Helga Refsum
University of Oslo, Department of Nutrition, Faculty Member
Amino acids (AAs) and dietary inflammatory potential play essential roles in muscle health. We examined the associations of dietary inflammatory index (DII) of habitual diet with serum AA profile, and ascertained if the associations... more
Amino acids (AAs) and dietary inflammatory potential play essential roles in muscle health. We examined the associations of dietary inflammatory index (DII) of habitual diet with serum AA profile, and ascertained if the associations between DII and muscle outcomes were mediated by serum AAs, in 2994 older Chinese community-dwelling men and women (mean age 72 years) in Hong Kong. Higher serum branched chain AAs (BCAAs), aromatic AAs and total glutathione (tGSH) were generally associated with better muscle status at baseline. A more pro-inflammatory diet, correlating with higher serum total homocysteine and cystathionine, was directly (90.2%) and indirectly (9.8%) through lower tGSH associated with 4-year decline in hand grip strength in men. Higher tGSH was associated with favorable 4-year changes in hand grip strength, gait speed and time needed for 5-time chair stands in men and 4-year change in muscle mass in women. Higher leucine and isoleucine were associated with decreased risk...
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Folate and vitamin B-12 are important for growth. Many children in low- and middle-income countries have inadequate intakes of these nutrients. We undertook a randomized, placebo controlled double-blind trial in 1000 North Indian... more
Folate and vitamin B-12 are important for growth. Many children in low- and middle-income countries have inadequate intakes of these nutrients. We undertook a randomized, placebo controlled double-blind trial in 1000 North Indian children, 6 to 35 months of age, providing twice the recommended daily allowance of folic acid and/or vitamin B-12, or placebo, daily for 6 months. By using a factorial design, we allocated children in a 1:1:1:1 ratio in blocks of 16. We measured the effect of giving vitamin B-12, folic acid, or the combination of both on linear and ponderal growth. We also identified predictors for growth in multiple linear regression models and effect modifiers for the effect of folic acid or vitamin B-12 supplementation on growth. The overall effect of either of the vitamins was significant only for weight; children who received vitamin B-12 increased their mean weight-for-age z scores by 0.07 (95% confidence interval: 0.01 to 0.13). Weight-for-age z scores and height-fo...
Research Interests: Pediatrics, Developing Countries, Folic acid, Medicine, Linear models, and 15 moreIndia, Humans, Placebo, Female, Male, Infant, Underweight, Randomized Controlled Trial, Body Weight, Combination drug therapy, Body Height, Confidence Interval, Child preschool, Psychology and Cognitive Sciences, and Medical and Health Sciences
Aterosclerotic cardiovascular disease, notably coronary heart disease, remains the major cause of death in developed countries [1]. A high-fat diet, hypertension, and smoking are regarded as causal factors [2], and changes in these... more
Aterosclerotic cardiovascular disease, notably coronary heart disease, remains the major cause of death in developed countries [1]. A high-fat diet, hypertension, and smoking are regarded as causal factors [2], and changes in these factors appear to contribute to coronary heart disease mortality trends [3]. Nevertheless, these factors remain incomplete predictors of both the occurrence of and changes in cardiovascular mortality.
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Research Interests: Psychology, Depression, Cognition, Medicine, Linear models, and 15 morePsychosomatic Medicine, Norway, Humans, Internal Medicine, Female, Male, Regression Analysis, Apolipoprotein E, Homocysteine, Aged, Cross Sectional Studies, Cognition disorders, Neuropsychological Tests, Psychology and Cognitive Sciences, and Medical and Health Sciences
People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 microg) and/or 100 g cooked green... more
People in India have a high prevalence of low vitamin B12 status and high plasma total homocysteine (tHcy) concentrations. In a proof of principle trial, we studied the effect of oral vitamin B12 (500 microg) and/or 100 g cooked green leafy vegetables (GLV) every alternate day in a 2x2 factorial design over a 6-week period. Forty-two non-pregnant vegetarian women (age 20-50 years) were randomly allocated to four study groups. Clinical measurements were made at the beginning and at the end of the study, and blood samples were collected before, and 2 and 6 weeks after commencement of intervention. Forty women completed the trial. Twenty-six women had low vitamin B12 status (<150 pmol/L) and 24 had hyperhomocysteinemia (>15 micromol/L). GLV supplementation did not alter plasma folate or tHcy. Vitamin B12 supplementation increased plasma vitamin B12 concentration (125 to 215 pmol/L, p <0.05) and reduced tHcy concentration (18.0 to 13.0 micromol/L, p <0.05) within first 2 wee...
