Iron biology in immune function, muscle metabolism and neuronal functioning.
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The estimated prevalence of iron deficiency in the world suggests that there should be widespread negative consequences of this nutrient deficiency in both developed and developing countries. In considering the reality of these estimates, the Belmont Conference seeks to reconsider the accepted relationships of iron status to physiological, biochemical and neurological outcomes. This review focuses on the biological processes that we believe are the basis for alterations in the immune system, neural systems, and energy metabolism and exercise. The strength of evidence is considered in each of the domains and the large gaps in knowledge of basic biology or iron-dependent processes are identified. Iron is both an essential nutrient and a potential toxicant to cells; it requires a highly sophisticated and complex set of regulatory approaches to meet the demands of cells as well as prevent excess accumulation. It is hoped that this review of the more basic aspects of the biology of iron will set the stage for subsequent in-depth reviews of the relationship of iron to morbidity, mortality and functioning of iron-deficient individuals and populations. (+info)
Is There a Causal Relationship between Iron Deficiency or Iron-Deficiency Anemia and Weight at Birth, Length of Gestation and Perinatal Mortality?
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An extensive literature review was conducted to identify whether iron deficiency, iron-deficiency anemia and anemia from any cause are causally related to low birth weight, preterm birth or perinatal mortality. Strong evidence exists for an association between maternal hemoglobin concentration and birth weight as well as between maternal hemoglobin concentration and preterm birth. It was not possible to determine how much of this association is attributable to iron-deficiency anemia in particular. Minimal values for both low birth weight and preterm birth occurred at maternal hemoglobin concentrations below the current cut-off value for anemia during pregnancy (110 g/L) in a number of studies, particularly those in which maternal hemoglobin values were not controlled for the duration of gestation. Supplementation of anemic or nonanemic pregnant women with iron, folic acid or both does not appear to increase either birth weight or the duration of gestation. However, these studies must be interpreted cautiously because most are subject to a bias toward false-negative findings. Thus, although there may be other reasons to offer women supplemental iron during pregnancy, the currently available evidence from studies with designs appropriate to establish a causal relationship is insufficient to support or reject this practice for the specific purposes of raising birth weight or lowering the rate of preterm birth. (+info)
The developmental and probabilistic nature of the functional consequences of iron-deficiency anemia in children.
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It is often assumed that the psychometric tools currently available measure accurately the effects of iron-deficiency anemia (IDA) on cognition in young children and that such effects are rooted in cerebral changes. It is also assumed that snapshots of development within a clinical trial can document such effects. I challenge these assumptions on the basis of four considerations. The first is that there are multiple biological, physical and social-psychological factors that reorient the trajectory of different psychobiological domains in early life after intense and prolonged stress. Further, psychobiological development changes are not necessarily caused by brain changes; there are other mechanisms that also affect development (e.g., biomechanics). A second consideration focuses on intraindividual, interindividual and intergroup differences concerning the nature of the effect of IDA and the response to iron treatment. Individual and group factors can moderate the effects of IDA; for example, different stages of iron deficiency involve different systemic changes, which in turn affect different psychobiological domains. The third consideration is that differences in the time of measurement of an intervention within a randomized trial could lead to detecting effects in different domains or effects of different intensity within the same domain. Finally, developmental assessments with the traditional developmental scales during the first 18 mo of life yield equivocal findings. Snapshots of development will overlook the course of effects of a nutrition intervention over time. Repeated measures over time within the same domain are considered particularly useful to draw the course of development. (+info)
Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship.
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The causal relationship between iron deficiency and physical work capacity is evaluated through a systematic review of the research literature, including animal and human studies. Iron deficiency was examined along a continuum from severe iron-deficiency anemia (SIDA) to moderate iron-deficiency anemia (MIDA) to iron deficiency without anemia (IDNA). Work capacity was assessed by aerobic capacity, endurance, energetic efficiency, voluntary activity and work productivity. The 29 research reports examined demonstrated a strong causal effect of SIDA and MIDA on aerobic capacity in animals and humans. The presumed mechanism for this effect is the reduced oxygen transport associated with anemia; tissue iron deficiency may also play a role through reduced cellular oxidative capacity. Endurance capacity was also compromised in SIDA and MIDA, but the strong mediating effects of poor cellular oxidative capacity observed in animals have not been demonstrated in humans. Energetic efficiency was affected at all levels of iron deficiency in humans, in the laboratory and the field. The reduced work productivity observed in field studies is likely due to anemia and reduced oxygen transport. The social and economic consequences of iron-deficiency anemia (IDA) and IDNA have yet to be elucidated. The biological mechanisms for the effect of IDA on work capacity are sufficiently strong to justify interventions to improve iron status as a means of enhancing human capital. This may also extend to the segment of the population experiencing IDNA in whom the effects on work capacity may be more subtle, but the number of individuals thus affected may be considerably more than those experiencing IDA. (+info)
O2 dependence of K+ transport in sickle cells: the effect of different cell populations and the substituted benzaldehyde 12C79.
