A preliminary examination of the effects of genetic variants of redox enzymes on susceptibility to oedematous malnutrition and on percentage cytotoxicity in response to oxidative stress in vitro.

BACKGROUND: The causes of oedematous vs non-oedematous childhood malnutrition (OM vs NOM) remain elusive. It is possible that inherited differences in handling oxidant stressors are a contributing factor. AIMS: To test for associations between polymorphisms in five genes and (i) risk of OM, a case-control study, and (ii) percentage cytotoxicity in peripheral blood mononuclear cells (PBMCs) exposed to hydrogen peroxide (H(2)O(2)), an in vitro cell challenge study. METHODS: Participants had been admitted previously for treatment of OM (cases, n = 74) or NOM (controls, n = 50), or were an independent set of healthy pregnant women (n = 47) who donated peripheral blood mononuclear cells. We tested for associations between genetic variation and outcome using single markers or a bivariate score constructed by counting numbers of deleterious alleles for each of 15 possible pairs of markers. RESULTS: In the case-control study there were no significant single-marker associations with OM. We did find that higher bivariate scores were associated with OM for the pair of NAD(P)H:quinone oxidoreductase 1 and catalase (odds ratio 2·00, 95% CI 1·05-3·82). In the cell challenge experiments, there were no significant associations with percentage cytotoxicity. CONCLUSIONS: Variation in this small set of genes seems unlikely to have a large impact on either risk of OM or cytotoxicity after H(2)O(2) exposure. The use of larger sample sizes to test the effects of a much larger set of genetic variants will be required in order to determine whether genetic variation contributes to the risk of OM. Such studies have potential for improving our understanding of causal pathways in OM.

Prevention. How much harm? How much benefit? 4. The ethics of informed consent for preventive screening programs.

Preventive interventions may have few or unproven benefits, or they may even be harmful. Since three of the fundamental precepts of Western biomedical ethics are beneficence, non-maleficence and respect for individual autonomy, failure to obtain truly informed consent for many current preventive interventions may be unethical. However, there are many impediments to obtaining such consent. Physicians need to be aware of an immense amount of up-to-date, complex information. It may be difficult for patients to assimilate this information, and there is rarely time for physicians to become informed and to inform their patients. Clinical practice guidelines may be helpful, but not all are based on evidence, and recommendations are often conflicting. Medical institutions, as well as individual clinicians, can help solve these dilemmas. Authors and journal editors can make a commitment to report and publish well-referenced evidence-based guidelines. Organizations such as the Canadian Task Force on the Periodic Health Examination and the US Preventive Services Task Force can develop balanced, evidence-based patient-information material. Faculty at all levels of medical education can increase their emphasis on the ethics of prevention. Individual clinicians should avoid making clinical decisions on the basis of relative reductions of morbidity or mortality, should use evidence-based clinical practice guidelines rather than those based on authority whenever possible, should make use of patient-information material and, most important, should have a consistent policy of obtaining informed consent from patients before they participate in potentially harmful preventive programs.

Prevention. How much harm? How much benefit? 3. Physical, psychological and social harm.

Harm caused by preventive programs may be physical, psychological, social or, if informed consent has not been obtained, ethical. Adverse effects of preventive screening programs may occur at any of the three levels of the "screening cascade", the screening procedure itself, the investigation of abnormal results of screening tests or the treatment of detected abnormalities or diseases. The greatest harm occurs at the second and third levels. Examples of procedures that may cause physical harm are venipuncture, mammography, colonoscopy, breast biopsy, transrectal ultrasonography, prostate biopsy, weight-reducing and cholesterol-lowering diets and radical prostatectomy. The psychological and social harm of preventive programs involves anticipated discomfort or perception of adverse effects of preventive interventions; unpleasant interactions with health care workers, time required for preventive programs, excessive overall awareness of health, anxiety over the results of a screening test implications of a positive screening test, consequences of being labelled as "sick" or "at risk," psychopathologic effects induced directly by preventive programs and, in the case of a false-negative test result, false assurance of disease-free status. Since the positive predictive value of screening tests in the general population is always low, most abnormal test results are "false-positive," these engender a great deal of psychological discuss among patients.

Prevention. How much harm? How much benefit? 2. Ten potential pitfalls in determining the clinical significance of benefits.

A preventive program is only of value if it has proven benefits that outweigh any adverse consequences; unfortunately, determination of the clinical significance of reported benefits is not always easy. The first article of this series discussed the confusion caused by reporting results in terms of relative rates. In this article, 10 other pitfalls that may lead to misunderstanding of the degree of benefits are reviewed. These pitfalls are: the type of outcome chosen (surrogate v. clinically significant), the risk level in the population screened, the interval between the intervention and the benefit, the duration of intervention required to achieve the benefit, the overshadowing of one benefit by another, the application of a benefit for one variant of a disease to another variant, lower benefits in community settings than in clinical trials, publication bias, preferential citation of studies showing beneficial effects and "false-negative" results of studies. These pitfalls are illustrated through examples from the current medical literature.

Prevention. How much harm? How much benefit? 1. Influence of reporting methods on perception of benefits.

Before a physician or a patient can decide whether a preventive program is worth while, each must understand the nature and degree of its benefits and the frequency and magnitude of its adverse effects. Preventive interventions can be divided into two major categories: those with infrequent or minor adverse effects and those with adverse effects that are frequent or serious. Accident prevention, avoidance of high-risk behaviour and healthy lifestyle choices such as breast-feeding and moderate exercise are associated with few adverse consequences. By contrast, screening populations for disease, risk classification for the purpose of selective preventive interventions, dietary intervention and prophylactic drug treatment may lead to more frequent and serious adverse effects. When assessing whether the benefits of a preventive intervention outweigh the harm, one must be aware that the methods used to report benefits of clinical trials may distort the reader's perception of their magnitude. The relative reduction of morbidity or mortality rate often grossly exaggerates benefits and should never be used as a basis for clinical decision making. More realistic ways of recording benefits are the absolute reduction of morbidity or mortality rate, the number of patients that need to be treated to avoid one adverse event, and the total cohort mortality rate.

Screening for prostate cancer. How can patients give informed consent?

Many urologists in North America are increasingly enthusiastic about prostatic cancer screening. Annual digital rectal examination is almost universally endorsed, and prostate-specific antigen testing is favored by most. But doctors really should not screen by either method without patients' informed consent. However, the information required for informed consent is complex and contradictory, difficult for physicians to give and for patients to absorb.

Kallikrein and kinin release using superfused disaggregated cortical cells from rat and human kidney: effects of AVP and dopamine.

Potential regulators of the renal Kallikrein-Kinin System are poorly defined. We have therefore examined the effect of arginine vasopressin and dopamine on the release of kallikrein and kinin from collagenase-dispersed rat and human renal cortical cells.