The association between proton pump inhibitors and hyperparathyroidism: a potential mechanism for increased fracture-results of a large observational cohort study.

Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture; however, the mechanism is unclear. PPI users taking calcium supplements were more likely to have hyperparathyroidism compared to non-users (OR 1.56, CI 1.08-2.23, p = 0.018). This highlights the importance of monitoring PPI use, especially in older adults. PURPOSE: Proton pump inhibitors (PPIs) are associated with increased risk of osteoporotic fracture. Hyperparathyroidism may be implicated, but few studies have considered this relationship. This study evaluated the relationship between PPI use and hyperparathyroidism in older adults. METHODS: Participants were from the TUDA study, a large cross-sectional cohort of older Irish adults. Participants with an estimated glomerular filtration rate (eGFR) < 30 ml/min and serum calcium > 2.5 mmol/l were excluded to avoid hyperparathyroidism due to chronic renal disease and primary hyperparathyroidism. Hyperparathyroidism was defined as a parathyroid hormone (PTH) > 65 pg/ml. Multivariate regression models were used to analyse the relationship between PPI use and hyperparathyroidism. RESULTS: A total of 4139 participants met the inclusion criteria, of whom 37.8% (n = 1563) were taking PPI medication. PPI use was identified in 41.4% of calcium supplement users and 35.4% of non-calcium supplement users. Overall, compared to non-users of PPIs, those taking PPIs were older (74.8 vs 72.9 years, p < 0.001) and had a higher prevalence of hyperparathyroidism (17.8 vs 11.0%, p < 0.001). In those taking calcium supplements (but not in non-users), PPI use was significantly associated with hyperparathyroidism (OR 1.56, CI 1.08-2.23, p = 0.018) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, timed-up-and-go, dairy intake, medications, and comorbidities. DISCUSSION: The results are consistent with the hypothesis of PPIs reducing calcium absorption, leading to a rise in PTH which could mediate increased fracture risk. No relationship of PPI use with hyperparathyroidism was observed in non-users of calcium supplements, possibly owing to lower dietary calcium intake. These results highlight the importance of monitoring PPI use, especially in older adults at risk of fracture.

Maternal fish consumption and child neurodevelopment in Nutrition 1 Cohort: Seychelles Child Development Study.

Maternal fish consumption exposes the fetus to beneficial nutrients and potentially adverse neurotoxicants. The current study investigated associations between maternal fish consumption and child neurodevelopmental outcomes. Maternal fish consumption was assessed in the Seychelles Child Development Study Nutrition Cohort 1 (n 229) using 4-day food diaries. Neurodevelopment was evaluated at 9 and 30 months, and 5 and 9 years with test batteries assessing twenty-six endpoints and covering multiple neurodevelopmental domains. Analyses used multiple linear regression with adjustment for covariates known to influence child neurodevelopment. This cohort consumed an average of 8 fish meals/week and the total fish intake during pregnancy was 106·8 (sd 61·9) g/d. Among the twenty-six endpoints evaluated in the primary analysis there was one beneficial association. Children whose mothers consumed larger quantities of fish performed marginally better on the Kaufman Brief Intelligence Test (a test of nonverbal intelligence) at age 5 years (ß 0·003, 95 % CI (0, 0·005)). A secondary analysis dividing fish consumption into tertiles found no significant associations when comparing the highest and lowest consumption groups. In this cohort, where fish consumption is substantially higher than current global recommendations, maternal fish consumption during pregnancy was not beneficially or adversely associated with children's neurodevelopmental outcomes.

Associations of long chain polyunsaturated fatty acids with bone mineral density and bone turnover in postmenopausal women.

