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Biomedical subjects

D G Weir

Publications and source records attributed to D G Weir.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Correlation of the ratio of S-adenosyl-L-methionine to S-adenosyl-L-homocysteine in the brain and cerebrospinal fluid of the pig: implications for the determination of this methylation ratio in human brain.

1. Pigs were maintained in air or in an atmosphere of nitrous oxide which dramatically changes the S-adenosyl-L-methionine to S-adenosyl-L-homocysteine ratio in neural tissues. Samples of cerebrospinal fluid, cortex, cerebellum and spinal cord were then extracted and analysed for S-adenosyl-L-methionine and S-adenosyl-L-homocysteine. Regression analyses were carried out on values obtained in cerebrospinal fluid and in neural tissues. 2. Highly significant correlations were obtained between levels of S-adenosyl-L-homocysteine (r2 = 0.42-0.69; P less than 0.001) and S-adenosyl-L-methionine/S-adenosyl-L-homocysteine ratios (r2 = 0.56-0.65; P less than 0.001) in cerebrospinal fluid and levels and ratios in cortex, cerebellum and spinal cord. The levels of S-adenosyl-L-methionine did not show a significant correlation. 3. We conclude that the ratio of these metabolites in the cerebrospinal fluid may reflect the ratio in the central nervous system and we suggest that this may also be true in human tissues. This finding will permit the determination of the probable methylation ratio in the central nervous system in human conditions, such as vitamin B12 deficiency and acquired immune deficiency syndrome, where a similar myelopathy occurs to that seen in the nitrous oxide-treated pig. All three myelopathies may arise from an inhibition of methyltransferases involved in the synthesis of myelin that would occur when the methylation ratio is reduced.

Animals↗
PubMed1992

Cobalt-vitamin B-12 deficiency decreases methionine synthase activity and phospholipid methylation in sheep.

Two groups of lambs were fed either a Co-deficient or a Co-sufficient whole barley-based diet for 28 wk to induce a severe Co-vitamin B-12 deficiency. Holo and apo methionine synthase activities were significantly lower in the liver, kidney and spinal cord of Co-deficient animals compared with controls. Neither form of this enzyme in the brain was affected by Co deficiency. The ratio of the tissue concentrations of S-adenosyl methionine to S-adenosyl homocysteine was significantly lower only in the liver of Co-deficient animals, suggesting that the activity of hepatic SAM-dependent methyltransferase enzymes would be impaired. Measurements of tissue concentrations of phosphatidyl choline and phosphatidyl ethanolamine revealed lower concentrations of phosphatidyl choline and a lower phosphatidyl choline:phosphatidyl ethanolamine ratio in both liver and brain of the Co-deficient animals. The latter finding occurred in the absence of changes in either methionine synthase activity or the methylation ratio and may result from impaired availability of hepatic phosphatidyl choline for transport into the brain.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Non-invasive diagnosis of portal vein occlusion by radionuclide angiography.

The accuracy of non-invasive radionuclide angiography in detecting portal vein occlusion was assessed in 61 patients--10 with portal vein occlusion confirmed by conventional portography, 25 with chronic liver disease and a patent portal vein (mild = 12, severe = 13), and 26 with normal liver function, who served as controls. The median percentage portal venous flow for the portal vein occlusion group was 8% (range 1-30) (consistent with negligible flow) compared with 78% (52-87) for control subjects (p < 0.005) and 68% (61-80) and 49% (23-59) respectively for patients with mild and severe liver disease (p < 0.001 and p < 0.005). At a portal venous inflow of < 20%, the procedure had a specificity of 100% and sensitivity of 90% in diagnosing portal vein occlusion. Non-invasive radionuclide angiography provides a safe and accurate screening method for evaluating portal vein patency or occlusion in the investigation of portal hypertension or before liver transplantation.

Adult↗
PubMed1991

Evidence of brain methyltransferase inhibition and early brain involvement in HIV-positive patients.

The myelopathy associated with human immunodeficiency virus (HIV) infection closely resembles that in subacute combined degeneration, a disorder of vitamin B12 metabolism. To investigate whether the disorders share a pathogenetic mechanism, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the cerebrospinal fluid (CSF) of 20 HIV-seropositive patients and 30 HIV-negative patients who were undergoing lumbar puncture for other medical reasons. The HIV-seropositive patients had significantly lower CSF concentrations of SAM (mean 77 [SD 25] vs 131 [35] nmol/l; p less than 0.001) and significantly higher concentrations of SAH (30.5 [6.8] vs 19.0 [7.1] nmol/l; p less than 0.001) than the controls. There was therefore a significant difference between the groups in the SAM/SAH (methylation) ratio (HIV 2.7 [1.0] vs control 7.6 [3.4]; p less than 0.001). There were no correlations between SAM or SAH concentrations or methylation ratio and age or sex in both groups, or serum B12 and folate concentrations, CSF folate, serum or CSF methylmalonic acid, risk factors, body mass index, specific drug treatment received, or disease stage in the HIV group. This finding suggests that HIV affects the brain from a very early stage of the infection. We suggest that, as in the pig, the CSF methylation ratio closely reflects that in the brain. In HIV-infected patients a reduced brain methylation ratio would inhibit methyltransferase enzymes, which would lead to hypomethylation in the central nervous system and ultimately to neurological lesions. In a pig model of subacute combined degeneration and in vitamin-B12-deficient human beings, the primary cause of the low methylation ratio is impaired recycling of SAH back to SAM, a process which requires vitamin-B12-dependent methionine synthase. The HIV patients in this study were vitamin B12 and folate replete, which suggests a different cause for the low methylation ratio.

Adult↗
PubMed1991

Betaine-homocysteine methyltransferase: organ distribution in man, pig and rat and subcellular distribution in the rat.

1. Conflicting reports exist as to the organ distribution of betaine-homocysteine methyltransferase (EC 2.1.1.5). It is important to establish its presence or absence in brain, since its substrate, betaine, has recently become established in the treatment of certain diseases involving this organ. 2. It remains unclear whether the reported success of this treatment results from the use of betaine to methylate homocysteine and produce methionine in situ in neural tissue, or whether the effect is secondary to these same reductions happening in other organs, such as the liver. The former would require the presence of betaine-homocysteine methyltransferase in neural tissue. 3. This study demonstrates the complete absence of any activity for this enzyme in the brain of the three species examined. The enzyme was found to be present in both the liver and kidney of man and pig, but only in the liver of the rat. 4. The only source of betaine in cells is via the oxidation of choline. Since the enzymes involved in this conversion have never been shown to exist anywhere other than the mitochondria, it has been assumed that the methyltransferase is also mitochondrial. In this study, it is demonstrated that the enzyme exists only in the cytoplasm of rat liver cells.

Animals↗
PubMed1991

Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy.

This study demonstrates gluten-sensitive recurrent oral ulceration (ROU) in the absence of gastrointestinal abnormalities which is associated with a humoral response to wheat protein. Ten patients with severe ROU were investigated; all had normal small intestinal biopsies. Four patients had raised levels of antibodies to alpha gliadin, a wheat protein fraction; in three of these four, the ulceration remitted on treatment with a gluten-free diet (G.F.D.) and relapsed on gluten challenge. None of the remaining six patients had raised alpha gliadin antibody (AGA) levels and none responded to G.F.D. Thus raised AGA levels can be used to identify patients with ROU who are likely to respond to a GFD.

Adult↗
PubMed1991

Dissolution of cholesterol gall stones using methyltertbutyl ether: a safe effective treatment.

