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Background Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children. Methods We assayed iron and inflammatory biomarkers in 4853 children aged 0–8 years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin < 12 μg/L or < 30 μg/L in the presence of inflammation in children < 5 years old or < 15 μg/L in children ≥ 5 years old). We compared this with a recently proposed gold standard, which uses regression-correction for ferritin levels based on the relationship between ferritin levels, inflammatory markers, and malaria. We further investigated the utility of other iron biomarkers in predicting ID using the inflammation and malaria regression-corrected estimate as a gold standard. Results The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation < 11% most closely predicted the prevalence of ID according to the regression-correction gold standard. Conclusions The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa.

Abstract Background It remains unclear whether improving iron status increases malaria risk, and few studies have looked at the effect of host iron status on subsequent malaria infection. We therefore aimed to determine whether a child’s iron status influences their subsequent risk of malaria infection in sub-Saharan Africa. Methods We assayed iron and inflammatory biomarkers from community-based cohorts of 1309 Kenyan and 1374 Ugandan children aged 0–7 years and conducted prospective surveillance for episodes of malaria. Poisson regression models were fitted to determine the effect of iron status on the incidence rate ratio (IRR) of malaria using longitudinal data covering a period of 6 months. Models were adjusted for age, sex, parasitemia, inflammation, and study site. Results At baseline, the prevalence of iron deficiency (ID) was 36.9% and 34.6% in Kenyan and Ugandan children, respectively. ID anemia (IDA) affected 23.6% of Kenyan and 17.6% of Ugandan children. Malaria risk was lower in children with ID (IRR, 0.7; 95% confidence interval [CI], 0.6, 0.8; P < .001) and IDA (IRR, 0.7; 95% CI, 0.6, 0.9; P = .006). Low transferrin saturation (<10%) was similarly associated with lower malaria risk (IRR, 0.8; 95% CI, 0.6, 0.9; P = .016). However, variation in hepcidin, soluble transferrin receptors (sTfR), and hemoglobin/anemia was not associated with altered malaria risk. Conclusions ID appears to protect against malaria infection in African children when defined using ferritin and transferrin saturation, but not when defined by hepcidin, sTfR, or hemoglobin. Additional research is required to determine causality. Clinical Trials Registration ISRCTN32849447 Decreased ferritin and transferrin saturation are associated with protection against malaria in African children. Hepcidin, soluble transferrin receptor, and hemoglobin concentrations are not associated with malaria protection. These findings may reflect differences in parasite iron acquisition.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6–hepcidin response to oral and parenteral iron is impaired, and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6–hepcidin axis, improving iron homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders. Iron homoeostasis is tightly orchestrated to avoid toxic iron overload. Here Lim and colleagues show that iron excess activates Nrf2 via mitochondrial reactive oxygen species, enhancing the expression of Bmp6 in liver sinusoidal endothelial cells, which in turn promotes hepcidin expression by hepatocytes, decreasing systemic iron levels.

Background Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children. Methods We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0–8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses. Results Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants. Conclusions Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.

The effects of vitamin D on osteoblast mineralization are well documented. Reports of the effects of vitamin D on osteoclasts, however, are conflicting, showing both inhibition and stimulation. Finding that resorbing osteoclasts in human bone express vitamin D receptor (VDR), we examined their response to different concentrations of 25-hydroxy vitamin D [25(OH)D ] (100 or 500 nmol L ) and 1,25-dihydroxy vitamin D [1,25(OH) D ] (0.1 or 0.5 nmol L ) metabolites in cell cultures. Specifically, CD14+ monocytes were cultured in charcoal-stripped serum in the presence of receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Tartrate-resistant acid phosphatase (TRAP) histochemical staining assays and dentine resorption analysis were used to identify the size and number of osteoclast cells, number of nuclei per cell and resorption activity. The expression of VDR was detected in human bone tissue ( ) by immunohistochemistry and cell cultures by western blotting. Quantitative reverse transcription-PCR (qRT-PCR) was used to determine the level of expression of vitamin D-related genes in response to vitamin D metabolites. VDR-related genes during osteoclastogenesis, shown by qRT-PCR, was stimulated in response to 500 nmol L of 25(OH)D and 0.1-0.5 nmol L of 1,25(OH) D , upregulating cytochrome P450 family 27 subfamily B member 1 ( ) and cytochrome P450 family 24 subfamily A member 1 ( ). Osteoclast fusion transcripts transmembrane 7 subfamily member 4 ( ) and nuclear factor of activated T-cell cytoplasmic 1 ( ) where downregulated in response to vitamin D metabolites. Osteoclast number and resorption activity were also increased. Both 25(OH)D and 1,25(OH) D reduced osteoclast size and number when co-treated with RANKL and M-CSF. The evidence for VDR expression in resorbing osteoclasts and low-dose effects of 1,25(OH) D on osteoclasts may therefore provide insight into the effects of clinical vitamin D treatments, further providing a counterpoint to the high-dose effects reported from experiments.

