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D G Weir

Publications and source records attributed to D G Weir.

At least 55 records · Page 3Linked to original sources
PubMed1998

Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention.

BACKGROUND: Results from prospective studies of serum homocysteine levels and ischemic heart disease (IHD) are inconclusive. We carried out a further prospective study to help clarify the position. METHODS: In the British United Provident Association (BUPA) prospective study of 21,520 men aged 35 to 64 years, we measured homocysteine levels in stored serum samples and analyzed data from 229 men without a history of IHD at study entry who subsequently died of IHD and 1126 age-matched control subjects (nested case-control design). RESULTS: Serum homocysteine levels were significantly higher in men who died of IHD than in men who did not (mean, 13.1 vs 11.8 micromol/L; P<.001). The risk of IHD among men in the highest quartile of serum homocysteine levels was 3.7 times (or 2.9 times after adjusting for other risk factors) the risk among men in the lowest quartile (95% confidence interval [CI], 1.8-4.7). There was a continuous dose-response relationship, with risk increasing by 41% (95% CI, 20%-65%) for each 5-micromol/L increase in the serum homocysteine level. After adjustment for apolipoprotein B levels and blood pressure, this estimate was 33% (95% CI, 22%-59%). In a meta-analysis of the retrospective studies of homocysteine level and myocardial infarction, the age-adjusted association was stronger: an 84% (95% CI, 52%-123%) increase in risk for a 5-micromol/L increase in the homocysteine level, possibly because the participants were younger; the relationship between serum homocysteine level and IHD seems to be stronger in younger persons than in older persons. CONCLUSIONS: Our positive results help resolve the uncertainty that resulted from previous prospective studies. The epidemiological, genetic, and animal evidence together indicate that the association between serum homocysteine level and IHD is likely to be causal. A general increase in consumption of the vitamin folic acid (which reduces serum homocysteine levels) would, therefore, be expected to reduce mortality from IHD.

Adult↗
PubMed1998

Regional differences in protein carboxymethylation in post-mortem human brain.

1. The aim of this study was to determine the pattern of protein carboxymethylation in different regions of the human brain. 2. The availability of protein methylation sites was determined by measurement of the incorporation of methyl-3H groups into proteins isolated from post-mortem brain tissue. The stability of protein carboxymethylation in post-mortem brain was determined by sampling post-mortem pig and human brain tissue at intervals during the first 24 h after death. This method has previously been used to demonstrate that decreased protein carboxymethylation occurred in post-mortem pig brain when methionine synthase was inhibited. 3. There were no significant differences in the protein carboxymethyltransferase activity in samples of pig brain obtained at the time of death compared with that obtained when the same tissue was maintained at room temperature for up to 24 h after death. Similarly, there were no significant differences in the protein carboxymethyltransferase activity in samples isolated from human brain 12 h after death compared with that obtained from the same human brain tissue maintained at room temperature for up to 24 h after death. These results suggest that the level of carboxymethylation of proteins from human post-mortem brain obtained within 24 h of death is not significantly different to the level present at the time of death. To characterize the distribution of protein carboxymethylation in human brain, nine regions of post-mortem brain were sampled from 16 human subjects. Protein carboxymethyltransferase activity was lowest in the cerebellum (P < 0.05) and highest in cortical white matter compared with other regions of the brain (P < 0.05). No significant differences in protein carboxymethyltransferase activity were noted between other regions of the cortex or the subcortical regions. 4. In human cortical white matter there are more available sites for protein carboxymethylation than other brain regions. This may explain the greater sensitivity of white matter to the adverse consequences of hypomethylation associated with vitamin B12 deficiency. Post-mortem brain tissue can serve as a tool for the study of physiological or pathological factors which influence human brain protein methylation in vivo.

Adult↗
PubMed1998

CD4+ CD8+ and CD8alpha+ beta- T lymphocytes in human small intestinal lamina propria.

