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Biomedical subjects

M W Spence

Publications and source records attributed to M W Spence.

At least 73 records · Page 4Linked to original sources
PubMed1982

Acid:coenzyme A ligase in brain: fatty acid specificity in cellular and subcellular fractions.

We measured long-chain fatty acid: coenzyme A (CoA) ligase (EC 6.2.1.3) activity with four fatty acids in brain homogenates, and cellular and subcellular fractions to determine whether there are differences in activity that could be correlated with differences in fatty acid composition and metabolism. In rat brain homogenates, ligase activity varied appreciably with the four acids, with 18:2 greater than 18:1 greater than 16:0 greater than 22:1 (nmol acyl-CoA formed/min/mg protein: 1.46, 1.20, 0.96, and 0.57, respectively). This order was similar under all incubation conditions tested, including variable pH and fatty acid concentrations. The relative specific activities (RSA, 16:0 = 1.0) with the four substrates were similar in rat brain homogenate, mitochondria, and microsomes, with the highest specific activities in the latter fraction. The RSA were also similar in ox brain homogenates, in rabbit brain microsomes prepared from gray and white matter, in neurons isolated from rat brain, and in cultured neuroblastoma cells. Rat liver homogenates had a significantly different pattern of RSA. These results indicate that the ligase(s) has a preference for certain fatty acids, but suggest that the major control of fatty acid composition and metabolism is a function of subsequent metabolic steps.

Animals↗
PubMed1982

Involvement of triacylglycerol in the metabolism of fatty acids by cultured neuroblastoma and glioma cells.

The metabolism (chain elongation, desaturation, and incorporation into complex lipids) of thirteen different radiolabeled fatty acids and acetate was examined in N1E-115 neuroblastoma and C-6 glioma cell lines in culture. During 6-hr incubations, all fatty acids were extensively (14-80%) esterified to complex lipids, mainly choline phosphoglycerides and triacylglycerol. With trienoic and tetraenoic substrates, inositol and ethanolamine phosphoglycerides also contained up to 30% of the labeled fatty acids; plasmalogen contained up to half of the label in the ethanolamine phosphoglyceride fraction of neuroblastoma cells. Chain elongation and delta 9, delta 6, and delta 5 desaturation occurred in both cell lines; delta 4 desaturation was not observed. Seemingly anomalous utilization of arachidic acid and some selectivity based on the geometric configuration of double bonds was observed. These studies indicate that these cell lines are capable of modulating cellular membrane composition by a combination of selective exclusion and removal of inappropriate acyl chains and of modification of other acyl chains by desaturation and chain elongation. The time courses and patterns of modification and incorporation of exogenous substrates into phospholipids and triacylglycerol suggest that exogenous unsaturated fatty acid may be incorporated into triacylglycerol and later released for further metabolism and incorporation into phospholipids. This supports a role for triacylglycerol in the synthesis of membrane complex lipids in cell lines derived from neural tissue.

Animals↗
PubMed1979

Neutral and acid sphingomyelinases: somatotopographical distribution in human brain and distribution in rat organs. A possible relationship with the dopamine system.

Acid and neutral sphingomyelinase activities have been measured in 22 regions of human brain, and in several rat organs. In general, acid sphingomyelinase activity was similar in most brain regions examined. By contrast neutral sphingomyelinase activity decreased 30-fold between the globus pallidus and white matter. In grey matter structures activity decreased in the order globus pallidus greater than substantia nigra greater than or equal to putamen greater than head of caudate greater than thalamus greater than cortical structures. Under the conditions of assay and in the presence of several possible donors or acceptors, there was no evidence of transfer of phosphoryl-choline to other lipid acceptors. Acid sphingomyelinase was ubiquitously distributed in all rat tissues examined, highest in liver and lowest in adipose tissue. Neutral sphingomyelinase activity was highest in brain; activity from 25 to 10% of that in brain was observed in testis, adrenal gland and aorta. Activity in the other organs examined was less than 10% of that in brain. We suggest that the neutral enzyme serves a special function in brain, perhaps related to the dopaminergic systems.

Adult↗
PubMed1978

Angiokeratoma corporis diffusum (Anderson-Fabry disease) in a single large family in Nova Scotia.

Eighteen males, 17 of whom were members of a single family, affected with angiokeratoma corporis diffusum were examined in detail to determine the extent of clinical variation of the expression of what was almost certainly the same X-linked mutation in each. The commonest symptom was episodic bouts of severe, painful dysaesthesia in hands and feet. This was a major complaint of 12, a minor complaint of 5, and absent in 1. In over half the subjects, the skin rash that is considered a characteristic sign of the disease was absent or inconspicuous. All exhibited mild clubbing of fingers and toes, and 15 showed variable limitation of active and passive extension of the 5th fingers bilaterally. Only 2 (age 36 and 47) had evidence of significant renal disease. Electrocardiograms showed abnormally short PR intervals in 4, and right ventricular conduction disturbances in 5. Echocardiograms on 9 showed no evidence of myocardial dysfunction. The marked variation of the expression of some features of the disease indicates that the clinical expression of the mutation is likely to be subject to considerable genetic or environmental modification in each individual.

Adolescent↗
PubMed1977

Niemann-Pick disease type D: lipid analyses and studies on sphingomyelinases.