Methyltertbutyl ether (MTBE) administered by percutaneous transhepatic catheter rapidly dissolves radiolucent cholesterol gall bladder stones. However, complete dissolution and clearance of non-cholesterol debris is essential to prevent recurrence. In this study we analysed 25 consecutive patients with reference to efficacy and recurrence based on the presence or absence of non-cholesterol stone fragments after dissolution. Placement of the catheter was successful in 24 patients, one patient requiring cholecystectomy for bile peritonitis. MTBE was infused and aspirated continuously, four to six cycles per minute, resulting in rapid stone dissolution (median six hours; range 4-23 hours for solitary stones and median seven hours, range 4-30 hours for multiple stones). In 18 patients who had complete dissolution, four (22%) had recurrent stones within six to 18 months. Five patients had residual debris which failed to clear completely despite bile acid treatment. One patient with an incomplete rim of calcium in a large stone did not respond to MTBE treatment. A further patient required cholecystectomy for symptomatic recurrence. There were no serious side effects observed. MTBE treatment is a rapid, safe, and effective treatment for patients who refuse surgery or who for medical reasons cannot undergo cholecystectomy. The results of this study confirm that complete dissolution of all fragments is essential and may prevent recurrence.

Adult↗
PubMed1990

Effects of an enteric anaerobic bacterial culture supernatant and deoxycholate on intestinal calcium absorption and disaccharidase activity.

Fifty two strains of anaerobic bacteria isolated from the upper gut of patients with small intestinal bacterial overgrowth were screened for phospholipase activity. Bacteroides melaninogenicus spp intermedius had the greatest activity. The effects of culture supernatants of this organism and deoxycholate on intestinal calcium absorption and disaccharidase activity were studied using a rat closed loop model. The supernatant decreased the in vitro uptake of calcium by 15% (p less than 0.001). Deoxycholate reduced calcium uptake by 16% (p less than 0.001). Combined culture supernatant and deoxycholate reduced calcium uptake by 39% (p less than 0.001) suggesting a potentiation of supernatant activity by deoxycholate. Culture supernatant and deoxycholate, both alone and combined, significantly reduced lactase, sucrase, and maltase activity. Electron microscopic evidence showed degeneration of microvilli, disruption of mitochondrial structure, and swelling of the endoplasmic reticulum after exposure of the intestinal loops to the supernatant or deoxycholate.

Animals↗
PubMed1978

Primary biliary cirrhosis and coeliac disease: an association?

The association of primary biliary cirrhosis and coeliac disease, not previously reported, was observed in 4 patients. In each case, the two conditions were diagnosed simultaneously, and although symptoms were due to coeliac disease, initial investigation drew attention to the liver condition. All the patients responded to a gluten-free diet and remain well 2 years later. Primary biliary cirrhosis remains asymptomatic in 3 patients, but pruritus has developed in the 4th. The significance of this association is unclear and may merit formal study. Coeliac disease should be considered as a possible cause of unexplained weight loss in primary biliary cirrhosis.

Aged↗
PubMed1978

The identification of the products of folate catabolism in the rat.

Further analysis of rat urine containing labelled catabolites derived from administered 3H- or 14C-labelled folic acid is described. The results support previously described studies, and show that folate catabolism in the rat takes place by cleavage of the C9-N10 bond, and not by excretion of inactive forms of the vitamin which still contain the intact folate skeleton.

Animals↗
PubMed1978

In vitro studies of suppressor cell function in human peripheral blood mononuclear cells.

Peripheral blood mononuclear cells (PBMC) from normal donors, pre-cultured at 37 degrees C for 24 hr before the addition of mitogen, demonstrated an enhanced proliferative response. This may be due to the loss of a subpopulation of suppressor cells during the incubation period. Still further enhancement was observed when pre-culturing was prolonged for 48 hr, while cells pre-incubated at 4 degrees C showed no increased responsiveness. Concanavalin A (Con A) pre-activated PBMC supressed the mitogen response of responder cells. More marked suppression was observed when the concentration of Con A used to induce the suppressor cells was increased. It was not possible to activate suppressor function in cells which had been kept in vitro for longer than 48 hr. These findings support the concept of the existence and function of suppressor cells, and that the suppressive influence is short-lived in vitro culture.

Adult↗