Determinants of fasting and post-methionine homocysteine levels in families predisposed to hyperhomocysteinemia and premature vascular disease.
(9/707)
Elevated plasma total homocysteine (tHcy) levels, either measured in the fasting state or after oral methionine loading, are associated with an increased risk of atherothrombotic disease. Fasting and post-methionine hyperhomocysteinemia (HHC) overlap to a limited extent; both can occur as familial traits. We investigated determinants of fasting, postmethionine and delta (ie, post-methionine minus fasting levels) tHcy levels in 510 subjects of 192 HHC-prone families including 161 patients with clinical vascular disease and 349 without vascular disease. We focused on tHcy levels in relation to levels of vitamin B12, B6 and folate and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Multivariate linear analyses adjusted for the presence of vascular disease showed that fasting tHcy was significantly related to folate and vitamin B12, and the presence of the MTHFR TT genotype and the T allele, and to age, smoking habits, and serum levels of creatinine. Both post-methionine and delta tHcy levels were related to serum folate levels, and the presence of the MTHFR TT genotype and the T allele, and to postmenopausal status, and body mass index. An interaction was found between MTHFR TT genotype and serum folate levels for both fasting and post-methionine tHcy, ie, for a given decrease in serum folate, homocysteine levels increased more in subjects with the TT genotype than in those with the CC genotype. Fasting, post-methionine and delta tHcy were higher in patients with vascular disease than in their healthy siblings, but these levels were less dependent on serum folate levels (P<0.05), whereas the effect of MTHFR genotype was stronger (P=0.01). This study found evidence that post-methionine and delta tHcy levels are not only influenced by factors affecting homocysteine transsulfuration but also by factors that affect remethylation. The explained variances of fasting, post-methionine and delta tHcy were 49%, 62%, and 78%, respectively. We also found evidence, in patients with premature vascular disease but not in their healthy siblings, for a factor that increases tHcy levels but weakens the normal inverse relation between folate and tHcy and amplifies the effect of the MTHFR genotype. (+info)
Homocysteine--a pathophysiological cornerstone in obstetrical and gynaecological disorders?
(10/707)
Homocysteine, a product of the methionine cycle, is known to play an important role in cardiovascular diseases, neurological disorders and embryology, and in very important, fast growing fields concerning obstetrics and gynaecology. Therefore, we attempted an actual overview on possible obstetrical and gynaecological disorders as a consequence of an impaired methionine cycle. We tried to evaluate all mechanisms concerning homocysteine metabolism in order to look for hypothetical possibilities of therapeutic interventions. Using MEDLINE starting in January 1966, a search was conducted for articles published in which homocysteine was included as a subject heading or a text word. This search was also specified in combination with other key words such as obstetrics, pregnancy, gynaecology and cancer. Additional sources were identified through cross-referencing. All sources found were examined with regard to providing substantial information on our topic. The information obtained was divided into articles dealing with homocysteine and the methionine cycle itself, homocysteine and pregnancy, and homocysteine and hormones, including menopause, hormone replacement therapy and oral contraceptives. Another group was concerned with other special gynaecological aspects of the methionine cycle. We suggest that elevated concentrations of homocysteine could be a marker and perhaps a cause of, or contributive to, a wide range of obstetrical and gynaecological disorders. (+info)
Is there a role for adjuvant therapy in patients being treated with epoetin?
(11/707)
Adjuvant therapy may allow patients being treated with epoetin to derive greater clinical benefits. Iron supplementation is currently the most widely used form of adjuvant therapy; intravenous (i.v.) iron is required by the majority of haemodialysis patients receiving epoetin. Measurement of hypochromic red blood cells is the most direct way of assessing iron supply to the bone marrow. During the correction phase, a dose of i.v. iron equivalent to 50 mg/day is recommended, with the total dose not exceeding 3 g. When subclinical vitamin C deficiency is suspected, ascorbic acid may be given orally (1-1.5 g/week) or i.v. (300 mg three times weekly at the end of dialysis). The active vitamin D metabolites alfacalcidol and calcitriol may, under some circumstances, improve anaemia and reduce epoetin dosage requirements. Vitamin B6 requirements are increased during epoetin therapy, and supplementation at a dose of 100-150 mg/week is recommended. Supplementation of vitamin B12 is optional. Folic acid is supplemented routinely in haemodialysis patients, though evidence that it increases the efficacy of epoetin is limited. Low doses (2-3 mg/week) should normally be sufficient to maintain optimal folic acid stores in epoetin-treated patients, although higher doses are necessary for patients with hyperhomocysteinaemia. L-Carnitine supplementation may be appropriate in some patients with anaemia of chronic renal failure (CRF) unresponsive to, or requiring large doses of, epoetin. Androgens potentially could reduce epoetin costs in countries with limited resources, but should only be used in men older than 50 years with a remnant kidney. Recent animal studies indicate that the combination of epoetin and insulin-like growth factor 1 might be beneficial in CRF patients. High doses of angiotensin-converting enzyme (ACE) inhibitors should be reserved for dialysis patients who have hypertension that cannot be controlled by other agents, or who require an ACE inhibitor for treatment of heart failure. (+info)
Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review.
