A powerful association test of multiple genetic variants using a random‐effects model

There is an emerging interest in sequencing‐based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance‐component score test [sequence kernel association test (SKAT)] was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, T _REM, is derived from a random‐effects model and allows for missing genotypes, and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non‐causal rare variant and/or causal common variant. The simulation results showed that T _REM was a valid test and less sensitive to the inclusion of non‐causal rare variants and/or low effect common variants or to the presence of missing genotypes. When the effects were more consistent in the same direction, T _REM also had better power performance. Finally, an application to the Shanghai Breast Cancer Study showed that rare causal variants at the FGFR2 gene were detected by T _REM and SKAT, but T _REM produced more consistent results for different sets of rare and common variants. Copyright © 2013 John Wiley & Sons, Ltd.     

A dynamic trajectory class model for intensive longitudinal categorical outcome

This paper presents a novel dynamic latent class model for a longitudinal response that is frequently measured as in our prospective study of older adults with monthly data on activities of daily living for more than 10 years. The proposed method is especially useful when the longitudinal response is measured much more frequently than other relevant covariates. The trajectory classes are latent classes that represent distinct temporal patterns of the longitudinal response wherein an individual may remain in a trajectory class or switch to another as the class membership predictors are updated periodically over time. The identification of a common set of trajectory classes allows changes among the temporal patterns to be distinguished from local fluctuations in the response. Within a trajectory class, the longitudinal response is modeled by a class‐specific generalized linear mixed model. An informative event such as death is jointly modeled by class‐specific probability of the event through shared random effects with that for the longitudinal response. We do not impose the conditional independence assumption given the classes. We illustrate the method by analyzing the change over time in activities of daily living trajectory class among 754 older adults with 70,500 person‐months of follow‐up in the Precipitating Events Project. We also investigate the impact of jointly modeling the class‐specific probability of the event on the parameter estimates in a simulation study. The primary contribution of our paper is the periodic updating of trajectory classes for a longitudinal categorical response without assuming conditional independence. Copyright © 2014 John Wiley & Sons, Ltd.     

Low-dose-rate radiation exposure leads to testicular damage with decreases in DNMT1 and HDAC1 in the murine testis

This study examined the effects of continuous low-dose-rate radiation exposure (3.49 mGy/h) of gamma rays on mice testicles. C57BL/6 mice were divided into sham and radiation groups (n = 8 each), and were exposed to either sham irradiation or 2 Gy for 21 days, 0.2 Gy for 2 days, or 0.02 Gy for 6 h of low-dose-rate irradiation. Testicular weight, seminiferous tubular diameter, and seminiferous epithelial depth were significantly decreased in the mice irradiated with 2 Gy at 1 and 9 days after exposure. Moreover, the low-dose-rate radiation exposure induced an increase in malondialdehyde levels, and a decrease in superoxide dismutase activity in the testis of mice irradiated with 2 Gy at 1 and 9 days after exposure. The sperm count and motility in the epididymis also decreased in mice irradiated with 2 Gy at 1 and 9 days after exposure, whereas there was no significant effect on the proportion of abnormal sperm. The expressions of DNA methlytransferases-1 and histone deacetylases 1 in testes irradiated with 2 Gy were significantly decreased compared with the sham group. In conclusion, the damage exerted on the testes and epididymis largely depended on the total dose of low-dose-rate radiation.     

A users' guide to understanding therapeutic substitutions

Therapeutic substitutions are common at the level of ministries of health, clinicians, and pharmacy dispensaries. Guidance in determining whether drugs offer similar risk–benefit profiles is limited. Those making decisions on therapeutic substitutions should be aware of potential biases that make differentiating therapeutic agents difficult. Readers should consider whether the biological mechanisms and doses are similar across agents, whether the evidence is sufficiently valid across agents, and whether the safety and therapeutic effects of each drug are similar. This article uses a problem-based format to address the biological mechanism, validity, and results of a scenario in which therapeutic substitutions may be considered.     

Spice plant Allium cepa: Dietary supplement for treatment of type 2 diabetes mellitus

ObjectiveDiabetes mellitus (DM) is associated with significant morbidity and mortality and its prevalence is increasing worldwide. Although conventional antidiabetic agents are known to ameliorate the symptoms of diabetes, they also may cause adverse effects. The purpose of this review was to organize and discuss various studies that have been previously conducted indicating the efficacy of Allium cepa in DM.MethodsA comprehensive English literature search was conducted using various electronic search databases. Different search terms were used and an advanced search was conducted by combining all the search fields in abstracts, keywords, and titles.ResultsAllium cepa, a spice plant, is commonly known as onion and belongs to the family liliaceae. Since ancient times, it has been used traditionally for the treatment of different diseases. Among various activities of Allium cepa, regulation of hypoglycemic activity is considered one of its important effects in DM. Sulfur compounds including S-methylcysteine and flavonoids such as quercetin are mainly responsible for the hypoglycemic activity of Allium cepa. S-methylcysteine and flavonoids help to decrease the levels of blood glucose, serum lipids, oxidative stress, and lipid peroxidation, as well as increasing antioxidant enzyme activity and insulin secretion. Extracts of onion also have been shown to have hypoglycemic and hypolipidemic effects by normalizing the activities of liver hexokinase, glucose 6-phosphatase and HMG coenzyme-A reductase. In preliminarily clinical trials, patients with diabetes safely consumed slices of Allium cepa, exhibiting sufficient hypoglycemic activity. In the future, further studies must be conducted to investigate and confirm the hypoglycemic activities of Allium cepa and its constituents and/or their synthetic analogs.ConclusionThis review will not only elucidate the nutritious facts of Allium cepa but may also help in understanding the molecular basis of its effects in DM. This review will explore in particular the medicinal characteristics of Allium cepa supporting that the consumption of dietary onion could lower blood glucose levels, thus contributing to the reduction of risk factors associated with DM.     

