Tryptophan, kynurenine and the KTR

@article{pmid11470726,

title = {Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians},

author = {H Refsum and C S Yajnik and M Gadkari and J Schneede and S E Vollset and L Orning and A B Guttormsen and A Joglekar and M G Sayyad and A Ulvik and P M Ueland},

doi = {10.1093/ajcn/74.2.233},

issn = {0002-9165},

year  = {2001},

date = {2001-08-01},

journal = {Am J Clin Nutr},

volume = {74},

number = {2},

pages = {233--241},

abstract = {BACKGROUND: In India, most people adhere to a vegetarian diet, which may lead to cobalamin deficiency.nnOBJECTIVE: The objective was to examine indicators of cobalamin status in Asian Indians.nnDESIGN: The study population included 204 men and women aged 27-55 y from Pune, Maharashtra, India, categorized into 4 groups: patients with cardiovascular disease (CVD) and diabetes, patients with CVD but no diabetes, patients with diabetes but no CVD, and healthy subjects. Data on medical history, lifestyle, and diet were obtained by interviews and questionnaires. Blood samples were collected for measurement of serum or plasma total cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA), and total homocysteine (tHcy) and hemetologic indexes.nnRESULTS: MMA, tHcy, total cobalamin, and holoTC did not differ significantly among the 4 groups; therefore, the data were pooled. Total cobalamin showed a strong inverse correlation with tHcy (r = -0.59) and MMA (r = -0.54). Forty-seven percent of the subjects had cobalamin deficiency (total cobalamin <150 pmol/L), 73% had low holoTC (<35 pmol/L), 77% had hyperhomocysteinemia (tHcy >15 micromol/L), and 73% had elevated serum MMA (>0.26 micromol/L). These indicators of impaired cobalamin status were observed in both vegetarians and nonvegetarians. Folate deficiency was rare and only 2.5% of the subjects were homozygous for the MTHFR 677C-->T polymorphism.nnCONCLUSIONS: About 75% of the subjects had metabolic signs of cobalamin deficiency, which was only partly explained by the vegetarian diet. If impaired cobalamin status is confirmed in other parts of India, it may have important health implications.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11451728,

title = {Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study},

author = {S E Vollset and H Refsum and A Tverdal and O Nygård and J E Nordrehaug and G S Tell and P M Ueland},

doi = {10.1093/ajcn/74.1.130},

issn = {0002-9165},

year  = {2001},

date = {2001-07-01},

journal = {Am J Clin Nutr},

volume = {74},

number = {1},

pages = {130--136},

abstract = {BACKGROUND: Few population-based studies have assessed relations between plasma or serum total homocysteine (tHcy) and all-cause mortality.nnOBJECTIVE: Our goal was to study associations between plasma tHcy and all-cause, cardiovascular, and noncardiovascular mortality.nnDESIGN: This was a prospective cohort study of 2127 men and 2639 women aged 65-67 y in 1992-1993 when they were recruited as part of a population-based national cardiovascular screening program carried out in Hordaland County, Norway.nnRESULTS: During a median of 4.1 y of follow-up, 162 men and 97 women died. A strong relation was found between plasma tHcy and all-cause mortality. The association was highly significant for noncardiovascular and for cardiovascular causes of death. In a comparison of individuals having tHcy concentrations of 9.0-11.9, 12.0-14.9, 15.0-19.9, or > or = 20 micromol/L with individuals having a tHcy concentration < 9 micromol/L, adjusted mortality ratios were 1.4, 1.9, 2.3, and 3.6 (P for trend = 0.0002) for noncardiovascular and 1.3, 2.1, 2.6, and 3.5 (P for trend = 0.0002) for cardiovascular causes of death. A tHcy increment of 5 micromol/L was associated with a 49% (95% CI: 28%, 72%) increase in all-cause mortality, a 50% (95% CI: 21%, 85%) increase in cardiovascular mortality (121 deaths), a 26% (95% CI: -2%, 63%) increase in cancer mortality (103 deaths), and a 104% (95% CI: 44%, 289%) increase in noncancer, noncardiovascular mortality (33 deaths).nnCONCLUSION: Plasma tHcy is a strong predictor of both cardiovascular and noncardiovascular mortality in a general population of 65-72-y-olds. These results should encourage studies of tHcy in a wider perspective than one confined to cardiovascular disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11424140,

title = {Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum},

author = {A Ulvik and E T Evensen and E A Lien and G Hoff and S E Vollset and B M Majak and P M Ueland},

doi = {10.1002/ajmg.1370},

issn = {0148-7299},

year  = {2001},

date = {2001-07-01},

journal = {Am J Med Genet},

volume = {101},

number = {3},

pages = {246--254},

abstract = {Most studies demonstrate increased risk of colorectal cancer (CRC) and adenomas in folate-deficient subjects or that high folate intake may afford some protection. Smoking increases such risk in some but not all studies. We investigated whether smoking, folate status and methylenetetrahydrofolate reductase (MTHFR) genotype predict the risk of adenomatous and hyperplastic polyps of colorectum. By colonoscopy, the type, number, size and extent of dysplasia of colorectal polyps were assessed in 443 subjects aged 63-72 years. We also determined RBC folate and the C667T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Smoking, folate status and the C677T MTHFR polymorphism were strong, interactive determinants of high-risk adenomas (HRAs, defined as adenomas > or =10 mm in diameter, adenomas with villous components or with severe dysplasia). The risk was particularly high in smokers with low folate and the CT/TT genotype (risk category T) and in smokers with high folate and the CC genotype (risk category C). With non-smokers with low folate and the CC genotype as reference, the odds ratios (OR, 95% CI) were 8.7 (2.5-29.7) in category T and 9.9 (2.6-38.4) in category C. Notably, this risk pattern was also observed for hyperplastic polyps. In conclusion, in smokers, high folate status may confer increased or decreased risk for HRAs, depending on the MTHFR genotype. These data demonstrate the strong gene-nutrition interaction involving the C677T MTHFR polymorphism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11463727,

title = {Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects},

author = {J C Chambers and P M Ueland and M Wright and C J Doré and H Refsum and J S Kooner},

doi = {10.1161/hh1401.093459},

issn = {1524-4571},

year  = {2001},

date = {2001-07-01},

journal = {Circ Res},

volume = {89},

number = {2},

pages = {187--192},

abstract = {Previous studies investigating homocysteine and vascular disease have relied on total plasma homocysteine as the sole index of homocysteine status. We examined the dynamic relationship between vascular endothelial function and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine to identify the homocysteine form associated with endothelial dysfunction in humans. We investigated 14 healthy volunteers (10 men, 4 women). Brachial artery flow-mediated dilatation was measured at baseline and at 30, 60, 120, 240, and 360 minutes after oral (1) L-methionine (50 mg/kg), (2) L-homocysteine (5 mg/kg), and (3) placebo. Plasma concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine were measured at each time point, and nitroglycerin-induced dilatation at was assessed at 0, 120, and 360 minutes. Flow-mediated dilatation fell, and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine increased after oral homocysteine and oral methionine (all P<0.05 for difference in time course compared with placebo). Flow-mediated dilatation showed a reciprocal relationship with reduced homocysteine during both homocysteine and methionine loading. In both loading studies, peak reduction in flow-mediated dilatation coincided with maximal reduced homocysteine concentrations. In contrast, there was no consistent relationship between flow-mediated dilatation and free oxidized homocysteine, protein-bound oxidized homocysteine, or related species. Nitroglycerin-induced dilatation was unchanged by oral homocysteine and oral methionine (P>0.10 compared with placebo). Reduced homocysteine is closely associated with endothelial dysfunction during oral methionine and oral homocysteine loading. Our observations support the hypothesis that reduced homocysteine is the deleterious form of homocysteine for vascular function in vivo and suggest a less important role for other homocysteine species.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11343305,

title = {Disposition of homocysteine in subjects heterozygous for homocystinuria due to cystathionine beta-synthase deficiency: relationship between genotype and phenotype},

