ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:This study was undertaken to determine whether 7SK small nuclear RNA (snRNA), which has been proposed to function as an inhibitor of Tat cofactor P-TEFb, plays a role in transcriptional latency in T cells.Design and methods:The association of 7SK snRNA with P-TEFb was investigated in resting and activated peripheral blood lymphocytes (PBLs). Primary PBLs were isolated by standard methods and activated with phytohemagglutinin (PHA). Levels of 7SK snRNA were determined by Northern blotting and levels of the P-TEFb subunits cyclin-dependent kinase 9 and cyclin T1 were analyzed by immunoblotting.Results:The association of 7SK snRNA with P-TEFb complexes was specific. Following activation of PBLs, the levels of 7SK snRNA increased in a manner similar to U1 and U6 snRNA, sn RNAs involved in positive aspects of cellular gene expression. Unexpectedly, the association of 7SK snRNA with P-TEFb increased dramatically following lymphocyte activation.Conclusion:Increased association of 7SK snRNA with P-TEFb in activated lymphocytes correlates with increased global transcription. This suggests that 7SK snRNA is unlikely to promote transcriptional latency in lymphocytes through an association with P-TEFb; it also suggests that the proposal that the association of 7SK snRNA with P-TEFb acts to inhibit transcriptional elongation needs to be re-evaluated.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To study whether HIV protease inhibitors could induce nuclear lamina alterations in adipocytes as observed in a genetic form of lipodystrophy due to lamin A/C mutation.Design:We have previously observed that indinavir (IDV) impairs adipocyte differentiation and sterol regulatory element-binding protein-1 (SREBP-1) nuclear localization in 3T3-F442A adipocytes. We compared here the effects of IDV with that produced by two other PIs, nelfinavir (NFV) and amprenavir (APV) on adipose conversion, cellular localization of SREBP-1, nuclear morphology, and maturation and stability of the lamina network.Results:IDV and NFV, but not APV, altered adipose cell differentiation, as shown by lipid staining and protein expression of SREBP-1, CAAAT/enhancer binding protein (C/EBP)α and fatty acid synthase (FAS). In IDV-treated cells, 50–60 % of the nuclei could not accumulate SREBP-1. Twenty percent of these SREBP-negative nuclei were grossly dysmorphic, with blebs and prominent herniations, and showed an altered distribution of lamin A/C and lamin B. In IDV-treated cells, nuclear fragilization was shown by the abnormal extractibility of lamina proteins and SREBP-1, and the accumulation of prelamin A. NFV similarly altered lamin A/C maturation whereas APV was almost ineffective.Conclusions:We show in an adipose cell line that IDV and NFV induced alterations at the nuclear level by promoting defects in lamin A/C maturation, organization and stability. We suggest that these lamina network alterations might be responsible for SREBP-1 nuclear mislocalization therefore resulting in altered adipocyte differentiation.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To identify the predictors of cytomegalovirus reactivation in AIDS patients on highly active antiretroviral therapy (HAART).Design:This prospective study enrolled cytomegalovirus-seropositive AIDS patients on or about to start HAART, who were not receiving anti-cytomegalovirus prophylaxis. Clinical and laboratory data were collected over 3.5 years at clinic visits, which coincided with the study visits.Methods:Blood was obtained at every study visit and was used for measurements of cytomegalovirus cell-mediated immunity (lymphocyte proliferation, IFN-γ, IL-2, and IL-10 production), cytomegalovirus viral load, CD4 cell count, and HIV viral load. A logistic-normal model was used to analyse outcome data with repeated observations.Results:Twenty-six patients had 40 episodes of cytomegalovirus reactivation (positive cytomegalovirus viral load) during the study. Their immunological and virological parameters were compared with 26 randomly selected control individuals from the same cohort. The risk of cytomegalovirus reactivation significantly decreased with every 6-month increase in HAART duration [odds ratio (OR) 0.5;P= 0.02] and marginally increased with every log10RNA copies/ml HIV viral load (OR 2;P= 0.07). CD4 cell counts, cytomegalovirus lymphocyte proliferation, IL-2, and IL-10 did not reach significance as predictors of cytomegalovirus reactivation. However, cytomegalovirus IFN-γ production significantly decreased the risk of cytomegalovirus reactivation (OR 0.03;P= 0.04).Conclusion:Cytomegalovirus-specific IFN-γ has a unique value as an immunological predictor of cytomegalovirus reactivation, demonstrating the importance of cellular immune responses in the control of cytomegalovirus replication in HAART recipients.