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PubMed2001

Homocysteine, vitamin B12, serum and erythrocyte folate in peritoneal dialysis patients.

Plasma homocysteine (tHcy) is an important risk factor for atherosclerosis in dialysis patients. Few data were reported on the prevalence and severity of hyperhomocysteinemia in peritoneal dialysis (PD) patients. In addition, little attention was paid to the search of factors possibly involved in the pathogenesis of hyperhomocysteinemia in these patients. A cross-sectional study was performed in 107 stable PD patients. None of them was given folate or vitamin B12 supplementation before or during the study. Plasma tHcy, serum vitamin B12, serum and erythrocyte folate were measured by immunoenzymatic methods. Genetic analysis of the methylentetrahydrofolate-reductase thermolabile mutation (tMTHFR) was performed in 61 patients. 97% of patients had tHcy levels higher than normal. tHcy was not different between men and women, patients with or without malnutrition, with or without clinically evident atherosclerotic vasculopathy, with or without anemia. tHcy levels were significantly higher in homozygotes for the tMTHFR mutation than in patients carrying the wild type form. Significant univariate correlation was found between hyperhomocysteinemia and time since the start of dialysis, serum and erythrocyte folate and vitamin B12. The best fitted model equation was log tHcy = 108.53 + 0.1606 (duration of dialysis) -1.1053 (s-F) -0.7980 (age) 0.0215 (vitamin B12). Our results agree with those reported by other authors in hemodialysis patients. Despite the large number of PD patients with normal serum vitamin B12 and folate status, the relation between tHcy and vitamin B12 or folate suggests that the supplementation of these vitamins could be useful irrespective of their serum levels, especially in younger patients or in those treated for a long period of time with peritoneal dialysis.

Aged↗

PubMed2002

Riboflavin is a determinant of total homocysteine plasma concentrations in end-stage renal disease patients.

The effect of thiamine (vitamin B(1)) or riboflavin (vitamin B(2)) availability on fasting total homocysteine (tHcy) plasma levels in end-stage renal disease patients is unknown. A cross-sectional study was performed in a population of non-vitamin supplemented patients maintained on continuous ambulatory peritoneal dialysis. Red blood cell availability of thiamine (alpha-ETK) and of riboflavin (alpha-EGR), along with other predictors of tHcy plasma levels, was considered in the analysis. There was a linear association of alpha-EGR with tHcy plasma concentrations (P = 0.009), which was not observed for alpha-ETK. Among red blood cell vitamins, alpha-EGR was the only predictor of tHcy levels (P = 0.035), whereas alpha-ETK, red blood cell pyridoxal-5-phosphate supply (alpha-EGOT) and red blood cell folate levels had no effect. The risk for having a high tHcy plasma levels within the fourth quartile (plasma tHcy >38.3 micromol/L) was increased by an alpha-EGR > median (odds ratio, 4.706; 95% confidence interval, 1.124 to 19.704; P = 0.026). By way of contrast, alpha-ETK had no effect in these analyses. Independent predictors of tHcy plasma levels were serum albumin, alpha-EGR, red blood cell folate, and certain MTHFR genotypes. A logistic regression analysis showed that the MTHFR genotype is a predictor for having a tHcy plasma concentration within the fourth quartile. In summary, riboflavin availability, as measured by alpha-EGR, is a determinant of fasting tHcy plasma levels in peritoneal dialysis patients. This finding may have implications for tHcy lowering therapy in individuals with end-stage renal disease.

Analysis of Variance↗

PubMed1991

Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study.

