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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromatographic separation of labeled globin chains was performed in stroma-free hemolysates prepared from peripheral blood and bone marrow cells of 11 patients with beta O-thalassemia and 2 patients with sickle cell anemia. A small radioactivity peak, slightly preceding the beta-chain and more prominent in bone marrow cells, was often observed. This peak, which represents synthesis of non-globin proteins, did not exceed 5% of the radioactivity incorporated in the alpha-chain. It is concluded that contamination of the beta-chain with non-globin proteins undoubtedly occurs, but its extent is insufficient to explain the different synthetic ratios which have been repeatedly observed in peripheral blood and in bone marrow cells of patients with heterozygous beta-thalassemia.
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PMID:Globin synthesis in bone marrow cells of patients with sickle cell anemia and beta O-thalassemia: contamination of the beta-chain with non-globin proteins. 47 78

Globin synthesis studies are useful in the analysis of thalassemia syndromes. We have applied globin synthesis and free alpha-chain pool studies of peripheral blood to characterize hematologic disorders where alpha- or beta-thalassemia was present in combination with HbS or HbC. In 60 non-thalassemic controls, the beta/alpha specific activity ratio was 1.01 +/- 0.06 (SD). In three patients with HbS-beta0-thalassemia, the (betas + gamma)/alpha ratios were 0.48-.067. In four patients with HbSS-alpha-thalassemia, the (BETAS/ALPHA RATIO was 1.26 +/- 0.18 (1.13-1.53). The radioactive free alpha-chain pool in three patients with HbS-beta0-thalassemia was elevated (35.1%-53.0%), while three patients with HbSS-alpha-thalassemia had decreased free radioactive alpha-chain pools (3.2%-6.4%); both were significantly different from the mean (15.1% +/- 2.6%) of the 17 iron-sufficient controls. Simultaneous studies of the fraction of newly synthesized alpha chain contained in the free alpha-chain pool in peripheral blood and bone marrow demonstrated that this fraction was larger in peripheral blood than in marrow, and that the differences between thalassemia patients and controls previously found in bone marrow using these methods were also present in peripheral blood. The results indicate that even when family studies are not possible, patients with HbS in combination with alpha- or beta0-thalassemia can be differentiated from those with homozygous sickle cell disease by globin synthesis and free alpha-chain pool studies using peripheral blood.
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PMID:Detection of sickle alpha- or beta0-thalassemia by studies of globin biosynthesis. 85 59

The present study indicates that newly completed haemoglobin S molecules rather than free betas-chains are preferentially bound to the reticulocyte stroma of individuals with sickle cell trait and sickle cell anaemia. Reticulocytes from indivdiuals with HbAA, AS and SS were incubated with [3H]eucine from 1.25 min to 120 min. Unlike the stroma-free haemolysates, the stroma of all individuals contained an excess of labelled beta-chains relative to alpha-chains after short incubation times. In haemoglobin AA and AS individuals, the stromal betaA radioactivity was 1--2% of the total cellular betaA radioactivity. In haemoglobin AS and SS individuals, the stromal betaS radioactivity was 3--5% and 10--20% of the total cellular betaS radioactivity, respectively. All of the stroma beta-chain radioactivity was associated with completed haemoglobin molecules. Because of the unlabelled free alpha-chain pool found in reticulocytes, after short incubation times newly completed haemoglobin molecules have predominantly labelled beta-chains and unlabelled alpha-chains. These findings suggest that part of the discrepancy between the stroma and stroma-free haemolysate alpha/beta radioactivities seen in HbAS and HbSS individuals may result from normal labelling kinetics. A pulse chase experiment performed on an individual with HbSS revealed that comleted HbS molecules, in addition to being associated with the stroma, were lost from the cell.
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PMID:Evidence for rapid loss of newly synthesized haemoglobin S molecules in sickle cell anaemia and sickle cell trait. 87 3

The wide range of globin synthesis ratios reported in patients with sickle cell disease casts doubt on whether the presence of genes for alpha- or beta-thalassemia in combination with Hb S can be detected by globin synthesis studies. We have studied globin synthesis in 20 patients with Hb SS who had a mean betaA/alpha ratio of 1.05+/-0.04, similar to that of 28 control children. In nine of these patients the percentage of newly synthesized radioactive alpha-chains in dimer or monomer forms was 16.3%+/-1.3, also similar to the control subjects. The remainder of alpha-chain was in hemoglobin tetramer. In nine patients with Hb SC, the (non-alpha)/alpha ratio was 0.97+/-0.04, and the free alpha-chain pool radioactivity in four patients was 14.1%+/-4.2. In three patients with Hb CC, betac/alpha ratios were 0.99, 1.07, and 1.10. These results indicate that globin synthesis ratios and alpha-chain radioactivity in the free alpha-chain pool of peripheral blood of patients with Hb SS, Hb SC, and Hb CC have narrow ranges, close to those of nonthalassemic controls. The data provide a basis for detecting syndromes with Hb S or Hb C associated with alpha- or beta-thalassemia. This precise differentiation is important for clinical studies of severity in sickle cell disease and for genetic counseling.
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PMID:Globin biosynthesis in sickle cell, Hb SC, and Hb C diseases. 87 50

The diseases commonly confused with sickle cell anemia include sickle cell beta-thalassemia in which synthesis of betaA-chains are completely suppressed (HbS-betao-thalassemia). We obtained hematologic measurements and studied globin biosynthesis in five patients with this disorder and compared the results with those obtained in five patients with "mild" sickle cell anemia and seven individuals with sickle cell-beta-thalassemia having hemoglobin A levels of 20-30% (HbS-beta+-thalassemia). A distinction between HbS-betao-thalassemia and sickle cell anemia was not always possible on clinical, hematologic, or electrophoretic grounds. Thalassemia heterozygotes had hypochromia and microcytosis, not generally a feature of sickle cell anemia, although overlap of values did exist. The ratio of alpha to non-alpha, or alpha to betaS-chains in sickle cell anemia approximated unity, whereas patients with HbS-betao-thalassemia had a deficit of beta-chain production relative to that of the alpha-chain. The differentiation of HbS-betao-thalassemia and sickle cell anemia can be best made on the basis of family or biosynthetic study. We estimated the regional prevalence of HbS-betao-thalassemia to be 1:23,000 of the black population.
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PMID:Clinical, hematologic and biosynthetic studies in sickle cell-betao-thalassemia: a comparison with sickle cell anemia. 98 35

There is evidence from both in vivo and in vitro studies that the synthesis of hemoglobin can be modified by posttranslational alterations in the assembly of the tetrameric molecule. Globin biosynthesis in reticulocytes of patients with sickle cell disease was studied to ascertain the effects of lead and ethanol on gamma-globin chain synthesis and hemoglobin assembly. In incubations containing lead (400 micrograms/dl) or ethanol (1.0 M) there were 86.7 +/- 139.7% and 542.7 +/- 397.0% increases in the relative synthesis of the gamma-globin chain. This was associated with a relative reduction in alpha-chain synthesis, as estimated by changes in the alpha/gamma + beta S synthesis ratio, as well as a marked reduction in total globin synthesis.
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PMID:Effect of lead and ethanol upon gamma-globin synthesis in sickle reticulocytes. 243 Apr 53

Methyl acetyl phosphate inhibits the sickling of erythrocytes in vitro. Its mechanism of action is through the selective acetylation of some of the amino groups at the 2,3-diphosphoglycerate (2,3-DPG) binding site of the hemoglobin molecule. Only 3 of a total 24 amino groups per alpha beta-dimer of hemoglobin are reactive. These groups are Val-1, Lys-82, and Lys-144 on the beta-chain of hemoglobin. None of the groups on the alpha-chain are acetylated. Acetylated hemoglobin S has an increased solubility as well as a reduced ability to bind to 2,3-DPG. Methyl acetyl phosphate is able to penetrate the erythrocyte membrane and successfully acetylate intracellular hemoglobin S without causing cell lysis. Sickle erythrocytes treated with methyl acetyl phosphate maintain an oxy-like profile of cell density distribution in a phthalate ester gradient. The oxygen binding property of erythrocytes after the treatment with methyl acetyl phosphate is not changed significantly from that of untreated cells. Our in vitro results indicate that further preclinical testing of methyl acetyl phosphate in sickle cell anemia is warranted.
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PMID:Methyl acetyl phosphate, a new type of antisickling agent: site-specific acetylating agent toward the 2,3-DPG binding site in hemoglobin S. 323 14