PURPOSE: The immunomodulatory properties of n-3 long chain polyunsaturated fatty acids (LCPUFA) are reported to reduce bone loss through alteration of bone remodelling and n-3 LCPUFA, therefore, may benefit bone health in post-menopausal women, a vulnerable group at high risk of osteoporosis. METHODS: Measures of bone mineral density (BMD) were determined using dual energy X-ray absorptiometry (DEXA) in 300 post-menopausal women. The bone turnover markers osteocalcin (OC), C-terminal telopeptides of type 1 collagen (CTX) and total alkaline phosphatase were quantified in serum along with urinary creatinine corrected deoxypyridinoline (DPD/Cr) and CTX/Cr and the CTX:OC ratio calculated. Total serum n-6 PUFA (LA + AA) and n - 3 LCPUFA (ALA + EPA + DPA + DHA) were measured and the n - 6:n - 3 ratio was calculated. RESULTS: Mean (SD) age and body mass index (BMI) were 61 (6.4) years and 27.4 (4.8) kg/m2, respectively with participants being 12.6 (7.6) years post-menopause. Multiple regression analysis identified no association between n-3 LCPUFA and any of the measures of T-score or BMD albeit a significant positive association between total n - 3 LCPUFA and femur BMD (ß = 0.287; p = 0.043) was observed within those women with a low n - 6:n - 3 ratio. There was a significant inverse association between ALA and urinary DPD/Cr (ß = - 0.141; p = 0.016). CONCLUSION: A favourable low n - 6:n - 3 ratio was associated with higher femur BMD and a higher n - 3 LCPUFA (ALA) was associated with lower bone resorption. These results support a beneficial role for n - 3 LCPUFA in reducing postmenopausal bone resorption and favourably influencing BMD. TRIAL NUMBER & DATE OF REGISTRATION: ISRCTN63118444, 2nd October 2009, "Retrospectively registered".

Reduced kidney function is associated with poorer domain-specific cognitive performance in community-dwelling older adults.

OBJECTIVES: Whilst chronic kidney disease has been associated with cognitive impairment, the association between reduced estimated Glomerular Filtration Rate (eGFR) and domain-specific cognitive performance is less clear and may represent an important target for the promotion of optimal brain health in older adults. METHODS: Participants aged >60 years from the Trinity-Ulster-Department of Agriculture study underwent detailed cognitive assessment using the Mini-Mental State Examination (Mini-Mental State Examination (MMSE)), Frontal Assessment Battery (FAB) and Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Poisson and linear regression models assessed the relationship between eGFR strata and cognitive performance. RESULTS: In 4887 older adults (73.9 ± 8.3 years; 67.7% female), declining eGFR strata was associated with greater likelihood of error on the MMSE/FAB and poorer overall performance on the RBANS. Following robust covariate adjustment, findings were greatest for GFR <45 ml/ml/1.73 m2 (Incidence Rate Ratio: 1.17; 95% CI 1.08, 1.27; p < 0.001 for MMSE; IRR: 1.13; 95% CI 1.04, 1.13; p < 0.001 for FAB; ß: -3.66; 95% CI -5.64, -1.86; p < 0.001 for RBANS). Additionally, eGFR <45 ml/ml/1.73 m2 was associated with poorer performance on all five RBANS domains, with greatest effect sizes for immediate memory, delayed memory and attention. Associations were strongest in those aged 60-70, with no associations observed in those >80 years. CONCLUSIONS: Reduced kidney function was associated with poorer global and domain-specific neuropsychological performance. Associations were strongest with eGFR <45 ml/min/1.73 m2 and in those aged 60-70 years, suggesting that this population may potentially benefit from potential multi-domain interventions aimed at promoting optimal brain health in older adults.

Serum cytokines are associated with n-3 polyunsaturated fatty acids and not with methylmercury measured in infant cord blood in the Seychelles child development study.

