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Aim: As part of a longitudinal nutrition study of adolescents, changes in serum ferritin (s-Ft), serum transferrin receptors (s-TfR) and the TfR/Ft ratio from 15 to 21 y of age were studied in randomly selected Swedish adolescents.Methods: Blood samples from 60 males and 66 females were drawn at 15, 17 and 21 y of age.Results: In males, median s-Ft increased significantly from 33 microg l(-1) at 15 y to 96 microg l(-1) at 21 y, and in females, after a non-significant decrease at 17 y, from 27 at 15 y to 34 microg l(-1) at 21 y. Between 15 and 17 y, s-TfR increased significantly, in males from 5.9 to 7.7 microg l(-1), and in females from 5.2 to 7.6 microg l(-1), whereas s-TfR decreased significantly in both genders between 17 and 21 y. The log (TfR/Ft) ratio did not change in males between 15 and 17 y, but decreased significantly from 2.2 +/- 0.3 to 1.8 +/- 0.3 by the age of 21 y. In females, the TfR/Ft ratio increased significantly between 15 and 17 y, whereas a significant decrease was found by the age of 21 y. S-Ft <12 microg l(-1) at 15, 17 and 21 y was 3, 2 and 2% in males, and in females 18, 26 and 21%, respectively.Conclusion: This study shows an increase in s-Ft and a decline in s-TfR in males, indicating increased iron stores. In females, s-Ft did not increase significantly, whereas s-TfR and the TfR/Ft ratio decreased between 17 and 21 y, indicating that cellular iron needs were met. [ABSTRACT FROM AUTHOR]

Unlabelled: Serum ferritin and serum transferrin receptor concentrations, growth and food habits were studied in healthy Swedish boys (n = 103) and girls (n = 124) at the age of 17 y and compared with those in the same adolescents at age 15. Between these ages, serum transferrin receptor increased significantly in both boys and girls. Serum ferritin increased significantly in boys but not in girls. The transferrin receptor/ferritin ratio increased significantly in girls but not in boys, indicating insufficient iron stores in the 17-y-old girls in relation to erythropoiesis and iron needs. Between 15 and 17 y the boys' frequency of consumption of milk and bread decreased, while they more often consumed pasta, cheese and coffee. The girls decreased their frequency intake of fat products, milk and meat. The frequency of meat consumption emerged as the single significant predictor for serum ferritin <12 microg/L in girls, but not in boys. The median daily iron intake, determined in a subsample, decreased in boys from 18.7 to 13.6 mg and in girls from 14.1 to 8.8 mg, and the decrease was to a large extent due to cessation of iron fortification of flour.Conclusions: The results indicate insufficient iron stores in the 17-y-old girls in relation to erythropoiesis and iron needs, but more favourable iron stores in the boys. The absence of a significant decrease in mean serum ferritin despite rapid growth suggests that the earlier iron fortification of flour only marginally contributed to the iron status of Swedish adolescents of this age group. [ABSTRACT FROM AUTHOR]

The Wnt/beta-catenin/TCF4 pathway plays critical roles in the maintenance of small intestinal epithelium; however, downstream targets of the beta-catenin/TCF4 complex are not extensively characterized. We identified miR-30e as an immediate target activated by the beta-catenin/TCF4 complex. miR-30e was detected in the peri-nuclear region of the intestinal crypt IEC-6 cells. Bioinformatics analysis revealed clustered beta-catenin/TCF4 binding sites within the miR-30e promoter region. This promoter region was cloned into pGL3-control luciferase reporter vector, with the enhancer region removed. Transfection of pCMV-SPORT6-beta-catenin expression vector dose-dependently increased luciferase activity, and co-transfection of pCMV-SPORT6-TCF4 expression vector further enhanced the promoter activity. Dexamethasone-induced IEC-6 cells differentiation caused a 2.5-fold increase in miR-30e expression, and upon beta-catenin siRNA transfection, miR-30e increased 1.3-fold. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed the binding between beta-catenin/TCF4 complexes from IEC-6 nuclear extracts and the putative sequences in the miR-30e promoter. These results demonstrate that beta-catenin/TCF4 transactivates miR-30e during intestinal cell differentiation. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs function as gene expression modulators that are critical for mammalian development. Lactoferrin receptor on the apical membrane of enterocytes has been suggested to play key roles in the absorption of lactoferrin-bound iron from breast milk. The objective of this study was to identify mechanisms of microRNA mediated post-transcriptional regulation of the lactoferrin receptor. Sequence analyses revealed that the miR-584 sequence is identical in human, mouse and rat, and there is a conserved region complementary to the seed region (5′ nucleotides 2–8) of miR-584 within the lactoferrin receptor mRNA-3′-untranslated region. miR-584 was further found to co-localize with lactoferrin receptor mRNA in mouse small intestine. The 3′-untranslated region of human lactoferrin receptor mRNA was cloned into pGL3-control luciferase reporter vector. By luciferase reporter assays in HEK293 cells, miR-584 mimic specifically repressed the reporter activity in a dose-dependent manner. miR-584 mimic reduced endogenous lactoferrin receptor protein expression in Caco-2 cells, without significantly affecting the mRNA level. We also determined that miR-584 expression is inversely correlated with lactoferrin receptor mRNA and protein expression. Taken together, we propose that miR-584 contributes to the post-transcriptional expression of lactoferrin receptor during the perinatal period. These findings demonstrate a novel example of how microRNAs may be involved in regulation of nutrient metabolism in the newborn. [Copyright &y& Elsevier]

