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J A Lowden

Publications and source records attributed to J A Lowden.

At least 55 records · Page 3Linked to original sources
PubMed1981

Heterozygote advantage in Tay-Sachs carriers?

Chi-square analyses of new data as well as data previously reported by Myrianthopoulos have shown that grandparents of Tay-Sachs carriers die from proportionally the same causes as grandparents of noncarriers. It is unlikely that there is any advantage to being a Tay-Sachs carrier insofar as resistance to tuberculosis is concerned. Our results are further evidence to support Fraikor's claim that the high carrier frequency of the allele in Ashkenazi Jews is probably caused by a combination of founder effect, genetic drift, and differential immigration patterns.

Alleles↗
PubMed1980

Kinetics of rat liver GM2 ganglioside-beta-D-N-acetylhexosaminidase.

The kinetics of beta-D-N-acetylhexosaminidase against GM2 ganglioside were examined. We used a crude preparation of rat liver as the enzyme source because purification of beta-D-N-acetylhexosaminidase results in a decrease in specific activity against GM2 ganglioside. Kinetic plots were not linear but showed a break. At substrate concentrations less than 50 microM the Vmax was 6 pmol GM2 hydrolyzed per hour per micromole 4-MU-GlcNAc hydrolyzed per hour (pmol GM2/mumol 4-MU-GlcNAc) and the Km was 5 microM. At substrate concentrations greater than 50 microM, the Vmax was 7 pmol GM2/mumol 4-MU-GlcNAc and the Km was 14 microM. The critical micelle concentration of GM2 ganglioside was 20-25 microM as determined by spectral shifts of the dye pinacyanol chloride in association with GM2, and 10-15 microM from electrical conductivity measurements which also showed the end of the monomer-micelle transition to occur at 40-50 microM GM2. The increasing excess of micellar substrate at greater than 50 microM GM2 explains the discontinuity in the kinetic plots. Sodium taurocholate had a critical micelle concentration of 9-11 mM using pinacyanol chloride and 2.5-3 mM using electrical conductivity. When included in the assay mixture at a concentration of 10 mM, sodium taurocholate produced a linear kinetic plot. This is probably due to the formation of mixed micelles of detergent and GM2 ganglioside. The Vmax was 200 pmol GM2/MUmol 4-MU-GlcNAc and the Km was 93 microM. The data suggest that ganglioside hydrolysis occurs more readily when the substrate is incorporated into a membrane-like environment.

Animals↗
PubMed1979

Serum beta-hexosaminidases in pregnancy.

Serum contains several hexosaminidase forms. Two, HEX A and HEX B, migrate in both DEAE cellulose and isoelectric focussing systems like their tissue counterparts. A major group of serum hexosaminidases migrate in an intermediate position. These forms, collectively named HEX 1, increase during pregnancy and obscure carrier detection for Tay-Sachs and Sandhoff's disease. Using DEAE-cellulose chromatography, HEX A, I, and B, can be clearly separated. In normals, activity ratios of A/B are 4.03 +/- 1.33. During pregnancy the ratio falls slightly to 3.01 +/- 1.08. In Tay-Sachs heterozygotes the ratio is only 1.08 +/- 0.35 and falls during early pregnancy to 0.53 +/- 0.23. In Sandhoff heterozygotes the DEAE chromatograms appear normal with higher than normal A/B ratios but in sera, from both pregnant and nonpregnant carriers, the HEX B and HEX I forms are 50% heat labile. During pregnancy, serum can be used as a reliable source of HEX for heterozygote identification for both Sandhoff's and Tay-Sachs disease.

Chromatography, DEAE-Cellulose↗
PubMed1979

Niemann-Pick disease in a poodle dog.

A 5-month-old minature Poodle dog had widespread cytoplasmic vacuolation of neurons in the central nervous system and foamy macrophages in the lung, spleen, renal lymph node, liver, adrenal gland and intestine. Concentric membranous cytoplasmic inclusions were seen in the neurons of the central nervous system by electron microscopy. There was no sphingomyelinase in the brain tissue. Sphingomyelin and cholesterol were increased in brain, kidney and liver. A diagnosis of Niemann-Pick Disease was based on absence of sphingomyelinase activity, as well as on histologic, histochemical and chemical findings.

Animals↗
PubMed1979

Infantile sialidosis: a phenocopy of type 1 GM1 gangliosidosis distinguished by genetic complementation and urinary oligosaccharides.

