Publications by authors named "Thomas E Gundersen"

35 Publications

Genetic regulation of liver lipids in a mouse model of insulin resistance and hepatic steatosis.

Mol Syst Biol 2021 01;17(1):e9684

Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.

To elucidate the contributions of specific lipid species to metabolic traits, we integrated global hepatic lipid data with other omics measures and genetic data from a cohort of about 100 diverse inbred strains of mice fed a high-fat/high-sucrose diet for 8 weeks. Association mapping, correlation, structure analyses, and network modeling revealed pathways and genes underlying these interactions. In particular, our studies lead to the identification of Ifi203 and Map2k6 as regulators of hepatic phosphatidylcholine homeostasis and triacylglycerol accumulation, respectively. Our analyses highlight mechanisms for how genetic variation in hepatic lipidome can be linked to physiological and molecular phenotypes, such as microbiota composition.
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http://dx.doi.org/10.15252/msb.20209684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792507PMC
January 2021

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.

Diabetes Care 2021 Jan 17;44(1):98-106. Epub 2020 Nov 17.

Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, U.K.

Objective: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

Research Design And Methods: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.

Results: We identified 11 genomic regions associated with plasma vitamin C ( < 5 × 10), with the strongest signal at , and 10 novel genetic loci including , , , , , , , , , and . Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

Conclusions: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
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http://dx.doi.org/10.2337/dc20-1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783939PMC
January 2021

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

PLoS Med 2020 10 16;17(10):e1003394. Epub 2020 Oct 16.

MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis.

Methods And Findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities.

Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.
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http://dx.doi.org/10.1371/journal.pmed.1003394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567390PMC
October 2020

Association of plasma biomarkers of fruit and vegetable intake with incident type 2 diabetes: EPIC-InterAct case-cohort study in eight European countries.

BMJ 2020 07 8;370:m2194. Epub 2020 Jul 8.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.

Objective: To investigate the association of plasma vitamin C and carotenoids, as indicators of fruit and vegetable intake, with the risk of type 2 diabetes.

Design: Prospective case-cohort study.

Setting: Populations from eight European countries.

Participants: 9754 participants with incident type 2 diabetes, and a subcohort of 13 662 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort of 340 234 participants: EPIC-InterAct case-cohort study.

Main Outcome Measure: Incident type 2 diabetes.

Results: In a multivariable adjusted model, higher plasma vitamin C was associated with a lower risk of developing type 2 diabetes (hazard ratio per standard deviation 0.82, 95% confidence interval 0.76 to 0.89). A similar inverse association was shown for total carotenoids (hazard ratio per standard deviation 0.75, 0.68 to 0.82). A composite biomarker score (split into five equal groups), comprising vitamin C and individual carotenoids, was inversely associated with type 2 diabetes with hazard ratios 0.77, 0.66, 0.59, and 0.50 for groups 2-5 compared with group 1 (the lowest group). Self-reported median fruit and vegetable intake was 274 g/day, 396 g/day, and 508 g/day for participants in categories defined by groups 1, 3, and 5 of the composite biomarker score, respectively. One standard deviation difference in the composite biomarker score, equivalent to a 66 (95% confidence interval 61 to 71) g/day difference in total fruit and vegetable intake, was associated with a hazard ratio of 0.75 (0.67 to 0.83). This would be equivalent to an absolute risk reduction of 0.95 per 1000 person years of follow up if achieved across an entire population with the characteristics of the eight European countries included in this analysis.

Conclusions: These findings indicate an inverse association between plasma vitamin C, carotenoids, and their composite biomarker score, and incident type 2 diabetes in different European countries. These biomarkers are objective indicators of fruit and vegetable consumption, and suggest that diets rich in even modestly higher fruit and vegetable consumption could help to prevent development of type 2 diabetes.
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http://dx.doi.org/10.1136/bmj.m2194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341350PMC
July 2020

Characteristics of participants who benefit most from personalised nutrition: findings from the pan-European Food4Me randomised controlled trial.

Br J Nutr 2020 Jun 27;123(12):1396-1405. Epub 2020 Feb 27.

Human Nutrition Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon TyneNE2 4HH, UK.

Little is known about who would benefit from Internet-based personalised nutrition (PN) interventions. This study aimed to evaluate the characteristics of participants who achieved greatest improvements (i.e. benefit) in diet, adiposity and biomarkers following an Internet-based PN intervention. Adults (n 1607) from seven European countries were recruited into a 6-month, randomised controlled trial (Food4Me) and randomised to receive conventional dietary advice (control) or PN advice. Information on dietary intake, adiposity, physical activity (PA), blood biomarkers and participant characteristics was collected at baseline and month 6. Benefit from the intervention was defined as ≥5 % change in the primary outcome (Healthy Eating Index) and secondary outcomes (waist circumference and BMI, PA, sedentary time and plasma concentrations of cholesterol, carotenoids and omega-3 index) at month 6. For our primary outcome, benefit from the intervention was greater in older participants, women and participants with lower HEI scores at baseline. Benefit was greater for individuals reporting greater self-efficacy for 'sticking to healthful foods' and who 'felt weird if [they] didn't eat healthily'. Participants benefited more if they reported wanting to improve their health and well-being. The characteristics of individuals benefiting did not differ by other demographic, health-related, anthropometric or genotypic characteristics. Findings were similar for secondary outcomes. These findings have implications for the design of more effective future PN intervention studies and for tailored nutritional advice in public health and clinical settings.
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http://dx.doi.org/10.1017/S0007114520000653DOI Listing
June 2020

Infant cholesterol and glycated haemoglobin concentrations vary widely-Associations with breastfeeding, infant diet and maternal biomarkers.

