Bayesian analysis for nonlinear regression model under skewed errors,with application in growth curves

We have considered a Bayesian approach for the nonlinear regression model by replacing the normal distribution on the error term by some skewed distributions, which account for both skewness and heavy tails or skewness alone. The type of data considered in this paper concerns repeated measurements taken in time on a set of individuals. Such multiple observations on the same individual generally produce serially correlated outcomes. Thus, additionally, our model does allow for a correlation between observations made from the same individual. We have illustrated the procedure using a data set to study the growth curves of a clinic measurement of a group of pregnant women from an obstetrics clinic in Santiago, Chile. Parameter estimation and prediction were carried out using appropriate posterior simulation schemes based in Markov Chain Monte Carlo methods. Besides the deviance information criterion (DIC) and the conditional predictive ordinate (CPO), we suggest the use of proper scoring rules based on the posterior predictive distribution for comparing models. For our data set, all these criteria chose the skew‐t model as the best model for the errors. These DIC and CPO criteria are also validated, for the model proposed here, through a simulation study. As a conclusion of this study, the DIC criterion is not trustful for this kind of complex model.     

脑弥漫性轴索损伤的MRI征象及与GCS计分及预后的关系

目的：探讨脑弥漫性轴索损伤（DAI）的磁共振成像（MRI）征象及其与格拉斯哥昏迷量表评分（GCS）计分和预后的关系。方 法：回顾性分析2012 年1 月-2014 年7 月我院收集的30 例DAI 患者的临床病历资料,根据病灶累及部位分析其与GCS 计分和 临床预后的关系。结果：30 例患者共53 个病灶,17例多发病灶,13 例单发病灶;42 个病灶T1WI显示出低信号或者是等信号,11 个病灶T1WI显示为高信号;T2WI显示为高信号,FLAIR 序列以及弥散加权像（DWI）上表现出的信号更高,范围更清晰;病灶形 态呈条索状27 例,斑片状11 例,卵圆形8 例,不规则斑点状7 例;病灶未累及脑中线部位的患者临床预后优于病灶累及脑中线 部位的患者,差异有统计学意义（Z=-2.636,P=0.008）,病灶累及脑中线部位的患者GCS 计分情况比未累及组严重,计分更低,差 异有统计学意义（Z=-2.519,P=0.012）。结论：DAI病灶累及脑中线部位的患者GCS计分较低、预后差,MRI检查是诊断DAI 首选 的影像学方法,临床有重要的参考价值。     

Chronic L‐DOPA induces hyperactivity,normalization of gait and dyskinetic behavior in MitoPark mice

Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L‐DOPA‐induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin‐induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long‐term L‐DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long‐term treatment with a moderate, clinically relevant dose of L‐DOPA (8 mg/kg) gradually produced age‐dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long‐term L‐DOPA treatment. The cylinder test showed an age‐dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long‐term L‐DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID.     

Risk‐Group‐Specific Dose Finding Based on an Average Toxicity Score

Summary We propose a Bayesian dose‐finding design that accounts for two important factors, the severity of toxicity and heterogeneity in patients' susceptibility to toxicity. We consider toxicity outcomes with various levels of severity and define appropriate scores for these severity levels. We then use a multinomial‐likelihood function and a Dirichlet prior to model the probabilities of these toxicity scores at each dose, and characterize the overall toxicity using an average toxicity score (ATS) parameter. To address the issue of heterogeneity in patients' susceptibility to toxicity, we categorize patients into different risk groups based on their susceptibility. A Bayesian isotonic transformation is applied to induce an order‐restricted posterior inference on the ATS. We demonstrate the performance of the proposed dose‐finding design using simulations based on a clinical trial in multiple myeloma.     

