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PubMed1996

The relationship between (CAG)n repeat number and age of onset in a family with dentatorubral-pallidoluysian atrophy (DRPLA): diagnostic implications of confirmatory and predictive testing.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder characterised by variability in both age of onset and clinical features. Despite the recent identification of the CAG expansion mutation in DRPLA, the number of molecularly confirmed cases remains small. Given its rarity and prominent phenotypic heterogeneity, some care needs to be exercised in the interpretation and dissemination of test results derived from direct gene testing for the DRPLA specific expansion mutation.

Adult↗
PubMed1999

Does the toe-touch test predict hamstring injury in Australian Rules footballers?

This prospective cohort study evaluated the relationship of hamstring and lumbar spine flexibility to hamstring injury. Sixty-seven senior male Australian Rules footballers were videotaped while performing a toe-touch test from erect standing. The Peak Motion Measurement System was used to obtain measurements of end range hip flexion, lumbar flexion, toe-touch distance (TTD) and the ratio of lumbar spine flexion to hip flexion. Over the following football season, eight subjects (11.9 per cent) sustained a hamstring strain. Results showed no significant difference between the hamstring injured or uninjured players for any of the measured variables with no variable able to predict the likelihood of injury (p > 0.05). In this cohort, the toe-touch test would not appear to be a useful screening tool to identify footballers at risk for hamstring strain.

Journal Article↗
PubMed1998

Antibody responses of rats after immunization with organic acid anhydrides as a model of predictive testing.

OBJECTIVES: The sensitizing properties of organic acid anhydrides (OAA) were evaluated in a rat model. METHODS: The development of specific immunoglobulin (Ig)E and Ig G in serum was investigated after immunization with 14 OAA and 3 OAA conjugates. Brown Norway rats were injected intradermally with 0.1 ml of 0.2 M OAA in liquid paraffin or 1.4 mg of rat serum albumin conjugate in saline. Serum samples were collected after 4 weeks. Antibodies were analyzed with enzyme-linked immunosorbent assay. RESULTS: The serum titers of specific Ig E after immunization with the different free OAA varied from <50 to 6400. The rats immunized with 4-methylphthalic anhydride exhibited the highest titers. The specificity of Ig E was demonstrated by enzyme-linked immunosorbent assay inhibition tests. A good correlation was observed between the Ig E and Ig G titers. Immunization with OAA conjugates showed results parallel to the findings for the free compounds. Importantly, the Ig E titers for the OAA agreed well with findings from guinea pigs and with literature data from epidemiologic studies of exposed workers. CONCLUSIONS: The present animal model may be a valuable tool for predicting the sensitizing potential of OAA and possibly the sensitizing potential of low-molecular-weight compounds in general. Furthermore, the antibody specificity of the haptens and the variations in the magnitude of the antibody titers indicate a valuable approach for studies of quantitative structure-activity relationships.

Anhydrides↗
PubMed2005

Development of the "Cell Chip": a new in vitro alternative technique for immunotoxicity testing.

Predictive testing of immunotoxicity associated with chemical compounds is complicated and cannot be accomplished with a single test. As most of the existing tests for immunotoxicity employ experimental animals, there is an increasing need for alternative tests in vitro. We have developed a new system for in vitro immunotoxicity testing, which employs changes in cytokine expression observed in vitro as an endpoint indicating potential for perturbation of the immune system in vivo. This system named "fluorescent cell chip" (FCC) is based on a number of genetically modified cell lines that regulate the expression of a transgene coding for fluorescent protein enhanced green fluorescent protein (EGFP) in a similar way as they regulate expression of IL-1beta, IL-2, IL-4, IFN-gamma, IL-10, TNF-alpha, and beta-actin. Morphological and functional features of selected cell lines expressing EGFP under the control of cytokine promotors were compared with maternal cell lines and this comparison showed that critical functional features of the maternal cell lines were preserved in EGFP expressing cells. Two chemicals with known immunotoxic activities, cyclosporine A and potassium tetrachloro-platinate(II), mediated compound-specific pattern of inhibition and activation of reporter gene expression. Thus, the "fluorescent cell chip" has demonstrated potential for application as a predictive screening test for immunomodulatory activities of chemicals. The major advantage of this approach is the possibility to apply this test in high throughput screening of high number of compounds for their well defined biological activity.

