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)

Hb Lulu Island [beta 107(G9)Gly-->Asp] was discovered in an East Indian female who carried a common beta zero-thalassemia allele, i.e., codon 15, TGG-->TAG (is a stop codon) in trans. Both abnormalities were detected through sequencing of the amplified beta-globin genes and were confirmed by hybridization with 32P-labeled probes. Hb Lulu Island is mildly unstable with a borderline decrease in oxygen affinity; its instability is less severe than that of Hb Burke or beta 107(G9)Gly-->Arg. The compound heterozygosity expresses as a thalassemia intermedia with moderate anemia, a variable need for blood transfusions, Heinz body formation, and a red cell morphology which is typical for such a condition. The level of HbA2 was greatly increased (6.5-7.0%) as was the delta chain level (12% of total non-alpha) probably because of the instability of Hb Lulu Island and the decreased ability of the beta x chain to form dimers with the normal alpha chain.
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PMID:Hb Lulu Island (alpha 2 beta 2 107[G9]Gly-->Asp)-beta zero- thalassemia (codon 15; TGG-->TAG), a form of thalassemia intermedia. 766 21

Sickle cell anemia is a disease of abnormal rheology caused by acute and reversible, as well as chronic and irreversible, changes in the properties and deformability of sickle erythrocytes. Deformability is determined by several factors, including intracellular sickle hemoglobin polymerization, the abnormal membrane properties of sickle cells, and the abnormal rheological properties of the soluble concentrated hemoglobin solution within dense sickle red blood cells. In this study, we used a 5-microns pore nickel mesh filter to evaluate quantitatively the effects of these factors on the filterability of erythrocytes containing sickle hemoglobin. We used sickle trait and sickle/beta(+)-thalassemia cells, because they have minimal membrane abnormalities or density heterogeneity, to investigate the effects of polymer formation on rheological properties. We found that filterability of these cells is sensitive to small amounts of intracellular polymer and that impaired filtration is linearly related to oxygen-dependent polymer formation, up to a polymer fraction of 0.3. By increasing the proportion of dense cells in populations of normal cells or cells from individuals with sickle syndromes and equilibrating these cells with gas ligands, we estimate that polymerization, even at 95% saturation, contributes twice as much to impaired filterability of sickle erythrocytes as the abnormal membranes in homozygous sickle cell disease. At lower saturation values, the effects of polymer are even greater. The viscosity of the concentrated hemoglobin in dense cells had the smallest effect, over physiologically relevant saturation values. These results emphasize the importance of sickle hemoglobin polymerization in the pathogenesis of sickle cell disease and should help define its pathophysiology and responses to therapy in quantitative terms.
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PMID:Contributions of sickle hemoglobin polymer and sickle cell membranes to impaired filterability. 777 50

Sickle cell disease pathophysiology is mediated by acute and chronic impairment of cell flexibility due to the formation of intracellular sickle hemoglobin (Hb S) polymer as cells are partially deoxygenated in the microcirculation. We have recently developed a method to measure the relationship between the formation of intracellular polymerized Hb S and cell filtration. In this study, we have used this method to examine whether sickle cell morphology, independent of Hb S polymer fraction, had an effect on cell rheology. We primarily use sickle trait (AS) and Hb S-beta(+)-thalassemia (S-beta(+)-thal) erythrocytes with low hemoglobin F levels, which have normal membranes and few or no dense cells, to remove these confounding effects. We find that the relationship between filtration and the percentages of each "type" of morphological deformation of AS erythrocytes was different from that of the S-beta(+)-thal erythrocytes. In addition, we find that while the filtration of AS erythrocytes as a function of oxygen saturation was similar, whether measured during deoxygenation or reoxygenation, the relationship between the percentages of each type of deformed erythrocyte and oxygen saturation demonstrated hysteresis during oxygenation-deoxygenation experiments. Transmission electron microscopy, for both elongated and irregularly shaped cells, showed that similarly distorted cells could have very different amounts and alignment of polymer. These results suggests that cell morphology per se is not strongly related to filtration, whereas calculated intracellular Hb S polymer fraction predicts loss of filtration of AS and S-beta(+)-thal erythrocytes well. Measured or calculated polymer fraction values would appear to be a better parameter for the study of sickle cell disease pathophysiology and response to treatment than cell morphology studies.
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PMID:Sickle cell rheology is determined by polymer fraction--not cell morphology. 783 88

We report an uncommon association of delta beta thalassaemia and a haemoglobin (Hb) variant with high oxygen affinity in an Asian Indian family. Minimal polycythaemia was seen in a heterozygote for this novel Hb variant, Hb Headington (beta 72 (E16) Ser-->Arg), while compound heterozygosity for Hb Headington and the Indian G gamma (A gamma delta beta)(0) thalassaemia produces a marked increase in erythrocytosis with a concomitant increase in the level of the variant Hb. The HbF in such compound heterozygotes remains at a level consistent with that usually observed in individuals heterozygous for the G gamma (A gamma delta beta)(0) thalassaemia alone. The purified Hb variant showed an increased oxygen affinity, moderately decreased co-operativity and a normal Bohr effect. Results of functional studies suggest that the high oxygen affinity of Hb Headington is due to the Ser-->Arg substitution which disrupts the normal and tight interaction between A, B and E helices leading to a destabilization of the T deoxy-structure of the abnormal haemoglobin.
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PMID:Association of a novel high oxygen affinity haemoglobin variant with delta beta thalassaemia. 801 19

Vital fluorochrome hydroethidine was used for measuring relative extra- and intracellular production of active oxygen in phagocytotic blood cells in hemoglobinopathies. Hydroethidine sensitivity to diverse free oxygen forms was studied in various model systems. Probability of false-positive results was estimated. It was established that hydroethidine interacts with superoxide anion radicals in molar ratio 1:1, that intracellular production of active oxygen forms in leukocytic mass cells stimulated by phorbol myristate acetate was enhanced in patients with major beta(+)-thalassemia and in a patient with hemoglobinopathy due to unstable hemoglobin Hb-Alesha. In thalassemia minor no significant differences compared to control were reported. Potential causes and value of the results obtained are under discussion.
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PMID:[A novel method for studying the free radical status of phagocytotic blood cells in patients with hemoglobinopathies]. 802 90

In a patient with congenital erythropoietin-dependent pure erythrocytosis (EDPE) associated with hypersensitivity of erythroid progenitor cells to erythropoietin (Epo), the investigations planned to elucidate the mechanism responsible for hormone hyperproduction revealed that Epo synthesis was (1) independent of normal oxygen-mediated feedback induced by phlebotomy; (2) not modulated by adenosine as a second messenger (the treatment with the adenosine antagonist theophylline in fact left unchanged the serum Epo levels); and (3) uninfluenced by iron therapy. The Epo dose-response curve for growth of erythroid progenitor was similar to that of three age-matched thalassemia patients with increased serum Epo levels, (sEpo) suggesting that the observed erythroid progenitors hypersensitivity to Epo could represent an ex vivo artifact induced by the increased sEpo levels.
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PMID:Regulation of erythropoietin production in a case of congenital erythropoietin-dependent pure erythrocytosis. 803 89

