Understanding eating disorders

The outcome in eating disorders remains poor and commonly used methods of treatment have little, if any effect. It is suggested that this situation has emerged because of the failure to realize that the symptoms of eating disorder patients are epiphenomena to starvation and the associated disordered eating. Humans have evolved to cope with the challenge of starvation and the neuroendocrine mechanisms that have been under this evolutionary pressure are anatomically versatile and show synaptic plasticity to allow for flexibility. Many of the neuroendocrine changes in starvation are responses to the externally imposed shortage of food and the associated neuroendocrine secretions facilitate behavioral adaptation as needed rather than make an individual merely eat more or less food. A parsimonious, neurobiologically realistic explanation why eating disorders develop and why they are maintained is offered. It is suggested that the brain mechanisms of reward are activated when food intake is reduced and that disordered eating behavior is subsequently maintained by conditioning to the situations in which the disordered eating behavior developed via the neural system for attention. In a method based on this framework, patients are taught how to eat normally, their physical activity is controlled and they are provided with external heat. The method has been proven effective in a randomized controlled trial.     

Pentamidine uptake and resistance in pathogenic protozoa: past,present and future

Diamidines, and pentamidine in particular, have a long history as valuable chemotherapeutic agents against infectious disease. Their selectivity is due mostly to selective accumulation by the pathogen, rather than the host cell; and acquired resistance is frequently the result of changes in transmembrane transport of the drug. Here, recent progress in elucidating the mechanisms of diamidine transport in three important protozoan pathogens, Trypanosoma brucei, Leishmania and Plasmodium falciparum, is reviewed, and the implications for drug resistance are discussed.     

A Review of the Adverse Effects of Peripheral Alpha-1 Antagonists in Hypertension Therapy

Background  

Doxazosin and its role as an antihypertensive agent have come under recent scrutiny as a result of the early termination of that treatment arm in ALLHAT. It is unclear why the cardiovascular (CV) event rate in this randomized, controlled trial (RCT), especially heart failure, is higher in those treated with a doxazosin-based regimen than with a chlorthalidone based-regimen. There has been little work in the past to summarize information on peripheral alpha-1 antagonists that may be helpful in evaluating the results of this randomized controlled trial.     

Controlled trial of azathioprine in chronic ulcerative colitis.

A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Among patients who completed the trial the mean dose of prednisolone necessary to control the disease decreased in those treated with azathioprine and those treated with placebo; the reduction was greater among those who took azathioprine (p less than 0.001). Activity of the disease apparently improved in both treatment groups but a significant (p less than 0.001) trend was observed only in those patients treated with azathioprine. No serious side effects from azathioprine occurred during the trial but seven of 24 patients had to stop the drug because of nausea. Azathioprine may have a role in the treatment of a few patients wih troublesome chronic colitis for whom conventional drug treatment is ineffectual, or for whom continuous systemic corticosteroid treatment is needed to control symptoms, and for whom surgical treatment is inappropriate.     

Analysis of Group Randomized Trials with Multiple Binary Endpoints and Small Number of Groups

The group randomized trial (GRT) is a common study design to assess the effect of an intervention program aimed at health promotion or disease prevention. In GRTs, groups rather than individuals are randomized into intervention or control arms. Then, responses are measured on individuals within those groups. A number of analytical problems beset GRT designs. The major problem emerges from the likely positive intraclass correlation among observations of individuals within a group. This paper provides an overview of the analytical method for GRT data and applies this method to a randomized cancer prevention trial, where multiple binary primary endpoints were obtained. We develop an index of extra variability to investigate group-specific effects on response. The purpose of the index is to understand the influence of individual groups on evaluating the intervention effect, especially, when a GRT study involves a small number of groups. The multiple endpoints from the GRT design are analyzed using a generalized linear mixed model and the stepdown Bonferroni method of Holm.     

Rho/ROCK信号通路与糖尿病肾病

糖尿病肾病(DN)是糖尿病最严重的微血管并发症之一,并已成为终末期肾脏病(ESRD)的重要原因,成为人类致死、致残的一个重要因素。因此,发现糖尿病肾病的新机制及关于此机制的新药研究,对改善糖尿病肾病预后非常重要。近年来,不断深入的研究提示,Rho/ROCK信号通路可能成为防治糖尿病肾病的药物新靶点。本文就Rho/ROCK信号通路与糖尿病肾病的关系作一综述。     

Current trends in the cardiovascular clinical trial arena (I)

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular).The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients.As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series.     

A Randomized Controlled Trial of Acetyl Salicyclic Acid in the Secondary Prevention of Mortality from Myocardial Infarction

The results of a randomized controlled trial of a single daily dose of acetyl salicylic acid (aspirin) in the prevention of reinfarction in 1,239 men who had had a recent myocardial infarct were statistically inconclusive. Nevertheless, they showed a reduction in total mortality of 12% at six months and 25% at twelve months after admission to the trial. Further trials are urgently required to establish whether or not this effect is real.     

