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H Refsum

Publications and source records attributed to H Refsum.

At least 73 records · Page 4Linked to original sources
PubMed1998

The C677T mutation in the methylenetetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine.

In children with familial hypercholesterolemia, heterozygosity and homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene was associated with low serum folate and increased susceptibility to elevation of plasma total homocysteine during cholestyramine treatment. Because of the independent relationship between elevated plasma total homocysteine and cardiovascular disease, folate supplementation may be prudent in these children.

Anticholesteremic Agents↗
PubMed1998

Plasma total homocysteine levels in hyperthyroid and hypothyroid patients.

We found a higher plasma concentration of total homocysteine (tHcy), an independent risk factor for cardiovascular disease, in patients with hypothyroidism (mean, 16.3 micromol/L; 95% confidence interval [CI], 14.7 to 17.9 micromol/L) than in healthy controls (mean, 10.5 micromol/L; 95% CI, 10.1 to 10.9 micromol/L). The tHcy level of hyperthyroid patients did not differ significantly from that of the controls. Serum creatinine was higher in hypothyroid patients and lower in hyperthyroid patients than in controls, whereas serum folate was higher in hyperthyroid patients compared with the two other groups. In multivariate analysis, these differences did not explain the higher tHcy concentration in hypothyroidism. We confirmed the observation of elevated serum cholesterol in hypothyroidism, which together with the hyperhomocysteinemia may contribute to an accelerated atherogenesis in these patients.

Adult↗
PubMed1998

The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.

All classes of iodinated water-soluble radiographic contrast media (RCM) are vasoactive with the iso-osmolar dimers inducing the least changes in the vascular tone. The mechanisms responsible for RCM-induced changes in the vascular tone are not fully understood and could be multifactorial. A direct effect on the vascular smooth muscle cells causing alterations in the ion exchanges across the cell membrane is thought to be an important factor in RCM-induced vasodilatation. The release of the endogenous vasoactive mediators adenosine and endothelin may also play a crucial role in the haemodynamic effects of RCM particularly in the kidney. In addition, the effects of RCM on blood rheology can cause a reduction in the blood flow in the microcirculation. The purpose of this review is to discuss the pathophysiology of the haemodynamic effects of RCM and to offer some insight into the biology of the endothelium and vascular smooth muscle cells as well as the pharmacology of the important vasoactive mediators endothelin and adenosine.

Adenosine↗
PubMed1998

Diet, an independent determinant for plasma total homocysteine. A cross sectional study of Norwegian workers on platforms in the North Sea.

OBJECTIVE: To examine whether diet is an independent determinant for total homocysteine (tHcy) levels. DESIGN: Data on background variables was collected by questionnaire interviews, food intake by one 24 h recall and tHcy levels in a blood sample in 310 healthy men (mean age, 38 y). SETTING: Two oil producing platforms in the Norwegian sector in the north sea. RESULTS: The arithmetic mean (s.d.) and median tHcy levels were 10.4 (2.9) mumol/L and 9.9 mumol/L, respectively. In a covariance analysis, mean adjusted plasma tHcy decreased by 7-21% from no intake to highest category of intake of bread, vegetables, and skimmed milk, and increased by 8-9% from less than 30% to above 35% energy from fat, and from no intake to one liter or more for coffee. Smokers had a lower intake of cereals, bread vegetables and fruits, but ate more fat and meat. Thus, smoking may have an indirect effect on the tHcy level through its effect on diet. In a multiple regression model, bread and vegetables were negatively associated with tHcy, while fat was positively associated. CONCLUSIONS: The results suggest that changes in diet may be an important means to lower the tHcy level in the overall population, and that dietary advice should be considered in subjects diagnosed with elevated tHcy levels.

Adult↗
PubMed1998

Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study.

We report on the location and skewness of the distribution of plasma total homocysteine (tHcy) according to lifestyle indexes in 11,941 apparently healthy participants of the Hordaland Homocysteine Study. Most subjects were in two age groups: 9165 subjects were aged 40-42 y and 2351 subjects were aged 65-67 y. The remaining 425 subjects were of intermediate ages. In multivariate analysis, sex, age, folate intake, smoking status, and coffee consumption were the strongest determinants of tHcy concentration. The combined effect of the three modifiable factors was larger than the effect from each factor alone. A lifestyle profile characterized by low folate intakes, smoking, and coffee consumption was associated with a high median tHcy concentration and a pronounced skewness toward high tHcy values. In subjects characterized by a contrasting lifestyle profile [high folate intakes, nonsmoking status, and low coffee consumption (< 1 cup/d)], tHcy values were almost normally distributed and the median concentration was 3.0-4.8 micromol/L lower. Among all 40-42-y-old subjects, the 95% reference ranges based on geometric mean tHcy concentrations were 5.1-16.5 micromol/L for women and 6.2-18.7 micromol/L for men. The corresponding ranges for subjects characterized by high folate intakes, nonsmoking status, and low or moderate coffee consumption (< 5 cups/d) were 4.8-12.8 micromol/L and 6.2-14.7 micromol/L. These findings are relevant for establishing adequate reference ranges for tHcy and emphasize folate intake, smoking status, and coffee consumption as major acquired determinants of tHcy concentration in this general population.

