基于临床参考及基因因素建立华法林稳定维持剂量预测模型

目的 探讨华法林应用的临床参考因素及基因因素与华法林稳定维持剂量的相关性,并尝试构建适用于非瓣膜病心房纤颤（non-valvular-disease atrial fibrillation,NVAF）患者华法林稳定维持剂量的预测模型。方法 按照纳入标准共纳入126例患者,应用测序反应通用试剂盒及荧光检测仪检测细胞色素P450 2C9和维生素K环氧化物还原酶基因多态性,同时记录华法林应用的临床参考因素：年龄、体质量、房颤栓塞风险评分系统（CHA₂DS₂-VASc）评分、房颤出血风险评分系统（HAS-BLED）评分、谷丙转氨酶（glutamic-pyruvic transaminase,ALT）、肾小球滤过率（glomerular filtration rate,GFR）、左心室射血分数（left ventricular ejection fraction,LVEF）、二尖瓣环水平左室侧壁组织多普勒S波;采用相关性分析探讨临床参考因素及基因多态性与华法林稳定维持剂量的相关性,并通过多元线性回归建立了华法林稳定维持剂量预测模型。结果 体质量、ALT水平、二尖瓣环水平左室侧壁组织多普勒S波与华法林稳定维持剂量成正相关,年龄、CHA₂DS₂-VASc评分、HAS-BLED评分则成负相关,而LVEF、GFR未显示明显的相关性。建立的预测模型对已有样本验证准确率达55.6%。结论 该模型可用于预测NVAF患者华法林稳定维持剂量。     

Enzymatic synthesis of glucuronidated metabolites of two neurological active agents using plant glucuronosyltransferases

Abstract

Glucuronidation is an important and popular metabolic reaction in vivo of drugs. The further evaluation of biological activity and toxicity of glucuronides is necessary in the course of the drug research and development. However, the synthesis of glucuronides is limited by the lack of efficient approach. Herein, we have developed a new glucuronide synthesis method using plant uridine diphosphate-dependent glucuronosyltransferases (UGTs), UGT88D4, UGT88D7, and EpGT8, enabling the convenient preparation for corresponding O-glucuronide metabolites (1a, 2a, 3a, and 3b) in milligram scale of two neurological active agents, IMM-H004 (1) and FLZ (2). Their structures were characterized by spectroscopic data analyses.     

Endoscopic molecular imaging of early gastric cancer using fluorescently labeled human H-ferritin nanoparticle

Optical imaging technologies improve clinical diagnostic accuracy of early gastric cancer (EGC). However, there was a lack of imaging agents exhibiting molecular specificity for EGCs. Here, we employed the dye labeled human heavy-chain ferritin (HFn) as imaging nanoprobe, which recognizes tumor biomarker transferrin receptor 1 (TfR1), to enable specific EGC imaging using confocal laser endomicroscopy (CLE). TfR1 expression was initially examined in vitro in gastric tumor cells and in vivo through whole-body fluorescence and CLE imaging in tumor-bearing mice. Subsequently, dye labeled HFn was topically applied to resected human tissues for EGC detection. CLE analysis of TfR1-targeted fluorescence imaging allowed distinction of neoplastic from non-neoplastic tissues (P?<?0.0001), and TfR1 expression level was found to correlate with EGC differentiation degrees (P?<?0.0001). Notably, the CLE evaluation correlated well with the immunohistochemical findings (κ-coefficient: 0.8023). Our HFn-nanoprobe-based CLE increases the accuracy of EGC detection and enables visualization of tumor margins and endoscopic resection.     

