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UNLABELLED: The aim of this study was to determine the impact on risk perceptions of disclosing genetic test results used to estimate the risk of Alzheimer's disease (AD). Adult children (n = 149) of people with AD were randomized to one of two groups--Intervention group: lifetime risk estimates of AD based on age, gender, family history, and Apolipoprotein E (APOE) genotype; CONTROL GROUP: lifetime risk estimates of AD based on the same risk factors excluding APOE genotype. Perceptions of personal risk (PPR) for AD were assessed six weeks after risk assessments. PPR were correlated with actual lifetime risk estimates (r = 0.501; p < 0.0001). After controlling for lifetime risks communicated to participants, age, and number of affected relatives, PPR scores among those with an epsilon4-positive test result (the test result associated with increased AD susceptibility) (adjusted mean: 3.4 (SD: 0.7)) were not different from the PPR scores in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,91= 1.98; p = 0.162). Again, controlling for lifetime risk estimates, age, and number of affected relatives, the PPR score of those receiving an epsilon4-negative test result was significantly lower (adjusted mean: 3.1 (SD: 0.8)) than those in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,95 = 6.23; p = 0.014). Perceptions of risk of developing AD are influenced by genetic test disclosure in those receiving epsilon4-negative, but not those receiving epsilon4-positive test results. Despite the reduced perceptions of risk in the former group, there was no evidence of false reassurance (i.e., perceiving risks as equal to or lower than population risks of AD), although this possibility should be assessed in other testing contexts.
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Ten chemically different compounds were applied to the skin of the backs of male and female volunteers to induce delayed hypersensitivity responses. The 10 compounds had a low, moderate, high or unknown allergenic potential and were divided among five test panels (modified Draize) consisting of 150 subjects each. In each panel, 75 subjects (mean age 31 years) were always male prisoners (50% Caucasians) and the remaining 75 subjects (greater than 90% Caucasians) were divided, age-matched free males and females (mean age 24 years). Three compounds, each on different panels, had a significantly higher sensitization rate in females than in free males or total males. The remaining compounds produced sensitization, usually in lower numbers, but females dominated in sensitization rates. Viewed as absolute rates of sensitization for the 10 compounds, females were higher on eight test compounds and tied on two when compared to all males. These studies show that females develop significantly more cell-mediated immune responses to some chemical haptenes than men and the data also points to an overall higher rate of haptene recognition. Seven of these 10 compounds were simultaneously tested for their sensitization potential by the modified Maximization method (all males) in order to compare the two tests' ability to disclose potential sensitizers. Female sensitizations on the modified Draize accounted for this test's superiority.
There has been much interest in recent years in the replacement of the Draize rabbit skin test for the identification of chemical skin irritants. A considerable effort has gone into the development of cell culture based assays. However, where ethical and safety considerations permit, the most obvious alternative is to use man himself. Data obtained using a suitable assay based on the endpoint of concern in the species of concern should be accurate and will represent a vital data base on which to develop sound in vitro assays. Thus, it is important to ensure the data produced in human assays is representative for man generally. To this end we have chosen to examine a number of variables and in this work report the effect of atopic status on the results obtained in a recently described human 4-h patch test. 30 atopic (defined by specific IgE to common allergens and by elevated total IgE) and 28 non-atopic volunteers were tested in this human 4-h patch test using 20% sodium dodecyl sulfate (SDS), 10% hydrochloric acid (HCl) and undiluted cocotrimethyl ammonium chloride (coco TAC). The level of irritant reaction was higher for SDS in the atopic panel, but was similar for HCl and coco TAC. The rank order of irritancy was the same in both panels. The results indicate that, whilst the intensity of reactions may be higher in atopics, their pattern of responses is similar to non-atopics. There is no evidence to indicate that they should either be deliberately included or excluded from the test panels recruited on a routine basis.