Five patients with documented recurrences of glioblastoma multiforme were given continuous infusions of methotrexate delivered intratumorally using implantable catheters and subcutaneous refillable pumps. A continuous infusion of methotrexate (1 mg/d) was begun with concomitant oral administration of folinic acid. The methotrexate dose was increased every 2 weeks to 3, 10, 30, and, ultimately, 75 mg/d in two patients. Samples of serum and ventricular cerebrospinal fluid (CSF) were obtained to determine the levels of methotrexate and total bioactive folates, and brain tissue was obtained from two patients for determination of methotrexate concentration. The patients survived from 7 to 49 weeks after the implantation of the infusion device. Neither the clinical examination nor sequential radiological studies gave clear evidence of reduction in tumor size. Pneumonia developed in one patient, and mild hepatitis and increased seizure frequency in another. Methotrexate was stable in the delivery system over 12 days, and ventricular CSF reached steady-state levels by 5 days. Steady-state ventricular CSF levels of methotrexate were higher than serum levels in some patients, while the reverse was true in others. Levels of total bioactive folates in the CSF did not increase above the normal range. Methotrexate concentrations were highest at the center of the tumor, but measurable amounts of methotrexate were detectable in all areas of the brain. At autopsy in four patients, variable liquefactive necrosis of the brain tumors was seen, and viable tumor was found at the periphery of the tumor bed. These preliminary results suggest that it is technically feasible to infuse methotrexate into brain tumor cavities, and show that little central nervous system or systemic toxicity was encountered in five patients. Better delineation of the safety and efficacy of this therapeutic approach will require further clinical trials.

Brain Chemistry↗

PubMed2006

No effect of folic acid and methionine supplementation on D4Z4 methylation in patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is associated with a contraction of the D4Z4 allele on chromosome 4qter. There is also marked DNA hypomethylation of the D4Z4 allele. The DNA hypomethylation may have a central role in the pathogenesis of FSHD. Supplemental folic acid can boost DNA methylation. We evaluated the effect of oral folic acid and methionine supplementation on the methylation level of 4qter D4Z4 alleles in peripheral-blood lymphocytes of nine patients affected with FSHD and six healthy controls. Methylation levels did not change, while recommended serum-folate concentrations were reached.

Adolescent↗

PubMed1999

Peritoneal elimination of homocysteine moieties in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: The amount of total homocysteine eliminated by peritoneal dialysis and its relationship to peritoneal transport characteristics in continuous ambulatory peritoneal dialysis (CAPD) patients are unknown. METHODS: The influence of total homocysteine, folate, and vitamin B12 plasma concentrations, serum albumin levels, age, sex, dialysate to plasma ratio (D/P) creatinine, D/D0 glucose, D/P albumin, dialysate effluent volume, and effluent albumin on the daily peritoneal excretion of total homocysteine was investigated in 39 CAPD patients. The relationship of D/P creatinine to D/P total homocysteine, D/P free homocysteine, and D/P protein-bound homocysteine was analyzed additionally in a subgroup of 25 patients. RESULTS: We observed a significant influence of plasma total homocysteine concentrations (P = 0.0001) of the daily dialysate effluent volume (P = 0.0221) and of the D/P creatinine (P = 0.0132) on peritoneal elimination of total homocysteine. The daily peritoneal excretion of total homocysteine was 38.94 +/- 20.82 mumol (5.27 +/- 2.81 mg). There was a positive linear association of the daily total homocysteine elimination with plasma total homocysteine concentrations (P = 0.0001). A significant linear correlation was observed between D/P creatinine and D/P total homocysteine (P = 0.0001), D/P free homocysteine (P = 0.0001), as well as D/P protein-bound homocysteine (P = 0.0001). CONCLUSIONS: The peritoneal elimination of total homocysteine primarily depends on the plasma total homocysteine concentration. Elevated total homocysteine plasma levels cannot be reduced efficiently by peritoneal dialysis.

Adult↗

PubMed2003

Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection.

