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Background: Noma is a quickly progressing, neglected opportunistic infection. It starts in the mouth as an oral lesion but can relatively quickly develop into extensive facial destruction and lead to death if not treated in time. This study aims to shed light on primary healthcare workers' practice competences in working with and knowledge of noma., Methods: A structured questionnaire using questions and case scenarios was filled out by 76 healthcare workers in Burkina Faso. Half of the nurses included in this study participated in a 2-day noma training. Data were analysed descriptively and Fisher's exact test was used to study differences between occupational groups using Stata., Results: Most healthcare workers reported having examined the mouth of children with diseases predisposing to noma. The total practice competence was poor, with almost 70% having suboptimal or very low competences. However, competences varied between different stages of noma disease. Knowledge scores varied between occupational groups. The majority of nurses and odontostomatology specialist nurses had optimal or good knowledge of noma. Significant differences in knowledge and practice competence were found between nurses who attended a 2-day training course on noma and those who did not., Conclusions: Health care workers in this study had quite poor practice competences in managing noma. The knowledge scores of these health workers were moderate. It is important for healthcare workers to be able to identify noma patients at an early stage, as at this point the disease can still be completely reversed., (© The Author(s) 2018. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been shown to be involved in the pathogenesis of atherosclerosis. The present study was initiated to investigate the role of ADMA as a risk marker of acute cerebrovascular disease (CVD). We examined 363 CVD patients and 48 controls. The ADMA concentration (mean+/-S.D., mumol/L) in controls was 0.50 +/- 0.06. Compared to controls, increased concentrations of ADMA were observed in cardio-embolic infarction (0.55 +/- 0.08; p < 0.001; n = 71), and TIA (0.54 +/-0 .05; p < 0.001; n = 31), but not in non-cardio-embolic infarction (0.51 +/- 0.07; p = 0.56; n = 239) and haemorrhagic stroke (0.51 +/- 0.11; p = 0.77; n = 22). In multivariate logistic regression models, CVD increased across quartiles of ADMA in all subgroups, but this association was only significant in the TIA group (odds ratio for highest versus lowest quartile 13.1; 95% CI: 2.9-58.6; p trend 0.001) A decreased arginine/ADMA ratio was significantly associated with CVD in the entire study population (p < 0.01). Our results indicate that ADMA is a weak independent marker for acute stroke and a strong marker for TIA and that relative arginine deficiency, measured as the l-arginine/ADMA ratio, is present in acute CVD.

Objective: Earlier studies have shown that the fatty acid binding protein 2 (FABP2) T54 allele is associated with dyslipidemia, which in turn correlates with the incidence of cerebrovascular disease (CVD). To assess whether the FABP2 gene A54T polymorphism is associated with an increased risk of CVD we undertook a case-control study., Materials and Methods: A total of 407 patients diagnosed with acute CVD and 158 control subjects were genotyped for the A54T polymorphism using a PCR-RFLP method., Results: Allele and genotype frequencies of the FABP2 A54T polymorphism did not differ between subjects with acute CVD (TT, 9.6%; TA, 41.0%; AA, 49.4%) and controls (TT, 7.6%; TA, 41.1%; AA, 51.3%; P = ns) or in the following subgroups of CVD compared with controls: non-cardioembolic infarction (n = 252), intracerebral hemorrhage (n = 23), and cardioembolic infarction (n = 91). In transient ischemic attacks (TIAs) (n = 41) the combined TT and TA genotype frequency (TT + TA, 65.9%) was more frequent than in controls (48.7%) (P = 0.05). Furthermore, the TT genotype was more frequent in non-smoking patients under the age of 70 (n = 77) with a non-cardioembolic infarction (TT, 18.2%) compared with controls (7.6%) (P = 0.024)., Conclusions: Our findings suggest an involvement of the FABP2 (A54T) gene polymorphism in the pathogenesis of CVD. The FABP2 T54 allele appears to be a genetic susceptibility marker for TIA and non-cardioembolic infarction at younger onset.

Objective: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency., Methods: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls., Results: The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age., Conclusions: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.

Background: Elevation of homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) in plasma are believed to be involved in the pathogenesis of cardiovascular disease (CVD). In humans, oral methionine loading results in acute elevation of plasma Hcy. This is associated with impaired NO-dependent vasodilatation, a mechanism that may explain the relationship between elevated Hcy and risk of CVD. ADMA, an endogenous competitive inhibitor of NO-synthase, may be elevated in plasma of patients with CVD. It was proposed that ADMA is synthesized in a methionine-dependent reaction which also forms Hcy. In this study plasma total homocysteine (tHcy) and ADMA concentrations were measured before and after oral methionine loading of human subjects., Methods: Plasma tHcy and ADMA levels were measured in 12 healthy males (age 32-58 years) before and after oral loading with L-methionine (100 mg/kg body weight in orange juice)., Results: At noon, 4 h after methionine loading, tHcy and ADMA levels (35.4 +/- 10.9 and 0.80 +/- 0.13 micromol/L, mean +/- SD) were significantly higher than the corresponding values obtained at noon the day before (15.6 +/- 7.4 and 0.63 +/- 0.10 micromol/L, both p<0.001). Noon values 4 h after methionine loading were also significantly higher than values obtained immediately before the methionine load (13.7 +/- 5.9 and 0.66 +/- 0.10 micromol/L, both p<0.001). Reinvestigation of 8 of 12 subjects showed that at 4 and 8 h after compared with levels immediately before methionine loading there was a significant increase in tHcy (28.4 +/- 10.2 and 33.45 +/- 11.1 vs. 10.8 +/- 3.3 micromol/L, both p<0.001). However, the corresponding ADMA levels did not increase (0.73 +/- 0.17 and 0.76 +/- 0.22 vs. 0.70 +/- 0.10 micromol/L, both not significant)., Conclusions: No clear evidence was found to support the supposition that methionine-induced hyperhomocysteinaemia may be accompanied by elevated levels of ADMA, an endogenous competitive NO-synthase inhibitor that may represent an alternative pathogenic mechanism for homocysteine-associated impairment of endothelial NO-dependent functions.

We described clinical manifestations, outcomes, prognostic indicators and clinico-epidemiological subgroups for 53 adult patients with Guillain-Barré syndrome (GBS) in Sweden during the period 1996-97. These patients were identified from a population of 2.8 million inhabitants and prospectively followed up for one year by a network of neurologists. An additional 10 cases, of whom five were adults who had not been prospectively followed up, were not included in the analyses. At 6 months after onset 80% of the patients could walk without aid, while at 1 year 46% were fully recovered, 42% had mild residual signs or symptoms, 4% had moderate and 6% severe disabilities, and 2% had died. Intravenous human immunoglobulin or plasmapheresis were used in 72% of the patients. The sum of the Medical Research Council (MRC) score at nadir was found as the only significant predictor for residual signs at 1 year in a multivariate model. Three subgroups, with different clinico-epidemiological characteristics, were identified by using cluster analysis. In conclusion, GBS in Sweden is frequently preceded by a respiratory infection, is often treated with immunomodulatory therapies, and exhibits a high recovery rate and a low fatality rate.

Both markedly and mildly elevated circulating homocysteine concentrations are associated with increased risk of vascular occlusion. Here we review possible mechanisms that mediate these effects. Inborn errors of homocysteine metabolism result in markedly elevated plasma homocysteine (200-300 micromol/L) and thromboembolic (mainly venous) disease: treatment to lower but not to normalize these concentrations prevents vascular events. Mild homocysteine elevation (>15 micromol/L) occurs in approximately 20-30% of patients with atherosclerotic disease. Usually, this is easily normalized with oral folate and ongoing trials are assessing the effect of folate treatment on outcomes. Although there is evidence of endothelial dysfunction with both markedly and mildly elevated homocysteine concentrations, the elevated homocysteine concentration in atherosclerotic patients is also associated with most standard vascular risk factors, and importantly, with early decline in renal function, which is common in atherosclerosis. Decline in renal function alone causes elevated plasma homocysteine (and cysteine). These observations suggest that mild hyperhomocysteinemia could often be an effect rather than a cause of atherosclerotic disease. Data on the common C677T methylenetetrahydrofolate reductase polymorphism supports this, in that, although homozygosity is a frequent cause of mild hyperhomocysteinemia when plasma folate is below median population concentrations, it appears not to increase cardiovascular risk. Indeed, there is recent evidence suggesting an acute antioxidant effect of folic acid independent of its effect on homocysteine concentrations. This antioxidant mechanism may oppose an oxidant effect of homocysteine and be relevant to treatment of patients with vascular disease, especially those with chronic renal insufficiency. Such patients have moderately elevated plasma homocysteine and greatly increased cardiovascular risk that is largely unexplained.

