Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta-thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta-thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.
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PMID:Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta-thalassemia. 804 75

The mechanism of the inhibitory effects of chelators (desferrioxamine, EDTA, rutin, phenanthroline and ADP) on the production of oxygen radicals in the Fenton reaction and on lipid peroxidation of rat brain homogenates has been studied. It was found that the inhibitory effects of the chelators correlated well with their abilities to oxidize ferrous ions in solution and brain homogenates. On these grounds, it was concluded that the oxidation of Fe2+ ions inside a ferrous ion-chelator complex is a major mechanism of inhibitory effects of these chelators on free radical processes. It is proposed that this mechanism is also realized during therapeutic treatment with chelators of patients with "free radical" pathologies such as Fanconi anemia, beta-thalassemia and Diamond-Blackfan anemia.
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PMID:Mechanism of inhibitory effects of chelating drugs on lipid peroxidation in rat brain homogenates. 813 55

In order to study the effects of acclimatization of Plasmodium in beta-thalassaemic mice, we used a mouse model of beta-thalassaemia (DBA/2J/beta-thal/beta-thal), similar to that observed in humans. We acclimatized 3 rodent malarias (P. berghei, P. chabaudi and P. yoelii) in DBA/2J and DBA/2J/beta-thal mice lines, by 4 intraperitoneal serial transfers. All 3 rodent malarias developed in red blood cells of beta-thalassaemic mice without losing their virulence. There was no delay in infection and peaks of parasitaemia were similar in beta-thalassaemic and normal mice. The mortality occurred earlier in beta-thalassaemic mice than in control mice for P. berghei and P. chabaudi. The difference was more pronounced for P. yoelii NS where normal mice did not die. These results could be explained by a failure of erythropoiesis in beta-thalassaemic mice, which are unable to compensate for the destruction of red blood cells by the parasites, and the mice died of anaemia. Ultrastructural examination of the rodent malaria parasites in beta-thalassaemic RBC showed a normal development even in the presence of Heinz bodies. In conclusion, no effective protection against malaria was provided by the beta-thalassaemia in this mouse model.
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PMID:The course of Plasmodium berghei, P. chabaudi and P. yoelii infections in beta-thalassaemic mice. 872 90

Few reports exist concerning heart transplantation in recipients with end-stage myocardiopathy-associated heart failure caused by iron overload occurring with beta-thalassaemia, Diamond-Blackfan syndrome or haemochromatosis. Seven potential transplant candidates (six male, one female, mean age 26 years) with such heart failure, following desferrioxamine application subcutaneously over a number of years, and intravenously during their hospitalization before transplantation, were retrospectively analysed. Five were New York Heart Association (NYHA) class IV, three experienced one or more resuscitations immediately before transplantation could be performed. Continuous, high-volume, veno-venous haemofiltration was necessary in two patients. One of these two candidates additionally had to be bridged, first with a right ventricular, then with a biventricular assist device. Five of the seven patients survived, two with haemochromatosis, one with beta-thalassaemia major and one with Diamond-Blackfan syndrome following transplantation. One non-transplanted candidate with beta-thalassaemia major has been recompensated for 5 years. Survival was 14-74 months. Our results demonstrate the feasibility and indication of transplantation in patients with such heart failure and the satisfying outcome of immunosuppression is described.
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PMID:Heart transplantation for end-stage heart failure caused by iron overload. 916 90

We describe the four most common groups of neonatal anemia and their treatments, with particular emphasis on erythropoietin therapy. The hemolytic anemias include the ABO incompatibility (much more frequent, nowadays, than the Rh incompatibility, which has nearly disappeared following the use of anti-D immunoglobulin in postpartum Rh-negative mothers), hereditary spherocytosis and G-6-PD deficiency. Among hypoplastic anemias, that caused by Parvovirus B19 predominates, by far, over Diamond-Blackfan anemia, alpha-thalassemia and the rare sideroblastic anemias. "Hemorrhagic" anemias occur during twin-to-twin transfusions, or during feto-maternal transfusions. Finally, the multifactorial anemia of prematurity develops principally as a result of the rapid expansion of the blood volume in this group of patients. Erythropoietin therapy, often at doses much higher than those used in the adult, should be seriously considered in most cases of non-hypoplastic neonatal anemias, to minimise maximally the use of transfusions.
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PMID:[Common anemias in neonatology]. 1006 73

There has been progress in the application of stem cell transplantation for treatment of an increasing number of severe congenital and acquired bone marrow disorders, currently restricted by the availability of human leukocyte antigen (HLA)-matched related donors. Preimplantation HLA typing has recently been introduced to improve the access to stem cell therapy for inherited bone marrow failures. Preimplantation genetic diagnosis (PGD) provides an option not only for avoiding an affected pregnancy with thalassemia and other inherited disorders but also for preselection of the HLA-compatible donors for affected siblings. Multiple short tandem repeat markers throughout the HLA region are applied for this purpose, allowing 100% accuracy of HLA typing, through picking up possible recombination in the HLA region, as well as the copy number of chromosome 6, which affect accuracy of preimplantation HLA typing. Present experience of preimplantation HLA typing includes preimplantation HLA typing in 180 cycles, 122 of which were done as part of PGD for Fanconi anemia, thalassemia, Wiscott-Aldrich syndrome, hyper-immunoglobulin M syndrome, hypohidrotic ectodermal dysplasia with immune deficiency, and X-linked adrenoleukodystrophy, and 58 for the sole purpose of HLA typing for leukemias and for aplastic and Diamond-Blackfan anemia. The applied method resulted in the accurate preselection and transfer of 100% HLA-matched embryos, yielding already three dozen clinical pregnancies and the birth of two dozen HLA-matched children to the siblings requiring stem cell transplantation. Successful therapy with HLA-matched stem cells, obtained from these PGD children, has been achieved already for Diamond-Blackfan anemia hypohidrotic ectodermal dysplasia with immune deficiency and thalassemia.
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PMID:Preimplantation genetics: Improving access to stem cell therapy. 1633 69

Hypocholesterolemia of unknown etiology has been previously described in various chronic anemias. Few small studies also suggested that those patients have a lower incidence of atherosclerotic events. The aim of our study was to determine the extent of hypocholesterolemia in various types of anemias. We studied 59 patients with chronic anemias associated with high-erythropoietic activity (thalassemia intermedia, congenital dyserythropoietic anemia type I, congenital spherocytosis), 8 patients with low-erythropoietic activity anemias (acquired aplastic anemia, Fanconi anemia, and Diamond Blackfan anemia), and 20 healthy controls. Mean serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, hemoglobin, serum ferritin, soluble transferrin receptor (STR), and serum erythropoietin levels were determined in each patient. All patients with chronic anemia and increased erythropoietic activity had hypocholesterolemia, whereas none of those with low erythropoietic activity was hypocholesterolemic. Mean serum cholesterol, HDL cholesterol, and LDL cholesterol levels were found to be significantly lower in the high-erythropoietic activity group (80+/-19 mg/dl; 31+/-10 mg/dl; 35+/-14 mg/dl, respectively) compared with the control group (P<0.001; 0.001; 0.001, respectively) and the low-erythropoietic activity group (P<0.001; 0.001; 0.01, respectively). Significant inverse correlation (R2=0.507) was observed between serum cholesterol and STR levels, which in the absence of iron deficiency reflect bone marrow activity. Taken together, our results imply that hypocholesterolemia accompanies anemias with high-erythropoietic activity. We suggest that the high-erythropoitic activity-associated hypocholesterolemia is due to increased cholesterol requirements by the proliferating erythoid cells. Further studies are needed to elucidate the exact mechanism and the possible clinical consequences of this phenomenon.
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PMID:Hypocholesterolemia in chronic anemias with increased erythropoietic activity. 1703 15

A 10-year-old girl with steroid-resistant Diamond-Blackfan anemia (DBA) developed agranulocytosis 9 weeks after chelation with deferiprone was initiated (45 mg/kg daily, 60% of recommended dose) in addition to her ordinary deferoxamine therapy. The blood counts, checked weekly, dropped markedly between weeks 8 and 9. She rapidly developed a septicemia and was admitted with high fever (40.9 degrees C), white blood cell count 0.4 x 10(9)/L, absolute neutrophil count 0.1 x 10(9)/L and platelets 114 x 10(9)/L. She was administered broad spectrum antibiotics, G-CSF (10 microgram/kg daily) and corticosteroids but remained neutropenic and died 6 weeks after admission. Bone marrow examination day 23 revealed areas with low cellularity (around 30%), but also areas with infiltrates of T cells; granulopoiesis and erythropoiesis were scarce. We conclude that weekly neutrophil monitoring is not sufficient to avoid fatal agranulocytosis. We suggest that deferiprone not be prescribed to DBA patients unless the clinical indications are particularly strong, and that the risk of agranulocytosis in thalassemia patients be carefully considered.
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PMID:Fatal agranulocytosis after deferiprone therapy in a child with Diamond-Blackfan anemia. 1734 64

Seventeen children (mean age: 7.2 years) with genetic defects involving hematopoietic cell production or function, underwent 19 allogeneic stem cell transplantations from HLA identical siblings. Twelve children were suffering from thalassemia major; 2 from Diamond Blackfan anemia; 2 from Fanconi anemia and 1 from congenital dyserythropoietic anemia. The disease free survival was 77% with a mean follow up of 36 months. The major complications were graft versus host disease, veno-occlusive disease, CMV infection and hemorrhage. One case each of thalassaemia major and Fanconi anemia rejected the graft after 1 year and 11 months, respectively. Both patients were successfully transplanted second time from the same donor with some modification in the conditioning regimen and stem cell source.
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PMID:Hematopoietic stem cell transplantation in children with genetic defects. 1921 90

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.
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PMID:Pituitary iron and volume predict hypogonadism in transfusional iron overload. 2221 95


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