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The Drakesmith group investigated an unusual aspect of iron regulation against infection, and stumbled upon a new antiviral pathway
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Credit RCSB Protein Data Bank (CC BY 4.0)
Stabilization of the prevalence of childhood obesity in Switzerland.
BACKGROUND: The prevalence of childhood obesity is increasing rapidly in most industrialised countries, but several countries, including Switzerland, have recently reported a levelling off or even a reversal of this alarming trend. STUDY AIM: Our aim was to evaluate the prevalence of childhood obesity in a national sample of Swiss school children recruited to assess iodine nutrition and with this to reconfirm a recently shown stabilising trend. DESIGN: Using a probability-proportionate-to-size cluster sampling, 6 to 12 year old children (n = 907) were recruited in a study of iodine status in Switzerland. Height and weight were measured and body mass index calculated in all children. RESULTS: The prevalence of overweight detected was 12.5% (SE = 1.6) in boys and 12.8% (1.6) in girls while 6.2% (1.1) of boys and 4.2% (0.9) of girls were classified as obese. The highest prevalence of overweight and obesity were found in the Southern region and in bigger cities (>100000 inhabitants). Compared to the most recent national study in 2007, the prevalence was slightly higher, but the differences were not significant, suggesting negative sampling bias does not strongly affect surveys of paediatric adiposity in Switzerland. CONCLUSION: This present study clearly confirms the stabilisation of the prevalence of childhood overweight and obesity in Switzerland.
Iodine requirements and the risks and benefits of correcting iodine deficiency in populations.
Iodine deficiency has multiple adverse effects on growth and development due to inadequate thyroid hormone production that are termed the iodine deficiency disorders (IDD). IDD remains the most common cause of preventable mental impairment worldwide. IDD assessment methods include urinary iodine concentration, goiter, thyroglobulin and newborn thyrotropin. In nearly all iodine-deficient countries, the best strategy to control IDD is salt iodization, one of the most cost-effective ways to contribute to economic and social development. When salt iodization is not possible, iodine supplements can be targeted to vulnerable groups. Introduction of iodized salt to regions of chronic IDD may transiently increase the incidence of thyroid disorders, and programs should include monitoring for both iodine deficiency and excess. Although more data on the epidemiology of thyroid disorders caused by differences in iodine intake are needed, overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency.
The influence of iron status on iodine utilization and thyroid function.
Despite significant progress, deficiencies of iron and iodine remain major public health problems affecting > or =30% of the global population. These deficiencies often coexist in children. Recent studies have demonstrated that a high prevalence of iron deficiency among children in areas of endemic goiter may reduce the effectiveness of iodized salt programs. These findings argue strongly for improving iron status in areas of overlapping deficiency, not only to combat anemia but also to increase the efficacy of iodine prophylaxis. The dual fortification of salt with iodine and iron may prove to be an effective and sustainable method to accomplish these important goals.
Comparison of manual and automated ELISA methods for serum ferritin analysis.
Serum ferritin concentration is a sensitive measure of body iron stores. The aim of this study was to compare the performance of two commercially available enzyme-linked immunoassays (ELISAs) for serum ferritin: a widely used manual assay kit (Spectro Ferritin MT), and a new fully automated assay (Immulite). We analyzed serum samples from Moroccan school-aged children (n=51) from a rural area with a high prevalence of iron deficiency anemia (IDA). Four replicates of each sample were analyzed using both assays. For the manual method, the interassay repeatability was 24%, 22%, and 11%, and intraassay precision was 18.3%, 9.2%, and 9.1% at increasing serum ferritin concentrations. Using the automated assay, the interassay repeatability was 7%, 6%, and 6%, and intraassay precision was 1.5%, 5.4%, and 5.5% at increasing serum ferritin concentrations. The two assays were well correlated (y=1.16x+1.83; r=0.98). However, the limits of agreement (LOAs) were wide, particularly at low concentrations. A comparison of the assay results with recommended cutoffs for serum ferritin generated sharply different estimates of the prevalence of iron deficiency (ID) in the sample. We conclude that the automated assay has several potential advantages compared to the manual method, including better precision, less operator dependence, and faster sample through-put.
