Pro-apoptotic BIM is an essential initiator of physiological endothelial cell death independent of regulation by FOXO3.

The growth of new blood vessels by angiogenesis is essential for normal development, but can also cause or contribute to the pathology of numerous diseases. Recent studies have shown that BIM, a pro-apoptotic BCL2-family protein, is required for endothelial cell apoptosis in vivo, and can contribute to the anti-angiogenic effect of VEGF-A inhibitors in certain tumor models. Despite its importance, the extent to which BIM is autonomously required for physiological endothelial apoptosis remains unknown and its regulation under such conditions is poorly defined. While the transcription factor FOXO3 has been proposed to induce Bim in response to growth factor withdrawal, evidence for this function is circumstantial. We report that apoptosis was reduced in Bim(-/-) primary endothelial cells, demonstrating a cell-autonomous role for BIM in endothelial death following serum and growth factor withdrawal. In conflict with in vitro studies, BIM-dependent endothelial death in vivo did not require FOXO3. Moreover, endothelial apoptosis proceeded normally in mice lacking FOXO-binding sites in the Bim promoter. Bim mRNA was upregulated in endothelial cells starved of serum and growth factors and this was accompanied by the downregulation of miRNAs of the miR-17∼92 cluster. Bim mRNA levels were also elevated in miR-17∼92(+/-) endothelial cells cultured under steady-state conditions, suggesting that miR-17∼92 cluster miRNAs may contribute to regulating overall Bim mRNA levels in endothelial cells.

Weekly chloroquine prophylaxis and the effect on maternal haemoglobin status at delivery.

Our aim was to determine the effectiveness of chloroquine prophylaxis in reducing the frequency of malaria-induced anaemia at delivery. We estimated the haemoglobin levels of 207 parturients; 82 (39.6%) had been on chloroquine prophylaxis [treatment group (TG)] while 125 (60.4%) did not take any malaria preventive medication antenatally [control group (CG)]. The proportion of women with malaria parasitaemia was significantly higher in CG than TG [risk ratio (RR=1.57, CI=1.05-2.34)]. The dose-response relationship between the severity of parasitaemia and the risk of being anaemic (P < 0.001) confirms a strong correlation between gestational malaria and maternal anaemia. There was a 35% reduction in risk for anaemia in the TG compared with the CG (RR=0.65, 0.40-1.06). The difference in risk was more pronounced after adjusting for disparity in place of residence, educational status and obstetric history (adjusted RR=0.54, CI=0.21-0.98). Primiparous mothers appeared to have benefited more from the antianaemic effects of malaria chemoprevention than mothers of higher parity (protective effectiveness 43% compared with 33%, respectively). In conclusion, despite reports of widespread Plasmodium falciparum resistance to chloroquine on the African continent, malaria chemosuppression with the drug was found beneficial in reducing the risk of anaemia at delivery among Cameroonian women.