The case for a new system for oversight of research on human subjects

The increasing emphasis on evidence-based clinical practice has thrown into sharp focus multiple deficiencies in current systems of ethical review. This paper argues that a complete overhaul of systems for ethical oversight of studies involving human subjects is now required as developments in medical, epidemiological and genetic research have outstripped existing structures for ethical supervision. It shows that many problems are now evident and concludes that sequential and piecemeal amendments to present arrangements an inadequate to address these. Ar their core present systems of ethical review still rely on the integrity and judgement of individual investigators. One possible alternative is to train and license research investigators, make explicit their responsibilities and have ethics committees devote much more of their time to monitoring research activity in order to detect those infringing the rules.

Effects of chronic exposure to low-level cadmium on renal tubular function and CYP2A6-mediated coumarin metabolism in healthy human subjects

Relationships between cadmium (Cd) body burden, kidney function and coumarin metabolism were investigated using two groups of 197 and 200 healthy Thais with men and women in nearly equal numbers. A mean age of one group was 30.5 years and it was 39.3 years for the other group. Of 397, 20 subjects (5%) excreted urine Cd between 1.4 mug/g and 3.8 mug/g creatinine and these subjects faced 10-15% increase in the probability of having abnormal urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG-uria). The prevalence of NAG-uria varied with Cd body burden in a dose-dependent manner (chi(2) = 22, P < 0.008). Also NAG-nuria was one of the three kidney effect markers tested that showed the greatest strength of correlation with urine Cd in both men and women (r = 0.48 P < 0.001). In addition, urine Cd excretion of men and women showed a positive correlation (r = 0.46 to 0.54. P < 0.001) with urine 7-hydroxycoumarin (7-OHC) excretion which was used as a marker of liver cytochrome P450 2A6 (CYP2A6) enzyme activity. Urinary CA excretion accounted for 25% of the total variation in urine 7-OHC excretion (P < 0.001). These data suggest that Cd may increase the expression of CYP2A6 in liver, resulting in enhanced coumarin metabolism in subjects with high Cd body burden. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

Ethical issues in neuroscience research on substance dependence treatment and prevention

Previous chapters have presented the latest findings in neuroscience research, and have pointed to potential treatment and prevention strategies. However, there are many ethical implications of the research itself, as well as the treatment and prevention strategies, that must be considered. The rapid pace of change in the field of neuroscience brings with it a host of new ethical issues, which need to be addressed. This chapter considers the important ethical and human rights issues that are raised by neuroscience research on psychoactive substance dependence.

Effects of rosiglitazone and linoleic acid on human preadipocyte differentiation

Background Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand-activated transcription factor known to be central to both adipose tissue development and insulin action. Growth of adipose tissue requires differentiation of preadipocytes with acquisition of specific cellular functions including insulin sensitivity, leptin secretion and the capacity to store triglyceride. Dietary fatty acids and members of the thiazolidinedione class of compounds have been reported to influence adipogenesis at the transcriptional level. Here, we compare the effects of a dietary fatty acid, linoleic acid, and a thiazolidinedione, rosiglitazone, on biochemical and functional aspects of human preadipocyte differentiation in vitro . Materials and methods Human omental and subcutaneous preadipocytes were subcultured 2-3 times and subsequently differentiated for 21 days in the presence of either linoleic acid or rosiglitazone. Differentiation was assessed using a number of biochemical and functional parameters. Results Omental and subcutaneous preadipocytes differentiated in the presence of linoleic acid showed marked cytoplasmic triacylglycerol accumulation however, no biochemical markers of differentiation (LPL expression, G3PDH gene expression and enzyme activity and leptin expression or secretion) were detected. In contrast, treatment of these cells with rosiglitazone induced full biochemical differentiation as judged by all markers assessed, despite comparatively little lipid accumulation. The rosiglitazone effects were subcutaneous depot-specific. Cells treated with linoleic acid showed decreased glucose uptake cf rosiglitazone-treated cells. A luciferase reporter assay demonstrated that rosiglitazone potently activates h-peroxisome proliferator activated receptor gamma while linoleic acid had no effect. Conclusions These studies demonstrate that (a) human preadipocytes have the potential to accumulate triacylglycerol irrespective of their stage of biochemical differentiation; (b) while omental preadipocytes are refractory to biochemical differentiation in vitro , they are able to accumulate triacylglycerol; and (c) rosiglitazone and linoleic acid may exert their effects via different biochemical pathways.

Therapeutic activation of V alpha 24(+)V beta 11(+) NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity

Human Valpha24(+)Vbeta11(+) natural killer T (NKT) cells are a distinct CD1d-restricted lymphoid subset specifically and potently activated by alpha-galactosylceramide (alpha-GalCer) (KRN7000) presented by CD1 d on antigen-presenting cells. Preclinical models show that activation of Valpha24(+)Vbeta11(+) NKT cells induces effective antitumor immune responses and potentially important secondary immune effects, including activation of conventional T cells and NK cells. We describe the first clinical trial of cancer immune therapy with alpha-GalCer-pulsed CD1d-expressing dendritic cells. The results show that this therapy has substantial, rapid, and highly reproducible specific effects on Valpha24(+)Vbeta11(+) NKT cells and provide the first human in vivo evidence that Valpha24(+)Vbeta11(+) NKT cell stimulation leads to activation of both innate and acquired immunity, resulting in modulation of NK, T-, and B-cell numbers and increased serum interferon-gamma. We present the first clinical evidence that Valpha24(+)Vbeta11(+) NKT cell memory produces faster, more vigorous secondary immune responses by innate and acquired immunity upon restimulation.

The policy and ethical implications of genetic research on attention deficit hyperactivity disorder

Objective: To review the policy and ethical implications of recent research on the molecular genetics of attention deficit hyperactivity disorder (ADHD). Method: MEDLINE and psycINFO database searches were used to identify studies on the genetics of ADHD. The implications of replicated candidate genes are discussed. Results: The findings for most genes have been inconsistent but several studies have implicated the genes in the dopaminergic pathway in the aetiology of ADHD. Conclusions: The current evidence on the genetics of ADHD is insufficient to justify genetic screening tests but it will provide important clues as to the aetiology of ADHD. Genetic information on susceptibility to ADHD has the potential to be abused and to stigmatize individuals. Researchers and clinicians need to be mindful of these issues in interpreting and disseminating the results of genetic studies of ADHD.

Expression profiling in alcoholism research

This article represents the proceedings of a symposium at the 2004 International Society for Biomedical Research on Alcoholism in Mannheim, Germany, organized and co-chaired by Susan E. Bergeson and Wolfgang Sommer. The presentations and presenter were (1) Gene Expression in Brains of AlcoholPreferring and Non-Preferring Rats, by Howard J. Edenberg (2) Candidate Treatment Targets for Alcoholism: Leads from Functional Genomics Approaches, by Wolfgang Sommer (3) Microarray Analysis of Acute and Chronic Alcohol Response in Brain, by Susan E. Bergeson (4) On the Integration of QTL and Gene Expression Analysis, by Robert J. Hitzemann (5) Microarray and Proteomic Analysis of the Human Alcoholic Brain, by Peter R. Dodd.

The ethics of paying drug users who participate in research: a review and practical recommendations

THE PAYMENT OF RESEARCH PARTICIPANTS raises ethical and empirical questions that have special importance in addictions research involving drug-dependent participants. Despite a now large literature on human subjects payment, what is still needed is practical guidance for investigators and ethics committees. This paper reviews the literature on: current payment practices and guidelines; defining features of undue and due incentives and fair reimbursement; and the significance of risks and harms that may arise from paying drug using participants. We conclude that research payments are ethically acceptable in most circumstances of addictions research, but should be closely scrutinized in situations where these may exacerbate existing harms or create additional risks for participants and investigators. General principles, key questions and procedural options are highlighted for an applied approach to ethical research payments. Future research directions are identified.

Separating politics and scientific research on heroin prescription - In reply [Letter]

No Abstract

Triggers of subarachnoid hemorrhage - Role of physical exertion, smoking, and alcohol in the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS)

Background and Purpose - Unaccustomed strenuous physical exertion can trigger myocardial infarction, but little is known about the mechanisms precipitating subarachnoid hemorrhage (SAH). Methods - We identified all cases of first-ever SAH among the combined populations (2.8 million) of 4 urban centers in Australia and New Zealand. Information on the type, time, and intensity of exposures in the 26 hours before the onset of SAH was ascertained by structured interviews. We used the case-crossover technique to assess the risk of SAH associated with transient exposures of moderate to extreme physical exertion, heavy cigarette smoking, and binge alcohol consumption. Results - We registered 432 first-ever cases of SAH (62% women; mean age, 56.5 years). A definite time of onset of SAH was established for 393 patients (91%), and information on the levels of physical activity in the preceding 26 hours was obtained in 338 ( 78%). Of these patients, 19% engaged in moderate to extreme exertion (greater than or equal to5 metabolic equivalents) in the 2 hours before SAH, which was associated with a tripling in the risk of SAH (odds ratio [OR], 2.7; 95% CI, 1.6 to 4.6). There was no evidence of any association between heavy cigarette smoking or binge drinking and risk of SAH in the subsequent 2 hours ( OR, 1.1; 95% CI, 0.4 to 3.7; and OR, 0.41; 95% CI, -infinity to 5.3). Habitual exercise did not appear to alter the risk of SAH associated with moderate to extreme exertion. Conclusions - Moderate to extreme physical exertion tripled the risk of SAH, but there was no association between transient heavy smoking or binge drinking and risk of SAH. These data suggest that heavy physical activity may trigger SAH.