreased E-selectin expression. TGF-beta 1 also enhanced expression of the adhesion molecules in cells that were pretreated with 1 microgram/mL LPS for 60 min. Concomitant treatment with TGF-beta 1/LPS resulted in significant increases in ICAM-1 but decreases in VCAM-1 expression. TGF-beta 1 effects on LPS induction of the adhesion molecules were more prominent at lower LPS levels (.001, .01 microgram/mL). Both LPS and TGF-beta 1 suppressed thymidine incorporation in a dose-related pattern. These data suggest that TGF-beta 1 has additive and antagonistic effects on LPS induction of the adhesion molecules and that the cell responsiveness to the stimuli in the expression is related to growth condition of the cells. In conclusion, our findings suggest that TGF-beta 1 exhibits pro-inflammatory and anti-inflammatory activities in human endothelial cells and may play an important role in regulating leukocyte adherence and extravasation under LPS-induced inflammatory conditions.

Conformation of Fibronectin Fibrils Varies: Discrete Globular Domains of Type III Repeats Detected.

: Cryo-high-resolution scanning electron microscopy was used to analyze the conformation of fibronectin fibrils formed in human skin fibroblast cultures or in a cell-free system by treating soluble plasma fibronectin with guanidine. Structurally, fibrils assembled in the cell-free system and in culture were similar. Assembly of both fibrillar networks involves interactions with the III1 and amino terminal repeats of fibronectin; their conformations consist of either smooth surfaces or patches of smooth surfaces and nodules randomly spaced along the fibril. The random distribution of these two conformations in fibrils indicates that fibronectin fibrils are capable of undergoing localized conformational changes. The nodules may be discrete domains of 3 to 4 type III repeats, as they can be labeled with the monoclonal antibody IST-2 to the III13-14 repeats in fibronectin and are found in 160 kDa and 85 kDa fragments of fibronectin that only contain type III repeats. In our study, smooth regions of fibrils were never recognized by the IST-2 antibody, suggesting that the epitope in the III13-14 repeats is masked in these regions. These results demonstrate that fibronectin fibrils are flexible and certain epitopes of fibronectin may be buried, or exposed, depending on the conformation of the fibril. They also show that fibrils assembled in cell-free conditions can be a powerful tool for studying fibril formation.

Distribution of the cellular uptake of phosphorothioate oligodeoxynucleotides in the rat kidney in vivo.

Previous animal studies have demonstrated that following systemic administration phosphorothioate oligodeoxynucleotides (S-ODNs) are primarily excreted by the kidneys and that renal tissue levels of S-ODNs exceed that of other organs. Thus, the kidney may be an ideal target organ for application of antisense S-ODNs in vivo. We examined which cells within the rat kidney have uptake of radiolabeled S-ODNs following intravenous infusion. A 20-base 35S-ODN was infused into 6 adult male Wistar rats. Three animals each were sacrificed 30 min and 4 h after infusion. The kidneys were then removed, fixed, and tissue autoradiography was performed. Similar results were obtained in both groups. The highest level of radioactivity was seen within the proximal tubules. Lower levels of activity were seen within the glomerulus, the parietal epithelial cells of Bowman's space, and distal tubular cells. Very weak activity was also detected within the cells of the loop of Henle and the medullary collecting ducts. These results demonstrated that within the kidney S-ODNs were taken up primarily by proximal tubular cells, with much lower uptake by cells in other segments of the nephron.