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Twenty volunteers were exposed to 191 +/- 7 p.p.m. 1,1,1-trichloroethane or 50 +/- 2 p.p.m. perchloroethylene vapour for 6 hr. They were then evaluated for their rate of caffeine metabolism, mephenytoin hydroxylation and debrisoquine hydroxylation. Seven subjects were identified as 'fast acetylators' of caffeine and one person as a slow metabolizer of debrisoquine. The "slow acetylators" exposed to perchloroethylene excreted an average of 3.83 +/- 0.35 mg trichloroacetic acid within 24 hr (N = 13, +/- S.E.) and the 'fast acetylators' 3.58 +/- 0.48 mg (N = 7, +/- S.E.). The excretion of trichloroethanol by the same persons after 1,1,1-trichloroethane exposure was 14.1 +/- 1.12 mg and 16.7 +/- 1.48 mg, respectively. The excretion of trichloroacetic acid in the latter exposure varied significantly between the seven 'fast' and 13 'slow acetylators' (0.43 +/- 0.08 mg versus 1.03 +/- 0.19 mg; +/- S.E.; P = 0.037). A multiple linear regression analysis confirmed this association when other factors, such as body weight, creatinine clearance, smoking habit and alcohol consumption, were taken into account. One volunteer proved to be a poor hydroxylator of debrisoquine and excreted half the amount of trichloroacetic acid in the perchloroethylene exposure and half the amount of trichloroethanol in the 1,1,1-trichloroethane exposure compared to the others. A reduction in the solvent metabolism could thus be predicted by the debrisoquine test. On the other hand, the caffeine test predicted faster oxidation of trichloroethanol which could be of toxicological and pharmacological importance e.g. in the clinical use of chloral.
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The role that genetic factors play in medicine has expanded, owing to such recent advances as those made by the Human Genome Project and the work that has spun off from it. The project is focusing particularly on localization and characterization of recognized human genetic disorders, which in turn increases awareness of the potential for improved treatment of these disorders. Technical advances in genetic testing in the absence of effective treatment has presented the health profession with major ethical challenges. The example of the identification of the BRCA1 and BRCA2 genes in families at high risk for breast and ovarian cancer is presented to illustrate the issues of the sensitivity of the method, the degree of susceptibility a positive result implies, the need for and availability of counseling and patient education, and confidentiality of the test results. A compelling need exists for adequate education about medical genetics to raise the "literacy" rate among health professionals.
Observations that fit a hypothesis may be made before or after the hypothesis is formulated. Can that difference be relevant to the amount of support that the observations provide for the hypothesis? Philosophers of science and statisticians are both divided on this question, but there is an argument that predictions ought to count more than accommodations, because of the risk of "fudging" that accommodations run and predictions avoid.
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Insulin stimulated gastric secretion was studied in 74 unoperated duodenal ulcer patients (DUs), (20 women and 54 men). Three indices of secretion were studied--observed volume, acid output, and volume of gastric juice corrected for pyloric loss and duodenal reflux (VG). These three measurements were expressed both as peak secretion and as secretion during the 1/2 to two hour period after insulin, and also both before and after standardisation for height, making 12 different indices in all. From the data a significant correlation between insulin-stimulated secretion and height in DUs was found. A method of standardising each patient's secretion for height is described. We confirm a significantly higher insulin-stimulated secretion in men than in women and show that this difference can be explained by their difference in height. For each of the 12 indices of secretion, the range of secretion for the unoperated subjects was obtained. The same indices were measured in 155 postvagotomy patients, including 33 patients with recurrent DUs, and compared with the ranges of secretion established in the unoperated patients. Responses above the lower 95% tolerance limit of the preoperative range were designated positive and those below negative. The Hollander status was determined. It was found that the least satisfactory criterion was Hollander's (7% false negative and 69% false positive). The best was 1/2-2 VG standardised for height (3% false negatives and 43% false positives). The improvement in predictably was significant at the 0-0005 level.
Attitudes about bipolar disorder (manic depressive disorder) and genetic testing were investigated. Three groups of subjects were surveyed including members of a manic depressive support group, medical students, and psychiatry residents. The questionnaire was intended to elicit impressions and attitudes about bipolar disorder (BP) from mental health consumers and health care providers with varying levels of personal and professional familiarity with the disorder. Attitudes towards prenatal testing and pregnancy termination were also assessed. The intention hypothetically to terminate a pregnancy was influenced by the likelihood of developing BP a well as the projected course and severity of illness. Nearly half of the total sample would terminate pregnancy if the fetus were definitely to develop an unspecified form of bipolar disorder. Presumed severity of illness was also found to be a modifying factor in the decision, with a low percentage of subjects electing to terminate for a mild course of bipolar disorder and a majority opting for termination in the case of an extremely severe presentation. Support group members were the least likely to terminate a hypothetical pregnancy in the case of a positive prenatal test and were the most likely to desire childhood testing in the absence of preventive or treatment options. The possible implications of these findings, as well as avenues of future research, are discussed.