Marginal zinc deficiency and suboptimal zinc status have been recognized in many groups of the population in both less developed and industrialized countries. Although the cause in some cases may be inadequate dietary intake of zinc, inhibitors of zinc absorption are most likely the most common causative factor. Phytate, which is present in staple foods like cereals, corn and rice, has a strong negative effect on zinc absorption from composite meals. Inositol hexaphosphates and pentaphosphates are the phytate forms that exert these negative effects, whereas the lower phosphates have no or little effect on zinc absorption. The removal or reduction of phytate by enzyme (phytase) treatment, precipitation methods, germination, fermentation or plant breeding/genetic engineering markedly improves zinc absorption. Iron can have a negative effect on zinc absorption, if given together in a supplement, whereas no effect is observed when the same amounts are present in a meal as fortificants. Cadmium, which is increasing in the environment, also inhibits zinc absorption. The amount of protein in a meal has a positive effect on zinc absorption, but individual proteins may act differently; e.g., casein has a modest inhibitory effect of zinc absorption compared with other protein sources. Amino acids, such as histidine and methionine, and other low-molecular-weight ions, such as EDTA and organic acids (e.g., citrate), are known to have a positive effect on zinc absorption and have been used for zinc supplements. Knowledge about dietary factors that inhibit zinc absorption and about ways to overcome or remove these factors is essential when designing strategies to improve the zinc nutrition of vulnerable groups. [ABSTRACT FROM AUTHOR]

A significant problem in diagnosing infants and young children with iron deficiency (ID) and iron deficiency anemia (IDA) is that it is not clear how the biochemical markers used correspond to physiological outcomes such as growth, neurodevelopment and morbidity. Thus, the prevalence of iron deficiency and iron deficiency anemia in infants and young children is difficult to assess and therefore not really known. Conclusion: Recent studies have shown that iron metabolism is subjected to developmental changes during infancy, which affect indicators of iron status. Hence, better defined cut-off values for the indicators used are needed and, in particular, how they are correlated to functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Phytate decreases iron and zinc bioavailability and contributes to deficiencies of iron and zinc, potentially causing anaemia, poor psychomotor development, impaired growth and increased risk of diarrhoea and respiratory infections.Aim: To investigate whether a reduced dietary intake of phytate, either via extensively phytate-reduced infant cereals [milk cereal drinks (MCDs) and porridge] or a milk-based infant formula, would improve growth and development and reduce morbidity in infants.Design: Infants (n = 300) were, in a double-blind design, randomized to three diet intervention groups from 6 to 12 mo of age-commercial MCD and porridge (CC group), phytate-reduced MCD and phytate-reduced porridge (PR group), or milkbased infant formula and porridge with regular phytate content (IF group)-then followed until 18 mo. Dietary intake, anthropometry, development (Bayley Scales of Infant Development) and episodes of infectious diseases were registered.Results: There were no significant differences between study groups in growth, development or morbidity until 12 mo of age. The IF group had a 77% higher risk (95% CI: 1.05-2.97) of diarrhoea compared to the PR group during the 12-17-mo period. Infants with haemoglobin concentration (Hb) < 110 g/l at 12 mo had lower attained weight at 18 mo (11.14 kg vs 11.73 kg, p = 0.012). Infants with serum zinc (S-Zn) <10.7 pmol/l at 12 mo had higher risk of respiratory infections (RR = 1.74, 95% CI: 1.19-2.56) compared to controls.Conclusion: Phytate reduction had no effect on growth, development or incidence of diarrhoeal or respiratory infections. Infants with low Hb or low S-Zn may be at higher risk of poor growth and respiratory infections, even in this high-income population. [ABSTRACT FROM AUTHOR]

