HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

Objective: The protective effect of physical activity (PA) on risk of stroke remains controversial as a result of lack of insight into the sources of heterogeneity between studies. We performed a comprehensive meta-analysis of studies to (1) quantify the association between PA level and risk of stroke outcomes and (2) test the hypothesis that the association of PA level with stroke outcomes will be similar between men and women. The outcome measures are stroke incidence, stroke mortality, or both. Methods: Cohort studies were identified by searching MEDLINE and EMBASE (from 1986 to 2005) and metaanalysis conducted according to meta-analysis of Observational Studies in Epidemiology (MOOSE) group recommendations. Data were reported as pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models to assess the association of stroke outcomes with PA level. Heterogeneity was investigated, and sensitivity analysis was performed. Stratified analysis by gender was performed. Results: Of 992 articles, 13 satisfied all eligibility criteria and were studied. Compared with low PA, moderate PA caused an 11% reduction in risk of stroke outcome (RR ¼ 0.89, 95% CI 0.86-0.93, p < 0.01) and high PA a 19% reduction (RR ¼ 0.81, CI 0.77-0.84, p < 0.01). Among the men, results showed a 12% reduction in risk associated with moderate PA (RR ¼ 0.88, CI 0.82-0.94, p < 0.01) and 19% reduction for high PA (RR ¼ 0.81, CI 0.75-0.87, p < 0.01). Among the women, results showed a 24% reduction in risk for high PA (RR ¼ 0.76, CI 0.64-.89, p < 0.01). There was, however, no significant risk reduction associated with a moderate PA level in women. Conclusions: Increased PA level appears beneficial in reduction of risk of stroke and related outcomes. However, higher levels of PA may be required in women to achieve as significant a risk reduction as in men. An exercise regimen tailored to women to improve related physiological mechanisms will likely be beneficial.

Although the mechanisms involved in the persistent clinical complications of sickle cell disease have not yet been fully delineated, previous studies suggest that sickle cell (HbSS) patients have a disposition to generate more thrombin and plasmin in vivo than normal subjects. The reasons for the impaired regulation of haemostasis in HbSS patients is poorly understood. We report studies evaluating the extent to which in vivo coagulation and fibrinolysis are altered in HbSS patients in steady state. The concentrations of total factor VII (F(VII)t), factor VII zymogen (F(VII)z), thrombin–antithrombin III (TAT), fibrinopeptide A(FPA), and fibrin D‐dimer in plasmas of 50 normal controls (HbAA) and 45 HbSS steady state patients, were measured using sensitive and specific enzyme‐linked immunoassays. The average plasma concentration of F(VII)t, in sickle cell plasma was significantly lower than that of the control subjects (0·70 ± 0·19 U/ml versus 1·16 ± 0·41 U/ml), whereas F(VII)z in the patients and controls were 0·47 ± 0·15 U/ml and 1·15 ± 0·33 U/ml respectively, P<0·001. Both measures of factor VII suggest a higher factor VII turnover in sickle cell disease. The mean concentration of TAT in the plasma of HbSS patients were significantly higher than those of HbAA controls (371 ± 44 pM versus 42 ± 2 pM) (P<0·001), a difference that is strongly indicative of higher rates of in vivo thrombin generation by HbSS patients. Plasmas of HbSS patients had significantly higher concentrations of FPA compared to those of the control subjects (12·85 ± 1·96 ng/ml versus 4·22 ± 0·37 ng/ml) (P<0·001). The D‐dimer levels were also higher in the HbSS than control plasmas (1029·6 ± 58·6 ng/ml versus 224·3 ± 27·6 g/ml) (P<0·001), with the patients’values being indicative of enhanced fibrinolysis. These results strongly suggest accelerated in vivo coagulation and fibrinolysis in HbSS patients even during steady state. They are consistent with the hypothesis that haemostasis is less tightly regulated in the HbSS patients than in HbAA controls. The altered regulation of haemostasis may contribute to the initiation of vaso‐occlusive processes associated with sickle cell painful episodes.