Animals↗
PubMed1992

Migration sedimentation technique as a predictive test for the fertilizing capacity of spermatozoa in an in-vitro fertilization programme.

The migration-sedimentation technique (MST) has been proposed as a means of separating high quality motile spermatozoa. The present study was conducted in order to evaluate whether sperm performance following separation by MST predicts their fertilizing capacity in an in-vitro fertilization (IVF) programme. Ninety semen specimens were analysed for use in an IVF-embryo transfer (ET) programme. Each specimens was divided into two parts: one was processed in the IVF programme and was used after sperm swim-up separation for insemination of human ova. The other aliquot (0.2 ml) was separated by MST, and the sperm then characterized by their concentration, motility, degree of motility and morphology. Sperm characteristics after separation by MST were then correlated with the results of the IVF-fertilization rates. In 79 of 90 IVF-ET cycles, at least one oocyte was fertilized. All post-MST sperm characteristics were significantly higher in cycles with fertilizations compared to IVF cycles without fertilization. A larger percentage of the total motile spermatozoa were recovered after MST in semen specimens with fertilization, compared to semen specimens without fertilization (39.9 +/- 3.6 and 20.6 +/- 6.6%, respectively; P < 0.05). This value was correlated with the percentage of fertilized oocytes (r = 0.24; P < 0.02). More IVF cycles with fertilizations were recorded in cases in which the recovery of motile sperm was > 25% (P < 0.005), or when more than 1.5 x 10(6) motile spermatozoa were recovered after MST (P < 0.0001). As sperm characteristics after MST correlated significantly with their fertilizing capacity, the MST test could be used in evaluation of the fertilizing capacity of spermatozoa.

Cell Separation↗
PubMed2004

Adverse effects of predictive testing for Huntington disease underestimated: long-term effects 7-10 years after the test.

The 7-10-year psychological effects of presymptomatic testing for Huntington disease are described in 142 individuals and 104 partners. Questionnaires included the Beck Hopelessness Scale (A. T. Beck, A. Weissman, D. Lester, & L. Trexler, 1974), the Impact of Event Scale (M. J. Horowitz, N. Wilner. & W. Alvarez. 1979). and the General Health Questionnaire (D. P. Goldberg. 1972). Carriers and their partners were more distressed immediately after the test result, although their outlooks improved somewhat in the 2-3-year posttest period. However, they became more pessimistic thereafter, when approaching the age of onset. Carriers, who were lost to follow-up after disclosure of test results, reported more distress pretest than did retained carriers. This demonstrates that studies that report few harmful effects may have underestimated the real impact. Moreover, follow-up studies need to investigate time effects for longer than a few years.

Adult↗
PubMed1994

Evaluation of the rat embryo culture system as a predictive test for human teratogens.

Ingestion of the anticonvulsant drug valproic acid and of the angiotensin converting enzyme inhibitor captopril during pregnancy has been associated with abnormal fetal outcome in humans. In contrast, the use of the antiinflammatory drug ibuprofen and the antihistamine diphenhydramine has not been documented to be embryotoxic in humans. We evaluated the rat embryo culture system as a predictive model of teratogenesis, using these four drugs as test agents. Valproic acid, ibuprofen, and diphenhydramine were embryotoxic, inducing concentration-dependent decreases in growth and a significant increase in anomalies. Valproic acid caused an increase in neural tube defects, ibuprofen increased the incidence of abnormal maxillary processes, and diphenhydramine increased the number of embryos with distorted body morphology. These abnormalities were induced at concentrations of valproic acid and diphenhydramine that are used clinically, but ibuprofen only induced toxicity at concentrations greatly exceeding the therapeutic range. Captopril was not embryotoxic up to 5 mM, the highest concentration tested. These results suggest that the rat embryo culture system produces both false positive and false negative data on the teratogenic potential of drugs. Although such an in vitro assay may be suitable to determine the mechanism of teratogenesis, it is not a sensitive indicator of potential human teratogens on its own. These data support the view that in vitro systems can only supplement clinical and epidemiological observations in humans, possibly as a method to determine mechanisms of actions of teratogens.

