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D G Weir

Publications and source records attributed to D G Weir.

At least 37 records · Page 2Linked to original sources
PubMed2000

Fluctuations in dietary methionine intake do not alter plasma homocysteine concentration in healthy men.

A moderate elevation in plasma total homocysteine (tHcy) has been established as an independent risk factor for vascular disease. An important exogenous source of homocysteine is methionine found in foods rich in animal protein. We investigated the response of tHcy to fluctuations in methionine intake in a cross-over intervention trial (two arms). Healthy men (n = 52; 19-29 y) were screened for habitual methionine intake using a food-frequency questionnaire. Subjects in the top quartile for methionine intake (n = 13), with a baseline fasting tHcy of 7.01 +/- 1.84 micromol/L (mean +/- SD), were randomly assigned to receive either a low-methionine intervention diet for 1 wk followed by a control diet for 1 wk or vice-versa. Simultaneously, those in the bottom quartile for methionine intake (n = 11), with a fasting plasma tHcy of 9.79 +/- 7. 20 micromol/L (mean +/- SD), received either a high methionine intervention diet for 1 wk followed by a control diet or vice-versa. All subjects had serum folate, red-cell folate, serum vitamin B-12 and plasma pyridoxal phosphate (PLP) concentrations within normal ranges. During the intervention, subjects in the top quartile for methionine intake reduced their daily methionine intake 79%, from 1969 +/- 639 to 407 +/- 83 mg/d (P: </= 0.001), and those in the bottom quartile almost doubled their methionine intake, from 1155 +/- 401 to 2112 +/- 379 mg/d (P: </= 0.001). Despite these changes in methionine intake, no corresponding changes in plasma tHcy were observed. These results suggest that in the absence of an obvious deficiency of relevant B-vitamins, fasting plasma tHcy is unaffected by intermediate-term fluctuations (up to 100% of usual intake) in dietary methionine.

Adult↗
PubMed2000

Mechanism of the antimicrobial drug trimethoprim revisited.

We tested the hypothesis that the mechanism of action of the antifolate drug trimethoprim is through accumulation of bacterial dihydrofolate resulting in depletion of tetrahydrofolate coenzymes required for purine and pyrimidine biosynthesis. The folate pool of a strain of Escherichia coli (NCIMB 8879) was prelabeled with the folate biosynthetic precursor [(3)H]-p-aminobenzoic acid before treatment with trimethoprim. Folates in untreated E. coli were present as tetrahydrofolate coenzymes. In trimethoprim-treated cells, however, a rapid transient accumulation of dihydrofolate occurred, followed by complete conversion of all forms of folate to cleaved catabolites (pteridines and para-aminobenzoylglutamate) and the stable nonreduced form of the vitamin, folic acid. Both para-aminobenzoylglutamate and folic acid were present in the cell in the form of polyglutamates. Removal of trimethoprim resulted in the reconversion of the accumulated folic acid to tetrahydrofolate cofactors for subsequent participation in the one-carbon cycle. Whereas irreversible catabolism is probably bactericidal, conversion to folic acid may constitute a bacteriostatic mechanism since, as we show, folic acid can be used by the bacteria and proliferation is resumed once trimethoprim is removed. Thus, the clinical effectiveness of this important drug may depend on the extent to which the processes of either catabolism or folic acid production occur in different bacteria or during different therapeutic regimes.

4-Aminobenzoic Acid↗
PubMed2000

The relationship between increased folate catabolism and the increased requirement for folate in pregnancy.

OBJECTIVES: To estimate the rate of folate catabolism in pregnant and nonpregnant women and to derive the recommended dietary allowance for folate. DESIGN: Prospective, observational study. SETTING: Rotunda Hospital, Dublin. WOMEN: Twenty-four healthy gravid women were studied once during each trimester and postpartum. Twenty-five nonpregnant controls were assessed before and after folic acid supplementation. INTERVENTIONS: Women provided 24-hour urine collections while adhering to a strict dietary regimen containing no exogenous folate catabolites. MAIN OUTCOME MEASURES: Urinary levels of p-acetamidobenzoylglutamate and p-aminobenzoylglutamate were measured by high pressure liquid chromatography. RESULTS: The 24-hour excretion of folate catabolites, expressed as mean [95% CI] folate equivalents in microg) progressively increased during pregnancy. A peak was reached in the third trimester (349.1 microg [308.1 to 390.1]) where the rate was more than twice the rate in the nonpregnant control group (136.4 microg [112.4 to 160.4]) (P < 0.001). Based on our results the recommended dietary allowance for folate in nonpregnant women should be 250 microg and this should rise during pregnancy to 430 microg in the second trimester and 540 microg in the third trimester. CONCLUSIONS: The rate of folate catabolism progressively increases during pregnancy reaching a peak in the third trimester at the time of maximal fetal growth. The increased demand for folate during pregnancy appears to be due to the accelerated breakdown of the vitamin because of its participation in cellular biosynthesis. These results provide a quantitative basis for the current debate on the appropriate recommended dietary allowance for folate in both pregnant and nonpregnant women.