Adult↗
PubMed1998

Recent data are not in conflict with homocysteine as a cardiovascular risk factor.

An elevated level of plasma total homocysteine is an independent, graded and strong risk factor for cardiovascular disease, which shows a strong interactive effect with conventional risk factors. It is a predictor of cardiovascular disease events in high-risk populations, but is weakly associated with risk in healthy individuals. A common polymorphism in the MTHFR gene is a major determinant of the total homocysteine level, but is unrelated to cardiovascular disease risk in most studies. This observation is in accordance with the view that high total homocysteine itself may not be particularly deleterious, but provokes vascular occlusion under conditions predisposing to cardiovascular disease.

Cardiovascular Diseases↗
PubMed1998

Homocysteine and cardiovascular disease.

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

Arteriosclerosis↗
PubMed1998

Simultaneous determination of methylenetetrahydrofolate reductase C677T and factor V G1691A genotypes by mutagenically separated PCR and multiple-injection capillary electrophoresis.

The C677T mutation of the methylenetetrahydrofolate reductase gene and the G1691A (Leiden) mutation of the factor V gene are established risk factors for thromboembolic disease. We here present an assay for the simultaneous genotyping of these common genetic variants. The assay involves a strategy based on multiplex mutagenically separated PCR performed in a single tube containing six primers. Separation of the resulting four PCR products (197, 207, 233, and 246 bp) was performed by capillary electrophoresis coupled with laser-induced fluorescence detection. The time for the automated electrophoresis was reduced to 2.5 min per sample by performing the capillary electrophoresis analysis in a multiple-injection mode.

Automation↗
PubMed1998

Variability and determinants of total homocysteine concentrations in plasma in an elderly population.

The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the within-person SD was 0.93 micromol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentrations were inversely related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35) concentrations. Median tHcy concentrations were approximately 1 micromol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetrahydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on single tHcy measurements may underestimate the magnitude of any risk associations with disease by 10-15%.

Aged↗
PubMed1998

Changes in folate status as determined by reduction in total plasma homocysteine levels during leucovorin modulation of 5-fluorouracil therapy in cancer patients.

We measured plasma total homocysteine (tHcy) in 14 patients (13 patients with colorectal cancer and 1 patient with breast cancer) during their first treatment with 5-fluorouracil (5-FU) plus leucovorin [LV (5-FULV)]. Eight of these patients were investigated a second time after 3-10 cycles (median, 4 cycles) with 5-FULV. Each cycle consisted of two administrations of 5-FU (500 mg/m2) and LV (60 mg/m2) given 24 h apart. The first administration of 5-FULV on day 1 of the first cycle induced a rapid reduction of the tHcy level from 12.5 micromol/liter (10.4-15.1 micromol/liter; geometric mean with 95% confidence interval of the mean) to 9.1 micromol/liter (7.5-11.1 micromol/liter) in 24 h. tHcy remained stable at this level after the second administration of 5-FULV. In addition, the 5-FULV regimen caused a concurrent 4-fold increase in both serum and erythrocyte folate. The fifth cycle with 5-FULV had only marginal effects on the tHcy level. 5-FU without LV modulation had no effect on the plasma tHcy or folate status in eight breast cancer patients. Our data establish the reduction of tHcy as a responsive indicator of LV pharmacodynamics.

Aged↗
PubMed1998

Chemical mismatch cleavage combined with capillary electrophoresis: detection of mutations exon 8 of the cystathionine beta-synthase gene.

Mutation detection by chemical mismatch cleavage (CMC) is based on the chemical modification and cleavage at the site of mismatched C or T in heteroduplexes, using hydroxylamine or osmium tetroxide (OsO4) as chemical probes. In the present study, we evaluated CMC in combination with capillary electrophoresis (CE) by determining the common T833C and G919A mutations in exon 8 of the cystathionine beta-synthase gene in heterozygous and homozygous samples. A 186-bp fragment encompassing exon 8 was amplified by PCR with both primers labeled with 5'-fluorescein. Labeled single strands of 40 and 61 nucleotides (nt) were formed from the coding strand of the T833C sample and non-coding strand from the G919A sample, respectively. These single-stranded DNA (ssDNA) products were analyzed under denaturing conditions by CE with short-chain linear polyacrylamide as the sieving matrix and were detected by laser-induced fluorescence (LIF), using a sensitive, one-channel sheath-flow detector. The CE-LIF format afforded relatively high resolution of ssDNA (down to 1 nt), precise size assessment of CMC products, sensitive detection with small sample requirements, and fast analysis. Thus, CMC combined with CE-LIF is suitable for screening of known mutations, giving expected CMC products, but will also detect unknown mutations, the locations of which are indicated by the fragment sizes.