BACKGROUND: Deficiency of vitamin B12 raises the serum and tissue levels of homocysteine. Atrophic corpus gastritis results in impaired secretion of intrinsic factor and may lead to malabsorption of vitamin B12 in the intestine. We examined how common an undiagnosed vitamin B12 deficiency is among elderly men in the general population and, in particular, how often this deficiency is related to atrophic corpus gastritis. METHODS: The serum level of pepsinogen I (S-PGI) was assayed in a population-based sample of 12,252 men (age 51-65 years) from two cities in Finland. In this sample, all 635 men with S-PGI < 25 microg/l formed Series A ('males with atrophic corpus gastritis'). Series C (controls--'males without atrophic corpus gastritis)' with a non-atrophic gastric corpus was formed as a random sample of men (n = 402) with S-PGI > or = 50 microg/l. Serum levels of vitamin B12 (S-B12), folate (S-Fol), total homocysteine (S-Hcy) and Helicobacter pylori antibodies (S-HpAb) were assayed in all, or in large subsamples, of the men in Series A and C. RESULTS The men in Series A had significantly lower S-B12 and S-Fol levels than those in Series C. In Series A, 172 of 613 men tested (28%) had S-B 12 < 170 pmol/ 1, and 133 men (22%) had S-B 12 in the range 170-219 pmol/l. The corresponding prevalences were 7% (P < 0.001) and 17% (P < 0.001) in Series C, respectively. The mean S-Hcy was significantly higher in Series A in men with low S-B12 than the mean S-Hcy in Series C in men with normal S-B12. The prevalence of S-Hcy > 15 ,micromol/l was 27% in Series A and 15% in Series C (P < 0.05; chi2 = 4.63). Among subjects with S-B 12 < 220 pmol/l, 46% (104 of 226 men tested) in Series A and 16% (16 of 99) in Series C had S-Hcy > or = 15 micromol/l (P < 0.001). The mean S-Hcy was significantly (P < 0.001) higher in men with S-B12 in the range 170-219 pmol/l in Series A (mean 14.6 +/- 5.0 micromol/l) than in Series C (11.3 +/- 3.0 micromol/l). It was extrapolated that 2.5% of men in the age group 51-65 years in the present study population had a low S-B12 (< 220 pmol/l) level that associated with atrophic corpus gastritis. Of these men, 72% (128 of 179 tested) had an elevated S-HpAb level. CONCLUSIONS: Low S-B12 related to atrophic corpus gastritis is relatively common (prevalence 2.5%) among elderly males in the general population. An ongoing H. pylori infection occurs in three-fourths of these cases.

Aged↗

PubMedDate not supplied

Effects of two continuous hormone therapy regimens on C-reactive protein and homocysteine.

OBJECTIVE: To compare the effects of two continuous hormone therapy (HT) regimens on the cardiovascular risk markers, C-reactive protein (CRP) and homocysteine. DESIGN: A prospective study in which 43 postmenopausal women were randomly assigned to either tibolone 2.5 mg/day (n = 20) or 0.625 mg/day conjugated equine estrogens (CEE) plus continuous medroxyprogesterone acetate (MPA) 5 mg/day (n = 23). Serum levels of CRP, homocysteine, vitamin B12, and folate were determined before and during 12 weeks of therapy. RESULTS: C-reactive protein levels were increased by tibolone (76%; P < 0.001) and CEE+MPA (81%; P < 0.001). Neither tibolone nor CEE+MPA had any significant effect on homocysteine levels, but there was a significant difference between the effects of treatment over time (P = 0.046). Both tibolone and CEE+MPA reduced vitamin B12 levels (11%; P < 0.001, and 8%; P < 0.01, respectively), but had no statistically significant effect on folate levels. Individual changes in homocysteine levels were negatively associated with changes in vitamin B12 levels (r = -0.68; P < 0.01) after tibolone therapy. CONCLUSION: Both tibolone and CEE plus MPA increased CRP levels and reduced levels of vitamin B12. Neither therapy had any significant effect on homocysteine levels. Further long-term studies into the effect of HRT on these markers, and the relationship to cardiovascular disease risk, are required.

Adult↗

PubMed1988

What happens to the microspherocytosis of hereditary spherocytosis in folate deficiency?

The case is presented of an elderly man in whom hereditary spherocytosis (HS) had been diagnosed many years previously. He also had diverticulitis and was referred because of increasing anaemia (Hb 7.7 g/dl). He was suffering from diarrhoea and anorexia, and was taking a very poor diet. Serum investigations showed low folate and vitamin B12 levels. His blood film, despite the history of HS, showed very few spherocytes, and the red cell osmotic fragility curve was virtually normal. Instead, the blood film showed normocytes and oval macrocytes, mostly with normal central pallor. He was treated with vitamin B12 injections and folic acid tablets. On this treatment, the Hb rapidly rose, the macrocytosis disappeared, the film appearances reverted to the classical picture of HS with large numbers of microspherocytes, and the osmotic fragility curve to the picture of markedly increased fragility typical of HS.

Aged↗

PubMed2006

Prevalence of low serum folate and vitamin B12 in an older Australian population.

OBJECTIVE: To examine the prevalence of low serum folate and vitamin B12, in association with elevated serum homocysteine, in a representative sample of older Australians. METHODS: During 1997-2000, 3,508 persons aged 50+ years were examined in a population-based cohort study conducted in two postcodes, west of Sydney, Australia. Of these, 2,901 participants (82.7%) provided fasting blood for estimates of serum folate, vitamin B12 and total homocysteine. RESULTS: Low serum B12 (< 185 pmol/L) was found in 22.9% of participants and low serum folate (< 6.8 nmol/L) in 2.3% of participants. Among those people with very low serum vitamin B12 (< 125 pmol/L) and low serum folate, 51% had elevated homocysteine. CONCLUSIONS: Low serum levels of vitamin B12 and elevated serum homocysteine are relatively frequent in older Australians. IMPLICATIONS: Appropriate public health action should be considered to reduce the prevalence of low serum vitamin B12 and elevated homocysteine in older Australians.

Aged↗

PubMed1974

Assessment of deoxyuridine suppression test in diagnosis of vitamin B12 or folate deficiency.

Deoxyuridine (dU) suppression tests have been performed on virtually all marrow samples aspirated at this hospital over the past 12 months. Of the 110 samples studied 26 gave abnormal results, and these 26 samples came from patients deficient in either vitamin B(12) or folate. The dU suppression test was found to be of particular value in the diagnosis of vitamin B(12) or folate deficiency in non-anaemic patients with macrocytosis and equivocal changes in marrow morphology and in patients in whom the serum vitamin B(12) or red cell folate levels were within the normal range.

Biological Assay↗

PubMed2000

Folate status in Italian blood donors: relation to gender and smoking.

BACKGROUND AND OBJECTIVES: Folate deficiency in the general population is associated with a risk of cardiovascular disease and various cancers. The aim of this study was to evaluate folate status in Italian blood donors and its relationship with gender and smoking habit. DESIGN AND METHODS: A prospective study of 201 first visit donors (99 males and 102 females) was undertaken to evaluate folate status by measuring serum folate (SF) and red blood cell folate (RCF) levels and relating those with gender and smoking habit (100 smokers and 101 non-smokers). RESULTS: The rates of SF level less than 6.8 nmol/L and RCF less than 340 nmol/L were 9.9% and 25.3%, respectively in Italian blood donors. Mean RCF level was significantly lower (p<0.05) in females than in males and in smokers compared to non-smokers (p<0.001). The risk of reduced RCF levels in smokers was related to the number of cigarettes smoked per day, more than nine cigarettes increased the relative risk (RR) of low RCF level to 2.93 (95% C.I.: 1.34-6.41). INTERPRETATION AND CONCLUSIONS: This study suggests that folate deficiency, evaluated by RCF and SF levels, is widespread in Italian blood donors. Moreover, RCF values seem related to gender in non-smokers and modified by smoking habit, according to the cigarettes number smoked per day.

Adult↗

PubMed1989

Folate status in tuberculosis: a study in the Guinea Savanna of Nigeria.

Information about folate status in tuberculosis in developing countries is scanty. It was therefore decided to study serum and red cell folate (SF and RCF) levels in this infection. SF and RCF measurements were carried out by a microbiological (L. casei) method on 152 patients before treatment and on 94 patients (58 defaulted) at varying intervals during treatment. Mean SF (3.9 micrograms/l) of tuberculous subjects was significantly lower than that of the normal mean (6.8 micrograms/l; P less than 0.001) but their mean RCF (212.9 micrograms/l) was not significantly different from the normal mean RCF (220 micrograms/l). These findings indicate at least a state of incipient folate depletion. Though the mean RCF was normal, 32 patients had low RCF values of less than 120 micrograms/l while in 16 patients RCF levels were less than 100 micrograms/l. Only 10 ill subjects--all with disseminated disease--showed both very low SF (less than 2.0 micrograms/l) and low RCF (less than 120 micrograms/l). Thus, established folate deficiency was also clearly demonstrated in a proportion of the affected individuals. In the patient population as a whole, however, no relationship was detected between folate levels (SF, RCF) and (a) extent of disease (b) haemoglobin or haematocrit. Antituberculous treatment was accompanied by a rise in mean SF and RCF which, however, were still less than the normal mean values.

Adolescent↗

PubMed1981

High-dose co-trimoxazole and its penetration through uninflamed meninges.

Normal doses of co-trimoxazole (two ampoules or two tablets twice a day) gave low cerebrospinal fluid concentrations of trimethoprim and sulphamethoxazole in neurosurgical patients. For two years, four ampoules of co-trimoxazole twice a day, followed by four tablets twice a day, which were administered to neurosurgical patients and to patients admitted to hospital with skull fractures, produced no toxicity and this regimen has not been associated with postoperative meningitis. After the high-dose regimen in patients with uninflamed meninges, trimethoprim concentrations in the cerebrospinal fluid ranged from 2.6 mumol/L to 12.4 mumol/L (0.75 mg/L to 3.6 mg/L), and in the serum from 9.6 mumol/L to 42.7 mumol/L (2.8 mg/L to 12.4 mg/L). However, the bacteriostatic and bactericidal activities of the spinal fluids and sera were very variable, some with high concentrations appearing to have negligible antibacterial activity in vitro. We have treated a few patients with serious infections with dosages of 12 ampoules or 12 tablets twice a day with successful results. Studies of serum folate, 5-methyltetrahydrofolate and granulocyte dihydrofolate reductase levels showed no toxic effects from the high-dose regimen.

Adolescent↗

PubMedDate not supplied

A long-term study of the absorption of large oral doses of folic acid.

Large daily doses of oral folic acid ranging from 25 to 1,000 mg and totalling between 1,875 and 16,000 mg per course of treatment were well tolerated without any evidence of toxic effects by four hyperuricemic men of the ages of 26, 38, 46 and 50 years. The minimum folate absorption in the gut as measured by urinary excretion ranged from 10.1 to 45.7 percent. The percentage of absorption within a give patient remained similar in successive courses and there was no evidence of saturation of the absorption process related to dose or time. The pattern of urinary excretion of folates did not indicate that appreciable fractions relative to the large folate doses were retained by the patients. Serum, erythrocyte, and urine folates returned to pretreatment levels within 120 days after treatment. These findings suggest that the folate stores of the body do not expand by orders of magnitude even when megadoses of folates are absorbed in the gut. The rise of the folate levels in erythrocytes was gradual and continuous during treatment and is best explained by postulating that incorporation of folate into red cell takes place mostly at the precursor and reticulocyte stages. The decrease of erythrocyte folate values seen 40 to 66 days after folate treatment indicates that the folate content of erythrocytes diminishes during their life span.

Adult↗

PubMed2003

Homocysteine as a risk factor for cognitive impairment in stroke patients.

BACKGROUND: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment. METHODS: We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97). Baseline measurements of tHcy, serum folate and B(12), creatinine and plasma fibrinogen levels were obtained. RESULTS: tHcy levels were higher in the stroke subjects by a mean 34%. These levels were significantly correlated with the first factor of a principal component analysis of the neuropsychological data, after controlling for age, folate, B(12) and creatinine levels. The correlation of Hcy levels was particularly significant with frontal-executive functioning and attention. tHcy levels were significantly correlated with number of infarcts and total stroke volume in the stroke group, but not with T(2)-weighted deep white matter hyperintensity scores, after correction for age. In the control group, tHcy levels were significantly correlated with ventricle-to-brain ratios as measures of brain atrophy. CONCLUSION: This study provides evidence that high tHcy levels are associated with cognitive impairment, in particular that of frontal-executive function. The major component of this association is accounted for by small and large strokes, but non-vascular neurotoxic effects of tHcy also appear to play a role. tHcy must receive greater attention as a risk factor for cognitive impairment.

Aged↗

PubMed2002

Plasma homocyst(e)ine concentrations and the risk of subtypes of cerebral infarction. The Hisayama study.

