Biomedical subjects

H Refsum

Publications and source records attributed to H Refsum.

At least 55 records · Page 3Linked to original sources

PubMed1999

Applications of short-chain polydimethylacrylamide as sieving medium for the electrophoretic separation of DNA fragments and mutation analysis in uncoated capillaries.

In capillary electrophoresis (CE), separation of DNA fragments is usually performed in covalently coated capillaries. Recent studies have demonstrated that certain polymers form a dynamic coating on the inner surface of the capillary, thereby suppressing the electroosmotic flow and DNA-capillary wall interactions. We developed a simple method for the synthesis of short-chain polydimethylacrylamide (PDMA) using isopropanol as a chain transfer agent. Capillary (<75 microm internal diameter) filling and replacement of this low-viscosity (14 cP at 4% PDMA) self-coating medium were easily carried out by commercial CE instruments. Using PDMA and uncoated capillaries, we first examined the separation of phi X174 HaeIII DNA digests and observed that the stability of the dynamic coating was markedly better at pH 7.8 than at pH 8.3. At this lower pH and nondenaturing conditions, high resolution of the phi X174 HaeIII DNA digests was obtained for more than 850 injections in the same capillary. We then exploited this sieving medium in CE using multiple approaches for mutation analysis of clinical DNA samples including separation of restriction enzyme cleavage products, analysis of single strand conformation polymorphisms, and simultaneous detection of several mutations using multiplex allele-specific PCR amplification. Our results demonstrate that CE in uncoated capillaries using PDMA as sieving medium is a simple, versatile, and reliable strategy for separation and mutation analysis of clinical DNA samples.

Acrylic Resins↗

PubMed1999

Serum homocysteine levels in postmenopausal breast cancer patients treated with tamoxifen.

Adjuvant treatment of breast cancer with tamoxifen may be associated with reduced risk of cardiovascular disease. Serum homocysteine level has been suggested to be a risk factor for cardiovascular disease influenced by estrogenic hormones. We evaluated a subset of postmenopausal women who had participated in a longitudinal, double-blind, randomized, placebo-controlled toxicity study of tamoxifen 10 mg orally, twice daily. Twenty-seven treated subjects and 37 placebo subjects had measurements of serum homocysteine levels made on previously frozen samples obtained at baseline and after 12 months. After treatment with tamoxifen, we found lower levels of serum homocysteine of borderline statistical significance.

Administration, Oral↗

PubMed1999

Co-ordinate variations in methylmalonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase.

We investigated the co-ordinate variations of the two cobalamin (Cbl)-dependent enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase (MCM), and measured the levels of their respective cofactors, methylcobalamin (CH3Cbl) and adenosylcobalamin (AdoCbl) in cultured human glioma cells during nitrous oxide exposure and during a subsequent recovery period of culture in a nitrous oxide-free atmosphere (air). In agreement with published data, MS as the primary target of nitrous oxide was inactivated rapidly (initial rate of 0.06 h(-1)), followed by reduction of CH3Cbl (to <20%). Both enzyme activity and cofactor levels recovered rapidly when the cells were subsequently cultured in air, but the recovery was completely blocked by the protein-synthesis inhibitor, cycloheximide. During MS inactivation, there was a reduction of cellular AdoCbl and holo-MCM activity (measured in the absence of exogenous AdoCbl) to about 50% of pre-treatment levels. When the cells were transferred to air, both AdoCbl and holo-MCM activity recovered, albeit more slowly than the MS system. Notably, the regain of the holo-MCM and AdoCbl was enhanced rather than inhibited by cycloheximide. These findings confirm irreversible damage of MS by nitrous oxide; hence, synthesis of the enzyme is required to restore its activity. In contrast, restoration of holo-MCM activity is only dependent on repletion of the AdoCbl cofactor. We also observed a synchronous fluctuation in AdoCbl and the much larger hydroxycobalamin pool during the inactivation and recovery phase, suggesting that the loss and repletion of AdoCbl reflect changes in intracellular Cbl homoeostasis. Our data demonstrate that the nitrous oxide-induced changes in MS and CH3Cbl are associated with reversible changes in both MCM holoactivity and the AdoCbl level, suggesting co-ordinate distribution of Cbl cofactors during depletion and repletion.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1999

Iodinated radiographic contrast media inhibit shear stress- and agonist-evoked release of NO by the endothelium.

