Bevital AS

Bergen, Norway

Bevital AS

Bergen, Norway
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Theofylaktopoulou D.,University of Bergen | Midttun O.,Bevital AS | Ulvik A.,Bevital AS | Ueland P.M.,University of Bergen | And 7 more authors.
Clinical and Experimental Immunology | Year: 2013

Circulating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data are sparse on other determinants of these markers and metabolites of the kynurenine pathway. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid in plasma in two age groups, 45-46 years (n=3723) and 70-72 years (n=3329). Differences across categories of the potential determinants, including age, gender, renal function, body mass index (BMI), smoking and physical activity, were tested by Mann-Whitney U-test and multiple linear regression including age group, gender, renal function and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20-30% higher in the older group, whereas tryptophan was 7% lower. Men had 6-19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the fourth age-specific estimated glomerular filtration rate (eGFR) quartile, the first quartile was associated with higher concentrations of neopterin (25%) and KTR (24%) and 18-36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2-8% higher in overweight and 3-17% higher in obese, than in normal-weight individuals. Heavy smokers had 4-14% lower levels of tryptophan and most kynurenines than non-smokers. Age and renal function were the strongest determinants of plasma neopterin, KTR and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases. © 2013 British Society for Immunology.

Vollset S.E.,Norwegian Institute of Public Health | Nygard O.,University of Bergen | Midttun O.,Bevital AS | Ueland P.M.,University of Bergen | And 2 more authors.
International Journal of Cardiology | Year: 2013

Background: Immune system activation is involved in atherosclerosis. Neopterin production and tryptophan catabolismthrough the kynurenine pathway, measured by the kynurenine-tryptophan ratio (KTR), are induced by interferon gamma, thus both are consideredmarkers of cell mediated immune activation. This study prospectively investigated their predictive value on acute coronary events among Norwegian community-dwelling older adults without previous coronary heart disease. Methods: 1112 men and 1631 women, 71-74 years old were examined during 1997-99 as part of the Hordaland Health Study. They were followed until an acute coronary event (defined as unstable angina, non-fatal or fatal acute myocardial infarction or sudden death) or December 31, 2006. Kaplan-Meier hazard curves were constructed for quartiles of plasma neopterin and KTR. Cox proportional hazards models adjusted for sex, body mass index, smoking, hypertension, renal function and cholesterol were used to examine the relation between neopterin and KTR quartiles and the study endpoint. Results:Median (interquartile range) valueswere 8.6 (7.2-10.4) nmol/L for neopterin and 25.8 (25.3-31.1) nmol/ μmol for KTR. During the follow up, 265 participants had at least one acute coronary event. Increased baseline levels of plasma neopterin and KTR were associated with continuous increased risk of developing the study endpoint (P-values for trend b0.001 and 0.019, respectively). Adjusted hazard ratios comparing the fourth quartile to the first were 1.65 (95% CI; 1.11-2.47; P=0.013) for neopterin and 1.57 (95% CI 1.03-2.39; P=0.036) for KTR. Conclusion: Plasma neopterin and KTR levels predict acute coronary events in older adults without previous coronary heart disease. © 2013 Elsevier Ireland Ltd. All rights reserved.

Pedersen E.R.,University of Bergen | Tuseth N.,University of Bergen | Eussen S.J.P.M.,University of Bergen | Eussen S.J.P.M.,Maastricht University | And 15 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015

OBJECTIVE - : Enhanced tryptophan degradation, induced by the proinflammatory cytokine interferon-γ, has been related to cardiovascular disease progression and insulin resistance. We assessed downstream tryptophan metabolites of the kynurenine pathway as predictors of acute myocardial infarction in patients with suspected stable angina pectoris. Furthermore, we evaluated potential effect modifications according to diagnoses of pre-diabetes mellitus or diabetes mellitus. APPROACH AND RESULTS - : Blood samples were obtained from 4122 patients (median age, 62 years; 72% men) who underwent elective coronary angiography. During median follow-up of 56 months, 8.3% had acute myocardial infarction. Comparing the highest quartile to the lowest, for the total cohort, multivariable adjusted hazard ratios (95% confidence intervals) were 1.68 (1.21-2.34), 1.81 (1.33-2.48), 1.68 (1.21-2.32), and 1.48 (1.10-1.99) for kynurenic acid, hydroxykynurenine, anthranilic acid, and hydroxyanthranilic acid, respectively. The kynurenines correlated with phenotypes of the metabolic syndrome, and risk associations were generally stronger in subgroups classified with pre-diabetes mellitus or diabetes mellitus at inclusion (Pint≤0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements (0.21 [0.08-0.35] and 0.21 [0.07-0.35], respectively). CONCLUSIONS - : In patients with suspected stable angina pectoris, elevated levels of plasma kynurenines predicted increased risk of acute myocardial infarction, and risk estimates were generally stronger in subgroups with evidence of impaired glucose homeostasis. Future studies should aim to clarify roles of the kynurenine pathway in atherosclerosis and glucose metabolism. © 2014 American Heart Association, Inc.

PubMed | Civic Mp Arezzo Hospital, Institute of Population based research, Norwegian Institute of Public Health, Finnish National Institute for Health and Welfare and 15 more.
Type: Journal Article | Journal: European urology | Year: 2016

Folate and vitamin BTo investigate the associations between circulating folate and vitamin BA study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin BIncident PCa and subtype by stage and grade.Higher folate and vitamin BThe association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Theofylaktopoulou D.,University of Bergen | Ulvik A.,Bevital AS | Midttun O.,Bevital AS | Ueland P.M.,University of Bergen | And 6 more authors.
British Journal of Nutrition | Year: 2014

Vitamins B2 and B6 are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2 and B6 as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2 and B6 vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2 and B6 was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2 vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0.20 (95 % CI 0.16, 0.23) and 0.24 (95 % CI 0.19, 0.28), at riboflavin concentrations below the median value (13.0 nmol/l). The vitamin B6 vitamer, pyridoxal 5′-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39.3-47.0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18.9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism. © The Authors 2014.

PubMed | University of Florida, University of Bergen and Bevital AS
Type: Journal Article | Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD | Year: 2016

Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease.We explored the association between a MTHFD1 polymorphism (rs1076991 C>T) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n=2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23-1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01-2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55-3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86-1.93) or folic acid/B12 (1.17; 95% CI, 0.83-1.65).A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors.

Meyer K.,Bevital AS | Ueland P.M.,University of Bergen
Analytical Chemistry | Year: 2014

The most common technologies for quantitative determination of protein biomarkers are immunoassays, which exist in various formats. Immunoassays offer sensitive and fast protein quantification, but can hardly discriminate between protein variants. Post-translational modifications and genetic variants increase protein microheterogeneity and may play important roles in biological processes. Mass spectrometry combined with immunoaffinity enrichment detects protein microheterogeneity and can quantify different isoforms. We here present an immuno-MALDI-MS approach for the combined quantification of two important biomarkers of inflammation and renal function, C-reactive protein (CRP) and cystatin C, respectively. Antibodies were immobilized onto reversed-phase tips, which allows easy and flexible sample processing. Quantification was performed in singleplex and duplex assays, and characteristics were evaluated for different internal standards, i.e., PEGylated and polyhistidine-tagged proteins. The best performances were obtained for polyhistidine-tagged standards with respect to limits of detection (CRP, 0.10 μg/mL; cystatin C, 0.003 μg/mL) and coefficients of variation (CRP, 2.4-7.0%; cystatin C, 3.0-8.9%). The methods were benchmarked against immunoturbidimetry and nephelometry and demonstrated good between-assay agreement (R2 = 0.989 for CRP; R2 = 0.939 for cystatin C). Several variants of cystatin C were identified and quantified, while none were observed for CRP. This immuno-MALDI method describes a novel approach for targeted quantitative investigation of protein microheterogeneity and is well suited for assessment of biomarker status in precious samples from biobanks due to its low sample consumption. © 2014 American Chemical Society.

De Vogel S.,University of Bergen | Meyer K.,BEVITAL AS | Fredriksen A.,BEVITAL AS | Ulvik A.,BEVITAL AS | And 8 more authors.
International Journal of Epidemiology | Year: 2013

Background Although individual studies have been inconsistent, meta-analyses of epidemiological data suggest that high folate and vitamin B12 levels may be associated with increased prostate cancer risk. Methods Within JANUS, a prospective cohort in Norway (n=317 000) with baseline serum samples, we conducted a nested case-control study among 3000 prostate cancer cases and 3000 controls, matched on age and time at serum sampling, and county of residence. Using conditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk were estimated according to quintiles of serum folate, vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy) and methionine, and according to MTHFR 677C→T genotypes. To correct for degradation during sample storage, folate concentration was measured as p-aminobenzoylglutamate (pABG) equivalents following oxidation and acid hydrolysis. Results We observed a weak positive association between folate concentration and prostate cancer risk [OR highest vs lowest quintile=1.15 (0.97-1.37), P-trend=0.04], which was more pronounced among individuals ≥50 years at inclusion [OR 1.40 (1.07-1.84), P-trend=0.02]. tHcy showed an inverse trend with risk [OR 0.92 (0.77-1.10), P-trend=0.03]. Vitamin B12, MMA and methionine concentrations were not associated with prostate cancer risk. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]. Conclusion This large-scale population-based study suggests that high serum folate concentration may be associated with modestly increased prostate cancer risk. We did not observe an association between vitamin B12 status and prostate cancer risk. © The Author 2013; All rights reserved.

Oyen J.,University of Bergen | Nygard O.K.,University of Bergen | Gjesdal C.G.,University of Bergen | Ueland P.M.,University of Bergen | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2014

Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect-modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69-2.37) and middle (OR = 1.39, CI 1.17-1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95-4.14; middle tertile: OR = 1.80, CI 1.22-2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87-11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08-1.94; middle tertile: HR = 1.13, CI 0.83-1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32-2.73) and 1.36 (CI 0.92-1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16-6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism. © 2014 American Society for Bone and Mineral Research.

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