Adequate sample size for developing prediction models is not simply related to events per variable

ObjectivesThe choice of an adequate sample size for a Cox regression analysis is generally based on the rule of thumb derived from simulation studies of a minimum of 10 events per variable (EPV). One simulation study suggested scenarios in which the 10 EPV rule can be relaxed. The effect of a range of binary predictors with varying prevalence, reflecting clinical practice, has not yet been fully investigated.Study Design and SettingWe conducted an extended resampling study using a large general-practice data set, comprising over 2 million anonymized patient records, to examine the EPV requirements for prediction models with low-prevalence binary predictors developed using Cox regression. The performance of the models was then evaluated using an independent external validation data set. We investigated both fully specified models and models derived using variable selection.ResultsOur results indicated that an EPV rule of thumb should be data driven and that EPV ≥ 20 ​ generally eliminates bias in regression coefficients when many low-prevalence predictors are included in a Cox model.ConclusionHigher EPV is needed when low-prevalence predictors are present in a model to eliminate bias in regression coefficients and improve predictive accuracy.     

Antimicrobial activity of selected synbiotics targeted for the elderly against pathogenic Escherichia coli strains

The aim of the present study was to evaluate the antimicrobial activity of two synbiotic combinations, Lactobacillus fermentum with short-chain fructooligosaccharides (FOS-LF) and Bifidobacterium longum with isomaltooligosaccharides (IMO-BL), against enterohaemorrhagic Escherichia coli O157:H7 and enteropathogenic E. coli O86. Antimicrobial activity was determined (1) by co-culturing the synbiotics and pathogens in batch cultures, and (2) with the three-stage continuous culture system (gut model), inoculated with faecal slurry from an elderly donor. In the co-culture experiments, IMO-BL was significantly inhibitory to both E. coli strains, while FOS-LF was slightly inhibitory or not inhibitory. Factors other than acid production appeared to play a role in the inhibition. In the gut models, both synbiotics effectively inhibited E. coli O157 in the first vessel, but not in vessels 2 and 3. E. coli O86 was not significantly inhibited.     

从中医脾瘅角度评价OLETF大鼠发病特点

[目的]观察自发2型糖尿病大鼠(OLETF)发病特点及病变过程,为深入研究脾瘅理论提供新的实验平台。[方法]引进OLETF大鼠及正常组同系非糖尿病对照大鼠(LETO),动态观察体质量、腹腔脂肪含量、脂体比、口服葡萄糖耐量、高胰岛素正葡萄糖钳夹实验葡萄糖输注率及血脂变化情况。[结果]模型组体质量、腹内脂肪含量及脂体显著高于正常组,其口服葡萄糖耐量葡萄糖曲线下面积(AUC)显著高于正常组,模型组大鼠稳态葡萄糖输注率均较正常组下降(P0.05)。血清甘油三酯、胆固醇、游离脂肪酸水平均较正常组显著增高。[结论]OLETF较好体现了中医脾瘅的发病过程及代谢综合征病变特点。     

牡丹皮、赤芍与白芍对急性血瘀模型大鼠活血功效的比较研究

目的观察牡丹皮、赤芍与白芍对急性血瘀模型大鼠的影响,揭示三者在功效方面的异同,并探讨牡丹皮、赤芍与白芍活血功效的机制。方法大鼠sc盐酸肾上腺素结合冰水浸泡制作急性血瘀模型,以丹参注射液为阳性对照,观察牡丹皮、赤芍与白芍对血液流变学、凝血功能指标、血小板系统、血清中血栓素B2(TXB2)、6-酮-前列腺素(6-keto-PGF1α)的影响。结果与模型组相比,牡丹皮能够延长急性血瘀模型大鼠的凝血酶原时间(PT)、凝血酶时间(TT)(P0.05),显著抑制血小板黏附(P0.01),且上调血小板内皮型一氧化氮合酶(e NOS)与Ser1177位磷酸化的e NOS(p-e NOS)蛋白表达水平(P0.01、0.001),减少血清中TXB2(P0.05)及增加6-keto-PGF1α的量(P0.01);赤芍能够显著改善不同切变率下血瘀模型大鼠的全血黏度,延长部分活化凝血活酶时间(APTT)、PT、TT(P0.05、0.01),降低血小板黏附率(P0.05),减少血清中TXB2的量(P0.01)、增加6-keto-PGF1α的量(P0.01),上调血小板e NOS、p-e NOS蛋白表达水平(P0.05);白芍则对血瘀模型大鼠的全血黏度的影响并不显著,但能够显著延长APTT、TT(P0.05),降低血小板黏附率(P0.05),增加血清中6-keto-PGF1α的量(P0.05),同时显著增加血小板e NOS、p-e NOS蛋白表达水平(P0.05)。结论牡丹皮、赤芍和白芍均具有不同程度改善血液流变性、凝血系统、抑制血小板黏附率、增加血小板e NOS、p-e NOS蛋白表达水平,但牡丹皮、赤芍较白芍活血化瘀作用强。     

药动学研究常用软件介绍

药动学是一门研究药物体内动态变化规律及其影响因素的学科。药动学模型研究从经典的房室模型,统计矩理论的应用,到复杂的群体药动学、生理药动学以及药动-药效学建模,都需要可靠的软件工具来完成复杂的数学计算过程。一些商业公司开发的药动学模型专业软件,已在药物研发和科学研究中广为应用;另一方面,开源工具正得到大力推广。本文总结目前用于药动学模型研究的主流软件工具,对其功能应用做简要介绍,以期为国内相关研究者提供有价值的信息。     