An elevated plasma total homocysteine (tHcy) level is considered a risk factor for coronary artery disease (CAD), but the relationship between plasma tHcy and well-defined CAD in women is still unclear. Plasma tHcy concentrations and the covariates serum folate, vitamin B12, and creatinine were analysed in 157 angiographically examined postmenopausal women with unstable CAD and in 101 healthy controls. At coronary angiography, 16% had normal vessels and 84% had coronary atherosclerosis. Mean plasma tHcy concentration (micromol/l, 95% confidence interval) did not differ in patients compared to controls (13.1 (12.3-13.8) vs. 12.5 (11.6-13.5)) or in patients with or without coronary atherosclerosis (13.3 (12.4-14.1) vs. 12.0 (10.8-13.2)). A trend to an increasing plasma tHcy with increasing degree of coronary atherosclerosis was attenuated after adjustment for age and the previous mentioned covariates. Odds ratio for the risk of coronary artery disease and coronary atherosclerosis in hyperhomocysteinemic patients (> or =90th percentile in controls) was approximately 3. However, the confidence interval included unity in half of the groups and the significance was therefore difficult to judge. Receiver operating characteristics showed age to be the only variable with a significant discriminatory ability regarding the presence of coronary atherosclerosis (area 0.77). Mild hyperhomocysteinemia seems not to be related to the risk of unstable CAD in postmenopausal women. The trend towards higher plasma tHcy with increasing degree of coronary atherosclerosis may be a marker of the disease. In future studies adjustment for age and the other three covariates should be considered.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare adult-onset inherited arterial disease with a distinctive neuropathological phenotype. Owing to its recent identification and variable mode of presentation, the disease is often misdiagnosed. The CADASIL gene is Notch 3 and has been mapped on chromosome 19q12 in several unrelated families. Knowledge of the phenotypic range of CADASIL, however, remains incomplete. Clinical, pathological radiological, and genetic findings in the first known Danish CADASIL pedigree are presented. Genetic testing confirmed a Notch 3 mutation. The mutation consisted of the substitution of a nucleotide at position 475 leading to the replacement of amino acid arginine for cysteine at position 133 in the third EGF motif.

Recent data have shown that an elevated plasma level of the amino acid homocysteine (Hcy) is a common, independent, easily modifiable and possibly causal risk factor for cardiovascular disease (CVD) which may be of equal importance to hypercholesterolemia, hypertension and smoking. This paper reviews the biochemical, clinical, epidemiological and experimental data underlying this conclusion and is critically questioning whether elevated tHcy is a causal factor.

