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Biomedical subjects

J Selhub

Publications and source records attributed to J Selhub.

At least 109 records · Page 6Linked to original sources
PubMed1996

High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients.

Hyperhomocysteinemia, an arteriosclerotic risk factor, persists in 75% of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine (Hcy) metabolism, and normal or supernormal plasma status of these vitamins (Atherosclerosis 114:93, 1995). We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid (15 mg/day), B-6 (100 mg/day), and B-12 (1 mg/day) to the usual daily dosing of 1 mg folic acid, 10 mg B-6, and 12 micrograms B-12, in 27 hyperhomocysteinemic dialysis patients. Total plasma homocysteine was measured at baseline, and after four and eight weeks. Blinded analyses revealed no evidence of toxicity in the group randomized to supraphysiologic dose B-vitamin supplementation. Plasma homocysteine was significantly reduced after both four weeks (-29.8% vs. -2.0%; P = 0.0024) and eight weeks (-25.8% vs. +0.6%; P = 0.0009) of active versus placebo treatment. Also, 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range (< 15 mumol/liter). Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients.

Adult↗
PubMed1996

Folate synthesized by bacteria in the human upper small intestine is assimilated by the host.

BACKGROUND & AIMS: Some intestinal flora are known to synthesize folate. The aim of this study was to determine whether folate synthesized by small intestinal flora is assimilated by the human host. METHODS: Subjects with atrophic gastritis and healthy volunteers were studied before and after omeprazole administration. A double-lumen perfusion tube was placed in the duodenum. 3H-labeled P-aminobenzoic acid, a precursor substrate for bacterial folate synthesis, was perfused. Downstream intestinal aspirates and a 48-hour urine collection were obtained. RESULTS: Atrophic gastritis and omeprazole administration were associated with increases in duodenal pH and in small intestinal flora. Bacterially synthesized folates were isolated from the intestinal aspirates. Tritiated 5-methyltetrahydrofolate, a major metabolite of folate, was isolated from the urine of omeprazole-treated subjects in greater quantities than from drug-free subjects (P<0.01); the quantity of tritiated 5-methyltetrahydrofolate in the urine of the subjects with atrophic gastritis was similarly elevated. CONCLUSIONS: (1) Mild bacterial overgrowth caused by atrophic gastritis and administration of omeprazole are associated with de novo folate synthesis in the lumen of the small intestine; (2) the human host absorbs and uses some of these folates; and (3) the contribution to folate nutriture from this source remains unclear.

4-Aminobenzoic Acid↗
PubMed1996

A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians.

OBJECTIVE: To assess prospectively the risk of myocardial infarction (MI) associated with decreased plasma levels of folate and pyridoxal phosphate (PLP, a form of vitamin B6) in relation to elevated levels of total homocysteine (tHcy). DESIGN: Nested case-control study using prospectively collected blood samples. SETTING: Participants in the Physicians' Health Study. SUBJECTS: 14,916 male physicians, aged 40-84 years, with no prior MI or stroke provided plasma samples at baseline and were followed for 7.5 years. Samples from 333 men who subsequently developed MI, and their paired controls matched by age and smoking, were analyzed for folate and PLP levels. MEASURES OF OUTCOME: Acute MI or death due to coronary disease. RESULTS: In a model controlling for diabetes, angina, hypertension, Quetelet's index, and total/high-density lipoprotein cholesterol, men with the lowest 20% of folate levels (< 2.0 ng/mL) had a relative risk of 1.4 (95% confidence interval 0.9-2.3) compared with those in the top 80%. For the lowest 20% of vitamin B6 values, the relative risk was 1.5 (95% CI: 1.0-2.2). When we included both folate and B6 in a model with cardiovascular risk factors, the relative risk of MI for low as compared to high levels of folate was 1.3 (95% CI: 0.8-2.1) and for PLP, 1.3 (95% CI: 0.9-2.1). Adding tHcy to this model did not add significant predictive value (chi sq = 2.0, p > 0.05), except in the first half of the follow-up interval when men with the top 5% of tHcy values had an almost three-fold increase in risk of MI. CONCLUSIONS: Although not statistically significant, these prospective data are compatible with the hypothesis that low dietary intake of folate and/or vitamin B6 contribute to risk of MI.

Adult↗
PubMed1996

Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status.