Cystathionine beta-Synthase↗
PubMed1997

A novel pathway for the conversion of homocysteine to methionine in eukaryotes.

Activation of amino acid homocysteine was compared with that of methionine in rabbit crude liver extracts and purified multi-enzyme complex of aminoacyl-tRNA synthetases. Activation was studied by measuring the incorporation of radioactive amino acid into unlabelled trichloroacetic-acid insoluble materials in the absence of protein synthesis. Homocysteine synthetase activity was found in the crude extract and in the purified multi-enzyme complex of aminoacyl-tRNA synthetases. On a molar basis, the activation of methionine by the crude extract was five times higher than the activation of homocysteine. There was a partial loss of Hcy-tRNA synthetase activity in the purified multi-enzyme complex. Preliminary reconstitution experiments indicated a requirement for an additional factor for Hcy-tRNA synthetase activity. TLC of the amino acid released from tRNA charged with [14C]homocysteine, revealed radioactivity in homocysteine, methionine and homocysteine thiolactone, indicating a conversion of tRNA-attached homocysteine to methionine. Total tRNA was separated on a benzoylated cellulose column into a fraction enriched in initiator tRNA and a methionine-accepting, but initiator tRNA-deficient, fraction. Homocysteine-accepting activity was present only in the initiator tRNA-enriched fraction. Based on the above data we propose that homocysteine activation in reticulocyte lysates, reported previously, also occurs in liver. Activated homocysteine is attached to initiator tRNA and then converted to methionine by a methylating enzyme. In the absence of methylation, tRNA-attached homocysteine is hydrolysed to produce homocysteine thiolactone.

Animals↗
PubMed1997

Association between plasma total homocysteine and parental history of cardiovascular disease in children with familial hypercholesterolemia.

BACKGROUND: Recently, we reported a relation between plasma total homocysteine (tHcy) in children and cardiovascular disease (CVD) in their male relatives, suggesting that tHcy may partly explain the increased risk related to a family history of CVD. Because individuals with familial hyperlipidemias have an exceptionally high risk of premature CVD, we explored the relationship between tHcy and parental history of CVD in children with familial hypercholesterolemia (FH). METHODS AND RESULTS: Study subjects were 91 boys and 64 girls (age range, 7 to 17 years) with FH who were treated with a standard lipid-lowering diet at a tertiary care lipid clinic. We conducted a cross-sectional analysis of demographics, the diet, tHcy level, presence of the C677T mutation in the methylenetetrahydrofolate reductase gene (a common genetic cause of elevated tHcy) in children, and the prevalence of parental CVD. tHcy increased after puberty and was inversely related to parental educational level. Intakes of folate, vitamin C, and fruits and vegetables were inversely associated with tHcy, as were serum folate and vitamin B12 (Spearman's rho, -0.2 to 0.4; P<.05). tHcy was increased in children whose parent with FH had experienced CVD compared with children without parental CVD (median [interquartile range], 6.6 [5.3, 8.0] micromol/L versus 5.6 [4.7, 6.8] micromol/L; P=.01). This difference remained significant in multivariate regression analysis. Homozygosity for the C677T mutation was associated with a higher tHcy level and tended to be more frequent in the group with than in the group without a parental history of CVD (18% versus 8%; P=.07). CONCLUSIONS: These findings suggest that a moderately elevated tHcy level may partly account for the contribution of the family history to risk of CVD in FH. Dietary recommendations for FH should include nutrients that affect homocysteine metabolism.

Adolescent↗
PubMed1997

Plasma homocysteine levels and mortality in patients with coronary artery disease.

BACKGROUND: Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. METHODS: We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. RESULTS: After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter, 2.8 for those with levels of 15.0 to 19.9 micromol per liter, and 4.5 for those with levels of 20.0 micromol per liter or higher (P for trend=0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened. CONCLUSIONS: Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.

Adult↗
PubMed1997

Response of the methionine synthase system to short-term culture with homocysteine and nitrous oxide and its relation to methionine dependence.

