Detecting association of rare and common variants based on cross‐validation prediction error

Despite the extensive discovery of disease‐associated common variants, much of the genetic contribution to complex traits remains unexplained. Rare variants may explain additional disease risk or trait variability. Although sequencing technology provides a supreme opportunity to investigate the roles of rare variants in complex diseases, detection of these variants in sequencing‐based association studies presents substantial challenges. In this article, we propose novel statistical tests to test the association between rare and common variants in a genomic region and a complex trait of interest based on cross‐validation prediction error (PE). We first propose a PE method based on Ridge regression. Based on PE, we also propose another two tests PE‐WS and PE‐TOW by testing a weighted combination of variants with two different weighting schemes. PE‐WS is the PE version of the test based on the weighted sum statistic (WS) and PE‐TOW is the PE version of the test based on the optimally weighted combination of variants (TOW). Using extensive simulation studies, we are able to show that (1) PE‐TOW and PE‐WS are consistently more powerful than TOW and WS, respectively, and (2) PE is the most powerful test when causal variants contain both common and rare variants.     

肝苏缓释胶囊的药代动力学研究

目的：研究肝苏缓释胶囊在狗体内的药代动力学，评价肝苏缓释胶囊在体内的缓释效果。方法：以有效成分之一没食子酸为指标成分，用高效液相色谱法测定狗分别服用肝苏缓释胶囊及普通胶囊后不同时间体内没食子酸的血药浓度。结果：肝苏缓释胶囊和普通胶囊中没食子酸在体内的药代动力学过程均选择一室模型。肝苏缓释胶囊有明显的缓释作用，能在体内较长时间的保持较高的血药浓度。体外累积释放百分率与体内吸收分数有极显著的相关性，表明肝苏缓释胶囊在体内的缓释效果可以用体外累积释放百分率来进行评价。结论：肝苏缓释胶囊在体内外都有较好的缓释作用。     

The causation of disease – The practical and ethical consequences of competing explanations

The prevention, treatment and management of disease are closely linked to how the causes of a particular disease are explained. For multi-factorial conditions, the causal explanations are inevitably complex and competing models may exist to explain the same condition. Selecting one particular causal explanation over another will carry practical and ethical consequences that are acutely relevant for health policy. In this paper our focus is two-fold; (i) the different models of causal explanation that are put forward within current scientific literature for the high and rising prevalence of the common complex conditions of coronary artery disease (CAD) and type 2 diabetes mellitus (T2D); and (ii) how these explanations are taken up (or not) within national health policy guidelines. We examine the causal explanations for these two conditions through a systematic database search of current scientific literature. By identifying different causal explanations we propose a three-tier taxonomy of the most prominent models of explanations: (i) evolutionary, (ii) lifecourse, and (iii) lifestyle and environment. We elaborate this taxonomy with a micro-level thematic analysis to illustrate how some explanations are semantically and rhetorically foregrounded over others. We then investigate the uptake of the scientific causal explanations in health policy documents with regard to the prevention and management recommendations of current National Service Frameworks for CAD and T2D. Our findings indicate a lack of congruence between the complexity and frequent overlap of causal explanations evident in the scientific literature and the predominant focus on lifestyle recommendations found in the mainstream health policy documents.     

用普通微波炉对草药进行清洁高效快速的消解研究

用普通微波炉对0.1 g样品量的回心草药材进行了封闭式消解,并用原子吸收测定了其中的Fe、Zn、Mn含量,与电炉消解比较,其更清洁、高效、快速。     

猪颈总动脉及股动脉小口径血管移植模型的比较

 目的  比较猪颈总动脉及股动脉小口径血管移植模型的优劣。方法  10只健康实验猪,共进行颈总动脉小口径血管移植10次,股动脉小口径血管移植6次。从猪颈总动脉及股动脉解剖、术中血管吻合的难易以及术后评价血管通畅等方面比较颈总动脉及股动脉血管移植模型的优劣。结果  从血管解剖角度,颈总动脉较深,吻合操作较困难,但血管较粗(直径4.8 mm±0.3 mm),分支少。股动脉较颈总动脉表浅,更易定位分离,术中操作易于暴露,吻合较为容易,但相对较细(直径3.9 mm±0.2 mm)且穿支较多。颈总动脉小口径血管移植血管闭塞6枚,股动移植模型闭塞4枚。当人工血管发生血栓形成时,均未能观察到术后猪有异常表现,术后临床观察不能帮助准确判断移植血管通畅与否。结论  猪颈总动脉及股动脉血管移植模型建立具有可行性,但两者各有利弊,均可以作为研究小口径人工血管的动物模型。     

社区常见病症中医药照顾的中西医结合教学方法

随着社会的进步与经济的发展,以慢性病为主的社区常见病症给患者、家庭和国家医疗保障体系带来了的巨大经济压力,中医药能够提供价格低廉、操作方便、疗效显著的社区常见病症治疗和康复方法,《社区常见病症中医药照顾》这一课程的设立对提高学生社区常见病中医药诊疗能力,进而改善社区医院的中医药医疗水平具有极大的经济和社会意义。作者通过中西医结合教学方法讲授"社区常见病症的中医药照顾",教学内容上强调以西医系统理论为框架,中医学辨证施治为主要内容,在全科医学学生已形成的西医理论知识结构基础上,对应地引入中医学理论与治疗方法,实现该领域中西医知识结构的正确衔接,以培养学生以中西医结合的思路解决医疗问题。     

Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation,butyrylation, succinylation,and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.     

Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia

The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in downregulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.     

超声内镜与内镜逆行胰胆管造影联合检查对胆总管壶腹区病变的诊断价值

目的 探讨超声内镜、内镜逆行胰胆管造影（ERCP）联合检查对胆总管壶腹区病变的诊断价值.方法 91例患者均行B型超声、CT及超声内镜检查,部分行ERCP检查.并将超声内镜及超声内镜联合ERCP与B型超声、CT、ERCP对胆总管壶腹区病变诊断结果进行比较.结果 超声内镜、ERCP对胆总管壶腹区病变诊断的阳性率分别为94.5%（86/91）、90.2%（74/91）.超声内镜诊断胆总管结石及慢性胰腺炎的准确率为100%,超声内镜联合ERCP检奁对结石及肿瘤的诊断阳性率分别为100%、97%.结论 超声内镜对胆总管壶腹区病变的诊断率高于腹部B型超声、CT及ERCP,联合ERCP对病变的定位及定性诊断有较高的价值,指导规范临床治疗.     

康泰克等五种不同药物治疗感冒的临床疗效观察

对456例次感冒患者分别应用五种常用的药物进行治疗,将各药间临床疗效对比及分别与对照组对比观察.结果显示五种药物均敏感,其敏感度依次为康泰克、速效伤风胶囊、维C银翘片、贯防感冒片、板兰根.并对治疗感冒选择用药进行了讨论.