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Research Interests: Engineering, Neurogenesis, Child Development, Folic acid, Medicine, and 15 moreIndia, Humans, Female, Male, Infant, Developmental disabilities, Nutritional Status, Homocysteine, Prevalence, Biological markers, Cognition disorders, Cohort Studies, Psychomotor Performance, folic acid deficiency, and Medical and Health Sciences
The Hordaland Homocysteine Study (HHS) is a population-based study of more than 18,000 men and women in the county of Hordaland in Western Norway. The first investigation (HHS-I) took place in 1992-93, when the subjects were aged 40-67 y.... more
The Hordaland Homocysteine Study (HHS) is a population-based study of more than 18,000 men and women in the county of Hordaland in Western Norway. The first investigation (HHS-I) took place in 1992-93, when the subjects were aged 40-67 y. In 1997-99, a follow-up study (HHS-II) of 7,053 subjects was carried out. In this large population, plasma levels of total homocysteine (tHcy) are associated with several physiologic and lifestyle factors and common diseases. Increasing age, male sex, smoking, coffee consumption, high blood pressure, unfavorable lipid profile, high creatinine, and the MTHFR 677C &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; T polymorphism are among the factors associated with increased tHcy levels; physical activity, moderate alcohol consumption, and a good folate or vitamin B-12 status are associated with lower tHcy levels. Subjects with raised tHcy levels have increased risk of cardiovascular morbidity, cardiovascular and noncardiovascular mortality, and are more likely to suffer from depression and from cognitive deficit (elderly). Among women, raised tHcy levels are associated with decreased bone mineral density and increased risk of osteoporosis. Women with raised tHcy levels also have an increased risk of having suffered from pregnancy complications and an adverse pregnancy outcome. Significant associations between tHcy and clinical outcomes are usually observed for tHcy levels &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 15 micromol/L, but for most conditions, there is a continuous concentration-response relation with no apparent threshold concentration. Overall, the findings from HHS indicate that a raised tHcy level is associated with multiple clinical conditions, whereas a low tHcy level is associated with better physical and mental health.
Research Interests: Epidemiology, Depression, Aging, Animal Production, Humans, and 15 moreHigh Blood Pressure, Female, Disease, Bone Density, Homocysteine, Alcohol Consumption, Association, Aged, Adult, Bone Mineral Density, Cardiovascular Diseases, Food Sciences, Cross Sectional Studies, Cognition disorders, and Cohort Studies
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Dietary and plasma total cysteine (tCys) have been associated with adiposity, possibly through interaction with stearoyl–CoA desaturase (SCD), which is an enzyme that is involved in fatty acid and energy metabolism. We evaluated the... more
Dietary and plasma total cysteine (tCys) have been associated with adiposity, possibly through interaction with stearoyl–CoA desaturase (SCD), which is an enzyme that is involved in fatty acid and energy metabolism. We evaluated the effect of a dietary intervention with low cysteine and methionine and high polyunsaturated fatty acids (PUFAs) on plasma and urinary sulfur amino acids and SCD activity indices. Fourteen normal-weight healthy subjects were randomized to a seven-day diet low in cysteine and methionine and high in PUFAs (Cys/Metlow + PUFA), or high in saturated fatty acids (SFA), cysteine, and methionine (Cys/Methigh + SFA). Compared with the Cys/Methigh + SFA group, plasma methionine and cystathionine decreased (p-values < 0.05), whereas cystine tended to increase (p = 0.06) in the Cys/Metlow + PUFA group. Plasma total cysteine (tCys) was not significantly different between the groups. Urinary cysteine and taurine decreased in the Cys/Metlow + PUFA group compared with ...
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The biosynthesis of B, involving up to 30 different enzyme-mediated steps, only occurs in bacteria. Thus, most eukaryotes require an external source of B, and yet the vitamin appears to have only two functions in eukaryotes: as a cofactor... more
The biosynthesis of B, involving up to 30 different enzyme-mediated steps, only occurs in bacteria. Thus, most eukaryotes require an external source of B, and yet the vitamin appears to have only two functions in eukaryotes: as a cofactor for the enzymes methionine synthase and methylmalonylCoA mutase. These two functions are crucial for normal health in humans, and in particular, the formation of methionine is essential for providing methyl groups for over 100 methylation processes. Interference with the methionine synthase reaction not only depletes the body of methyl groups but also leads to the accumulation of homocysteine, a risk factor for many diseases. The syndrome pernicious anemia, characterized by lack of intrinsic factor, leads to a severe, sometimes fatal form of Bdeficiency. However, there is no sharp cutoff for Bdeficiency; rather, there is a continuous inverse relationship between serum Band a variety of undesirable outcomes, including neural tube defects, stroke, an...
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A 19-year-old male with 22q11.2 deletion syndrome presented with a 4-year history of cognitive decline and symptoms suggestive of atypical psychosis. Potential for elevated homocysteine and NMDA-receptor antibodies in the pathogenesis of... more
A 19-year-old male with 22q11.2 deletion syndrome presented with a 4-year history of cognitive decline and symptoms suggestive of atypical psychosis. Potential for elevated homocysteine and NMDA-receptor antibodies in the pathogenesis of his symptoms was investigated. He had elevated blood homocysteine level (18.7 μmol/l), low-normal vitamin B12 and folate levels and was positive for NMDA-receptor antibodies. Treatment with daily folinic acid (0.8 mg) and vitamin B12 (1 mg) led to dramatic improvement in his cognitive and behavioural presentation. Subsequent plasma exchange resulted in a further, significant clinical improvement. Homocysteine levels and NMDA-R antibodies should be investigated as potential causes of behavioural and cognitive symptoms in patients with 22q11.2 deletion syndrome.
Research Interests: Medicine()
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Research Interests: Endocrinology, Treatment, Folic acid, Medicine, Humans, and 13 moreFemale, Clinical, Blood sampling, Male, Clinical Sciences, Aged, Middle Aged, Arginine, Serum Asymmetric Dimethylarginine (ADMA), Peripheral artery disease, hyperhomocysteinemia, vitamin b complex, and Paediatrics and reproductive medicine
Research Interests: Cardiology, Folic acid, Medicine, India, Humans, and 15 moreFemale, Male, Risk factors, Homocysteine, Aged, Middle Aged, Adult, Cardiovascular Diseases, Risk Factors, Coronary Artery Disease, vitamin B deficiency, hyperhomocysteinemia, folic acid deficiency, vitamin B, and Cardiovascular medicine and haematology
Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from... more
Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from retrospective and prospective studies, supports an association between elevated HCY levels and increased risk of cardiovascular disease (CVD). However, whether lowering HCY levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate. Although the major studies that have reported to date show that vitamin supplementation was associated with a decrease in HCY levels, this failed to have any significant effect on cardiovascular risk. Furthermore, although some lipid-modifying treatments have been shown to increase HCY levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk. Taken together, th...