Missing Data in Randomized Clinical Trials for Weight Loss: Scope of the Problem,State of the Field,and Performance of Statistical Methods

Background

Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods.

Methodology/Principal Findings

We searched PubMed and Cochrane databases (2000–2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e^−λt) where λ was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive.

Conclusion/Significance

Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.     

Research of a holiday kind: A clinical trial gone awry: the Chocolate Happiness Undergoing More Pleasantness (CHUMP) study

The randomized controlled trial is the “gold standard” for evaluating the benefits and harms of interventions. The Chocolate Happiness Undergoing More Pleasantness (CHUMP) study was designed to compare the effects of dark chocolate, milk chocolate and normal chocolate consumption on happiness. Although the intention-to-treat analysis showed that participants who received either dark or milk chocolate were happier than those who received no additional chocolate, the actual-consumption analysis showed that there were no differences between any of the groups. The reason for this result is that many participants switched groups mid-study because of their personal chocolate preferences. Although the CHUMP study was pleasurable, it demonstrated the difficulties associated with performing a truly blinded clinical trial.The randomized controlled trial is the “gold standard” for testing the beneficial and harmful effects of interventions. There has been a growing concern in the literature about the potential for bias during randomization of participants in clinical trials.^1–5 I designed the Chocolate Happiness Undergoing More Pleasantness (CHUMP) study to compare the effects of dark chocolate, milk chocolate and “normal” chocolate consumption on happiness. The CHUMP study was a double-blinded clinical trial, and it demonstrated the difficulties associated with performing a truly blinded clinical trial.     

The role of computers in preventive medicine in a rural family practice.

Five family physicians in a group practice in rural Quebec have introduced a computer system to improve the delivery of preventive medicine. In addition to billing, the computer is used mainly to recall specific groups of patients for preventive measures, to prompt the physicians to carry out certain procedures at the patient''s next visit, to indicate which procedures are required for the family members and to generate reminder letters. The physicians are conducting a randomized controlled trial to evaluate the impact of computer-generated reminder letters on patient compliance and disease prevention among families in their practice.     

Correlates of Participation in a Pediatric Primary Care‐Based Obesity Prevention Intervention

The purpose of this study was to examine the correlates of participation in a childhood obesity prevention trial. We sampled parents of children recruited to participate in a randomized controlled trial. Eligible children were 2.0–6.9 years with BMI ≥95th percentile or 85th to <95th percentile if at least one parent was overweight. We attempted contact with parents of children who were potentially eligible. We recruited 475 parents via telephone following an introductory letter. We also interviewed 329 parents who refused participation. Parents who refused participation (n = 329) did not differ from those who participated (n = 475) by number of children at home (OR 0.94 per child; 95% CI: 0.77–1.15) or by child age (OR 1.07 per year; 95% CI: 0.95–1.20) or sex (OR 1.06 for females vs. males; 95% CI: 0.80–1.41). After multivariate adjustment, parents who were college graduates vs. <college graduates were less likely to participate (OR 0.62; 95% CI: 0.46–0.83). In addition, parents were less likely (OR 0.41; 95% CI: 0.31–0.56) to participate if their child was overweight vs. obese. Among the 115 refusers with obese children, 21% cited as a reason for refusal that their children did not have a weight problem, vs. 30% among the 214 refusers with overweight children. In conclusion, parents of preschool‐age children with a BMI 85–95th%ile are less likely to have their children participate in an obesity prevention trial than parents of children with BMI >95th%ile. One reason appears to be that they less frequently consider their children to have a weight problem.     

Effect of statins in stroke prevention

PURPOSE OF REVIEW: This paper reviews recent studies into the outcomes of clinical trials in which statin therapy has been used in the prevention and treatment of strokes. RECENT DEVELOPMENTS: Epidemiologic studies found no or little association between blood cholesterol levels and stroke. Randomized trials have confirmed that LDL lowering decreased the risk of stroke, in diabetic or hypertensive patients with 'normal' LDL cholesterol at baseline, and in patients with coronary artery disease, with respectively 48, 27 and 25% reduction in stroke incidence. A meta-analysis of trials showed that the greater the LDL cholesterol reduction, the greater the intima-media thickness and stroke risk reductions. Even if statins also have 'pleiotropic' effects, their main action seems to be through LDL reduction. The Heart Protection Study only included strokes that occurred 4.6 years before--a time when the stroke event rate is low and the cardiac event rate is high, and so may not have had the power to find a true effect of LDL cholesterol lowering in preventing recurrent stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial may give a definite answer because SPARCL investigators included 4732 patients with brain infarction or transient ischemic attacks and no history of myocardial infarction within 6 months of their stroke event, at a time when the expected stroke rate is very high and the myocardial infarction rate is very low. The results should be announced by mid-2006. SUMMARY: The positive effect of statins on stroke observed in trials of patients with coronary heart disease depended mainly on between-group LDL reduction, but other mechanisms could be involved. Though effective in prevention of major coronary events after a first stroke, statins have not yet been proven effective in prevention of recurrent stroke.     

