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Biomedical subjects

J McPartlin

Publications and source records attributed to J McPartlin.

At least 19 recordsLinked to original sources
PubMed2002

Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease.

Fortification of food with folic acid to prevent neural-tube defects in babies also lowers plasma total homocysteine, which is a risk factor for vascular disease. We investigated the effect of folate and vitamin B12 on homocysteine concentrations. 30 men and 23 women received sequential supplementation with increasing doses of folic acid. After supplementation, the usual dependency of homocysteine on folate diminished, and vitamin B12 became the main determinant of plasma homocysteine concentration. This finding suggests that a fortification policy based on folic acid and vitamin B12, rather than folic acid alone, is likely to be much more effective at lowering of homocysteine concentrations, with potential benefits for reduction of risk of vascular disease.

Adult↗
PubMed2002

Effect of riboflavin supplementation on plasma homocysteine in elderly people with low riboflavin status.

OBJECTIVE: To investigate the effect of riboflavin supplementation on plasma homocysteine (tHcy) concentrations in healthy elderly people with sub-optimal riboflavin status. DESIGN: A double-blind, randomized, placebo-controlled riboflavin supplementation trial. SETTING: Community based study in Northern Ireland. SUBJECTS: From a screening sample of 101 healthy elderly people, 52 had sub-optimal riboflavin status (erythrocyte glutathione reductase activation coefficient, EGRAC>or=1.20) and were invited to participate in the study. INTERVENTION: The intervention had two parts. Part 1 was a 12 week randomized double blind, placebo-controlled intervention with riboflavin (1.6 mg/day). Following completion of part 1, the placebo group went on to part 2 of the study which involved supplementation with folic acid (400 micro g/day) for 6 weeks followed by folic acid and riboflavin (1.6 mg/day) for a further 12 weeks, with a 16 week washout period post-supplementation. The purpose of part 2 was: (a) to address the possibility that homocysteine-lowering in response to riboflavin may be obscured by a much greater effect of folate, and that, once folate status was optimized, a dependence of homocysteine on riboflavin might emerge; and (b) to demonstrate that these subjects had homocysteine concentrations which could be lowered by nutritional intervention. RESULTS: Although riboflavin supplementation significantly improved riboflavin status in both parts 1 and 2 of the study (P<0.001 for each), tHcy concentrations were unaffected (P=0.719). In contrast, folic acid supplementation (study part 2) resulted in a homocysteine lowering of 19.6% (P=0.001). CONCLUSION: Despite the metabolic dependency of tHcy on riboflavin, it did not prove to be an effective homocysteine-lowering agent, even in the face of sub-optimal riboflavin status.

Aged↗
PubMed2002

Low-dose folic acid lowers plasma homocysteine levels in women of child-bearing age.

BACKGROUND: Ongoing clinical trials are investigating whether lowering plasma homocysteine reduces the risk of vascular disease. If so, food fortification with folic acid will be the likely result, and sub-optimal amounts are likely to be preferred, for safety reasons. Dose-finding studies are needed before the outcomes of these trials, to establish the benefits and risks of folic acid consumption over the widest intake range likely to be encountered. AIM: To find the lowest dose of folic acid that effectively reduces plasma homocysteine in premenopausal women. DESIGN: Double-blind, randomized placebo-controlled trial. METHODS: Women of child-bearing age (n=95) were randomly allocated to 0, 100, 200, or 400 microg/day of folic acid. Red-cell folate and plasma homocysteine were measured at baseline and after 10 weeks supplementation. RESULTS: Median red cell folate levels increased significantly in the 200 microg(p=0.0001) and 400 microg(p=0.0001) groups; but not in the placebo (0 microg) (p=0.25) or the 100 microg (p=0.5) groups. Only the 200 microg and the 400 microg groups had significant decreases in plasma homocysteine, (p=0.04 and p=0.0008, respectively). However, when subjects whose initial plasma homocysteine was <8 micromol/l (already optimally low) were removed from the analysis, there were significant plasma homocysteine decreases in all three treatment groups, but not the placebo group. DISCUSSION: In this sub-population, low doses of folic acid significantly lower plasma homocysteine. This could be achieved safely by fortification.

Adult↗
PubMed2001

Randomized trial of folic acid supplementation and serum homocysteine levels.