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The molecular basis of sickle cell disease (SCD) is well known but the pathophysiology is poorly understood. It remains intractable to therapy. Hyperactivity of several membrane transport systems, including the K+-Cl- cotransporter (termed KCC), cause HbS-containing red cells (termed HbS cells) to dehydrate and sickle, leading to the development of sickle cell crises (SCCs). Contrary to normal red cells (HbA cells), KCC in HbS cells is active at low O2 tensions (PO2s), remaining responsive to low pH or urea. Since these stimuli are usually encountered in hypoxic regions, the abnormal O2 dependence increases the contribution of KCC to dehydration, and hence development of SCCs. These differences with HbA cells may be due to the younger population of cells or to polymerization of HbS. We used 86Rb+ as a K+ congener to investigate the activity of KCC at different PO2s, and density gradient separation to investigate different red cell fractions. We found no correlation of O2 dependence with cell fractions. We also used the substituted benzaldehyde 12C79 to increase the O2 affinity of HbS and found that its effect on HbS O2 saturation and cell sickling correlated with that on both Cl--independent and Cl--dependent K+ transport, implying that, at low PO2s, KCC activity correlated with HbS polymerization. The importance of these results to understanding the pathophysiology of SCD, and for the design of chemotherapeutic agents to ameliorate or prevent SCC, is discussed. (+info)
Anesthetic-like interactions of nitric oxide with albumin and hemeproteins. A mechanism for control of protein function.
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Noncovalent bonding interactions of nitric oxide (NO) with human serum albumin (HSA), human hemoglobin A, bovine myoglobin, and bovine cytochrome c oxidase (CcO) have been explored. The anesthetic nitrous oxide (NNO) occupies multiple sites within each protein, but does not bind to heme iron. Infrared (IR) spectra of NNO molecules sequestered within albumin, with NO present, support the binding of NO and NNO to the same sites with comparable affinities. Perturbations of IR spectra of the Cys(34) thiol of HSA indicate NO, NNO, halothane, and chloroform can induce similar changes in protein structure. Experiments evaluating the relative affinities of binding of NO and carbon monoxide (CO) to iron(II) sites of the hemeproteins led to evidence of NO binding to noniron, nonsulfur sites as well. With HbA, IR spectra of cysteine thiols and/or the iron(II) N-O stretching region denote changes in protein structure due to NO, NNO, or CO occupying noniron sites with an order of decreasing affinities of NO > NNO > CO. Loss of NO from some, not all, noniron sites in hemeproteins is very slow (t(1/2) approximately hours). These findings provide examples in which NO and anesthetics alter the structure and properties of protein similarly, and support the hypothesis that some physiological effects of NO (and possibly CO) result from anesthetic-like noncovalent bonding to sites within protein or other tissue components. Such bonding may be involved in mechanisms for control of oxygen transport, mitochondrial respiration, and activation of soluble guanylate cyclase by NO. (+info)
The Bohr effect of hemoglobin intermediates and the role of salt bridges in the tertiary/quaternary transitions.
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Understanding mechanisms in cooperative proteins requires the analysis of the intermediate ligation states. The release of hydrogen ions at the intermediate states of native and chemically modified hemoglobin, known as the Bohr effect, is an indicator of the protein tertiary/quaternary transitions, useful for testing models of cooperativity. The Bohr effects due to ligation of one subunit of a dimer and two subunits across the dimer interface are not additive. The reductions of the Bohr effect due to the chemical modification of a Bohr group of one and two alpha or beta subunits are additive. The Bohr effects of monoliganded chemically modified hemoglobins indicate the additivity of the effects of ligation and chemical modification with the possible exception of ligation and chemical modification of the alpha subunits. These observations suggest that ligation of a subunit brings about a tertiary structure change of hemoglobin in the T quaternary structure, which breaks some salt bridges, releases hydrogen ions, and is signaled across the dimer interface in such a way that ligation of a second subunit in the adjacent dimer promotes the switch from the T to the R quaternary structure. The rupture of the salt bridges per se does not drive the transition. (+info)
Conformation-specific antibodies to the alpha chain COOH terminus of hemoglobin A0.
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An anti-hemoglobin antiserum obtained from a sheep immunized with human carboxyhemoglobin A0 demonstrated little difference in its reactivity with deoxy- or carboxyhemoglobin A0. However, a subpopulation of this antiserum isolated by synthetic peptide affinity chromatography clearly distinguished between these two hemoglobin species. This subpopulation, designated alpha(129-141) anti-hemoglobin antibodies, represents less than 1% of the total anti-hemoglobin antibodies. They are nonprecipitating by Ouchterlony analysis, and fluorescence-quenching studies demonstrate the interaction of a single antibody binding site per hemoglobin dimer. These antibodies bind preferentially to carboxyhemoglobin with a median affinity constant of 5 X 10(8) M-1 compared to binding to deoxyhemoglobin with a binding affinity of less than 1 X 10(8) M-1. Furthermore, the presence of these antibodies in stoichiometric amounts increases the oxygen affinity of hemoglobin, and thus antibody and oxygen binding to hemoglobin can be considered as a linked function. (+info)