Serum homocysteine concentrations have been shown to be a sensitive functional indicator of intracellular folate, vitamin B-12, and vitamin B-6 status. Chronic alcoholism is known to interfere with one-carbon metabolism, for which the above vitamins serve as coenzymes. In the present study, these vitamins were assessed in 32 chronic alcoholics and 31 healthy volunteers by measuring blood vitamin concentrations as well as serum homocysteine concentrations. In chronic alcoholics, serum pyridoxal 5'-phosphate and red blood cell folate concentrations were significantly lower than in the control subjects (P < 0.001 and P = 0.008, respectively). Mean serum homocysteine was twice as high in chronic alcoholics than in nondrinkers (P < 0.001). Beer consumers had significantly lower concentrations of homocysteine compared with drinkers of wine or spirits (P = 0.05). These results suggest that by interfering with folate or vitamin B-6 metabolism, chronic alcohol intake may impair the disposal of homocysteine through the transmethylation or transsulfuration pathways.

Adult↗
PubMed1996

Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits.

Fasting plasma total homocysteine (tHcy) concentration was measured in 380 men and 204 women selected for health on the basis of clinical history, physical examination, and normal results of a biochemical profile. We sought to define tHcy reference values in healthy individuals and to determine relations between tHcy and plasma folic acid, vitamin B-12, and pyridoxal phosphate (vitamin B-6) concentrations. Men had significantly higher plasma tHcy than women (9.7 +/- 4.9 compared with 7.6 +/- 4.1 mumol/L, x +/- SD) and lower folate concentrations (8.6 +/- 5.2 compared with 9.8 +/- 6.6 nmol/L, P < 0.05). Significant correlations were found between tHcy and uric acid, creatinine, albumin, folate, and vitamin B-12 concentrations. There was no correlation with age, body mass index, blood pressure, glucose, and total and lipoprotein lipids. When divided in quartiles of vitamin concentrations, subjects with the lowest vitamin B-12 and folate values had significantly higher tHcy concentrations than those in the other three quartiles. Interestingly, after exclusion of subjects in the lowest quartiles of folate and vitamin B-12 concentration, correlations between tHcy and vitamin concentrations were no longer observed, except for vitamin B-12 in men. Stepwise-multiple-regression analyses showed that the sex-specific influence of biological variables on tHcy concentrations was twice as important in healthy women than in healthy men. This study emphasizes the significance of sex-associated differences in the biology of homocysteine and underlines the importance of considering these in the determination of threshold values.

Adult↗
PubMed1996

Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study.

We examined the relationship between intake of food group (and supplement) sources of folate and plasma folate and homocysteine concentrations among 885 elderly subjects in the Framingham Heart Study. Dietary data were collected by food-frequency questionnaire, and blood samples analyzed for folate and homocysteine concentrations. Top contributors to total folate intake were ranked. Mean folate intake, plasma folate and homocysteine concentrations were estimated for users vs. non-users of supplements, and key foods--those which both contribute to total folate intake and are known to be good sources of folate--and examined statistically with adjustment for age, gender and total energy intake. Plasma folate and homocysteine concentrations were also determined by quintile of intake frequency for breakfast cereals and for fruits and vegetables. Plasma folate was significantly greater and homocysteine lower in women than in men. Despite somewhat greater plasma folate concentrations with age, homocysteine was significantly higher in those over 80 y of age than in younger subjects. Major contributors to folate intake were cold breakfast cereals (13.3%), multivitamins (12.8%) and orange juice (12.4%). Users of supplements, breakfast cereals, or green leafy vegetables had significantly greater plasma folate and lower homocysteine levels than non-users. Plasma folate concentration was also greater in those who drank orange juice. We identified clear dose-response relationships for both plasma folate and homocysteine with increased quintile of breakfast cereal and of fruit and vegetable use. Frequent consumption of these foods is associated with higher folate and lower homocysteine concentrations.

Aged↗
PubMed1996

Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population.

Recent studies demonstrated associations between occlusive vascular disease and hyperhomocysteinemia of both genetic and nutritional origin. In the present study we analyzed plasma samples from the 20th biannual examination of the Framingham Heart Study cohort to determine distribution of plasma homocysteine concentrations with emphasis on relationships to B vitamins and prevalence of carotid artery stenosis. Results showed that homocysteine exhibited strong inverse association with plasma folate and weaker associations with plasma vitamin B-12 and pyridoxal-5'-phosphate (PLP). Homocysteine was also inversely associated with intakes of folate and vitamin B-6, but not vitamin B-12. Prevalence of high homocysteine (>14 micromol/l) was 29.3% in this cohort, and inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine. Prevalence of stenosis > or = 25% was 43% in men and 34% in women with an odds ratio of 2.0 for individuals in the highest homocysteine quartile (> or = 14.4 micromol/l) compared with those in the lowest quartile (< or = 9.1 micromol/l), after adjustment for sex, age, high density lipoprotein cholesterol, systolic blood pressure and cigarette smoking (Ptrend < 0.001). Plasma concentrations of folate and pyridoxal-5'-phosphate and folate intake were inversely associated with extracranial carotid stenosis after adjustment for age, sex and other risk factors.

Aged↗
PubMed1995

Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease.

BACKGROUND: High plasma homocysteine is associated with premature coronary artery disease in men, but the threshold concentration defining this risk and its importance in women and the elderly are unknown. Furthermore, although low B vitamin status increases homocysteine, the link between these vitamins and coronary disease is unclear. METHODS AND RESULTS: We compared 304 patients with coronary disease with 231 control subjects. Risk factors and concentrations of plasma homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate were documented. A homocysteine concentration of 14 mumol/L conferred an odds ratio of coronary disease of 4.8 (P < .001), and 5-mumol/L increments across the range of homocysteine conferred an odds ratio of 2.4 (P < .001). Odds ratios of 3.5 in women and of 2.9 in those 65 years or older were seen (P < .05). Homocysteine correlated negatively with all vitamins. Low pyridoxal 5'-phosphate (< 20 nmol/L) was seen in 10% of patients but in only 2% of control subjects (P < .01), yielding an odds ratio of coronary disease adjusted for all risk factors, including high homocysteine, of 4.3 (P < .05). CONCLUSIONS: Within the range currently considered to be normal, the risk for coronary disease rises with increasing plasma homocysteine regardless of age and sex, with no threshold effect. In addition to a link with homocysteine, low pyridoxal-5'-phosphate confers an independent risk for coronary artery disease.

Age Factors↗
PubMed1995

Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate.

We determined plasma levels of homocysteine in 584 healthy subjects (380 men and 204 women) from a major utility company in the province of Québec, Canada, and in 150 subjects (123 men and 27 women) with angiographically documented coronary artery disease (CAD) (age < 60 years). Plasma levels of vitamins B12, B6, pyridoxal phosphate (a vitamin B6 derivative), and folate were also determined. Mean homocysteine levels were higher (p < 0.05) in the bottom quartiles for folate, vitamin B12, and pyridoxal phosphate. A significant correlation was noted between homocysteine levels and folate and vitamin B12 levels. No significant correlation was found between plasma homocysteine levels and age, lipids and lipoprotein cholesterol, glucose, and the presence of hypertension or cigarette smoking in healthy subjects or in patients with CAD. Control men had higher homocysteine levels than control women (p < 0.005). Men and women with CAD had higher levels of homocysteine than controls (11.7 +/- 5.8 vs 9.7 +/- 4.9 nmol/ml [p < 0.001] and 12.0 +/- 6.3 vs 7.6 +/- 4.1 nmol/ml, p < 0.01, respectively). Women and men with CAD had similar homocysteine levels. The proportion of patients with CAD having homocysteine levels > 90th percentile of controls was 18.1% for men and 44.4% for women (both p < 0.01). Significantly lower pyridoxal phosphate levels were seen in subjects with CAD, men and women combined (27.7 +/- 29.5 vs 42.1 +/- 38.4 ng/ml, p < 0.005). No significant differences were observed for B12, folate, or total B6.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.

BACKGROUND: Epidemiologic studies have identified hyperhomocysteinemia as a possible risk factor for atherosclerosis. We determined the risk of carotid-artery atherosclerosis in relation to both plasma homocysteine concentrations and nutritional determinants of hyperhomocysteinemia. METHODS: We performed a cross-sectional study of 1041 elderly subjects (418 men and 623 women; age range, 67 to 96 years) from the Framingham Heart Study. We examined the relation between the maximal degree of stenosis of the extracranial carotid arteries (as assessed by ultrasonography) and plasma homocysteine concentrations, as well as plasma concentrations and intakes of vitamins involved in homocysteine metabolism, including folate, vitamin B12, and vitamin B6. The subjects were classified into two categories according to the findings in the more diseased of the two carotid vessels: stenosis of 0 to 24 percent and stenosis of 25 to 100 percent. RESULTS: The prevalence of carotid stenosis of > or = 25 percent was 43 percent in the men and 34 percent in the women. The odds ratio for stenosis of > or = 25 percent was 2.0 (95 percent confidence interval, 1.4 to 2.9) for subjects with the highest plasma homocysteine concentrations (> or = 14.4 mumol per liter) as compared with those with the lowest concentrations (< or = 9.1 mumol per liter), after adjustment for sex, age, plasma high-density lipoprotein cholesterol concentration, systolic blood pressure, and smoking status (P < 0.001 for trend). Plasma concentrations of folate and pyridoxal-5'-phosphate (the coenzyme form of vitamin B6) and the level of folate intake were inversely associated with carotid-artery stenosis after adjustment for age, sex, and other risk factors. CONCLUSIONS: High plasma homocysteine concentrations and low concentrations of folate and vitamin B6, through their role in homocysteine metabolism, are associated with an increased risk of extracranial carotid-artery stenosis in the elderly.

Aged↗
PubMed1995

Abnormal vitamin B6 status in rheumatoid cachexia. Association with spontaneous tumor necrosis factor alpha production and markers of inflammation.

OBJECTIVE: To compare vitamin B6 levels in rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: We measured levels of vitamin B6 in 23 adults with well-controlled RA, and in 23 healthy control subjects matched for age, sex, race, and weight. RESULTS: Although plasma folate and vitamin B12 concentrations and erythrocyte B6 activity coefficients were similar in the patients and controls, plasma levels of pyridoxal-5'-phosphate (PLP) were lower in the RA patient group (mean +/- SD 46.1 +/- 48.1 versus 69.3 +/- 58.4 nmoles/liter; P < 0.004). In multivariate analyses, PLP was inversely associated with tumor necrosis factor alpha (TNF alpha) production by peripheral blood mononuclear cells (PBMC) (P < 0.001), after adjustment for age, pain score, erythrocyte sedimentation rate, and use of nonsteroidal antiinflammatory drugs. CONCLUSION: PLP levels are reduced in patients with RA. This reduction is associated with TNF alpha production by PBMC.

Adult↗
PubMed1995

Net uptake of plasma homocysteine by the rat kidney in vivo.

Hyperhomocysteinemia is a common finding in dialysis-dependent end-stage renal disease (ESRD) patients, but its etiology and refractoriness to standard homocysteine-lowering B-vitamin therapy are poorly understood. In the absence of actual in vivo data, it has been hypothesized that loss of normal renal parenchymal uptake and metabolism of homocysteine is an important determinant of hyperhomocysteinemia in ESRD, given that urinary homocysteine excretion by healthy kidneys is trivial. We assessed net renal uptake and metabolism of homocysteine using an established rat model for measuring arteriovenous amino acid differences across the rat kidney, along with simultaneous determination of renal plasma flow, urine flow, and urinary homocysteine concentration. Substantial homocysteine uptake and metabolism by normal rat kidneys was demonstrated, and we also confirmed that urinary homocysteine excretion is minimal. These data suggest that loss of the sizable homocysteine metabolizing capacity of the intact kidneys may be an important determinant of the refractory, potentially atherothrombotic hyperhomocysteinemia frequently observed in ESRD.

Animals↗
PubMed1995

Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study.

Hyperhomocysteimia, either fasting or after oral methionine loading, appears to be an independent risk factor for coronary heart disease (CHD). It remains unclear whether fasting total homocysteine determination alone adequately detects the full spectrum of hyperhomocysteinemic individuals. We measured fasting and 4-h post methionine loading (0.1 g L-methionine/kg body weight) total plasma homocysteine in 274 participants in The NHLBI Family Heart Study, a population-based investigation of genetic and non-genetic determinants of CHD. Of the total number (n = 47) of hyperhomocysteinemic persons, 43% (20/47) were identified only by methionine loading, while 32% (15/47) of the total number, and 75% of those with post-methionine loading hyperhomocysteinemia only (15/20), had fasting total homocysteine concentrations below the 75th percentile (10.7 mumol/l). We conclude that fasting total plasma homocysteine determination alone fails to identify a sizable percentage (> 40%) of persons who may have clinically relevant hyperhomocysteinemia post methionine loading.

Adult↗
PubMed1995

Behavioral and neurochemical changes in folate-deficient mice.

Weanling mice were fed an amino acid-based diet supplemented with 0 or 11.3 mumol folic acid/kg diet for approximately 38 days to study behavior and neurochemistry in folate deficiency. After approximately 5 wk, mice fed the unsupplemented diet weighted approximately 70% as much those fed the supplemented diet. After 2 wk, mice fed the unsupplemented diet consistently discarded (spilled) more food, and after approximately 5 wk, they had spilled 3 times more than mice fed the supplemented diet. Serum folate, brain folate and brain S-adenosylmethionine of mice fed the unsupplemented diet were 4, 53, and 60% as high, respectively, as those of mice fed the supplemented diet. Pathologic changes were not evident in brain, spinal cord, or skeletal muscle of folate-deficient mice. The hypothalamic 5-hydroxyindole acetic acid/serotonin ratio and caudate dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations were lower in deficient than control mice. Folate-deficient mice develop a behavioral activity, food spilling, which may have a neurochemical basis in the serotonin and dopamine systems.

Animals↗
PubMed1995

Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats.

Global and gene-specific DNA hypomethylation is considered to be an important early epigenetic event in several human neoplasms. A growing body of evidence has suggested that DNA methylation can be altered by dietary manipulation of methyl group donors. This study investigated whether moderate depletion of folate, a dietary component needed for the synthesis of methyl groups, would cause decreased hepatic and colonic S-adenosylmethionine concentrations, and thereby lead to global and/or protooncogene-specific DNA hypomethylation. Weanling rats were fed an amino acid-defined diet containing either 0 or 8 mg folate/kg diet for 15 or 24 wk. Significantly lower systemic, hepatic and colonic folate concentrations were observed in the moderately folate-depleted rats than in controls at both 15 and 24 wk (P < 0.005). Although hepatic S-adenosylmethionine was significantly lower in the moderately folate-depleted rats than in controls at the two time points (P < 0.03), colonic S-adenosylmethionine concentrations were not significantly different between the two groups at either time point. No significant differences between the folate-depleted and control animals could be detected with regard to global DNA methylation in the liver or colonic mucosa. Furthermore, c-myc protooncogene-specific DNA methylation in the colonic mucosa was not significantly different between these two groups of animals. These results indicate that moderate folate depletion does not cause a significant reduction in global DNA methylation in liver or colonic mucosa or in c-myc-specific colonic mucosal DNA methylation in this rat model.

Animals↗
PubMed1995

Trait shyness in the elderly: evidence for an association with Parkinson's disease in family members and biochemical correlates.

The emergence of potential treatments to slow the progression of idiopathic Parkinson's disease (PD) has increased the need for early identification of persons at risk. Although considered controversial, some prior studies indicate that PD patients may have premorbid histories of greater trait introversion or shyness as well as increased rates of disorders associated with shyness (e.g., anxiety, affective disorders, and irritable bowel syndrome). Essential features of trait shyness include (a) inhibited and avoidant behaviors and (b) physiological hyperreactivity to the novel or unfamiliar. In parallel, (a) depression in PD patients is associated with increased harm avoidance (a possible serotonergic function), and (b) PD patients have premorbid and comorbid decreases in novelty-seeking (a possible dopaminergic function). Taken together, previous research suggests the following hypotheses: (1) given evidence for marked heritability of shyness, shy elderly should report higher rates of PD in their family members than would nonshy elderly; and (2) shy elderly without PD should exhibit psychological and biologic characteristics similar to those reported in PD. Two groups, representing the top 27% (n = 37) and bottom 31% (n = 43) of scores on a standardized shyness scale, were drawn from a larger cohort of 138 older adults (ages 50-90) living in an active retirement community. Seventeen percent of the shy versus 2% of the nonshy reported PD in a family member or self (P < .05). Shy elderly were significantly more anxious (P < .01) and depressed (P < .05) than were the nonshy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