2016年上海市浦东新区高东社区儿童青少年乙肝病毒感染及乙肝疫苗接种状况调查

目的 调查上海市浦东新区高东社区儿童青少年乙肝病毒感染现状及乙肝疫苗接种状况,为该社区的乙肝防控工作提供依据。 方法 2016年3-4月,随机抽取高东社区幼儿园、小学及初级中学各1所,对每所学校每个年级抽取的1个班级中所有学生开展乙肝病毒感染及乙肝疫苗接种相关问卷调查,同时采集静脉血进行乙肝血清指标及HBV DNA定量检测,分析该社区儿童青少年乙肝疫苗接种情况、乙肝病毒感染血清标志物分布情况及其影响因素。 结果 高东社区儿童青少年乙肝疫苗接种率95.50%(276/289),年龄组越小的儿童青少年乙肝疫苗接种率越高(P<0.01);10岁以下学生接种率高于≥10岁学生(P<0.01);HBsAg、HBcAb和HBsAb阳性率分别为1.04%(3/289)、1.38%(4/289)和32.18%(93/289);未接种乙肝疫苗及未全程接种者HBsAg和HBcAb阳性率均高于接种乙肝疫苗及全程接种者(P<0.05);女性HBcAb阳性率高于男性(P<0.05);≥10岁学生HBcAb阳性率高于3~＜10岁学生(P<0.05);年龄组越大的儿童青少年HBsAb阳性率越低(P<0.01);HBsAb阳性学生抗体滴度水平分布以低水平(10 mIU/ml≤HBsAb<100 mIU/ml)为主(占81.33%,61/75),无年龄分布差异(P>0.05)。 结论 2016年该社区儿童青少年的乙肝疫苗接种率高于95%,HBsAg、HBcAb阳性率较2012年上海市的调查结果下降明显。     

Maternal Socioeconomic Mobility and Preterm Delivery: A Latent Class Analysis

Objective Growing evidence suggests that maternal socioeconomic mobility (SM) is associated with pregnancy outcomes. Our study investigated the association between maternal SM from childhood to adulthood and the risk of preterm delivery (PTD), and examined heterogeneity of associations by race/ethnicity. Methods In this study, 3019 pregnant women enrolled from 5 Michigan communities at 16–27 weeks’ gestation (1998–2004) provided their parents’ socioeconomic position (SEP) indicators (education, occupation, receipt of public assistance) and their own and child’s father’s SEP indicators (education, occupation, Medicaid status, and household income) at the time of enrollment. Latent class analysis was used to identify latent classes of childhood SEP indicators, adulthood SEP indicators, and SM from childhood to adulthood, respectively. A model-based approach to latent class analysis with distal outcome assessed relations between latent class and PTD, overall and within race/ethnicity groups. Results Three latent classes (low, middle, high) were identified for childhood SEP indicators and adulthood SEP indicators, respectively; while four latent classes (static low, upward, downward, and static high) best described SM. Women with upward SM had decreased odds of PTD (Odds ratio?=?0.60, 95% confidence interval: 0.42, 0.87), compared to those with static low SEP. This SM advantage was true for all women and most pronounced in white/others women. Conclusions Maternal experiences of upward SM may be important considerations when assessing PTD risk. Our results support the argument that policies and programs aimed at improving women’s SEP could lower PTD rates.     

The contribution of intestinal UDP-glucuronosyltransferases in modulating 7-ethyl-10-hydroxy-camptothecin (SN-38)-induced gastrointestinal toxicity in rats

Life-threatening diarrhea afflicts a considerable percentage of patients treated with irinotecan, an anticancer agent with effects elicited through its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). The primary detoxification pathway for SN-38 is glucuronidation. The purpose of this study was to evaluate the role that intestinal UDP-glucuronosyltransferases (UGTs) have from hepatic UGTs in modulating this diarrhea. To investigate this, Gunn rats devoid of UGT1A activity were injected with recombinant adenoviral vectors expressing UGT1A1, 1A6, and 1A7, resulting in reconstituted hepatic UGT expression comparable to a heterozygote. Hepatic microsome studies indicated that 4 to 7 days after adenoviral injection, transfected Gunn rats (j/jAV) had SN-38 glucuronide (SN-38G) formation rates three times higher than control heterozygote rats (j+AV). The adenovirus did not impart any glucuronidating capacity to the intestine in j/jAV rats, whereas j+AV rats possessed intestinal UGT function. After the administration of 20 mg/kg/day irinotecan i.p. to j/jAV rats 4 days after adenovirus injection, diarrhea ensued before the fourth irinotecan dose. j+AV rats were spared the diarrhea, and the toxicity was mild compared with the j/jAV rats, as measured by diarrhea scores, weight loss, and histological assessments of the cecum and colon. The pharmacokinetics of irinotecan, SN-38, and SN-38G indicate that the systemic exposure of SN-38 and SN-38G was higher and lower, respectively, in j/jAV rats. Despite this, the biliary excretion of irinotecan and metabolites was similar. Because intestinal UGTs are the main discriminating factor between j/jAV and j+AV rats, their presence seems to be critical for the gastrointestinal protection observed in j+AV rats.     

