Genetic linkage in hereditary ataxia.
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Biomedical subjects
Publications and source records attributed to H W Goedde.
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The distribution of properdin factor B (Bf) phenotypes and gene frequencies was studied in four populations of Afghanistan: Hazaras, Pushtoons, Tajiks and Usbeks. Significant differences between Usbeks and the other three ethnic groups were observed. The distribution of gene frequencies in Usbeks was similar to that of European populations.
Monoamine oxidase activity was measured in blood platelets of 7 pairs of identical (MZ) twins and a similar number of age- and sex-matched control pairs. Mean intrapair difference in platelet MAO activity was significantly smaller (0.01 less than p less than 0.025) in MZ compared to controls. Kinetic studies of the enzyme revealed mean Km value of 1.0 x 10(-5) mol/l for tryptamine. Platelet MAO activity is higher in women than in men.
Human liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play an important role in alcohol metabolism. It has been shown that both enzymes are polymorphic and that different variants may be responsible for individual and racial differences in biological sensitivity to ethanol. However, for lack of a suitable peripheral enzyme source, no information is available regarding family data and the mode of inheritance of ADH and ALDH. Using sensitive micro-methods, we report here the detection of these enzymes and their variant forms in human hair root cells. The isozyme pattern of both enzymes obtained by isoelectric focusing from human liver, cultured fibroblast and hair root cell extracts are presented. Several German, Japanese and Vietnamese families were investigated. ALDH was found polymorphic only in Mongoloid populations. Phenotype distribution in a random Japanese population and families suggest a direct relationship between the absence of ALDH I isozyme and alcohol-induced biological sensitivity commonly observed in individuals of Mongoloid origin.
Tryptophan hydroxylase activity was measured in mesencephalon and pons medulla of rabbits receiving reserpine or other neuroleptics which are chemically related to phenothiazines (chlorpromazine), dibenzothiazepine (imipramine), dibenzobicyclooctadiene (maprotiline), dibenzothiepines (methiothepin), butyrophenones (haloperidol) and tetrahydro-isoquinolines (nomifensine). Chronic i.m. administration of imipramine and nomifensine increased the affinity of mesencephalic tryptophan hydroxylase for tryptophan. The injection of chlorpromazone increased the enzyme activity significantly in comparison to control values.
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Forty autopsy livers from Japanese individuals were studied concerning alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isozymes using electrophoretic and enzyme assay methods. A remarkably high frequency (85%) was found for the atypical ADH phenotype. The gene frequencies of ADH22 and ADH32 were .625 and .05, respectively. The usual ALDH phenotype showed two major isozyme bands, a faster migrating (low Km for acetaldehyde) and a slower migrating isozyme (high Km for acetaldehyde). Fifty-two percent of the specimens had an unusual phenotype of ALDH, which showed only the slower migrating isozyme. The usual phenotype was inhibited about 20%--30% by disulfiram and the unusual type up to 90%. Such a high incidence in the Japanese of the unusual phenotype, which lacks in the low Km isozyme, suggests that the initial intoxicating symptoms after alcohol drinking in these subjects might be due to delayed oxidation of acetaldehyde rather than its higher-than-normal production by typical or atypical ADH.
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Some examples of ecogenetics--including pharmacogenetics--demonstrate the tremendous variability in genetic constitution within a population as well as between different populations. They are the reason for different atypical responses to xenobiotics, synthetics like drugs, pesticides, insecticides, herbicides, industrial irritation, smog, cigarettes, alcohol, as well as naturally occurring substances like aflatoxines. It is unknown to what extent individuals differ in their susceptibilities and which genetic consequences of exposure of the human population to toxic environmental agents will occur. It is referred to genetic traits causing a predisposition for atypical reactions against chemicals of different structure as well as to the mutagenic and inductive action of such compounds. In this connection, population genetic aspects will be considered. All examples have to be seen in the context of ecogenetics, the genetically determined individual differences in adverse responses to environmental pollutants, and they are of special interest for preventive and industrial medicine.
Population genetic studies in Saudi Arabia are performed for EsD, GPT, AcP, ADA, AK, 6-PGD, PGM, C3, Tf, Hp, Gc, Pi, Bf, Hb, ABO-blood groups and Rh-factor, level of the third component of complement and immunoglobulins. The data are compared with reported frequencies in European and African populations.
Plasma tryptophan level varied diurnally with highest concentrations at 12 noon (P less than 0.001); at that time free tryptophan level was lowest. The mean 8 h and 16 h cortisol levels were 70% higher compared to levels obtained at 24 h. Chronic administration of haloperidol and chlorpromazine led to significant increase in the plasma tryptophan (P less than 0.001 and P less than 0.1, respectively) compared to saline-treated rabbits. This change was associated with corresponding constant or reduced free tryptophan levels, and a diminution in plasma cortisol level (10 microgram/l) compared with controls (34 microgram/l). The results suggest that tryptophan in plasma is poorly transported in the brains of rabbits treated with chlorpromazine, and that treatment with haloperidol or chlorpromazine may lead to a reduced tryptophan flux into the kynurenine pathway.
Rapid and sensitive micromethods for the study of alcohol dehydrogenase and adehyde dehydrogenase isozymes in skin extracts, cultured fibroblasts and other organs are presented. Possibilities for the application of these techniques to the study of interindividual variations in response to alcohol are discussed. While fibroblasts cultured from a skin biopsy from one Japanese individual revealed a heterodimer (ADH2 2-1) of alcohol dehydrogenase, skin extract from another Japanese showed a homodimer (ADH2 2-2). Up to four isozyme sets for aldehyde dehydrogenase (ALDH) were detected in various human organs and at least three sets were found in skin and fibroblasts extracts. Our preliminary data on liver, stomach, and skin indicate that ALDH is polymorphic and several loci are concerned in the determination of these isozyme sets.