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Low vitamin B12 concentration in South Asian Indians is common, but the exact prevalence is not known. To investigate prevalence and associations of low vitamin B12 concentration and hyperhomocysteinemia in rural and urban Indian men... more
Low vitamin B12 concentration in South Asian Indians is common, but the exact prevalence is not known. To investigate prevalence and associations of low vitamin B12 concentration and hyperhomocysteinemia in rural and urban Indian men living in and around Pune, Maharashtra. We studied 441 middle-aged men (149 rural, 142 slum and 150 urban middle-class residents, mean age 39 y). Data on lifestyle, socio-economic status, nutrition and medical history were obtained. Circulating concentrations of vitamin B12, folate, ferritin, total homocysteine (tHcy), and haematological indices, and cardiovascular risk variables were measured. Median plasma B12 concentration was low (110 pmol/L): Overall, 67% of men had low vitamin B12 concentration (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;150 pmol/L) and 58% had hyperhomocysteinemia (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;15 micromol/L). Of the urban middle class, 81% had low vitamin B12 concentration and 79% had hyperhomocysteinemia. Low vitamin B12 concentration contributed 28% to the risk of hyperhomocysteinemia (population attributable risk) while low red cell folate contributed 2%. Vegetarians had 4.4 times (95% CI 2.1, 9.4) higher risk of low vitamin B12 concentrations and 3.0 times (95% CI 1.4, 6.5) higher risk of hyperhomocysteinemia compared to those who ate non-vegetarian foods frequently. Urban middle-class residence was an additional independent risk factor of hyperhomocysteinemia (odds ratio 7.6 (95% CI 2.5, 22.6), compared to rural men). Low vitamin B12 concentration was related to lower blood haemoglobin concentration and higher mean corpuscular volume, but macrocytic anemia was rare. Low vitamin B12 concentration and hyperhomocysteinemia are common in Indian men, particularly in vegetarians and urban middle class residents. Further studies are needed to confirm these findings in other parts of India.
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Research Interests: Nutrition, Randomization, Folic acid, Medicine, Humans, and 15 moreInternal Medicine, Female, Male, Patient Compliance, Risk factors, Homocysteine, Clinical Sciences, Middle Aged, Myocardial Infarction, Internal, Risk Factors, Capsules, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, and Myocardial Ischemia
Background: A deficiency of cystathionine β-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... more
Background: A deficiency of cystathionine β-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...
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We constructed an assay to detect the common C677T mutation in the methylenetetrahydrofolate reductase gene. The mutation creates a Hinfl recognition site detected by restriction cleavage of a 198-bp fragment amplified in the polymerase... more
We constructed an assay to detect the common C677T mutation in the methylenetetrahydrofolate reductase gene. The mutation creates a Hinfl recognition site detected by restriction cleavage of a 198-bp fragment amplified in the polymerase chain reaction (PCR). Digested samples were subjected to capillary electrophoresis with laser-induced fluorescence detection (CE-LIF), with hydroxypropylmethylcellulose as the sieving matrix and SYBR Green I as the fluorescent dye. After amplification but before digestion, we added to the PCR mixture a fragment with the HinfI recognition site and a 15-bp truncation at the 3′ end. Using this procedure, we could (a) verify completeness of digestion and monitor injection, (b) assign genotypes on the basis of pattern recognition, and (c) develop a multiple-injection mode with simultaneous separation of as many as eight samples. A seminested PCR protocol in combination with CE-LIF allowed genotyping of plasma/serum samples 20 years old.
Research Interests: Pattern Recognition, Capillary electrophoresis, Clinical Chemistry, Mutation, Medical Biotechnology, and 11 morePolymerase Chain Reaction, Risk factors, Homocysteine, Laser Induced Fluorescence, Clinical Sciences, Electrophoresis, Risk Factors, Electroforesis, restriction enzyme, Methylenetetrahydrofolate Reductase, and Medical biochemistry and metabolomics
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Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n... more
Plasma sulphur-containing amino acids and related metabolites are associated with insulin sensitivity, although the mechanisms are unclear. We examined the effect of exercise on this relationship. Dysglycemic (n = 13) and normoglycemic (n = 13) men underwent 45 min cycling before and after 12 weeks exercise intervention. We performed hyperinsulinemic euglycemic clamp, mRNA-sequencing of skeletal muscle and adipose tissue biopsies, and targeted profiling of plasma metabolites by LC-MS/MS. Insulin sensitivity increased similarly in dysglycemic and normoglycemic men after 12 weeks of exercise, in parallel to similar increases in concentration of plasma glutamine, and decreased concentrations of plasma glutamate, cysteine, taurine, and glutathione. Change in plasma concentrations of cysteine and glutathione exhibited the strongest correlations to exercise-improved insulin sensitivity, and expression of a cluster of genes essential for oxidative phosphorylation and fatty acid metabolism ...
