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Biomedical subjects

J M Scott

Publications and source records attributed to J M Scott.

At least 91 records · Page 5Linked to original sources
PubMed1995

Effect of N2O treatment/vitamin B12 deficiency in pigs on tissue concentrations of odd-numbered, branched-chain fatty acids.

Activity of the vitamin B12-dependent enzyme, methylmalonyl CoA mutase, was measured in the tissues of pigs, fed a diet which was low in cobalt and vitamin B12, and which were intermittently exposed to nitrous oxide until they displayed marked ataxia. Methylmalonyl CoA mutase activity was reduced in liver, kidney and brain. However, the methylmalonic acid concentration was reduced in liver and heart, in marked contrast to the expected increase which was only observed in brain. Liver and kidney also showed an unexpected reduction in the concentration of C17 odd-numbered fatty acids, possibly as a consequence of reduced propionate availability. Brain however, which had elevated methylmalonic acid concentrations showed no change in either odd-numbered or branched-chain fatty acids. These results suggest that nitrous oxide-induced neuropathy does not occur as a result of misincorporation of odd-numbered/branched-chain fatty acids in brain.

Animals↗
PubMed1994

Folic acid metabolism and mechanisms of neural tube defects.

Folate acts as a cofactor for enzymes involved in DNA and RNA biosynthesis. Folate is also involved in the supply of methyl groups to the so-called methylation cycle, which uses methionine and makes homocysteine. The folate cofactor, N5-methyltetrahydrofolate, donates its methyl group to a vitamin B12-dependent enzyme, methionine synthase, which recycles homocysteine back to methionine. The cell's ability to methylate important compounds such as proteins, lipids and myelin will be compromised by deficiency of folate or vitamin B12, resulting in impaired cellular function. Methionine synthase plays another role: it converts circulating N5-methyltetrahydrofolate into tetrahydrofolate. The latter but not the former can act as a substrate for polyglutamate synthase, thereby becoming retained in the cell as polyglutamate. Interruption of DNA biosynthesis or methylation reactions could prevent the proper closure of the neural tube. Such inhibition could be caused by simple deficiency of either folic acid or vitamin B12. Studies comparing serum folate and vitamin B12 status in women who have had an affected pregnancy to those in control women indicate no difference between the two groups and show that most cases are not clinically deficient in either vitamin. A small number of studies using the level of folate in red blood cells, which is a better reflection of tissue stores, confirm this, suggesting instead a metabolic impairment in the biochemical functions of one of these vitamins. The trials using folic acid to prevent neural tube defects thus seem to be effectively overcoming a metabolic block rather than treating folate deficiency.

Female↗
PubMed1994

Collagen organization in the crural interosseous membrane and its relationship to fibular osteotomy.

The organization of collagen fibres in the crural interosseous membrane was measured using X-ray diffraction. The fibres were found to be highly aligned and steeply angled in a distal direction from tibia to fibula with a mean angle of 13 degrees. This organization will lead to a very stiff, ligament-like structure which will transmit forces to the tibia generated by the muscles attached to the fibula. It also suggests an optimum site for a fibular osteotomy about 4 cm distal to the tibial fracture site.

Aged↗
PubMed1994

Cobalt-vitamin B12 deficiency causes accumulation of odd-numbered, branched-chain fatty acids in the tissues of sheep.

Nine 5-month-old lambs were randomly allocated to two groups and were fed on either a Co-deficient whole-barley diet (n5), or the same diet supplemented with Co (n4). The lambs were fed on their respective diets for 28 weeks. Plasma vitamin B12 concentrations fell below the lower limit of normality after 6 weeks, and plasma methylmalonic acid (MMA) concentrations rose above the upper limit of normality after 10 weeks. However, plasma MMA concentrations fell to near normal levels towards the end of the experiment suggesting that diagnosis of more severe Co deficiency based on determination of plasma MMA concentrations may be of limited value. Analysis of tissue samples collected at slaughter revealed a marked reduction in the vitamin B12 concentration and the activity of methylmalonyl-CoA mutase (EC5.4.99.2) in the tissues taken from the Co-deficient sheep, by comparison with the controls. Although tissue concentrations of MMA in the Co-deficient animals were not significantly different from those of the controls, we did detect increased concentrations of branched-chain fatty acids. This suggested that misincorporation of MMA, but not propionic acid, into fatty acids had occurred. The Co-deficient lambs did not develop any neurological signs, suggesting that accumulation of branched-chain fatty acids may not be involved in the development of neurological lesions.

Animals↗
PubMed1994

Effects of the disruption of transmethylation in the central nervous system: an animal model.