益母草的研究进展

益母草为唇彤科植物益母草的全草,是常用的中药。现代研究表明,益母草具有广泛的医药用途和应用前景。通过查阅近几年对其化学作用以及药理作用研究成果的文献,对其化学成分及药理作用进行分析、归纳、总结,完成本篇综述,目的是希望能为益母草的进一步开发利用提供一定的参考。     

两种术式治疗痔疮效果比较及发病危险因素分析

目的：探讨吻合器痔上黏膜环切术（PPH）与开放式外剥内扎术治疗痔疮的疗效,并分析痔疮的发病危险因素。方法以2012年1月~2014年7月本院收治的98例环状混合痔患者为研究对象,根据入院顺序分成试验组和对照组,两组人数均为49例。试验组接受 PPH 治疗,对照组接受开放式外剥内扎术治疗,观察并比较两种术式的疗效。同时,根据患者人口学特征抽取98例社区普通人群进行问卷调查,分析痔疮的发病危险因素。结果 PPH术治疗有效率（95.9%）明显高于开放式外剥内扎术组的有效率（81.6%）,差异有统计学意义。痔疮的发生与便秘、低纤维饮食、饮酒、缺乏锻炼、遗传有关。结论 PPH术值得在痔疮的治疗中推广使用;提倡高纤维饮食、适量饮酒和加强体育锻炼以预防痔疮的发生。     

重症肌无力的免疫修饰治疗

重症肌无力是一种主要由乙酰胆碱受体抗体介导累及神经-肌肉接头的自身免疫疾病.免疫修饰治疗可明显减少重症肌无力患者病死率并提升社会生活质量,但可用免疫抑制剂品种多样且均有剂量相关性的不良反应.目前国内外研究者对符合重症肌无力的免疫抑制剂选取、具体使用方法等问题尚无确切定论,因此有必要对重症肌无力常用免疫修饰治疗的临床应用进行综述,为临床医师在重症肌无力个体化免疫修饰治疗方面提供参考.     

间充质干细胞治疗肺损伤的作用机制及研究进展

文题释义： 急性肺损伤：是各种直接和间接致伤因素导致的肺泡上皮细胞及毛细血管内皮细胞损伤,出现弥漫性肺间质及肺泡水肿,导致急性低氧性呼吸功能不全。以肺容积减少、肺顺应性降低、通气/血流比例失调为病理生理特征,其发展至严重阶段(氧合指数<200)被称为急性呼吸窘迫综合征。 外泌体：是细胞外泌囊泡中体积较小的一种,包含了复杂RNA和蛋白质的小膜泡(30-150 nm),所有培养的细胞类型均可分泌外泌体,且外泌体天然存在于体液中,间充质干细胞分泌的外泌体是近来研究的热点,其可以直接或者激活细胞内的信号通路进而发挥保护损伤细胞的作用。 背景：间充质干细胞疗法作为一种新兴的治疗方案,在治疗肺损伤方面具有很大的前景优势。 目的：综述间充质干细胞治疗肺损伤的作用和保护机制,以期为临床治疗肺损伤提供理论依据。 方法：检索万方、CNKI、PubMed、Web of Science等数据库2001年5月至2019年5月期间关于间充质干细胞应用于肺损伤的文献,检索词分别为“间充质干细胞,肺损伤,肺”和“mesenchymal stem cells,lung injury,pulmonary injury”。排除陈旧以及重复的观点,将检索到的文献进行整理,共纳入53篇文献来进行分析。 结果与结论：①梳理了间充质干细胞的定义、生物学特性及治疗肺损伤的机制,发现其可通过自身作用以及产生多种细胞因子和外泌体来治疗肺损伤;②总结了间充质干细胞治疗肺损伤的相关信号通路,例如PI3K/AKT信号通路、Wnt信号通路、NF-κB信号通路;③总结发现间充质干细胞与其他药物联合应用可以增强治疗肺损伤的效果,例如与促红细胞生成素、皮质类固醇联合应用等;④上述研究为临床上应用间充质干细胞治疗肺损伤提供了理论依据。 ORCID: 0000-0002-4555-9102(梁贵友) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Bilirubin as a signaling molecule

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.