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PubMed1997

Ethical issues in genetic testing for Alzheimer's disease.

The discovery of genetic mutations that increase the risk of developing Alzheimer's disease (AD) brings new promise of predictive testing for the disease. But the quality of information yielded by genetic tests for AD and the implications of this information raise serious questions about the use of such tests. This article examines some of the ethical issues related to predictive genetic testing for AD by examining the interpretation and potential misuses of such data, as well as the factors affecting the development and use of such testing technology. Finally, it poses some recommendations for how genetic testing for AD and the information it yields should be used.

Alzheimer Disease↗
PubMed1988

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper No. 5. Genotoxicity tests as predictors of carcinogens: an analysis.

Differences between the results of numerical validation studies comparing in vitro and in vivo genotoxicity tests with the rodent cancer bioassay are leading to the perception that short-term tests predict carcinogenicity only with uncertainty. Consideration of factors such as the pharmacokinetic distribution of chemicals, the systems available for metabolic activation and detoxification, the ability of the active metabolite to move from the site of production to the target DNA, and the potential for expression of the induced lesions, strongly suggests that the disparate sensitivity of the different test systems is a major reason why numerical validation is not more successful. Furthermore, genotoxicity tests should be expected to detect only a subset of carcinogens, namely genotoxic carcinogens, rather than those carcinogens that appear to act by non-genetic mechanisms. Instead of relying primarily on short-term in vitro genotoxicity tests to predict carcinogenic activity, these tests should be used in a manner that emphasizes the accurate determination of mutagenicity or clastogenicity. It must then be determined whether the mutagenic activity is further expressed as carcinogenicity in the appropriate studies using test animals. The prospects for quantitative extrapolation of in vitro or in vivo genotoxicity test results to carcinogenicity requires a much more precise understanding of the critical molecular events in both processes.

Animals↗
PubMedDate not supplied

Low back pain: risk evaluation and preplacement screening.

As screening tests in a currently asymptomatic population, all of the available methods for predicting low back pain and disability have serious technical, ethical and legal limitations. From a technical point of view, none of the predictive tests appear to have sufficient sensitivity or specificity to justify routine usage. The most sensitive indicator (a past history of low back pain) lacks reliability and specificity. Muscle strength-testing may be predictive of future musculoskeletal injury as part of a well-designed program that considers specific job demands in relation to specific worker capabilities. Unfortunately, the conditions necessary for a well designed program--a large number of predictable high-risk jobs that have measurable specific demands that can be reproduced reliably in a testing situation--are rarely met. In the future, the use of computer-assisted multivariate models analogous to those used in the prediction of cardiovascular risk may be capable of integrating information about an individual's medical history, physical exam, physical capacity and other tests with specific job requirements to give us a more accurate prediction of the future risk of back pain and disability. If such predictive models are ever developed and verified, it would then be appropriate to examine various interventions and their effectiveness in modifying risks for the population and the individual worker. From a legal point of view, all of the techniques described hold potential for significant discrimination against legally protected groups. Making employment decisions with regard to a past history of low back pain or on the basis of an x-ray will lead to systematic age discrimination and discrimination against the handicapped. The use of muscle strength-testing will systematically discriminate against women and certain ethnic groups. The ethical implications of predictive screening for low back pain clearly depends on what is done with the information that is garnered from such tests. If the information is used only to make a safe job placement for an individual, and this placement does not affect the individual's salary or future job possibilities, then the testing program may have a net social value to the extent that it leads to true prevention of low back pain and disability. If the tests are used merely to reduce employer liability by refusing employment to those who are thought to be at "high risk," the technical, legal and ethical limitations will far outweigh any perceived benefits.

Back Pain↗
PubMed1998

The ecological validity of tests of executive function.

Ninety-two mixed etiology neurological patients and 216 control participants were assessed on a range of neuropsychological tests, including 10 neuropsychological measures of executive function derived from 6 different tests. People who knew the patients well (relatives or carers) completed a questionnaire about the patient's dysexecutive problems in everyday life, and this paper reports the extent to which the tests predicted the patients' everyday life problems. All of the tests were significantly predictive of at least some of the behavioral and cognitive deficits reported by patients' carers. However, factor analysis of the patients' dysexecutive symptoms suggested a fractionation of the dysexecutive syndrome, with neuropsychological tests loading differentially on 3 underlying cognitive factors (Inhibition, Intentionality, and Executive Memory), supporting the conclusions that different tests measure different cognitive processes, and that there may be limits to the fractionation of the executive system.