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

The primary pathophysiological event in the erythrocytes of individuals with the various sickle syndromes is the intracellular aggregation or polymerization of sickle haemoglobin (HbS). The extent of polymerization is determined by the intracellular haemoglobin composition (% HbS and % HbS A, A2 and F), concentration (MCHC and % of dense cells) and oxygen saturation, as well as minor factors such as intracellular pH and DPG concentration. Intracellular HbS polymerization leads to a marked decrease in the flexibility or rheological properties of the sickle erythrocytes and obstruction in various microcirculatory beds, as well as chronic anaemia. Other abnormalities in the properties of the sickle erythrocytes, including membrane abnormalities, changes in ion fluxes and volume and endothelial adhesion, result from acute and chronic oxygen-linked polymerization events and may, in turn, modify polymerization. However, within a good approximation, many aspects of sickle cell disease pathophysiology--for example variations in anaemia among the different sickle syndromes--can be explained in terms of differences in polymerization tendency. Thus, the effects of alpha-thalassaemia can be explained with reference to changes in MCHC and syndromes with high HbF are understandable in terms of the sparing effect of HbF on polymerization. Recent therapeutic approaches to sickle cell disease focus on attempts to reduce intracellular HbS polymerization by altering the haemoglobin molecules, erythrocyte properties, or the distribution of intracellular haemoglobin species. The last, through pharmacological elevation of HbF, has become the central focus of much laboratory and clinical research in recent years. Agents such as hydroxyurea (with or without recombinant erythropoietin) and butyrate compounds elevate HbF (and reduce HbS) in a majority of sickle erythrocytes, thus decreasing intracellular polymerization. Current prospective protocols are designed to see if these changes cause clinical improvement at acceptable doses. Other treatment strategies, including bone marrow transplantation and possible gene replacement therapies, are also under active clinical or laboratory investigation.
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PMID:Sickle cell disease pathophysiology. 835 18

In patients with Thalassaemia Major the iron overload with alteration both of systolic and diastolic properties of left and right ventricles finally leads to symptoms of cardiac failure and is the most frequent cause of death in these patients. In the majority of asymptomatic thalassemic patients with normal myocardial mass it is possible to demonstrate an alteration of the diastolic function both with echocardiographic study and with radionuclide angiography (subclinical cardiac disease). We have also demonstrated in "ex thalassemics" with stable and heavy iron overload in the subclinical cardiac disease phase a subnormal systolic function and a slight impairment of the contractility state. Therefore our purpose was to evaluate cardiac performance emphasising the contractility properties of the left ventricle during moderate inotropic stimulation with dobutamine in thalassemic patients in subclinical cardiac disease. We are now also using this test to evaluate cardiac performance in adults thalassemic patients as a screening for marrow transplantation procedure. Dobutamine is a sympathomimetic drug (beta 1 agonist) that increases myocardial contractility and at high doses also systolic arterial blood pressure and heart rate. The half-life is extremely short and at low doses the drug has no major side effects. Continuous intravenous dobutamine infusion is largely used in the therapeutic field to treat cardiac failure and it is reported to be a very efficacious and safe therapeutic agent. Recently dobutamine stress echocardiography was reported to be an accurate non-invasive diagnostic technique for detecting cardiac dysfunction in adults with coronary artery disease (Dobutamine is used for this purpose at high dose to increase the myocardial oxygen consumption).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiac study by dobutamine stress echocardiography in thalassemic patients. 837 53

The interaction of rare Hb variants with beta(0)-thalassaemia results in a quasihomozygous state where the erythrocytes contain the variant as the only major adult Hb component. Such a situation is a unique model that enables functional studies even in the case of a neutral variant that could not be isolated from Hb A. We report here an unusual patient carrying Hb Arta, a novel Hb variant [beta 45 (CD4) Phe-->Cys], in trans with beta(0)-thalassaemia gene (beta(0) 39). The aminoacid substitution at the critical CD corner of this Hb molecular renders the molecule unstable. In addition, haem is displaced in a position that favours the deoxy (T) conformation of the variant, but less than in Hb Cheverly [beta 45 (CD4) Phe-->Ser], and results in a p50 of 43 mmHg (pH 7.4, 37 degrees C) in the red cells with preservation of cooperativity. Solution studies of the almost pure Hb Arta show a 50% decrease in oxygen affinity and normal cooperativity; the Bohr effect and the interaction with organic phosphates are similar to those of Hb A. Hb Arta retains both normal homo- and heterotropic effects allowing a well-preserved oxygen transport in vivo despite a mild anaemia.
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PMID:Hb Arta [beta 45 (CD4) Phe-->Cys]: a new unstable haemoglobin with reduced oxygen affinity in trans with beta-thalassaemia. 855 60


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