介绍几种诱发性糖尿病动物模型

目的：综述诱发性糖尿病动物模型。方法：主要对诱发性糖尿病动物模型的制备方法、机理进行综述，并评价各自的优缺点。结果：诱发性糖尿病动物模型可分为化学试剂诱发模型、转基因模型、基因敲除模型等。结论：诱发性糖尿病动物模型的制备方法很多，各有其特点。糖尿病动物模型研究的不断进展，为深入探讨糖尿病病因、病机及其药物治疗提供了借鉴。     

稳定表达人有机阳离子转运体1的细胞模型构建

 目的 建立能稳定表达人有机阳离子转运体1（human organic cation transporter1, hOCT1）野生型及两个突变体的马丁达比狗肾上皮（Madin-Darby canine kidney, MDCK）细胞模型。方法 从人肝组织中提取hOCT1野生型基因,经定点突变获得hOCT1_P341L,hOCT1_M420del两个突变型基因,构建表达质粒pcDNA3.1(+)-hOCT1,pcDNA3.1(+)-hOCT1_P341L,pcDNA3.1(+)-hOCT1_M420del。将质粒转染MDCK细胞,通过G418筛选获得抗性克隆,并通过hOCT1的荧光底物(4-二甲氨基苯乙烯基)-N-甲基吡啶 (ASP+)筛选得到具有较高活性的MDCK-hOCT1细胞。经反转录聚合酶链式反应(RT-PCR)及经典底物N-甲基-4-苯基吡啶(MPP+)的摄取实验,鉴定筛选得到的单克隆细胞株hOCT1 mRNA的表达及功能。结果 本实验获得的hOCT1野生型及2个突变体细胞模型与转染空载体的MDCK细胞相比,其 hOCT1 mRNA表达量显著增高,对经典底物MPP+的摄取为转染空载体细胞的12.5,13.7,12.0倍,hOCT1抑制剂可显著抑制细胞对MPP+的摄取。结论 建立的细胞模型可用于hOCT1抑制剂及底物的筛选。     

细胞模型在降糖中药研究中的应用

对近年糖尿病胰岛素抵抗细胞模型及胰岛系细胞模型的相关文献进行综述,介绍降糖中药复方含药血清及中药单体在体外研究中取得的进展。糖尿病体外细胞模型以肝、脂肪、骨骼肌三大胰岛素靶组织细胞和胰腺、胰岛素瘤分离细胞为主,功能特点不同的细胞模型可为降糖中药的筛选和降糖机制的进一步研究提供支持。     

Suppression of Leukocyte-Enhanced Cold Ischemia/Reperfusion Injury of Liver Endothelium with the Benzoquinone Antioxidant Idebenone

Objective: Despite the large body of evidence for a major role of neutrophils and oxidant stress, the exact pathogenesis of the early ischemia/reperfusion injury after cold preservation of the liver is not well understood. The potential benefit of an antioxidant on metabolic liver function during reperfusion has been demonstrated in several studies.

Materials and Methods: We describe a cold storage/reperfusion damage model with isolated perfused pig livers, where the effects of neutrophils and idebenone, a recently developed benzoquinone antioxidant were studied. The integrity of sinusoidal endothelial cells (SEC) was estimated by hyaluronic acid concentration in perfusate and the expression of endothelial constitutive nitric oxide synthase (ecNOS) after reperfusion and compared to lipid peroxidation and antioxidant content.

Results: Hyaluronic acid displayed the highest levels and ecNOS mRNA was most depressed in livers reperfused with neutrophils after 20 h cold storage; this was accompanied by an increase in lipid peroxidation (TBARS) and a breakdown of endogenous lipophilic antioxidants (-tocopherol and coenzyme Q-10). These effects were attenuated, when neutrophils were excluded from reperfusion and almost completely abolished by the addition of 200 μmol/L idebenone.

Conclusions: These data suggest that a leukocyte-mediated damage based on reactive oxygen species markedly contributes to the reperfusion injury of SEC after cold preservation of the liver. Therefore, the presence of effective antioxidants in the early reperfusion phase may be beneficial for liver graft integrity.     

全责护理模式在慢性心力衰竭患者康复训练中的应用效果

目的观察全责护理模式在慢性心力衰竭患者康复训练中的应用效果。方法采用随机数字表法将86例患者随机分为观察组（n=43）和对照组（n=43）;16名护士分为A、B两组,A组实行全责护理模式,B组实行责任制和功能制相结合的护理模式;观察组由A组护士负责康复训练4周,对照组由B组护士负责康复训练4周。比较两组患者人院时和出院时的射血分数（EF）、6rain步行试验的距离（6MWT）和出院时患者对康复训练知识的知晓率和满意度得分之间的差异。结果入院时两组EF、6MWT比较,差异无统计学意义（t值分别为1．598,1．523;P均〉0．05）。出院时观察组EF（54．13±9．12）、6MWF（402．63±74．81）,均高于对照组EF（43．26±8．57）、6MWT（336．16±75．82）,两组比较差异有统计学意义（t值分别为2．093,2．145;P均〈0．05）;各组EF、6MWT出院与入院时比较,差异有统计学意义（t值分别为2．681,2．010,2．791,2．185;P均．〈0．01）。出院时两组患者满意度得分比较,差异有统计学意义（t=2．145,P〈0．05）。结论全责护理模式用于慢性心力衰竭患者的康复训练中可取得显著效果。