Adult↗
PubMed1986

Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case.

Three sets of criteria are proposed for assessing animal models of human mental disorders: predictive validity (performance in the test predicts performance in the condition being modelled), face validity (phenomenological similarity) and construct validity (theoretical rationale). The problems inherent in each of these validation procedures are discussed, and their application to the learned helplessness model of depression is examined. It is concluded that whilst the model has good predictive validity, important questions about face validity remain unanswered, and construct validity has not yet been established. The distinctions between animal models and some related experimental procedures are also discussed.

Animals↗
PubMed1998

[Genetic and molecular diagnostics in retinoblastoma].

Retinoblastoma is a childhood malignancy of the eye. Almost all patients with familial or bilateral disease suffer from the hereditary form of the disease that is caused by germline mutations in one allele of the RB1 gene. Tumor development is initiated by the loss of the second RB allele in a retinal progenitor cell. Most patients with isolated unilateral disease have nonhereditary retinoblastoma and thus do not carry a mutant allele in their germline. In no patient, the presence of a germline mutation can be excluded clinically. Consequently, relatives are at an increased risk for retinoblastoma. Molecular testing, however, enables accurate risk prediction provided that samples are available. In some relatives an increased risk can be excluded by segregation analysis. Most often, however, identification of the disease causing mutation is necessary for accurate risk prediction. Mutation analysis, which is impeded by the size and complexity of the RB gene, is facilitated by use of efficient screening methods. Using these methods, the oncogenic mutation can be identified in most patients. Therefore, predictive testing has become an integral part of contemporary management of retinoblastoma.

Female↗
PubMed1984

The diffusing capacity as a predictor of arterial oxygen desaturation during exercise in patients with chronic obstructive pulmonary disease.

We evaluated 48 patients with chronic obstructive pulmonary disease by means of pulmonary-function and exercise testing to determine whether any tests of pulmonary function could predict the development of arterial desaturation during exercise. We found that only two indexes--diffusing capacity and forced expiratory volume in one second (FEV1)--were predictive of desaturation. The diffusing capacity was more specific and sensitive than FEV1. A diffusing capacity above 55 per cent of predicted was 100 per cent specific in excluding desaturation, as compared with an 82 per cent specificity for an FEV1 above 55 per cent of predicted. With this cutoff point, the sensitivity of the diffusing capacity was 68 per cent, as compared with 46 per cent for the FEV1. Both the frequency and the magnitude of arterial desaturation increased substantially when the diffusing capacity was below 55 per cent of predicted. Testing the diffusing capacity should be useful in identifying which patients with chronic obstructive lung disease are likely to become desaturated during exercise and may therefore benefit from oxygen therapy.

Aged↗
PubMed2026

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article↗
PubMedDate not supplied

A developmental approach to preschool vision screening.

A developmental approach to preschool vision screening is described. The choice of acuity testing material in this test is determined by the child's capabilities, assessed prior to acuity testing. When compared with the Society for Prevention of Blindness test, this approach yields approximately half the number of untestables. Further, the acuity data from the two screening tests are quite similar, and both agree well with data from an additional screening by a pediatric ophthalmologist. Screening of preschool children usually requires a number of compromises in methods felt to be ideal for adults. Sacrifices in cost (i.e., additional personnel to assist the tester), additional effort (i.e., prior training of the children), or precision of acuity measures (i.e., cruder picture type targets for all children and use of isolated targets) are typically made to assure testability. These problems have been minimized by the Experimental method. Because of its low untestability rate and its apparently valid acuity data, this developmental vision screening test can be recommended as a cost effective approach to preschool vision screening. Previous research has shown that ratings of a child's behavior during this developmentally oriented vision screening test predict results of diagnostic cognitive tests as accurately as extensive tests designed exclusively for developmental screening. This test is then extremely cost effective when used for comprehensive preschool screening.

Child, Preschool↗
PubMed2003

Indirect enzyme-linked immunosorbent assay for the detection of antibody against Rift Valley fever virus in domestic and wild ruminant sera.