author = {A B Guttormsen and P M Ueland and W D Kruger and C E Kim and L Ose and I Følling and H Refsum},

doi = {10.1002/ajmg.1247},

issn = {0148-7299},

year  = {2001},

date = {2001-05-01},

journal = {Am J Med Genet},

volume = {100},

number = {3},

pages = {204--213},

abstract = {We have investigated 31 subjects from five unrelated families with one or more members with cystathionine beta-synthase (CBS) deficiency. On the basis of their CBS genotype, the subjects were grouped as normal (n = 11) or heterozygotes (n = 20). Based on pyridoxine effect in the probands, the heterozygotes were further classified as pyridoxine-responsive (n = 9) or non-responsive (n = 11). Heterozygous subjects had normal fasting total plasma homocysteine (tHcy), but median urinary tHcy excretion rate was significantly elevated compared to healthy controls (0.39 micromol/h vs 0.24 micromol/h, P < 0.05). An abnormal tHcy response after methionine loading identified 73% of the pyridoxine non-responsive heterozygotes, but only 33% of the pyridoxine responsive participants. The increase in cystathionine or the change in tHcy relative to cystathionine did not improve diagnostic accuracy of the methionine loading test. After Hcy loading, the maximal increase in tHcy was significantly elevated, whereas t(1/2) was normal in heterozygotes. In conclusion, a single biochemical test cannot discriminate CBS heterozygotes from controls. Abnormal tHcy response after methionine loading was the most sensitive test. Our data suggest that the urinary tHcy excretion rate is a simple, non-invasive approach for studying mild disturbances in Hcy metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11382721,

title = {Plasma total cysteine as a risk factor for vascular disease: The European Concerted Action Project},

author = {L El-Khairy and P M Ueland and H Refsum and I M Graham and S E Vollset and },

doi = {10.1161/01.cir.103.21.2544},

issn = {1524-4539},

year  = {2001},

date = {2001-05-01},

journal = {Circulation},

volume = {103},

number = {21},

pages = {2544--2549},

abstract = {BACKGROUND: Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. Although cysteine is structurally similar and metabolically linked to tHcy, its relation to the risk of cardiovascular disease has received little attention. We studied the relation between plasma total cysteine (tCys) levels and the risk of vascular disease in the coronary, cerebral, and peripheral vessels.nnMETHODS AND RESULTS: This case-control study included 750 patients with vascular disease and 800 age- and sex-matched control subjects recruited from 19 centers in 9 European countries. Conventional risk factors for cardiovascular disease were recorded. In addition, plasma levels of tCys, tHcy, folate, B(6), B(12), and creatinine were measured. Overall, a U-shaped relationship was observed between tCys and risk of vascular disease. With the middle range of 250 to 275 micromol/L tCys used as the reference category, the adjusted risk of vascular disease at low (300 micromol/L) tCys levels was 1.6 (95% CI 1.1 to 2.3). Different shapes of the dose-response relationship were seen for the 3 vascular disease categories. The relation with peripheral vascular and cerebrovascular disease was U-shaped, whereas a weak positive relation was observed with coronary heart disease.nnCONCLUSIONS: Our data show a significant U-shaped relationship between tCys and cardiovascular disease after adjustment for tHcy, creatinine, and other cardiovascular disease risk factors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11282420,

title = {Biological and clinical implications of the MTHFR C677T polymorphism},

author = {P M Ueland and S Hustad and J Schneede and H Refsum and S E Vollset},

doi = {10.1016/s0165-6147(00)01675-8},

issn = {0165-6147},

year  = {2001},

date = {2001-04-01},

journal = {Trends Pharmacol Sci},

volume = {22},

number = {4},

pages = {195--201},

abstract = {The enzyme methylenetetrahydrofolate reductase (MTHFR) directs folate species either to DNA synthesis or to homocysteine (Hcy) remethylation. The common MTHFR C677T polymorphism affects the activity of the enzyme and hence folate distribution. Under conditions of impaired folate status, the homozygous TT genotype has been regarded as harmful because it is associated with a high concentration of plasma total Hcy, increased risk of neural tube defects and colorectal neoplasias, and can also predispose individuals to adverse effects from drugs with antifolate effects. The MTHFR C677T polymorphism shows no consistent correlation with cardiovascular risk and longevity but, in combination with positive folate balance, the TT genotype is associated with decreased risk of colorectal neoplasias. Because of the high prevalence of this polymorphism in most populations, the TT variant might represent an ancestral genetic adaptation to living constraints (tissue injury or unbalanced vitamin intake) that has become a determinant of disease profiles in modern times.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11285329,

title = {Plasma total homocysteine is influenced by prandial status in humans: the Hordaland Hhomocysteine Sstudy},

author = {E Nurk and G S Tell and O Nygård and H Refsum and P M Ueland and S E Vollset},

doi = {10.1093/jn/131.4.1214},

issn = {0022-3166},

year  = {2001},

date = {2001-04-01},

journal = {J Nutr},

volume = {131},

number = {4},

pages = {1214--1216},

abstract = {Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease, adverse pregnancy outcomes and impaired cognitive function. No population-based studies on the possible influence of prandial status on tHcy have been published. The aim of this study was to investigate the variation in plasma tHcy levels in relation to time since last meal. A cross-sectional, population-based study including 18,044 individuals in Western Norway was conducted. Most subjects were in the age groups 40-42 and 65-67 y. Participants who had not eaten during the past 6 h before the blood sampling had significantly higher mean tHcy levels compared with those who had eaten; 11.7 [95% confidence interval (CI): 11.4-12.1] vs. 11.2 (95% CI: 11.1-11.3) micromol/L among men (P = 0.03) and 10.2 (95% CI: 9.9-10.6) vs. 9.7 (95% CI: 9.6-9.7) micromol/L among women (P = 0.003). In all groups except older women, tHcy concentrations were generally higher with increasing time after a meal (P-trend <0.01 in all 3 groups). These findings suggest that fasting status and time since last meal may influence levels of tHcy and should be considered in studies of tHcy as a risk factor for cardiovascular and other diseases, and when comparing tHcy values among studies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11257267,

title = {The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study},

author = {V Dekou and P Whincup and O Papacosta and S Ebrahim and L Lennon and P M Ueland and H Refsum and S E Humphries and V Gudnason},

doi = {10.1016/s0021-9150(00)00522-0},

issn = {0021-9150},

year  = {2001},

date = {2001-02-01},

journal = {Atherosclerosis},

volume = {154},

number = {3},

pages = {659--666},

abstract = {Total blood levels of homocysteine (tHcy) have been shown to depend on both environmental and genetic factors, and to be associated with the risk of developing atherosclerosis with its complications of coronary heart disease (CHD) and stroke. In this study, 408 men and 346 women from two towns, Dewsbury and Maidstone were examined for tHcy levels and genotyped for the C677T and the A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. Blood tHcy was significantly higher in men from the CHD high risk town of Dewsbury (12.7 micromol/l) than in the low CHD risk town of Maidstone (11.5 micromol/l) P<0.001, but not in women (10.7 vs. 10.5 micromol/l), with women in both towns, thus, showing significantly lower tHcy than men. There was no difference between towns in folate or vitamin B12 levels but the conventional inverse relationship with tHcy was seen. Smoking men and women from both towns had significantly higher tHcy and lower folate levels than non-smoking individuals (P<0.001). The frequency of the 677T allele in Dewsbury was 0.35 (95% CI; 0.32-0.39) compared with 0.29 (95% CI; 0.26-0.32) in Maidstone (P<0.01). Similar frequency difference of borderline statistical significance was seen both for men (P=0.054) and women (P=0.048) in both the towns, suggesting a true regional frequency difference. The effect of the 677T on tHcy was highly significant in the group as a whole with the most profound effect seen in men (12.0 micromol/l for CC vs. 14.1 micromol/l for TT, P<0.001). By contrast, there was no significant effect of the A1298C polymorphism on tHcy, folate or vitamin B12 levels, with no evidence for an interaction with the C677T genotype. The regional differences in tHcy levels were still present after the adjustment for folate and vitamin B12 levels, smoking and the effect of the C677T polymorphism. This suggests that there may be other unidentified factors, either environmental or genetic, affecting tHcy levels, and thus potentially having an impact on the risk of developing hyperhomocysteinaemia and CHD. These observations may have a bearing on regional differences in tHcy levels and the variation in CHD risk between regions in the UK.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11837990,

title = {The Hordaland Homocysteine Studies},

author = {P M Ueland and O Nygård and S E Vollset and H Refsum},

doi = {10.1007/s11745-001-0679-7},

issn = {0024-4201},

year  = {2001},

date = {2001-01-01},

journal = {Lipids},

volume = {36 Suppl},

pages = {S33--S39},

abstract = {The Hordaland Homocysteine Study is a population-based screening of total plasma homocysteine (tHcy) in approximately 18,000 men and women aged 40-67 yr that took place in 1992-1993 in the county of Hordaland in Western Norway. In this cohort, tHcy was associated with several physiologic and life-style factors, including age and gender, blood pressure, serum cholesterol, smoking, alcohol and coffee consumption, physical activity, diet, and vitamin status. All associations with established cardiovascular risk factors were in the direction expected to confer increased risk. In a subset of 5,883 women aged 40-42 yr, tHcy was associated with previous pregnancy outcomes, including preeclampsia, placental abruption, and neural tube defects. This article reviews the published results from the Hordaland Homocysteine Study in the light of relevant literature. The Hordaland Homocysteine cohort will be used for future investigations of the stability of tHcy and vitamin status over time, and to investigate associations with mortality and morbidity including cancer incidence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11067808,

title = {Evaluation of indicators of cobalamin deficiency defined as cobalamin-induced reduction in increased serum methylmalonic acid},

author = {B J Bolann and J D Solli and J Schneede and K A Grøttum and A Loraas and M Stokkeland and A Stallemo and A Schjøth and R B Bie and H Refsum and P M Ueland},

issn = {0009-9147},

year  = {2000},

date = {2000-11-01},

journal = {Clin Chem},

volume = {46},

number = {11},

pages = {1744--1750},

abstract = {BACKGROUND: Early detection of cobalamin deficiency is clinically important, and there is evidence that such deficiency occurs more frequently than previously anticipated. However, serum cobalamin and other commonly used tests have limited ability to diagnose a deficiency state.nnMETHODS: We investigated the ability of hematological variables, serum cobalamin, plasma total homocysteine (tHcy), serum and erythrocyte folate, gastroscopy, age, and gender to predict cobalamin deficiency. Patients (n = 196; age range, 17-87 years) who had been referred from general practice for determination of serum cobalamin were studied. Cobalamin deficiency was defined as serum methylmalonic acid (MMA) >0.26 micromol/L with at least 50% reduction after cobalamin supplementation. ROC and logistic regression analyses were used.nnRESULTS: Serum cobalamin and tHcy were the best predictors, with areas under the ROC curve (SE) of 0. 810 (0.034) and 0.768 (0.037), respectively, but age, intrinsic factor antibodies, and gastroscopy gave additional information.nnCONCLUSIONS: When cobalamin deficiency is suspected in general practice, serum cobalamin should be the first diagnostic test, and the result should be interpreted in relation to the age of the patient. When a definite diagnosis cannot be reached, MMA and tHcy determination will provide additional discriminative information, but MMA, being more specific, is preferable for assessment of cobalamin status.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid11076820,

title = {Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine},

author = {J C Chambers and P M Ueland and O A Obeid and J Wrigley and H Refsum and J S Kooner},

doi = {10.1161/01.cir.102.20.2479},

issn = {1524-4539},

year  = {2000},

date = {2000-11-01},

journal = {Circulation},

volume = {102},

number = {20},

pages = {2479--2483},

abstract = {BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD.nnMETHODS AND RESULTS: We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B(12) (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B(12) were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5+/-3.2% to 4.0+/-3.7%, P:=0.002) but not placebo (2.3+/-2.6% to 1.9+/-2.6%, P:=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0+/-3.4 to 9.3+/-1.9 micromol/L, P:<0.001), protein-bound homocysteine (from 8.7+/-2.8 to 6.2+/-1.4 micromol/L, P:<0.001), and free homocysteine (from 4.3+/-1.2 to 3.0+/-0.6 micromol/L, P:<0.001) and raised concentrations of serum folate (from 10.3+/-4.3 to 31.2+/-10.8 ng/mL, P:<0.001) and vitamin B(12) (from 314+/-102 to 661+/-297 pg/mL, P:<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P:=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B(12). Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.nnCONCLUSIONS: Folic acid and vitamin B(12) supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10966896,

title = {Signs of impaired cognitive function in adolescents with marginal cobalamin status},

author = {M W Louwman and M van Dusseldorp and F J van de Vijver and C M Thomas and J Schneede and P M Ueland and H Refsum and W A van Staveren},

doi = {10.1093/ajcn/72.3.762},

issn = {0002-9165},

year  = {2000},

date = {2000-09-01},

journal = {Am J Clin Nutr},

volume = {72},

number = {3},

pages = {762--769},

abstract = {BACKGROUND: Lack of cobalamin may lead to neurologic disorders, which have been reported in strict vegetarians.nnOBJECTIVE: The objective of this study was to investigate whether cognitive functioning is affected in adolescents (aged 10-16 y) with marginal cobalamin status as a result of being fed a macrobiotic diet up to an average age of 6 y.nnDESIGN: Data on dietary intake, psychological test performance, and biochemical variables of cobalamin status were collected from 48 adolescents who consumed macrobiotic (vegan type) diets up to the age of 6 y, subsequently followed by lactovegetarian or omnivorous diets, and from 24 subjects (aged 10-18 y) who were fed omnivorous diets from birth onward. Thirty-one subjects from the previously macrobiotic group were cobalamin deficient according to their plasma methylmalonic acid concentrations. Seventeen previously macrobiotic subjects and all control subjects had normal cobalamin status.nnRESULTS: The control subjects performed better on most psychological tests than did macrobiotic subjects with low or normal cobalamin status. A significant relation between test score and cobalamin deficiency (P: = 0.01) was observed for a test measuring fluid intelligence (correlation coefficient: -0.28; 95% CI: -0.48, -0.08). This effect became more pronounced (P: = 0.003) within the subgroup of macrobiotic subjects (correlation coefficient: -0.38; 95% CI: -0.62, - 0.14).nnCONCLUSION: Our data suggest that cobalamin deficiency, in the absence of hematologic signs, may lead to impaired cognitive performance in adolescents.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10926884,

title = {Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism},

author = {S Hustad and P M Ueland and S E Vollset and Y Zhang and A L Bjørke-Monsen and J Schneede},

issn = {0009-9147},

year  = {2000},

date = {2000-08-01},

journal = {Clin Chem},

volume = {46},

number = {8 Pt 1},

pages = {1065--1071},

abstract = {BACKGROUND: Plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease. tHcy concentrations are partly determined by folate, cobalamin, and vitamin B(6) status, and methylenetetrahydrofolate reductase (MTHFR) and other flavoenzymes are important for the biotransformation of these vitamins. This motivates the investigation of the possible relationship between riboflavin status and tHcy.nnMETHODS: The study had a cross-sectional design and included 423 healthy blood donors, ages 19-69 years. We determined plasma tHcy, serum folate, serum cobalamin, serum creatinine, and MTHFR C677T genotype. In addition, we measured riboflavin and its two coenzyme forms, flavin mononucleotide and flavin adenine dinucleotide, in EDTA plasma by capillary electrophoresis and laser-induced fluorescence detection.nnRESULTS: Riboflavin determined tHcy independently in a multiple linear regression model with adjustment for sex, age, folate, cobalamin, creatinine, and MTHFR genotype (P = 0.008). tHcy was 1.4 micromol/L higher in the lowest compared with the highest riboflavin quartile. The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and was essentially confined to subjects with the C677T transition of the MTHFR gene.nnCONCLUSIONS: Plasma riboflavin is an independent determinant of plasma tHcy. Studies on deficient populations are needed to evaluate the utility of riboflavin supplementation in hyperhomocysteinemia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10919921,

title = {The controversy over homocysteine and cardiovascular risk},

author = {P M Ueland and H Refsum and S A Beresford and S E Vollset},

doi = {10.1093/ajcn/72.2.324},

issn = {0002-9165},

year  = {2000},

date = {2000-08-01},

journal = {Am J Clin Nutr},

volume = {72},

number = {2},

pages = {324--332},

abstract = {Elevated plasma total homocysteine (tHcy) is a risk factor for occlusive cardiovascular disease (CVD). This concept is based on the observations of premature vascular disease in patients with homocystinuria, the relation between tHcy and both clinical CVD as well as preclinical atherosclerotic disease, the relation between tHcy in children and CVD in their parents or relatives, and reduction in CVD or surrogate endpoints after tHcy-lowering intervention with B vitamins. Plausible mechanisms include the in vivo interference with nitric oxide-dependent reactive vasodilatation. Some observations have raised questions about tHcy as a risk factor. 1) Some prospective studies showed a weak relation or no relation between tHcy and CVD. 2) Several traditional risk factors are associated with tHcy and may confound the relation between tHcy and CVD. 3) tHcy is related to renal function, and hyperhomocysteinemia may reflect early nephrosclerosis. 4) The C677T transition of the methylenetetrahydrofolate reductase gene causes a moderate increase in tHcy but no or only minor increased CVD risk. However, the strength of some of these arguments can be questioned because there is increasing evidence that tHcy is a proximate risk factor provoking the acute event, it strongly interacts with traditional risk factors, and it may predict CVD or death in patients with chronic renal failure. Furthermore, the studies of the C677T polymorphism lack statistical power, and the TT genotype may even modulate CVD risk independently of homocysteine. Thus, only placebo-controlled intervention studies with tHcy-lowering B vitamins and clinical endpoints can provide additional valid arguments for the debate over whether tHcy is a causal CVD risk factor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10926896,

title = {Evaluation of novel assays in clinical chemistry: quantification of plasma total homocysteine},

author = {E Nexo and F Engbaek and P M Ueland and C Westby and P O'Gorman and C Johnston and B F Kase and A B Guttormsen and I Alfheim and J McPartlin and D Smith and J Møller and K Rasmussen and R Clarke and J M Scott and H Refsum},

issn = {0009-9147},

year  = {2000},

date = {2000-08-01},

journal = {Clin Chem},

volume = {46},

number = {8 Pt 1},

pages = {1150--1156},

abstract = {BACKGROUND: There is a need for systematic evaluation of methods before their release to the market. We addressed this problem in novel homocysteine assays as part of an European Demonstration Project involving six centers in four countries.nnMETHODS: Two immunological methods for measurement of plasma total homocysteine (P-tHcy), the fluorescence polarization immunoassay (FPIA) and the enzyme immunoassay (EIA), were compared with two comparison methods, HPLC and gas chromatography-mass spectrometry (GC-MS). All laboratories performed the following procedures: (a) familiarization; (b) determination of linearity and precision by analyzing five plasma samples with interrelated concentrations for 20 days; (c) correlation using patients' samples; and (d) assessment of long-term performance.nnRESULTS: Both immunological methods were linear for P-tHcy between 5 and 45 micromol/L. The intralaboratory imprecision (CV) was <5% for FPIA and <9% for EIA used with a sample processor. The bias was -2% to 3% for FPIA and 2-4% for EIA used with a sample processor.nnCONCLUSIONS: The immunological methods provide results with little bias compared with HPLC and GC-MS. The imprecision of the assays must be considered in the context of their intended use(s).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10894806,

title = {Homocysteine and its disulfide derivatives: a suggested consensus terminology},

author = {S H Mudd and J D Finkelstein and H Refsum and P M Ueland and M R Malinow and S R Lentz and D W Jacobsen and L Brattström and B Wilcken and D E Wilcken and H J Blom and S P Stabler and R H Allen and J Selhub and I H Rosenberg},

