Biomedical subjects
Publications and source records attributed to J G Adams.
The current concepts of alpha-thalassemia including incidence, genetics, clinical spectrum and diagnosis are reviewed. Speculation concerning clinical application of the molecular biology of alpha-thalassemia is also presented.
Presented is a 12-year-old girl with epidermolysis bullosa who required anesthesia for extensive dental rehabilitation. Patients with epidermolysis bullosa can be given anesthetics with minimal complications if the preoperative evaluation is complete, the selection of anesthesia is appropriate, and certain procedures which cannot be safely used in patients with this disease are conscientiously avoided.
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.
Hemoglobin Arlington Park was detected accidentally as result of the use of a hemolysate which contained hemoglobin with normal electrophoretic mobility as a control for peptide mapping. Peptide maps of this hemolysate revealed 3 new peptides resulting from 2 amino acid substitutions to give to new variant with the composition (beta6 Glu replaced by Lys, 95 Lys replaced by Glu).
A patient with Hb Hasharon had severe hemolytic anemia after several days of daily ingestion of 2 gm of sulfisoxazole. After recovery, her erythrocytes were incubated with the drug, leading to preferential oxidation and precipitation of the abnormal hemoglobin. Since carboxyhemoglobin and cyanmethemoglobin Hasharon were as stable in the heat stability test as identically liganded Hb A, we conclude that the substitution of the hydrophilic aspartate residue by histidine on the surface of the molecule at alpha47 has led by a still unknown mechanism to an interaction of hemoglobin with the drug that labilized the heme-globin bond. Since Hb Hasharon has been found in several unrelated families, the risk of drug-induced hemolytic anemia in such carriers deserves emphasis.
Explore the source record for details and available documents.
The extent of variability in the number of human hemoglobin (Hb) alpha chain loci has not yet been conclusively determined. There is evidence that in some populations individuals may possess two alpha-chain loci, while in other populations only one locus is present. Electrophoresis of peripheral blood from 53 heterozygotes for Hb G Philadelphia (alpha 68 Asn leads to Lys) revealed that the proportion of Hb G is trimodally distributed, with modes at approximately 20, 30, and 40% Hb G. Familial, hematologic, and statistical studies suggest that hte proportion of Hb G is not random but is genetically controlled and inversely correlated with mean cell volume. Two alternative genetic models are proposed to explain these findings: one assums alpha-thalassemia, while the other postulates variability in the number of alpha-chain loci in the American Black population. Biosynthetic studies of blood from 15 subjects revealed balanced synthesis of alpha and beta globin chains in heterozygotes from all three classes, strongly supporting variable gene dosage rather than alpha-thalassemia as the mechanism underlying the observed trimodality in the proportion of Hb G. Incompatibilities between out results and current concepts of alpha-thalassemia are discussed in the context of differences between Black compared with Oriental and Italian forms of Hb H disease.
Hemoglobin Hope (beta(H14)136gly leads to asp), a mildly unstable variant, was found to have decreased oxygen affinity, a normal Bohr effect and diminished cooperativity. Decreased oxygen affinity of hemoglobin Hope may explain the previous failure to find an appropriate response to hemolysis in individuals studied who were heterozygous for both hemoglobin Hope and sickle hemoglobin. Salt bridge formation between NA1 valine and H14 aspartic acid may stabilize the beta Hope subunit in its deoxy form thus producing intrinsically low oxygen affinity and reduced cooperativity.
Mild forms of alpha thalassaemia are difficult to detect in adults. Since alpha thalassaemia existing with structural defects of the beta chain of haemoglobin may lead to decreased levels of the abnormal haemoglobin, we examined individuals having sickle-cell trait for the possible coexistence of alpha thalassaemia. Patients with sickle-cell trait having haemoglobin-S (Hb-S) levels less than commonly expected were compared to two control groups--one with sickle-cell trait and the usual levels of Hg S and one with normal haemoglobin. Twenty-one patients with sickle-cell trait having Hb-S concentrations below 35% had 65.8% Hb A, 31.8% Hb S, and a mean corpuscular volume of 81.6 fl. Studies of the relative rates of alpha-, betaS- and betaA-chain synthesis in 14 of these individuals showed a mean alpha:beta ratio of 0.76. In patients with normal haemoglobin as well as in sickle-cell trait with Hb-S levels above 35%, this ratio was unity. These findings are consistent with the presence of alpha thalassaemia in patients with sickle-cell trait who have lower than usual levels of Hb S and microcytosis.
An electrophoretically fast-moving hemoglobin variant was found in a 2-yr-old boy who was referred for evaluation with findings of iron deficiency anemia. The anemia was corrected, and no hematologic abnormality remained after treatment with iron. Oxygen affinity of the blood was normal, and no evidence was found of instability of the variant hemoglobin. Structural studies demonstrated a substitution of aspartic acid for alanine at beta76 (E20). This change did not appear to cause any functional disruption of the hemoglobin in this patient, as would be predicted by the position of the affected animo acid residue on the surface of the molecule.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Hemoglobin Ann Arbor, in which arginine replaces leucine in position 80 of the a chain, occurs in aflected individuals in low proportion to hemoglobin A. Biosynthetic studies were perforined on reticulocytes of a patient heterozygous for this hemoglobin. These studies suggested that the low percentage of hemoglobin Ann Arbor is prinlarily due to preferential destruction of the abnormal component. The reduced concentration of alpha Ann Arbor chains was also reflected in a decreased synthesis of normal beta chains.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.