1 We have used isolated arterial preparations from the rabbit and dog to investigate whether non-ionic iodinated radiographic contrast media (IRCM) modulate nitric oxide (NO) release. The tri-iodinated monomers iopromide and iohexol were compared with the hexa-iodinated dimer iodixanol. 2 The vasodilator effects of iohexol (300 mg ml-1) and iodixanol (320 mg ml-1) were assessed in cascade bioassay. Increasing concentrations of iohexol or iodixanol caused concentration-dependent relaxations of the detector tissue which were insensitive to 100 microM NG-nitro L-arginine methyl ester (L-NAME) and 10 microM indomethacin, whereas viscosity-associated relaxations induced by the 'inert' agent dextran (MW 80,000; 1-4%) were attenuated by inhibition of NO synthesis. 3 Relaxations of endothelium-intact rings to acetylcholine (ACh) were attenuated by preincubation with iohexol or iodixanol, whereas relaxations to sodium nitroprusside (SNP) in endothelium-denuded rings were unaffected. Inhibitory activity did not correlate with either molarity or iodine concentration. Mannitol caused inhibition of both ACh- and SNP-induced responses. 4 In isolated perfused arteries the depressor responses to iodixanol (320 mg ml-1) and iopromide (300 mg ml-1) administered as close arterial bolus attained a plateau with maximal dilatations of approximately 25% and approximately 60%, respectively. Addition of 100 microM NG-nitro L-arginine (L-NOARG) and/or 10 microM indomethacin to the perfusate had no effect on the responses to either agent. 5 We conclude that IRCM exert direct effects on the endothelium that inhibit NO production rather than its action on vascular smooth muscle. Shear stress-induced stimulation of NO production by IRCM is unlikely to contribute to their vasodilator activity in vivo when administered during angiography despite high intrinsic viscosity.

Acetylcholine↗

PubMed1999

Total homocysteine and cardiovascular disease.

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.

Animals↗

PubMed1999

Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus.

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.

Adult↗

PubMed1999

Risk of persistent cobalamin deficiency in adolescents fed a macrobiotic diet in early life.

BACKGROUND: Cobalamin deficiency has been described in children consuming macrobiotic diets. OBJECTIVE: We investigated whether moderate consumption of animal products is sufficient for achieving normal cobalamin function in 73 adolescents who had received a macrobiotic diet until 6 y of age and had then switched to a lactovegetarian, lactoovovegetarian, or omnivorous diet (macrobiotic adolescents). DESIGN: Hematologic indexes and serum concentrations of methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured. Current consumption frequency of animal products and cobalamin intake from dairy products were assessed by questionnaire. Data from 94 age-matched adolescents who received an omnivorous diet from birth were used as a reference. RESULTS: Serum cobalamin concentrations were significantly lower and concentrations of MMA and folate and mean corpuscular volume (MCV) were significantly higher in macrobiotic adolescents than in control adolescents: of macrobiotic adolescents, 21% had abnormal MMA concentrations (>0.41 micromol/L), 37% had abnormal cobalamin concentrations (<218 pmol/L), 10% had abnormal tHcy concentrations (> 12.8 micromol/L), and 15% had abnormal MCV (> 89 fL). In macrobiotic adolescents, dairy products (200 g milk or yogurt and 22 g cheese/d) supplied on average 0.95 microg cobalamin/d; additionally, these adolescents consumed fish, meat, or chicken 2-3 times/wk. In girls, meat consumption contributed more to cobalamin status than the consumption of dairy products, whereas in boys these food groups were equally important. CONCLUSIONS: A substantial number of the formerly strict macrobiotic adolescents still had impaired cobalamin function. Thus, moderate consumption of animal products is not sufficient for restoring normal cobalamin status in subjects with inadequate cobalamin intake during the early years of life.

Adolescent↗

PubMed1999

Lifestyle and cardiovascular disease risk factors as determinants of total cysteine in plasma: the Hordaland Homocysteine Study.

BACKGROUND: Plasma total homocysteine (tHcy) is a cardiovascular disease risk factor and is related to several components of the established cardiovascular disease risk profile. Cysteine is structurally and metabolically related to homocysteine, but data on its association with cardiovascular disease and cardiovascular disease risk factors are sparse. OBJECTIVE: Our objective was to search for the determinants of plasma total cysteine (tCys) and compare them with those of tHcy. DESIGN: In this cross-sectional study, we studied 7591 healthy men and 8585 healthy women aged 40-67 y with no history of hypertension, diabetes mellitus, coronary heart disease, or cerebrovascular disease. RESULTS: In the group aged 40-42 y, tCys was significantly higher in men (&mean;: 273 micromol/L; 2.5-97.5 percentile: 219-338 micromol/L) than in women (253 micromol/L; 202-317 micromol/L) (P < 0.001). In the group aged 65-67 y, there was no significant sex difference in tCys: men (296 micromol/L; 233-362 micromol/L) and women (296 micromol/L; 234-361 micromol/L). As with tHcy, tCys was positively associated with age, total cholesterol concentration, diastolic blood pressure, and coffee consumption. Body mass index was a strong determinant of tCys but was not related to tHcy. Several factors known to influence tHcy, including smoking status, folate and vitamin intake, heart rate, and physical activity, were not associated or were only weakly associated with tCys. CONCLUSION: Plasma tCys is strongly related to several factors that constitute the cardiovascular disease risk profile. This should be an incentive to determine the role of tCys in cardiovascular disease.

Adult↗

PubMed1999

Serum total homocysteine and coronary heart disease: prospective study in middle aged men.

OBJECTIVES: To examine the prospective relation between total homocysteine and major coronary heart disease events. DESIGN: A nested case-control study carried out within the British regional heart study, a prospective investigation of cardiovascular disease in men aged 40-59 years at entry. Serum total homocysteine concentrations were analysed retrospectively and blindly in baseline samples from 386 cases who had a myocardial infarct during 12.8 years of follow up and from 454 controls, frequency matched by age and town. RESULTS: Geometric mean serum total homocysteine was slightly higher in cases (14.2 micromol/l) than in controls (13.5 micromol/l), a proportional difference of 5.5% (95% confidence interval (CI) -0.02% to 10.8%, p = 0.06). Age adjusted risk of myocardial infarction increased weakly with log total homocysteine concentration; a 1 SD increase in log total homocysteine (equivalent to a 47% increase in total homo cysteine) was associated with an increase in odds of myocardial infarction of 1.15 (95% CI 1.00 to 1. 32; p = 0.05). The relation was particularly marked in the top fifth of the total homocysteine distribution (values >16.5 micromol/l), which had an odds ratio of 1.77 (95% CI 1.28 to 2.42) compared with lower levels. Adjustment for other risk factors had little effect on these findings. Total homocysteine concentrations more than 16.5 micromol/l accounted for 13% of the attributable risk of myocardial infarction in this study population. Serum total homocysteine among control subjects varied between towns and was correlated with town standardised mortality ratios for coronary heart disease (r = 0.43, p = 0.08). CONCLUSIONS: Serum total homocysteine is prospectively related to increased coronary risk and may also be related to geographical variation in coronary risk within Britain. These results strengthen the case for trials of total homocysteine reduction with folate.

Adult↗

PubMed1999

Coronary endothelium-derived vasodilation during cooling and rewarming of the in situ heart.