Pharmacokinetic and pharmacodynamic properties of a single intravenous dose of ibutilide fumarate: a phase I, randomized, open-label, increasing-dose study in healthy Chinese men

BACKGROUND: Atrial flutter is a common sustained atrial tachyarrhythmia whose frequency increases with age. Ibutilide is a class III antiarrhythmic agent used for the cardioversion of atrial flutter or atrial fibrillation. OBJECTIVE: This study assessed the pharmacokinetic (PK) and pharmacodynamic properties and tolerability of a single intravenous dose of ibutilide fumarate in healthy Chinese men. METHODS: This Phase I, randomized, open-label, increasing-dose trial was conducted at the Clinical Pharmacology Center, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking men aged 18 to 45 years and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 6 treatment groups: ibutilide 0.005, 0.01, or 0.02 mg/kg, or 0.5, 0.75, or 1.0 mg. Each volunteer received a 10-minute infusion of ibutilide under fasting conditions. For analysis of PK properties, blood samples were obtained at the following times: immediately before administration of study drug; 3, 5, 8, 10, 30, and 60 minutes after administration; and 2, 4, 6, 8, 12, and 24 hours after administration. Plasma ibutilide concentrations were determined using a validated high- performance liquid chromatography method with tandem mass-spectrometric detection. Continuous electrocardiographic monitoring was performed, and 12-lead electrocardiograms were recorded before dosing and at defined times from the start of infusion until 24 hours after dosing. Tolerability was assessed throughout the study based on physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse effects. RESULTS: Forty healthy Chinese men were enrolled (mean [SD] age, 24.0 [3.9] years [range, 19-36 years]; mean [SD] body weight, 62.8 [7.9] kg [range, 48- 80 kg]). The plasma ibutilide end-of-infusion concentration and AUC(0-infinity) increased approximately linearly with increasing doses of ibutilide. No statistically significant differences in the principal PK parameters were found among dosage groups; t(1/2) ranged from 7.5 to 9.1 hours, systemic clearance from 68 to 85 mL/min per kg, and Vd from 51 to 60 L/kg. The mean QTc interval was significantly increased during and after ibutilide infusion (baseline range, 406-418 milliseconds; maximum range, 469-683 milliseconds; P < 0.05 vs baseline). The changes in QTc interval were dose dependent, and there was a significant correlation between plasma ibutilide concentrations and changes in the QTc interval (r = 0.7244; P < 0.01). There were no significant changes in blood pressure or the QRS and PR intervals. One volunteer complained of dizziness, but no other apparent adverse effects were observed. CONCLUSIONS: The results of this study in a selected population of healthy Chinese men suggest that the PK properties of ibutilide are linear with respect to dosing. A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration- dependent manner. Ibutilide was generally well tolerated.     

Scoping Review研究主题分析

目的：了解Scoping review的研究现状,以期为Scoping review的进一步发展提供依据。方法：通过检索主要的外文数据库纳入Scoping review外文研究,采用BICOMS 2分析软件对主题词进行抽取和整理,并生成主题词共现矩阵,利用NetDraw绘制网络关系图,利用gCLUTO进行聚类分析。结果：Scoping review研究有1 516个具有实质意义的主要主题词,研究领域分为6个研究主题,其中5个主题关注健康管理和医疗卫生保健,1个主题关注医药卫生和循证转化医学研究。结论：Scoping review研究的主题主要集中在不同人群的健康管理和医疗卫生保健方面,研究主题较为局限,相关学者应该努力拓展新的研究主题。     

MiR⁃484通过靶向MAPK8抑制人前体脂肪细胞的增殖与分化

目的：探讨miRNA?484在肥胖发生中的作用及其临床意义。方法：利用RT?qPCR 、CCK?8法、油红O染色及甘油三酯定量检测研究miR?484对人脂肪细胞增殖及成脂分化的作用。运用Targetscan7.2对miR?484的下游靶基因进行预测分析,并使用双荧光素酶实验验证miR?484与靶基因的结合,使用Western blot及RT?qPCR验证miR?484对靶基因的作用。结果：miR?484在人脂肪细胞分化成熟过程中逐渐低表达。过表达miR?484抑制人前体脂肪细胞的增殖及分化,而沉默miR?484与过表达作用相反。生物信息学预测发现MAPK8是miR?484的下游靶基因,且miR?484可抑制其mRNA及蛋白表达,同时过表达MAPK8可部分挽救miR?484对人前体脂肪细胞增殖分化的抑制。结论：miR?484可以通过抑制MAPK8的表达从而抑制人前体脂肪细胞的增殖与成脂分化。