BACKGROUND: Maternal fish consumption increases infant methylmercury (MeHg) exposure and polyunsaturated fatty acid (PUFA) concentrations. The n-3 PUFA are regulators of inflammation while MeHg may impact the cord cytokine profile and, subsequently, contribute to immune mediated outcomes. This study aimed to investigate associations between infant MeHg exposure and cord cytokine concentrations while adjusting for cord PUFA. METHODS: We studied participants in the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2), a large birth cohort in a high fish-eating population. Whole blood MeHg, serum PUFA and serum cytokine concentrations (IFN-γ, IL-1ß, IL-2, IL-12p70, TNF-α, IL-4, IL-10, IL-13, IL-6 and IL-8) were measured in cord blood collected at delivery (n = 878). Linear regression examined associations between infant MeHg exposure and cord cytokines concentrations, with and without adjustment for cord PUFA. An interaction model examined cord MeHg, cytokines and tertiles of the n-6:n-3 ratio (low/medium/high). RESULTS: There was no overall association between cord MeHg (34.08 ± 19.98 µg/L) and cytokine concentrations, with or without adjustment for PUFA. Increased total n-3 PUFA (DHA, EPA and ALA) was significantly associated with lower IL-10 (ß = -0.667; p = 0.007) and lower total Th2 (IL-4, IL-10 and IL-13) (ß = -0.715; p = 0.036). In the interaction model, MeHg and IL-1ß was positive and significantly different from zero in the lowest n-6:n-3 ratio tertile (ß = 0.002, p = 0.03). CONCLUSION: Methylmercury exposure from fish consumption does not appear to impact markers of inflammation in cord blood. The association of cord n-3 PUFA with lower IL-10 and total Th2 cytokines suggests that they may have a beneficial influence on the regulation of the inflammatory milieu. These findings are important for public health advice and deserve to be investigated in follow up studies.

Impact of the MTHFR C677T polymorphism on blood pressure and related central haemodynamic parameters in healthy adults.

BACKGROUND: The C677T polymorphism in the gene-encoding methylenetetrahydrofolate reductase (MTHFR) is associated with an increased risk of hypertension and cardiovascular disease. Riboflavin, the MTHFR cofactor, is an important modulator of blood pressure (BP) in adults homozygous for this polymorphism (TT genotype). The effect of this genetic variant on BP and related central haemodynamic parameters in healthy adults has not been previously investigated and was examined in this study. METHODS: Brachial BP, central BP and pulse wave velocity (PWV, SphygmoCor XCEL) were measured in adults aged 18-65 years prescreened for MTHFR genotype. Riboflavin status was assessed using the erythrocyte glutathione reductase activation coefficient assay. RESULTS: Two hundred and forty-two adults with the MTHFR 677TT genotype and age-matched non-TT (CC/CT) genotype controls were identified from a total cohort of 2546 adults prescreened for MTHFR genotype. The TT genotype was found to be an independent determinant of hypertension (p = 0.010), along with low-riboflavin status (p = 0.002). Brachial systolic and diastolic BP were higher in TT versus non-TT adults by 5.5 ± 1.2 and 2.4 ± 0.9 mmHg, respectively (both p < 0.001). A stronger phenotype was observed in women, with an almost 10 mmHg difference in mean systolic BP in TT versus non-TT genotype groups: 134.9 (95% confidence interval [CI] 132.1-137.6) versus 125.2 (95% CI 122.3-128.0) mmHg; p < 0.001. In addition, PWV was faster in women with the TT genotype (p = 0.043). CONCLUSION: This study provides the first evidence that brachial and central BP are significantly higher in adults with the variant MTHFR 677TT genotype and that the BP phenotype is more pronounced in women.

Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial.

BACKGROUND: Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child. METHODS: Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 µg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging. RESULTS: Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13-30 Hz, p = 0.01) and High Gamma (49-70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language. CONCLUSIONS: Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered on 15 May 2013.

Glycated haemoglobin (HbA1c ), diabetes and neuropsychological performance in community-dwelling older adults.

AIMS: Given that diabetes is associated with cognitive impairment and dementia in later life, we aimed to investigate the relationship between glycated haemoglobin (HbA1c ), diabetes and domain-specific neuropsychological performance in older adults. METHODS: Cross-sectional cohort study using data from the Trinity-Ulster-Department of Agriculture (TUDA) study. Participants underwent detailed cognitive and neuropsychological assessment using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Assessment for Neuropsychological Status (RBANS). Linear regression was used to assess associations between HbA1c , diabetes status and neuropsychological performance, with adjustment for important clinical covariates. RESULTS: Of 4938 older adults (74.1 ± 8.3 years; 66.9% female), 16.3% (n = 803) had diabetes (HbA1c  ≥ 6.5%; 48 mmol/mol), with prediabetes (HbA1c  ≥ 5.7%-6.4%; 39-47 mmol/mol) present in 28.3% (n = 1395). Increasing HbA1c concentration was associated with poorer overall performance on the FAB [ß: -0.01 (-0.02, -0.00); p = 0.04 per % increase] and RBANS [ß = -0.66 (-1.19, -0.13); p = 0.02 per % increase]. Increasing HbA1c was also associated with poorer performance on immediate memory, visuo-spatial, language and attention RBANS domains. Diabetes was associated poorer performance on neuropsychological tests of immediate memory, language, visual-spatial and attention. CONCLUSIONS: Both increasing HbA1c and the presence of diabetes were associated with poorer cognitive and domain-specific performance in older adults. HbA1c , and not just diabetes status per se, may represent an important target in the promotion of optimal brain health in older adults.

Maternal and child fatty acid desaturase genotype as determinants of cord blood long-chain PUFA (LCPUFA) concentrations in the Seychelles Child Development Study.

Optimal maternal long-chain PUFA (LCPUFA) status is essential for the developing fetus. The fatty acid desaturase (FADS) genes are involved in the endogenous synthesis of LCPUFA. The minor allele of various FADS SNP have been associated with increased maternal concentrations of the precursors linoleic acid (LA) and α-linolenic acid (ALA), and lower concentrations of arachidonic acid (AA) and DHA. There is limited research on the influence of FADS genotype on cord PUFA status. The current study investigated the influence of maternal and child genetic variation in FADS genotype on cord blood PUFA status in a high fish-eating cohort. Cord blood samples (n 1088) collected from the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2) were analysed for total serum PUFA. Of those with cord PUFA data available, maternal (n 1062) and child (n 916), FADS1 (rs174537 and rs174561), FADS2 (rs174575), and FADS1-FADS2 (rs3834458) were determined. Regression analysis determined that maternal minor allele homozygosity was associated with lower cord blood concentrations of DHA and the sum of EPA + DHA. Lower cord blood AA concentrations were observed in children who were minor allele homozygous for rs3834458 (ß = 0·075; P = 0·037). Children who were minor allele carriers for rs174537, rs174561, rs174575 and rs3834458 had a lower cord blood AA:LA ratio (P < 0·05 for all). Both maternal and child FADS genotype were associated with cord LCPUFA concentrations, and therefore, the influence of FADS genotype was observed despite the high intake of preformed dietary LCPUFA from fish in this population.

The influence of fish consumption on serum n-3 polyunsaturated fatty acid (PUFA) concentrations in women of childbearing age: a randomised controlled trial (the iFish Study).

PURPOSE: Long-chain polyunsaturated fatty acids (LCPUFA) can be synthesised endogenously from linoleic acid (LA) and α-linolenic acid (ALA) in a pathway involving the fatty acid desaturase (FADS) genes. Endogenous synthesis is inefficient; therefore, dietary intake of preformed LCPUFA from their richest source of fish is preferred. This study investigated the effect of fish consumption on PUFA concentrations in women of childbearing age while stratifying by FADS genotype. The influence of fish consumption on lipid profile, and markers of inflammation and oxidative stress was also examined. METHODS: Healthy women (n = 49) provided a buccal swab which was analysed for FADS2 genotype (rs3834458; T/deletion). Participants were stratified according to genotype and randomised to an intervention group to receive either no fish (n = 18), 1 portion (n = 14) or 2 portions (n = 17) (140 g per portion) of fish per week for a period of 8 weeks. Serum PUFA was analysed at baseline and post-intervention. Lipid profile, and markers of inflammation and oxidative stress were also analysed. RESULTS: Participants consuming 2 portions of fish per week had significantly higher concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and total n-3 PUFA, and a lower n-6:n-3 ratio compared to those in the no fish or 1 portion per week group (all p < 0.05). Fish consumption did not have a significant effect on biomarkers of oxidative stress, inflammation and lipid profile in the current study. CONCLUSION: Consumption of 2 portions of fish per week has beneficial effects on biological n-3 PUFA concentrations in women of childbearing age; however, no effects on oxidative stress, inflammation or lipid profile were observed. This trial was registered at www.clinicaltrials.gov (NCT03765580), registered December 2018.

Long-term anticholinergic, benzodiazepine and Z-drug use in community-dwelling older adults: What is the impact on cognitive and neuropsychological performance?

BACKGROUND: Long-term use of anticholinergics, benzodiazepines and related drugs (or "Z-drugs") have been associated with cognitive impairment and dementia. However, the relationship of these medications with cognitive function and domain-specific neuropsychological performance in older adults without dementia, is unclear. METHODS: 5135 older adults (74.0 ± 8.3 years; 67.4% female) without a diagnosis of dementia were recruited in Ireland to the Trinity-Ulster-Department of Agriculture (TUDA) study. Detailed cognitive and neuropsychological assessment was conducted using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Battery for Assessment of Neuropsychological Status (RBANS). RESULTS: A total of 44% (2259 of 5153) used either a potential or definite anticholinergic medication. Overall, 9.7% (n = 500) used a definite anticholinergic medication. Regular benzodiazepine use was reported by 7% (n = 363), whilst 7.5% (n = 387) used a "Z-drug". Use of definite, but not potential anticholinergic medication was associated with poorer performance on all three assessments (ß: -0.09; 95% CI: -0.14, -0.03, p = 0.002 for MMSE; ß: -0.04; 95% CI: -0.06, -0.02; p < 0.001 for FAB; ß: -4.15; 95% CI: -5.64, -2.66; p < 0.001 for RBANS) in addition to all domains of the RBANS. Regular benzodiazepine use was also associated with poorer neuropsychological test performance, especially in Immediate Memory (ß: -4.98; 95% CI: -6.81, -3.15; p < 0.001) and Attention (ß: -6.81; 95% CI: -8.60, -5.03; p < 0.001) RBANS domains. CONCLUSIONS: Regular use of definite anticholinergic medications and benzodiazepines, but not potential anticholinergics or "Z-drugs", was associated with poorer overall and domain-specific neuropsychological performance in older adults.

Serum levels of miR-199a-5p correlates with blood pressure in premature cardiovascular disease patients homozygous for the MTHFR 677C > T polymorphism.

This investigation profiled circulating serum concentrations of microRNAs (miRNAs) in premature cardiovascular disease (CVD) patients screened for the 677C > T polymorphism in methylenetetrahydrofolate reductase (MTHFR), a risk factor for hypertension. Serum samples from 75 premature CVD patients of known MTHFR genotype were analysed for CVD-related miRNA expression, to identify those that were associated with blood pressure. Samples were collected at baseline and following intervention with riboflavin as part of a randomized controlled trial. In patients with the MTHFR 677TT genotype, expression of miR-199a-5p in serum was inversely correlated with hypertension at baseline, and with change in blood pressure in TT genotype patients who responded to riboflavin intervention. These correlations were not observed in MTHFR 677CC genotype patients. In vitro experiments and in silico data analysis provided evidence that miR-199a-5p targets SMAD4. This is the first study to link miR-199a-5p expression with hypertension in a genetically at-risk cohort of premature CVD patients.

Vitamin D3 content of cows' milk produced in Northern Ireland and its efficacy as a vehicle for vitamin D fortification: a UK model.

Cows' milk is a relatively poor source of vitamin D but figures listed in UK food composition tables may be outdated. Samples of milk were collected for 1-year and vitamin D3 concentrations analysed using HPLC. Milk consumption data were obtained from the National Diet and Nutrition Survey (Years 1-4). A theoretical model applied vitamin D3 fortifications of 1 µg, 1.5 µg and 2 µg/100g to simulate improvements in vitamin D intakes. Mean ± SD vitamin D3 in whole milk was 0.06 ± 0.02 µg/100g. No seasonal differences were apparent. Fortification of cows' milks with 1 µg, 1.5 µg and 2.0 µg/100g, theoretically increased median vitamin D intakes from 2.0 µg/day to 4.2 µg, 5.1 µg and 5.9 µg/day, respectively. Higher vitamin D3 in milk from this study than that currently in food composition tables, suggests further analysis is warranted. This model suggests vitamin D fortification of cows' milk is an effective strategy to help more of the population achieve recently revised RNIs for vitamin D.

Impact of the common MTHFR 677C→T polymorphism on blood pressure in adulthood and role of riboflavin in modifying the genetic risk of hypertension: evidence from the JINGO project.

BACKGROUND: Genome-wide and clinical studies have linked the 677C→T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. METHODS: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods. RESULTS: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ≥ 140 and/or a diastolic BP ≥ 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027). CONCLUSIONS: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.

A Novel Urinary Biomarker Approach Reveals Widespread Exposure to Multiple Low-Calorie Sweeteners in Adults.

BACKGROUND: Observational investigations into the health impacts of low-calorie sweeteners (LCSs) in humans fail to adequately identify or fully characterize LCS consumption. OBJECTIVES: We aimed to utilize a novel biomarker approach to investigate exposure to 5 LCSs and to test whether reported low-calorie sweetened beverage (LCSB) consumption effectively identifies exposure to LCSs in adults. METHODS: In this cross-sectional analysis, 2 population studies were conducted in adults. Urinary excretions of 5 LCSs, namely acesulfame-K, saccharin, cyclamate, sucralose, and steviol glycosides, were simultaneously determined using LC tandem-MS. In Study 1, previously collected 24-h urine samples (n = 357) were analyzed. In Study 2, previously collected 24-h urine samples (n = 79) were analyzed to compare urinary excretions of LCSs with self-reported LCSB consumption for identifying LCS exposure. Exposure to LCSs was characterized using descriptive statistics and chi-square tests were performed to assess associations between age-groups and LCS excretion, and to assess the proportion of individuals identified as LCS consumers using biomarker data or reported LCSB consumption. RESULTS: A total of 341 adults (45% men) and 79 adults (39% men) were included in the final analysis of Studies 1 and 2, respectively. In Study 1, >96% of samples contained ≥1 LCS and almost 60% contained ≥3 LCSs. A greater proportion of younger adults (<40 y old) excreted ≥3 LCSs than older adults (>40 y old) (P < 0.001). In Study 2, a much higher prevalence of LCS consumption was observed using biomarker data (92%) than reported LCSB consumption (6%) (P < 0.001). CONCLUSIONS: This work indicates widespread exposure to LCSs, suggesting that population-based research to date into LCS exposure and health may be flawed. Therefore, a urinary biomarker approach offers considerable potential for more robust investigations in this area.

Riboflavin Is an Important Determinant of Vitamin B-6 Status in Healthy Adults.

