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Biomedical subjects

D G Weir

Publications and source records attributed to D G Weir.

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

A metastatic neuroendocrine anaplastic small cell tumor in a patient with multiple endocrine neoplasia type 1 syndrome. Assessment of disease status and response to doxorubicin, cyclophosphamide, etoposide chemotherapy through scintigraphic imaging with 111In-pentetreotide.

Extrapulmonary small cell and small cell neuroendocrine tumors of unknown primary site are, in general, aggressive neoplasms with a short median survival. Like small cell lung cancer (SCLC), they often are responsive to chemotherapy and radiotherapy. Small cell lung cancer and well differentiated neuroendocrine carcinomas of the gastrointestinal tract and pancreas tend to express somatostatin receptors. These tumors may be localized in patients by scintigraphic imaging using radiolabeled somatostatin analogues. A patient with anaplastic neuroendocrine small cell tumor arising on a background of multiple endocrine neoplasia type 1 syndrome is reported. The patient had a known large pancreatic gastrinoma and previously treated parathyroid adenopathy. At presentation, there was small cell cancer throughout the liver and skeleton. Imaging with a radiolabeled somatostatin analogue, 111In-pentetreotide (Mallinckrodt Medical B. V., Petten, Holland), revealed all sites of disease detected by routine biochemical and radiologic methods. After six cycles of chemotherapy with doxorubicin, cyclophosphamide, and etoposide, there was almost complete clearance of the metastatic disease. 111In-pentetreotide scintigraphy revealed uptake consistent with small areas of residual disease in the liver, the abdomen (in mesenteric lymph nodes), and posterior thorax (in a rib). The primary gastrinoma present before the onset of the anaplastic small cell cancer showed no evidence of response to the treatment. The patient remained well for 1 year and then relapsed with brain, lung, liver, and skeletal metastases. Despite an initial response to salvage radiotherapy and chemotherapy with carboplatin and dacarbazine, the patient died 6 months later.

Antineoplastic Combined Chemotherapy Protocols↗
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

Isolated pulmonary valve endocarditis: a rare or an underdiagnosed disease?

A 48 year old patient with resistant coeliac disease developed prolonged unexplained pyrexia after surgery for small bowel volvulus. Despite extensive investigations and intensive antibiotic therapy, he deteriorated and died eight weeks postoperatively and significant isolated pulmonary valve endocarditis was discovered at autopsy. This diagnosis should be considered in all critically ill patients with unexplained pyrexia even in the absence of clinical features of endocarditis and transoesophageal echocardiography performed to exclude or confirm this lesion.

Endocarditis, Bacterial↗
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

Microalbuminuria in inflammatory bowel disease.

Microalbuminuria independently predicts the development of nephropathy and increased cardiovascular morbidity and mortality in diabetic patients, but it may be an indicator of the acute phase response. This study examined microalbuminuria as a marker of the acute phase response in patients with inflammatory bowel disease and correlated it with the disease activity in 95 patients with inflammatory bowel disease (ulcerative colitis (n = 52), Crohn's disease (n = 43)) determined by the simple index of Harvey and Bradshaw. Fifty patients were in complete clinical remission and 45 patients had active disease. Microalbuminuria was detected in all patients with inflammatory bowel disease (147 (17) v 18 (2) microgram/min, inflammatory bowel disease v controls mean (SEM), p < 0.007). Patients with active inflammatory bowel disease had higher concentrations of microalbuminuria compared with patients in remission (206 (19) v 65 (8) microgram/min, mean (SEM), p < 0.0001). Eight patients with active inflammatory bowel disease who were sequentially followed up with measurements of microalbuminuria had significantly lower values, when the disease was inactive (active inflammatory bowel disease 192 (44) v inactive inflammatory bowel disease 64 (14) microgram/min, p < 0.03). There was a significant correlation with the simple index of Harvey and Bradshaw (r = 0.818, p < 0.0001). Microalbuminuria values were significantly lower in inflammatory bowel disease patients in remission, maintained with olsalazine compared with those patients maintained with mesalazine and salazopyrine, but no significant difference was seen in values of microalbuminuria in active inflammatory bowel disease patients receiving different salicylates. This study also measured serum amyloid-A as an indicator of the acute phase response in the same patients. Serum amyloid-A was significantly increased in active disease compared with inactive disease (151 (43) v 33 (7) or controls 11 (2) micrograms/ml, p < 0.05). In conclusion microalbuminuria is present in abnormal amounts in all patients with active inflammatory bowel disease, and values fall when the disease is quiescent. Microalbuminuria is probably a consequence of an acute phase response and provides a simple, rapid, and inexpensive test, which has the potential to monitor inflammatory bowel disease activity and response to treatment.