People with intellectual disabilities have a high risk of osteoporosis and fractures, which could partly be as a result of vitamin D deficiency. To compare the serum vitamin D (25(OH)D) levels of 155 patients with intellectual disabilities under psychiatric care and 192 controls, investigate potential risk factors for vitamin D deficiency in people with intellectual disabilities and assess available treatments. Cross-sectional observational study followed by treatment evaluation. Results Almost twice as many patients with intellectual disabilities had vitamin D deficiency (25(OH)D <50 nmol/l) compared with controls (77.3% v. 39.6%, P<0.0001). In the intellectual disabilities group, winter season (P<0.0001), dark skin pigmentation (P<0.0001), impaired mobility (P = 0.002) and obesity (P = 0.001) were independently associated with lower serum 25(OH)D. In most patients, 800 IU colecalciferol daily normalised 25(OH)D levels. Vitamin D deficiency is highly prevalent in people with intellectual disabilities, partly because of insufficient exposure to sunlight. Screening and treatment strategies, aiming to reduce these patients' high fracture risk, should be introduced. Similar strategies may be required in other psychiatric populations at risk for fractures and with a tendency to spend excessive time indoors.

Despite differences in the phamacokinetics of 25-hydroxycholecalciferol (25(OH)D3) and 25-hydroxyergocalciferol (25(OH)D2) in man, the effects of these and their 1α-hydroxylated forms (1,25(OH)2D3 and 1,25(OH)2D2) on cellular activity of vitamin D-responsive cells have hardly been compared. We studied differences in the effects of these metabolites on cell number, gene transcription, protein expression and mineralisation of cultured human bone marrow-derived stromal cells (hBMSC) and rapidly mineralising mouse 2T3 osteoblasts. 50-1000 nM 25(OH) and 0.05-10 nM 1,25(OH)2 metabolites were used. At high concentrations, 25(OH)D2/D3 and 1,25(OH)2D2/D3 suppressed cell number in both human and mouse cells. The suppression was greater with cholecalciferol (D3) metabolites than with those of ergocalciferol (D2). In both cell types, 25(OH)D2 and 25(OH)D3 increased the expression of osteopontin, osteocalcin, collagen-1, receptor activator of nuclear factor kappa-B ligand, vitamin D receptor, CYP24A1 and CYP27B1 genes. Whereas there was little or no difference between the effects of 25(OH)D2 and 25(OH)D3 in hBMSCs, differences were observed in the magnitude of the effects of these metabolites on the expression of most studied genes in 2T3 cells. Alkaline phosphatase (ALP) activity was increased by 25(OH)D2/D3 and 1,25(OH)2D2/D3 in hBMSC and 2T3 cells, and the increase was greater with the D3 metabolites at high concentrations. In hBMSCs, mineralisation was also increased by 25(OH)D2/D3 and 1,25(OH)2D2/D3 at high concentrations, with D3 metabolites exerting a greater influence. In 2T3 cells, the effects of these compounds on mineralisation were stimulatory at low concentrations and inhibitory when high concentrations were used. The suppression at high concentrations was greater with the D3 metabolites. These findings suggest that there are differences in the effects of 25-hydroxy and 1α,25(OH)2 metabolites of D3 and D2 on human preosteoblasts and mouse osteoblasts, with the D3 metabolites being more potent in suppressing cell number, increasing ALP activity and influencing mineralisation.