The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire.
BACKGROUND: Iron is essential for the growth and virulence of many pathogenic enterobacteria, whereas beneficial barrier bacteria, such as lactobacilli, do not require iron. Thus, increasing colonic iron could select gut microbiota for humans that are unfavorable to the host. OBJECTIVE: The objective was to determine the effect of iron fortification on gut microbiota and gut inflammation in African children. DESIGN: In a 6-mo, randomized, double-blind, controlled trial, 6-14-y-old Ivorian children (n = 139) received iron-fortified biscuits, which contained 20 mg Fe/d, 4 times/wk as electrolytic iron or nonfortifoed biscuits. We measured changes in hemoglobin concentrations, inflammation, iron status, helminths, diarrhea, fecal calprotectin concentrations, and microbiota diversity and composition (n = 60) and the prevalence of selected enteropathogens. RESULTS: At baseline, there were greater numbers of fecal enterobacteria than of lactobacilli and bifidobacteria (P < 0.02). Iron fortification was ineffective; there were no differences in iron status, anemia, or hookworm prevalence at 6 mo. The fecal microbiota was modified by iron fortification as shown by a significant increase in profile dissimilarity (P < 0.0001) in the iron group as compared with the control group. There was a significant increase in the number of enterobacteria (P < 0.005) and a decrease in lactobacilli (P < 0.0001) in the iron group after 6 mo. In the iron group, there was an increase in the mean fecal calprotectin concentration (P < 0.01), which is a marker of gut inflammation, that correlated with the increase in fecal enterobacteria (P < 0.05). CONCLUSIONS: Anemic African children carry an unfavorable ratio of fecal enterobacteria to bifidobacteria and lactobacilli, which is increased by iron fortification. Thus, iron fortification in this population produces a potentially more pathogenic gut microbiota profile, and this profile is associated with increased gut inflammation. This trial was registered at controlled-trials.com as ISRCTN21782274.
Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization: a double stable-isotope study in young Beninese women.
BACKGROUND: Iron deficiency anemia (IDA) affects many young women in sub-Saharan Africa. Its etiology is multifactorial, but the major cause is low dietary iron bioavailability exacerbated by parasitic infections such as malaria. OBJECTIVE: We investigated whether asymptomatic Plasmodium falciparum parasitemia in Beninese women would impair absorption of dietary iron or utilization of circulating iron. DESIGN: Iron absorption and utilization from an iron-fortified sorghum-based meal were estimated by using oral and intravenous isotope labels in 23 afebrile women with a positive malaria smear (asexual P. falciparum parasitemia; > 500 parasites/μL blood). The women were studied while infected, treated, and then restudied 10 d after treatment. Iron status, hepcidin, and inflammation indexes were measured before and after treatment. RESULTS: Treatment reduced low-grade inflammation, as reflected by decreases in serum ferritin, C-reactive protein, interleukin-6, interleukin-8, and interleukin-10 (P < 0.05); this was accompanied by a reduction in median serum hepcidin of ≈ 50%, from 2.7 to 1.4 nmol/L (P < 0.005). Treatment decreased serum erythropoietin and growth differentiation factor 15 (P < 0.05). Clearance of parasitemia increased geometric mean dietary iron absorption (from 10.2% to 17.6%; P = 0.008) but did not affect systemic iron utilization (85.0% compared with 83.1%; NS). CONCLUSIONS: Dietary iron absorption is reduced by ≈ 40% in asymptomatic P. falciparum parasitemia, likely because of low-grade inflammation and its modulation of circulating hepcidin. Because asymptomatic parasitemia has a protracted course and is very common in malarial areas, this effect may contribute to IDA and blunt the efficacy of iron supplementation and fortification programs. This trial was registered at clinicaltrials.gov as NCT01108939.
The Swiss iodized salt program provides adequate iodine for school children and pregnant women, but weaning infants not receiving iodine-containing complementary foods as well as their mothers are iodine deficient.