An indirect enzyme-linked immunosorbent assay (I-ELISA) for the detection of specific IgG immunoglobulins against Rift Valley fever virus (RVFV) was validated in-house. A total of 3055 sera from sheep (n = 1159), goats (n = 636), cattle (n = 203), African buffalo (n = 928), and other wild ruminants (n = 129), including eland, kudu, and black wildebeest, was used. Sera from domestic ruminants were collected in West (n = 10), South (n = 1654) and East Africa (n = 334), and sera from wild ruminants (n = 1064) were collected in South Africa. In addition, 136 sera from eight experimentally RVFV-infected sheep, taken during a period of 28 days post infection (dpi), were used to study the kinetics of RVFV antibody production. Field sera were tested by the serum neutralization (VN) test and experimental sera by VN and haemagglutination-inhibition (HI) test. Based on VN test results, negative sera were regarded as reference controls from RVFV-free, and positive sera were regarded as reference controls from RVFV-infected subpopulations of animals. ELISA data were expressed as the percentage positivity (PP) of an internal high positive control. The two-graph receiver operating characteristics approach was used for the selection and optimization of I-ELISA cut-offs including the misclassification costs term and Youden index (J). In addition, cut-off values were determined as the mean plus two-fold standard deviation of the result observed with the RVFV-free subpopulations. Established optimal cut-offs were different for each of the data sets analyzed, and ranged from 1.65 PP (buffalo) to 9.1 PP (goats). At the cut-off giving the highest estimate of combined measure of diagnostic accuracy (highest J value), the I-ELISA test parameters were determined as follows: (1) Diagnostic sensitivity (%): cattle--84.31, buffalo--94.44, sheep--98.91, goats--99.18. (2) Diagnostic specificity (%): cattle--99.34, buffalo--98.28, sheep--99.16, goats--99.23 and other game ruminants--99.26. In the group of RVFV-experimentally infected sheep, seroconversion In all individuals was detected by VN on 4-6 dpi, by HI on 5-7 dpi, and by I-ELISA on 6-7 dpi. All tests showed the same kinetic pattern of immunological response. Antibody levels were low for a very short period before increasing to high titres, after which it was easily detectable by all tests. Compared to traditional tests, the lower sensitivity of I-ELISA in the detection of the earliest stage of immunological response may be practically insignificant, particularily when this assay is used in population-based, disease-surveillance programmes. The high sensitivity and specificity of I-ELISA established in this study, especially for the statistically more representative subpopulations of animals tested, seem to support this prediction. Test parameters determined in this study should, however, be regarded as in-house diagnostic decision limits, for which further updating is recommended, particularly for specimens from other countries, and preferably by applying a standardized method for sampling of new subpopulations of animals to be targeted by the assay.

Animals↗
PubMed1991

[Molecular genetics: a new approach of clinical neurosciences].

Genetically determined diseases with neurological expression are frequent. Recent progress in molecular biological techniques, particularly the availability of markers distributed throughout the whole human genome, has given birth to the concept of reverse genetics, with consists in localizing the gene responsible for a disease, then identifying it and its corresponding protein. This approach is illustrated by the studies that led to the localization of the gene responsible for Huntington's chorea on the short arm of chromosome 4 and the identification of dystrophic, the abnormal gene product in Duchenne's and Becker's muscular dystrophies. These discoveries have medical repercussions, leading to predictive tests or new therapies. However, predictive medicine raises ethical issues that are largely debated.

Animals↗
PubMedDate not supplied

Correlations between cytochrome P-450 and oxidative metabolism of benzo[a]pyrene and 7-ethoxycoumarin in human liver in vitro and antipyrine elimination in vivo.

Cytochrome P-450 content was correlated to aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-de-ethylase activities in human liver biopsy samples in vitro. Antipyrine half-life and clearance were measured in the same patients in vivo. The results were compared with data obtained in rat liver in vitro. The correlation of cytochrome P-450 content with aryl hydrocarbon hydroxylase activity in human liver biopsy samples was relatively good (r = 0.75, p < 0.001), but that with 7-ethoxycoumarin O-de-ethylase activity was much poorer (r = 0.42, p < 0.001). The good correlation between cytochrome P-450 content and aryl hydrocarbon hydroxylase activity in biopsy samples from patients with widely varying hepatic disease processes, exposure to inducers, history of cigarette smoking, etc., is in contrast with the data obtained in the rat, where the corresponding correlation in a population treated with different inducers and inhibitors was rather poor (r = 0.37, p < 0.01). This poor correlation was caused mainly by the nonequal effects of polycyclic aromatic hydrocarbons on cytochrome P-450 and aryl hydrocarbon hydroxylase. Cigarette smoking was not found to induce human liver drug or carcinogen metabolism. Aryl hydrocarbon hydroxylase activity in vitro and antipyrine half-life or clearance in vivo were correlated (r = 0.36, p < 0.01 and r = 0.35, p < 0.01, respectively), indicating a weak, but statistically significant association between these parameters. This study suggests that correlations between in vitro and in vivo measurements of drug metabolism are not strong enough for the tests to be used as predictive tests in experimental or clinical research.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1980

[Methodical problems in detecting new allergens in ;animal experiments (author's transl)].

