大鼠异位辅助性肝移植模型建立

目的 建立大鼠异位辅助性肝移植模型。方法 根据Yu Weiming介绍的方法经以简化建立大鼠异位辅助性肝移植模型。阐明手术操作技巧和术前术后处理等因素对肝移植大鼠的成活率的影响。结果 在30例异位辅助性肝移植大鼠中，供肝热缺血时间为1-2min，安装袖套时间约为4min，肝下腔静脉吻合时间为12min，供肝冷缺血时间为30min,1wk存活率为80%（n=30)。结论 成功复制大鼠辅助性肝移植模型。同时，大鼠的质量，术前状态和精细的手术操作及管理是决定大鼠异位辅助性肝移植成败的关键因素。     

Concepts of health and disease and caries prediction: a literature review

Abstract— Biomedical determinants of dental caries have been more extensively investigated than psychosocial factors and their impact on caries prevalence and incidence seems to be greater. However, a majority of these investigations relate to children and adolescents. An implementation of social and psychologic variables may be more relevant regarding dental caries in adults. In addition, a multidisciplinary approach might improve our understanding of dental caries as a multifactorial disease and bridge the gap between a biomedical concept and a more holistic approach to dental health.     

建立筋膜间室综合征模型的新方法

目的：建立一种更符合临床的筋膜间室综合征动物模型，以便于基础及临床研究。方法：用宽度和犬小腿肌腹长度相当的袖带包绕小腿，然后充气使实验肢体全长受压、缺血。12只犬随机分为两组，I组：袖带充气至40kPa，压迫8h；Ⅱ组：袖带充气至80kPa，压迫8h。结果：动态监测组织压并对神经、肌肉行组织学检查，发现实验动物肢体胫前筋膜间室内组织压远远超过4.0kPa，神经、肌肉发生不可逆变性、坏死。结论：用充气袖带压迫法建立的动物模型是成功的，各项指标均达到筋膜间室综合征的诊断标准。     

葡聚糖硫酸钠致溃疡性结肠炎小鼠模型的建立

目的　建立小鼠溃疡性结肠炎模型。方法　给小鼠自由饮用5％葡聚糖硫酸钠（DSS）溶液7d后,改为蒸馏水自由饮用10d,如此进行4个循环,每天观察症状。在第1个循环和第4个循环后剖杀小鼠,取出整段结肠行实体显微镜观察及切片组织学研究。结果　所观察的症状、实体显微镜像、组织学病理改变均与人类溃疡性结肠炎类似。结论　此模型制作方法简便,重复性良好,可应用于多种实验研究。     

建立一种新的多药耐药的诱导方法

目的建立裸鼠原位肝癌耐药模型。方法培养肝癌细胞系HepG2,建立裸鼠的皮下肿瘤,形成“供瘤鼠”。开腹直视下将瘤块种植于裸鼠的肝包膜下建立原位肝癌模型,通过表阿霉素间歇腹腔化疗,建立裸鼠原位肝癌耐药模型。用体检、B超、CT、剖腹探查监测肝内瘤块生长情况。用逆转录聚和酶链反应(RT-PCR)和免疫组织化学方法检测肿瘤耐药基因mdrl-mRNA和p-gp蛋白的表达。结果(1)模型建立无手术死亡(0/25),种植成瘤率为88%(22/25),补种3例全部成功,耐药诱导成功率为80%(16/20);(2)诱导组mdrl-mRNA和P-gp蛋白的表达均明显高于对照组,分别约是对照组的23倍和13倍。结论成功地建立了与临床肝癌相似的裸鼠原位肝癌耐药模型,为进一步研究肝癌多药耐药基因的诊断和逆转提供了良好的动物平台。     

胸大肌肌皮瓣脂肪液化的相关危险因素探讨

目的探讨胸大肌肌皮瓣术后发生脂肪液化的相关危险因素。方法对1998年5月至2005年12月采用胸大肌肌皮瓣修复口腔癌术后组织缺损的82例中10例术后发生不同程度脂肪液化的病例,进行Logistic回归分析。结果Logistic单因素回归分析结果表明：肥胖、电刀切开皮下组织、皮岛设计低于第7肋、吸烟等因素与胸大肌肌皮瓣术后发生脂肪液化有关;Logistic多因素回归分析结果表明：胸大肌肌皮瓣术后发生脂肪液化与肥胖、电刀切开皮下组织、皮岛设计低于第7肋等因素有关,而与吸烟无关。结论肥胖、电刀切开皮下组织、皮岛设计低于第7肋等因素是胸大肌肌皮瓣术后发生脂肪液化的危险因素。     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

出血性脑梗死危险因素的Logistic回归分析

目的探讨出血性脑梗死的危险因素。方法根据专业知识确定与出血性脑梗死有关的因素,采用非条件Logistic回归确定危险因素。结果大面积梗死灶、使用抗凝剂或溶栓治疗、糖尿病史是出血性脑梗死的独立危险因素,与年龄、高血压史、高血脂关系不大。结论大面积脑梗死、使用抗凝剂或溶栓、糖尿病患者发生梗死后出血的几率增大,及时行影像学检查可以早期发现。     

Fisher information matrix for nonlinear mixed effects multiple response models: Evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model

We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd.