Stable isotope studies into the kinetics and bioavailablity of vitamin K₁ in humans

In Britain, vitamin K1 (phylloquinone) is the primary form of vitamin K in the human diet and blood. Evidence is accumulating for roles of vitamin K1 beyond established functions in blood coagulation, particularly in bone metabolism. To aid the determination of recommended intakes vitamin K1 kinetics and bioavailability were investigated in adult volunteers using stable isotopes. Methods to measure reliably and accurately the isotopic enrichment of plasma vitamin K1 using gas chromatography mass spectrometry (GCMS) were developed. Two stable isotope labelled forms of vitamin K1 (13C and ring-D4) measured simultaneously disposal kinetics of intravenous doses and absolute absorption of 4 μg oral doses in ten lean, healthy volunteers (1 male and 9 female), aged 22 - 31 y. Isotopic data were fitted to a 2-compartment model with input and output from the sampled (blood plasma) pool, and exchange between it and a remote compartment. Mean half-times for vitamin K1 disappearance were 0.2 and 2.7 h and mean absolute absorption of oral doses was 13%. A three-way crossover measured vitamin K1 bioavailability in twelve lean, healthy volunteers (7 male and 5 female) aged 22 - 49 y. Each volunteer consumed 20 μg of capsulated 13C-labelled vitamin K1 with one of three test-meals representing convenience, cosmopolitan or animal-oriented diets and balanced for fat, protein and carbohydrate but containing vitamin K1 in different components. Blood was sampled over 8 h. Relative bioavailability was greater from the convenience meal (relative bioavaiiability = 1.00), in which most vitamin K1 was in oils and fats not intact vegetables, compared to either the cosmopolitan (0.46) or animal-oriented (0.29) meals. These studies demonstrate that stable isotope-based methods successfully measure vitamin K1 bioavaiiability and metabolism and their potential for use in establishing recommended dietary intakes

Predictors of intact and C-terminal fibroblast growth factor 23 in Gambian children

Elevated C-terminal fibroblast growth factor 23 (C-FGF23) concentrations have been reported in Gambian children with and without putative Ca-deficiency rickets. The aims of this study were to investigate whether i) elevated C-FGF23 concentrations in Gambian children persist long term; ii) they are associated with higher intact FGF23 concentrations (I-FGF23), poor iron status and shorter 25-hydroxyvitamin D half-life (25OHD-t1/2); and iii) the persistence and predictors of elevated FGF23 concentrations differ between children with and without a history of rickets. Children (8-16 years, n=64) with a history of rickets and a C-FGF23 concentration >125 RU/ml (bone deformity (BD), n=20) and local community children with a previously measured elevated C-FGF23 concentration (LC+, n=20) or a previously measured C-FGF23 concentration within the normal range (LC-, n=24) participated. BD children had no remaining signs of bone deformities. C-FGF23 concentration had normalised in BD children, but remained elevated in LC+ children. All the children had I-FGF23 concentration within the normal range, but I-FGF23 concentration was higher and iron status poorer in LC+ children. 1,25-dihydroxyvitamin D was the strongest negative predictor of I-FGF23 concentration (R(2)=18%; P=0.0006) and soluble transferrin receptor was the strongest positive predictor of C-FGF23 concentration (R(2)=33%; P≤0.0001). C-FGF23 and I-FGF23 concentrations were poorly correlated with each other (R(2)=5.3%; P=0.07). 25OHD-t1/2 was shorter in BD children than in LC- children (mean (s.d.): 24.5 (6.1) and 31.5 (11.5) days respectively; P=0.05). This study demonstrated that elevated C-FGF23 concentrations normalised over time in Gambian children with a history of rickets but not in local children, suggesting a different aetiology; that children with resolved rickets had a shorter 25OHD-t1/2, suggesting a long-standing increased expenditure of 25OHD, and that iron deficiency is a predictor of elevated C-FGF23 concentrations in both groups of Gambian children

Examining the Antecedent Role of Movement Proficiency in Child Development: Study Protocol

Background: Decades of research, largely from associational studies, show that the relationships of movement proficiency with the cognitive and social aspects of development are particularly strong in early childhood. Children who move proficiently tend to have better cognitive skills and social behaviors. However, the mechanisms that underpin these relationships remain unclear and research that explores causation is necessary. This study will explore the antecedent role of movement proficiency in the cognitive and social domains of child development, by examining whether a targeted movement skills training program facilitates improvements in cognitive and social skills. Methods: A group-randomized controlled trial will be conducted, implementing a fundamental movement skills training program in Hong Kong kindergartens. Participants will consist of children aged 3–5 years (N = 158) who will be randomly allocated by class to either a training or active control condition. The training program (10 weeks × 2 bouts) will be informed by an error-reduced approach to skills learning, which will involve careful design and manipulation of equipment and training environment to minimize practice errors. The active control condition will consist of typical movement activities implemented in the kindergartens in the context of the local curriculum guide. Outcomes will be measured using standardized tests of gross motor skills proficiency, executive functioning, and social skills. Measurements will occur at baseline, mid-training, post-training, and follow-up. Latent variable longitudinal modeling will be used to analyze changes in the outcomes, with covariates that include sex, body composition, fine motor skills, and physical activity. Expected Results: The findings will subsequently be reported consistent with the Consolidated Standards of Reporting Trials (CONSORT) statement. Contributions to knowledge and understanding of child development are expected, through evidence of causal mechanisms surrounding the relationship of motor with cognitive and social development. The findings will also inform policy and practice related to early childhood development and education

National Diet and Nutrition Survey Rolling programme Years 9 to 11 (2016/2017 to 2018/2019) - A survey carried out on behalf of Public Health England and the Food Standards Agency

The National Diet and Nutrition Survey Rolling Programme (NDNS RP) is a continuous crosssectional survey, designed to assess the diet, nutrient intake and nutritional status of the general population aged 1.5 years and over living in private households in the UK. A representative sample of around 1,000 people (500 adults and 500 children) take part in the NDNS RP each year. Fieldwork for Years 9 to 11 of the NDNS RP was carried out between April 2016 and June 2019. The survey comprised an interview, a 4-day estimated diet diary, physical measurements and a blood and urine sample. Results are used by government to monitor progress toward diet and nutrition objectives of UK Health Departments and to develop policy interventions. The foods, nutrients and blood and urine measures presented in this report were selected for their nutritional and public health relevance to current dietary concerns in the UK. Results are analysed for 7 age groups: 1.5 to 3 years; 4 to 10 years; 11 to 18 years; 19 to 64 years; 65 years and over; 65 to 74 years and 75 years and over, split by sex in all except the youngest age group. The report includes: • descriptive statistics of food consumption, nutrient intake and nutritional status including proportion of the population meeting government recommendations for NDNS RP Years 9 to 11 (2016/17 to 2018/19) and comparison with results from years 7&8 (2014/15 to 2015/16). • trends over time in relation to food consumption, nutrient intakes and nutritional status in the UK for the first 11 years of the NDNS RP (2008/09 to 2018/19)PHE and Food Standards Agenc

Quantification and reporting of vitamin D concentrations measured in human milk by LC–MS/MS

Vitamin D is essential for optimal bone health, and vitamin D deficiency has been associated with an increased risk of adverse pregnancy, growth and developmental outcomes. In early life, and in the absence of endogenous vitamin D production from UVB light, infants are reliant on vitamin D stores established in utero and the vitamin D supply from human milk (HM). However, comprehensive data on vitamin D in HM is lacking. Thus, in this review we explore the application of liquid-chromatography tandem mass spectrometry (LC–MS/MS) to the assessment of vitamin D in HM. We discuss the challenges of extracting and measuring multiple vitamin D metabolites from HM including the frequent requirement for a large sample volume, and inappropriate poor sensitivity. Shortcomings in the reporting of experimental procedures and data analysis further hinder advances in the field. Data collated from all studies that have applied LC–MS/MS reveal that, in general, cholecalciferol concentration is greater and more variable than 25-hydroxyvitamin D concentration, and that the vitamin D content of HM is low and less than the currently recommended dietary requirement of infants, although maternal supplementation can increase the vitamin D content of HM. Improvements in analytical methods and their validation and larger, more representative studies are required to better characterize HM milk vitamin D metabolite concentrations and their relationship with maternal status. These data are essential to understand relationships with infant health and to inform public health policies around vitamin D fortification and supplementation

Vitamin D expenditure is not altered in pregnancy and lactation despite changes in vitamin D metabolite concentrations.