With the help of the Tina-test partial aspects of the predictive testing of potential allergens were examined in animal experiments. The Tina-test is based on the intramuscular, intracutaneous and epicutaneous application of the allergen in question using Freund's adjuvant and sodium laurylsulphate. The test has been acknowledged by the authorities as a standardized method. the following aspects were examined. A prolongation of the exposition times causes an increase of the sensitization rates. Freund's adjuvant should be used in every case, since the percentage of sensitized animals may be clearly increased. Outbred guinea pigs are well suited. the use of inbred animals is not necessary. In cases where more than 30% of the experimental group fall ill during the procedure of sensitization, the results are not reliable. Neither the sex of the animals nor the seasons influence sensitization rates. Per experimental group at least 25 animals should be used. Pilot studies with different quantities of allergens (potassium bichromate: 131 mg: 13.1 mg and 1.31 mg) did not show a clear influence on the results. Similar results we received also with nickel-2-sulphate. The sensitization rate corresponded well with our clinical experience in 19 out of 24 substances. With turpentine, nickel, mercury and a low-molecular phenol resin the number of the sensitized animals was somewhat too low, whereas with tetramethylthiuramdisulfide the percentage was somewhat too high.

Allergens↗
PubMed2002

Mechanisms linking under-nutrition and ovarian function in beef heifers.

Prolonged reduction in energy intake in beef heifers has been reported to suppress ovulation but the mechanisms involved are poorly understood. The objective of this study was to examine whether changes in the pattern of LH secretion following each of three different tests predicted the functional state of the hypothalamo-pituitary-ovarian (H-P-O) axis. Test 1 examined the ratio of LH secretion during the 1h before and 2h after naloxone (NAL) administration. The other two tests assessed the LH surge following an exogenous oestradiol positive feedback signal (Test 2) or exogenous progesterone priming (Test 3). In phases 1 and 3, each of 8 weeks duration, the heifers were fed 100% of their maintenance energy requirements. In phase 2, of 9 weeks duration, they were fed 50% of their maintenance energy requirements. Oestrus was induced in all heifers by PG administration at the start of the experiment. Heifers were administered a naloxone challenge of 50, 100, 200 or 400mg naloxone hydrochloride i.v. (one dose per heifer) during the mid-luteal period of phase 1 and all four naloxone treated heifers received 400mg naloxone hydrochloride at the end of phases 2 and 3. Doses of 10, 20 or 40 mg oestradiol benzoate (EB) i.m. were each administered to two of the remaining heifers during the mid-luteal period of phase 1. One heifer on each dose of oestradiol benzoate in phase 1 had the same dose administered at the end of phases 2 and 3. The progesterone challenge was administered to three heifers by insertion of a PRID for 12 days starting in the middle of phase 2. In Test 1, the ratio of LH secretion before and after naloxone administration in phase 1 was 1:1 (50mg), 1:4 (100mg), 1:4 (200mg) and 1:9 (400mg) (50mg versus 100mg and 100mg versus 200mg doses, P<0.05); 50mg versus 400mg doses, P<0.001). In phase 2, this ratio was 1:1 and there was no response to 400mg dose of naloxone in any of the four heifers. In phase 3, the ratio depended on the ovarian activity in the heifer and ranged from 1:1 to 1:4 (P<0.05). In Test 3, a positive oestradiol feedback signal was detected in cyclic heifers in phases 1-3 but not in the acyclic heifer in phase 2. Heifers challenge with exogenous progesterone did not have oestradiol or LH values above threshold levels. We conclude that all three tests successfully predicted the functional state of the hypothalamo-pituitary-ovarian axis. In nutritionally undernourished beef heifers onset of ovarian acyclicity is either preceded or accompanied by the loss of a positive feedback signal (Test 2) and progesterone priming ability (Test 3), and that a plasma LH ratio of > or =1:2 following naloxone challenge (Test 1) is a sign of recovery of the functional state of the hypothalamo-pituitary-ovarian axis.

Animals↗
PubMed2003

Preventive surgery for colon cancer in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome.