Abnormalities, Drug-Induced↗
PubMed1984

Clinical investigations into antidepressive mechanisms. II. Dexamethasone suppression test predicts response to nomifensine or amitriptyline.

This prospective study investigates the possibility of a central noradrenergic-cholinergic imbalance in subgroups of depressed inpatients using the dexamethasone suppression test (DST) as one peripheral indicator. The DST was performed in 43 depressed inpatients. Subsequently, a group (n = 20) of DST suppressors (DST-) and a group (n = 23) of DST nonsuppressors (DST+) were treated under double blind conditions with either nomifensine (NOM) a noradrenaline potentiating drug, or amitriptyline (AMI) a noradrenaline potentiating and strong anticholinergic compound. DST+ depressives responded favorably to AMI, but not to NOM. Conversely, DST- depressives responded favorably to NOM but less well to AMI. Together with other biochemical findings this data suggests: 1) a hypofunction of the noradrenergic system in DST- patients who may, from a clinical point of view, usually show minor or 'neurotic' depressions; 2) a hypofunction of the noradrenergic and a hyperfunction of the cholinergic system in DST+ patients who may present a more severe or 'endogenous' depression. These data suggest a biochemical heterogeneity of depression and offer an aid for a more specific antidepressive drug therapy.

Adult↗
PubMed1992

Predictive testing for multiple endocrine neoplasia type 1 using DNA polymorphisms.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited predisposition to neoplastic lesions of the parathyroids, pancreas, and the pituitary. We have previously located the predisposing genetic defect to the long arm of chromosome 11 by genetic linkage. In this study, 124 members of six MEN1 families, including 59 affected individuals, were genotyped for restriction fragment length polymorphisms with different DNA probes, and the genetic linkage between these marker systems and MEN1 was determined. 13 marker systems (17 DNA probes) were found to be linked to MEN1. These markers are located within a region on chromosome 11 spanning 14% meiotic recombinations, with the MEN1 locus in the middle. Four of the marker systems are on the centromeric side of MEN1, and four on the telomeric side, based on meiotic crossovers. The remaining five DNA probes are closely linked to MEN1, with no crossovers in our set of families. The 13 marker systems can be used for an accurate and reliable premorbid test for MEN1. In most clinical situations it is possible to identify a haplotype of this part of chromosome 11 with the mutant MEN1 allele in the middle. The calculated predictive accuracy is greater than 99.5% if three such marker systems are informative. Therefore, genetic linkage testing can be used for informed genetic counseling in MEN1 families, and to avoid unnecessary biochemical screening programs.

Chromosome Mapping↗
PubMed1998

Appraisal and implications of predictive testing for insulin-dependent diabetes mellitus.