A clinical description of an apparently classical case of type 1 GM1 gangliosidosis is presented. The patient was the first-born child of first cousins. She was diagnosed at 6 weeks and died at 6 months. beta-Galactosidase activity was deficient in cultured fibroblasts using [3H]GM1 ganglioside and [3H]ceramide-lactose as substrates. Genetic complementation studies performed after cell fusion between cultured fibroblasts from the patient and from two other type 1, one type 2, and one juvenile GM1 gangliosidosis strain were positive with all strains. Subsequent studies revealed an increased excretion of a sialic acid-containing hexasaccharide in the patient's cells. Parents' fibroblasts contained normal levels of beta-galactosidase. The case emphasizes the variability of the clinical expression in sialidosis and the importance of demonstrating a primary gene defect in establishing a diagnosis of an inborn error or metabolism.

Consanguinity↗
PubMed1979

Evidence for a hybrid hexosaminidase isoenzyme in heterozygotes for Sandhoff disease.

Patients with Sandhoff disease have less than 5% of normal levels of serum or tissue hexosaminidase activity. They are thought to have a defect in the structural gene for the beta chain of hexosaminidase (HEX). Heterozygotes for Sandhoff disease have approximately 50% of the total serum HEX activity of normals and more than 75% of the HEX is heat-labile. In normals, only 55%--65% of serum HEX is heat-labile. Serum HEX separates into three forms on DEAE cellulose chromatography: HEX A, a tetramer of 2 alpha and 2 beta chains, and HEX I and B composed solely of beta chains. The DEAE chromatograms from normals and Sandhoff heterozygotes did not differ in the relative distribution of HEX activity between peaks. In normals, the HEX A peak was heat-labile (60 degrees C for 9 min), but HEX I and B were heat-stable. In Sandhoff heterozygotes, however, HEX I and B were only 50%--53% heat-stable. This suggests the heterozygotes synthesized a hybrid enzyme containing both mutant and wild-type beta chains for HEX. The mutant beta chain renders the isoenzyme less stable to heating.

Female↗
PubMed1979

Preparation of radiolabeled GM2 and GA2 gangliosides.

GM2 and GA2 gangliosides from the brain of a patient who died of Sandhoff's disease were purified by solvent partition, silicic acid and silica gel column chromatography, and silica gel preparative thin-layer chromatography. They were tritiated in the terminal N-acetylgalactosamine residue using galactose oxidase and sodium [3H]borohydride with the inclusion of catalase and peroxidase into the oxidation reaction. The specific activities were 4.62 X 10(8) dpm/mumol of GM2 ganglioside and 5.54 X 40(7) dpm/mumol of GA2 ganglioside. The addition of catalase and peroxidase to the tritiation procedure is recommended.

Brain Chemistry↗
PubMed1978

Concanavalin A promotes the uptake of lysosomal hydrolases by human fibroblasts.

Human placental hexosaminidase B and beta-galactosidase are taken up very poorly by human fibroblasts in culture. However, if fibroblasts manifesting genetically determined deficiencies of these lysosomal hydrolases are first treated with concanavalin A, then enzyme uptake is markedly increased. Enzyme activity which becomes associated with concanavalin A-treated fibroblasts maintained at 4 degrees C can be greatly removed by treatment with haptene sugar, while enzyme activity which becomes associated with cells maintained at 37 degrees C is refractory to haptens treatment. These results are interpreted as an initial binding of enzyme to concanvalin A molecules located at the cell surface, followed by an active cellular process leading to internalization of the lectin-enzyme complexes.

Biological Transport, Active↗
PubMed1978

Role of the physician in screening for carriers of Tay-Sachs disease.

A screening test for carriers of Tay-Sachs disease has been available in Toronto for more than 6 years. In that time more than 11 000 Jewish residents have been tested. Most had requested testing after hearing about the screening program from friends or the media; few had been advised by their physicians to be tested. To sample the attitudes of physicians in Toronto towards carrier screening, we studied questionnaire responses of 42 physicians whose practices were composed largely of Jewish patients. Only 31% regularly advised their young adult Jewish patients to have a carrier screening test but 76% said they had patients who asked if they should be tested. Of the 14 (33%) who had had one or more patients with Tay-Sachs disease 6 did not advise carrier testing. There was a positive correlation between specialty training and support for the screening program. Methods for increasing physician advocacy of these programs are discussed.

Abortion, Induced↗
PubMed1978

Immunoglobulin (Gm) allotypes in a sample of Canadian Ashkenazic Jews.