4-Aminobenzoic Acid↗
PubMed2000

Increased incidence of non-Hodgkin's lymphoma in inflammatory bowel disease patients on immunosuppressive therapy but overall risk is low.

BACKGROUND: There is concern that the incidence of non-Hodgkin's lymphoma (NHL) will rise with increasing use of immunosuppressive therapy. AIMS: Our aim was to determine the risk of NHL in a large cohort of patients with inflammatory bowel disease (IBD), and to study the association between IBD, NHL, and immunosuppressive therapy. METHODS: We studied 782 IBD patients (238 of whom received immunosuppressive therapy) who attended our medical centre between 1990 and 1999 (median follow up 8.0 years). Standardised incidence ratios (SIRs) and 95% confidence intervals (CI) were calculated. Expected cases were derived from 1995 age and sex specific incidence rates recorded by the National Cancer Registry of Ireland. RESULTS: There were four cases of NHL in our IBD cohort (SIR 31.2; 95% CI 2.0-85; p=0.0001), all of whom had received immunosuppressive therapy: azathioprine (n=2), methotrexate (n=1), and methotrexate and cyclosporin (n=1). Our immunosuppressive group had a significantly (59 times) higher risk of NHL compared with that expected in the general population (p=0.0001). Three cases were intestinal NHL and one was mesenteric. Mean age at NHL diagnosis was 49 years, mean duration of IBD at the time of NHL diagnosis was 3.1 years, and mean duration between initiation of immunosuppressive therapy and diagnosis of NHL was 20 months. CONCLUSIONS: Although underlying IBD may be a causal factor in the development of intestinal NHL, our experience suggests that immunosuppressive drugs can significantly increase the risk of NHL in IBD. This must be weighed against the improved quality of life and clinical benefit immunosuppressive therapy provides for IBD patients.

Adult↗
PubMed1999

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.

Child↗
PubMed1999

Symptomatic gastro-oesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. The European Study Group.

OBJECTIVE: To assess intermittent treatment over 12 months in patients with symptomatic gastro-oesophageal reflux disease. DESIGN: Randomised, multicentre, double blind, controlled study. Patients with heartburn and normal endoscopy results or mild erosive changes received omeprazole 10 mg or 20 mg daily or ranitidine 150 mg twice daily for 2 weeks. Patients remaining symptomatic had omeprazole 10 mg or ranitidine dose doubled for another 2 weeks while omeprazole 20 mg was continued for 2 weeks. Patients who were symptomatic or mildly symptomatic were followed up for 12 months. Recurrences of moderate or severe heartburn during follow up were treated with the dose which was successful for initial symptom control. SETTING: Hospitals and primary care practices between 1994 and 1996. SUBJECTS: 677 patients with gastro-oesophageal reflux disease. MAIN OUTCOME MEASURES: Total time off active treatment, time to failure of intermittent treatment, and outcomes ranked from best to worst. RESULTS: 704 patients were randomised, 677 were eligible for analyses; 318 reached the end of the study with intermittent treatment without recourse to maintenance antisecretory drugs. The median number of days off active treatment during follow up was 142 for the entire study (281 for the 526 patients who reached a treatment related end point). Thus, about half the patients did not require treatment for at least 6 months, and this was similar in all three treatment groups. According to outcome, 378 (72%) patients were in the best outcome ranks (no relapse or one (or more) relapse but in remission until 12 months); 630 (93%) had three or fewer relapses in the intermittent treatment phase. Omeprazole 20 mg provided faster relief of heartburn. The results were similar in patients with erosive and non-erosive disease. CONCLUSIONS: Intermittent treatment is effective in managing symptoms of heartburn in half of patients with uncomplicated gastro-oesophageal reflux disease. It is simple and applicable in general practice, where most patients are seen.

Adult↗
PubMed1999

Folate status and neural tube defects.

Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1999

The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.

Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.

Alleles↗
PubMed1999

The influence of 5,10 methylenetetrahydrofolate reductase genotypes on enzyme activity in placental tissue.

