Browsing by Author "Chien S."

Vascular endothelial cells (ECs) are constantly exposed to blood flow-induced shear stress, but the mechanism of force-specific activation of their signaling to modulate cellular function remains unclear. We have demonstrated that bone morphogenetic protein receptor (BMPR)-specific Smad1/5 can be force-specifically activated by oscillatory shear stress (OSS) in ECs to cause cell cycle progression. Smad1/5 is highly activated in ECs of atherosclerotic lesions in diseased human coronary arteries from patients with end-stage heart failure undergoing heart transplantation and from apolipoprotein E-deficient mice. Application of OSS (0.5 ± 4 dyn/cm2) causes the sustained activation of Smad1/5 in ECs through activations of mammalian target of rapamycin and p70S6 kinase, leading to up-regulation of cyclin A and down-regulations of p21CIP1 and p27KIP1 and, hence, EC cycle progression. En face examination of rat aortas reveals high levels of phospho-Smad1/5 in ECs of the straight segment of thoracic aorta and the inner, but not the outer, curvature of aortic arch. Immunohistochemical and en face examinations of the experimentally stenosed abdominal aorta in rats show high levels of phospho-Smad1/5 in ECs at poststenotic sites, where OSS occurs. These OSS activations of EC Smad1/5 in vitro and in vivo are not inhibited by the BMP-specific antagonist Noggin and, hence, are independent of BMP ligand. Transfecting ECs with Smad1/5-specific small interfering RNAs inhibits the OSS-induced EC cycle progression. Our findings demonstrate the force-specificity of the activation of Smad1/5 and its contribution to cell cycle progression in ECs induced by disturbed flow.

Objectives: The safety of rifabutin replacing rifampicin among adults having rifampicin-related adverse reactions (ARs) during the treatment of tuberculosis remains unknown. Methods: From June 2006 to June 2010, a total of 2868 newly treated tuberculosis patients without HIV infection in a referral hospital were screened in this retrospective cohort study. Results: Among the screened patients, a total of 221 (8%) patients who received rifabutin replacing rifampicin were included. Of these patients, 158 (72%) tolerated rifabutin during treatment, but 47 (21%) and 16 (7%) experienced mild and severe rifabutin-related ARs (including neutropenia, severe hepatitis and uveitis), respectively, and needed to discontinue rifabutin. Those having previous rifampicin-related arthralgia, dermatological events and cholestasis had a higher AR recurrence rate (60%, 23% and 9%, respectively) than others (5% for hepatitis and gastrointestinal intolerance and 0% for flu-like syndrome, neutropenia and others; P<0.01). Multivariate logistic regression analysis showed that females (OR 3.35; 95% CI 1.06-10.56; P0.04) and patients with hepatitis virus B (HBV) or hepatitis C virus (HCV) coinfection (OR 3.72; 95% CI 1.19-11.67; P=0.02) were at a higher risk of rifabutin-related severe ARs. No development of new drug resistance and no relapse of tuberculosis were found during 2 years of follow-up. Conclusions: Rifabutin replacing rifampicin was well tolerated in most adults who had rifampicin-related ARs. Females and those with HCV or HBV coinfection were more prone to rifabutin-related severe ARs and required more cautious monitoring. ? The Author 2013.