BACKGROUND: Riboflavin is required to generate the active form of vitamin B-6 (pyridoxal 5'-phosphate; PLP) in tissues, but the relevance of this metabolic interaction for nutritional status of vitamin B-6 is unclear because riboflavin biomarkers are rarely measured in human studies. OBJECTIVES: The purpose of this study was to identify the determinants of biomarkers of vitamin B-6 and riboflavin status and to examine the relationship between these nutrients in healthy adults. METHODS: Multiple linear regression was performed on observational data in 407 healthy adults aged 18-92 y who did not use B-vitamin supplements. Vitamin B-6 status was assessed by plasma PLP concentrations and erythrocyte glutathione reductase activation coefficient (EGRac) was used as a functional indicator of riboflavin status. RESULTS: Dietary intakes of vitamin B-6 and riboflavin were below the average requirements in 10% and 29% of participants, respectively. Suboptimal status of vitamin B-6 (PLP ≤30.0 nmol/L) was more prevalent in adults aged ≥60 y than in younger participants (i.e., 14% compared with 5%), whereas a high proportion (i.e., overall 37%) of both age groups had deficient riboflavin status (EGRac ≥1.40). In multiple regression analysis, EGRac (P = 0.019) was a significant determinant of plasma PLP, along with dietary vitamin B-6 intake (P = 0.003), age (P < 0.001), BMI (kg/m2) (P = 0.031), and methylenetetrahydrofolate reductase gene (MTHFR) genotype (P < 0.001). Significant determinants of EGRac were dietary riboflavin intake (P < 0.001), age (P < 0.001) and MTHFR genotype (P = 0.020). Plasma PLP showed a stepwise decrease across riboflavin status categories from optimal (EGRac ≤1.26) to low (EGRac 1.27-1.39) to deficient status (P = 0.001), independent of dietary vitamin B-6 intake. CONCLUSIONS: The findings are consistent with the known metabolic dependency of vitamin B-6 on riboflavin status and indicate that riboflavin may be the limiting nutrient, particularly in older people, for maintaining adequate vitamin B-6 status.

Maternal Long-Chain Polyunsaturated Fatty Acid Status, Methylmercury Exposure, and Birth Outcomes in a High-Fish-Eating Mother-Child Cohort.

BACKGROUND: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth. OBJECTIVE: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes. METHODS: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity. RESULTS: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, ß = 0.205, P = 0.03; TC compared with CC, ß = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, ß = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, ß = 0.109, P = 0.04). CONCLUSIONS: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations.

Methylmercury and long chain polyunsaturated fatty acids are associated with immune dysregulation in young adults from the Seychelles child development study.

BACKGROUND: Exposure to the environmental toxicant mercury (Hg) has been associated with immune dysregulation, including autoimmune disease, but few human studies have examined methylmercury (MeHg) exposure from fish consumption. OBJECTIVES: We examined associations between MeHg exposure and biological markers of autoimmunity and inflammation while adjusting for long chain polyunsaturated fatty acids (LCPUFA). METHOD: At age 19 years, hair total Hg (Y19Hg), LCPUFA status, a panel of 13 antinuclear antibodies (ANA), total serum immunoglobulins (Ig) IgG, IgA, and IgM and serum markers of inflammation (IL-1, IL-2, IL-6, IL-10, C-reactive protein (CRP), IFN-γ, TNF-α) were measured in the Seychelles Child Development Study (SCDS) Main Cohort (n = 497). Multivariable regression models investigated the association between Y19Hg and biomarkers, adjusting for prenatal total hair Hg (MatHg) and other relevant covariates, and with and without adjustment for LCPUFA. RESULTS: With each 1 ppm increase in Y19Hg (mean 10.23 (SD 6.02) ppm) we observed a 4% increased odds in a positive Combined ANA following adjustment for the n6:n3 LCPUFA ratio (ß = 0.036, 95%; CI: 0.001, 0.073). IgM was negatively associated with Y19Hg (ß = -0.016, 95%CI: 0.016, -0.002) in models adjusted for n-3, n-6 LCPUFA and when separately adjusted for the n-6:n-3 LCPUFA ratio. No associations were observed with MatHg. Total n-3 LCPUFA status was associated with reduced odds of a positive anti-ribonuclear protein (RNP) A. The n-3 LCPUFA were negatively associated with IL-6, IL-10, CRP, IFN-γ, TNF-α and positively with TNF-α:IL-10. There were positive associations between the n-6:n-3 ratio and IL-6, IL-10, CRP, IFN-γ, TNF-α and a negative association with TNF-α:IL-10. DISCUSSION: The Y19Hg exposure was associated with higher ANA and lower IgM albeit only following adjustment for the n-3 LCPUFA or the n-6:n-3 LCPUFA ratio. The clinical significance of these findings is unclear, but warrant follow up at an older age to determine any relationship to the onset of autoimmune disease.