Pregnancy and lactation are associated with changes in vitamin D and calcium metabolism but the impact of these changes on vitamin D expenditure is unknown. We measured plasma 25(OH)D3 half-life with a stable-isotope tracer and investigated relationships with vitamin D metabolites in pregnant, lactating and 'non-pregnant, non-lactating' (NPNL) women. Vitamin D metabolites, vitamin D binding protein (DBP), PTH and 25(OH)D3 half-life were measured in third-trimester pregnant women (n22) and repeated during lactation 12 weeks post-partum (n14) and twice in NPNL women (n23 and n10, respectively) in rural Gambia where calcium intakes are low with little seasonality in UVB-exposure. 25(OH)D3 half-life was not significantly different between groups (mean(SD): 20.6(6.8), 22.6(7.7), 18.0(4.7) and 17.7(9.5) days in pregnant, lactating and NPNL women, respectively). Plasma 25(OH)D3, 1,25(OH)2D, and DBP were higher in pregnancy, and calculated free-25(OH)D3 and PTH were lower (P < 0.05). In lactation, 25(OH)D3 and 24,25(OH)2D3 were lower compared to pregnant (P < 0.001, P = 0.02) and NPNL women (P = 0.04, P = 0.07). Significant associations were observed between half-life and 25(OH)D3 (+ve) in pregnancy, and in all groups between 25(OH)D3 and free-25(OH)D3 (+ve) and PTH and 25(OH)D3 (-ve) (P < 0.0001). These data suggest that adaptive changes in pregnancy and lactation occur that prevent pronounced changes in vitamin D expenditure

Free 25-hydroxyvitamin D is low in obesity, but there are no adverse associations with bone health

Background: The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D–binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone. Objective: We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight. Design: We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25–75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health. Results: Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people. Conclusions: Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3. We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status

Death Reminders Increase Agreement With Extremist Views but Not Violent Extremist Action in Indonesian Muslims

Using terror management theory, we examined whether mortality salience (MS; death-related cognitions) increased support for religious and political extremism and/or violent extremism in young Indonesian Muslims. Muslim and non-Muslim Indonesian students studying in Australia were randomized to an MS or control condition. Following completion of a distracter task, participants were asked to rate their agreement/disagreement with another Indonesian Muslim student&rsquo;s (bogus) statements toward extremist views and violent extremist actions. After controlling for alienation, Muslim students in the MS condition reported significantly higher levels of support for extremist views than did non-Muslims. There was no significant effect of MS on violent extremist action in either Muslims or non-Muslims. The results suggest that reminders of death (MS) may lead young Muslims to be more supportive of politically and religiously extreme views, but not violent action. Our findings lend partial support to previous research in Iranian Muslim students; however, further research is needed to establish factors that can result in increased support for violent extremism

Antenatal iron supplementation, FGF23, and bone metabolism in Kenyan women and their offspring: secondary analysis of a randomized controlled trial.

BACKGROUND: Fibroblast growth factor-23 (FGF23) regulates body phosphate homeostasis primarily by increasing phosphaturia. It also acts as a vitamin D-regulating hormone. Maternal iron deficiency is associated with perturbed expression and/or regulation of FGF23 and hence might be implicated in the pathogenesis of hypophosphatemia-driven rickets in their offspring. OBJECTIVES: We aimed to determine the effect of antenatal oral iron supplementation on FGF23 concentration and maternal and infant markers of bone-mineral regulation. METHODS: We performed a secondary analysis of a trial in which 470 rural Kenyan women with singleton pregnancies and hemoglobin concentrations ≥ 90 g/L were randomly allocated to daily, supervised supplementation with 60 mg elemental iron as ferrous fumarate or placebo from 13-23 weeks of gestation until 1 mo postpartum. As previously reported, iron supplementation improved iron status in mothers and neonates. For the present study, we reanalyzed all available plasma samples collected in mothers and neonates at birth, with primary outcomes being concentrations of FGF23, measured by 2 assays: 1 that detects intact hormone and C-terminal cleavage products (total-FGF23) and another that detects the intact hormone only (intact-FGF23). RESULTS: Analysis was performed on 433 women (n = 216, iron group; n = 217, placebo group) and 414 neonates (n = 207, iron group; n = 207, placebo group). Antenatal iron supplementation reduced geometric mean total-FGF23 concentrations in mothers and neonates by 62.6% (95% CI: 53.0%, 70.3%) and 15.2% (95% CI: -0.3%, 28.4%, P = 0.06), respectively. In addition, it increased geometric mean neonatal intact-FGF23 concentrations by 21.6% (95% CI: 1.2%, 46.1%), increased geometric mean maternal hepcidin concentrations by 136.4% (95% CI: 86.1%, 200.3%), and decreased mean maternal 25-hydroxyvitamin D concentrations by 6.1 nmol/L (95% CI: -11.0, -1.2 nmol/L). CONCLUSIONS: Analysis of this randomized trial confirms that iron supplementation can reverse elevated FGF23 production caused by iron deficiency in iron-deficient mothers and their neonates. Further investigations are warranted to assess to what extent iron supplementation can prevent FGF23-mediated hypophosphatemic rickets or osteomalacia