Lipids and sphingomyelinase activity were studied in spleen, liver, and brain tissues of a 13-year-old boy with Niemann-Pick disease type D (NPD-D). The greatest lipid changes occurred in spleen; cholesterol, cholesterol esters, total phospholipids, sphingomyelin, and bis-(monoacylglyceryl)phosphate were increased above normal range. In liver, striking increases were observed in cholesterol and bis-(monoacylglyceryl)phosphate. Minor changes in neutral and acidic glycolipid patterns occurred in liver, spleen, and brain. Sphingomyelinase activity (optimal at pH 5.0) was elevated above mean control levels in liver and spleen, but not in brain, kidney, or leukocytes. Enzyme properties were generally normal. Activity of NPD-D liver crude homogenate, but not that of normal liver homogenates, was inhibited at high protein concentrations. Activity levels of a second sphingomyelinase, optimal at pH 7.4, in NPD-D brain were apparently normal. These findings are generally consistent with the classification of NPD-D as a sphingomyelin lipidosis.

Adolescent↗
PubMed1977

Heterozygote detection in angiokeratoma corporis diffusum (Anderson-Fabry disease). Studies on plasma, leucocytes, and hair follicles.

Heterozygote detection for angiokeratoma corporis diffusum (Anderson-Fabry disease, ACD), an X-linked disorder of glycosphingolipid metabolism was examined using alpha-galactosidase activity, an alpha-galactosidase/beta-galactosidase activity ratios (alpha/beta ratio) in leucocytes, plasma, and hair follicles; For leucocytes, 22 obligate heterozygotes, 25 suspected heterozygotes, and 47 control subjects were studied, while for plasma, the groups were 17 obligate heterozygotes and 35 controls. The alpha/beta ratio in plasma and leucocytes was clearly a better discriminator between obligate heterozygotes and controls than alpha-galactosidase activity alone, but still failed to detect 3 obligates with leucocytes and 2 with plasma. Discrimination was not improved by joint use of plasma and leucocyte alpha/beta ratios, but was improved by measurement of hair-follicle alpha/beta ratios. The interdecile range of log (alpha-galactosidase/beta-galactosidase activity) in 20 hair follicles from each of 4 obligate and 7 suspected heterozygotes was clearly different from 11 control subjects. Accordingly, for rapid screening for carriers of ACD, we recommend use of leucocyte or plasma alpha/beta ratios which should detect greater than 85% of heterozygotes. When results are equivocal, and ancillary information suggests heterozygous status, the more time-consuming measurement of hair-follicle alpha/beta ratios is a useful additional test.

Fabry Disease↗
PubMed1976

Inborn errors of metabolism in the Maritimes, with special reference to maple-syrup-urine disease and Fabry's disease.

1. The study of inborn errors of metabolism in man is of wide, general relevance to human biology and medicine, because these derangements are unique human models for the study of the sequence of normal metabolic events and their dependence upon genetic control. These disorders constitute naturally occurring mutations in man; as such, they afford the same opportunity for major contributions to human biology that bacterial mutants provide for molecular biology. 2. In terms of human suffering and cost, to affected kindred and the community at large, the importance of inborn errors of metabolism is out of all proportion to their small numerical incidence. Therefore, efforts must be intensified to identify affected individuals and carriers and to formulate methods of prevention and treatment. 3. The overall study of inborn errors of metabolism is illustrated by experience with two such disorders in the Maritime provinces.

Amino Acids↗
PubMed1976

Failure to correct the metabolic defect by renal allotransplantion in Fabry's disease.

Plasma neutral glycolipid levels and plasma and leukocyte alpha-galactosidase activities were measured serially before and after renal allotransplantation in two men, aged 47 and 45 years, with renal failure due to Fabry's disease. The patients were followed posttransplantation for 92 and 64 weeks, respectively. No significant elevation of plasma or leukocyte alpha-galactosidase activities above levels in untreated men with Fabry's disease or decrease in the levels of trihexosyl ceramide was observed in either patient. The results do not support the use of renal allotransplantation for enzyme replacement in Fabry's disease.

Fabry Disease↗
PubMed1976

Sphingomyelinase activity at pH 7.4 in human brain and a comparison to activity at pH 5.0.

A hitherto undescribed sphingomyelinase (sph'ase 7.4) of human brain has been studied in crude and partially purified (3- to 4- fold) extracts of grey matter, and compared to the known sphingomyelinase with an acid pH optimum (sph'ase 5.0). Its specificity for sphingomyelin as substrate is similar to that of sph'ase 5.0, but it differs from sph'ase 5.0 in its pH optimum (7.4 vs 5.0) and in a requirement for Mg2+ for optimal activity. Other properties of sph'ase 7.4 that distinguish it from sph'ase 5.0 include (a) its lack of appreciable solubilization during dialysis of crude homogenates (b) a more marked concentrations in grey matter than in white matter (9- to 13- fold vs 1.5- to 2-fold for sph'ase 5.0); (c) inhibition by Ca2+ and Cd2+ ions, and by EDTA; (D) stimulation by dithiothreitol, and inhibition by cysteine, N-ethylmaleimide, and p-hydroxymercuribenzoate; (e) lack of inhibition by nucleotides (AMP.ADP, and ATP) and by NAD plus NADH; and (f) relative instability to storage or manipulation between -20degrees C and 40degrees C. These differences indicate the SPH'ASE 7.4 is a different enzyme protein from sph'ase 5.0. Unlike sph'ase 5.0, which is widely distributed in mammalian tissues, sph'ase 7.4 occurs predominantly in grey matter and little activity was observed is spleen, liver, or leukocytes. The high levels of this enzyme in brain suggest a role related to the specific functions of this organ or to the need for a more stringent control of sphingomyelin catabolism in brain as compared to other organs.

Brain↗