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This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure,... more
This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure, status, and function. As with the other 5 reports in this series, which focused on iodine, folate, zinc, iron, and vitamin A, this B12 report was developed with the assistance of an expert panel (BOND B12 EP) and other experts who provided information during a consultation. The experts reviewed the existing literature in depth in order to consolidate existing relevant information on the biology of B12, including known and possible effects of insufficiency, and available and potential biomarkers of status. Unlike the situation for the other 5 nutrients reviewed during the BOND project, there has been relatively little previous attention paid to B12 status and its biomarkers, so this report is a landmark in terms of the consolidation and interpretatio...
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Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the... more
Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Methods Cox proportional hazards models were used to assess the prospective relationships between tHcy and acute myocardial infarction in 2205 patients from Western Norway undergoing elective coronary angiography for suspected stable angina pectoris. Results are reported as hazard ratio per standard deviation increase in log-transformed tHcy. An interaction term for tHcy × Vit-A was added to multivariate models including age, sex, smoking, apolipoprotein B fasting, statin and aspirin prescription and estimated glomerular filtration rate. Results Geometric mean (geometric standard deviation) age of the participants (64.3% men) was 62.3 (1.24) year...
We compared Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) and body mass index (BMI) as correlates of body fat percent (BF%) and the association with future risk of cardiovascular disease (CVD) and type 2 diabetes in a... more
We compared Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) and body mass index (BMI) as correlates of body fat percent (BF%) and the association with future risk of cardiovascular disease (CVD) and type 2 diabetes in a Caucasian population. We used data from 6796 individuals (born 1925-27 and 1950-52) from the Hordaland Health Study, a prospective cohort study in Norway. The study was conducted in 1992-1993 and 1997-1999. Cross-sectional analyses were conducted with data from 1997/99, including BF% measured by dual-energy X-ray absorptiometry. Longitudinal analyses included BMI and CUN-BAE calculated in 1992/93, and self-reported information on CVD events and diabetes in 1997/99. The correlation between CUN-BAE and BF% (=0.88) was stronger than between BMI and BF% (=0.56). In sex-stratified analyses, CUN-BAE and BMI correlated similarly with BF% in men (=0.77 and =0.76, respectively) and women (=0.82 and =0.81, respectively). In longitudinal analyses, the odds rat...
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To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid... more
To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (µg/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA β = 0.28, ALA β = 0.13, EPA β = 0.34, and DHA β = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influen...
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Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may... more
Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Int...
