Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain

Intrauterine growth retardation and diabetes mellitus during human gestation result in significant losses of fetal and neonatal brain iron. Brain iron deficiency is associated with impaired cognitive processes including memory and attention. The regional distribution of iron staining and cytochrome c oxidase (CytOx) activity have not been mapped in the iron-sufficient or -deficient neonatal rat. CytOx is the iron-containing terminal enzyme in oxidative phosphorylation; its activity reflects neuronal metabolism. We hypothesized that neonatal brain iron deficiency differentially decreases iron and CytOx activity in brain regions, with more pronounced losses in structures involved in recognition memory. Pregnant Sprague Dawley rats were fed either an iron-deficient or -fortified diet from gestational d 1 until postnatal d 10. Iron staining and CytOx activity of 20 brain structures were mapped histochemically in 25 rats from each group. Brain iron staining was reduced from 75% to 100% and CytOx staining was decreased from 0% to 42% in the iron deficient group (p < 0.001). Areas with significantly reduced CytOx activity (p < 0.001) included all measured subareas of the hippocampus (CA1: 42%, CA3ab: 34%, CA3c: 33%, and dentate gyrus: 32%), the piriform cortex (17%), the medial dorsal thalamic nucleus (28%), and the cingulate cortex (41%). In contrast, the anterior thalamic nucleus, the lateral amygdaloid nucleus, and the medial habenula, areas not involved in higher cognitive functions, did not have significantly reduced CytOx activity (0%, 10%, and 16%, respectively). We conclude that perinatal iron deficiency differentially reduces neuronal metabolic activity, specifically targeting areas of the brain involved in memory processing.     

Effects of iron deficiency anemia on hemoglobin A1c in type 1 diabetes mellitus

BACKGROUND: The relationship between hemoglobin A1c (HbA1c) and iron status in type 1 diabetes mellitus (DM) has not been adequately studied. In this prospective investigation, we aimed to determine the effect of iron deficiency on HbA1c in diabetic patients who also had insufficient iron stores. METHODS: Thirty-seven patients with type 1 DM were included in the study. Eleven of them were also iron deficient (ID) and the remaining 26 were iron-sufficient (IS). Two non-diabetic control groups were selected for the ID and IS groups. All patients with ID were treated with iron at 6 mg/kg per day for 3 months. Glycemia in diabetic patients was monitored at home before breakfast and supper by a glycometer. Hemoglobin A1c was measured in all subjects at the beginning and the end of the study. RESULTS: Patients with ID DM had higher levels of HbA1c than those in the control group (P < 0.001). There were no significant differences in the weekly average glucose concentration of the patients with ID DM before and after iron supplementation. In contrast, HbA1c decreased from a mean of 10.1 +/- 2.7% to a mean of 8.2 +/- 3.1% (P < 0.05). Additionally, HbA1c in ID non-diabetic patients decreased from a mean of 7.6 +/- 2.6% to 6.2 +/- 1.4% after iron therapy (P < 0.05). CONCLUSIONS: We conclude that among type 1 DM patients with similar level of glycemia, iron deficiency anemia is associated with higher concentrations of HbA1c. In addition, iron replacement therapy leads to a drop in HbA1c in both diabetic and non-diabetic patients. The iron status of the patient must be considered during the interpretation of HbA1c concentrations in type 1 DM.     

铁缺乏对早产儿神经发育影响的研究进展

铁缺乏是儿童最常见的微量营养素缺乏性疾病,早产儿出生时铁储备不足,加上生后快速的追赶性生长,缺铁的发生率更高。在脑发育关键期,铁缺乏通过改变铁依赖的神经代谢、神经化学、神经解剖以及基因/蛋白组分,影响中枢神经系统,最终导致神经认知和行为发育改变。婴幼儿期的铁剂补充无法恢复围产期缺铁对神经发育的负性影响。缺铁对神经系统发育的影响具有时间、区域特异性,对高危人群应该早期诊断,尽早给予适宜铁剂治疗,对于早产儿脑功能的恢复、生存质量的提高、远期预后的改善具有十分重要的意义。     

Neurodegeneration,neuronal loss,and neurotransmitter changes in the adult guinea pig with perinatal asphyxia