Background: The plasma concentrations of total homocysteine (tHcy) and total cysteine (tCys) are determined by intracellular metabolism and by renal plasma clearance, and we hypothesized that glomerular filtration is a major determinant of plasma tHcy and tCys. We studied the relationships between the glomerular filtration rate (GFR) and plasma tHcy and tCys in populations of diabetic patients with particularly wide ranges of GFR., Methods: We measured GFR, urine albumin excretion rate (UAER), plasma tHcy, tCys, methionine, vitamin B12, folate, C-peptide, and routine parameters in 50 insulin-dependent diabetes mellitus (IDDM) and 30 non-insulin-dependent diabetes mellitus (NIDDM) patients. All patients underwent intensive insulin treatment and had a serum creatinine concentration below 115 micromol/liter., Results: Mean plasma tHcy in diabetic patients (0.1 micromol/liter) was lower than in normal persons (11.1 micromol/liter, P = 0.0014). Mean plasma tCys in diabetic patients (266.1 micromol/liter) was also lower than in normal persons (281.9 micromol/liter, P = 0.0005). Seventy-three percent of the diabetic patients had relative hyperfiltration. Plasma tHcy and tCys were closely and independently associated with GFR, serum folate, and serum B12. However, plasma tHcy was not independently associated with any of the 22 other variables tested, including age, serum creatinine concentration, UAER, total daily insulin dose, and glycemic control., Conclusions: Glomerular filtration rate is an independent determinant of plasma tHcy and tCys concentrations, and GFR is rate limiting for renal clearance of both homocysteine and cysteine in diabetic patients without overt nephropathy. Declining GFR explains the age-related increase in plasma tHcy, and hyperfiltration explains the lower than normal mean plasma tHcy and tCys concentrations in populations of diabetic patients.

Background: The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677C-->T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute approximately 12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis., Methods and Results: We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 micromol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37)., Conclusions: We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.

Homozygotes (TT genotype) for the C677T mutation in the gene of methylenetetrahydrofolate reductase (C677T/MTHFR mutation) constitute about 12% of the Caucasian population. They have mild hyperhomocysteinemia which is an established risk factor for cardiovascular disease. If the mutation is associated with premature death its prevalence is expected to be lower in the elderly than in the young. To test this we determined the C677T/MTHFR genotypes in 220 newborn and 222 elderly 80-108-year-old Swedes. In the newborn and elderly, the allele frequency, of the C677T/MTHFR mutation was 29.1 and 27.0% and the mutant homozygote frequency was 10.0 and 9.5%, respectively. In a meta analysis of the present and three previous studies including a total of 1388 elderly and 1415 younger subjects, the odds ratio (OR) representing the likelihood of the TT genotype to attain old age relative to the CC genotype was 0.87 (95% confidence interval (CI), 0.69-1.11) and relative to both the CC and CT genotypes was 0.83 (95% CI, 0.66-1.04). This finding does not suggest that the C677T/MTHFR mutation is a strong risk factor for diseases frequently leading to premature death.

Background: A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis., Methods: In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6., Results: In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 micromol/L) or after a methionine load (38.0 micromol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B6 below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B6 and atherosclerosis was independent of homocysteine levels both before and after methionine loading., Conclusions: Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.

Plasma homocysteine concentration is a sensitive marker for cobalamin and folate deficiency. The previously reported high incidence of increased plasma homocysteine in psychogeriatric patients and the association between reduced concentrations of cobalamin, folate and neuropsychiatric symptoms led to the present study on 741 consecutive psychogeriatric patients. The concentrations of plasma homocysteine correlated significantly with blood folate, serum cobalamin and serum creatinine both in demented (n = 295) and in non-demented patients with other psychiatric disorders (n = 215). Plasma homocysteine concentrations were significantly increased in both the demented and the non-demented patients, whereas only the demented patients had lower blood folate and serum creatinine concentrations than 163 control subjects. Almost all of the different diagnostic groups of demented and non-demented patients exhibited significantly increased plasma homocysteine concentrations compared with control subjects. Significantly decreased blood folate concentrations were mainly found in the different diagnosis groups of demented patients. Plasma homocysteine concentrations in both demented and non-demented patients with serum cobalamin and blood folate above the lower 20th percentile of these vitamins in the control subjects were also studied. Despite these vitamin concentrations, both groups of patients still exhibited significantly higher plasma homocysteine concentrations than the control subjects, which may indicate an increased frequency of impaired genetic capacity to metabolize homocysteine in these patients. Patients with either dementia of vascular cause or a history of other occlusive arterial disease had a significantly higher plasma homocysteine concentration than those without a history of vascular disease.

Moderate hyperhomocysteinemia is, today, considered an established risk factor for cardiovascular disease. A graded dose-response relationship between plasma homocysteine concentration over its full range and cardiovascular risk strongly supports causality. Therefore, intervention studies with homocysteine-lowering vitamins are needed. This mini review shows that supplementation with folic acid not only markedly reduces elevated plasma homocysteine concentrations but also reduces normal homocysteine concentrations. Folic acid doses of < 1 mg/d may be effective. Supplementation with a combination of folic acid and cyanocobalamin will secure full homocysteine-lowering effect and prevent occurrence of vitamin B-12 deficiency during the course of therapy.

Background and Purpose: Stroke patients frequently manifest moderate hyperhomocysteinemia. In most published studies, plasma homocysteine was measured at least 1 month after stroke (or the interval was not reported). To determine whether plasma homocysteine concentrations change in the acute phase, we compared acute-phase values with both convalescent-phase and control values., Methods: Plasma homocysteine concentrations were measured in the acute phase (mean, 2 days after stroke onset) in 162 first-ever stroke patients aged 50 years or more (median, 75 years) and again at a median interval of 583 days (range, 460 to 645 days) after stroke onset in a subgroup of 17 patients, with values for 60 age-matched subjects serving as controls. Twenty of the control subjects were reexamined 2 to 3 years after their initial examination., Results: The median plasma homocysteine concentration was 13.4 mumol/L in the patient group compared with 13.8 mumol/L for control subjects (NS, Mann-Whitney U test) and increased from 11.4 mumol/L in the acute phase to 14.5 mumol/L in the convalescent phase in the subgroup of patients examined twice (P < .01, Wilcoxon signed rank test). In the 20 reexamined control subjects, no significant change over time in plasma homocysteine concentration was found., Conclusions: The post-acute-phase increase in plasma homocysteine may explain why higher values were obtained for stroke patients than for control subjects in previous studies. Possible reasons for the variation in plasma homocysteine concentrations over time are (1) an acute-phase reduction secondary to a decrease in plasma albumin and (2) an increase in plasma homocysteine during the convalescent phase due to modified vitamin intake and/or lifestyle. The timing of plasma homocysteine measurements relative to stroke onset is a factor to be considered in the interpretation of results.

Objectives: Moderate hyperhomocysteinaemia is an independent risk factor for cardiovascular disease which may be causal. We investigated whether the concentration of plasma homocysteine changes between the acute phase of myocardial infarction and follow-up, and whether treatment with oral folic acid was effective in lowering homocysteine levels in patients with myocardial infarction., Design and Subjects: Plasma total homocysteine levels 24-36 h (baseline) after onset of acute myocardial infarction were compared with the levels obtained at 6 weeks' follow-up and with the levels in the controls. In the same patients, we studied the effect on plasma homocysteine of 6 weeks' treatment with daily oral folic acid doses of 2.5 or 10 mg compared to no treatment., Results: At baseline, 12 of 68 patients (18%) had moderate hyperhomocysteinaemia (> 17.3 mumol L-1; P < 0.05). Between baseline and follow-up, plasma homocysteine levels increased from 13.1 +/- 4.6 to 14.8 +/- 4.8 mumol L-1 (mean +/- SD; P < 0.001). Treatment with nitroglycerin, streptokinase, beta blockers, or acetylsalicylic acid seemed not to have caused this change. Folic acid lowered plasma homocysteine in all but two of 33 treated patients with a mean decrease of 4.4 mumol L-1 (-27%; P < 0.001). There was no difference between the effect of 2.5 and 10 mg of folic acid. In the untreated group (n = 20), plasma homocysteine increased with a mean increase of 0.6 mumol L-1 (+4%; P < 0.05)., Conclusions: Plasma homocysteine seems to increase in the post myocardial infarction period, the cause of which warrants further study. Folic acid appears to be an effective treatment for the reduction of both normal and increased plasma homocysteine concentrations in patients with myocardial infarction. This suggests that folic acid should be used for intervention when studying the effect of homocysteine-lowering therapy on the risk on myocardial infarction.

Objectives: Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. We explored possible determinants of plasma homocysteine and cysteine concentrations amongst middle-aged and elderly subjects., Design and Subjects: Of 501 35-95-year-old randomly selected residents of Lund and Malmö, Sweden, 244 (49%; 131 men, 113 women) were investigated., Results: Total plasma homocysteine concentrations were higher in men than in women (mean +/- SD: 13.9 +/- 4.1 and 12.3 +/- 4.1 mumol L-1; P < 0.001), increased markedly with age (Spearman's rho = 0.488; P < 0.001), and were correlated (P < 0.001) to concentrations of blood folate, serum vitamin B12, and serum creatine (rho = -0.366, -0.338, and 0.463). Users of multivitamins had lower homocysteine levels than nonusers [10.5 +/- 3.3 mumol L-1 (n = 31) and 13.5 +/- 4.2 mumol L-1 (n = 213), respectively; P < 0.001]. Total plasma cysteine concentrations also increased significantly with age and increasing serum creatinine, but were unrelated to gender, blood folate, serum vitamin B12 and use of multivitamins., Conclusions: Age, gender, folate, serum vitamin B12, serum creatinine and multivitamin usage are all important determinants of the plasma homocysteine concentration, whereas only age and serum creatinine are determinants of the plasma cysteine concentration. The age-related increase in homocysteine and cysteine may be linked to the age-related impairment of renal function, whereas the sex difference in plasma homocysteine may be because of the fact that more homocysteine is formed in men than in women in conjunction with creatine-creatinine synthesis.

Pyridoxine and folic acid supplementation in dialysis patients is a matter of debate. This study was performed to estimate the effects of pharmacologic doses of these vitamins on serum lipid and plasma homocysteine concentrations, which are known to be high in dialysis patients. Both hemodialysis and continuous ambulatory peritoneal dialysis patients were included in the study. Pyridoxine supplementation had a mild but significant cholesterol-lowering effect (7%). Folic acid supplementation significantly lowered plasma homocysteine concentrations by a mean of 30%. There was a strong, inverse correlation between blood folate and plasma homocysteine concentrations. These results indicate that daily supplementation with pyridoxine 300 mg and folic acid 5 mg has a beneficial effect on the cardiovascular risk profile in dialysis patients.

We describe a versatile high-performance liquid-chromatographic method for determining homocysteine and other plasma sulfhydryls. Using three different procedures for preparation of plasma, we determined total, free (non-protein-bound), and reduced forms of homocysteine, cysteine, glutathione, cysteinylglycine, and gamma-glutamylcysteine in human plasma. Sample preparation involves disulfide reduction with dithiothreitol and protein precipitation with sulfosalicylic acid. The assay utilizes isocratic reversed-phase ion-pair liquid chromatography at pH 2.4, postcolumn derivatization with 4,4'-dithiodipyridine, and colorimetric detection at 324 nm. The intra-assay precision (CV) of the method for total homocysteine is 1.5%; the interassay precision over 2.5 months is 2.5%. The detection limit for homocysteine is < 50 nmol/L plasma.

Findings in several retrospective studies have supported the hypothesis that hyperhomocysteinaemia may be an independent risk factor for premature arteriosclerotic disease. This prompted us to investigate whether frozen plasma samples could be used to study the question prospectively. Total plasma homocysteine concentrations in 6-16-year-old (10.9 +/- 2.5, mean +/- SD) frozen (-20 degrees C) and fresh samples from the same 76 men were 11.6 +/- 4.9 and 14.1 +/- 4.3 mumol l-1 respectively, the values being significantly correlated (r = 0.58, p < 0.001). The difference was not correlated to storage time. After the first sampling, 13 subjects had survived a stroke, 16 a myocardial infarction, and 51 were still healthy, being used as matched controls. In stroke patients, values from old and fresh samples were 14.2 +/- 5.5 and 16.4 +/- 4.8 mumol l-1, respectively, and tended to be higher (p = 0.06) than in matched controls whose respective values were 11.4 +/- 2.8 and 13.8 +/- 3.8 mumol l-1 (n = 22). No such differences were seen between patients with myocardial infarction and their matched controls. We conclude that total plasma homocysteine can be measured in up to 10-year-old frozen plasma samples, indicating that such samples can be used for prospective studies on the relationship between plasma homocysteine and vascular disease.

Urinary beta-hexosaminidase is a sensitive indicator of renal damage. The urinary excretion of this enzyme was measured in 31 patients with ischaemic stroke in the acute phase and in 126 patients 21-43 weeks after their stroke. Both immediately and after 21-43 weeks the patients showed a similar and a significantly increased level of urinary beta-hexosaminidase. This indicates the presence of renal injury in the stroke patients, which in turn might reflect a generalized vascular disease.

Total serum homocysteine was found to be significantly decreased in the first trimester of pregnancy, became maximal in the second trimester (about 50% compared with non-pregnant women), whereafter the concentration remained stable throughout the remainder of pregnancy. A return to normal concentrations was seen within 2-4 days post partum. Possible reasons for the decrease of serum homocysteine in pregnancy could be haemodilution and increased remethylation of homocysteine due to increased demands for methionine by the foetus.

The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.

The excretion of urinary beta-hexosaminidase in 203 apparently healthy males and females correlated significantly with their tobacco consumption (r = 0.26; p less than 0.001). Those who smoked more than 10 g tobacco per day excreted significantly more beta-hexosaminidase in urine than non-smokers, which indicates the presence of a low grade renal injury in smokers.

Moderate hyperhomocysteinaemia is a frequent finding in atherothrombotic cerebrovascular disease. This study confirms and extends this observation. Hyperhomocysteinaemia was present in 57 of 142 survivors with stroke (40%) and in four of 66 controls (6%). Plasma homocysteine concentrations were increased not only in carotid artery disease or lucunar stroke but also in haemorrhagic or embolic strokes. Homocysteine values were unrelated to the presence of hypertension, smoking, or hypercholesterolaemia, or to the concentrations of blood glucose, glycosylated haemoglobin, and plasma fibrinogen. Multiple regression analysis of the patient data showed that about 40% of the variation in plasma homocysteine concentrations could be predicted by the values for the homocysteine metabolism cofactors, blood folate and plasma pyridoxal 5-phosphate and by renal function as reflected in the values for serum creatinine. In patients, urine excretion of homocysteine per unit creatinine was significantly increased and strongly correlated both to the plasma homocysteine concentration and to the values for blood folate, plasma pyridoxal 5-phosphate, and serum vitamin B12. We conclude that moderate hyperhomocysteinaemia is frequently present in cases of stroke, is independent of other stroke risk factors or the type of stroke, and is partly related to renal function and the concentrations of homocysteine metabolism cofactors.

Homocysteine is a probably atherogenic amino acid, the fasting and post-methionine load serum concentrations of which have been reported to be much lower in premenopausal women than in men and postmenopausal women. This difference has been proposed to explain the reduced proneness of premenopausal women to vascular disease. We measured both free and total plasma homocysteine concentrations both fasting and post-methionine load, in 169 healthy subjects. Twelve subjects (7%) had distinctly abnormal plasma homocysteine values. Among the remaining 157 subjects, neither fasting nor post-load values of free or total homocysteine were lower in premenopausal women (n = 46) than in men of similar age (n = 41) or postmenopausal women (n = 37). Fasting but not post-load values were lower in postmenopausal women than in men of similar age (n = 33), and lower among the women as a whole (n = 83) than among the men (n = 74). In men, fasting values increased with age, and paralleled age-related decreases in the concentrations of homocysteine metabolism cofactors (serum vitamin B12, blood folate, and plasma pyridoxal 5-phosphate). Both in men and in women, fasting total plasma homocysteine values were significantly and negatively correlated to serum vitamin B12 and blood folate concentrations. Whether the small differences in plasma homocysteine values between the present men and women may be a contributory factor vis-à-vis their different proneness to vascular disease has yet to be settled.