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Plasma cysteine is strongly associated with body fat mass in human cohorts and diets low in cysteine prevents fat accumulation in mice. It is unclear if plasma cysteine affects fat development or if fat accumulation raises plasma... more
Plasma cysteine is strongly associated with body fat mass in human cohorts and diets low in cysteine prevents fat accumulation in mice. It is unclear if plasma cysteine affects fat development or if fat accumulation raises plasma cysteine. To determine if cysteine affects adipogenesis, we differentiated 3T3-L1 preadipocytes in medium with reduced cysteine. Cells incubated in media with 10-20μM cysteine exhibited reduced capacity to differentiate into triacylglycerol-storing mature adipocytes compared with cells incubated with 50μM cysteine. Low cysteine severely reduced expression of peroxisome proliferator-activated receptor gamma2 (Pparγ2) and its target genes perlipin1 (Plin1) and fatty acid binding protein-4 (Fabp4). Expression of stearoyl-CoA desaturase-1 (Scd1), known to be repressed with cysteine depletion, was also reduced with low cysteine. Medium depletion of the essential amino acids leucine, valine, and isoleucine had only a modest effect on adipocyte specific gene expression and differentiation. Stimulation with the PPARγ agonist BRL-49653 or addition of a hydrogen sulfide donor enhanced differentiation of 3T3-L1 cells cultured in low cysteine. This demonstrates that the ability to induce PPARγ expression is preserved when cells are cultured in low cysteine. It therefore appears that cysteine depletion inhibits adipogenesis by specifically affecting molecular pathways required for induction of PPARγ expression, rather than through a general reduction of global protein synthesis. In conclusion, we show that low extracellular cysteine reduces adipocyte differentiation by interfering with PPARγ2 and PPARγ target gene expression. Our results provide further evidence for the hypothesis that plasma cysteine is a casual determinant for body fat mass.
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Plasma concentrations of several amino acids (AAs) are positively correlated with obesity. The aim of this study was to examine if selected plasma AAs are associated with weight regain from 2 to 4 years after Roux-en-Y gastric bypass... more
Plasma concentrations of several amino acids (AAs) are positively correlated with obesity. The aim of this study was to examine if selected plasma AAs are associated with weight regain from 2 to 4 years after Roux-en-Y gastric bypass (RYGB). In a prospective study with 165 patients, we examined the relationship between plasma aromatic AAs (AAAs), branched chain AAs (BCAAs), and total cysteine (tCys) 2 years after RYGB, with BMI at 2 years and with weight change from 2 to 4 years after surgery. Analyses were adjusted for relevant covariates. The investigated AAs at 2 years correlated positively with BMI at 2 years (P ≤ 0.003 for all). BCAAs and AAAs at 2 years correlated inversely with % weight loss from 0 to 2 years (P = 0.002 and P = 0.001, respectively), while the association was not significant for tCys (r = -0.14, P = 0.08). Plasma tCys at 2 years correlated positively with BMI at 4 years (P = 0.010) and with weight regain from 2 to 4 years (P = 0.015). Plasma AAAs, BCAAs, and tCys at 2 years were associated with BMI at 2 years. In addition, plasma AAAs and BCAAs at 2 years were associated with weight loss from 0 to 2 years, while tCys at 2 years was associated with weight regain from 2 to 4 years after RYGB. These results suggest that high tCys at 2 years may be used as a prognostic marker for future weight regain. The study was registered in ClinicalTrials.gov (NCT0 1270451).
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Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results. To compare differences in plasma kynurenine levels between AD and... more
Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results. To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition. The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05. Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not...
Research Interests: Cognitive Science, Nonparametric Statistics, Aging, Signal Transduction, Humans, and 14 moreFemale, Male, Tryptophan, Clinical Sciences, Aged, Middle Aged, Kynurenine pathway, Alzheimer Disease, Neurosciences, Cognition disorders, Cohort Studies, Neuropsychological Tests, quinolinic acid, and 3-hydroxyanthranilic acid
Apolipoproteins B (apoB) and A1 (apoA1) are major protein constituents of low-density and high-density lipoproteins, respectively, and serum concentrations of these apolipoproteins are associated with risk of atherosclerosis. Vitamin A... more
Apolipoproteins B (apoB) and A1 (apoA1) are major protein constituents of low-density and high-density lipoproteins, respectively, and serum concentrations of these apolipoproteins are associated with risk of atherosclerosis. Vitamin A (VA) has been implicated in lipoprotein metabolism. We evaluated the associations of serum apoB, apoA1 and their ratio (apoBAR) with risk of incident acute myocardial infarction (AMI) and the possible modification by serum VA. Risk associations were assessed by Cox regression, and presented as hazard ratios (HRs) per standard deviation (SD) increment in log-transformed values of the lipid parameters, among 4117 patients with suspected stable angina pectoris, located in Western Norway. Interactions with VA were evaluated by including interaction terms in the models. The multivariate model included age, sex, smoking, hypertension, number of stenotic coronary arteries, left ventricular ejection fraction, C-reactive protein, estimated glomerular filtratio...