BACKGROUND: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Adult↗
PubMed2001

Effect of supplemental methionine on plasma homocysteine concentrations in healthy men: a preliminary study.

Hyperhomocysteinaemia is an established risk factor for vascular disease. The only source of homocysteine in humans is the amino acid methionine found in dietary protein. In an 8-week study, fasting plasma homocysteine concentrations were examined in a group of healthy male subjects (n = 6) under usual dietary conditions (weeks 1-4) and in response to weekly graded (25, 50 and 75 mg/kg/d) supplementary methionine (weeks 5, 6, 7). Nutrient intakes, including methionine, were calculated from 4 x 3 day food records. Under usual dietary conditions (mean methionine intake; 0.95 +/- 0.51 mg/d) weekly mean plasma homocysteine concentrations for the group were not significantly different (ANOVA) from each other ranging from 6.82 +/- 1.77 to 9.42 +/- 2.73 mumol/l. Doubling (supplementing with 25 mg/kg/d; + 2.04 g/d) or quadrupling (50 mg/kg/d; + 4.08 g/d) methionine intakes did not result in a significant increase in plasma homocysteine (8.56 +/- 3.68 mumol/l and 13.37 +/- 5.09 mumol/l respectively). A significant increase, however, was achieved when diets were supplemented with methionine at the highest level of 75 mg/kg/d (+6.14 g/d) resulting in a mean plasma homocysteine concentration of 18.05 +/- 11.8 mumol/l. Mean plasma homocysteine concentration returned to baseline (8.76 +/- 3.42 mumol/l), 10 days post-supplementation. The results of this study indicate that an increased dietary methionine will only cause elevated fasting homocysteine concentrations if ingested at intakes equivalent to five times usual intake. Because it is very unlikely that such levels could be achieved through dietary means alone we conclude that plasma homocysteine is unlikely to be affected by longer-term changes in food methionine intake.

Adult↗
PubMed2001

Low-dose vitamin B-6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete.

BACKGROUND: Current data suggest that physiologic doses of vitamin B-6 have no significant homocysteine-lowering effect. It is possible that an effect of vitamin B-6 was missed in previous trials because of a much greater effect of folic acid, vitamin B-12, or both. OBJECTIVE: The aim of this study was to investigate the effect of low-dose vitamin B-6 supplementation on fasting total homocysteine (tHcy) concentrations in healthy elderly persons who were made replete with folate and riboflavin. DESIGN: Twenty-two healthy elderly persons aged 63-80 y were supplemented with a low dose of vitamin B-6 (1.6 mg/d) for 12 wk in a randomized, double-blind, placebo-controlled trial after repletion with folic acid (400 microg/d for 6 wk) and riboflavin (1.6 mg/d for 18 wk); none of the subjects had a vitamin B-12 deficiency. RESULTS: Folic acid supplementation lowered fasting tHcy by 19.6% (P < 0.001). After folic acid supplementation, baseline tHcy concentrations ranged from 6.22 to 23.52 micromol/L and 10 subjects had suboptimal vitamin B-6 status (plasma pyridoxal-P < 20 nmol/L). Two-way analysis of variance showed that the significant improvement in vitamin B-6 status in response to vitamin B-6 supplementation (on the basis of both pyridoxal-P: and the erythrocyte aspartate aminotransferase activation coefficient) was reflected in a significant reduction in plasma tHcy of 7.5%. CONCLUSIONS: Low-dose vitamin B-6 effectively lowers fasting plasma tHcy in healthy subjects who are both folate and riboflavin replete. This suggests that any program aimed at the treatment or prevention of hyperhomocysteinemia should include vitamin B-6 supplementation.

Aged↗
PubMed2001

Plasma homocysteine is not subject to seasonal variation.