INTRODUCTION: Central nervous system (CNS) methyltransferases methylate a wide range of substrates including proteins, lipids, nucleic acids and hormones. In every instance the methyl donor is S-adenosylmethionine (SAMe) and the demethylated product is S-adenosylhomocysteine (SAH). Methylation can be disrupted when there is an inadequate supply of methionine synthase (following vitamin B12 deficiency or folate deficiency), SAMe synthetase (due to ethanol), or SAH hydrolase (for unknown reasons). MATERIAL AND METHODS: 5-week-old pigs were maintained in an environment of either air or nitrous oxide, which inhibits methionine synthase, and were fed either a methionine-unsupplemented or methionine-enriched diet. After 3 to 10 weeks, pigs were killed by pentobarbitone injection and the levels of methionine and SAMe in the pigs' brain, spinal cord, plasma, liver, and kidney assessed. RESULTS: Pigs maintained in nitrous oxide displayed a dramatic fall in methionine levels in plasma and brain tissues but maintained relatively normal SAMe levels in these tissues. Brain and spinal cord cystathionine levels were markedly elevated, especially in those animals receiving oral methionine, as in the absence of methionine synthase homocysteine can be metabolized only through the catabolic pathway to cystathionine and cysteine. CONCLUSION: Disorders such as vitamin B12 deficiency or folate deficiency inhibit methylation by limiting the availability of SAMe or by elevating levels of the inhibitor SAH. In either case, the disruption of a wide range of methylation reactions can cause clinical sequelae ranging from structural abnormalities such as myelopathy to functional abnormalities such as depression.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1994

Non-Mendelian inheritance of macronuclear mutations is gene specific in Paramecium tetraurelia.

Paramecium tetraurelia contains two types of nuclei, a diploid germinal micronucleus and a large transcriptionally active macronucleus. The macronuclear genome is formed from the micronuclear DNA during sexual reproduction. Previous studies have shown that the processing of the A-type variable surface protein gene during formation of a new macronucleus is dependent on the presence of the A gene in the old macronucleus. It is not clear if this is a general feature that controls the formation of the Paramecium macronuclear genome or a unique feature of the A locus. Using micronuclear transplantation, we have constructed a strain that has a wild-type micronucleus but has macronuclear deletions of the A- and B-type surface protein genes. Neither the A nor the B gene is incorporated into the new macronucleus after sexual reproduction. Macronuclear transformation of this strain with the B gene rescues the B-gene deletion after formation of the next macronucleus but has not effect on the A deletion. Similarly, transformation with the A gene shows gene-specific rescue for A but not B. The effect of the old macronucleus on the processing of the new macronucleus results in a pattern of non-Mendelian inheritance of both macronuclear deletions. Progeny from the wild-type exconjugant are all wild type, and progeny from the A- B- exconjugant are mutant. The features of this A- B- non-Mendelian mutant demonstrate that the regulation of macronuclear DNA processing is gene specific, and our results open the possibility that this type of regulation affects many regions of the Paramecium genome.

Animals↗
PubMed1994

Deriving a useful packed cell volume estimate from haemoglobin analysis.

A method is described whereby the packed cell volume (PCV) of a blood sample can be estimated from the haemoglobin concentration. The method defines the relation existing between haemoglobin concentration and the PCV of blood samples and uses the mathematical formula thus obtained to estimate an unknown PCV value for a sample by extrapolation from the known haemoglobin value of the same sample. The method could be used in large scale field studies where haematological services are not available and where an evaluation of red cell status of vitamins such as folate is required.

Erythrocyte Indices↗
PubMed1994

Cobalt-vitamin B12 deficiency causes lipid accumulation, lipid peroxidation and decreased alpha-tocopherol concentrations in the liver of sheep.

A disease, known as ovine white liver disease (OWLD) was experimentally reproduced in lambs by feeding a diet depleted of cobalt. At necropsy, affected animals had pale, swollen, friable fatty livers, and showed marked accumulation of lipofuscin. Control animals, fed the same diet to which adequate amounts of cobalt had been added, were clinically normal. In animals with OWLD, liver triglyceride and free fatty acid concentrations were increased. A decrease in the ratio of phosphatidyl choline to phosphatidyl ethanolamine in the liver may result in a reduced ability to export triglycerides as very low density lipoprotein. This may cause the lipid accumulation characteristic of OWLD. Lipofuscin accumulation, another feature of OWLD, is a consequence of lipid peroxidation. Evidence for a peroxidative challenge was provided by the finding of reduced concentrations of alpha-tocopherol, elevated concentrations of induced 4-hydroxynonenal, and decreased amounts of the most readily peroxidizable fatty acids in the liver of animals with OWLD, by comparison with controls. The initiator of the peroxidative challenge is unknown, but may be related to the finding of increased concentrations of homocysteine in the plasma of animals with OWLD.

Aldehydes↗
PubMed1993

Renal effects of neutral endopeptidase inhibition in euvolemic and hypervolemic rats.

Candoxatrilat is a potent and selective inhibitor of neutral endopeptidase (EC 3.4.24.11), the enzyme responsible for the degradation of atrial natriuretic factor (ANF). In these studies, the renal effects of candoxatrilat were investigated in euvolemic and hypervolemic anaesthetised rats. In euvolemic rats, candoxatrilat (675 micrograms/kg per h) had no effect on urine output, sodium and potassium excretion or urinary cyclic GMP excretion. However, in hypervolemic rats, the natriuretic and diuretic responses to volume expansion were markedly potentiated by the candoxatrilat infusion, with a concomitant increase in urinary cyclic GMP. Acute volume expansion was characterised by natriuresis, diuresis and increased levels of plasma ANF and cyclic GMP (1.5-fold and 2-fold increases respectively, when compared to euvolemic rats). The results presented suggest that plasma ANF levels and volume status modulate responses to neutral endopeptidase inhibition. The development of the neutral endopeptidase inhibitor, candoxatrilat, provides the opportunity to exploit endogenous ANF effectively in disease states with elevated ANF.

