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Brucella abortus is the etiological agent of bovine brucellosis, an infectious disease of humans and cattle. Its pathogenesis is mainly based on its ability to survive and multiply inside macrophages. It has been demonstrated that if B. abortus ferrochelatase cannot incorporate iron into protoporphyrin IX to synthesize heme, the intracellular replication and virulence in mice is highly attenuated. Therefore, it can be hypothesized that the unavailability of iron could lead to the same attenuation in B. abortus pathogenicity. Thus, the purpose of this work was to obtain a B. abortus derivative unable to keep an internal iron pool and test its ability to replicate under iron limitation. To achieve this, we searched for iron-storage proteins in the genome of brucellae and found bacterioferritin (Bfr) as the sole ferritin encoded. Then, a B. abortus bfr mutant was built up and its capacity to store iron and replicate under iron limitation was investigated. Results indicated that B. abortus Bfr accounts for 70% of the intracellular iron content. Under iron limitation, the bfr mutant suffered from enhanced iron restriction with respect to wild type according to its growth retardation pattern, enhanced sensitivity to oxidative stress, accelerated production of siderophores, and altered expression of membrane proteins. Nonetheless, the bfr mutant was able to adapt and replicate even inside eukaryotic cells, indicating that B. abortus responds to internal iron starvation before sensing external iron availability. This suggests an active role of Bfr in controlling iron homeostasis through the availability of Bfr-bound iron.

Diagnosis of iron deficiency is not easily performed in inflammatory situation as usually encountered in elderly hospitalized patients (>70 years old). At first, we determined serum soluble receptor transferrin (RsTf), RsTf/serum ferritin ratio (RsTf-F index) and biochemical and haematological values used to evaluate iron status, in iron-depleted subjects (ferritinemia≤50 μg/L) (group 2) (n=22, 82±7 years) or not (group 1, reference group) (n=18, 82±6 years), without inflammatory diseases. Relevance of the biological parameters to diagnose iron deficiency was evaluated (ROC curve) and a cut-off value of RsTf-F (>1.85) was established. Then, we selected 60 patients (group 3) suspect of iron deficiency as previously validated with an inflammatory syndrome (CRP>12 mg/L). Almost all patients (95%) presented at least one risk factor of iron deficiency (anticoagulant drugs, nutritional or gastrointestinal diseases). In group 3, index RsTf-F values were increased (RsTf-F: 2.69±0.82 versus group 1: 1.25±0.34, p<0.05), in anemic patients (women Hb<120 g/L, men Hb<130 g/L) (n=42) and in non-anemic patients (n=18) (respectively RsTf-F: 2.84±0.87 versus 2.35±0.58, p<0.05). Thus, in elderly patients with inflammatory disorders, RsTf-F index could suspect iron deficiency before appearance of biological anemia.

Mitochondrial disease is an energy metabolic disorder with various organ involvement. Iron is widely known to be one of the most important nutriments required for normal brain development and several essential metabolic functions. We retrospectively studied the laboratory data on iron deficiency (ID) in 69 children with mitochondrial respiratory chain complex (MRC) defects by biochemical enzyme assay using muscle tissue. We analyzed the differences between groups of mitochondrial disease based on the presence of ID. ID has higher prevalence in children with mitochondrial disease than in the normal population. There were 6 (9%) patients with low hemoglobin, 12 (17%) with low serum ferrtin, and 22 (32%) with low transferrin saturation levels among children with MRC defects. In comparisons between the ID and the non-ID group of MRC-defect patients, the frequency of MRC I defect was significantly higher in the ID group while that of MRC IV defect was higher in the non-ID group. Abnormal brain magnetic resonance imaging (MRI) findings were more frequently detected in the ID group. The incidence of failure to thrive and gastrointestinal symptoms were significantly higher in the ID group. Early diagnosis and proper treatment of ID are recommended. Especially in cases with risk factors such as failure to thrive or gastrointestinal manifestation, active evaluation of ID should be encouraged.

Despite long-standing supplementation of iodine in Iran, the prevalence of goitre among general people remains high in some regions. The study investigated the role of iron status in the aetiology of goitre in school children in Isfahan, Iran. Two thousand three hundred and thirty-one school children were selected by multi-stage random sampling. Thyroid size was estimated by inspection and palpation. Urinary iodine concentration (UIC) and serum ferritin (SF) were measured. Overall, 32.9% of the children had goitre. The median UIC was 195.5 microg/L. The mean +/- SD of SF in the goitrous and non-goitrous children was 47.65 +/- 42.51 and 44.55 +/- 37.07 microg/L respectively (p=0.52). The prevalence of iron deficiency in goitrous and non-goitrous children was 9.6% and 3.1% respectively (p=0.007). Goitre is still prevalent in school children of Isfahan. However, their median UIC was well in the accepted range. Iron deficiency is associated with goitre in a small group of goitrous children. The role of goitrogens should also be investigated in this region.

Purpose: This study aimed to prove the usefulness of the diagnostic plot, using the haemoglobin content of reticulocytes as a measure of functional iron deficiency (FID) and the ferritin index as a measure of iron availability, to customise anaemia treatment in cancer patients., Methods: Based on results of this plot, cancer patients fulfilling practice guideline criteria to receive erythropoiesis-stimulating agents (ESAs) were allocated to treatment with ESAs alone, iron alone or the combination of both. Primary endpoint was the percentage of patients identified to require iron in addition or as an alternative to ESA therapy., Results: Out of 303 patients screened, 286 were allocated to treatment: 204 patients were normochromic and iron replete and treated with ESAs alone, 22 had both FID and anaemia of chronic disease and were treated with ESAs and parenteral iron, and 60 were iron-depleted and treated with iron only. After 8 weeks, a haemoglobin increase >1 g/dL from baseline was shown by 56% of patients treated with ESAs alone, by 100% of patients receiving the combination, by 50% of normochromic and by 73% of hypochromic iron-depleted patients receiving iron only. Acute phase reaction did not diminish the response rate to ESAs., Conclusions: The diagnostic plot was superior to transferrin saturation and ferritin in predicting iron availability in hypochromic patients treated with ESAs and proved useful to select treatment for anaemia in cancer patients.

We used magnetic resonance imaging (MRI) to compare the effect of iron chelation on liver, spleen and bone marrow. We examined 21 beta-thalassemic patients undergoing deferoxamine (DFO) (9/21) or combined therapy [DFO and deferiprone (L1), 12/21] with two abdominal MRI studies using T1-w/Pd-w/T2*-wGRE and T1-wTSE sequences. Changes in serum ferritin (DF%), and liver, spleen and marrow to paraspinous muscles signal intensity ratios (SI) in T1-wTSE sequence were calculated as D%=[(2(nd)value-1(st) value)/1(st) value] x100%. Negative DF% and positive D(SI)% indicated reduction of iron. Although 17/21 (80.9%) patients demonstrated reduction in ferritin, only 8/21 (38%), 7/21 (33.3%) and 7/21 (33.3%) patients had decreased liver, spleen and marrow iron. Patients undergoing combined therapy showed significantly greater reduction (Student's t-test, p < 0.05) or less increase (t-test, p <0.05) in iron stores. Combined therapy is more effective than DFO for removing and preventing liver, spleen and bone marrow iron accumulation in beta-thalassemic patients. Magnetic resonance imaging is valuable for organ-specific monitoring of chelation therapy.

Objective: To investigate the associations between maternal iron status, pregnancy outcome and newborn iron status using sensitive and specific red blood cell indices reflecting iron-deficient erythropoiesis., Design and Setting: Cross-sectional study in Kuopio University Hospital, Finland., Population: One hundred and ninety-two pregnant women and their full-term newborns (cord blood)., Methods: Quartile analysis and Spearman correlations were used to investigate the associations of the iron status of pregnant women with that of their newborns, and with pregnancy outcome., Main Outcome Measures: Maternal and cord blood analysis including indices reflecting the hemoglobin (Hb) content of red blood cells as well as serum iron, transferrin saturation, transferrin receptor and ferritin. Gestational age, birthweight and placental weight., Results: The highest quartile of the maternal percentage of hypochromic red blood cells (%HYPOm) indicating the lowest iron status was associated with a high birthweight and a long duration of pregnancy. The newborns in this group did not show any signs of iron deficiency even though the maternal %HYPOm was elevated., Conclusions: In a well-nourished maternal population, lower maternal iron status did not affect the iron accumulation on the fetal side. However, longer duration of pregnancy and growth of the fetus appeared to be associated with a lower amount of iron for Hb synthesis in maternal red blood cells, as reflected by the increased maternal %HYPOm, birthweight and length of gestation.

Restless legs syndrome (RLS) has gradually been recognized as a cause for insomnia in adults, but there have been few reports about children with RLS in Japan. Here we described seven pediatric RLS patients. All of the parents of our patients had difficult times to make their children sleep due to irritability, restlessness, and demanding bedtime routines. All patients had asked their parents to rub their feet in bed, and it took more than half an hour to soothe them until they fell asleep. Their mothers had been exhausted from this night-time routine. However, they did not consider the routine abnormal, as it had been their habitual behavior since infancy. Some parents were too distressed or embarrassed to describe the symptoms of their child properly. Five patients had clear family history and none had obvious periodic leg movements during sleep. All patients showed low levels of ferritin and iron supplementation was effective in five cases. In the severest two cases, pramipexole, but not iron, was dramatically effective. Both patients started to show RLS symptoms in the early days of infancy, which may suggest more severe hereditary dopaminergic dysfunction. RLS does occur in childhood and pediatricians should bear it in mind as one of the differential diagnoses when seeing children who are irritated and/or having difficulty in initiating their sleep.

A platelet donor may lose 80-100 mL of blood both in the harness and by blood sampling at each donation, the equivalent of four to five whole blood donations per annum for a donor attending at 2-weekly intervals. A 54-year-old male multidose platelet donor had donated platelets at regular 2-weekly intervals for 6 years. He developed an impairment of anterograde memory (new learning). A self-rating scale revealed a moderate degree of depression [Beck Depression Inventory (BDI) score 22]. Memory testing (Doors and People Memory Battery) showed low scores, particularly for verbal recall and verbal recognition memory. He was found to have a normal haemoglobin of 157 g L(-1) with normal red blood cell indices, but a low serum ferritin (15 ng mL(-1)) and a low serum iron (8.1 mmol L(-1)). Following iron therapy and a return of his iron stores to normal levels, there was an improved BDI score of 13 (minimal level of depression) and a marked improvement in memory test scores. This has been maintained even though he has resumed platelet donation but at reduced intervals.

Objective: To investigate the nutritional status of individuals from a rural area of Brazil, and associations with helminth infections in an age-stratified sample., Method: A total of 1113 individuals aged from 6 months to 83 years from the rural community of Americaninhas in Minas Gerais were investigated. Assessments comprised anthropometric measurements of weight, height and body composition, examining faecal samples for helminth eggs, and peripheral blood assays for albumin, haemoglobin and ferritin concentrations., Results: Ten percent of the participants were underweight, 12.8% were overweight and 28.3% of the children and adolescents were stunted. 11.6% had low lean body mass and 28.8% had low fat body mass. Hypoalbuminaemia was seen in 5.5%, anaemia in 12.5% and iron deficiency in 13.1%, although the prevalence of these two indices increased with age. Multivariate analysis showed that, after controlling for age, sex and socio-economic status, stunting was significantly associated with Ascaris lumbricoides infection among children and adolescents, whereas low body mass was significantly associated with hookworm infection among adults and the elderly., Conclusions: Helminth infections are associated with undernutrition in endemic populations, with important differences between the effects of hookworm and A. lumbricoides on age-related nutritional status.

Background: In Mexico, as in other developing countries, micronutrient deficiencies are common in infants between 6 and 24 months of age and are an important public health problem. The objective of this study was to determine the prevalence of anemia and of iron, folic acid, and zinc deficiencies in Mexican children under 2 years of age who use the health care services provided by the Mexican Institute for Social Security (IMSS)., Methods: A nationwide survey was conducted with a representative sample of children younger than 2 years of age, beneficiaries, and users of health care services provided by IMSS through its regular regimen (located in urban populations) and its Oportunidades program (services offered in rural areas). A subsample of 4,955 clinically healthy children was studied to determine their micronutrient status. A venous blood sample was drawn to determine hemoglobin, serum ferritin, percent of transferrin saturation, zinc, and folic acid. Descriptive statistics include point estimates and 95% confidence intervals for the sample and projections for the larger population from which the sample was drawn., Results: Twenty percent of children younger than 2 years of age had anemia, and 27.8% (rural) to 32.6% (urban) had iron deficiency; more than 50% of anemia was not associated with low ferritin concentrations. Iron stores were more depleted as age increased. Low serum zinc and folic acid deficiencies were 28% and 10%, respectively, in the urban areas, and 13% and 8%, respectively, in rural areas. The prevalence of simultaneous iron and zinc deficiencies was 9.2% and 2.7% in urban and rural areas. Children with anemia have higher percentages of folic acid deficiency than children with normal iron status., Conclusion: Iron and zinc deficiencies constitute the principal micronutrient deficiencies in Mexican children younger than 2 years old who use the health care services provided by IMSS. Anemia not associated with low ferritin values was more prevalent than iron-deficiency anemia. The presence of micronutrient deficiencies at this early age calls for effective preventive public nutrition programs to address them.

Traditionally, transferrin has been considered the primary mechanism for cellular iron delivery, despite suggestive evidence for additional iron delivery mechanisms. In this study we examined ferritin, considered an iron storage protein, as a possible delivery protein. Ferritin consists of H- and L-subunits, and we demonstrated iron uptake by ferritin into multiple organs and that the uptake of iron is greater when the iron is delivered via H-ferritin compared with L-ferritin. The delivery of iron via H-ferritin but not L-ferritin was significantly decreased in mice with compromised iron storage compared with control, indicating that a feedback mechanism exists for H-ferritin iron delivery. To further evaluate the mechanism of ferritin iron delivery into the brain, we used a cell culture model of the blood-brain barrier to demonstrate that ferritin is transported across endothelial cells. There are receptors that prefer H-ferritin on the endothelial cells in culture and on rat brain microvasculature. These studies identify H-ferritin as an iron transport protein and suggest the presence of an H-ferritin receptor for mediating iron delivery. The relative amount of iron that could be delivered via H-ferritin could make this protein a predominant player in cellular iron delivery.

Iron is a critical component of the CNS that must be tightly regulated; too little iron can result in energy insufficiency and too much iron can result in oxidative stress. The intracellular iron storage protein ferritin is central to the regulation of iron. In this study, we determined the neurochemical profile of brains of animals deficient in heavy-chain ferritin (H-ferritin) using high-resolution magic angle spin proton magnetic resonance spectroscopy (HR-MAS (1)H MRS). Spectra of 2 mm-thick coronal tissue punches ( approximately 4 mg) were obtained using a CPMG pulse sequence on Bruker Avance 500 and quantified (nmol/mg tissue) using customized LCModel software (16 metabolites). In H-ferritin deficient mice, we found significant increases in striatal glutamate, hippocampal choline, and N-acetyl-aspartyl-glutamate in both the cortex and the hippocampus (t-test, p < 0.05). Neurochemical profiling with principal component analysis (PCA) revealed increased glutamate in the hippocampus, striatum, and ventral tegmental area (VTA) in H-ferritin deficient animals as compared to wild-type. While lactate was increased in the VTA of deficient animals, it was decreased in the striatum. Also, GABA was increased in both cortical and striatal regions of deficient mice. These changes reveal the importance of proper iron management for maintaining neurochemical balance and provide new evidence for region specific differences in neurochemical profiles as a result of compromised ability of neurons to store iron while overall iron status is normal. Because H-ferritin is predominantly expressed in neurons, the neurochemical profile is suggestive of neuronal iron deficiency and may have relevance to the functional consequences associated with brain iron deficiency.

Objective: Cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and autopsy studies have suggested that brain iron may be reduced in restless legs syndrome (RLS). Further analysis of the data also suggests that diminished brain iron may selectively be for early-onset RLS. This study was designed to replicate and extend our previous findings, specifically with regard to early-onset RLS. In this study our primary hypothesis was that substantia nigra (SN) iron index would be decreased in early-onset RLS compared to controls., Methods: The iron concentration or 'iron index' in 10 brain regions was determined using MRI in 39 controls and in 22 early-onset and 19 late-onset RLS subjects. The Johns Hopkins RLS severity (JHRLSS) scale was used to define disease severity., Results: The mean iron index from the SN was significantly lower in the early-onset RLS compared to controls (t=2.5, P=0.016), while late-onset RLS and controls did not differ. There was a significant negative Spearman rank correlation between SN iron index and JHRLSS scale for the control-early-onset-RLS cohort (rho=-0.32, P=0.016)., Conclusions: The current MRI results in combination with previous autopsy data support the role of low brain iron in the SN in at least those with early-onset RLS symptoms.