Acta Paediatr 2020 01 4;109(1):115-121. Epub 2019 Aug 4.

Department of Nutrition, University of Oslo, Oslo, Norway.

Aim: Elevated total cholesterol (TC) and glycated haemoglobin (HbA1c) are risk factors for cardiovascular disease; however, little is known about their determinants in infants. We aimed to describe TC and HbA1c concentrations in infants aged 8-14 months and explore the relation between infant TC, HbA1c, breastfeeding, infant diet, and maternal TC and HbA1c.

Methods: In this cross-sectional pilot study, mothers of infants aged 6 and 12 months were invited to complete a food frequency questionnaire and to take home-based dried blood spot samples from themselves and their infants.

Results: Among the 143 included infants, the mean (SD, range) concentration was 4.1 (0.8, 2.3-6.6) mmol/L for TC and 4.9 (0.4, 3.7-6.0)% for HbA1c. There was no significant difference between age groups and sexes. There was a positive relation between TC concentrations of all infants and mothers (B = 0.30 unadjusted, B = 0.32 adjusted, P < .001 for both) and a negative relation between infant TC and intake of unsaturated fatty acids in the oldest age group (B = -0.09, P = .03 unadjusted, B = -0.08, P = .06 adjusted). Infant HbA1c was not significantly related to diet or maternal HbA1c.

Conclusion: TC and HbA1c concentrations varied widely among infants aged 8-14 months. Infant TC was associated with macronutrient intake and maternal TC.
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http://dx.doi.org/10.1111/apa.14936DOI Listing
January 2020

Association of Plasma Vitamin D Metabolites With Incident Type 2 Diabetes: EPIC-InterAct Case-Cohort Study.

J Clin Endocrinol Metab 2019 04;104(4):1293-1303

Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D.

Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis.

Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)].

Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.
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http://dx.doi.org/10.1210/jc.2018-01522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397435PMC
April 2019

Author Correction: Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men.

Sci Rep 2018 May 15;8(1):7885. Epub 2018 May 15.

Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-26061-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951798PMC
May 2018

Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR.

J Lipid Res 2018 07 8;59(7):1164-1174. Epub 2018 May 8.

Division of Cardiology University of California at Los Angeles, Los Angeles, CA

Elevated hepatic ceramide levels have been implicated in both insulin resistance (IR) and hepatic steatosis. To understand the factors contributing to hepatic ceramide levels in mice of both sexes, we have quantitated ceramides in a reference population of mice, the Hybrid Mouse Diversity Panel that has been previously characterized for a variety of metabolic syndrome traits. We observed significant positive correlations between Cer(d18:1/16:0) and IR/hepatic steatosis, consistent with previous findings, although the relationship broke down between sexes, as females were less insulin resistant, but had higher Cer(d18:1/16:0) levels than males. The sex difference was due in part to testosterone-mediated repression of ceramide synthase 6. One ceramide species, Cer(d18:1/20:0), was present at higher levels in males and was associated with IR only in males. Clear evidence of gene-by-sex and gene-by-diet interactions was observed, including sex-specific genome-wide association study results. Thus, our studies show clear differences in how hepatic ceramides are regulated between the sexes, which again suggests that the physiological roles of certain hepatic ceramides differ between the sexes.
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http://dx.doi.org/10.1194/jlr.M081398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027922PMC
July 2018

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men.

Sci Rep 2018 04 25;8(1):6531. Epub 2018 Apr 25.

Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.

Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) composition in skeletal muscle have been linked to insulin sensitivity. We evaluated the relationships between skeletal muscle PC:PE, physical exercise and insulin sensitivity. We performed lipidomics and measured PC and PE in m. vastus lateralis biopsies obtained from 13 normoglycemic normal weight men and 13 dysglycemic overweight men at rest, immediately after 45 min of cycling at 70% maximum oxygen uptake, and 2 h post-exercise, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. Insulin sensitivity was monitored by euglycemic-hyperinsulinemic clamp. RNA-sequencing was performed on biopsies, and mitochondria and lipid droplets were quantified on electron microscopic images. Exercise intervention for 12 w enhanced insulin sensitivity by 33%, skeletal muscle levels of PC by 21%, PE by 42%, and reduced PC:PE by 16%. One bicycle session reduced PC:PE by 5%. PC:PE correlated negatively with insulin sensitivity (β = -1.6, P < 0.001), percent area of mitochondria (ρ = -0.52, P = 0.035), and lipid droplet area (ρ = 0.55, P = 0.017) on EM pictures, and negatively with oxidative phosphorylation and mTOR based on RNA-sequencing. In conclusion, PC and PE contents of skeletal muscle respond to exercise, and PC:PE is inversely related to insulin sensitivity.
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http://dx.doi.org/10.1038/s41598-018-24976-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916947PMC
April 2018

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.

Authors:
Xia Jiang Paul F O'Reilly Hugues Aschard Yi-Hsiang Hsu J Brent Richards Josée Dupuis Erik Ingelsson David Karasik Stefan Pilz Diane Berry Bryan Kestenbaum Jusheng Zheng Jianan Luan Eleni Sofianopoulou Elizabeth A Streeten Demetrius Albanes Pamela L Lutsey Lu Yao Weihong Tang Michael J Econs Henri Wallaschofski Henry Völzke Ang Zhou Chris Power Mark I McCarthy Erin D Michos Eric Boerwinkle Stephanie J Weinstein Neal D Freedman Wen-Yi Huang Natasja M Van Schoor Nathalie van der Velde Lisette C P G M de Groot Anke Enneman L Adrienne Cupples Sarah L Booth Ramachandran S Vasan Ching-Ti Liu Yanhua Zhou Samuli Ripatti Claes Ohlsson Liesbeth Vandenput Mattias Lorentzon Johan G Eriksson M Kyla Shea Denise K Houston Stephen B Kritchevsky Yongmei Liu Kurt K Lohman Luigi Ferrucci Munro Peacock Christian Gieger Marian Beekman Eline Slagboom Joris Deelen Diana van Heemst Marcus E Kleber Winfried März Ian H de Boer Alexis C Wood Jerome I Rotter Stephen S Rich Cassianne Robinson-Cohen Martin den Heijer Marjo-Riitta Jarvelin Alana Cavadino Peter K Joshi James F Wilson Caroline Hayward Lars Lind Karl Michaëlsson Stella Trompet M Carola Zillikens Andre G Uitterlinden Fernando Rivadeneira Linda Broer Lina Zgaga Harry Campbell Evropi Theodoratou Susan M Farrington Maria Timofeeva Malcolm G Dunlop Ana M Valdes Emmi Tikkanen Terho Lehtimäki Leo-Pekka Lyytikäinen Mika Kähönen Olli T Raitakari Vera Mikkilä M Arfan Ikram Naveed Sattar J Wouter Jukema Nicholas J Wareham Claudia Langenberg Nita G Forouhi Thomas E Gundersen Kay-Tee Khaw Adam S Butterworth John Danesh Timothy Spector Thomas J Wang Elina Hyppönen Peter Kraft Douglas P Kiel

Nat Commun 2018 01 17;9(1):260. Epub 2018 Jan 17.

Institute for Aging Research, Hebrew SeniorLife, 1200 Centre Street, Boston, MA, 02131, USA.

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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http://dx.doi.org/10.1038/s41467-017-02662-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772647PMC
January 2018

Association between Diet-Quality Scores, Adiposity, Total Cholesterol and Markers of Nutritional Status in European Adults: Findings from the Food4Me Study.

Nutrients 2018 Jan 6;10(1). Epub 2018 Jan 6.

Hugh Sinclair Unit of Human Nutrition and Institute for Cardiovascular and Metabolic Research, University of Reading, Reading RG6 6AP, UK.

Diet-quality scores (DQS), which are developed across the globe, are used to define adherence to specific eating patterns and have been associated with risk of coronary heart disease and type-II diabetes. We explored the association between five diet-quality scores (Healthy Eating Index, HEI; Alternate Healthy Eating Index, AHEI; MedDietScore, MDS; PREDIMED Mediterranean Diet Score, P-MDS; Dutch Healthy Diet-Index, DHDI) and markers of metabolic health (anthropometry, objective physical activity levels (PAL), and dried blood spot total cholesterol (TC), total carotenoids, and omega-3 index) in the Food4Me cohort, using regression analysis. Dietary intake was assessed using a validated Food Frequency Questionnaire. Participants ( = 1480) were adults recruited from seven European Union (EU) countries. Overall, women had higher HEI and AHEI than men ( < 0.05), and scores varied significantly between countries. For all DQS, higher scores were associated with lower body mass index, lower waist-to-height ratio and waist circumference, and higher total carotenoids and omega-3-index ( trends < 0.05). Higher HEI, AHEI, DHDI, and P-MDS scores were associated with increased daily PAL, moderate and vigorous activity, and reduced sedentary behaviour ( trend < 0.05). We observed no association between DQS and TC. To conclude, higher DQS, which reflect better dietary patterns, were associated with markers of better nutritional status and metabolic health.
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http://dx.doi.org/10.3390/nu10010049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793277PMC
January 2018

Capturing health and eating status through a nutritional perception screening questionnaire (NPSQ9) in a randomised internet-based personalised nutrition intervention: the Food4Me study.

Int J Behav Nutr Phys Act 2017 12 11;14(1):168. Epub 2017 Dec 11.

Centre for Nutrition Research, Department of Nutrition, Food Science and Physiology, University of Navarra, C/Irunlarrea, 1, 31008, Pamplona, Spain.

Background: National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet.

Methods: Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively.

Results: A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (β = -0.181, p < 0.001) and waist circumference (Β = -0.155, p < 0.001), and positively associated with total carotenoids (β = 0.198, p < 0.001), omega-3 fatty acid index (β = 0.155, p < 0.001), Healthy Eating Index (HEI) (β = 0.299, p < 0.001) and Mediterranean Diet Score (MDS) (β = 0. 279, p < 0.001). Findings from the longitudinal intervention study showed a greater reduction in BMI and improved dietary indices among participants with lower NPSQ9 scores.

Conclusions: Healthy eating perceptions and dietary habits captured by the NPSQ9 score, based on nine questionnaire items, were associated with reduced body weight and improved diet quality. Likewise, participants with a lower score achieved greater health improvements than those with higher scores, in response to personalised advice, suggesting that NPSQ9 may be used for early evaluation of nutritional status and to tailor nutritional advice.

Trial Registration: NCT01530139 .
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http://dx.doi.org/10.1186/s12966-017-0624-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725967PMC
December 2017

Combining traditional dietary assessment methods with novel metabolomics techniques: present efforts by the Food Biomarker Alliance.

Proc Nutr Soc 2017 11;76(4):619-627

Division of Human Nutrition,Wageningen University,PO Box 17,6700 AA Wageningen,The Netherlands.

FFQ, food diaries and 24 h recall methods represent the most commonly used dietary assessment tools in human studies on nutrition and health, but food intake biomarkers are assumed to provide a more objective reflection of intake. Unfortunately, very few of these biomarkers are sufficiently validated. This review provides an overview of food intake biomarker research and highlights present research efforts of the Joint Programming Initiative 'A Healthy Diet for a Healthy Life' (JPI-HDHL) Food Biomarkers Alliance (FoodBAll). In order to identify novel food intake biomarkers, the focus is on new food metabolomics techniques that allow the quantification of up to thousands of metabolites simultaneously, which may be applied in intervention and observational studies. As biomarkers are often influenced by various other factors than the food under investigation, FoodBAll developed a food intake biomarker quality and validity score aiming to assist the systematic evaluation of novel biomarkers. Moreover, to evaluate the applicability of nutritional biomarkers, studies are presently also focusing on associations between food intake biomarkers and diet-related disease risk. In order to be successful in these metabolomics studies, knowledge about available electronic metabolomics resources is necessary and further developments of these resources are essential. Ultimately, present efforts in this research area aim to advance quality control of traditional dietary assessment methods, advance compliance evaluation in nutritional intervention studies, and increase the significance of observational studies by investigating associations between nutrition and health.
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http://dx.doi.org/10.1017/S0029665117003949DOI Listing
November 2017

Mediterranean Diet Adherence and Genetic Background Roles within a Web-Based Nutritional Intervention: The Food4Me Study.

Nutrients 2017 Oct 11;9(10). Epub 2017 Oct 11.

Department of Nutrition, and Food Science Physiology, Centre for Nutrition Research, University of Navarra, 31008 Pamplona, Spain.

Mediterranean Diet (MedDiet) adherence has been proven to produce numerous health benefits. In addition, nutrigenetic studies have explained some individual variations in the response to specific dietary patterns. The present research aimed to explore associations and potential interactions between MedDiet adherence and genetic background throughout the Food4Me web-based nutritional intervention. Dietary, anthropometrical and biochemical data from volunteers of the Food4Me study were collected at baseline and after 6 months. Several genetic variants related to metabolic risk features were also analysed. A Genetic Risk Score (GRS) was derived from risk alleles and a Mediterranean Diet Score (MDS), based on validated food intake data, was estimated. At baseline, there were no interactions between GRS and MDS categories for metabolic traits. Linear mixed model repeated measures analyses showed a significantly greater decrease in total cholesterol in participants with a low GRS after a 6-month period, compared to those with a high GRS. Meanwhile, a high baseline MDS was associated with greater decreases in Body Mass Index (BMI), waist circumference and glucose. There also was a significant interaction between GRS and the MedDiet after the follow-up period. Among subjects with a high GRS, those with a high MDS evidenced a highly significant reduction in total carotenoids, while among those with a low GRS, there was no difference associated with MDS levels. These results suggest that a higher MedDiet adherence induces beneficial effects on metabolic outcomes, which can be affected by the genetic background in some specific markers.
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http://dx.doi.org/10.3390/nu9101107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691723PMC
October 2017

Vitamin D supplementation and vitamin D status in children of immigrant background in Norway.

Public Health Nutr 2017 Nov 9;20(16):2887-2892. Epub 2017 Aug 9.

1Department of Community Medicine and Global Health,Institute of Health and Society,University of Oslo,Pb 1130 Blindern, 0318 Oslo,Norway.

Objective: Sufficient vitamin D status during infancy is important for child health and development. Several initiatives for improving vitamin D status among immigrant children have been implemented in Norway. The present study aimed to evaluate the vitamin D status and its determinants in children of immigrant background in Oslo.

Design: Cross-sectional study.

Setting: Child health clinics in Oslo.

Subjects: Healthy children with immigrant background (n 102) aged 9-16 months were recruited at the routine one-year check-up from two child health clinics with high proportions of immigrant clients. Blood samples were collected using the dried blood spot technique and analysed for serum 25-hydroxyvitamin D (s-25(OH)D) concentration using LC-MS/MS.

Results: Mean s-25(OH)D was 52·3 (sd 16·7) nmol/l, with only three children below 25 nmol/l and none below 12·5 nmol/l. There was no significant gender, ethnic or seasonal variation in s-25(OH)D. However, compared with breast-fed children, s-25(OH)D concentration was significantly higher among children who were about 1 year of age and not breast-fed. About 38 % of the children were anaemic, but there was no significant correlation between s-25(OH)D and Hb (Pearson correlation, r=0·1, P=0·33).

Conclusions: Few children in the study had vitamin D deficiency, but about 47 % of the children in the study population were under the recommended s-25(OH)D sufficiency level of ≥50 nmol/l.
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http://dx.doi.org/10.1017/S136898001700180XDOI Listing
November 2017

Within-person reproducibility and sensitivity to dietary change of C15:0 and C17:0 levels in dried blood spots: Data from the European Food4Me Study.

Mol Nutr Food Res 2017 10 20;61(10). Epub 2017 Jul 20.

Human Nutrition Research Centre and Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.

Scope: Previous work highlighted the potential of odd-chain length saturated fatty acids as potential markers of dairy intake. The aim of this study was to assess the reproducibility of these biomarkers and their sensitivity to changes in dairy intake.

Methods And Results: Fatty acid profiles and dietary intakes from food frequency questionnaires (FFQs) were measured three times over six months in the Food4Me Study. Reproducibility was explored through intra-class correlation coefficients (ICCs) and within-subject coefficients of variation (WCV). Sensitivity to changes in diet was examined using regression analysis. C15:0 blood levels showed high correlation over time (ICC: 0.62, 95% CI: 0.57, 0.68), however, the ICC for C17:0 was much lower (ICC: 0.32, 95% CI: 0.28, 0.46). The WCV for C15:0 was 16.6% and that for C17:0 was 14.6%. There were significant associations between changes in intakes of total dairy, high-fat dairy, cheese and butter and C15:0; and change in intakes of high-fat dairy and cream and C17:0.

Conclusion: Results provide evidence of reproducibility of C15:0 levels over time and sensitivity to change in intake of high-fat dairy products with results comparable to the well-established biomarker of fish intake (EPA+DHA).
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http://dx.doi.org/10.1002/mnfr.201700142DOI Listing
October 2017

Exploring the association of dairy product intake with the fatty acids C15:0 and C17:0 measured from dried blood spots in a multipopulation cohort: Findings from the Food4Me study.

Mol Nutr Food Res 2016 Apr 28;60(4):834-45. Epub 2016 Jan 28.

Human Nutrition Research Centre and Institute for Health and Society, Newcastle University, Newcastle upon Tyne, UK.

Scope: The use of biomarkers in the objective assessment of dietary intake is a high priority in nutrition research. The aim of this study was to examine pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) as biomarkers of dairy foods intake.

Methods And Results: The data used in the present study were obtained as part of the Food4me Study. Estimates of C15:0 and C17:0 from dried blood spots and intakes of dairy from a Food Frequency Questionnaire were obtained from participants (n = 1180) across seven countries. Regression analyses were used to explore associations of biomarkers with dairy intake levels and receiver operating characteristic analyses were used to evaluate the fatty acids. Significant positive associations were found between C15:0 and total intakes of high-fat dairy products. C15:0 showed good ability to distinguish between low and high consumers of high-fat dairy products.

Conclusion: C15:0 can be used as a biomarker of high-fat dairy intake and of specific high-fat dairy products. Both C15:0 and C17:0 performed poorly for total dairy intake highlighting the need for caution when using these in epidemiological studies.
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http://dx.doi.org/10.1002/mnfr.201500483DOI Listing
April 2016

Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma.

Nutr Cancer 2015 28;67(7):1120-30. Epub 2015 Aug 28.

a Comprehensive Cancer Center and Division of Epidemiology, College of Public Health , Ohio State University , Columbus , Ohio , USA.

There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case-control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D [25(OH)D], an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P = .04). Men diagnosed ≤ 56 showed a borderline positive trend (P = .08). High levels (>66 nmol/L) of 25(OH)D in men >56 were inversely related to high grade glioma from ≥2 yr before diagnosis (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr before diagnosis (OR = 0.61; 95% CI = 0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease.
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http://dx.doi.org/10.1080/01635581.2015.1073757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827350PMC
July 2016

Vitamin D status in pre-school children in rural Nepal.

Public Health Nutr 2016 Feb 1;19(3):470-6. Epub 2015 Apr 1.

1Department of Community Medicine,Institute of Health and Society,University of Oslo,Postboks 1130,Blindern 0318 Oslo,Norway.

Objective: Vitamin D plays a major role in Ca and bone metabolism, and its extraskeletal functions are being appraised. Although inadequate vitamin D concentrations have been reported in populations worldwide, too little is known about vitamin D status and its determinants among children in developing countries. We aimed to determine vitamin D status and its determinants in Nepalese children of pre-school age.

Design: A community-based, cross-sectional study.

Setting: Rural Nepal at latitude 27.39° N.

Subjects: Healthy children (n 280) aged 12-60 months, selected randomly from the records of a vitamin A supplementation programme. Blood samples were collected using the dried blood spot technique and analysed for serum 25-hydroxyvitamin D (s-25(OH)D) concentration using liquid chromatography-tandem mass spectrometry. Ca intake and background variables were assessed with a structured questionnaire.

Results: Hypovitaminosis D, defined as s-25(OH)D concentration less than 50 nmol/l, was found in 91.1% of the children. S-25(OH)D concentration was not related to gender, socio-economic indicators, sun exposure or nutritional status. Currently breast-fed children had higher s-25(OH)D concentrations (36.4 (sd 13.2) nmol/l) than those who were not (28.6 (sd 9.8) nmol/l, P<0.001). Adjustment for sociodemographic factors did not alter the results.

Conclusion: There is widespread vitamin D deficiency among pre-school children in a rural area of Nepal. In our sample, sociodemographic factors did not affect the vitamin D status of children, but prolonged breast-feeding was associated with higher s-25(OH)D concentrations. Further research is required to investigate the health consequences of poor vitamin D status for this population.
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http://dx.doi.org/10.1017/S136898001500083XDOI Listing
February 2016

Design and baseline characteristics of the Food4Me study: a web-based randomised controlled trial of personalised nutrition in seven European countries.

Genes Nutr 2015 Jan 10;10(1):450. Epub 2014 Dec 10.

Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.

Improving lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing well-being. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Therefore, the aim of this study was to conduct a multi-centre, web-based, proof-of-principle study of personalised nutrition (PN) to determine whether providing more personalised dietary advice leads to greater improvements in eating patterns and health outcomes compared to conventional population-based advice. A total of 5,562 volunteers were screened across seven European countries; the first 1,607 participants who fulfilled the inclusion criteria were recruited into the trial. Participants were randomly assigned to one of the following intervention groups for a 6-month period: Level 0-control group-receiving conventional, non-PN advice; Level 1-receiving PN advice based on dietary intake data alone; Level 2-receiving PN advice based on dietary intake and phenotypic data; and Level 3-receiving PN advice based on dietary intake, phenotypic and genotypic data. A total of 1,607 participants had a mean age of 39.8 years (ranging from 18 to 79 years). Of these participants, 60.9 % were women and 96.7 % were from white-European background. The mean BMI for all randomised participants was 25.5 kg m(-2), and 44.8 % of the participants had a BMI ≥ 25.0 kg m(-2). Food4Me is the first large multi-centre RCT of web-based PN. The main outcomes from the Food4Me study will be submitted for publication during 2015.
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http://dx.doi.org/10.1007/s12263-014-0450-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261071PMC
January 2015

Dried blood spot (DBS) sample collection for determination of the oxidative stress biomarker 8-epi-PGF(2α) in humans using liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2012 Mar;26(6):645-52

Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046 Blindern, N-0316, Oslo, Norway.

Rationale: F2-isoprostanes are a series of prostaglandin F2-like compounds that are formed by free-radical-catalyzed peroxidation of arachidonic acid (ARA). Several F2-isoprostanes, but in particular 8-epi-PGF(2α), are widely used as oxidative stress biomarkers. In this study we have developed an analytical tool for finger-tip blood sampling and analysis of 8-epi-PGF(2α) from dried blood spots (DBS).

Methods: We have applied solid-phase extraction (SPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the extraction, separation and detection of 8-epi-PGF(2α) in DBS and have studied the stability of this marker using the DBS collection platform.

Results: The mass limit of detection (mLOD) for 8-epi-PGF(2α) extracted from DBS samples was 1.5 pg while the concentration limit of detection (cLOD) and concentration limit of quantitation (cLOQ) were 6 pg/mL and 18 pg/mL, respectively. All values based on triplicate analysis. Sufficient stability of 8-epi-PGF(2α) in DBS was achieved by preconditioning DBS paper with vitamin E and BHT.

Conclusions: The developed method is sensitive, specific, robust, efficient, and can accurately measure endogenous concentrations of 8-epi-PGF(2α) in DBS. Thus, it offers an analytical approach to measure 8-epi-PGF(2α) by a novel sample collection technique that is less invasive and costly than conventional techniques.
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http://dx.doi.org/10.1002/rcm.6149DOI Listing
March 2012

Determination of 8-epi PGF(2alpha) concentrations as a biomarker of oxidative stress using triple-stage liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2009 Sep;23(18):2885-90

Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046 Blindern, N-0316 Oslo, Norway.

F2-isoprostanes are a family of prostaglandin F2-like compounds that are formed by free-radical-catalyzed peroxidation of arachidonic acid. Several F2-isoprostanes, but in particular 8-epi PGF(2alpha), are widely used as oxidative stress biomarkers. An analytical method based on liquid chromatography with negative electrospray ionization (ESI) coupled to tandem mass spectrometric detection (LC/MS/MS) was developed for the determination of 8-epi PGF(2alpha) concentrations in human plasma, whole blood, erythrocytes and urine. 8-epi PGF(2alpha)-d4, a stable isotope derivative of 8-epi PGF(2alpha), was used as an internal standard (IS). A 50 microL sample was focused on-column and separated on two 3 microm particle size SUPELCOSIL ABZ+Plus HPLC columns (15 cm x 4.6 mm and 7.5 cm x 4.6 mm) connected in series. An Applied Biosystems 4000 Q TRAP LC/MS/MS system with ESI was operated in multiple reaction monitoring (MRM) mode with the precursor-to-product ion transitions m/z 353.4 --> 193.1 (8-epi PGF(2alpha)), 357.4 --> 197.1 (8-epi PGF(2alpha)-d4), used for quantification. The assay was fully validated and found to have adequate accuracy, precision, linearity, sensitivity and selectivity. The mass limit of detection (mLOD) was 1 pg of analyte eluting from the column. The assay has been successfully applied to the analysis of human plasma, whole blood, erythrocytes and urine samples.
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http://dx.doi.org/10.1002/rcm.4197DOI Listing
September 2009

Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb.

Mol Cell Biol 2009 May 9;29(10):2716-29. Epub 2009 Mar 9.

Division of Cell and Developmental Biology, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.

Cytochrome P450 oxidoreductase (POR) is the obligate electron donor for all microsomal cytochrome P450 enzymes, which catalyze the metabolism of a wide spectrum of xenobiotic and endobiotic compounds. Point mutations in POR have been found recently in patients with Antley-Bixler-like syndrome, which includes limb skeletal defects. In order to study P450 function during limb and skeletal development, we deleted POR specifically in mouse limb bud mesenchyme. Forelimbs and hind limbs in conditional knockout (CKO) mice were short with thin skeletal elements and fused joints. POR deletion occurred earlier in forelimbs than in hind limbs, leading additionally to soft tissue syndactyly and loss of wrist elements and phalanges due to changes in growth, cell death, and skeletal segmentation. Transcriptional analysis of E12.5 mouse forelimb buds demonstrated the expression of P450s involved in retinoic acid, cholesterol, and arachidonic acid metabolism. Biochemical analysis of CKO limbs confirmed retinoic acid excess. In CKO limbs, expression of genes throughout the whole cholesterol biosynthetic pathway was upregulated, and cholesterol deficiency can explain most aspects of the phenotype. Thus, cellular POR-dependent cholesterol synthesis is essential during limb and skeletal development. Modulation of P450 activity could contribute to susceptibility of the embryo and developing organs to teratogenesis.
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http://dx.doi.org/10.1128/MCB.01638-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682028PMC
May 2009

Hormone-sensitive lipase (HSL) is also a retinyl ester hydrolase: evidence from mice lacking HSL.

FASEB J 2009 Jul 26;23(7):2307-16. Epub 2009 Feb 26.

Division of Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, SE-221 84 Lund, Sweden.

Here, we investigated the importance of hormone-sensitive lipase (HSL) as a retinyl ester hydrolase (REH). REH activity was measured in vitro using recombinant HSL and retinyl palmitate. The expression of retinoic acid (RA)-regulated genes and retinoid metabolites were measured in high-fat diet fed HSL-null mice using real-time quantitative PCR and triple-stage liquid chromatography/tandem mass spectrometry, respectively. Age- and gender-matched wild-type littermates were used as controls. The REH activity of rat HSL was found to be higher than that against the hitherto best known HSL substrate, i.e., diacylglycerols. REH activity in white adipose tissue (WAT) of HSL-null mice was completely blunted and accompanied by increased levels of retinyl esters and decreased levels of retinol, retinaldehyde and all-trans RA. Accordingly, genes known to be positively regulated by RA were down-regulated in HSL-null mice, including pRb and RIP140, key factors promoting differentiation into the white over the brown adipocyte lineage. Dietary RA supplementation partly restored WAT mass and the expression of RA-regulated genes in WAT of HSL-null mice. These findings demonstrate the importance of HSL as an REH of adipose tissue and suggest that HSL via this action provides RA and other retinoids for signaling events that are crucial for adipocyte differentiation and lineage commitment.
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http://dx.doi.org/10.1096/fj.08-120923DOI Listing
July 2009

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen.

Am J Physiol Lung Cell Mol Physiol 2007 Oct 17;293(4):L1079-87. Epub 2007 Aug 17.

Department of Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported.
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http://dx.doi.org/10.1152/ajplung.00286.2007DOI Listing
October 2007

Reduced serum concentrations of retinol and alpha-tocopherol and high concentrations of hydroperoxides are associated with community levels of S. mansoni infection and schistosomal periportal fibrosis in Ethiopian school children.

Am J Trop Med Hyg 2007 May;76(5):943-9

Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia.

To study the relationship between micronutrient malnutrition and schistosomiasis mansoni, a cross-sectional study was undertaken involving 421 schoolchildren (mean age 12.6 years; 333 from schistosomiasis mansoni-endemic villages (Workemado and Sille) and 88 non-endemic controls from Sheno). Prevalence of schistosomiasis mansoni infection in Workemado and Sille was comparable (90.6% versus 95%, respectively), and prevalence of PPF in Workemado was significantly higher than in Sille (7.0% versus 0.6%, P < 0.001). Compared with non-endemic controls, serum retinol concentrations were significantly lower and hydroperoxides were significantly higher in subjects from schistosomiasis mansoni-endemic areas. Furthermore, serum alpha-tocopherol concentrations in subjects from an area with high prevalence of PPF were significantly reduced while the concentrations in subjects from an area with low prevalence of PPF were comparable to the levels found in non-endemic healthy controls. In conclusion, micronutrient malnutrition and oxidative stress are associated with Schistosoma mansoni infection and levels of schistosomal PPF.
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May 2007

Quantitative high-throughput determination of endogenous retinoids in human plasma using triple-stage liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2007 ;21(7):1176-86

Institute of Basic Medical Sciences, University of Oslo, P. O. Box 1046 Blindern, N-0316 Oslo, Norway.

A high-throughput ultrasensitive analytical method based on liquid chromatography with positive ion atmospheric pressure chemical ionization (APCI) coupled to tandem mass spectrometric detection (LC/MS/MS) was developed for the determination of all-trans-4-oxo-retinoic acid (at4oxoRA), 13-cis-4-oxo-retinoic acid (13c4oxoRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (atRA) and all-trans-retinol (atROH) in human plasma. A stable isotope of atRA was used as internal standard (IS). The analytes and IS were isolated from 100 microL plasma by acetonitrile mono-phase extraction (MPE) performed in black 96-well microtiterplates. A 100 microL injection was focused on-column and chromatographed on an Agilent ZORBAX SB-C18 rapid-resolution high-throughput (RRHT) column with 1.8-microm particles (4.6 mmx50 mm) maintained at 60 degrees C. The initial mobile phase composition was acetonitrile/water/formic acid (10:90:0.1, v/v/v) delivered at 1.8 mL/min. Elution was accomplished by a fast gradient to acetonitrile/methanol/formic acid (90:10:0.1, v/v/v). The method had a chromatographic total run time of 7 min. An Applied Biosystems 4000 Q TRAP linear tandem mass spectrometer equipped with a heated nebulizer (APCI) ionization source was operated in multiple reaction monitoring (MRM) mode with the precursor-to-product ion transitions m/z 315.4-->297 (4-oxo-retinoic acids), 301.2-->205 (retinoic acids), 305.0-->209 (IS) and 269.2-->93 (retinol) used for quantification. The assay was fully validated and found to have acceptable accuracy, precision, linearity, sensitivity and selectivity. The mean extraction recoveries from spiked plasma samples were 80-105% for the various retinoids at three different levels. The intra-day accuracy of the assay was within 8% of nominal and intra-day precision was better than 8% coefficient of variance (CV) for retinoic acids. Inter-day precision results for quality control samples run over a 12-day period alongside clinical samples showed mean precision better than 12.5% CV. The limit of quantification was in the range of 0.1-0.2 ng/mL and the mass limit of detection (mLOD) was in the range 1-4 pg on column for the retinoic acids. The assay has been successfully applied to the analysis of 1700 plasma samples.
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http://dx.doi.org/10.1002/rcm.2946DOI Listing
May 2007

Simultaneous and trace determination of reduced and oxidized glutathione in minute plasma samples using dual mode fluorescence detection and column switching high performance liquid chromatography.

J Chromatogr A 2007 Feb 20;1142(2):178-84. Epub 2006 Dec 20.

Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, PO Box 1046 Blindern, N-0316 Oslo, Norway.

A robust method for the simultaneous quantification of endogenous reduced glutathione (GSH) and oxidized glutathione (GSSG) in as little as 5 microl human plasma employing two-dimensional chromatographic system with parallel Hypercarb columns coupled with dual fluorescence detectors (FLD) has been developed. After sample preparation, 10 microl of supernatant was injected into the chromatographic system. The limits of detection (LOD) of GSH and GSSG were 0.5 and 0.040 pmol on column, respectively. Derivatization of GSH and GSSG with monobromobimane (MBB) and ortho-phthalaldehyde (OPA) provides a sensitivity and specificity that allows analysis after fingertip sampling, blood sampling from infants or multiple blood sampling from mice or other small experimental animals without sacrificing the animal.
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http://dx.doi.org/10.1016/j.chroma.2006.12.051DOI Listing
February 2007

Methods for detecting and identifying retinoids in tissue.

J Neurobiol 2006 Jun;66(7):631-44

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, N-0316 Oslo, Norway.

Methods for retinoid analysis in tissue include direct spectrophotometry or fluorometry and retinoid responsive reporter constructs in the form of cell reporter assays or transgenic reporter animals, but chromatographic methods dominate and posses several superior features in quantitative analysis. The multitude of extraction protocols used can coarsely be divided into manual liquid-liquid extraction protocols and semi- or fully automated solid phase extraction-based protocols. Liquid chromatographic separation in reversed phase dominates although normal phase is also used. Detection is mainly performed with UV detectors although electrochemical and fluorescence detection is also used. Mass spectrometry in combination with LC is more often used in retinoid analysis and is likely to dominate in the future.
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http://dx.doi.org/10.1002/neu.20243DOI Listing
June 2006