Acute-Phase Reaction↗
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

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↗
PubMed1993

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects.

Blood was taken at the first antenatal clinic from 56,049 pregnant women. Neural tube defect (NTD) pregnancies (81) were compared to controls (247) for plasma vitamin B12 (B12) (ng/l), plasma folate (microgram/l), and red cell folate (RCF) (microgram/l). Median values were significantly different and were, respectively, 243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269 and 338 (p < 0.001). There was a significant correlation between plasma B12 and RCF in cases (r = 0.31, p = 0.004) but not in controls (r = 0.02, p = 0.725). In cases only, multiple regression showed that both plasma B12 and plasma folate influenced the maternal RCF (multiple r = 0.68, p < 0.001). Plasma folate and plasma B12 were independent risk factors for NTDs, suggesting that the enzyme methionine synthase is involved directly or indirectly in the aetiology. The levels of folate and B12 where increased risk occurred were not those usually associated with deficiency, calling for a re-evaluation of their recommended daily allowances. Whether the aetiology is purely nutritional or a metabolic defect, this study suggests that consideration should be given to including B12 as well as folic acid in any programme of supplementation or food fortification to prevent NTDs.

Adult↗
PubMed1992

The relationship between the activity of methionine synthase and the ratio of S-adenosylmethionine to S-adenosylhomocysteine in the brain and other tissues of the pig.

Using nitrous oxide to inactivate methionine synthase in vivo, the relationship of the activity of methionine synthase to the S-adenosylmethionine (AdoMet)/S-adenosylhomocysteine (AdoHcy) ratio was examined in neural and other tissues of the pig. Pigs were exposed to 15% nitrous oxide for varying intervals of up to 7 days or studied at varying intervals of recovery in air after 7 days nitrous oxide inhalation, and the rate of inactivation or resynthesis of methionine synthase was related to the corresponding AdoMet/AdoHcy ratios. The rate of inactivation of enzyme during nitrous oxide exposure was considerably faster in the liver and kidney than in the brain and spinal cord with activity levelling off between 10% and 20% of control values. The AdoMet/AdoHcy ratio fell in all tissues during nitrous oxide treatment, the fall being most marked in the brain and spinal cord where a 10-fold change occurred. This change was attributed mainly to a rise in AdoHcy levels. The recovery pattern of methionine synthase was broadly linear but was slower in the spinal cord (0.10 +/- 0.03% per hr; mean +/- SEM) than in any other tissue examined including brain (0.35 +/- 0.04% per hr). Correspondingly, the recovery of the AdoMet/AdoHcy ratio was also significantly slower in the spinal cord. When values for exposure and recovery were combined there was a significant correlation between the activity of methionine synthase and the AdoMet/AdoHcy ratio in both the brain (r = 0.90; P < 0.001) and the spinal cord (r = 0.92; P < 0.001). These results support the concept that the AdoMet/AdoHcy ratio is closely related to the pathogenic process which produces the neurologic lesions associated with a reduction in methionine synthase activity.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Randomised comparison of olsalazine and mesalazine in prevention of relapses in ulcerative colitis.

Sulphasalazine extends remissions and lessens disease activity during relapses of ulcerative colitis, but it also causes many adverse side-effects. The adverse reactions are mostly attributable to the sulphapyridine carrier moiety rather than the active principle 5-aminosalicylic acid (5-ASA), so agents to deliver 5-ASA to the colon by other means have been designed. We have compared the efficacy and tolerability of two such agents, olsalazine and mesalazine, in maintenance therapy of ulcerative colitis. 100 patients with ulcerative colitis in remission were recruited at one centre and assigned randomly to treatment with olsalazine (Dipentum; 1.0 g daily) or mesalazine (Asacol, with Eudragit-S coating; 1.2 g daily). Compliance, biochemical and haematological variables, and clinical evidence of disease activity were assessed every 3 months for 12 months by observers unaware of treatment allocation. In intention-to-treat analysis, which included as treatment failures patients withdrawn for protocol violations, adverse reactions, intercurrent illness, or non-compliance as well as those with relapses of ulcerative colitis, the olsalazine group had a significantly lower rate of treatment failure than the mesalazine group (12/49 [24%] vs 23/50 [46%]; p = 0.025). Analysis restricted to 64 patients still in remission at 1 year and 18 with relapses also showed a significant difference in relapse rate (olsalazine 5/42 [12%] vs mesalazine 13/40 [33%]; p = 0.024). Both drugs were well tolerated; only 9 patients reported substantial side-effects. Olsalazine was clearly superior to mesalazine in prevention of relapses in ulcerative colitis, especially in patients with left-sided disease.

Adolescent↗