BACKGROUND: If children and pregnant women in the population are iodine sufficient, it is generally assumed infants are also sufficient. But weaning infants may be at risk of iodine deficiency because iodized salt contributes little dietary iodine during this period. To fill this gap, iodine fortification of infant formula milk (IFM) and complementary foods (CF) is likely important. OBJECTIVES: The objective of the study was to first confirm that Swiss school children and pregnant women remain iodine sufficient and then to assess iodine status in infancy and the relative contribution of breast milk and IFM/CF to their iodine intakes. METHODS: We measured urinary iodine concentrations (UIC) in national cross-sectional samples of: 1) pregnant women (n=648); 2) school children (n=916); 3) infants at three time points: at 3-4 d after birth and at 6 and 12 months (n=875); and 4) breast-feeding mothers (n=507). We measured breast milk iodine concentrations in the mothers, assessed iodine sources in infant diets, and analyzed iodine content of commercial IFM/CFs (n=22) and salt samples from the school children's households (n=266). RESULTS: Median (m) UICs in pregnant women (162 μg/liter) and school children (120 μg/liter) were sufficient, and 80% of the household salt was adequately iodized (≥15 ppm). However, mUICs in infants not receiving IFM/CF were not sufficient: 1) mUIC in breast-fed infants (82 μg/liter) was lower than in non-breast-fed infants (105 μg/liter) (P<0.001) and 2) mUIC in breast-fed weaning infants not receiving IFM/CF (70 μg/liter) was lower than infants receiving IFM (109 μg/liter) (P<0.01). mUIC was low in lactating mothers (67 μg/liter) and median breast milk iodine concentration was 49 μg/kg. CONCLUSIONS: In countries in which iodized salt programs supply sufficient iodine to older children and pregnant women, weaning infants, particularly those not receiving iodine-containing IFM, may be at risk of inadequate iodine intakes.
During rapid weight loss in obese children, reductions in TSH predict improvements in insulin sensitivity independent of changes in body weight or fat.
BACKGROUND: Although serum TSH is often elevated in obesity and may be linked to disorders of lipid and glucose metabolism, the clinical relevance of these relationships remains unclear. SUBJECTS: Subjects were obese children and adolescents (n=206; mean age 14 yr) undergoing rapid weight and fat loss in a standardized, multidisciplinary, 2-month, in-patient weight loss program. DESIGN: This was a prospective study that determined thyroid function, glucose and lipid parameters, leptin, anthropometric measures, and body composition measured by dual-energy x-ray absorption at baseline and at the end of the intervention. RESULTS: At baseline, 52% of children had TSH concentrations in the high normal range (>2.5 mU/liter), but TSH was not correlated with body weight, body mass index sd scores, lean body mass, or body fat percentage. At baseline, independent of adiposity, TSH significantly correlated with total cholesterol (P=0.008), low-density lipoprotein cholesterol (P=0.013), fasting insulin (P=0.010), homeostatic model assessment (HOMA) (P=0.004), and leptin (P=0.006). During the intervention, mean body fat, TSH, HOMA, and fasting insulin decreased by 21, 11, 53, and 54%, respectively. Change (Δ) in TSH did not correlate with Δbody weight or Δbody composition, but ΔTSH significantly correlated with, Δfasting insulin and ΔHOMA, independent of Δbody weight or Δbody composition (P<0.05). CONCLUSION: TSH concentrations are elevated in obese children but are not correlated with the amount of excess body weight or fat. During weight loss, independent of changes in body weight or composition, decreases in elevated serum TSH predict decreases in fasting insulin and HOMA. These findings suggest interventions that target high TSH concentrations during weight loss in obese subjects may improve insulin sensitivity.
Dietary determinants of subclinical inflammation, dyslipidemia and components of the metabolic syndrome in overweight children: a review.