Two compounds that inhibit the sickling of erythrocytes in vitro are sodium cyanate and glyceraldehyde. The former compound reacts selectivity with the NH2-terminus of the alpha-chain of hemoglobin S and thereby leads to an increased oxygen affinity of the protein and inhibition of erythrocyte sickling. The toxicity associated with oral administration of sodium cyanate precludes its use in the treatment of sickle cell anemia; administration by extracorporeal routes is still under consideration. The compound glyceraldehyde also inhibits the sickling of erythrocytes in vitro but does so by a different mechanism than sodium cyanate; it interferes directly with the gelation of deoxyhemoglobin S. Glyceraldehyde also displays selectivity; only five of a total 24 amino groups per alpha beta dimer of hemoglobin S are reactive. Preclinical studies on this compound as a potential treatment for sickle cell anemia are in progress.
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PMID:The mechanism of action of two anti-sickling agents: sodium cyanate and glyceraldehyde. 671 64

Using the restriction endonucleases, Bam HI, Bgl II, Hind III and EcoRI, the alpha-gene arrangements were investigated in heterozygotes and homozygotes for the sickle cell haemoglobin (Hb S). In the heterozygotes (Hb AS) group the Hb S level showed a trimodal distribution due to presence of the normal alpha-globin genes (alpha alpha/alpha alpha) or of one (-alpha/alpha alpha) or two (-alpha/-alpha) alpha-genes deletions. The haematological analytes inversely correlated with the associated alpha-thalassaemia (alpha-thal.) genes. In the Hb S homozygotes (Hb SS), associated alpha-thalassaemia was found to ameliorate the clinical manifestations and improved the haematological values. Co-existing triple alpha-gene arrangement, alpha alpha alpha anti 3.7/, with Hb AS did not influence the haematological analytes. In Hb SS, presence of alpha alpha alpha anti 3.7/ resulted in a severe sickle cell anaemia (SCA) with a high severity index (> 11) and with frequent crises, transfusion requirements and hospitalizations. It is suggested that reduced level of alpha-chain ameliorates SCA while excess of alpha-globin chain production gives rise to a severe form of SCA.
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PMID:On the molecular interactions between alpha-thalassaemia and sickle cell gene. 841 13

Three novel recombinant mutants of sickle hemoglobin (Hb S, beta 6Glu-->Val) have been constructed to assess the role of proline at alpha 114 and threonine at beta 87 in the polymerization of deoxygenated Hb S. Using the hemoglobin expression system (pHE2) designed in our laboratory, four plasmids were expressed separately in Escherichia coli to produce the four recombinant hemoglobins: r Hb S (beta 6Glu-->Val); r Hb S-Chiapas (beta 6Glu-->Val, alpha 114Pro-->Arg); r Hb S-D-Ibadan (beta 6Glu-->Val, beta 87Thr-->Lys); and r Hb S-Chiapas-D-Ibadan (beta 6Glu-->Val, alpha 114Pro-->Arg, beta 87Thr-->Lys). The structural features of these four recombinant hemoglobins were analyzed by proton nuclear magnetic resonance spectroscopy, and were found to be similar to those of human normal adult hemoglobin (Hb A) under identical conditions. The recombinant hemoglobins were further investigated by measuring the oxygen-binding properties, which were found to be comparable to those of Hb A. Delay-time gelation studies of the three mutants of r Hb S were carried out in 1.8 M potassium phosphate (pH 7.34) by a temperature jump from 4 degrees C to 30 degrees C and an increase in delay time over that of r Hb S was observed, as well as an overall decrease in the polymerization of these three mutants of Hb S. A more detailed and quantitative investigation has also been carried out to determine the equilibrium solubility (Csat) in 0.1 M potassium phosphate (pH 7.35) at 25 degrees C of the three Hb S mutants as well as of mixtures of these mutants with Hb S versus mixtures of fetal hemoglobin (Hb F) and Hb A with Hb S. The inhibition of polymerization demonstrated in these experiments suggests that the interactions involving the two amino acid residues alpha 114Pro and beta 87Thr are very important to the formation of Hb S polymer, and modification of these amino acids results in an anti-sickling potential. Of particular interest is the inhibitory effect of alpha 114Pro-->Arg, which offers a novel opportunity to use an alpha-chain construct, in addition to a beta-chain construct in the same vector, in gene therapy for sickle cell anemia, with the objective of modifying a larger number of hemoglobin tetramers at a given level of expression.
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PMID:Roles of alpha 114 and beta 87 amino acid residues in the polymerization of hemoglobin S: implications for gene therapy. 891 2


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