Animals↗
PubMed1993

Characterization of betaine efflux from rat liver mitochondria.

In order to investigate the control of endogenous betaine supply to the cytoplasmic enzyme betaine-homocysteine methyltransferase, it was necessary to understand how betaine synthesized within the mitochondrial matrix is transported across the mitochondrial inner membrane. Mitochondria were loaded with radiolabelled betaine and efflux was measured in a medium at physiological ionic strength. Efflux of radiolabelled betaine occurred continuously with time. The efflux rate was unaffected by the presence or absence of a source of energy except at high membrane potentials, where betaine efflux rate increased 2-3-fold. Titration of the membrane potential demonstrated a non-ohmic relationship between betaine efflux rate and membrane potential. The rate of betaine efflux was proportional to the matrix betaine concentration up to 9 mM. Efflux was unaffected by addition of analogues of betaine and known mitochondrial transport inhibitors. N-Ethylmaleimide did inhibit efflux by 50%, but evidence suggested that the effect was non-specific. The lack of saturability or other evidence for a transport system suggests that betaine escapes from mitochondria by simple diffusion. The relative diffusion rates of glycine, sarcosine, dimethylglycine and betaine suggest that increasing the degree of N-methylation lowers diffusion rate.

Animals↗
PubMed1993

Accelerated folate breakdown in pregnancy.

During pregnancy there is an increased requirement for folate. We studied pregnant women to determine whether the increased requirement might be due to enhanced catabolism of the vitamin. Six normal pregnant women provided 24 h urine samples during each trimester and postpartum while taking a defined diet. The urines were assayed for the folate breakdown products p-amino-benzoylglutamate (pABGlu) and its acetylated derivative p-acetamidobenzoylglutamate (apBGlu) by high-pressure liquid chromatography. Mean concentration of excreted apABGlu rose significantly in the second trimester but returned to baseline postpartum. This increased rate of folate catabolism produces an extra demand for dietary folate of about 200-300 micrograms per day in pregnant women, a considerably greater value than recent recommendations.

4-Aminobenzoic Acid↗
PubMed1993

The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage.

Deficiency of choline and methionine produces hepatic steatosis similar to that seen with ethanol, and supplementation with these lipotropes can prevent ethanol-induced fatty liver. These effects are thought to occur through alterations in membrane phospholipid metabolism, but the mechanism whereby this occurs and the precise nature of the changes brought about by ethanol in the interactions of choline and methionine metabolism remain unclear. Through the known effects on hepatic glutathione (which requires as a precursor a product of methionine catabolism), ethanol might affect hepatic one-carbon metabolism, which requires the participation of both methionine and choline in the transfer of methyl groups. This has been investigated with a radiorespirometric technique to assess the in vivo oxidation of the methyl groups of lipotropes and their intermediates in ethnaol- and control-fed rats. Enzyme activities of one-carbon transfer reactions and the hepatic levels of methionine and alpha-aminobutyrate, an end product of methionine catabolism, have been measured. The effect of ethanol feeding on hepatic S-adenosylmethionine and S-adenosylhomocysteine has also been assessed. Ethanol increases the oxidation to carbon dioxide of the methyl group of methionine by a factor of 2.9 (p = 0.002) and produces a 3.6-fold (p = 0.0001) accumulation of alpha-aminobutyrate, indicating a marked increase in methionine catabolism. Hepatic methionine levels are unchanged by ethanol, however, and this may be explained by a dramatic increase in the turnover of the methyl groups of choline and betaine in response to ethanol (times 3.6 and 4.2, respectively, p < 0.003), suggesting greatly increased use of the choline oxidation pathway to remethylate homocysteine through betaine homocysteine methyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Folate catabolism is increased during pregnancy in rats.

The hypothesis examined in the present study is that pregnancy results in a greater rate of folate catabolism. Mammalian folate catabolism proceeds by cleavage of the vitamin at the C9-N10 position to yield p-aminobenzoylglutamate, which is quantitatively excreted in the urine after its acetylation. A recently developed HPLC method for the determination of endogenous levels of this catabolite, acetamidobenzoylglutamate, in rat urine was used to investigate folate catabolism in three groups of female rats (n = 6/group), one nonpregnant and two pregnant groups. One of the pregnant groups was allowed to feed freely whereas the other was pair-fed to the nonpregnant control group. The daily excretion of acetamidobenzoylglutamate was stable in the nonpregnant group over the experimental period but increased significantly with progression of gestation in both pregnant groups, in which values peaked at d 18 to concentrations of up to three times those of the nonpregnant animals. In both pregnant groups the values fell significantly before parturition, demonstrating that increased catabolism of folate is a feature of pregnancy per se and not simply due to increased weight. These results suggest that increased catabolism may make an important contribution to the folate deficiency associated with pregnancy.

Animals↗