BACKGROUND: A better understanding of the molecular basis of hereditary colorectal cancer syndromes such as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and familial adenomatous polyposis (FAP) has profound consequences for both the diagnosis and (prophylactic) treatment of (pre)malignant neoplastic lesions. DISCUSSION: Sequence analysis of the underlying genes for these conditions and the detection of disease-causing genetic alterations in an index patient enable predictive testing for individuals at risk within an affected family. However, the clinical implications of predictive molecular testing depend on the overall penetrance and variability in the expression of pathogenic mutations. The extent of these parameters differs considerably among the various known hereditary colorectal cancer syndromes. Hence the integration of genetic information into the daily surgical practice remains challenging. CONCLUSIONS: This review provides an update on the indications for family assessment, purpose and limitations of the genetic testing and resulting recommendations for prophylactic surgery in FAP and HNPCC.

Adenomatous Polyposis Coli↗
PubMed1987

Mitomycin C-induced renal toxicity, a dose-dependent side effect?

Mitomycin C (MMC) has been known to be nephrotoxic since 1971. Whether this side effect was dose-dependent is unknown, while data on incidence are scanty. The presently-reported prospective study was initiated with the objective to obtain more data on these subjects. Forty-four patients treated with MMC entered the study, 37 were evaluable. All patients were subjected to extensive serial laboratory tests to study renal function and to detect hemolysis or coagulation disorders. The results were evaluated per cumulative dose level. One patient developed a lethal hemolytic uremic syndrome after 40 mg/m2 MMC. None of the laboratory tests predicted this side effect. None of the other patients developed renal toxicity, while all laboratory tests remained within normal ranges. All available literature on this subject was also reviewed. Based on the results of the present study, as well as on the literature review, it is concluded that MMC-related renal toxicity is a dose-dependent side effect, occurring at cumulative dose levels of 30 mg/m2 or more. The incidence is likely to be less than 10%. Predictive laboratory test could not be indicated.

Adult↗
PubMed1982

Pharmaco-EEG study of 6-azamianserin (ORG 3770): dissociation of EEG and pharmacologic predictors of antidepressant activity.

The effects of a single oral dose of 6-azamianserin (2 mg) were compared to those of mianserin (6 mg), flurazepam (10 mg), and placebo in 11 healthy male volunteers, in a crossover design. Quantitative EEG, heart rate, blood pressure, task performance, and subjective state were measured. EEG and behavioral measures distinguished the substances from placebo. 6-Azamianserin was similar to mianserin in type and duration of effects. In a separate study in 12 volunteers, 0.5 and 1.0 mg of the (+) and (-) enantiomers of 6-azamianserin elicited dose-related EEG and behavioral effects, distinguishable from placebo. These effects were similar to those elicited by racemic 6-azamianserin and mianserin. Clinical trials of 6-azamianserin in depressed patients, particularly the elderly and those with cardiovascular disease, are warranted. Dosages selected should be one-third those of mianserin. The stereospecific properties of the enantiomers in preclinical tests predict that any clinical 'antidepressant' activity will reside in the (+) isomer only, while the pharmaco-EEG trials predict that both enantiomers will be clinically 'antidepressant'. Clinical testing of the isomers, particularly the (-) isomer, is indicated as a test of the predictive value of pharmacologic and pharmaco-EEG models of clinical antidepressant activity.

Adult↗
PubMed1993

Attitudes of Dutch general practitioners towards presymptomatic DNA-testing for Huntington disease.

The attitudes of 1020 Dutch GP's towards presymptomatic and prenatal testing for Huntington disease (HD) were studied by means of a postal questionnaire. The questionnaire contained questions about: approval of presymptomatic DNA-testing, informing individuals at-risk who do not request predictive testing, referral to a clinical genetics center, and opinions about different strategies of informing and supporting individuals at-risk. The response rate was 62%. More than two-thirds of the GP's considered post-test counselling and support as their responsibility. Twenty-six per cent were of the opinion that the test results should be disclosed by the GP. Fifty-nine per cent of GP's who had an individual at-risk in their practice were familiar with the test. The attitudes of GP's towards giving support and giving test results were independent of familiarity with the test and the incidence of HD-patients or at-risk individuals in the practice. Although GP's were willing to play an important role in presymptomatic DNA-testing procedures, there is a risk that they might underestimate the difficulties in communicating genetic information and the psychosocial effects of DNA-testing. Hence, we favor the premise that extensive pretest counselling and test disclosure should remain the prime responsibility of the clinical geneticist. Increasing involvement of GP's should, however, be encouraged and combined with appropriate postgraduate education about predictive DNA-testing in general.

Adult↗