Introduction: The aim of this study was to evaluate the spectrum of cardiac involvement and its outcome in beta-thalassaemia major., Methods: There were 75 patients with a mean age of 13.8 (+/- 5.5) years, of whom 33 were male and 42 were female. Clinical history, examination and laboratory investigations were assessed. Electrocardiograms, chest radiographs and echocardiograms were reviewed., Results: 44 patients had cardiac involvement in the form of left ventricular systolic dysfunction in 17, diastolic dysfunction in 22, pericardial effusion in 12 and pulmonary hypertension in 12 patients. With intense chelation therapy and cardiac medications, the condition of 13 of 17 patients with systolic dysfunction, and four of 22 with diastolic dysfunction, improved., Conclusion: Cardiac disease is a common complication of siderotic disease in thalassaemia major and it can be prevented with regular chelation. This study has shown improved systolic function after regular chelation therapy.

Few data exist concerning preoperative nutritional status in patients undergoing bariatric surgery. We retrospectively analyzed the preoperative values of serum albumin, calcium, 25-OH vitamin D, iron, ferritin, hemoglobin, vitamin B12, and thiamine in 379 consecutive patients (320 women and 59 men; mean body mass index 51.8 +/- 10.6 kg/m2; 25.8% white, 28.4% African American, 45.8% Hispanic) undergoing bariatric surgery between 2002 and 2004. Preoperative deficiencies were noted for iron (43.9%), ferritin (8.4%), hemoglobin (22%; women 19.1%, men 40.7%), thiamine (29%), and 25-OH vitamin D (68.1%). Low ferritin levels were more prevalent in females (9.9% vs. 0%; P = 0.01); however, anemia was more prevalent in males (19.1% vs. 40.7%; P < 0.005). Patients younger than 25 years were more likely to be anemic than patients over 60 years (46% vs. 15%; P < 0.005). This correlated with iron deficiency, which was more prevalent in younger patients (79.2% vs. 41.7%; P < 0.005). Whites (78.8%) and African Americans (70.4%) had a higher prevalence of vitamin D deficiency than Hispanics (56.4%), P = 0.01. Whites were the least likely group to be thiamine deficient (6.8% vs 31.0% African Americans and 47.2% Hispanics; P < 0.005). Nutritional deficiencies are common in patients undergoing Roux-en-Y gastric bypass, and these deficiencies should be detected and corrected early to avoid postoperative complications.

DMT1 mediates the pH-dependent uptake of Fe(2+) from the diet in duodenal enterocytes and in most other cells. It transfers iron from the endosomes to the cytosol following the uptake of the transferrin-transferrin receptor complex. DMT1 mutations are responsible for severe hypochromic microcytic anemia in rodents and in 2 human patients described recently. We report a compound heterozygote for 2 new DMT1 mutations, associated with microcytic anemia from birth and progressive liver iron overload. The first mutation is a GTG deletion in exon 5, leading to the V114 in-frame deletion in transmembrane domain 2, and the second is a G --> T substitution in exon 8 leading to the G212V replacement in transmembrane domain 5. Together with the 2 previously reported cases, this patient defines a new syndrome of congenital microcytic hypochromic anemia, poorly responsive to oral iron treatment, with liver iron overload associated paradoxically with normal to moderately elevated serum ferritin levels.

Objective: To evaluate relations among measures of iron and zinc status, C-reactive protein (CRP), and leukocytes in low-income children participating in the Head Start program., Design: Cross-sectional correlational study with samples collected at Head Start centers in May 2003., Subjects/setting: Forty-seven children (aged 3 to 5 years) attending Head Start centers in three rural communities., Measures: Zinc, ferritin, CRP, and complete blood count were analyzed in nonfasting blood samples., Statistical Analyses: Correlations were computed among leukocyte levels, CRP levels, and measures of micronutrient status. Children having two abnormal measures (ie, leukocytes and CRP) were compared by univariate analysis of variance with children having zero or one abnormal measure., Results: Most (72%) of the children had elevated CRP levels. Four percent were anemic (hemoglobin<11.0 g/dL [<110 g/L]); 11% had low iron stores (serum ferritin

The prevalence of oral candidiasis and its association with malnutrition in terms of protein-energy malnutrition and mineral and vitamin depletion were evaluated in ninety-seven hospitalised older adults aged 82.1 (SD 8.6) years. Patients underwent a complete oral examination with microbiological investigation on admission to our geriatric rehabilitation unit. Patients were assessed nutritionally by evaluation of dietary intake and measurement of anthropometric variables, serum nutritional proteins, ferritin, Zn, folate, vitamins B12 and C. The prevalence of oral candidiasis was 37% (n 36); the proportion of patients with BMI <20 kg/m(2) was 32% (n 31). The nutritional status of the population was studied by comparing two groups defined according to the absence (group I; n 61) or presence (group II; n 36) of oral candidiasis. The two groups did not differ on the basis of BMI and mid-arm circumference. However, group II had a smaller leg circumference, lower daily energy and protein intakes, lower albumin and transthyretin levels. Patients successfully treated with fluconazole increased their intake on day 30. The proportion of patients with hypozincaemia (<12.5 micromol/l) and vitamin C deficiency (<0.7 mg/l) was higher in group II. Treatment with antibiotics, poor oral hygiene, denture wearing, and vitamin C deficiency appeared as the most significant independent risk factors associated with oral candidiasis. The present findings show that oral candidiasis appears to be related to malnutrition and results in mucosal lesions that have a negative impact on energy intake, which may subsequently worsen nutritional status.

Purpose of Review: Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration., Recent Findings: Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area., Summary: In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease.

Study Objectives: To assess potential relationships between serum iron and ferritin levels and the severity of periodic limb movement in sleep (PLMS) in a pediatric population, and to evaluate the response to supplemental iron therapy., Design: A prospective study of all consecutively diagnosed children with PLMS (periodic limb movement index [periodic limb movements per hour of total sleep time, [PLMI] > 5) who underwent overnight polysomnographic evaluation. In all patients, complete blood count and serum iron and ferritin levels were obtained. Patients with serum ferritin concentrations less than 50 microg/L were prescribed iron sulfate at 3 mg/kg of elemental iron per day for 3 months. At the end of treatment, serum iron and ferritin levels and sleep studies were repeated., Setting: Comprehensive Sleep Medicine Center, Tulane University Health Sciences Center, and Kosair Children's Hospital Sleep Medicine and Apnea Center., Patients: Twenty boys and 19 girls with PLMS with a mean age of 7.5 +/- 3.1 years., Intervention: Iron therapy., Results: Twenty-eight (71.8%) patients had ferritin levels less than 50 microg/L. There was no significant correlation between serum ferritin concentration and PLMS severity as indicated by the PLMI (r = -0.19). The PLMI in patients with serum ferritin levels less than 50 microg/L (29.9 +/- 15.5 PLM/h) was higher than in patients with serum ferritin levels greater than 50 microg/L (21.9 +/- 11.8 PLM/h); however, the difference did not achieve statistical significance (P = 0.09). In contrast, serum iron was significantly correlated with PLMI (r = -0.43, P < 0.01). Indeed, patients with serum iron concentrations less than 50 microg/dL had a higher PLMI compared to patients with serum iron concentrations greater than 50 microg/dL (42.8 +/- 18.3 PLM/h and 23.1 +/- 10.1 PLM/h, respectively; P = 0.02). Twenty-five out of the 28 PLMS patients with serum ferritin levels less than 50 microg/L received treatment with iron sulfate, and 19 (76%) responded favorably. Among the responders to iron therapy, PLMI decreased from 27.6 +/- 14.9 PLM per hour to 12.6 +/- 5.3 PLM per hour after 3 months of iron supplements (P < 0.001) and coincided with increases in serum ferritin levels (pre: 40.8 +/- 27.4 microg/L vs post: 74.1 +/- 13.0 microg/L; P < 0.001)., Conclusions: In children, the presence of PLMS is frequently associated with low serum iron and a tendency toward low serum ferritin levels. In addition, iron therapy is associated with clinical improvement in most of these patients.

Objective: To assess neuropathology in individuals with restless legs syndrome (RLS)., Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls., Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased., Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

The purpose of the research presented in this article was to characterize restless leg syndrome (RLS) in a headache population and correlate treatment induced risks with dopamine blockers. Fifty patients with severe headache who were admitted to an outpatient infusion center were enrolled. The diagnosis of RLS was established using the International Restless Leg Syndrome Study Group criteria. Patients were screened for baseline akathisia using an akathisia scale and reexamined for akathisia after receiving intravenous infusion with one of four dopamine receptor blocking agents as treatment for their headaches. A change from baseline to post-infusion assessment of two points on a global assessment of akathisia was considered positive for drug-induced akathisia. Our results indicated that 41 (82%) of patients had episodic or chronic migraine. The rest had new daily persistent headache, cluster, or posttraumatic headache. Seventeen subjects (34%) met the criteria for RLS. Nineteen (38%) of the subjects developed drug-induced akathisia. Thirteen (76.5%) of the subjects with RLS developed akathisia compared with only 6 of the 33 (18.2%) without RLS (P<.0001). Finally, we concluded that headache patients with RLS are at a greatly increased risk of developing drug-induced akathisia when treated with intravenous dopamine receptor blocking agents.

Several neurodegenerative disorders such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) are associated with elevated brain iron accumulation relative to the amount of ferritin, the intracellular iron storage protein. The accumulation of more iron than can be adequately stored in ferritin creates an environment of oxidative stress. We developed a heavy chain (H) ferritin null mutant in an attempt to mimic the iron milieu of the brain in AD and PD. Animals homozygous for the mutation die in utero but the heterozygotes (+/-) are viable. We examined heterozygous and wild-type (wt) mice between 6 and 8 months of age. Macroscopically, the brains of +/- mice were well formed and did not differ from control brains. There was no evidence of histopathology in the brains of the heterozygous mice. Iron levels in the brain of the +/- and wild-type (+/+) mice were similar, but +/- mice had less than half the levels of H-ferritin. The other iron management proteins transferrin, transferrin receptor, light chain ferritin, Divalent Metal Transporter 1, ceruloplasmin, were increased in the +/- mice compared to +/+ mice. The relative amounts of these proteins in relation to the iron concentration are similar to that found in AD and PD. Thus, we hypothesized that the brains of the heterozygote mice should have an increase in indices of oxidative stress. In support of this hypothesis, there was a decrease in total superoxide dismutase (SOD) activity in the heterozygotes coupled with an increase in oxidatively modified proteins. In addition, apoptotic markers Bax and caspase-3 were detected in neurons of the +/- mice but not in the wt. Thus, we have developed a mouse model that mimics the protein profile for iron management seen in AD and PD that also shows evidence of oxidative stress. These results suggest that this mouse may be a model to determine the role of iron mismanagement in neurodegenerative disorders and for testing antioxidant therapeutic strategies., (Copyright 2002 Wiley-Liss, Inc.)

Background: A lack of information about the role that iron and folate stores (erythrocyte folate) play on the anemia incidence in pregnant women., Objective: To evaluate the predictive value of ferritin and erythrocyte folate before pregnancy in relationship to the incidence of anemia throughout pregnancy., Methods: Thirty-five non-anemic non-pregnant women were evaluated 1 or 2 months before the pregnancy. After becoming pregnant they were evaluated every 4 weeks starting in the 8th week of pregnancy until 1 month post-partum. Every evaluation included determination of hemoglobin, ferritin and erythrocyte folate., Results: When the women started gestation with an insufficient iron store (<20 microg/l), the trend was to present anemia at significantly earlier gestational ages, in such a way that at week 20 of gestation almost 60% of the women with an inadequate store had anemia and only 25% of the women with an adequate store had this condition. On the other hand, the pregestational erythrocyte folate did not predict anemia incidence., Conclusions: Pregestational ferritin concentration predicts value of incidence of anemia throughout pregnancy., (Copyright 2003 S. Karger AG, Basel)

Background: Low iron and ferritin blood levels have been observed in patients with Restless Legs Syndrome (RLS) with an inverse relation between symptom severity and ferritin level. All reports are based on single cases or case series of hospitalized patients or those from outpatient clinics. No data from population studies are available., Methods: Cross-sectional study examining the associations between 5 measures of iron metabolism and RLS in an elderly general population in southern Germany. All 365 participants, aged 65 to 83 years, were examined neurologically and interviewed using standardized questions addressing the four minimal criteria for RLS. Iron, ferritin, transferrin, soluble transferrin receptor and C-Reactive Protein were analysed with standard laboratory methods., Results: The prevalence of Restless Legs Syndrome in this population was 9.8 %. Odds Ratios associated with Restless Legs were significantly increased in the fourth quintile of iron (OR 3.08 95 % CI 1.02-9.29) and transferrin saturation (OR 5.68 95 % CI 1.18-27.26) compared with the third (middle) quintile. Increases in the first (lowest) quintile of both measures were not or borderline significant. No associations with ferritin and soluble transferrin receptor were found., Conclusions: No evidence was found that iron or ferritin deficiency are a major cause of RLS in this population study. The results support the hypothesis that changes in the complex regulation of iron metabolism contribute to the occurence of RLS.

Unlabelled: In up to 90% of cases, severe halitosis is a result of gastrointestinal or orolaryngeal problems. This case study reports on a girl with bad breath caused by increased formation of malodorous intestinal gases (halitosis), which could be successfully treated with a suspension of living non-pathogenic bacteria Escherichia coli., Conclusion: in unclear cases of bad breath, an increased formation of intestinal gases should also be considered.

Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)

The iron status and diet of Inuit infants living in northern Quebec who were part of a prospective cohort study was described. The prevalence of anemia (hemoglobin values > 2 SD below the reference mean) was 21.1% (23/109), 47.4% (55/116) and 37.7% (46/122) at 2, 6 and 12 months, respectively. The corresponding prevalence of microcytic anemia was 0.0%, 4.3% and 21.3%. At 2, 6 and 12 months, iron-deficiency anemia (serum ferritin < 10 micrograms/L coupled with anemia) was present in 1.3% (1/79), 24.4% (21/86) and 26.3% (25/95) of infants, respectively. Compared with breastfeeding, the odds ratio for iron deficiency (serum ferritin < 10 micrograms/L) for bottle-feeding with cows' milk or low iron formula was 3.02 (95% CI 1.25-7.27) at 6 months and 3.05 (95% CI 1.28-7.28) at 12 months. This study shows iron-deficiency anemia to be a problem in Inuit infants as young as 6 months old. Breastfed infants were better protected against iron deficiency than infants fed cow's milk or low-iron formula.

Previous studies employing rabbit polyclonal anti-human liver ferritin have shown an absence of L ferritin immunoreactivity in liver and spleen tissue from patients with Niemann-Pick disease type C1 (NPC1). The great majority of NPC cases is caused by defects of the NPC1 gene, and a minority by those of another (NPC2). In this study using polyclonal and monoclonal antibodies we show the deficiency of H and L ferritin isoforms in various NPC tissues, including fetal NPC1, not previously described. In particular, evidence is provided for deficiency in H and L ferritins in tissues, except lung, from a patient with Niemann-Pick disease type C2 (NPC2). The present findings indicate that H and L ferritins are deficient in both NPC types characterized by accumulation of unesterified cholesterol and additional metabolites in the endosomal/lysosomal system. We hypothesize that the lesions in NPC1 and NPC2 block the intracellular utilization not only of cholesterol, but also that of iron for the synthesis of cytosolic ferritin., (Copyright 2000 Academic Press.)

Background: In developing countries, incomplete resolution of anemia with iron supplementation is often attributed to poor compliance or inadequate duration of supplementation, but it could result from deficiencies of other micronutrients., Objective: Our objective was to assess children's hematologic response to supervised, long-term iron supplementation and the relation of this response to other micronutrient deficiencies, anthropometry, morbidity, and usual dietary intake., Design: Rural Mexican children aged 18-36 mo (n = 219) were supplemented for 12 mo with either 20 mg Fe, 20 mg Zn, both iron and zinc, or placebo. Children were categorized as iron-unsupplemented (IUS; n = 109) or iron supplemented (IS; n = 108). Hemoglobin, hematocrit, mean corpuscular volume, mean cell hemoglobin, plasma concentrations of micronutrients that can affect hematopoiesis, anthropometry, and diet were assessed at 0, 6, and 12 mo; morbidity was assessed biweekly., Results: At baseline, 70% of children had low hemoglobin (

Even in industrialized countries, the iron-deficiency anemia is frequent in menstruating women. However, the systematic measurement of serum ferritin is not justified. In this study, a strategy for ferritin measurement has been determined from data of centers for health screening, obtained in 6,098 menstruating women. This strategy is based on biological results (hemoglobin, MCV, RDW, GGT, ALAT) and on responses to the questions about blood donation, birth country and contraceptive habits. The measurement of serum ferritin is realized in 64% menstruating women and 23% have an hypoferritinemia (< 20 mg/l).

Objective: Some studies have suggested that increased iron stores may impact negatively on the response to interferon in patients with chronic hepatitis C infection. We performed this prospective trial to determine the effects of iron depletion on ALT and HCV-RNA levels in patients with chronic hepatitis C infection and to assess whether the response to interferon in patients who had previously failed to respond to interferon was enhanced by iron depletion., Methods: Patients with chronic hepatitis C resistant to interferon therapy and no evidence of iron overload underwent weekly phlebotomies until the serum ferritin level was below lower limits of normal for the subject's age and sex. Patients were then started on interferon-alpha2b, 3 million units subcutaneously three times per week for a period of 24 weeks. Iron studies, ALT, and HCV-RNA levels were monitored at baseline, after phlebotomy and at 12 and 24 weeks of interferon therapy., Results: Thirty-three patients were enrolled, 28 completed the study. A mean of 7.2 units of blood were removed to achieve iron depletion. ALT levels decreased significantly with phlebotomy (142 IU/L before phlebotomy vs 82 IU/L after phlebotomy; p < 0.001), but log HCV-RNA levels remained unchanged (6.49 before phlebotomy vs 6.51 after phlebotomy). Interferon therapy did not improve ALT levels further. HCV-RNA levels were minimally reduced during interferon therapy (log HCV-RNA 6.49 before interferon vs 6.00 after 24 weeks of interferon therapy). Two patients achieved a virologic end of treatment response, both relapsed within 3 months after discontinuation of interferon. No patient achieved a sustained virologic response., Conclusions: In patients who previously failed treatment with interferon, iron depletion induced by phlebotomy improves ALT levels but is ineffective in achieving viral eradication in patients retreated with interferon 3 million units three times per week.

Background: It is well known that prolonged anemia causes atrophy of tongue papillae, glossal pain, and dysphagia, but it is uncertain whether iron (Fe) deficiency induces glossal pain without any objective manifestation. To resolve this matter, the relationship between Fe deficiency and glossal pain was examined., Methods: Eighteen patients with Fe deficiency and 7 anemic patients manifesting spontaneous irritation or pain of the tongue without any objective abnormalities participated in this study. To ascertain the cause of glossal pain and the oral pathophysiology in Fe deficiency and anemia, peripheral blood was examined and the glossal pain threshold and salivary flow rates (SFRs) were estimated along with Candida albicans cell culture tests., Results: Compared with patients with Fe deficiency, those with anemia had a longer history of tongue pain. In patients with anemia, painful areas of the tongue were more numerous than in patients with Fe deficiency. Pain thresholds were decreased in the painful portions, and both nonstimulated and stimulated SFRs were suppressed. Each patient was treated with oral Fe; within 2 months, most patients exhibited increased serum ferritin level (P< 0.02, paired t-test), pain threshold (P < 0.05) and salivation (P < 0.05) and glossal pain subsided., Conclusions: Fe deficiency causes glossal pain and the degree of glossal pain increases as Fe deficiency advances to anemia, manifesting hyposalivation and abnormalities of glossal papillae.

Background and Objective: Recent studies have shown that the serum transferrin receptor (sTfR) is a sensitive, quantitative measurement of tissue iron deficiency. The objective of the study was to evaluate the diagnostic efficiency of some laboratory tests, including sTfR measurements, in the diagnosis of iron depletion in patients with anemia of chronic disorders., Design and Methods: The patient population consisted of 37 anemic patients: 10 hypoferritinemic patients (serum ferritin < 25 micrograms/L), and 27 anemic in-patients with hyperferritinemia (serum ferritin > 200 micrograms/L) and clinical/analytical criteria of anemia of chronic disorders, who were submitted to a bone marrow aspirate with iron stain. The sensitivity and specificity of serum TfR was evaluated according to the results of bone marrow iron status. Statistical analysis employed Student's t-test, one way analysis of variance and a logistic regression model using the Wald test., Results: Serum TfR was high in all the patients with hypoferritinemic anemia. In 12 patients with low bone marrow iron, the mean sTfR was 5.63 mg/L. In 6 of these 12 patients the sTfR was normal. On the other hand, sTfR was high in 4/15 patients with normal or increased iron stores. On multivariate analysis the most sensitive predictor of true iron deficiency was MCH (mean corpuscular hemoglobin). No other variables remained independently significant, including sTfR, after the inclusion of MCH in this model., Interpretation and Conclusions: In our opinion, the iron status of patients with anemia of chronic diseases can not be accurately assessed by sTfR, as its sensitivity and specificity are low. In these patients, the gold standard for iron stores evaluation continues to be bone marrow aspirate and Perls stain.

We analysed whether 12-month-old Swedish infants who have been fed iron-fortified and relatively zinc-rich foods, according to current recommendations, have adequate iron and zinc status. A cohort of 76 healthy, full term Swedish infants was followed regarding feeding habits and growth from birth to 12 months of age, when haemoglobin, iron and zinc status were evaluated. Twenty-six percent of the infants had low (<12 microg/l) s-ferritin values, indicative of iron depletion, and 36% of the infants had low s-zinc concentrations (<10.7 micromol/l). Only two infants had both low haemoglobin and low s-ferritin values. s-Zinc and s-iron were positively correlated, and s-zinc and s-transferrin receptor values were negatively correlated. Lower birthweight was associated with lower s-ferritin levels at 12 months in boys, and with increased s-transferrin receptor values in girls. Feeding habits during infancy were relatively homogeneous, dominated by breastfeeding, iron-fortified milk- and cereal-based follow-on formula. No clear association between feeding pattern and iron and zinc status was found. The results indicate that in a group of healthy, well growing 12-month-old Swedish infants one-quarter is iron-depleted, although iron deficiency anaemia is rare, and one-third may be zinc-depleted. The high cereal intake of Swedish infants from 6 months of age may have limited the bioavailability of both iron and zinc from the diet.