OBJECTIVE: To examine CD8 expression by T-lymphocyte subpopulations from disease-free human lamina propria. METHODS: Single-cell suspensions were prepared from the epithelial layer and the lamina propria of small intestinal biopsies obtained endoscopically from disease-free patients. Monoclonal antibodies against CD3, CD4, CD8, CD56, CD8alphabeta, CD8alpha, TCR alphabeta and TCR gammadelta were used for dual and three-colour flow cytometric analysis. RESULTS: In addition to classical CD4+ and CD8+ T lymphocytes a substantial proportion of lamina propria T lymphocytes were CD4+ CD8+ or 'double positive' (mean 14%, range 4-26%). This population was significantly lower in the epithelial layer of the same patients (mean 7%, range 3-21%, P < 0.007). Three-colour flow cytometric analysis revealed that expression of the CD8 molecule on double positive T cells in the lamina propria was limited to the CD8alpha chain. Furthermore, of the CD8+ population, CD8+ T cells which only expressed the alpha chain were present in greater numbers in the lamina propria (mean 35%, range 14-54%) than in the epithelial layer (mean 18%, range 5-37%, P < 0.02). NK (CD56+) cells were not detected and few gammadeltaTCR+ T lymphocytes were detected in the lamina propria (mean 2%, range 0.5-6.6%) when compared with the epithelial layer (mean 8%, range 0.2-14%, P < 0.008). CONCLUSION: A significant population of CD4+ CD8alpha+ T lymphocytes which are CD8beta chain negative have been detected in the intestinal lamina propria. These cells form a more significant component of the lamina propria than the epithelial layer T-cell repertoire and may have a unique function in intestinal immunoregulation.

Adolescent↗
PubMed1998

Plasma homocysteine concentrations in patients with type 1 diabetes.

OBJECTIVE: To determine the plasma concentration of total homocysteine (tHcy), a recognized risk factor for vascular disease, in patients with type 1 diabetes and to examine the relationships with age, sex, duration of diabetes, microvascular complications and neuropathy, and folic acid concentration. RESEARCH DESIGN AND METHODS: Plasma tHcy and folic acid concentrations were measured in a randomly selected cohort of type 1 diabetic patients (n = 119), well characterized as regards microvascular complications, and in a matched control group (n = 51). RESULTS: Plasma tHcy was higher in male than in female control subjects (geometric mean [95% CI]: 9.3 [8.0-10.9] vs. 6.1 [5.2-7.2] micromol/l, P < 0.001), as previously described, but there was no sex difference in diabetic patients. Plasma tHcy significantly correlated with age in patients (r = 0.348, P < 0.01) but not in control subjects (r = 0.007, P = 0.96). Male patients without microvascular complications had lower plasma tHcy concentrations than did male control subjects (6.2 [5.1-7.5] vs. 9.3 [8.0-10.9] micromol/l, P < 0.001), but values in female patients without complications were similar to those of female control subjects. Plasma folic acid concentration was higher in diabetic patients than in control subjects. The expected negative association between plasma tHcy and folic acid was stronger in control subjects than in patients. CONCLUSIONS: Subnormal tHcy concentrations in male patients, the absence of a sex difference, and the positive association with age indicate that homocysteine metabolism differs between type 1 diabetic patients and control subjects. Homocysteine is unlikely to be of pathogenic significance in patients, particularly male subjects, with early microvascular disease and/or neuropathy.

Adult↗
PubMed1998

Diagnosis of gluten-sensitive enteropathy: is exclusive reliance on histology appropriate?

OBJECTIVE: Coeliac disease is a prevalent disorder but frequently remains undiagnosed because of varied modes of clinical presentation. In this study, methods for the detection of coeliac disease were evaluated in a clinical practice setting. METHODS: Small intestinal histology, IgA anti-endomysial and IgG anti-gliadin antibody tests were performed on 441 unselected, consecutive patients under investigation for small intestinal disease. Response to treatment and other clinical events were monitored over the ensuing years. RESULTS: Untreated coeliac disease was diagnosed in 97 patients and was excluded in 344. At clinical presentation, the endomysial antibody test was positive in 84 of the 97 untreated coeliac patients (sensitivity 87%) and negative in 340 of the 344 non-coeliac patients (specificity 99%). A typical histological lesion was found in 83 of the 97 coeliac patients (sensitivity 86%) but was absent in all 344 non-coeliacs (specificity 100%). The sensitivity of the gliadin antibody test was 69% and the specificity was 71%. CONCLUSIONS: In unselected patients attending a gastroenterology clinic, small bowel histology and endomysial antibody serology show similar predictive value in the diagnosis of coeliac disease. These results emphasize that a combination of clinical, histological and serological criteria are required for effective diagnosis of this disorder. Exclusive reliance on histology or serology will result in failure to make a diagnosis in a significant proportion of patients.

Adolescent↗
PubMed1997

Minimum effective dose of folic acid for food fortification to prevent neural-tube defects.