There is only limited morphologic information on long-term alterations and neurotransmitter changes after perinatal asphyxia, and no long-term study showing neurodegeneration has been reported so far. We used an animal model for perinatal asphyxia well documented in the rat to investigate the guinea pig as a species highly mature at birth. Cesarean section was performed on full-term pregnant guinea pigs, and pups, still in membranes, were placed into a water bath at 37 degrees C for asphyxia periods from 2 to 4 min. Thereafter pups were given to surrogate mothers and examined at 3 mo of age. We studied brain areas reported to be hypoxia-sensitive. Neurodegeneration was evaluated by fluoro-jade, neuronal loss by Nissl, reactive gliosis by glial fibrillary acidic protein staining, and differentiation by neuroendocrine-specific protein C immunoreactivity. We tested tyrosine hydroxylase, the vesicular monoamine transporter, and dopamine beta-hydroxylase, representing the monoaminergic system; the vesicular acetylcholine transporter; and the excitatory amino acid carrier 1. Neurodegeneration was evident in cerebellum, hippocampal area CA1, and hypothalamus, and neuronal loss could be observed in cerebellum and hypothalamus; gliosis was observed in cerebellum, hippocampus, hypothalamus, and parietal cortex; dedifferentiation was found in hypothalamus and striatum; and monoaminergic, cholinergic, and amino acidergic deficits were shown in several brain regions. The major finding of the present study was that neurodegeneration and dedifferentiation evolved in the guinea pig, a species highly mature at birth. The relevance of this contribution is that a simple animal model of perinatal asphyxia resembling the clinical situation of intrauterine hypoxia-ischemia and presenting with neurodegeneration was characterized.     

甲状腺功能低下对新生期大鼠海马神经元凋亡及Bcl-2、Bax基因表达的影响

目的　探讨甲状腺功能低下 (简称甲低 )对新生期大鼠海马神经元凋亡及Bcl 2、Bax基因表达的影响。方法　孕 15天SD大鼠丙基硫氧嘧啶 (5 0mg/d)灌胃造成仔鼠甲低动物模型。采用化学发光法测定 1、5、10、15日龄仔鼠血清FT3 及FT4水平。取各日龄海马组织 ,应用光镜和透射电镜观察神经元形态学特点 ,琼脂糖凝胶电泳检测DNA降解片段 ,WesternBlotting检测Bcl 2和Bax基因蛋白表达的变化。结果　模型仔鼠各日龄血清FT4水平始终接近于药盒检测限 (2 8nmol/L) ,显著低于对照仔鼠 (1、5日龄P均 <0 0 1;10、15日龄P均 <0 0 0 1) ;血清FT3 较同日龄对照仔鼠降低 (1日龄P <0 0 5 ;其他日龄P均 <0 0 1)。模型仔鼠海马组织光镜下变性神经元增多 ,透射电镜下神经元凋亡明显增加 ,以 10、15日龄为著。DNA片段分析显示模型仔鼠各日龄均出现不同程度的DNA降解片段 ,对照仔鼠仅在 10日龄可见少量DNA降解片段。WesternBlotting结果显示对照仔鼠Bcl 2蛋白各日龄间表达水平不同 (P <0 0 5 ) ,1、5日龄表达较高 ,10日龄有所下降 ,15日龄回升 ;各日龄模型仔鼠与对照组相比表达水平明显下降 (1日龄 1 95± 0 2 7比 2 5 9± 0 19,P <0 0 5 ;5日龄 1 86± 0 2 4比 2 4 7± 0 17,P <0 0 5 ;10日龄 1 2 9± 0 2 2比 1     

Short-term developmental outcome of iron prophylaxis in infants

BACKGROUND: Previous studies on the cognitive effects of iron treatment have focused on anemic or non-anemic iron-deficient infants. The effect of iron supplementation on cognitive development among iron-sufficient infants has not been studied. The aim of the present study was to examine the effect of iron supplementation on performance in the Bayley Scales of Infant Development (BSID) and anthropometric measurement in 6-month-old iron-sufficient healthy infants. METHODS: Healthy, iron-sufficient infants who were 6 months of age and were attending the Well Baby Clinic were considered for enrollment. Infants were randomly assigned to take ferrous sulfate supplementation (1 mg/kg per day) or no supplementation and were followed for 3 months. Anthropometric measurement, hematologic status and BSID were evaluated on admission and after 3 months. RESULTS: Seven infants in the intervention group and nine in the control group completed the study. No significant differences were observed in anthropometric measurements and complete blood counts between the two groups after the 3 month study period. The mean transferrin saturation (TS) level decreased significantly in the control group during the study period (from 15.3+/-2.6 to 7.8+/-5.1%; P = 0.0117), but no such reduction was seen in the intervention group. At the end of the study, the TS of the control group was found to be significantly lower than that of the intervention group (7.8+/-5.1 vs. 19.9+/-7.9%, respectively; P = 0.0033). The BSID scores of infants in both groups were within the normal range on admission and at the end of the study period. CONCLUSIONS: Short-term iron supplementation did not change developmental test scores despite the hematologic response in iron-sufficient healthy infants. The high prevelance of iron-deficiency anemia and its relationship with adverse developmental outcome suggests that prevention of iron-deficiency anemia with prophylaxis needs to be emphasized, rather than treatment.     

中国7个月～7岁儿童铁缺乏症流行病学的调查研究

目的　调查我国儿童铁减少 (ID)、缺铁性贫血 (IDA)及铁缺乏症患病率。方法　采用分层抽样的方法 ,以全国 15个省 ,2 6个市县为调查点 ,随机抽取 9118名 7个月～ 7岁儿童为调查对象 ,检测末梢血血红蛋白 (Hb)、锌原卟啉 (ZPP)、血清铁蛋白 (SF)等指标。结果　 7个月～ 7岁儿童ID32 5 %、IDA 7 8% ;7～ 12个月ID 4 4 7%、IDA 2 0 8% ;13～ 36个月ID 35 9%、IDA 7 8% ;37个月～ 7岁ID 2 6 5 %、IDA 3 5 %。不同年龄组儿童ID、IDA、铁缺乏症患病率由高到低依次为 7～ 12个月 (婴儿组 ) ,13～ 36个月 (幼儿组 ) ,37个月～ 7岁 (学前组 ) ,各年龄组差异有显著意义 (P <0 0 1)。农村婴儿组ID 35 8%、IDA 30 1%、Hb ( 98 8± 9 1)g/L ;城市婴儿组ID 4 8 1%、IDA 16 8%、Hb ( 10 1 0± 6 8)g/L。农村幼儿组ID 31 0 %、IDA 15 5 %、Hb ( 98 2± 10 5 )g/L ;城市幼儿组ID 38 0 %、IDA 4 4 %、Hb( 10 2 8± 6 9)g/L。农村学前儿童组ID 2 7 6 %、IDA 6 3%、Hb( 10 1 2± 8 6 )g/L ;城市学前儿童组ID2 6 0 %、IDA 1 9%、Hb( 10 4 2± 4 4 )g/L。农村 7个月～ 7岁儿童铁缺乏症患病率 4 2 0 % ,城市 7个月～ 7岁儿童铁缺乏症患病率 39 5 % (P <0 0 1)。城市婴儿和幼儿ID患病率显著高于农村 (P <0     

Perinatal corticosteroid effect on amygdala and hippocampus volume during brain development in the rat model

Exposure of the fetus to corticosteroid during brain development has been suggested to cause permanent change in brain structure and has been associated with long term cognitive, behavioral and emotional impairment. We evaluated the effect of perinatal corticosteroid, at a dose similar to that which human fetuses are exposed, on cerebral cortex, corpus collosum, hippocampus, dentate gyrus and amygdala in a rat model. Rat pups were given betamethasone at day 1 (P1). Brain sections from the rat pups at postnatal day 45 (P45) were then analyzed. No differences were noted in the volumes of cerebral cortex, corpus collosum, hippocampus, dentate gyrus, or three nuclei of the amygdala compared to the control and sham groups. We concluded that a single course of betamethasone, at a comparable dose to that which the human fetus is exposed in clinical practice, had no effect on these regional brain volumes at this stage of development.     

Granulocyte-colony stimulating factor alleviates perinatal hypoxia-induced decreases in hippocampal synaptic efficacy and neurogenesis in the neonatal rat brain

Using various animal models, studies have greatly expanded our understanding of perinatal hypoxia-induced neuronal injury in the newborn at the cellular/molecular levels. However, the synapse-basis pathogenesis and therapeutic strategy for such detrimental alterations in the neonatal brain remain to be addressed. We investigated whether the damaged synaptic efficacy and neurogenesis within hippocampal CA1 region (an essential integration area for mammalian learning and memory) of the neonatal rat brain after perinatal hypoxia were restored by granulocyte-colony stimulating factor (G-CSF) therapy. Ten-day-old (P10) rat pups were subjected to experimentally perinatal hypoxia. G-CSF (10, 30, or 50 μg/kg, single injection/d, P11-16) was s.c. administered to neonatal rats which were analyzed on P17. Perinatal hypoxia reduced the expression in pRaf-pERK1/2-pCREB(Ser-133) signaling, the synaptic complex of postsynaptic density protein-95 (PSD-95) with N-methyl-D-aspartate receptor (NMDAR) subunits (NR1, NR2A, and NR2B), synaptic efficacy, and neurogenesis. A representatively effective dosage of G-CSF (30 μg/kg) alleviated the perinatal hypoxia-induced detrimental changes and improved the performance in long-term cognitive function. In summary, our results suggest a novel concept that synaptic efficacy defects exist in the neonatal brain previously exposed to perinatal hypoxia and that G-CSF could be a clinical potential for the synapse-basis recovery in the perinatal hypoxia suffers.     

Lipopolysaccharide-induced preconditioning against ischemic injury is associated with changes in toll-like receptor 4 expression in the rat developing brain

Lipopolysaccharide (LPS) preconditioning reduces ischemic injury in adult brain by activating Toll-like receptor 4 (TLR-4). We sought to investigate the effect of brain maturity on the efficacy of LPS preconditioning against hypoxic-ischemic (HI) injury in the developing rat brain. Rat pups at the specified age were randomly assigned to LPS-treated (0.1 mg/kg) or saline-treated groups. HI injury was induced 48 h later by occluding the right common carotid artery followed by transient hypoxia. Brains were removed 1 wk after HI injury, and infarct volumes were compared between the two groups. TLR-4 expression was also compared among different ages. We found that LPS treated P7, P9, and P14 rat pups had significantly smaller infarct volume compared with saline-treated pups (p = 0.006, 0.03, and 0.01, respectively). This significant reduction in infarct volume was not observed in P3 and P5 rats. TLR-4 expression was significantly higher in older rats compared with P3 and P5 rats (p < 0.01). These findings indicate that LPS-induced preconditioning is a robust neuroprotective phenomenon in the ischemic developing brain that is age dependent. Pattern of TLR-4 expression is also affected by brain maturity and likely to be responsible for differences in the efficacy of LPS preconditioning.     

Developmental and Neurophysiologic Deficits in Iron Deficiency in Children

Introduction  

Several studies in animals and humans have clearly demonstrated the effect of ID on development, cognition, behavior and neurophysiology. The effect of ID have been shown: on brain metabolism, neurotransmitter function, and myelination. Changes in brain iron content caused by early ID in animals are not reversible by iron therapy, inspite of correction of anemia and other tissue deficits and result in changes in behavior which continue into adulthood. ID has repercussions in the perinatal period, infancy and childhood. Some effects are irreversible while other defects may be corrected: timing of ID in a child may be critical.     

Selective impairment of cognitive performance in the young monkey following recovery from iron deficiency

OBJECTIVE: While poor nutrition during development is an obvious concern, the magnitude and duration of the neural and cognitive deficits that occur after moderate iron deficiency in infancy have remained controversial. A nonhuman primate model of infancy anemia was refined to investigate the effects on cognitive performance. METHODS: Young rhesus monkeys that experienced a delimited period of iron deficiency were tested on a series of cognitive tasks following normalization of their hematological status. Beginning at 8 to 9 months of age, 2 months after weaning from their mothers and consumption of solid food, the previously iron-deficient (ID) monkeys (n = 17) were compared to age- and gender-matched, iron-sufficient (IS) (n = 27) monkeys on a series of three tests of cognitive performance. Using the Wisconsin General Testing Apparatus, a Black/White Discrimination task was followed by acquisition of Black/White Reversal (BWR). RESULTS: ID monkeys were significantly slower at mastering the BWR task (p < .04), which required reversing and inhibiting the previously learned response. In addition, ID infants were significantly less object oriented (p < .017) and more distractible (p < .018). However, on two subsequent tests, the Concurrent Object Discrimination and Delayed Non-Match-to-Sample, there were no differences in acquisition, performance, or behavioral reactivity. CONCLUSIONS: The initial cognitive and behavioral deficits are similar to those seen in follow-up evaluations of anemic children, but the limited extent of the impairment after this moderate iron deficiency that involved a select nutrient deficiency is encouraging for the benefits attainable through early identification and iron supplementation.     

