A study of selected catecholamine metabolizing enzymes: a comparison of depressive suicides and alcoholic suicides with controls

—The regional distributions of monamine oxidase (MAO) (EC 1.4.3.4), catechol-O-methyltransferase (COMT) (EC 2.1.1.6), tyrosine hydroxylase (TH) (EC 1.14.3.2), and dopamine-β-hydroxylase (DBH) (EC 1.14.2.1) have been examined in human brains obtained at autopsy from persons who died of natural causes (controls), and from persons who committed suicide and were further categorized as suffering from affective disorder (depression) or from alcoholism. Post mortem animal studies showed no changes in MAO or COMT activities in rabbit brain or in DBH activity in rat brain when the intact bodies were left at room temperature up to 24 h. TH activity in rabbit brains, however, began to decline immediately after death and after 24 h at room temperature it was approximately 48 per cent of the fresh brain level. There was no significant variation in activity of COMT, TH and DBH in human brain attributable to age or sex. MAO activities in the 60–70 yr decade were 34 per cent higher than in the 30–40 yr decade. MAO activities were highest in the hypothalamus and substantia nigra, TH activities were highest in substantia nigra, putamen and head of caudate, and DBH activities were greatest in tegmentum of pons and hypothalamus. Only minimal regional differences in COMT activities were observed. No significant differences were found between enzyme activities in brain areas of controls and suicides with the possible exception of TH in the substantia nigra, where the depressive suicides (but not the alcoholics) showed greater activity (P < 0·02). These findings appear not to support the catecholamine hypothesis of affective disorder.     

Nonparametric estimation of the joint distribution of a survival time subject to interval censoring and a continuous mark variable

This article considers three nonparametric estimators of the joint distribution function for a survival time and a continuous mark variable when the survival time is interval censored and the mark variable may be missing for interval-censored observations. Finite and large sample properties are described for the nonparametric maximum likelihood estimator (NPMLE) as well as estimators based on midpoint imputation (MIDMLE) and coarsening the mark variable (CMLE). The estimators are compared using data from a simulation study and a recent phase III HIV vaccine efficacy trial where the survival time is the time from enrollment to infection and the mark variable is the genetic distance from the infecting HIV sequence to the HIV sequence in the vaccine. Theoretical and empirical evidence are presented indicating the NPMLE and MIDMLE are inconsistent. Conversely, the CMLE is shown to be consistent in general and thus is preferred.     

Differential regulation of embryonic and adult β cell replication

Diabetes results from an inadequate functional β cell mass, either due to autoimmune destruction (Type 1 diabetes) or insulin resistance combined with β cell failure (Type 2 diabetes). Strategies to enhance β cell regeneration or increase cell proliferation could improve outcomes for patients with diabetes. Research conducted over the past several years has revealed that factors regulating embryonic β cell mass expansion differ from those regulating replication ofβ cells post-weaning. This article aims to compare and contrast factors known to control embryonic and postnatal β cell replication. In addition, we explore the possibility that connective tissue growth factor (CTGF) could increase adult β cell replication. We have already shown that CTGF is required for embryonicβ cell proliferation and is sufficient to induce replication of embryonic β cells. Here we examine whether adult β cell replication and expansion of β cell mass can be enhanced by increased CTGF expression in mature β cells.     

Sample Size Estimation in Cluster Randomized Studies with Varying Cluster Size

Cluster randomized studies are common in community trials. The standard method for estimating sample size for cluster randomized studies assumes a common cluster size. However often in cluster randomized studies, size of the clusters vary. In this paper, we derive sample size estimation for continuous outcomes for cluster randomized studies while accounting for the variability due to cluster size. It is shown that the proposed formula for estimating total cluster size can be obtained by adding a correction term to the traditional formula which uses the average cluster size. Application of these results to the design of a health promotion educational intervention study is discussed.     

Data-Driven Asthma Endotypes Defined from Blood Biomarker and Gene Expression Data

The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels.     