Gm typing on the serum specimens of 507 Ashkenazic Jews (pre-dominantly of Polish-Russian ancestry) from Toronto, Canada has established the presence of haplotypes Gm3;5, Gm1;21, Gm1,2;21, and Gm1,17;5, and the absence of haplotypes Gm1;13,15,16, Gm1;5,6, and Gm1;5,6,24 which have been found in other Jewish peoples. It is suggested that Ashkenazic populations have lower frequencies of haplotype Gm1,17;5 than non-European Jewish populations, and that some eastern European Jewish populations have acquired the Gm1;13,15,16 haplotype through gene flow from Central Asia. Thus Jewish populations show differences in the Gm system; many of the differences may be in the direction of similarities to neighbouring non-Jewish populations.

Canada↗
PubMed1978

Psychosocial aspects of a Tay-Sachs screening clinic.

The authors administered questionnaires to participants in a Tay-Sachs screening clinic. They received 322 responses. Although the majority of the respondents expressed anxiety about the possibility that they might be carriers, most indicated that this anxiety brought them to the clinic. The authors conclude that a well-publicized and well-organized screening clinic can function successfully and deal with the issue of anticipated loss without producing mass fear. An important factor in their clinic was the fact that they were able to offer an alternative to a Tay-Sachs child through amniocentesis.

Adult↗
PubMed1978

Carrier detection in Sandhoff disease.

Three new cases of Sandhoff disease are reported. One infant was the second affected child in a large family. The parents, who were cousins, were part of a large kindred from an isolated community in northern Saskatchewan. We assayed total and heat-stable hexosaminidases in 38 other members of the kindred and found two distinct cohorts. Sixteen individuals had low total and low heat-stable hexosaminidase and were diagnosed as carriers of Sandhoff disease. The values for the remainder were within normal limits. In a retrospective study of data from more than 14,000 Ashkenazi Jews, who were screened for Tay-Sachs disease, six were identified as Sandhoff carriers. Our data indicate that carrier detection requires measurement of both total and heat-stable enzyme activity.

Consanguinity↗
PubMed1977

Brain isoenzyme of creatine kinase. I. Purification of rabbit enzyme and production of specific antibodies.

Creatine kinase (EC 2.7.3.2) of rabbit brain (BB) was purified to hemogeneity as judged by sedimentation velocity analysis in the ultracentrifuge. Nevertheless, the purified enzyme contained as many as seven extraneous protein species when examined by disc electrophoresis in polyacrylamide gel. The purified preparation also showed antigenic heterogeneity when it reacted in agar gel double immunodiffusion analysis with antibodies produced against it in the rooster. At least some of the extraneous proteins appeared to arise from BB during storage. Subsequently BB was purified to hemogeneity by disc electrophoresis in polyacrylamide gel. It was excised from the gel and injected repeatedly with Freund's complete adjuvant into roosters. A single immunoprecipitin line was noted in agar gel double immunodiffusion analysis when partially pure enzyme reacted with the antibodies raised to the electrophoretically pure protein. These antibodies inhibited the enzymatic activity of BB in both soluble and insoluble immune complexes. They did not, however, form immunoprecipitates with or inhibit rabbit muscle (MM) or rabbit hybrid (MB) creatine kinases. The antibodies were therefore specific for BB and did not react with MM or MB.

Animals↗
PubMed1977

Brain isoenzyme of creatine kinase. II. Species specificity of enzyme and presence of inactive form in striated muscle of rabbit and man.

Antibodies specific for the brain isoenzymes (BB) of creatine kinase were prepared by the injection of the highly purified rabbit enzyme into roosters. The antibodies were found to cross-react only partially with BB of rat, guinea pig, sheep, monkey, and man, demonstrating that these proteins are not entirely identical with respect to their antigenic sites. A greater degree of species specificity seems to exist for BB than for the muscle isoenzyme (MM) suggesting that BB may have undergone considerable evolutionary modification. Developmentally mature rabbit cardiac and skeletal muscles contained large quantites of an enzymatically inactive BB which can be detected immunochemically. It is antigenically identical with active rabbit BB but the two proteins can be separated by DEAE-cellulose chromatography. Enzymatically inactive BB is also present in human skeletal muscle. The presence of MM in muscle provides sufficient catalytic function and may have permitted the evolution of inactive BB in an additional (noncatalytic) metabolic role.

Animals↗