OBJECTIVE: To study the effects of heterozygosity and homozygosity for the C677T mutation of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene on the activity of this enzyme in placental tissue from pregnancies not affected by neural tube defect. DESIGN: Placental tissue was genotyped for the C677T variants of MTHFR. Total enzyme activity and residual activity after heating to 46 degrees C for 5 minutes was then measured. SETTING: A teaching hospital. SAMPLE: Placental samples (n = 200), one from each of 200 uncomplicated term deliveries. MAIN OUTCOME MEASURES: Total and residual enzyme activity for MTHFR. RESULTS: Placentae heterozygous for the C677T mutation of the MTHFR gene had significantly lower total enzyme activity than those without the mutation; the lowest activity occurred in homozygotes for the mutation. The same pattern was seen in relation to enzyme activity after heating. CONCLUSION: This study demonstrates that reduced enzyme activity is associated with the C677T variant of MTHFR in placental tissue. This is an important metabolic step in folic acid metabolism and pro-

Biomarkers↗
PubMed1999

Lactase enzyme, detected immunohistochemically, is lost in active celiac disease, but unaffected by oats challenge.

OBJECTIVES: The loss of lactase activity that occurs in active celiac disease resolves on adherence to a gluten-free diet that excludes the cereals wheat, barley, rye, and oats. Recently, an immunohistochemical technique has been described to evaluate lactase expression in primary hypolactasia. We have adapted this method to study lactase activity in adult celiac patients and to assess its value as a diagnostic tool. In addition, given the results of two recent studies suggesting the safety of reintroducing oats cereal into the celiac diet, we have also evaluated the response of lactase expression to oats exposure. METHODS: Duodenal biopsies from 26 patients were stained for lactase expression using an indirect immunoperoxidase method. Eleven disease control patients had normal architecture and nine had features of active celiac disease. Ten patients, who had celiac disease in clinical and histological remission, underwent oats challenge for 12 wk. RESULTS: Confluent expression of lactase was observed in the 11 control patients with normal histology, whereas staining was absent in the nine patients with active celiac disease. All 10 patients with treated celiac disease had normal lactase expression after exposure to oats. CONCLUSIONS: The immunohistochemical technique used in this study provides an easy, reliable method of assessing lactase enzyme and confirms the value of this index as a marker of celiac disease activity. The results of two recent studies demonstrating the lack of oats toxicity in adult celiac patients have been further corroborated by our findings, which show the preservation of lactase enzyme after oats challenge.

Adult↗
PubMed1999

Methylation of cortical brain proteins from patients with HIV infection.

OBJECTIVES: Experimental models of vitamin B12 deficient-neuropathy are characterized by central nervous system protein hypomethylation. The encephalitis/vacuolar myelopathy complicating HIV infection and subacute combined degeneration of the cord due to vitamin B12 deficiency share similar biochemical and pathological abnormalities. Altered central nervous system methylation may be important in the pathogenesis of HIV encephalitis. To test this hypothesis we compared brain protein methylation of HIV-positive, and control, subjects. MATERIALS AND METHODS: Carboxymethyltransferase activity was assayed in postmortem cortical brain samples obtained from 16 control patients (9 males); mean age (59+/-5.1 years, range 21-87 years), 9 HIV-positive patients (7 males, 6 IVDA, 3 homosexual, 4 with HIV encephalitis, mean age 37, range 23-45), and 3 patients with Alzheimer's disease (mean age 78 years). RESULTS: The amount of radiolabelled SAM (S-adenosylmethionine) incorporated into carboxymethyl, and N-methylation sites within brain proteins from cortical white matter in vitro was significantly lower (P<0.05) in the HIV+ group vs controls. Carboxymethyltransferase activity was similar in the HIV-infected brains irrespective of the presence or absence of HIV encephalitis. Mean cortical methyl group incorporation was also lower in the Alzheimer's disease group compared to controls. CONCLUSION: The observation of reduced in vitro methylation of brain proteins from patients with HIV infection and Alzheimer's disease suggests that fewer unmethylated sites exist due to relative protein hypermethylation in vivo. The absence of hypomethylation in the brains of patients with HIV encephalitis suggests that hypomethylation is not necessary for the development of HIV encephalitis.

Adult↗
PubMed1999

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5, 10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD. AIMS: To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD. METHODS: Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC). RESULTS: Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B(12) levels were lower in patients with IBD irrespective of MTHFR genotype. CONCLUSIONS: There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B(12) therapy to protect against the thromboembolic complications of raised tHcy.

Adolescent↗
PubMed1999

Brain function in the elderly: role of vitamin B12 and folate.