The integrity of coronary vascular endothelial vasodilator function during core cooling and rewarming was investigated in a pentobarbital-anesthetized open-chest dog model. Vasodilator response was assessed as the change from baseline blood flow by injecting the endothelial-dependent vasodilator acetylcholine (ACh) (1.0 microg) or the endothelial-independent vasodilator nitroglycerin (NTG) (50 microg) into the left anterior descending (LAD) coronary artery. Change in blood flow was measured using a transit time ultrasonic volume flowmeter technique. During cooling and rewarming LAD blood flow was significantly decreased. After rewarming, aortic pressure was artificially elevated to reach control. This procedure restored heart work (LV-RPP, left ventricular rate pressure product) and coronary perfusion pressure, but LAD blood flow remained lowered. Ability to dilate the vascular bed supplied by LAD, after injections of ACh or NTG, was present both during cooling and rewarming. At 25 degrees C coronary blood flow (LAD) increased from 3 +/- 1 to 9 +/- 1 mL x min(-1) in response to both ACh and NTG. Posthypothermic blood flow increased from 7 +/- 1 to 19 +/- 2 and 20 +/- 3 mL x min(-1) in response to ACh and NTG, respectively. Measured as the percent change from baseline LAD blood flow, the response was not significantly different from the one obtained in prehypothermic hearts. In conclusion, coronary vasodilator function, both endothelium dependent and endothelium independent, is present but not maintained at the same level during cooling to 25 degrees C and rewarming. In spite of the deterioration of cardiac function, no selective defect in the endothelium-dependent response was detected, either during hypothermia or after rewarming.

Acetylcholine↗

PubMed1999

Four common mutations of the cystathionine beta-synthase gene detected by multiplex PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

BACKGROUND: A deficiency of cystathionine beta-synthase (CBS) is the most frequent cause of homocystinuria. The effect of therapy is related to the underlying CBS genotype, which makes early diagnosis of this genetic defect important. Our aim was to develop a fast and reliable method based on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for the determination of common mutations of the CBS gene. METHODS: We used MALDI-TOF mass spectrometry to detect four common CBS mutations (G307S, T272M, I278T, and V320A). The method is based on multiplex PCR of exons 7, 8, and 9, followed by single nucleotide extension in the presence of dideoxy NTPs of four primers targeted at the separate mutation sites. The extension products, as well as the 3-hydroxypicolinic acid matrix, were incubated with cation-exchange beads to remove disturbing salt contaminants. RESULTS: The above-mentioned mutations were determined in samples from 12 homocystinuria patients. The MALDI-TOF spectra allowed unambiguous discrimination between primers and extension products (>9 Da) in the mass range between 4500 and 7500 Da. No labeled primers or ddNTPs were required. The genotyping was verified by reference technique. CONCLUSION: Our results demonstrate fast, simple, and unambiguous multiplex genotyping of four common CBS mutations by MALDI-TOF mass spectrometry.

Cystathionine beta-Synthase↗

PubMed1999

Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies.

Diagnosing cobalamin deficiency is often difficult. We investigated the diagnostic strategies that 224 general practitioners used to assess cobalamin status and the criteria on which they based their decisions to supplement patients. From all serum cobalamin analyses carried out at a single laboratory during 1993, individuals with serum cobalamin concentrations <300 pmol/L were identified, and one patient per general practitioner was included. When serum methylmalonic acid (s-MMA) values >0.376 micromol/L were used as the "reference standard" for cobalamin deficiency, the serum cobalamin assay had a diagnostic sensitivity of 0.40 and a specificity of 0.98. With the same reference standard, the diagnostic accuracy of the physicians' decision to supplement patients had the same specificity but a higher sensitivity (0.51). Cost-benefit analysis indicated that measurement of s-MMA can be recommended in patients with serum cobalamin >60-90 pmol/L and <200-220 pmol/L, depending on its diagnostic accuracy.

Adolescent↗

PubMed1999

Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients.