doi = {10.1161/01.atv.20.7.1704},

issn = {1079-5642},

year  = {2000},

date = {2000-07-01},

journal = {Arterioscler Thromb Vasc Biol},

volume = {20},

number = {7},

pages = {1704--1706},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10731504,

title = {Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study},

author = {S E Vollset and H Refsum and L M Irgens and B M Emblem and A Tverdal and H K Gjessing and A L Monsen and P M Ueland},

doi = {10.1093/ajcn/71.4.962},

issn = {0002-9165},

year  = {2000},

date = {2000-04-01},

journal = {Am J Clin Nutr},

volume = {71},

number = {4},

pages = {962--968},

abstract = {BACKGROUND: Total homocysteine (tHcy) measured in serum or plasma is a marker of folate status and a risk factor for cardiovascular disease.nnOBJECTIVE: Our objective was to investigate associations between tHcy and complications and adverse outcomes of pregnancy.nnDESIGN: Plasma tHcy values measured in 1992-1993 in 5883 women aged 40-42 y were compared with outcomes and complications of 14492 pregnancies in the same women that were reported to the Medical Birth Registry of Norway from 1967 to 1996.nnRESULTS: When we compared the upper with the lower quartile of plasma tHcy, the adjusted risk for preeclampsia was 32% higher [odds ratio (OR): 1. 32; 95% CI: 0.98, 1.77; P for trend = 0.02], that for prematurity was 38% higher (OR: 1.38; 95% CI: 1.09, 1.75; P for trend = 0.005), and that for very low birth weight was 101% higher (OR: 2.01; 95% CI: 1.23, 3.27; P for trend = 0.003). These associations were stronger during the years closest to the tHcy determination (1980-1996), when there was also a significant relation between tHcy concentration and stillbirth (OR: 2.03; 95% CI: 0.98, 4.21; P for trend = 0.02). Neural tube defects and clubfoot had significant associations with plasma tHcy. Placental abruption had no relation with tHcy quartile, but the adjusted OR when tHcy concentrations >15 micromol/L were compared with lower values was 3.13 (95% CI: 1.63, 6. 03; P = 0.001).nnCONCLUSION: Elevated tHcy concentration is associated with common pregnancy complications and adverse pregnancy outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid10720038,

title = {Plasma total homocysteine levels during short-term iatrogenic hypothyroidism},

author = {E A Lien and B G Nedrebø and J E Varhaug and O Nygård and A Aakvaag and P M Ueland},

doi = {10.1210/jcem.85.3.6439},

issn = {0021-972X},

year  = {2000},

date = {2000-03-01},

journal = {J Clin Endocrinol Metab},

volume = {85},

number = {3},

pages = {1049--1053},

abstract = {Hypothyroidism is associated with increased cardiovascular morbidity, which cannot be fully explained by the atherogenic lipid profile observed in these patients. We have previously found elevated levels of the cardiovascular risk factor, plasma total homocysteine (tHcy), in hypothyroidism. We conducted a longitudinal study on 17 patients who had undergone total thyroidectomy for thyroid cancer. During 6 weeks of discontinued T4 substitution before radioscintigraphy (phase I), they attained a hypothyroid state, which was reversed by resupplementation (phase II). Plasma tHcy, serum creatinine, serum and red blood cell folate, serum cobalamin, and serum cholesterol were determined at 2-week intervals throughout phases I and II. There was a progressive and parallel increase in tHcy (mean, 27%), serum creatinine (37%), and serum cholesterol (100%) during phase I, and these values returned to the original level within 4-6 weeks after reinitiating T4 therapy. Serum and red blood cell folate levels showed only minor, but statistically significant, changes. In a bivariate model, serum creatinine and serum cholesterol were strongly associated with the changes observed in tHcy during short term hypothyroidism. In conclusion, we found a transient increase in both plasma tHcy and serum cholesterol during short term iatrogenic hypothyroidism, and the tHcy response is probably mainly explained by concurrent changes in renal function. The increase in both plasma tHcy and serum cholesterol may confer increased cardiovascular risk in hypothyroid patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}