BACKGROUND: Although a daily supplement of 400 micrograms folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 micrograms. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 micrograms/L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration. METHODS: We screened 323 women. 172 with red-cell folate between 150 micrograms/L and 400 micrograms/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 micrograms, 200 micrograms, or 400 micrograms daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study. FINDINGS: There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 micrograms/L (95% CI 43-120) and 375 micrograms/L (354-444) in the 100 micrograms/day group, 130 micrograms/L (108-184) and 475 micrograms/L (432-503) in the 200 micrograms/day group, and 200 micrograms/L (125-312) and 571 micrograms/L (481-654) in the 400 micrograms/day group. INTERPRETATION: A fortification programme that delivered 400 micrograms folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 micrograms daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 micrograms daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.

Adult↗
PubMed1997

Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations.

BACKGROUND: The dietary reference values for folate, as for other nutrients, are targeted to the general and supposedly normal population, not people with special needs, such as those with genetic or metabolic abnormalities or diseases. However, 5-15% of general populations are homozygous for a thermolabile variant of 5,10-methylenetetrahydrofolate reductase (C677T) which causes mild hyperhomocysteinaemia and is positively associated with the development of vascular disease and the risk of neural-tube defects. If tissue-folate status is compromised in large sectors of the population by this or other genetic variants, the present dietary reference values may need to be changed. METHODS: We identified the C677T genotype and measured red-cell folate concentrations in two groups of healthy women (pregnant, 242, not pregnant, 318). We then analysed the effect of genotype on red-cell folates, which are a reliable marker for tissue folate stores. FINDINGS: In the pregnant group there were 20 TT homozygotes, 114 wild-type CC homozygotes, and 108 CT heterozygotes. In the non-pregnant group, the numbers were 41, 148, and 129. In both pregnant and non-pregnant groups, red-cell folate was significantly lower among TT homozygous than CC homozygous women (mean 252 [95% CI 202-317] vs 347 [321-372] micrograms/L, p = 0.002 for pregnant women; 284 [250-327] vs 347 [342-372] micrograms/L, p = 0.01 for non-pregnant women). Plasma folate was also significantly lower in TT homozygous than in CC homozygous women in the pregnant group (p = 0.009) but not in the non-pregnant group. INTERPRETATION: These results suggest that a substantial minority of people in general populations may have increased folate needs. Future studies may show the presence of other common genetic variants that interact with particular nutrients and place doubts on the validity of assuming "normality" for nutrient requirements in any general population.

Diet↗
PubMed1997

Lipid peroxidation induced in vivo by hyperhomocysteinaemia in pigs.

Much attention has been focused recently on the relationship between homocysteinaemia and the development of premature atherosclerosis. Hyperhomocysteinaemia constitutes as strong a risk factor for the development of the disease as either hypercholesterolaemia or smoking. Although the mechanism involved is unclear homocysteine exhibits prooxidative activity in vitro. This finding suggests that it may be involved in the oxidative modification of low density lipoprotein (LDL). In the current study hyperhomocysteinaemia was induced in eight domestic pigs by intermittent exposure to nitrous oxide for 4 weeks. At necropsy, cardiac tissue was removed and malondialdehyde (MDA) and the unsaturated fatty acid content were measured and compared with values obtained from air-breathing control animals. Nitrous oxide treated animals had significantly higher tissue concentrations of MDA than the controls. There was also a reduction in the contribution of linoleic and linolenic acids to the total fatty acid content of heart. The hyperhomocysteinaemic animals also had a significantly higher iron concentration in the heart than controls. Hyperhomocysteinaemia was associated with elevations in tissue iron stores and increased in vivo lipid peroxidation.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1997

Epithelial cell folate depletion occurs in neoplastic but not adjacent normal colon mucosa.

BACKGROUND & AIMS: Restricted folate supply is associated with the development of carcinoma, and folate supplements have a protective effect in colorectal carcinoma. This effect may be mediated through correction of local folate deficiency. The aim of this study was to define the folate content of neoplastic colonic epithelial cells and its relation to that of adjacent normal tissue and circulating levels. METHODS: Epithelial cells were isolated from endoscopic biopsy specimens of normal, adenocarcinoma, adenoma, and adjacent normal colonic mucosa by ion chelation. Intracellular folate levels were determined by microbiological assay. RESULTS: Folate levels in carcinoma specimens were lower than in adjacent normal tissue (P < 0.02). Levels in adenoma epithelial cells were lower than in adjacent normal tissue, although this did not reach statistical significance (P < 0.06). Epithelial cells from normal tissue and mucosa adjacent to tumors and adenomata had similar folate contents. Blood folate and vitamin B12 indices for all groups were normal. CONCLUSIONS: Malignant colon epithelial cells show a relative localized folate deficiency. However, there is no evidence for the occurrence of generalized mucosal folate deficiency. This finding suggests that folate supplements do not inhibit carcinogenesis through correction of localized folate depletion.

