Neuronal nitric oxide synthase is up-regulated by angiotensin II and attenuates NADPH oxidase activity and facilitates relaxation in murine left ventricular myocytes

Angiotensin II (Ang II) is critical in myocardial pathogenesis, mostly via stimulating NADPH oxidase. Neuronal nitric oxide synthase (nNOS) has recently been shown to play important roles in modulating myocardial oxidative stress and contractility. Here, we examine whether nNOS is regulated by Ang II and affects NADPH oxidase production of intracellular reactive oxygen species (ROS(i)) and contractile function in left ventricular (LV) myocytes. Our results showed that Ang II induced biphasic effects on ROS(i) and LV myocyte relaxation (TR(50)) without affecting the amplitude of sarcomere shortening and L-type Ca(2+) current density: TR(50) was prolonged at 30 min but was shortened after 3h (or after Ang II treatment in vivo). Correspondingly, ROS(i) was increased, followed by a reduction to control level. Quantitative RT-PCR and immunoblotting experiments showed that Ang II (3h) increased the mRNA and protein expression of nNOS and increased NO production (nitrite assay) in LV myocyte homogenates, suggesting that nNOS activity may be enhanced and involved in mediating the effects of Ang II. Indeed, n(omega)-nitro-l-arginine methyl ester (l-NAME) or a selective nNOS inhibitor, S-methyl-l-thiocitrulline (SMTC) increased NADPH oxidase production of superoxide/ROS(i) and abolished faster myocyte relaxation induced by Ang II. The positive lusitropic effect of Ang II was not mediated by PKA-, CaMKII-dependent signaling or peroxynitrite. Conversely, inhibition of cGMP/PKG pathway abolished the Ang II-induced faster relaxation by reducing phospholamban (PLN) Ser(16) phosphorylation. Taken together, these results clearly demonstrate that myocardial nNOS is up-regulated by Ang II and functions as an early adaptive mechanism to attenuate NADPH oxidase activity and facilitate myocardial relaxation.     

嗜酸乳杆菌对人舌癌细胞增殖的影响

目的研究嗜酸乳杆菌对人舌癌细胞Tca8113增殖及细胞周期的影响。方法体外培养Tca8113细胞,分别将不同稀释度（原液和4、16倍稀释）的嗜酸乳杆菌上清液、灭活菌液和无细胞提取物与Tca8113细胞共培养,采用倒置显微镜观察细胞形态并行细胞计数,磺酰罗丹明B（SRB）法测定细胞增殖率,流式细胞术分析嗜酸乳杆菌各组分对Tca8113细胞增殖及细胞周期的影响,激光扫描共聚焦显微镜（CLSM）检测细胞内自由基和Ca2+含量。结果嗜酸乳杆菌各组分作用于Tca8113细胞48 h后,在倒置显微镜下观察,细胞由菱形、多角形、铺路石状变为细长形。细胞计数与SRB实验分析：在不同稀释度同一培养时间与不同培养时间同一稀释度培养条件下,嗜酸乳杆菌各组分均可明显抑制Tca8113细胞增殖,抑制力随稀释度增加而降低,随培养时间延长而增强。流式细胞术分析：嗜酸乳杆菌各组分作用Tca8113细胞48 h后,细胞增殖指数降低（P<0.01）。CLSM检测：嗜酸乳杆菌各组分作用Tca8113细胞48 h后细胞内自由基和Ca2+含量均升高（P<0.01）。结论嗜酸乳杆菌代谢产物、灭活菌液、无细胞提取物均可抑制Tca8113细胞增殖,可能与菌体及其代谢产物引起细胞内自由基含量增多、Ca2+超载有关。     

Pharmacogenetic assessment of clinical outcome in patients with metastatic breast cancer treated with docetaxel plus capecitabine

Purpose

Docetaxel plus capecitabine, a commonly used chemotherapeutic regimen for metastatic breast cancer (MBC), is highly variable in its effectiveness. We aimed to investigate whether allelic variants of cytochrome P450 (CYP450) affected objective response, progression-free survival (PFS), and overall survival (OS) in MBC.

Patients and methods

79 SNPs in CYP450, whose minor allele frequency were ≥10%, were genotyped in 69 MBC patients who were treated with docetaxel plus capecitabine. Pearson’s χ² test or Fisher’s exact test was used to investigate the influence of SNPs on objective response as appropriate. Log-rank test was used to assess the association between SNPs and survival outcomes.

Results

There is no significant association between polymorphisms and both objective response and OS. Only one SNP, CYP1A1 rs1048943 A>G (Ile462Val), was significantly associated with PFS (P?=?0.0003). Multivariate analysis confirmed its prognostic significance for PFS (P?=?0.004).

Conclusion

CYP1A1 rs1048943 A>G (Ile462Val) polymorphism is a potential prognostic marker for survival outcome after docetaxel plus capecitabine chemotherapy in MBC patients. However, confirmatory study is needed to validate this finding.     

Factors associated with hospital mortality in community-acquired legionellosis in France

The aims of this study were to describe the clinical, biological and radiological features of community-acquired (CA) Legionnaires' disease (LD) and identify the predictors of mortality in hospitalised patients. Demographic data, risk factors, clinical and biological features, medical management, complications, and outcome from 540 hospitalised patients with confirmed CA LD were prospectively recorded. 8.1% of patients (44 out of 540) died. The predictors of survival after Kaplan-Meier analysis were male sex (p = 0.01), age <60 yrs (p = 0.02), general symptoms (p = 0.006), intensive care unit (ICU) stay (p<0.001), and class II-III Pneumonia Severity Index score (p = 0.004). Six predictors of death were identified by multivariate analysis: age (per 10-yr increment) (relative hazard (RH) 1.50, 95% CI 1.21-1.87), female sex (RH 2.00, 95% CI 1.08-3.69), ICU admission (RH 3.31, 95% CI 1.67-6.56), renal failure (RH 2.73, 95% CI 1.42-5.27), corticosteroid therapy (RH 2.54, 95% CI 1.04-6.20) and C-reactive protein (CRP) >500 mg · L(-1) (RH 2.14, 95% CI 1.02-4.48). Appropriate antibiotic therapy was prescribed for 70.8% (292 out of 412) of patients after admission and for 99.8% (537 out of 538) of patients after diagnosis confirmation. In conclusion, female sex, age, ICU stay, renal failure, corticosteroid treatment and increased level of CRP are significant risk factors for mortality in CA LD.     

破裂与未破裂镜像后交通动脉瘤形态与血流动力学分析

目的探讨破裂与未破裂颅内动脉瘤的血流动力学与形态学差异,分析动脉瘤破裂的危险因素。方法回顾性分析8例镜像后交通动脉瘤病人（均为一侧破裂,一侧未破裂）的临床资料,均行3D—DSA检查,建立数值模型。将16个动脉瘤按是否破裂分组,分析破裂组与未破裂组之间的形态学与血流动力学参数特征。结果破裂组动脉瘤平均擘面切应力（WSS）明显低于未破裂组（P〈0．05）;而低壁面切应力面积（LSA）比率和体颈比值明显高于未破裂组（P〈0．05）。剪切震荡指数（OSI）、动脉瘤直径、大小比率、血管角度和动脉瘤倾角组间差异无统计学意义（P〉0．05）。结论镜像后交通动脉瘤可能是研究动脉瘤破裂风险的理想模型,血流动力学与形态学在判断动脉瘤破裂风险方面同等重要。