Efficacy of daily and weekly iron supplementation on iron status in exclusively breast-fed infants

Iron deficiency anemia (IDA) remains the most prevalent nutritional deficiency in infants worldwide. The purpose of this study was to determine the efficacy of daily and weekly iron supplementation for 3 months to improve the iron status in 4-month-old, exclusively breast-fed healthy infants. Infants 4 months of age were eligible for the open, randomized controlled trial if their mothers intended to continue exclusive breast-feeding until the infants were 6 months of age. Infants or mothers with iron deficiency (ID) or IDA on admission were excluded. The infants (n = 79) were randomly assigned to three groups, the first group receiving daily (1 mg/kg daily), the second group weekly (7 mg/kg weekly), and the third group no iron supplementation. Anthropometric measurements were taken on admission and at 6 and 7 months of age. Iron status was analyzed on admission and monthly for 3 months. Both hematologic parameters and anthropometric measurements were found to be similar among the three groups during the study period. Seven infants (31.8%) in the control group, six (26.0%) in the daily group, and three (13.6%) in the weekly group developed ID or IDA (P > 0.05). Infants whose mothers had ID or IDA during the study period were more likely to develop ID or IDA independently from iron supplementation. Serum ferritin levels decreased between 4 and 6 months of age in the control and daily groups; the weekly group showed no such decrease. In all groups, the mean levels of serum ferritin were significantly increased from 6 months to 7 months of age during the weaning period. In this study, which had a limited number of cases, weekly or daily iron supplementation was not found to decrease the likelihood of IDA. In conclusion, exclusively breast-fed infants with maternal IDA appeared to be at increased risk of developing IDA.     

Effects of iron therapy on infant blood lead levels

OBJECTIVES: To determine the effects of iron therapy on blood lead levels in infants with mildly elevated lead levels and varied iron status. METHODS: Infants from a community-derived sample in Costa Rica were categorized into five groups. Group 1 had iron-deficiency anemia with hemoglobin levels 相似文献   

Effects of protein deprivation on growth and small intestine morphology are not improved by glutamine or glutamate in gastrostomy-fed rat pups

OBJECTIVES: Critically ill neonates often have their enteral intake severely limited shortly after birth. Whether glutamine (Gln) or glutamate (Glu) can preserve intestinal structure and function in the neonate undergoing limited enteral feeding is not clear. We hypothesize that Gln and Glu can similarly preserve intestinal structure in the developing small intestine of infant rats fed a low protein diet. METHODS: Using a gastrostomy-fed "pup-in-a-cup" rat model, the effects of Gln and Glu on the developing rat small intestine were examined. Four groups of 6- to 7-day-old pups were fed rat milk substitute (RMS) via gastrostomy tube. One group was provided 100% and three were provided 25% of the protein normally received from their mothers. Two of the groups fed 25% protein received additional Gln or Glu for 6 days. RESULTS: Pups receiving the 100% protein RMS were larger than pups receiving the 25% protein RMS with or without Gln/Glu supplementation (P < 0.001). Average villus height (P < 0.01) and area (P < 0.01) were greater in pups receiving 100% protein RMS than in pups given 25% protein RMS formula. There was no significant difference among the groups in mucosal maltase or alkaline phosphatase activities. Tight junction protein claudin-1 was significantly higher in the group fed 100% protein RMS diet, while occludin did not differ among the 4 groups. Neither Gln nor Glu increased claudin-1 or occludin in rats fed 25% protein. CONCLUSIONS: These results suggest that neither Gln nor Glu supplementation can substitute effectively for whole protein in the developing rat small intestine for the outcomes that were evaluated.     