Research Interests: Atherosclerosis, Risk assessment, Vitamin A, Prospective studies, Humans, and 13 moreFemale, Male, Risk factors, Apolipoprotein B, apolipoprotein A-I, Clinical Sciences, Aged, Middle Aged, Myocardial Infarction, Cardiovascular Diseases, Risk Factors, Risk Assessment, and Cardiovascular medicine and haematology
Although reduced glutathione (rGSH) is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO) results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors,... more
Although reduced glutathione (rGSH) is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO) results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors, cysteine and glutamate. Plasma total cysteine (tCys) is positively associated with stearoyl-coenzyme A desaturase (SCD) activity and adiposity in humans and animal models. To explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice. Male C3H/HeH mice aged 11 weeks were fed a high-fat diet with or without BSO in drinking water (30 mmol/L) for 8 weeks. Amino acid and fatty acid changes were assessed, as well as food consumption, energy expenditure, locomotor activity, body composition and liver vacuolation (steatosis). Despite higher food intake, BSO decreased particularly fat mass but also lean mass (both P<0.001), and prevented fatty liver vacuolation. Physical activity increased during the dark phase. BSO decreased plasma fre...
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The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. In a randomized placebo controlled trial in low-to-middle... more
The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. In a randomized placebo controlled trial in low-to-middle income neighborhoods in New Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6 months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children. Mean Hb concentration decreased in all four study groups during the six months of follow up and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at study end. Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation to combat anemia. Our results also call for alternative strategies to improve iron status and treat iron deficiency anemia. NCT00717730 at www.clinicaltrials.gov, CTRI No.: CTRI/2010/091/001090 at www.ctri.nic.in.
Research Interests: Nutrition and Dietetics, Biomarkers, Risk, Folic acid, Urban Health, and 15 moreIndia, Clinical Nutrition, Humans, Female, Male, Infant, Dietary Supplements, Homocysteine, Solubility, Prevalence, Iron Deficiency Anemia, Hemoglobins, Child preschool, vitamin B, and Infant nutritional physiological phenomena
Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting... more
Data on the relation between linoleic acid (LA) and alpha-linolenic acid (ALA) and type 2 diabetes mellitus (T2DM) risk are scarce and inconsistent. The aim of this study was to investigate the association of serum LA and ALA with fasting and 2 h post-load plasma glucose and glycated hemoglobin (HbA1c). This study included 667 participants from third examination (2000) of the population-based Hoorn study in which individuals with glucose intolerance were overrepresented. Fatty acid profiles in serum total lipids were measured at baseline, in 2000. Diabetes risk markers were measured at baseline and follow-up in 2008. Linear regression models were used in cross-sectional and prospective analyses. In cross-sectional analyses (n = 667), serum LA was inversely associated with plasma glucose, both in fasting conditions (B = -0.024 [-0.045, -0.002]) and 2 h after glucose tolerance test (B = -0.099 [-0.158, -0.039]), but not with HbA1c (B = 0.000 [-0.014, 0.013]), after adjustment for rele...
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A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial. To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age... more
A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial. To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age seven years when the diagnosis is more reliable than at preschool age. This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age seven was defined by asthma medications dispensed at least twice in the year (1,901 cases, n=39,846) or by maternal questionnaire report (1,624 cases, n=28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Risk of asthma was increased in the highest vs. lowest quintile of total folate intake with an adju...
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Research Interests:
Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain... more
Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia. Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process. Homocysteine may interact with both risk factors and protective factors, thereby identifying people at risk but also providing potential strategies for early intervention. Public health steps to slow cognitive decline should be promo...