Moderately elevated plasma total homocyst(e)ine (tHcy) levels have been linked with cardiovascular disease. However, the findings of previous studies regarding the relationship between tHcy levels and subtypes of cerebral infarction (CI) have been conflicting. The aim of the present study was to examine this issue in a community-based case-control study performed in Hisayama Town in Japan. Fasting tHcy levels were compared among 75 CI cases, of which 43 were lacunar (LI), 24 atherothrombotic (ATI) and 8 cardioembolic infarctions (CEI), and 248 age- and sex-matched healthy controls. The mean tHcy concentrations were higher in CI than in controls (13.0 vs. 11.8 micromol/l; p = 0.018). LI and CEI also had significantly higher tHcy levels than did the corresponding controls (12.3 vs. 11.3 micromol/l for LI; p = 0.037 and 16.3 vs. 12.7 micromol/l for CEI; p = 0.036). The same tendency was also observed for ATI, but the difference was only marginally significant probably due to the small number of the cases (13.4 vs. 11.9 micromol/l; p = 0.087). After adjustment for age, sex, hypertension, serum creatinine, total protein, folate and vitamin B(12) levels, the risk of LI was not significant in the second tertile of the tHcy distribution, but significantly increased in the third compared with the first tertile (adjusted odds ratio, AOR, 3.4; 95% confidence limits, CL, 1.3-8.9; p = 0.015), while the risk of ATI was significant even in the second tertile (AOR, 5.0; 95% CL, 1.0-23.7; p = 0.042) and higher in the third tertile (AOR, 7.5; 95% CL, 1.5-38.3; p = 0.015). However, the odds ratios for CEI could not be estimated, as there was no case of CEI in the first tertile. These findings suggest that elevated tHcy is an independent risk factor for all subtypes of CI, but that its impact is higher in ATI and probably in CEI than in LI.

Aged↗

PubMed1986

Serum folates in gestating swine after folic acid addition to diet.

Folic acid was added to the diet as a simple means to increase serum folates in gestating sows. At weaning, 95 multiparous sows were randomly assigned to five treatments. Of these sows, 67 farrowed and were used for this trial. Three supplementation levels of folic acid added to a commercial diet at 3, 9 and 27 mg per kg were studied. A commercial diet without any supplementation of folic acid was used as a control treatment. A fifth treatment consisted of eight im injections of 15 mg of folic acid each, according to a predetermined schedule that was previously effective in improving the reproductive performance of sows when combined with flushing. Each sow was kept in an individual cage and received 2 kg of feed daily. Serum folates were measured at weaning, mating and on d 14, 28, 42 and 56 after mating. The time-response curve of serum folates in sows injected with folic acid was higher than that of sows fed the unsupplemented diet (P = .057). Adding folic acid to diet may be as efficient as folic acid injections to elevate serum folates when compared with sows fed the control diet. The mean supplementary level of folic acid sufficient to maintain the serum folate concentration at approximately the same levels as those observed in sows injected with folic acid was estimated to be near 4.3 mg per kg of feed.

Animals↗

PubMed1995

Plasma levels of the atherogenic amino acid homocysteine in post-menopausal women with breast cancer treated with tamoxifen.

Long-term treatment of breast-cancer patients with the anti-oestrogen tamoxifen has been found to be associated with reduced cardiovascular mortality. Plasma homocysteine is an independent risk factor for atherosclerotic disease, and its level is determined by folate and cobalamin status, and possibly also by oestrogen status. We measured the effect of tamoxifen on plasma homocysteine, serum cholesterol, serum cobalamin and serum and erythrocyte folate in 31 post-menopausal women with breast cancer. The plasma homocysteine level was decreased by a mean value of 29.8% after 9-12 months and by 24.5% after 13-18 months of treatment. Tamoxifen suppressed serum cholesterol by mean values varying between 7.2% and 17.6% after 3 to 19 months of treatment. There was no correlation between changes in plasma homocysteine and serum cholesterol. These findings suggest that the homocysteine-lowering effect of tamoxifen may contribute to the reduction of cardiovascular mortality observed in patients on adjuvant therapy with tamoxifen.

Aged↗