Vitamin B12 (cobalamin) deficiency associated neuropathy, originally called subacute combined degeneration, is particularly common in the elderly. The potential danger today is that with supplementation with folic acid of dietary staples such as flour, that the incidence of this disease could rise as folic acid, as opposed to natural folate (N5CH3HFGlu1), enters the cell and the metabolic cycle by a cobalamin independent pathway. This chapter briefly describes the clinical presentation of the disease, which unless treated will induce permanent CNS damage. The biochemical basis of the interrelationship between folate and cobalamin is the maintenance of two functions, nucleic acid synthesis and the methylation reactions. The latter is particularly important in the brain and relies especially on maintaining the concentration of S-adenosylmethionine (SAM) which, in turn, maintains the methylation reactions whose inhibition is considered to cause cobalamin deficiency associated neuropathy. SAM mediated methylation reactions are inhibited by its product S-adenosylhomocysteine (SAH). This occurs when cobalamin is deficient and, as a result, methionine synthase is inhibited causing a rise of both homocysteine and SAH. Other potential pathogenic processes related to the toxic effects of homocysteine are direct damage to the vascular endothelium and inhibition of N-methyl-D-aspartate receptors.

Aged↗
PubMed1999

Cost effectiveness of omeprazole and ranitidine in intermittent treatment of symptomatic gastro-oesophageal reflux disease.

OBJECTIVE: This 1-year study compared the cost effectiveness of omeprazole and ranitidine when used as initial therapy in an intermittent treatment strategy for the management of patients with symptomatic gastro-oesophageal reflux disease with or without erosive oesophagitis. DESIGN AND SETTING: A prospective health economic analysis was conducted alongside an international multicentre randomised, double-blind clinical study. The economic analysis was performed from a societal perspective. PATIENTS: A total of 704 patients in the UK, the Republic of Ireland, Germany, France, Italy and Spain were randomised to 1 of the 3 treatment groups. INTERVENTIONS: Patients were randomised to receive either omeprazole 20 mg once daily, omeprazole 10 mg once daily or ranitidine 150 mg twice daily. Initial treatment failure resulted in dose titration and drug switching from ranitidine to omeprazole, and subsequently open maintenance treatment. MAIN OUTCOME MEASURES AND RESULTS: The estimated mean direct medical costs (medication and number of visits and endoscopies) were found to be lower for both dosages of omeprazole than for ranitidine in all countries except Germany. However, none of the differences were statistically significant. The differences between omeprazole 10 mg and omeprazole 20 mg were small and nonsignificant. With regard to numbers of symptom-free days, both omeprazole 20 mg and omeprazole 10 mg were found to be more effective than ranitidine. However, none of the differences were statistically significant. CONCLUSIONS: Following a pragmatic interpretation, incorporating intermediate short term results, the results in this study give no support to the notion that a step-up approach, either as dose titration from omeprazole 10 mg to omeprazole 20 mg or as drug switching from ranitidine to omeprazole, will result in cost savings and thereby be cost effective.

Algorithms↗
PubMed1998

Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: low folate status alone may be the critical factor.

Thermolabile 5,10-methylenetetrahydrofolate reductase (MTHFR) is the first folate-related variant to be associated with an increased risk of neural tube defects (NTDs). The variant causes high plasma homocysteine levels and reduced red cell folate (RCF) levels, both of which have also been linked to an increased risk of NTDs. We examined the relationship between folate status and presence of the common mutation MTHFR C677T in 82 NTD-affected and 260 control mothers. Homozygosity for the TT genotype was associated with very low folate status among both the cases (n = 13) and the controls (n = 21). However, after exclusion of TT homozygotes, only 10% of the remaining 240 controls had RCF levels less than 200 microg/L compared with 29% of the 69 cases (odds ratio, 3.67; 95% confidence interval, 1.88-7.18; P < 0.001), and those with RCF less than 150 microg/L had eight times higher risk of NTD than subjects with levels over 400 microg/L. Plasma homocysteine levels of non-TT cases were also higher than those of controls (P = 0.047). This study shows that homozygosity for the C677T MTHFR variant cannot account for reduced blood folate levels in many NTD-affected mothers. Thus, a strategy of genetic screening of all childbearing women for this variant would be ineffective as a method of primary prevention of NTDs. The data suggest that low maternal folate status is itself the major determinant of NTD risk, or else that other folate-dependent genetic variants confer risk through the reduction of folate levels. These results emphasize the importance of a food-fortification program as a population strategy for reducing the occurrence of NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