Induced changes in island fox (Urocyon littoralis) activity do not mitigate the extinction threat posed by a novel predator

Prey response to novel predators influences the impacts on prey populations of introduced predators, bio-control efforts, and predator range expansion. Predicting the impacts of novel predators on native prey requires an understanding of both predator avoidance strategies and their potential to reduce predation risk. We examine the response of island foxes (Urocyon littoralis) to invasion by golden eagles (Aquila chrysaetos). Foxes reduced daytime activity and increased night time activity relative to eagle-na?ve foxes. Individual foxes reverted toward diurnal tendencies following eagle removal efforts. We quantified the potential population impact of reduced diurnality by modeling island fox population dynamics. Our model predicted an annual population decline similar to what was observed following golden eagle invasion and predicted that the observed 11% reduction in daytime activity would not reduce predation risk sufficiently to reduce extinction risk. The limited effect of this behaviorally plastic predator avoidance strategy highlights the importance of linking behavioral change to population dynamics for predicting the impact of novel predators on resident prey populations.     

Commentary on "Principal stratification - a goal or a tool?" by Judea Pearl

This commentary takes up Pearl's welcome challenge to clearly articulate the scientific value of principal stratification estimands that we and colleagues have investigated, in the area of randomized placebo-controlled preventive vaccine efficacy trials, especially trials of HIV vaccines. After briefly arguing that certain principal stratification estimands for studying vaccine effects on post-infection outcomes are of genuine scientific interest, the bulk of our commentary argues that the "causal effect predictiveness" (CEP) principal stratification estimand for evaluating immune biomarkers as surrogate endpoints is not of ultimate scientific interest, because it evaluates surrogacy restricted to the setting of a particular vaccine efficacy trial, but is nevertheless useful for guiding the selection of primary immune biomarker endpoints in Phase I/II vaccine trials and for facilitating assessment of transportability/bridging surrogacy.     

Effects of long-term consumption of sewage solids on reproductive performance and serum progesterone and estradiol-17beta in mature fine-wool ewes

Eighty-four mature fine-wool ewes were randomly allotted to one of three dietary treatments to examine the influence of dietary sewage solids on reproductive performance. Treatments were a basal diet or basal plus either 3.5% cottonseed meal (CSM) or 7% sewage solids. Serum progesterone and estradiol-17beta measured in blood samples collected through an estrous cycle just before the breeding season of the first and second years were not adversely influenced by sewage feeding. Progesterone concentrations quantified in weekly blood samples collected during gestation and lactation of both years did not differ (P>0.10) among treatments. During the first lambing season, lambing data showed that ewes consuming CSM produced slightly more lambs per ewe exposed (P<0.10) than either basal- or sewage-fed ewes. During the second breeding season, midventral laparotomies revealed that ovaries from ewes receiving CSM contained more (P<0.10) corpora lutea than did those from either basal- or sewage-fed animals. However, at the end of the second lambing season, no differences (P>0.10) among treatments in the number of lambs born or weaned were observed. A third year's lambing data also revealed no difference (P>0.10) among treatments for lambing rates. These data indicate that prolonged consumption of a diet containing 7% sewage solids has little, if any, detrimental effect on reproductive performance of mature fine-wool ewes.     

Initial results and long-term clinical follow-up of an amorphous hydrogenated silicon-carbide-coated stent in daily practice

The hemocompatibility and biocompatibility of a stent are determined by the physical and electrochemical properties of the stent surface. The aim of this study was to determine the feasibility, safety and efficacy of implantation of a stent coated with silicon carbide. Baseline characteristics were collected prospectively. The occurrence of cardiac adverse events and the angina score were assessed at clinical follow-up. A total of 193 Tensum stents were implanted in 174 patients. In hospital, one patient experienced stent thrombosis and in 6% of the patients a creatinine kinase elevation to 240 U/l or more occurred. Long-term follow-up was performed in 172 patients, with a mean follow-up of 454 +/- 181 days. Ninety-seven per cent were still alive, 15% had undergone target-vessel revascularization, and 2% had angiographic restenosis and were treated with medication only. Seventy-one per cent of the patients were free of anginal complaints, and 20% had anginal complaints in Canadian Cardiac Society class I or II. The Tensum coronary stent showed to be a safe and efficacious device in this study, with a high primary success rate and favorable long-term clinical followup.     

Evaluating candidate principal surrogate endpoints

SUMMARY: Frangakis and Rubin (2002, Biometrics 58, 21-29) proposed a new definition of a surrogate endpoint (a "principal" surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. Although the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate(s) that predicts the biomarker. Given case-cohort sampling of such a baseline predictor and the biomarker in a large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the "surrogate value" of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection.