Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Folate fortification of bread and grains has been directed to prevent neural tube birth defects. Research has also challenged previous concepts of folate nutritional status and suggested that folate may play a role in reducing the risk of vascular disease. Although folate status of many elderly people is adequate according to traditional, hematologic criteria, some elderly persons have elevated blood concentrations of the metabolite homocysteine, which indicates subclinical deficiency of folate or vitamin B-12. Higher homocysteine concentrations, even within the normal range, are associated with increased risk of vascular disease. Elderly people with better folate and vitamin B-12 status have lower homocysteine concentrations and may have lower risk for vascular disease. Although the new folate fortification rules provide the benefit of increasing folate in the food supply, they could be a risk for the elderly because excess folate intake can mask vitamin B-12 deficiency, thereby delaying diagnosis. Elderly people have a higher prevalence of vitamin B-12 deficiency as a result of absorption problems. Those deficient in vitamin B-12 should be treated to prevent irreversible neurologic damage. Modern approaches to screening the elderly include using higher cutoff points for serum vitamin B-12 and obtaining blood concentrations of the metabolite methylmalonic acid, which is elevated in deficiency of vitamin B-12 but not folate. To examine current folate intake and food sources, food frequency questionnaires were administered to 308 elderly volunteers aged 65 to 94 years. Mean (+/-standard error) folate intake from food was 299.6+/-5.8 microg/day. Supplements (median dose=400 microg/day) were consumed by 47% of participants. Only 3.2% of the sample had total folate intake greater than 1,000 microg/day, the recommended upper limit, and these were taking high-dose folate supplements (> or = 800 microg/day). Breakfast cereals provided 25.6% of folate intake; vegetables, 23.2%; fruit, 20.8%; refined breads/grains, 6.7%; dark bread, 5.0%; legumes/nuts, 5.9%; dairy products, 5.8%; meat/poultry/fish/eggs, 5.1%; other, 1.9%. Mean folate intake would increase 16.5% if enriched bread and grains were fortified. Such fortification could help some persons to lower serum homocysteine concentration and vascular disease risk. Dietitians should be aware of modern protocols for screening the elderly for vitamin B-12 deficiency.
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PMID:Folate nutrition and older adults: challenges and opportunities. 902 Feb 45

L-Dopa is the most effective drug known for the treatment of Parkinson's disease. However, the large doses required to treat this neurodegenerative disorder can significantly affect tissue concentrations of sulfur amino acid metabolites due to peripheral and central O-methylation. These effects include decreases in tissue concentrations of the biochemical methyl donor S-adenosylmethionine (SAM), increases in tissue concentrations of the methylation inhibitor S-adenosylhomocysteine (SAH), and increases in plasma concentrations of homocysteine, recently identified as an independent risk factor for vascular disease. In the present study, the ability of the catechol-O-methyltransferase inhibitor Ro 41-0960 to prevent L-Dopa-induced changes in SAM, SAH, and homocysteine concentrations was determined in rats. Rats were injected intraperitoneally with Ro 41-0960 or vehicle 30 min prior to an intraperitoneal injection of L-Dopa or vehicle. One hour after the second injection, the rats were killed and their brains, livers, spleens, kidneys, and plasma collected. SAM and SAH concentrations were then determined in discrete brain regions and peripheral tissues, and total homocysteine concentrations were determined in plasma. In the rats treated with only L-Dopa, decreased SAM concentrations and increased SAH concentrations were found in all brain regions and peripheral tissues measured, and increased homocysteine concentrations were found in plasma, consistent with previous reports. In rats pretreated with Ro 41-0960, however, these L-Dopa-induced effects on sulfur amino acid metabolite concentrations were attenuated or prevented entirely. It remains to be determined if this sparing effect of Ro 41-0960 on sulfur amino acid metabolites has clinical significance.
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PMID:Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats. 903 74

Homocysteine is an intermediate compound formed during metabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.
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PMID:Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease. 912 8

It has been reported that patients with vascular disease seem to increase their concentration of plasma homocysteine after the acute episode, whereas reexamined control subjects do not change their concentration of plasma homocysteine over time. Since the main determinants of plasma homocysteine are serum cobalamin, blood folate and serum creatinine we measured these quantities in 20 control subjects and 49 stroke patients in the acute phase and at reexamination 1.5-2 years after acute stroke onset. There were no significant differences between the levels of blood folate, serum cobalamin and serum creatinine in the acute and convalescent phase of all 49 stroke patients. However, we noted a significant decrease of blood folate concentrations in a subgroup of patients (n = 25) who had increased plasma homocysteine concentrations. Thus the increase in plasma homocysteine concentrations in this group of patients may partly be caused by a marginal folate deficiency.
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PMID:Marginal folate deficiency as a possible cause of hyperhomocystinaemia in stroke patients. 915 62

Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine's neurotoxic (agonist) attributes at 10-100 microM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.
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PMID:Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. 915 76

Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677-->Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2l93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogenemia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease and also for venous thrombosis.
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PMID:The mutation Ala677-->Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. 918 84

A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, a C to T substitution at nucleotide 677, is responsible for reduced MTHFR activity and associated with modestly increased plasma homocysteine concentrations. Since underlying maternal vascular disease increases the risk of pre-eclampsia, we had the working hypothesis that pre-eclampsia patients would have an increased T677 allele frequency compared with controls. The MTHFR genotypes were determined in 67 pre-eclampsia patients, 98 normal pregnant women, and 260 healthy adults by the PCR/RFLP method. The T677 allele and the genotype homozygous for the T677 allele were significantly increased in the pre-eclamptic group compared with the controls (p < 0.02 and p < 0.004, respectively). The data indicate that the T677 variant of the MTHFR gene is one of the genetic risk factors for pre-eclampsia.
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PMID:Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. 919 80

First recognized in patients with rare inborn errors of metabolism, the association of elevated plasma homocysteine concentrations with atherosclerosis and thrombosis now seems relevant to the general population as well. The mechanism of injury appears to involve oxidative damage to endothelial cells. Vitamin supplementation can normalize homocysteine levels and may lower the incidence of atherothrombotic vascular disease.
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PMID:Homocysteine, oxidative stress, and vascular disease. 927 60

This review of recent advances covers (1) the metabolism of methionine and its regulation, emphasizing interactions with the three important vitamins folate, cobalamin and pyridoxine; (2) present knowledge of enzymological and moleculargenetic aspects of homozygous deficiencies of the three enzymes which cause elevated homocyst(e)ine; (3) recent clinical findings, post-methionine loading results related to enzyme and mutation studies in obligate heterozygotes for cystathionine beta-synthase deficiency; (4) important new evidence for disturbed homocysteine metabolism in neural tube defects, particularly based on studies of the thermolabile methylene-tetrahydrofolate reductase mutation which is also of importance in vascular disease; (5) the suitability and limitations of animal models that have so far been described.
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PMID:Disorders of homocysteine metabolism. 921 Nov 99

The high incidence of vascular complications in severe hyperhomocysteinaemia in homozygotes for cystathionine beta-synthase deficiency has focused attention upon homocysteine as an atherogenic and thrombophilic agent. For two decades there has been accumulating evidence of mild hyperhomocysteinaemia as risk factor of vascular disease. Pooled data on hundreds of coronary, cerebrovascular and peripheral arterial disease patients show that mild hyperhomocysteinaemia was detectable in about 20-30%. In a recent meta-analysis of 27 studies up to 1994, including about 4000 patients and as many controls, it is calculated that the summary odds ratio of elevated homocysteine levels was 1.7, with 95% confidence interval (CI) 1.5-1.9, for coronary heart disease; it was 2.5, with 95% CI 2.0-3.0, for cerebro-vascular disease; and it was 6.8, with 95% CI 2.9-15.8, for peripheral vascular disease. The relevance of this newly recognized risk factor will be demonstrated by the outcome of the European Comac study on 'Hyperhomocysteinaemia and Vascular Disease', a multicentre case-control study on 800 vascular patients and 750 controls. Despite the selection for epidemiological reasons of a relatively low cut-off level as the criterion for mild hyperhomocysteinaemia in this study-the upper 20% of the distribution of control levels-the relative risk of thus-defined hyperhomocysteinaemia for arterial disease is about 2. This equals the relative risk of hypercholesterolaemia and of smoking; hypertension leads to a higher excess risk. The observed synergistic interaction between hyperhomocysteinaemia and hypertension and smoking may warrant a change in the now generally followed procedure of screening for hyperhomocysteinaemia only if conventional risk factors have not been detected in the patient. Those vascular patients with combined risk factors leading to synergism in their joint effect may profit most from homocysteinelowering intervention.
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PMID:The case for mild hyperhomocysteinaemia as a risk factor. 921 Dec 2


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