Ouchterlony double immunodiffusion clearly demonstrated absence of ferritin, the principal iron storage protein, in spleen and/or liver extracts from nine patients with Niemann-Pick disease type C (NPC). The patients died from different clinical forms of this disease of still unknown etiology. The absence of ferritin immunoreactivity was shown using two different antisera raised in rabbits against ferritin from human spleen or liver, organs which predominantly contain light chain subunits (L-ferritin). A diagnostic double immunodiffusion assay of ferritin is, therefore, feasible with small amounts of NPC liver tissue, e.g., needle biopsy specimens. Furthermore, SDS-polyacrylamide gel electrophoresis after Coomassie blue staining revealed an almost complete absence of the L-ferritin protein band in crude spleen heat extracts from two NPC patients. The absence of visceral ferritin in all nine patients studied is suggestive of a biochemical abnormality that is as characteristic as the known impairment of cellular trafficking of LDL-derived cholesterol in this complex lysosomal storage disorder. According to recent data a relationship exists between ferritin-dependent lipid peroxidation and oxidative modification of LDL. We suggest that deficiency of the antioxidant ferritin-whatever the nature of this deficiency might be-could lead to uncontrolled LDL oxidation with subsequent multisubstrate lipidosis in NPC disease.

Ferritin, the major iron storage protein, was found to be undetectable on immunoblot analysis of spleen and liver extracts from four patients with Niemann-Pick disease type C (NPC). The patients had died from different clinical forms of this storage disease of still unknown etiology. The absence of ferritin immunoreactivity was shown using two different antisera, raised in rabbits, against ferritin from human spleen containing predominantly light-chain subunits (L-ferritin). Further evidence of absent L-ferritin in visceral tissues was provided by immunohistochemical studies performed in one of the four NPC patients. However, heavy-chain and light-chain ferritin mRNAs could be identified in cultured fibroblasts from this patient. The finding of deficient ferritin immunoreactivity is suggestive of an additional biochemical abnormality that is as marked as the known impairment of the transport of exogenously derived cholesterol in this complex lysosomal storage disorder.

We studied effects of dose and treatment duration during low-dose iron supplementation in premenopausal, non-pregnant women, with initial serum ferritin and haemoglobin concentrations < 20 micrograms x l-1 and > or = 120 g x l-1, respectively. The study was randomized, double-blind and placebo-controlled. Three groups completed a 6-month study: placebo (n = 27), FE-9 (9 mg iron x day-1, n = 18) and FE-27 group (27 mg iron x day-1, n = 19). The supplement consisted of 11% heme and 89% inorganic iron. In FE-27, serum ferritin increased from (mean, 95% confidence interval) 11.8 (9.7; 14.4) to 25.3 (18.6; 34.4) micrograms x l-1 in 1 month, and remained stable after that (ANOVA: group effect, P = 0.0003). In both FE-9 and FE-27, blood haemoglobin levels increased from 136 (132; 140) to 142 (139; 145) g x l-1 in 1 month, remaining constant after that (group effect, P = 0.001). Hence, the 27 mg daily dose of organic/inorganic iron corrected both mild anaemia and storage iron depletion, whereas the 9 mg dose did not affect iron stores. Elongation of treatment duration above 1 month brought about only minor changes.

Purpose: To assess the haematological values of a rural population of school children in the province of Cádiz and to estimate the incidence of iron deficiency amongst them., Methods: The study was performed on 250 children of both sexes aged between 5 and 16 years. Informed consent was obtained from their parents in every case. White cell count, red cell count, haemoglobin, MCV, MCH, MCHC and RDW were assessed with a Coulter S Plus Jr automatic cell counter; serum iron was measured with a Ferrochem II analyser; turbidimetric measure of transferrin was performed with turbitimer, and ferritin was measured by microparticle enzymoimmunoassay. The normality criteria for children given by WHO were used as a reference., Results: Of the 250 samples, 245 were evaluable, corresponding to 138 boys (56.3%) and 107 girls (43.7%) and the findings were stratified according to age. The mean values attained in each group were similar to those reported in other Mediterranean countries, and their age distribution was parallel in both sexes until age 11, when haemoglobin and haematocrit increase in boys due to the erythropoietic stimulus exerted by androgens. Iron deficiency was found in 35 children (14.2%); of them, 17 (6.9%) had hypo-ferritinaemia, 13 (5.3%) had hyposideraemia and 5 (2%) had a combination of the two. Iron-lack anaemia was present in 2 cases (0.8%)., Conclusions: The group under study is a sample of the normal school-age population of the area. The detection of iron deficiency in children is important due to the influence of this precursor in the physical and intellectual development.

To determine the effects of depleted iron stores on endurance performance and blood lactate concentration, eight active women with normal (> 26 ng/ml) and eight with low (< 12 ng/ml) plasma ferritin concentrations were studied while performing a VO2max and an endurance test (80% VO2max) on a cycle ergometer. The low ferritin group had significantly lower serum iron concentration and transferrin saturation and higher TIBC than the normal ferritin group. Mean VO2max was not significantly different between groups. No significant difference was found in total time to exhaustion during the endurance test for low (23.2 min) and normal (27.0 min) ferritin groups; however, the normal ferritin group exercised 14% longer. Blood lactate concentrations following the VO2max and endurance test did not differ significantly between groups. Food diaries revealed lower daily absorbable iron intake by the low ferritin group compared to the normal ferritin group. Ferritin concentration was significantly related to absorbable iron (r = .72) and total iron (r = .70) intake. The results suggest that women with depleted iron stores who are not anemic may have less endurance, but do not have higher blood lactate during exercise than women with normal iron stores.

Iron metabolism parameters were studied in pregnant women in time course of trimesters depending on the pregnancy character and in newborns and infants in relation to the antenatal period. The dynamic study of serum and erythrocytic ferritins has confirmed the expediency of iron therapy during pregnancy for prevention of iron deficiency in infants. Differences detected in the rate of using iron reserves by infants of the first year of life depending on the antenatal period character have necessitated an individual approach to preventive iron therapy.

This study was designed to investigate serum levels of iron, ferritin, vitamin B12 and folic acid in 18 Huntington's disease patients and 86 healthy control subjects. Serum iron, vitamin B12 and folic acid levels were normal. Ferritin concentrations were significantly diminished in the choreic patients. The importance of this finding in our attempt to understand the underlying biochemical defect and the chemical nature of the iron deposits found in several brain nuclei in Huntington's disease patients is unknown.