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OBJECTIVE: To evaluate the efficacy of vitamin B-6 in the treatment of premenstrual syndrome. DESIGN: Systematic review of published and unpublished randomised placebo controlled trials of the effectiveness of vitamin B-6 in the management of premenstrual syndrome. SUBJECTS: Nine published trials representing 940 patients with premenstrual syndrome. MAIN OUTCOME MEASURES: Proportion of women whose overall premenstrual symptoms showed an improvement over placebo. A secondary analysis was performed on the proportion of women whose premenstrual depressive symptoms showed an improvement over placebo. RESULTS: Odds ratio relative to placebo for an improvement in overall premenstrual symptoms was 2.32 (95% confidence interval 1.95 to 2.54). Odds ratio relative to placebo for an improvement in depressive symptoms was 1.69 (1.39 to 2.06) from four trials representing 541 patients. CONCLUSION: Conclusions are limited by the low quality of most of the trials included. Results suggest that doses of vitamin B-6 up to 100 mg/day are likely to be of benefit in treating premenstrual symptoms and premenstrual depression. (+info)
Effects of high-dose folic acid and pyridoxine on plasma and erythrocyte sulfur amino acids in hemodialysis patients.
(13/707)
In this investigation, sulfur amino acids (sAA) and sulfhydryls were determined in the plasma and erythrocytes (RBC) of 10 uremic patients on regular hemodialysis (HD) treatment and 10 healthy subjects, before and after supplementation with 15 mg/d of folic acid and 200 mg/d of pyridoxine for 4 wk. The basal total plasma concentrations of homocysteine (Hcy), cysteine (Cys), cysteinylglycine (Cys-Gly), gamma-glutamylcysteine (gamma-Glu-Cys), glutathione (GSH), and free cysteinesulfinic acid (CSA) were significantly higher in HD patients when compared to healthy subjects, whereas methionine (Met) and taurine (Tau) concentrations were the same in the two groups. HD patients showed significantly higher RBC levels of Hcy and Cys-Gly, whereas the RBC concentrations of Met, Cys, Tau, and GSH were not different from those in the healthy subjects. The plasma concentrations of sAA and sulfhydryls differed compared with RBC levels in the healthy subjects and HD patients. In both groups, supplementation with high doses of folic acid and pyridoxine reduced the plasma Hcy concentration. In addition, increased plasma concentrations of Cys-Gly and GSH were found in the HD patients and of CSA in the healthy subjects. After vitamin supplementation, the RBC concentrations of Hcy, Cys, and GSH increased and that of Tau decreased in healthy subjects. The only significant finding in RBC of HD patients was an increase in GSH levels after supplementation. This study shows several RBC and plasma sAA and sulfhydryl abnormalities in HD patients, which confirms earlier findings that RBC and plasma pools play independent roles in interorgan amino acid transport and metabolism. Moreover, high-dose supplementation with folic acid and pyridoxine significantly reduced Hcy levels, but did not restore the sAA and sulfhydryl abnormalities to normal levels. The increase that was observed in GSH after vitamin supplementation may have a beneficial effect in improving blood antioxidant status in uremic patients. Finally, the findings of elevated plasma Cys levels correlating to the elevated plasma Hcy levels in the presence of elevated plasma CSA levels, both before and after vitamin supplementation, led to the hypothesis that a block in decarboxylation of CSA is linked to hyperhomocysteinemia in end-stage renal failure. (+info)
The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment.
(14/707)
Homocystinuria due to cystathionine beta-synthase (CBS) deficiency, inherited as an autosomal recessive trait, is the most prevalent inborn error of methionine metabolism. Its diverse clinical expression may include ectopia lentis, skeletal abnormalities, mental retardation, and premature arteriosclerosis and thrombosis. This variability is likely caused by considerable genetic heterogeneity. We investigated the molecular basis of CBS deficiency in 29 Dutch patients from 21 unrelated pedigrees and studied the possibility of a genotype-phenotype relationship with regard to biochemical and clinical expression and response to homocysteine-lowering treatment. Clinical symptoms and biochemical parameters were recorded at diagnosis and during long-term follow-up. Of 10 different mutations detected in the CBS gene, 833T-->C (I278T) was predominant, present in 23 (55%) of 42 independent alleles. At diagnosis, homozygotes for this mutation (n=12) tended to have higher homocysteine levels than those seen in patients with other genotypes (n=17), but similar clinical manifestations. During follow-up, I278T homozygotes responded more efficiently to homocysteine-lowering treatment. After 378 patient-years of treatment, only 2 vascular events were recorded; without treatment, at least 30 would have been expected (P<.01). This intervention in Dutch patients significantly reduces the risk of cardiovascular disease and other sequelae of classical homocystinuria syndrome. (+info)
Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.
(15/707)
Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12. (+info)
A highly conserved sequence is a novel gene involved in de novo vitamin B6 biosynthesis.
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The Cercospora nicotianae SOR1 (singlet oxygen resistance) gene was identified previously as a gene involved in resistance of this fungus to singlet-oxygen-generating phototoxins. Although homologues to SOR1 occur in organisms in four kingdoms and encode one of the most highly conserved proteins yet identified, the precise function of this protein has, until now, remained unknown. We show that SOR1 is essential in pyridoxine (vitamin B6) synthesis in C. nicotianae and Aspergillus flavus, although it shows no homology to previously identified pyridoxine synthesis genes identified in Escherichia coli. Sequence database analysis demonstrated that organisms encode either SOR1 or E. coli pyridoxine biosynthesis genes, but not both, suggesting that there are two divergent pathways for de novo pyridoxine biosynthesis in nature. Pathway divergence appears to have occurred during the evolution of the eubacteria. We also present data showing that pyridoxine quenches singlet oxygen at a rate comparable to that of vitamins C and E, two of the most highly efficient biological antioxidants, suggesting a previously unknown role for pyridoxine in active oxygen resistance. (+info)