Mammalian lactoferrin (Lf) receptors are suggested to have pivotal roles for mediating multiple functions of Lf. In this review, we focus on current knowledge of the structure and function of mammalian Lf receptors, mainly the first cloned Lf receptor that has been shown to be expressed in the infant small intestine at high levels but also in virtually all other tissues. The small intestinal Lf receptor takes up iron from Lf into cells and presumably exerts other physiological functions. Other Lf receptors in various tissues have also been reported to mediate some functions of Lf, such as modulating immune function, inhibiting platelet aggregation and enhancing collagen gel contractile strength. The detailed mechanisms behind the receptor-Lf interactions still need to be elucidated. [ABSTRACT FROM AUTHOR]

Objective: To study the prevalence of anaemia and its association with measures of iron deficiency (ID) among a group of pregnant women.Design: Cross-sectional survey.Setting: Pregnant women identified through house-to-house visits and participating in community-based antenatal care activities in a rural location of Mymensingh, Bangladesh.Subjects: The estimates are based on 214 reportedly healthy pregnant women in their second trimester. Information on socio-economic status and reproductive history were obtained through home visits and venous blood samples were collected at antenatal care centres. Haemoglobin concentration (Hb) was measured by HemoCue, serum ferritin (sFt) by radioimmunoassay and serum transferrin receptor (sTfR) by enzyme-linked immunosorbent assay methods. ID was defined as presence of either low sFt (<12 microg l(-1)) or high sTfR (>8.5 mg l(-1)).Results: The prevalence of anaemia (Hb <110 g l(-1)) was 50%, but severe anaemia (Hb <70 g l(-1)) was absent. Low sFt was observed in 42%, high sTfR in 25%, either low sFt or high TfR in 54% and both low sFt and high TfR in 13% of the pregnant women. Two out of three anaemic women had an indication of ID, which was present in 80% of women with moderate (Hb 70-99 g l(-1)) and 50% with mild (Hb 100-109 g l(-1)) anaemia. Four out of 10 non-anaemic women (Hb >/=110 g l(-1)) also had ID, but the prevalence was significantly lower than that observed in anaemic women (P=0.001).Conclusions: Despite the high prevalence of anaemia, severe cases were absent. The prevalence of ID increased at lower Hb. However, an increased prevalence was also found among women in the highest category of Hb. [ABSTRACT FROM AUTHOR]

Abstract: Experimental studies indicate that zinc (Zn) and calcium (Ca) status, in addition to iron (Fe) status, affect gastrointestinal absorption of cadmium (Cd), an environmental pollutant that is toxic to kidneys, bone and endocrine systems. The aim of this study was to evaluate how various nutritional factors influence the uptake of Cd in women, particularly during pregnancy. The study was carried out in a rural area of Bangladesh, where malnutrition is prevalent and exposure to Cd via food appears elevated. The uptake of Cd was evaluated by associations between erythrocyte Cd concentrations (Ery-Cd), a marker of ongoing Cd exposure, and concentrations of nutritional markers. Blood samples, collected in early pregnancy and 6 months postpartum, were analyzed by inductively coupled plasma mass spectrometry (ICPMS). Ery-Cd varied considerably (range: 0.31–5.4μg/kg) with a median of 1.1μg/kg (approximately 0.5μg/L in whole blood) in early pregnancy. Ery-Cd was associated with erythrocyte manganese (Ery-Mn; positively), plasma ferritin (p-Ft; negatively), and erythrocyte Ca (Ery-Ca; negatively) in decreasing order, indicating common transporters for Cd, Fe and Mn. There was no evidence of Cd uptake via Zn transporters, but the association between Ery-Cd and p-Ft seemed to be dependent on adequate Zn status. On average, Ery-Cd increased significantly by 0.2μg/kg from early pregnancy to 6 months postpartum, apparently due to up-regulated divalent metal transporter 1 (DMT1). In conclusion, intestinal uptake of Cd appears to be influenced either directly or indirectly by several micronutrients, in particular Fe, Mn and Zn. The negative association with Ca may suggest that Cd inhibits the transport of Ca to blood. [Copyright &y& Elsevier]

Intestinal zinc (Zn) absorption and liver Zn mobilization are presumed to regulate Zn homeostasis. Several Zn transporters have been identified; however, their contribution to Zn homeostasis is poorly understood. Moreover, their regulation during periods of growth is unknown. To characterize the mechanisms that maintain Zn status, weanling rats were fed control (25 mg/kg), marginally low (MLZ; 15 mg/kg), low (LZ; 7 mg/kg), or very low (VLZ; <1 mg/kg) Zn diets for 3 wk and effects on jejunum Zip4 and ZnT1 and hepatic Zip1 and ZnT1 were assessed. Another control group was pair-fed (PF) to VLZ. The MLZ rats had lower jejunum ZnT1 protein abundance than the control. In the LZ group, we detected increased jejunum Zip4 mRNA expression and hepatic ZnT1 protein abundance and reduced jejunum Zip4 and ZnT1 and hepatic Zip1 protein abundance. VLZ had lower jejunum ZnT1 mRNA and protein abundance and hepatic Zip1 and ZnT1 protein abundance compared with the PF group. Zip4 protein was present at the intestinal villus tip in controls but was detected on the apical membrane throughout the entire villus in LZ rats. ZnT5 protein in jejunum was always detected at the apical membrane and also at the basolateral membrane of VLZ rats. In contrast, ZnT7 was found intracellularly in jejunum. Our data suggest that effects of Zn deficiency on Zn homeostasis occurs biphasically during marginal Zn deficiency through increased intestinal Zn uptake capacity and reduced intestinal Zn efflux, then during more pronounced degrees of Zn deficiency through decreased liver Zn accretion and increased hepatic Zn efflux back into circulation. These results assist in our understanding of how mammals regulate Zn homeostasis. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To examine effects of iron supplementation on vigilance, attention and conceptual learning in preschool children in Greece. DESIGN:: Randomized Double-Blind Placebo Controlled trial of iron. Randomization stratified by iron status and day care center (DCC). SETTING:: Nine public DCCs in Athens, Greece. SUBJECTS:: In all, 49 3-4-y olds (21 anemic, 28 good iron status) with birth weight not less than 2500?g, currently healthy; benign past medical history, IQ=1 s.d. below the age-adjusted mean, serum Pb=200?ppb (none exceeded 50?ppb), and height, weight and head circumference for age=10th percentile. Anemia defined as: (1) pretreatment Hgb<112?g/l and TS<16%and ferritin<12?µg/L OR (2) Hgb rise of>10?g/l (T2-T0) with iron supplementation. Good iron status was defined as baseline levels of Hgb>120?g/l and either TS>20%or serum ferritin>12?µg/l. INTERVENTION:: The intervention consisted of a 2-month supplementation of 15?mg iron (and MV) vs placebo (MV alone). RESULTS:: After iron treatment, the anemic subjects made significantly fewer errors of commission (14%higher specificity, P<0.05), exhibited 8%higher accuracy (P<0.05) and were significantly more efficient (mean difference=1.09, P<0.05) than those given placebo. These effects of iron were not found among preschoolers with good iron status. No effects of iron treatment were found on the Oddity Learning task. CONCLUSIONS:: This study demonstrated that iron supplementation of iron-deficient anemic preschoolers results in an improvement in discrimination, specifically selective attention. SPONSORSHIP:: University of California, Davis and Nutricia Corporation.European Journal of Clinical Nutrition (2004) 58, 1532-1542. doi:10.1038/sj.ejcn.1602005 Published online 30 June 2004 [ABSTRACT FROM AUTHOR]

Marginal zinc or vitamin A intake is more common than previously thought in industrialized and developing countries, with pregnant and lactating women believed to be particularly at risk. However, the lack of sensitive indicators of zinc and vitamin A status precludes accurate assessment of marginal nutriture. Concurrent deficiencies in zinc and vitamin A intake often coexist, and the interaction between zinc deficiency and vitamin A metabolism may confound results from epidemiologic or intervention studies. To investigate effects of a maternal diet chronically restricted in zinc or vitamin A intake on indices of vitamin A metabolism, we fed rats a control diet (C) or a diet marginal in zinc (ZD), marginal in vitamin A (AD), marginal in both (DD) or pair-fed to DD (PF), preconception through lactation. Plasma retinol (ROH) was greater and retinol binding protein (RBP) was lower in rats fed ZD, AD and DD compared with those fed C. Hepatic cellular retinol binding protein (CRBP) expression was greater than controls in rats fed ZD and AD and lower in those fed DD, whereas RBP expression was greater in the DD- and PF-fed groups compared with rats C. Mammary gland CRBP and RBP expression were not affected by the diets. Milk ROH was lower in rats fed AD, and milk RBP was lower in those fed ZD and DD compared with rats fed C. In summary, chronic, marginal intake of zinc or vitamin A resulted in alterations in tissue retinol metabolism and milk retinol levels without decreasing plasma zinc, retinol or ROH:RBP during lactation. These observations are of concern because these parameters, which are commonly used to assess zinc and vitamin A status, may lead to misassessment of marginal zinc or vitamin A nutriture in some human populations. [ABSTRACT FROM AUTHOR]

Several cases of zinc (Zn) deficiency in human infants caused by abnormally low concentrations of Zn in breast milk were recently reported, the underlying mechanism of which is not known. Alpha2-macroglobulin (alpha2-M), a major Zn-binding ligand in serum, presents a potential vehicle for mammary Zn uptake. This study was conducted to determine if an alpha2-M receptor is present in human mammary epithelial cells, where it may be involved in the endocytosis of alpha2-M into the mammary gland. Normal human mammary epithelial cells were grown to confluency in serum-free medium. For all binding and uptake studies, alpha2-M, preactivated with methylamine and labeled with 125I, was added to cells for varied lengths of time to determine saturation over time and at varied concentrations to determine saturation over increasing concentration of ligand. Nonspecific and competitive binding were measured by addition of a 100-fold molar excess of unlabeled alpha2-M and serum albumin or lactoferrin, respectively. Binding at 4 degreesC was specific for alpha2-M and approached saturation kinetics at 56 nmol/L. Scatchard plot analysis of the binding data demonstrated more than one binding site: a high affinity, saturable binding site and a low affinity, nonsaturable binding site. Uptake of alpha2-M at 37 degreesC was rapid and continuous over increasing concentrations of alpha2-M, and internalized alpha2-M was rapidly degraded. Results from this study present evidence for receptor-mediated uptake of alpha2-M in human mammary epithelial cells, which in turn, provides a potential mechanism for Zn acquisition by the cell. [ABSTRACT FROM AUTHOR]

Children with or without cow's milk protein intolerance were investigated for serum antibodies to native cow's milk proteins, processed cow's milk proteins and native- and pepsin-digested β-lactoglobulin. Antibodies of IgG and IgA isotypes were determined with ELISA and those of IgE isotype with RAST. Children who exhibited slowly appearing untoward reactions to cow's milk feeding had significantly higher titres of IgG antibodies against both native and digested β-lactoglobulin than children with an immediate type of reaction or no intolerance. The IgG antibodies to pepsin-digested β-lactoglobulin were efficiently inhibited by native β-lactoglobulin even at low concentrations, which suggests that there were no antibodies specific for the degraded proteins. The children with slow reactions to cow's milk also tended to have higher antibody levels of the IgG and IgA isotypes to both native and processed cow's milk. Antibodies to this mix of antigens discriminated less well, however, than the antibodies to isolated β-lactoglobulin between the groups of children with slowly appearing reactions, with immediate reactions and the controls. Seven out of nine children with an immediate type of reaction to cow's milk protein had IgE antibodies against cow's milk protein determined with the RAST, while this type of antibodies could not be demonstrated in any child in the two other groups. Using processed or digested protein as antigen did not increase the sensitivity of the antibody determinations. [ABSTRACT FROM AUTHOR]

The impact of zinc supplementation on the growth and body composition of Guatemalan infants was assessed in a community-based, double-blind intervention trial. Infants aged 6-9 mo were assigned randomly to receive 4 mL of a beverage containing 10 mg of zinc as zinc sulfate (n = 45) or a placebo (n = 44) daily (7 d/wk) for an average of 6.9 mo. The children's weight, length, mid-upper arm and head circumferences, and triceps skinfolds were measured at baseline and at 1-2 mo intervals until the end of supplementation. Midarm muscle area (MMA) was derived from the mid-upper arm circumference and triceps skinfolds measurements. Maternal anthropometry and family socioeconomic and demographic characteristics also were obtained. Zinc supplementation was associated with an overall increase of 0.61 cm2 in MMA (P = 0.02). Children who received zinc supplements had a mean length increment that was 0.75 cm greater than those who did not (P = 0.12). However, there was a significant interaction between treatment group and initial length-for-age status (P = 0.04), such that supplemented children who were stunted at baseline (length-for-age Z score less than -2) gained 1.40 cm more than stunted children who received the placebo. We conclude that zinc supplementation of these rural Guatemalan infants during 6. 9 mo increased accretion of fat-free mass and enhanced the linear growth of those who were stunted at baseline. Further research is required to determine whether zinc supplementation during longer periods of time may achieve larger and more generalized effects on physical growth. [ABSTRACT FROM AUTHOR]