We compared the metabolic response of a methionine(Met)-dependent (P60) human glioma cell line with that of a Met-independent variant (P60H) when cultured in a homocysteine (Hcy) medium and exposed to N2O. In Hcy medium (without Met), remethylation of Hcy in P60H cells was enhanced and supported growth, whereas remethylation was low in P60 cells, which failed to thrive under these conditions. Both cell types seemed to contain adequate amounts of folates and total cobalamin (Cbl). P60 cells showed increased total and methylcobalamin (CH3Cbl) content after the shift to a Hcy medium, but the high, stable level of CH3Cbl detected in P60H cells was not attained. Further metabolic differences were induced by N2O exposure, which markedly reduced Met-synthase activity in cell-free extracts in both cell lines and completely blocked intact-cell Hcy remethylation in P60, whereas Hcy remethylation was only partly inhibited in P60H cells cultured in Met medium. The residual Hcy remethylation in P60H cells may be related to only a moderate depletion of CH3Cbl. The resulting high CH3Cbl level relative to Met-synthase activity during N2O exposure was even higher in Hcy medium. These findings in P60H cells probably reflect increased provision of Cbl to support Hcy remethylation under metabolic strain. The inability of P60 to furnish CH3Cbl to the enzyme may explain both the Met-dependent phenotype and the increased sensitivity of Hcy remethylation to N2O exposure in these cells.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1997

The 677C-->T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease.

Homozygosity for a 677C-->T mutation at the locus that codes for 5,10-methylenetetrahydrofolate reductase (MTHFR), a folate-dependent crucial enzyme in homocysteine metabolism, may render the enzyme thermolabile and less active and has been associated with increased levels of plasma total homocysteine (tHcy). We assessed whether this mutation was associated with increased risk of coronary atherosclerosis and plasma levels of tHcy and furthermore studied whether folate status would modify the associations. Data were collected from subjects with substantial coronary atherosclerosis (> or = 90% occlusion in one and > or = 40% occlusion in a second coronary artery, referred to as cases, n = 131) or virtually no coronary narrowing (referred to as coronary controls, n = 87) and from a population-based control group (n = 100), all residing in the Rotterdam area, The Netherlands. Both males and females, aged 25-65 years were studied. The frequency of homozygosity for the mutation (+/+) in cases (10.0%) did not significantly differ statistically from that observed in coronary controls (11.5%, P = 0.71), population-based controls (7.0%, P = 0.43), or combined control groups (9.1%, P = 0.80). In the overall group (as well as in the three subgroups), plasma tHcy levels, fasting and to a lesser extent after a methionine-loading test, were higher in +/+ subjects than in homozygous normal subjects (-/-), whereas heterozygous subjects (+/-) had intermediate levels (Ptrend = 0.001). The +/+ subjects with erythrocyte folate levels < 790 nmol/l (population median) had a 77%, (95% CI, 27-144%) higher geometric mean fasting tHcy (21.4, micromol/l) than those with higher erythrocyte folate (12.1 micromol/l). The odds ratio (OR) of coronary atherosclerosis for +/+ subjects, with +/- and -/- subjects as the reference group, in analyses with combined control groups, was 1.1 (95% CI, 0.5-2.4). The ORs were 2.2 (95% CI, 0.7-6.8) and 0.6 (95% CI, 0.2-1.7) among subjects with low and high folate levels, respectively. Our study indicates that homozygosity for the 677C-->T MTHFR mutation, especially in combination with low folate status, predisposes to high plasma levels of fasting tHcy. However, homozygosity for this mutation, whether or not in combination with low folate status, was not associated with increased risk of coronary artery disease.

Adult↗
PubMed1997

Analysis of single-strand conformation polymorphism by capillary electrophoresis with laser-induced fluorescence detection using short-chain polyacrylamide as sieving medium.

A rapid analysis of single-strand conformation polymorphism (SSCP) by capillary electrophoresis with laser-induced fluorescence (CE-LIF) detector was developed using a short-chain, linear polyacrylamide (PA) as sieving medium. Capillary filling of this low-viscosity medium and medium replacement were carried out by commercial capillary electrophoresis instruments. The approach was successfully applied to detect the C677T mutation of methylenetetrahydrofolate reductase gene. The influences of factors such as the concentration of polymers, voltage, temperature, and additives on the SSCP analysis were systematically investigated. Using 6% PA sieving medium and high electric field, four strands were resolved within 11 min in a DNA sample heterozygous for the C677T mutation, and a characteristic pattern was apparent for each of the three genotypes. When using multiple injection mode, the average analysis time per sample was reduced to about 4 min. In conclusion, our results indicate that CE-LIF may be an alternative to conventional SSCP analysis based on slab gel electrophoresis for the detection of genetic mutations. The technique is simple and rapid and is well suited to analysis of large numbers of clinical samples.

Acrylic Resins↗