OBJECTIVE: To review and summarize the dietary determinants of the metabolic syndrome, subclinical inflammation and dyslipidemia in overweight children. DESIGN: Review of the current literature, focusing on pediatric studies. PARTICIPANTS: Normal weight, overweight, or obese children and adolescents. RESULTS: There is a growing literature on the metabolic effects of excess body fat during childhood. However, few pediatric studies have examined the dietary determinants of obesity-related metabolic disturbances. From the available data, it appears that dietary factors are not only important environmental determinants of adiposity, but also may affect components of the metabolic syndrome and modulate the actions of adipokines. Dietary total fat and saturated fat are associated with insulin resistance and high blood pressure, as well as obesity-related inflammation. In contrast to studies in adults, resistin and adiponectin do not appear to be closely linked to insulin resistance or dyslipidemia in childhood. However, circulating leptin and retinol-binding protein (RBP) 4 correlate well with obesity, central obesity and the metabolic syndrome in children. Intakes of antioxidant vitamins tend to be low in obese children and may be predictors of subclinical inflammation. Higher fructose intake from sweets and sweetened drinks in overweight children has been linked to decreased low-density lipoprotein (LDL) particle size. CONCLUSIONS: Dietary interventions aimed at reducing intakes of total fat, saturated fat and free fructose, whereas increasing antioxidant vitamin intake may be beneficial in overweight children. More research on the relationships between dietary factors and the metabolic changes of pediatric obesity may help to identify the dietary changes to reduce health risks.
The impact of iodised salt or iodine supplements on iodine status during pregnancy, lactation and infancy.
OBJECTIVES: Monitoring of iodine status during pregnancy, lactation and infancy is difficult as there are no established reference criteria for urinary iodine concentration (UI) for these groups; so it is uncertain whether iodized salt programs meet the needs of these life stages. DESIGN AND SUBJECTS: The method used in this paper was: 1) to estimate the median UI concentration that reflects adequate iodine intake during these life stages; and 2) to use these estimates in a review of the literature to assess whether salt iodisation can control iodine deficiency in pregnant and lactating women, and their infants. RESULTS: For pregnancy, recommended mean daily iodine intakes of 220-250 microg were estimated to correspond to a median UI concentration of about 150 microg l- 1, and larger surveys from the iodine sufficient countries have reported a median UI in pregnant women > or = 140 microg l- 1. Iodine supplementation in pregnant women who are mild-to-moderately iodine deficient is beneficial, but there is no clear affect on maternal or newborn thyroid hormone levels. In countries where the iodine intake is sufficient, most mothers have median breast milk iodine concentration (BMIC) greater than the concentration (100-120 microg l- 1) required to meet an infant's needs. The median UI concentration during infancy that indicates optimal iodine nutrition is estimated to be > or = 100 microg l- 1. In iodine-sufficient countries, the median UI concentration in infants ranges from 90-170 microg l- 1, suggesting adequate iodine intake in infancy. CONCLUSIONS: These findings suggest pregnant and lactating women and their infants in countries with successful sustained iodised salt programs have adequate iodine status.
Assessment of iodine status using dried blood spot thyroglobulin: development of reference material and establishment of an international reference range in iodine-sufficient children.
CONTEXT: Thyroglobulin (Tg) may be a valuable indicator of improving thyroid function in children after salt iodization. A recently developed Tg assay for use on dried whole blood spots (DBS) makes sampling practical, even in remote areas. OBJECTIVE: The study aim was to develop a reference standard for DBS-Tg, establish an international reference range for DBS-Tg in iodine-sufficient children, and test the standardized DBS-Tg assay in an intervention trial. DESIGN, PARTICIPANTS, AND INTERVENTIONS: Serum Tg reference material of the European Community Bureau of Reference (CRM-457) was adapted for DBS and its stability tested over 1 yr. DBS-Tg was determined in an international sample of 5- to 14-yr-old children (n = 700) who were euthyroid, anti-Tg antibody negative, and residing in areas of long-term iodine sufficiency. In a 10-month trial in iodine-deficient children, DBS-Tg and other indicators of iodine status were measured before and after introduction of iodized salt. RESULTS: Stability of the CRM-457 Tg reference standard on DBS over 1 yr of storage at -20 and -50 C was acceptable. In the international sample of children, the third and 97th percentiles of DBS-Tg were 4 and 40 microg/liter, respectively. In the intervention, before introduction of iodized salt, median DBS-Tg was 49 microg/liter, and more than two thirds of children had DBS-Tg values greater than 40 microg/liter. After 5 and 10 months of iodized salt use, median DBS-Tg decreased to 13 and 8 microg/liter, respectively, and only 7 and 3% of children, respectively, had values greater than 40 microg/liter. DBS-Tg correlated well at baseline and 5 months with urinary iodine and thyroid volume. CONCLUSIONS: The availability of reference material and an international reference range facilitates the use of DBS-Tg for monitoring of iodine nutrition in school-age children.
Comparison of the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced elemental iron: randomized, double-blind, controlled trial in Thai women.
BACKGROUND: Although elemental iron powders are widely used to fortify cereal products, little data exist on their efficacy in humans. OBJECTIVE: We compared the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in Thai women with low iron stores. DESIGN: A double-blind intervention was conducted in 18-50-y-old women (n = 330) randomly assigned into 4 groups to receive either no fortification iron or 12 mg Fe/d for 6 d/wk for 35 wk as ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in a baked, wheat-flour-based snack. Snacks were not consumed with meals, and consumption was monitored. At baseline, 20 wk, and 35 wk, hemoglobin status and iron were measured and the groups were compared. RESULTS: Between baseline and 35 wk, geometric mean serum ferritin (SF) increased significantly in all 3 groups receiving iron (P < 0.01), and geometric mean serum transferrin receptor (TfR) decreased significantly in the groups receiving ferrous sulfate and electrolytic iron (P < 0.05). Calculated mean (+/-SD) body iron stores increased from 1.5 +/- 2.8 to 5.4 +/- 2.9 mg/kg in the ferrous sulfate group, from 1.5 +/- 3.5 to 4.4 +/- 3.6 mg/kg in the electrolytic iron group, and from 1.3 +/- 3.2 to 3.2 +/- 4.3 mg/kg in the hydrogen-reduced iron group (P < 0.01 for all 3 groups) but did not change significantly in the control group. CONCLUSIONS: Ferrous sulfate, electrolytic iron, and hydrogen-reduced iron, fortified into wheat-based snacks, significantly improved iron status. On the basis of the change in body iron stores during the 35-wk study, the relative efficacy of the electrolytic and hydrogen-reduced iron compared with ferrous sulfate was 77% and 49%, respectively.
Particle size reduction and encapsulation affect the bioavailability of ferric pyrophosphate in rats.
Particle size is an important determinant of Fe absorption from poorly soluble Fe compounds in foods. Decreasing the particle size of elemental iron powders increases their absorption. The effect of a reduction in particle size on the bioavailability of ferric pyrophosphate (FePP) is unclear. Encapsulation of iron compounds for food fortification may protect against adverse sensory changes, but at the same time may reduce bioavailability. The hemoglobin (Hb) repletion method in weanling Sprague-Dawley rats (n = 100) was used to compare the relative bioavailability (RBV) of 4 forms of FePP: 1) regular FePP [mean particle size (MPS) approximately 21 microm]; 2) MPS approximately 2.5 microm; 3) MPS approximately 2.5 microm encapsulated in hydrogenated palm oil; and 4) MPS approximately 0.5 microm with emulsifiers. The RBV compared with ferrous sulfate was calculated by the slope-ratio technique. The RBV was 43% for encapsulated MPS approximately 2.5 microm, significantly lower than the other FePP compounds (P < 0.05), 59% for the regular FePP, and 69% for MPS approximately 2.5 microm, not different from each other but significantly lower than ferrous sulfate (P < 0.05), and 95% for emulsified MPS approximately 0.5 microm, comparable to ferrous sulfate. Encapsulation of FePP with hydrogenated palm oil at a capsule:substrate ratio of 60:40 decreased RBV. Particle size reduction increases the RBV of FePP and may make this compound more useful for food fortification.
Addition of microencapsulated iron to iodized salt improves the efficacy of iodine in goitrous, iron-deficient children: a randomized, double-blind, controlled trial.
OBJECTIVE: In many developing countries, children are at high risk for both goiter and anemia. Iron (Fe) deficiency adversely effects thyroid metabolism and reduces efficacy of iodine prophylaxis in areas of endemic goiter. The study aim was to determine if co-fortification of iodized salt with Fe would improve efficacy of the iodine in goitrous children with a high prevalence of anemia. DESIGN AND METHODS: In a 9-month, randomized, double-blind trial, 6-15 year-old children (n=377) were given iodized salt (25 microg iodine/g salt) or dual-fortified salt with iodine (25 microg iodine/g salt) and Fe (1 mg Fe/g salt, as ferrous sulfate microencapsulated with partially hydrogenated vegetable oil). RESULTS: In the dual-fortified salt group, hemoglobin and Fe status improved significantly compared with the iodized salt group (P<0.05). At 40 weeks, the mean decrease in thyroid volume measured by ultrasound in the dual-fortified salt group (-38%) was twice that of the iodized salt group (-18%) (P<0.01). Compared with the iodized salt group, serum thyroxine was significantly increased (P<0.05) and the prevalence of hypothyroidism and goiter decreased (P<0.01) in the dual-fortified salt group. CONCLUSION: Addition of encapsulated Fe to iodized salt improves the efficacy of iodine in goitrous children with a high prevalence of anemia.
Thyroid ultrasound compared with World Health Organization 1960 and 1994 palpation criteria for determination of goiter prevalence in regions of mild and severe iodine deficiency.
OBJECTIVES: In 1994, WHO/International Council for the Control of Iodine Deficiency Disorders recommended replacing the WHO 1960 four-grade goiter classification with a simplified two-grade system. The effect of this change in criteria on the estimation of goiter prevalence in field studies is unclear. In areas of mild iodine deficiency disorders (IDD) where goiters are small, ultrasound is preferable to palpation to estimate goiter prevalence. However, in areas of moderate to severe IDD, goiter screening by palpation may be an acceptable alternative to thyroid ultrasound. To address these two issues, we compared WHO 1960 and 1994 criteria with thyroid ultrasound for determination of goiter prevalence in areas of mild and severe IDD in Morocco. DESIGN: A cross-sectional study of 400 six- to 13-year-old children from two mountain villages (Ait M'hamed and Brikcha) in rural Morocco was carried out. METHODS: Urinary iodine concentration (UI), whole blood TSH and serum thyroxine were measured. Thyroid size was graded by inspection and palpation by two examiners using both WHO 1960 and 1994 criteria. Thyroid volume was determined by ultrasound. Variation between examiners and examination methods was assessed. Sensitivity and specificity of the two classification systems compared with ultrasound were calculated. RESULTS: Median UIs in Aït M'hamed and Brikcha were 183 and 24 microg/l respectively. In Ait M'hamed, using 1960 and 1994 criteria, goiter prevalence was 21 and 26% respectively, compared with 13% by ultrasound. In Brikcha, with 1960 and 1994 criteria, goiter prevalence was 64 and 67% respectively, compared with 64% by ultrasound. Agreement between observers was better with the 1994 criteria than with the 1960 criteria in Ait M'hamed (kappa=0.53 and 0.47 respectively), while in Brikcha observer agreement was similar with the two systems (kappa=0.67). Using either the 1994 or 1960 criteria, agreement with ultrasound was only moderate in Ait M'hamed (kappa=0.41-0.44), but good in Brikcha (kappa=0.55-0.64). Overall, compared with ultrasound, sensitivity increased 3-4% using 1994 criteria, while specificity decreased 4-5%. CONCLUSIONS: The WHO 1994 criteria are simpler to use than the 1960 criteria and provide increased sensitivity with only a small reduction in specificity. Agreement between observers is better with the 1994 criteria than with the 1960 criteria, particularly in areas of mild IDD. Like the 1960 criteria, the 1994 criteria overestimate goiter prevalence in areas of mild IDD, compared with ultrasound. However, the 1994 palpation criteria provide an accurate estimate of goiter prevalence in areas of severe IDD, and may be an acceptable and affordable alternative to thyroid ultrasound in these areas.
Random serial sampling to evaluate efficacy of iron fortification: a randomized controlled trial of margarine fortification with ferric pyrophosphate or sodium iron edetate.
BACKGROUND: Random serial sampling is widely used in population pharmacokinetic studies and may have advantages compared with conventional fixed time-point evaluation of iron fortification. OBJECTIVE: Our objective was to validate random serial sampling to judge the efficacy of iron fortification of a low-fat margarine. DESIGN: We conducted a 32-wk placebo-controlled, double-blind, iron-intervention trial in 18-40-y-old Swiss women (n = 142) with serum ferritin (SF) concentrations <25 μg/L. Women were randomly assigned to 3 groups to receive 20 g margarine, with 14 mg added iron as either micronized ground ferric pyrophosphate (MGFePP) or sodium iron edetate (NaFeEDTA), or placebo daily. We measured hemoglobin and iron status of subjects at 2 fixed time points (at baseline and the endpoint) plus 3 randomly assigned time points between 4 and 28 wk. With the use of bootstrapping, the number of observations per individual was reduced to 3 and then compared with the 5-time-point data. Mixed-effects models were used to estimate iron repletion over time for random sampling, and analysis of covariance was used for fixed time-point sampling. RESULTS: Body iron stores increased in women who received MGFePP or NaFeEDTA compared with women who received placebo (P < 0.05). The increase in body iron stores with NaFeEDTA fortification was 2-3 times the increase with MGFePP fortification (P < 0.05); the difference was more marked in women with baseline SF concentrations <15 μg/L (P < 0.05). Random serial sampling reduced the required sample size per group to one-tenth of that for 2 fixed time points. Compared with the 5-time-point analysis, the 3-time-point sparse sampling generated comparable estimates of efficacy. CONCLUSIONS: When used to evaluate the efficacy of iron fortificants, random serial sampling can reduce the sample size, invasiveness, and costs while increasing sensitivity. Random serial sampling more clearly describes the pattern of iron repletion and may prove useful in evaluating other micronutrient interventions.
Homodimerization of the death-associated protein kinase catalytic domain: development of a new small molecule fluorescent reporter.
BACKGROUND: Death-Associated Protein Kinase (DAPK) is a member of the Ca2+/calmodulin regulated serine/threonine protein kinases. Its biological function has been associated with induced cell death, and in vivo use of selective small molecule inhibitors of DAPK catalytic activity has demonstrated that it is a potential therapeutic target for treatment of brain injuries and neurodegenerative diseases. METHODOLOGY/PRINCIPAL FINDINGS: In the in vitro study presented here, we describe the homodimerization of DAPK catalytic domain and the crucial role played by its basic loop structure that is part of the molecular fingerprint of death protein kinases. Nanoelectrospray ionization mass spectrometry of DAPK catalytic domain and a basic loop mutant DAPK protein performed under a variety of conditions was used to detect the monomer-dimer interchange. A chemical biological approach was used to find a fluorescent probe that allowed us to follow the oligomerization state of the protein in solution. CONCLUSIONS/SIGNIFICANCE: The use of this combined biophysical and chemical biology approach facilitated the elucidation of a monomer-dimer equilibrium in which the basic loop plays a key role, as well as an apparent allosteric conformational change reported by the fluorescent probe that is independent of the basic loop structure.
Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable-isotope appearance curves, increases plasma hepcidin.
BACKGROUND: Plasma hepcidin appears to be a major regulator of iron absorption and homeostasis, but there are few data in humans. OBJECTIVES: With the use of iron stable isotopes, we aimed to determine whether circulating hepcidin predicts dietary iron bioavailability, to quantify the amount of absorbed iron after oral iron loading, and to measure the plasma hepcidin response. DESIGN: In the first study, young women (n = 98) with an iron status varying from iron deficiency anemia to iron sufficiency (women with serum ferritin concentrations 25-40 microg/L were not included) were given stable isotope-labeled test meals (n = 196) containing ferrous sulfate, ferrous fumarate, or ferric pyrophosphate, after which plasma hepcidin and iron bioavailability were measured. In the second study, iron-sufficient men (n = 4) were given 3.8- and 60-mg oral doses of labeled ferrous sulfate. The stable isotope appearance curve was determined, and the plasma hepcidin response was measured over 6 h. RESULTS: In study 1, plasma hepcidin and plasma ferritin were strongly correlated (r = 0.79, P < 0.001). Plasma hepcidin significantly, but modestly, predicted iron bioavailability from ferrous sulfate and ferrous fumarate (r = -0.51 and -0.46, respectively; P < 0.0001) but not from ferric pyrophosphate (r = -0.30, P = 0.056, respectively). In study 2, the 3.8-mg dose increased mean circulating absorbed iron to a peak of 0.42 micromol/L at 60 min but did not increase plasma hepcidin, The 60-mg dose increased mean circulating absorbed iron to a peak of 5.9 micromol/L at 120 min and produced an approximately 30% increase in mean plasma hepcidin at 6 h (P < 0.01). CONCLUSIONS: Plasma hepcidin is only a modest predictor of dietary iron bioavailability in humans. Oral iron loading, measured by stable-isotope appearance curves, increases circulating hepcidin.
Iodine: it's important in patients that require parenteral nutrition.
Iodine deficiency has multiple adverse effects on growth and development because of inadequate thyroid hormone production. Four methods are generally recommended for assessment of iodine nutrition: urinary iodine concentration, thyroid size, and blood concentrations of thyroid-stimulating hormone and thyroglobulin. Iodine intakes < or = 1 mg/d are well tolerated by most adults, because the thyroid is able to adjust to a wide range of intakes. A daily dose of 1 microg iodine/kg body weight is recommended for infants and children receiving parenteral nutrition (PN), but this is far below their requirement. Daily iodine requirements in adults receiving enteral nutrition or PN are estimated to be 70-150 microg, but most PN formulations do not contain iodine. Despite this, deficiency is unlikely because absorption from iodine-containing skin disinfectants and other adventitious sources can provide sufficient iodine. However, if chlorhexidine replaces iodine-containing disinfectants for catheter care, iodine deficiency may occur during long-term PN, and periodic testing of thyroid functions may be prudent. Infants may be particularly vulnerable because of their small thyroidal iodine store, but available data do not yet support routine supplementation of preterm infants with iodine. Adults may be less vulnerable because thyroidal iodine stores may be able to support thyroid hormone production for several months. More studies to clarify this issue would be valuable.
Efficacy of wheat-based biscuits fortified with microcapsules containing ferrous sulfate and potassium iodate or a new hydrogen-reduced elemental iron: a randomised, double-blind, controlled trial in Kuwaiti women.
Adverse sensory changes prevent the addition of highly bioavailable ferrous sulfate (FeSO4) to most wheat flours. Poorly absorbable reduced Fe powders are commonly used. Encapsulation of FeSO4 can overcome these sensory changes, but the particle size of commercial compounds is too large to be used by flour mills. The first objective of the study was to measure the efficacy in wheat flour of two newly developed Fe compounds, an H-reduced Fe powder (NutraFine RS; North America Höganäs High Alloys LLC, Johnstown, PA, USA) and small particle-sized (40 microm) encapsulated FeSO4. As a second objective, the microcapsules were evaluated as a vehicle for iodine fortification. A randomised, double-blind controlled intervention trial was conducted in Kuwaiti women (n 279; aged 18-35 years) with low body Fe stores (serum ferritin (SF) < 25 microg/l) randomly assigned to one of three groups (20 mg Fe as NutraFine RS, 10 mg Fe as encapsulated FeSO4 and 150 microg iodine, or no fortification Fe) who consumed wheat-based biscuits 5 d per week. At baseline and 22 weeks, Hb, SF, transferrin receptor, urinary iodine and body Fe stores were measured. Relative to control, mean SF in the encapsulated FeSO4 group increased by 88 % (P < 0.001) and body Fe stores increased from - 0.96 to 2.24 mg/kg body weight (P < 0.001), while NutraFine RS did not significantly increase SF or body Fe stores. The median urinary iodine concentration increased from 140 to 213 microg/l (P < 0.01). NutraFine RS added at double the amount of Fe as FeSO4 was not efficacious in improving Fe status. The newly developed microcapsules were highly efficacious in improving both Fe stores and iodine status.