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To evaluate the efficacy and safety of simplified maintenance therapy (SMT) compared with continued protease inhibitor (PI) therapy.Design:Meta-analysis of nine randomized controlled trials in which 833 patients were switched to SMT (abacavir, efavirenz or nevirapine) and 616 continued PI, assessing virologic failure (primary outcome), discontinuation of therapy for reasons other than virologic failure, CD4 cell count, total plasma cholesterol and triglycerides.Results:The risk ratio for virologic failure for SMT compared to continued PI was 1.06 [95% confidence interval (CI) 0.58–1.92; test for homogeneityP= 0.01] for SMT, 2.56, (95% CI, 1.17–5.64) for abacavir, 0.83 (95% CI, 0.36–1.91) for efavirenz and 0.54 (95% CI, 0.29–1.02) for nevirapine. The risk ratio for premature discontinuation of therapy with SMT was 0.61 (95% CI, 0.48–0.77; test for homogeneityP< 0.10). The difference in absolute mean cholesterol for SMT compared to continued PI was −0.15 mmol/l, (95% CI, −0.40 to 0.09; test for homogeneityP< 0.01) for SMT, −0.51 mmol/l (95% CI, −0.70 to −0.33) for abacavir, 0.22 mmol/l (95% CI, 0 to 0.43) for efavirenz and −0.19 mmol/l (95% CI, −0.48 to 0.09) for nevirapine.Conclusions:Current evidence suggests that SMT with abacavir rather than continued PI increases the risk of virologic failure, this increased risk may be confined to patients with prior mono or dual therapy with reverse transcriptase inhibitors. There is not enough evidence on whether SMT with efavirenz and nevirapine influences the risk of virologic failure. SMT with any of the three drugs reduces the risk of discontinuation of therapy, and SMT with abacavir reduces plasma cholesterol.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To examine the impact of high-dose multiple micronutrient supplementation on survival and disease progression among HIV-infected individuals in Thailand.Design:Randomized placebo-controlled trial.Methods:Four-hundred and eighty-one HIV-infected men and women living in and around Bangkok with CD4 cell counts in the range 50 × 106– 550 × 106/l were randomized to receive micronutrients or placebo for a period of 48 weeks. Trial participants were examined clinically 12-weekly and tested for CD4 cell count 24-weekly. A subset were tested for HIV plasma viral load at 48 weeks.Results:Seventy-nine (16%) trial participants were lost to follow-up and 23 (5%) died. The death rate was lower in the micronutrients arm with the mortality hazard ratios [95% confidence interval (CI)] of 0.53 (0.22–1.25;P= 0.1) overall and 0.37 (0.13–1.06;P= 0.052) and 0.26 (0.07–0.97;P= 0.03) among those with CD4 cell counts < 200 × 106/l and < 100 × 106/l respectively. There was no impact on CD4 cell count or plasma viral load.Conclusions:Multiple micronutrient supplementation may enhance the survival of HIV-infected individuals with CD4 cell counts < 200 × 106/l. This could have important public health implications in the developing world where access to antiretrovirals remains poor. The clinical findings need to be reproduced in other settings and the mechanism, which appears to be independent of change in CD4 cell count, merits further investigation.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:In the absence of currently available therapy to manage facial lipoatrophy, strategies used to compensate for facial fat loss warrant clinical evaluation.Methods:The goal of this open-label, single-arm, pilot study was to evaluate the efficacy and safety of facial injections of poly-L-lactic acid (PLA) (New-Fill)® in HIV-infected patients with severe facial lipoatrophy. Patients received four sets of injection at day 0 and then every 2 weeks for 6 weeks. Patients were evaluated by clinical examination, facial ultrasonography, and photography at screening and at weeks 6, 24, 48, 72, and 96.Results:Fifty patients were enrolled. At entry, the median facial fat thickness was equal to zero (range, 0.0–2.1 mm). The median total cutaneous thickness (TCT) increased significantly from baseline : +5.1 mm (range, 2.2–8.6 mm) at week 6, +6.4 mm (range, 3.1–9.1 mm) at week 24, +7.2 mm (range, 4.2–9.6 mm) at week 48, +7.2 mm (range, 3.5–9.6 mm) at week 72 and +6.8 mm (range, 3.9–10.1 mm) at week 96 (P< 0.001). The proportion of patients with TCT > 10 mm was observed in 19% at week 6, 41% at week 24, 61% at week 48, 52% at week 72 and 43% at week 96. In 22 (44%) patients, palpable but non-visible subcutaneous micronodules were observed with a spontaneous resolution in six patients at week 96.Conclusion:The benefit of PLA for the correction of the facial lipoatrophy in HIV-infected patients was clearly demonstrated, with an evident aesthetic and quality of life improvement. The efficacy, safety profile, and the simplicity of the injection schedule of PLA make this filling material a potentially attractive treatment.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:In the current context of dyslipidaema, hyperglycaema and lipodystrophia observed among HIV-seropositive subjects, it is important to study the risk of myocardial infarction (MI) in this population. The French Hospital Database on HIV, which includes a large number of seropositive subjects followed for substantial periods, offers the opportunity to analyse the impact of protease inhibitors (PI) on the risk of MI among men.Methods:Cox model was used to study the risk factors of MI occurrence. Standardized morbidity ratios (SMR) in men exposed to PI were calculated with data from the French general male population (FGMP) of the same age as reference.Results:Between 1996 and 1999, MI was diagnosed in 60 men among 88 029 person-years (PY), including 49 cases among men exposed to PI. In the Cox model, exposure to PI was associated with a higher risk of MI [relative hazard (RH), 2.56; 95% confidence interval (CI), 1.03–6.34]. The expected incidence in the FGMP was 10.8/10 000 PY. The SMR relative to the FGMP was 0.8 (95% CI, 0.5–1.3) for men exposed to PI for < 18 months (G1), 1.5 (95% CI, 0.8–2.5) for men exposed for 18–29 months (G2) and 2.9 (95% CI, 1.5–5.0) for men exposed for ⩾ 30 months (G3). With G1 as reference, the SMR was 1.9 (95% CI, 1.0–3.1) for G2 and 3.6 (95% CI, 1.8–6.2) for G3.Conclusion:Our results point to a duration-related effect relationship between PI and MI, with a higher MI incidence rate among men exposed to PI for 18 months or more.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID