Outcomes of Donation After Circulatory Death Heart Transplantation in Australia

Background

Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice.

A note on permutation tests for genetic association analysis of quantitative traits when variances are heterogeneous

The genetic dissection of quantitative traits, or endophenotypes, usually involves genetic linkage or association analysis in pedigrees and subsequent fine mapping association analysis in the population. The ascertainment procedure for quantitative traits often results in unequal variance of observations. For example, some phenotypes may be clinically measured whilst others are from self‐reports, or phenotypes may be the average of multiple measures but with the number of measurements varying. The resulting heterogeneity of variance poses no real problem for analysis, as long as it is properly modelled and thereby taken into account. However, if statistical significance is determined using an empirical permutation procedure, it is not obvious what the units of sampling are. We investigated a number of permutation approaches in a simulation study of an association analysis between a quantitative trait and a single nucleotide polymorphism. Our simulations were designed such that we knew the true p‐value of the test statistics. A number of permutation methods were compared from the regression of true on empirical p‐values and the precision of the empirical p‐values. We show that the best procedure involves an implicit adjustment of the original data for the effects in the model before permutation, and that other methods, some of which seemed appropriate a priori, are relatively biased. Genet. Epidemiol. 33:710–716, 2009. © 2009 Wiley‐Liss, Inc.     

Understanding MCP‐MOD dose finding as a method based on linear regression

MCP‐MOD is a testing and model selection approach for clinical dose finding studies. During testing, contrasts of dose group means are derived from candidate dose response models. A multiple‐comparison procedure is applied that controls the alpha level for the family of null hypotheses associated with the contrasts. Provided at least one contrast is significant, a corresponding set of “good” candidate models is identified. The model generating the most significant contrast is typically selected. There have been numerous publications on the method. It was endorsed by the European Medicines Agency. The MCP‐MOD procedure can be alternatively represented as a method based on simple linear regression, where “simple” refers to the inclusion of an intercept and a single predictor variable, which is a transformation of dose. It is shown that the contrasts are equal to least squares linear regression slope estimates after a rescaling of the predictor variables. The test for each contrast is the usual t statistic for a null slope parameter, except that a variance estimate with fewer degrees of freedom is used in the standard error. Selecting the model corresponding to the most significant contrast P value is equivalent to selecting the predictor variable yielding the smallest residual sum of squares. This criteria orders the models like a common goodness‐of‐fit test, but it does not assure a good fit. Common inferential methods applied to the selected model are subject to distortions that are often present following data‐based model selection.     

Amelioration of anti-cancer agent adriamycin-induced nephrotic syndrome in rats by Wulingsan (Gorei-San), a blended traditional Chinese herbal medicine

Anti-cancer agent adriamycin (ADR) has demonstrated high anti-tumor efficacy. However, its use in chemotherapy has been limited largely due to its diverse toxicities, including renal toxicity, such as nephrotic syndrome with proteinuria. Podocyte injury leads to glomeruli proteinuria. Wulingsan (WLS) is a blended traditional Chinese herbal medicine specifically used for various kidney diseases. In the present study, we found that a water extract of WLS (480 mg/kg, p.o., x 28 days) reduced ADR-induced increase in urine protein excretion, plasma total cholesterol and triglyceride, and decrease in plasma total protein and albumin in rats. Furthermore, the results of electron microscopy demonstrated suppression by WLS of ADR-induced increase in width of foot process, increase in surface density and decrease in volume density. These results suggest that WLS ameliorates ADR-induced proteinuria and podocyte injury. Gene analysis results demonstrated a suppression of renal overexpression of nephrin mRNA and protein by WLS. Radioimmunoassay showed that WLS suppressed ADR-induced increased renal angiotensin II content in rats. Thus our results demonstrate that WLS ameliorates ADR-induced nephrotic syndrome in rats possibly by suppressing ADR-induced hyperactivity of renal renin-angiotensin system to modulate renal nephrin gene expression, thereby protecting podocyte from injury.     

五苓散的毒性评价

目的对五苓散（WLS）的长毒作用进行评价。方法观察给药后大鼠的一般症状、血液学、血液生化学、系统尸检和恢复期的有关指标,对WLS进行安全毒理学评价。结果对血液学及血液生化指标有一定的影响,主要表现在白细胞数分类及血红蛋白的改变（有统计学意义）,但停药后基本恢复。三个剂量组大鼠的心、脾、肺、肾上腺、前列腺、卵巢、子宫或睾丸（连附睾）、脑等脏器系数均无明显改变。结论临床应用需注意肝、肾脏和睾丸等脏器的毒性表现。