BACKGROUND: Studies investigating the relationship between plasma total homocysteine (tHcy) and vascular disease usually rely on a single measurement. Little information is available, however, on the seasonal variability of plasma tHcy. The aim of this study was to investigate the seasonal variation in fasting plasma tHcy and related B-vitamin intake and status in a group of people who did not consume fortified foods or take B-vitamin supplements. METHODS: In this longitudinal study, a group of 22 healthy people were followed for 1 year. A fasting blood sample and dietary information were collected from each individual every 3 months, i.e., at the end of each season. RESULTS: There was no significant seasonal variation in plasma tHcy or in B-vitamin intake or status with the exception of red cell folate (significantly lower in spring compared with autumn or winter) and serum folate (significantly lower in spring compared with the other seasons). Although the between-person variation in plasma tHcy was high (47%), the within-person variation was low (11%). This low variation, combined with the low methodologic imprecision of 3.8%, yielded a high reliability coefficient for plasma tHcy (0.97). CONCLUSIONS: Although there was a small seasonal variation in folate status, there was no corresponding seasonal variation in plasma tHcy. The high reliability coefficient for plasma tHcy suggests that a single measurement is reflective of an individual's average plasma tHcy concentration, thus indicating its usefulness as a potential predictor of disease. This, however, needs to be confirmed in different subgroups of the population.

Adolescent↗
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

Optimization of routine plasma homocysteine monitoring.

An elevated plasma homocysteine (Hcy) level is now considered to be an important risk factor in arterial and venous thromboembolic events. As a result of this relatively recent finding, there has been a dramatic increase in the number of requests for Hcy measurement. In our laboratory, this demand has been met by employing an automated immunoassay and improving the pre-analytical handling of blood samples. An automated fluorescent polarization immunoassay (FPIA) gave similar results to a reference high-pressure chromatographic (HPLC) method (r2 = 0.98, enzyme immunoassay = 0.998 HPLC - 0.3) and excellent between-run reproducibility (coefficient of variation <3%). The new assay also required less specialized technical input, and improved the sample throughput two-fold. Pre-analytical stability of plasma Hcy concentrations in blood samples is crucial to the accuracy of Hcy monitoring. This stability was improved 10-fold by adopting the anticoagulant acidic citrate instead of ethylenediamine tetraacetic acid for Hcy screening by FPIA. Acidic citrate dramatically inhibits time-related plasma contamination by red-cell Hcy, resulting in improved accuracy and a reduced number of 'spoiled' specimen discards.

Drug Monitoring↗
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

Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine.

BACKGROUND: There is a need for systematic evaluation of methods before their release to the market. We addressed this problem in novel homocysteine assays as part of an European Demonstration Project involving six centers in four countries. METHODS: Two immunological methods for measurement of plasma total homocysteine (P-tHcy), the fluorescence polarization immunoassay (FPIA) and the enzyme immunoassay (EIA), were compared with two comparison methods, HPLC and gas chromatography-mass spectrometry (GC-MS). All laboratories performed the following procedures: (a) familiarization; (b) determination of linearity and precision by analyzing five plasma samples with interrelated concentrations for 20 days; (c) correlation using patients' samples; and (d) assessment of long-term performance. RESULTS: Both immunological methods were linear for P-tHcy between 5 and 45 micromol/L. The intralaboratory imprecision (CV) was <5% for FPIA and <9% for EIA used with a sample processor. The bias was -2% to 3% for FPIA and 2-4% for EIA used with a sample processor. CONCLUSIONS: The immunological methods provide results with little bias compared with HPLC and GC-MS. The imprecision of the assays must be considered in the context of their intended use(s).

Fluorescence Polarization Immunoassay↗
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↗
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

The effects of fasting and refeeding healthy volunteers on serum folate levels.

Fasting serum folate levels are commonly used in assessing folate status and also in estimating the bioavailability of synthetic folic acid and food folate. Previous work has shown that serum folate more than doubles in concentration during a 48 hour fast. Following a 24-hour standardisation procedure, serum and urinary folate levels were measured in nine healthy female volunteers fasting for 36 hours and in the first 6 hours during refeeding. Serum folate concentration increased from a mean of 14.8 ng/ml to 29.3 ng/ml during the 36 hour fast and fell to 22.1 ng/ml during the 6 hour refeeding period. The rise in serum folate concentration during the fast was negatively related to serum folate concentration at 0 hours fasting. It is hypothesised that the enterohepatic recirculation of folate plays an important role in the underlying physiological mechanism. These findings highlight the need to standardise energy intake to control for hepatic influences on folate metabolism in future studies assessing the bioavailability of folate in food.

Adolescent↗
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↗