A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin.

Methylmalonic acid (MMA) is a by-product of propionic acid metabolism through the vitamin B12 (cobalamin)-dependent enzyme methylmalonyl CoA mutase. Elevated MMA concentrations are a hallmark of several inborn errors of metabolism and indicators of cobalamin deficiency in older persons. In a genome-wide analysis of 2,210 healthy young Irish adults (median age 22 years) we identified a strong association of plasma MMA with SNPs in 3-hydroxyisobutyryl-CoA hydrolase (HIBCH, p = 8.42 × 10(-89)) and acyl-CoA synthetase family member 3 (ACSF3, p = 3.48 × 10(-19)). These loci accounted for 12% of the variance in MMA concentration. The most strongly associated SNP (HIBCH rs291466; c:2T>C) causes a missense change of the initiator methionine codon (minor-allele frequency = 0.43) to threonine. Surprisingly, the resulting variant, p.Met1?, is associated with increased expression of HIBCH mRNA and encoded protein. These homozygotes had, on average, 46% higher MMA concentrations than methionine-encoding homozygotes in young adults with generally low MMA concentrations (0.17 [0.14-0.21] µmol/L; median [25(th)-75(th) quartile]). The association between MMA levels and HIBCH rs291466 was highly significant in a replication cohort of 1,481 older individuals (median age 79 years) with elevated plasma MMA concentrations (0.34 [0.24-0.51] µmol/L; p = 4.0 × 10(-26)). In a longitudinal study of 185 pregnant women and their newborns, the association of this SNP remained significant across the gestational trimesters and in newborns. HIBCH is unique to valine catabolism. Studies evaluating flux through the valine catabolic pathway in humans should account for these variants. Furthermore, this SNP could help resolve equivocal clinical tests where plasma MMA values have been used to diagnose cobalamin deficiency.

Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial).

BACKGROUND: Periconceptional folic acid prevents neural tube defects (NTDs), but it is uncertain whether there are benefits for offspring neurodevelopment arising from continued maternal folic acid supplementation beyond the first trimester. We investigated the effect of folic acid supplementation during trimesters 2 and 3 of pregnancy on cognitive performance in the child. METHODS: We followed up the children of mothers who had participated in a randomized controlled trial in 2006/2007 of Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) and received 400 µg/d folic acid or placebo from the 14th gestational week until the end of pregnancy. Cognitive performance of children at 7 years was evaluated using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and at 3 years using the Bayley's Scale of Infant and Toddler Development (BSITD-III). RESULTS: From a total of 119 potential mother-child pairs, 70 children completed the assessment at age 7 years, and 39 at age 3 years. At 7 years, the children of folic acid treated mothers scored significantly higher than the placebo group in word reasoning: mean 13.3 (95% CI 12.4-14.2) versus 11.9 (95% CI 11.0-12.8); p = 0.027; at 3 years, they scored significantly higher in cognition: 10.3 (95% CI 9.3-11.3) versus 9.5 (95% CI 8.8-10.2); p = 0.040. At both time points, greater proportions of children from folic acid treated mothers compared with placebo had cognitive scores above the median values of 10 (girls and boys) for the BSITD-III, and 24.5 (girls) and 21.5 (boys) for the WPPSI-III tests. When compared with a nationally representative sample of British children at 7 years, WPPSI-III test scores were higher in children from folic acid treated mothers for verbal IQ (p < 0.001), performance IQ (p = 0.035), general language (p = 0.002), and full scale IQ (p = 0.001), whereas comparison of the placebo group with British children showed smaller differences in scores for verbal IQ (p = 0.034) and full scale IQ (p = 0.017) and no differences for performance IQ or general language. CONCLUSIONS: Continued folic acid supplementation in pregnancy beyond the early period recommended to prevent NTD may have beneficial effects on child cognitive development. Further randomized trials in pregnancy with follow-up in childhood are warranted. TRIAL REGISTRATION: ISRCTN ISRCTN19917787 . Registered 15 May 2013.