In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer. Treatment with 1 g/day aminoglutethimide for 2 and 3-5 months increased plasma tHcy by a mean value of 24.5% [95% confidence interval, 10.5-40.4%] at 2 months and 35.8% (95% confidence interval, 18.2-55.9%) at 3-5 months, corresponding to increases in the mean plasma tHcy of 1.90 and 3.67 micromol/L, respectively. In contrast, none of the other treatment options influenced plasma tHcy concentrations. The finding that aminoglutethimide, but none of the other aromatase inhibitors or megestrol acetate, influenced plasma tHcy suggests that this effect is achieved by mechanisms not related to suppression of plasma estrogens or to the glucocorticoids administered in concert.

Aminoglutethimide↗

PubMed1998

Disruption of a regulatory system involving cobalamin distribution and function in a methionine-dependent human glioma cell line.

Cobalamin metabolism and function were investigated at the levels from transcobalamin II (TCII) receptor to the cobalamin-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase, in a methionine-dependent (P60) and a methionine-independent (P60H) glioma cell line. Using P60H as reference, the P60 cells cultured in a methionine medium had slightly lower TCII receptor activity and normal total cobalamin content, a moderately reduced microsomal and mitochondrial cobalamin(III) reductase activity but only trace amounts of the methylcobalamin and adenosylcobalamin cofactors. When transferred to a homocysteine medium without methionine, P60H cells showed a slightly enhanced TCII receptor activity, but the other cobalamin-related functions were essentially unchanged. In contrast, the methionine-dependent P60 cells responded to homocysteine medium with a nearly 6-fold enhancement of TCII receptor expression and a doubling of both the hydroxycobalamin content and the microsomal reductase activity. The mitochondrial reductase and the cobalamin-related processes further down the pathway did not change markedly. In both cell lines, TCII receptor activity was further increased when growth in homocysteine medium was combined with N2O exposure. These data suggest that low methionine and/or high homocysteine exert a positive feedback control on TCII receptor activity. The concurrent increase in hydroxycobalamin content and in microsomal reductase activity are either subjected to similar regulation or secondary to increased cobalamin transport. This regulatory network is most prominent in the methionine-dependent P60 cells harboring a disruption of the network in the proximity of cobalamin(III) reductase.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1998

Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group.

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.

Adult↗

PubMed1998

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.

BACKGROUND: Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. OBJECTIVE: To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. DESIGN: Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. SETTING: Referral population to a hospital clinic between July 1988 and April 1996. MAIN OUTCOME MEASURES: Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. RESULTS: Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. CONCLUSIONS: Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

Aged↗

PubMed1998

Hyperhomocysteinemia in terms of steady-state kinetics.

The plasma level of homocysteine (Hcy) and its oxidized products, i.e., plasma total Hcy (tHcy), is a function of the influx rate of Hcy to plasma and the plasma tHcy clearance. In vitro experiments show that proliferating cells usually export more Hcy than stationary cells and that the Hcy export increases in response to high methionine, low folate or low cobalamin level, and to agents interfering with Hcy remethylation. Comparison between various cell types suggests that hepatocytes have a unique ability to increase the Hcy export in response to extracellular methionine, probably due to its capacity to form adenosylmethionine. Some but not all cell types have an ability to use extracellular Hcy as a methionine source. Clearance studies in healthy subjects indicate that about 1.2 mmol Hcy is supplied from the cells to plasma per 24 h, which is only about 5-10% of total Hcy formed. Comparison of area under the curves after administration of Hcy and methionine shows that about 10% of the methionine administered is released to plasma as Hcy. Notably, only a few percent of Hcy from plasma is excreted unchanged in the urine, and this shows that most tHcy in plasma is metabolized. Folate or cobalamin deficient patients have normal plasma tHcy clearance, which suggests that their elevated tHcy level is due to increased Hcy export from tissues into the plasma compartment. In contrast, the hyperhomocysteinemia in renal failure is accounted for by a marked reduction in tHcy clearance, suggesting an important role of kidney in elimination of Hcy from plasma.

Cells, Cultured↗

PubMed1998

A common methylenetetrahydrofolate reductase gene mutation and longevity.

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.

Aged↗