Parameters of iron deficiency in children with cyanotic congenital heart disease

A group of 67 children with cyanotic congenital heart disease (CCHD) were studied, and 35 were given iron treatment according to a regimen that gives iron to patients with a hematocrit (Hct) below 60%. The patients were categorized as iron-deficient and iron-sufficient according to their transferrin saturation and ferritin values. The pretreatment hemoglobin (Hb) and Hct values of the groups were similar. The mean Hct was nearly three times as much as the mean Hb in the iron-sufficient group and more than three times as much as the Hb in the iron-deficient group. Excessive erythrocytosis in the iron-deficient group was impressive. Mean corpuscular volume (MCV) values were below 72.7 fl in all of the iron-deficient patients. After treatment the Hb, Hct, transferrin saturation, and ferritin increased significantly in both groups, with the increments greater in the iron-deficient group. Increments in the erythrocyte (RBC) count were significant in the iron-sufficient group but insignificant in the iron-deficient one. Increments of MCV in the iron-deficient group were significant but insignificant in the iron-sufficient group. Our study demonstrated that prediction of Hb, RBC count, and MCV, measurements of which are easy and inexpensive and require little blood, can suffice for the diagnosis of iron deficiency in patients with CCHD without altering systemic perfusion.     

Transferrin receptor in children and its correlation with iron status and types of milk consumption

AIM: This study compared transferrin receptor (TfR) concentrations with iron parameters relative to a child's intake of cow's milk and follow-on formula. METHODS: TfR, beta-haemoglobin, serum ferritin and mean corpuscular volume (MCV) of red blood cells were analysed in a study population of 263 children aged 2.5 y. The amounts of cow's milk and follow-on formula consumed were recorded. RESULTS: There was a significant difference in concentrations of TfR/log ferritin between children whose milk intake was < 500 ml and those with a milk intake > or = 500 ml (p = 0.003). There were significantly higher values of TfR/log ferritin in children whose MCV of red blood cells was < or = 75 fl than in those with > 75 fl (p < 0.0001). The TfR concentrations were significantly lower after iron therapy than before treatment. CONCLUSION: Higher concentrations of TfR were correlated with lower concentrations of haemoglobin and MCV of red blood cells. Milk consumption increases the risk of a higher ratio of TfR/log ferritin. TfR concentrations were significantly lower after iron therapy.     

Prenatal exposure to toluene results in abnormal neurogenesis and migration in rat somatosensory cortex

Toluene inhalant abuse during pregnancy may result in growth-retarded microcephalic newborns who subsequently demonstrate developmental impairment. By using a rat model of toluene-abuse embryopathy, we studied the effects of prenatal toluene exposure on the generation and migration of cortical neurons. Dams were exposed by gavage to either corn oil or toluene diluted in corn oil on d 6-21 of gestation. The time of origin of cortical neurons was determined in the mature pups of dams injected with the thymidine analogue 5'-bromodeoxyuridine on 1 d during the period from d 13-21 of gestation. 5'-Bromodeoxyuridine-labeled neurons were identified by immunohistochemistry in a 400-microm-wide column of somatosensory cortex. The brains of the toluene-exposed pups had a significant reduction in the number of neurons within each cortical layer (p < 0.001). Depending on the cortical layer, the generation of neurons in the toluene-exposed pups was delayed by 1 or 2 d. In addition, the brains of the toluene-exposed pups also showed evidence of abnormal neuronal migration. However, there were no differences in either brain weight or body weight between the control and toluene-exposed pups. These observations suggest that although prenatal toluene exposure results in abnormal neuronal proliferation and migration, brain weight in the toluene-exposed pups may be preserved by enhanced development of glia or the neuropil.     

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??Iron is an essential mineral to human body. It is necessary for the synthesis of hemoglobin and myoglobin as well as for the function of many vital iron-dependent enzymes. Many studies have reported that the changes in brain structure??neurotransmitter??neurometabolism with altered gene and protein profiles related to early iron deficiency may result in changes in sensory/motor??cognitive/ language??and social-emotional development. Iron status in early life time should be determined by various factors during prenatal??perinatal and postnatal periods. The physiological needs for iron vary to meet the requirements for growth and development of fetus and infants. Updated research findings imply an iron-dependent time window existing for developing brain??emphasizing the importance of optimal supplementary of iron during different periods in early life time.