Selenium intake and cardiovascular risk: what is new?

PURPOSE OF REVIEW: Selenium is an essential element with a narrow safety margin. Adequate selenium intake is needed to maximize the activity of glutathione peroxidases and other selenoproteins. This review discusses recent experimental and epidemiologic contributions on the role of selenium for the prevention of atherosclerotic cardiovascular disease. RECENT FINDINGS: Few randomized trials have evaluated the efficacy of selenium supplementation on cardiovascular endpoints. Most trials, conducted in selenium-replete populations, found no evidence of cardiovascular protection. A meta-analysis of 13 prospective cohort studies found a moderate inverse relationship between plasma/serum selenium and coronary heart disease. The interpretation of these data is complicated, however, by potential residual confounding and publication bias. In contrast, recent data from trials of selenium-containing supplements and from epidemiologic studies suggest that chronically increased selenium intake in selenium-replete populations can induce diabetes and maybe also hypercholesterolemia. SUMMARY: Current evidence is insufficient to support a protective role for selenium in cardiovascular prevention. Large high-quality randomized controlled trials and observational studies are needed across populations with different levels of selenium intake. Furthermore, subjects living in regions with high selenium intake should be aware that selenium supplements may increase their risk of diabetes and hypercholesterolemia.     

Inflammation — a lifelong companion

Inflammation is a key component of the immune system. It has important functions in both defense and pathophysiological events maintaining the dynamic homeostasis of a host organism including its tissues, organs and individual cells. On the cellular level it is controlled by more than 400 currently known genes. Their polymorphisms and environmental conditions give rise to different genotypes in human population. Pro-inflammatory genotype, which dominates in the present population, may be advantageous in childhood but not in elderly people because it is characterized by an increased vulnerability to, and intensity of, inflammatory reactions. These reactions may be the possible reasons of chronic inflammatory diseases, especially in old age. Better understanding of complex molecular and cellular inflammatory mechanisms is indispensable for detailed knowledge of pathogenesis of many diseases, their prevention and directed drug therapy. Here we summarize the basic current knowledge on these mechanisms.     

The cluster-randomized trial

Within the framework of a clinical trial, one is sometimes brought to randomize groups of subjects rather than the subjects themselves. This type of experimental design has methodological consequences of importance (in particular biostatistical consequences) and can limit the extrapolation of the results. A cluster randomized trial is thus justified only if the context or the question of interest imposes it and biostatistical issues have then to be handled in a rigorous way.     

Hormone replacement therapy and cardiovascular disease

This year's work on hormone replacement therapy (HRT) and cardiovascular disease has been remarkable for the publication of the first randomised controlled trial of HRT use, the Heart Estrogen Replacement Study (HERS). The findings go against not only the trend of previous observational epidemiological studies, but also against findings in the very many studies which have previously shown and continue to show this year a beneficial effect of HRT on a large variety of cardiovascular risk factors, including endothelial function, here reviewed. The aspect of the effect of HRT on clotting variables is clearly crucial given the increased risk of venous thrombosis, and also increased number of cardiac events in the first 4 months of the HERS. Prothrombotic factors increase with age in women, and HRT alters these, particularly fibrinogen, factor VII, and PAI (less change with transdermal HRT) and antithrombin III. In normal women therefore the balance should be towards fibrinolysis rather than coagulation. Work has been presented in abstract for clarifying the effects of HRT on coagulation markers and grasping the problem of differences according to its route of administration. The full publications on this work are expected shortly. We are still awaiting evidence from randomized controlled trials of HRT in primary prevention; one is now recruited but will not report until 2005.     

慢性病轨迹模式在射血分数保留型心力衰竭患者中的应用研究进展

近年来,射血分数保留型心力衰竭(HFpEF)的防治进展已成为国内外心血管医生关注的热点。HFpEF的防治是一个长期、综合的过程,虽然在规范化药物治疗方面有所进步,但是HFpEF患者的症状仍未得到理想控制。因此,以合理防治为主的全周期健康管理模式对HFpEF患者具有极其重要的意义。随着对HFpEF患者长期随访管理及预后相关研究的深入,慢性病轨迹模式逐步成为具有良好前景的规范化管理模式。科学、合理的慢性病轨迹模式管理可以更好地控制HFpEF患者症状,持续改善其生活质量。本文就慢性病轨迹模式管理在HFpEF患者中的最新进展做一综述。