Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders.
(49/690)
Iron overload is highly prevalent, but its molecular pathogenesis is poorly understood. Recently, DMT1 was shown to be a major apical iron transporter in absorptive cells of the duodenum. In vivo, it is the only transporter known to be important for the uptake of dietary non-heme iron from the gut lumen. The expression and subcellular localization of DMT1 protein in 3 mouse models of iron overload were examined: hypotransferrinemic (Trf(hpx)) mice, Hfe knockout mice, and B2m knockout mice. Interestingly, in Trf(hpx) homozygotes, DMT1 expression was strongly induced in the villus brush border when compared to control animals. This suggests that DMT1 expression is increased in response to iron deficiency in the erythron, even in the setting of systemic iron overload. In contrast, no increase was seen in DMT1 expression in animals with iron overload resembling human hemochromatosis. Therefore, it does not appear that changes in DMT1 levels are primarily responsible for iron loading in hemochromatosis. (+info)
Hepatic iron storage in very low birthweight infants after multiple blood transfusions.
(50/690)
OBJECTIVE: To investigate the effect of multiple blood transfusions on hepatic iron storage in preterm, very low birthweight (VLBW) infants. METHODS: Seventeen VLBW infants who died within the first six months of life and underwent postmortem examination were studied. Serum ferritin, iron, and total iron binding capacity were measured within the week before the infants' death. Liver iron concentration was quantitatively determined by atomic absorption spectrophotometry and semiquantitatively assessed by histochemical liver iron grading. The clinical characteristics and the iron results were compared between infants receiving < 100 ml of blood (group A) and those receiving >/= 100 ml (group B). Spearman's correlation coefficient was used to evaluate the relation between the volume of blood transfused and serum/liver iron concentrations. Statistically significant variables associated with liver iron concentration were further subjected to multivariate stepwise regression analysis. RESULTS: Infants in group B had significantly higher serum iron (p < 0.01), serum ferritin (p < 0.01), and liver iron concentration (p < 0.01) than those in group A. The total and net volume of blood transfused were significantly associated with liver iron concentration (p < 0.001, r = 0.86; p < 0.001, r = 0.71 respectively), semiquantitative histochemical liver iron grading (p < 0.001, r = 0.80; p < 0.005, r = 0.71 respectively), and serum ferritin (p < 0.001, r = 0.84; p < 0.01, r = 0.69 respectively). In addition, both liver iron concentration and liver iron grading were found to be significantly associated with serum ferritin (p < 0.001, r = 0.76; p < 0.005, r = 0.68 respectively). Multivariate stepwise regression analysis indicated that the (log) liver iron concentration was significantly associated with the (log) volume of blood transfusion (p < 0.001; regression coefficient 0.39, SE 0.09), after adjustment for gestational age (R(2) = 0.84). CONCLUSIONS: This study showed a significant positive relation between the volume of blood transfused and the liver iron concentration in preterm VLBW infants. Although the transfusional blood volume correlated closely with the amount of iron deposited in hepatic tissues, clinical manifestations of iron overload were not observed. Carers should be aware of this potential harmful effect before prescribing blood or routine iron supplement to vulnerable preterm infants. (+info)
Real-time polymerase chain reaction with fluorescent hybridization probes for the detection of prevalent mutations causing common thrombophilic and iron overload phenotypes.
(51/690)
We evaluated more than 450 patients with thrombophilia or iron overload for the presence of a factor V Leiden (R506Q), prothrombin G20210A, or HFE C282Y mutation using a standard method (polymerase chain reaction [PCR]-restriction fragment length polymorphism) and a comparative real-time PCR fluorescent resonance energy transfer (FRET) hybridization probe melting curve method. There was 100% concordance between the genotypes ascertained by the 2 methods (at each loci). In addition, phenotypic biochemical laboratory parameters measured on a subset of referred patients correlated with their respective genotypes. In the iron overload cohort, HFE C282Y homozygotes (n = 74) had significantly higher (P < .0001) transferrin saturation levels (74% +/- 25%) than did nonhomozygotes (n = 340; 51.4% +/- 28%), suggesting a genotype-dependent increase in body iron loads. In the thrombophilic cohort, the degree of activated protein C resistance (APCR), measured by a clotting time-based test, was associated significantly with the presence of 0 (n = 255; APCR = 2.59 +/- 0.26), 1 (n = 84; APCR = 1.61 +/- 0.13), or 2 (n = 5; APCR = 1.16 +/- 0.04) copies of the mutant factor V Leiden allele. As the fluorescent genotyping method required no postamplification manipulation, genotypes could be determined more quickly and with minimized risk of handling errors or amplicon contamination. In addition to these practical advantages, the FRET method is diagnostically accurate and clinically predictive of phenotypic, disease-associated manifestations. (+info)
Iron overload without the C282Y mutation in patients with epilepsy.
(52/690)
To test the hypothesis that iron overload predisposes to epilepsy, transferrin saturation in 130 patients with epilepsy and sex and age matched 128 control subjects without epilepsy were studied. Mean transferrin saturation was significantly higher in the epilepsy group (39.9 (SD 19.6)%) than in the control group (29.1 (SD 14.9)%). Abnormally high transferrin saturations (men>60%, women>48%) were found in 10 patients with epilepsy but in only one subject without epilepsy. Antiepileptic drugs did not affect the transferrin saturation. Of the 11 with abnormally high transferrin saturation, two with epilepsy were heterozygotic for H63D in the haemochromatosis gene but no patient had the C282Y mutation. These results indicate that iron overload other than the C282Y mutation underlies epilepsy. (+info)
Reticulocyte transferrin receptor (TfR) expression and contribution to soluble TfR levels.
(53/690)
BACKGROUND AND OBJECTIVES: Transferrin receptor (TfR) expression in erythroid cells is regulated by a number of factors, including iron status and erythropoietin (Epo) stimulation. However, the impact of these factors on reticulocyte TfR expression in vivo has never been studied. A soluble form of TfR (sTfR) is present in serum in proportion to the mass of cellular TfR. Although sTfR shedding by reticulocytes and erythroblasts has been demonstrated in vitro, the contribution of reticulocyte TfR to serum sTfR has never been evaluated in vivo. DESIGN AND METHODS: We measured directly the total number of reticulocyte TfR in normal rats of different age and iron status, as well as in animals experiencing various conditions and treatments aimed at altering erythropoietic activity and iron status, including rHuEpo therapy, hemolytic anemia, phlebotomies, hypertransfusions, thiamphenicol-induced red cell aplasia or inflammation. In addition, we examined the impact of repeated hypertransfusions with normal, reticulocyte-poor and reticulocyte-rich blood on serum sTfR levels. RESULTS: The number of TfR molecules per reticulocyte was around 50,000 in young rats but was around 100,000 in older animals. These values remained constant in most conditions and in particular were not influenced by iron supplementation or iron overload. However, functional iron deficiency as well as rHuEpo therapy resulted in increased reticulocyte TfR expression. In addition, TfR numbers in reticulocytes were elevated in the early phase of recovery after acute hemolysis or red cell aplasia but normalized soon after. Hypertransfusion experiments clearly demonstrated that reticulocytes can contribute substantially to sTfR levels in vivo. INTERPRETATION AND CONCLUSIONS: TfR numbers are regulated in vivo by the same factors as in vitro, in particular iron deficiency and erythropoietin stimulation. Circulating reticulocytes contribute significantly to serum sTfR levels. (+info)
Nutritional support at home and in the community.
(54/690)
Technical developments in feeding, together with the growth of support structures in the community has lead to a steady increase in the number of children receiving home enteral tube feeding and home parenteral nutrition. In many cases the adverse nutritional consequences of disease can be ameliorated or prevented, and long term parenteral nutrition represents a life saving intervention. Careful follow up of children receiving home nutritional therapy is necessary to establish the ratio of risks to benefits. A considerable burden is sometimes placed on family or other carers who therefore require adequate training and ongoing support. The respective responsibilities of different agencies relating to funding and support tasks require more clear definition. (+info)
Stearoyl coenzyme A desaturase 1 expression and activity are increased in the liver during iron overload.
(55/690)
In humans, hepatic iron overload can lead to hepatocellular carcinoma development. Iron related dysregulation of hepatic genes could play a role in this phenomenon. We previously found that the carbonyl-iron overloaded mouse was a useful model to study the mechanisms involved in the development of hepatic lesions related to iron excess. The aim of the present study was to identify hepatic genes overexpressed in conditions of iron overload by using this model. A suppressive subtractive hybridization was performed between hepatic mRNAs extracted from control and 3% carbonyl-iron overloaded mice during 8 months. This methodology allowed us to identify stearoyl coenzyme A desaturase 1 (SCD1) mRNA overexpression in the liver of iron loaded mice. The corresponding enzymatic activity was also found to be significantly increased. In addition, we demonstrated that both SCD1 mRNA expression and activity were increased in another iron overload model in mice obtained by a single iron-dextran subcutaneous injection. Moreover, we found, in both models, that SCD1 mRNA was not only influenced by the quantity of iron in the liver but also by the duration of iron overload since SCD1 mRNA upregulation was not detected in earlier stages of iron overload. In addition, we found that cellular repartition likely influenced SCD1 mRNA expression. In conclusion, we demonstrated that iron excess in the liver induced both the expression of SCD1 mRNA and its corresponding enzymatic activity. The level and duration of iron overload, as well as cellular repartition of iron excess in the liver likely play a role in this induction. The fact that the expression and activity of SCD1, an enzyme adding a double bound into saturated fatty acids, are induced in two models of iron overload in mice leads to the conclusion that iron excess in the liver may enhance the biosynthesis of unsaturated fatty acids. (+info)
Iron overload following manganese exposure in cultured neuronal, but not neuroglial cells.
(56/690)
Our previous studies show that manganese (Mn) exposure inhibits aconitase, an enzyme regulating the proteins responsible for cellular iron (Fe) equilibrium. This study was performed to investigate whether Mn intoxication leads to an altered cellular Fe homeostasis in cultured neuronal or neuroglial cells as a result of disrupted Fe regulation. Our results reveal a significant increase in the expression of transferrin receptor (TfR) mRNAs and a corresponding increase in cellular 59Fe net uptake by PC12 cells, but not astrocytes, following Mn exposure. These findings suggest that alteration by Mn of cellular Fe homeostasis may contribute to Mn-induced neuronal cytotoxicity. (+info)