Adenocarcinoma↗
PubMed1997

Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements.

Periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. The strategy of universal fortification of staple foodstuffs with folic acid presents the possibility of life-long exposure to unmetabolized folic acid. Chief among the risks of exposure to folic acid in the circulation is that of masking the diagnosis of cobalamin deficiency in pernicious anemia and the progression of neurologic disease. Other effects are unknown. For instance, the effect of in vivo chronic exposure of adult and fetal cells to the synthetic form of the vitamin has never been investigated at the population level. This study examined the acute appearance of unmetabolized folic acid in serum in response to the consumption of some fortified foodstuffs by young and elderly volunteers. Subjects on a 5-d regimen of fortified ready-to-eat-cereal and bread in addition to their normal diet had a threshold intake of 266 micrograms folic acid per meal at which unaltered folic acid appeared in the serum. Subjects given folic acid in either isotonic saline, milk, or white bread also had a threshold > 200 micrograms. From patterns of food consumption in the United States, the implementation of flour fortification at 1.4 mg/kg is unlikely to lead to folic acid appearance in serum, assuming that consumption is spread throughout the day. Increasing this level of fortification, however, as has been advocated by some agencies, may result in the repeated appearance of folic acid in serum over many years, particularly in consumers in nontargeted populations of large amounts of fortified foods. The "safe level of intake" of 1 mg folate/d set by the US Food and Drug Administration may cause a serum folic acid effect. Furthermore, a repeated serum folic acid response is likely to be found in many women complying with the advice to take 400 micrograms folic acid/d to prevent the occurrence of neural tube defects.

Adolescent↗
PubMed1997

Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid.

Elevated plasma homocysteine, an independent risk factor for cardiovascular disease (CVD) can be lowered by administration of pharmacological doses of folic acid. The effect of lower doses in apparently normal subjects is currently unknown but is highly relevant to the question of food fortification. Healthy male volunteers (n = 30) participated in a chronic intervention study (26 weeks). Folic acid supplements were administered daily at doses increasing from 100 micrograms (6 weeks), to 200 micrograms (6 weeks), to 400 micrograms (14 weeks). Fasting blood samples collected before, during and 10 weeks post intervention were analysed for plasma homocysteine, serum and red-cell folate levels. Results, expressed as tertiles of baseline plasma homocysteine concentration, showed significant (p < or = 0.001) homocysteine lowering in the top (10.90 +/- 0.83 mumol/l) and middle (9.11 +/- 0.49 mumol/l) tertiles only. In the low tertile, where the mean baseline homocysteine level was 7.07 +/- 0.84 mumol/l, no significant response was observed. Of the three folic acid doses, 200 micrograms appeared to be as effective as 400 micrograms, while 100 micrograms was clearly not optimal. There is thus a minimal level of plasma homocysteine below which folic acid has no further lowering effect, probably because an optimal folate status has been reached. A dose as low as 200 micrograms/day of folic acid is effective in lowering plasma homocysteine concentrations in apparently normal subjects. Any public health programme for lowering homocysteine levels, with the goal of diminishing CVD risk, should not be based on unnecessarily high doses of folic acid.

Adult↗
PubMed1997

Endomysium: autoantigen in coeliac disease.

In coeliac disease, dietary exposure to gluten is associated with an autoimmune response to gastrointestinal antigens, including endomysium. Measurement of autoantibodies to endomysium is a highly specific and sensitive method of diagnosing coeliac disease. Analysis of the interaction between gluten and endomysium should provide a critical insight into the pathogenesis of this condition.

Autoantibodies↗
PubMed1997

Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects?

Mildly elevated maternal plasma homocysteine (Hcy) levels (hyperhomocysteinemia) have recently been observed in some neural tube defect (NTD) pregnancies. Plasma levels of Hcy are governed by both genetic and nutritional factors and the aetiology of NTDs is also known to have both genetic and nutritional components. We therefore examined the frequency of relatively common mutations in the enzyme cystathionine beta-synthase (CBS), which is one of the main enzymes that controls Hcy levels, in the NTD population. Neither the severely dysfunctional G307S CBS allele nor the recently reported 68 bp insertion/I278T CBS allele was observed at increased frequency in the cases relative to controls. We therefore conclude that loss of function CBS alleles do not account for a significant proportion of NTDs in Ireland.

Cystathionine beta-Synthase↗