黑木耳多糖对急性脑缺血/再灌注损伤影响的研究

目的:观察黑木耳多糖(APP)对急性脑缺血大鼠的保护作用并探讨其相关机制。方法:成年雄性SD大鼠给予不同浓度的AAP灌胃20d,每天1次,腹腔注射银杏叶提取物(ginkgo biloba extract,EGb671)作为阳性对照,20d后实施右侧大脑中动脉栓塞(MCAO)建立局灶性脑缺血模型。MCAO60min后复灌,复灌24h后进行Longa神经功能损伤评分,并用2,3,5-氯化三苯基四氮唑(TTC)染色法测定脑梗死面积。复灌48h后用TUNEL免疫组化检测神经元凋亡,测定脑组织线粒体内活性氧簇(ROS)的生成量判断氧化应激水平。结果:黑木耳多糖能降低神经功能损伤评分,减小脑梗死面积,减少神经元凋亡,并且能够使缺血复灌脑组织线粒体ROS生成显著减少。高剂量AAP组的凋亡神经元数量、ROS生成量和阳性对照组相比有显著性差异。结论:黑木耳多糖能够对抗大鼠的局灶性脑缺血损伤,其保护作用和减轻氧化应激水平有关,并优于银杏叶提取物。     

A dysmorphology score system for assessing embryo abnormalities in rat whole embryo culture

BACKGROUND: The rodent whole embryo culture (WEC) system is a well‐established model for characterizing developmental toxicity of test compounds and conducting mechanistic studies. Laboratories have taken various approaches in describing type and severity of developmental findings of organogenesis‐stage rodent embryos, but the Brown and Fabro morphological score system is commonly used as a quantitative approach. The associated score criteria is based upon developmental stage and growth parameters, where a series of embryonic structures are assessed and assigned respective scores relative to their gestational stage, with a Total Morphological Score (TMS) assigned to the embryo. This score system is beneficial because it assesses a series of stage‐specific anatomical landmarks, facilitating harmonized evaluation across laboratories. Although the TMS provides a quantitative approach to assess growth and determine developmental delay, it is limited to its ability to identify and/or delineate subtle or structure‐specific abnormalities. Because of this, the TMS may not be sufficiently sensitive for identifying compounds that induce structure or organ‐selective effects. METHOD: This study describes a distinct morphological score system called the “Dysmorphology Score System (DMS system)” that has been developed for assessing gestation day 11 (approximately 20–26 somite stage) rat embryos using numerical scores to differentiate normal from abnormal morphology and define the respective severity of dysmorphology of specific embryonic structures and organ systems. This method can also be used in scoring mouse embryos of the equivalent developmental stage. RESULT AND CONCLUSION: The DMS system enhances capabilities to rank‐order compounds based upon teratogenic potency, conduct structure‐ relationships of chemicals, and develop statistical prediction models to support abbreviated developmental toxicity screens. Birth Defects Res (Part B) 89:485–492, 2010. © 2010 Wiley‐Liss, Inc.     

Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population

A Clock polymorphism T to C situated in the 3' untranslated region (3'-UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning-type subjects were compared with extreme evening-type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5' UTR region and the T3111C in the 3' UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

An analysis approach to identify specific functional sites in orthologous proteins using sequence and structural information: Application to neuroserpin reveals regions that differentially regulate inhibitory activity

The analysis of sequence conservation is commonly used to predict functionally important sites in proteins. We have developed an approach that first identifies highly conserved sites in a set of orthologous sequences using a weighted substitution‐matrix‐based conservation score and then filters these conserved sites based on the pattern of conservation present in a wider alignment of sequences from the same family and structural information to identify surface‐exposed sites. This allows us to detect specific functional sites in the target protein and exclude regions that are likely to be generally important for the structure or function of the wider protein family. We applied our method to two members of the serpin family of serine protease inhibitors. We first confirmed that our method successfully detected the known heparin binding site in antithrombin while excluding residues known to be generally important in the serpin family. We next applied our sequence analysis approach to neuroserpin and used our results to guide site‐directed polyalanine mutagenesis experiments. The majority of the mutant neuroserpin proteins were found to fold correctly and could still form inhibitory complexes with tissue plasminogen activator (tPA). Kinetic analysis of tPA inhibition, however, revealed altered inhibitory kinetics in several of the mutant proteins, with some mutants showing decreased association with tPA and others showing more rapid dissociation of the covalent complex. Altogether, these results confirm that our sequence analysis approach is a useful tool that can be used to guide mutagenesis experiments for the detection of specific functional sites in proteins. Proteins 2015; 83:135–152. © 2014 Wiley Periodicals, Inc.