The risk of developing insulin-dependent diabetes mellitus (IDDM) is 50 times greater in first-degree relatives than in the general population. Although parents of a diabetic child are generally aware of the risk of disease recurrence in the family, the practice of screening for IDDM is often questioned by physicians themselves because of the likelihood that parents will experience anxiety. This paper reports the results of a questionnaire distributed to parents attending a pediatric clinic for their diabetic child who were asked to evaluate their attitudes about screening tests. One hundred and thirty-one families recruited over a 2-month period replied to the questionnaire without the assistance of medical staff. The mean age of diabetic children was 10 +/- 4.05 years, and the duration of IDDM 3 +/- 3.6 years. The results show that parents were stressed by the possible development of a second case of IDDM among their children. Eighty percent of them practised home strip--analysis on a regular basis for all their children. The parents wanted biological tests to be performed on their children before the occurrence of any clinical symptoms. They expected the screening tests "to reveal the truth about the health status of their children" (92%) and to "help prepare for an uncertain future" (60%). They indicated that recognition of an increased risk would not change their attitude toward their child. Recurrence of the disease was regarded as a problem with which the parents could cope realistically. Our data indicate that parents should continue to be informed about familial risk and the possibility of screening, despite the lack of preventive treatment.

Child↗
PubMed2000

Predictive testing for pathogenic autoimmunity: the morphological approach.

The term autoimmunity refers to physiologically normal immune processes against self-antigens. In rare cases, the regulatory mechanisms become deflective and the uncontrolled production of autoantibodies or activation of autoreactive T-cells can subsequently cause disease. Substances may be capable of evoking autoimmune disease, and it is a challenge in routine toxicology to recognize such substances. In in vivo toxicity studies, uncommon inflammation in exposed animals should be discussed in terms of non-immune toxicity (e.g. irritation), infection, allergy and autoimmunity, taking into account that a response in even a few animals may be significant. Moreover, early morphological indicators of inflammation and lymphoid organ alterations can direct further investigation.

Animals↗
PubMed2001

Food allergy--towards predictive testing for novel foods.

The risks associated with IgE-mediated food allergy highlight the need for methods to screen for potential food allergens. Clinical and immunological tests are available for the diagnosis of food allergy to known food allergens, but this does not extend to the evaluation, or prediction of allergenicity in novel foods. This category, includes foods produced using novel processes genetically modified (GM) foods, and foods that might be used as alternatives to traditional foods. Through the collation and analysis of the protein sequences of known allergens and their epitopes, it is possible to identify related groups which correlate with observed clinical cross-reactivities. 3-D modelling extends the use of sequence data and can be used to display eptiopes on the surface of a molecule. Experimental models support sequence analysis and 3-D modelling. Observed cross-reactivities can be examined by Western blots prepared from native 2-D gels of a whole food preparation (e.g. hazelnut, peanut), and common proteins identified. IgEs to novel proteins can be raised in Brown Norway rat (a high IgE responder strain) and the proteins tested in simulated digest to determine epitope stability. Using the CSL serum bank, epitope binding can be examined through the ability of an allergen to cross-link the high affinity IgE receptor and thereby release mediators using in vitro cell-based models. This range of methods, in combination with data mining, provides a variety of screening options for testing the potential of a novel food to be allergenic, which does not involve prior exposure to the consumer.

Allergens↗
PubMed2005

Compared tolerance to osmotic stress in various microorganisms: towards a survival prediction test.

The osmotic tolerance of microbial cells of different microorganisms was investigated as a function of glycerol concentration and temperatures. Cells displayed specific sensitivity to dehydration in glycerol solutions. The viability of Gram-negative strains (Escherichia coli, Bradyrhizobium japonicum), Gram-positive strains (Lactobacillus plantarum, L. bulgaricus), and yeasts (Saccharomyces cerevisiae, Candida utilis) decreased with increasing osmotic pressure. For each strain, a characteristic osmotic pressure threshold causing a loss of 40% of the population at the growth temperature was determined: 26-40 MPa for E. coli, 15-25 MPa for B. japonicum, 7-15 MPa for L. bulgaricus, 40-133 MPa for L. plantarum, 50-100 MPa for S. cerevisiae, and 15-26 MPa for C. utilis. Because this threshold varies with temperature, it was possible to construct a diagram that could be helpful to the determination of the sensitivity of each strain to osmotic stress as a function of osmotic pressure and temperature.

Gram-Negative Bacteria↗