Despite frequent use, little is known about the metabolic and endocrine side-effects of antipsychotics in individuals with intellectual disability. To compare indices of obesity, glucose, lipids and prolactin between antipsychotic-treated and antipsychotic-naive individuals with intellectual disability and also between participants with intellectual disability and controls from the general population. Observational study comparing 138 antipsychotic-treated and 64 antipsychotic-naive participants with intellectual disability in one National Health Service trust with general population controls. Antipsychotic treatment comprised: risperidone 48%,olanzapine 18%, thioxanthenes 10%, other 24%; monotherapy 95% of participants; mean treatment duration 8 years;median daily chlorpromazine equivalent dose 108 mg(range 16–667). Metabolic indices were the same or more favourable in the intellectual disability group than the general population control group but overweight/obesity and type 2 diabetes were more prevalent in the women in the intellectual disability group than the control group. Metabolic indices were similar, statistically or clinically, between the antipsychotic-treated and the antipsychotic-naive groups but there was a non-significant trend towards a higher rate of type 2 diabetes in the antipsychotic group. A total of 100%and 70% of participants on amisulpride/sulpiride and risperidone respectively had hyperprolactinaemia, with secondary hypogonadism in 77% and 4% of affected women and men. Antipsychotics, on average, did not increase metabolic risk,although the existence of a susceptible subgroup at risk of diabetes cannot be excluded. Some antipsychotics induced hyperprolactinaemic hypogonadism, requiring active management. However, our findings suggest that antipsychotics at the low doses routinely prescribed for people with intellectual disability are generally safe in relation to metabolic adverse effects, even if efficacy remains poorly defined.

Background : Mitochondrial diabetes is primarily caused by β-cell failure, a cell type whose unique properties are important in pathogenesis. Methods : By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results : Culturing rat insulin-secreting INS-1 cells in low glucose conditions caused a rapid reduction in whole cell respiration, associated with elevated mitochondrial reactive oxygen species production, and an altered glucose-stimulated insulin secretion profile. Prolonged exposure to reduced glucose directly impaired mitochondrial function and reduced autophagy. Conclusions : Insulinoma cell lines have a very different bioenergetic profile to many other cell lines and provide a useful model of mechanisms affecting β-cell mitochondrial function.

BackgroundPoint-of-care testing allows rapid analysis of samples to facilitate prompt clinical decisions. Electrolyte and calcium abnormalities are common in acutely ill patients and can be associated with life-threatening consequences. There is uncertainty whether clinical decisions can be based on the results obtained from blood gas analysers or if laboratory results should be awaited.ObjectivesTo assess the agreement between sodium, potassium and calcium results from blood gas and laboratory mainstream analysers in a tertiary centre, with a network consisting of one referral and two peripheral hospitals, consisting of three networked clinical biochemistry laboratories.MethodUsing the laboratory information management system database and over 11 000 paired samples in three hospital sites, the results of sodium, potassium and ionised calcium on blood gas analysers were studied over a 5-year period and compared with the corresponding laboratory results from the same patients booked in the laboratory within 1 h.ResultsThe Pearson's linear correlation coefficient between laboratory and blood gas results for sodium, potassium and calcium were 0.92, 0.84 and 0.78, respectively. Deming regression analysis showed a slope of 1.04 and an intercept of −5.7 for sodium, slope of 0.93 and an intercept of 0.22 for potassium and a slope of 1.23 with an intercept of −0.55 for calcium. With some strict statistical assumptions, percentages of results lying outside the least significant difference were 9%, 26.7% and 20.8% for sodium, potassium and calcium, respectively.ConclusionsMost clinicians wait for the laboratory confirmation of results generated by blood gas analysers. In a large retrospective study we have shown that there is sufficient agreement between the results obtained from the blood gas and laboratory analysers to enable prompt clinical decisions to be made.