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Biomedical subjects

S Charache

Publications and source records attributed to S Charache.

At least 109 records · Page 6Linked to original sources
PubMed1977

Hemoglobin SC, SS/GPhiladelphia and SOArab diseases diagnostic importance of an integrative analysis of clinical, hematologic and electrophoretic findings.

Hemoglobin studies are presented on two children in whom electrophoretic analysis of hemolysates at alkaline pH initially suggested the diagnosis of hemoglobin SC disease. In both patients the course of the disease was unusually severe, blood smears contained irreversibly sickled cells, and crystal formation did not occur when red cells were incubated in 3 per cent sodium chloride solution. Each of these findings is inconsistent with the interpretation of the electrophoretic patterns. Family studies demonstrated that one of the patients had sickle cell anemia and was also a carrier of an alpha chain variant; citrate agar electrophoresis at pH 6.2 of the second child's hemolysate revealed that the "C-like" hemoglobin was not hemoglobin C. Tryptic peptide analyses of the nonhemoglobin S fractions showed that the first child has SS/GPhiladelphia disease and that the second child has SOArab disease. These observations emphasize the importance of integrating the clinical and hematologic data with the results of electrophoretic procedures in order to define precisely the hemoglobin abnormality in patients with sickling disorders.

Anemia, Sickle Cell↗
PubMed1977

Postsynthetic deamidation of hemoglobin Providence (beta 82 Lys replaced by Asn, Asp) and its effect on oxygen transport.

Carriers of hemoglobin Providence have three types of beta chain in their hemolysates. The two abnormal chains have asparagine (Providence N, Prov N) or aspartic acid (Providence D) at position beta 82, instead of lysine. In vitro, only two beta chains are synthesized by reticulocytes of carriers, betaA and betaProv N. In vivo studies showed that the specific activity of Providence N was initially 10-fold higher than that of Providence D; the specific activities of the two labeled hemoglobins were approximately equal 5 wk after injection of isotope. Oxygen affinity of carriers' blood was somewhat increased, but they were not polycythemic. The affinity of the purified hemoglobins Providence was decreased. Addition of 2, 3 diphosphoglycerate had little effect on the affinity of either hemoglobin component, and addition of inositol hexaphosphate produced no change in the affinity of Providence D. These studies demonstrate that Providence N is deamidated to Providence D during the life span of the erythrocyte, and suggest this finding may represent only an easily observed prototype of posttranslational modification of proteins in general. Despite and abnormal P50 of the blood, oxygen transport is probably normal in carriers of the abnormal hemoglobins.

Adolescent↗
PubMed1976

Delta-beta-thalassemia is due to a gene deletion.

DNA has been prepared from peripheral blood or cultured skin fibroblasts obtained from three Sicilian and one Greed deltabeta-thalassemia homozygotes. Globin-gene analysis was carried out using a cDNAbeta probe, and the results indicate that deltabeta-thalassemia has arisen from a deletion of the beta-globin genes. A similar result was obtained using DNA prepared from cultured skin fibroblasts from an individual homozygous for the Negro form of hereditary persistence of fetal hemoglobin (HPFH). In both cases, the deletion has spared the Ggamma and Agamma loci directing the gamma chains of hemoglobin F, but it has not been possible to demonstrate any difference between the size of the deletion involved in the production of delta-beta-thalassemia and that which gave rise to HPFH. These experiments provide further direct evidence that deletions of critical areas of the gamma-delta-beta gene cluster result in persistent gamma chain synthesis in adult life.

Chromosome Aberrations↗
PubMed1976

The Negro variety of hereditary persistence of fetal haemoglobin is a mild form of thalassaemia.

Further studies have been carried out on blood of the 15-year-old Negro male from Baltimore who was the first reported case of the homozygous state for hereditary persistence of fetal haemoglobin. His red cells contain only Hb F; Hbs A and A2 have never been detected. Over a 15-year period of follow up the red cells of this individual have shown persistent microcytosis with reduced MCH and MCV values. His whole-blood p50 value is decreased, probably because of lack of interaction between Hb F and 2,3-diphosphoglycerate. However, his haemoglobin level at the age of 15 years is lower than would be predicted from the degree of increased oxygen affinity. Globin-chain synthesis studies suggest that this is because he has a mild thalassaemia disorder with an alpha/gamma-chain production ratio of about 1.5, similar to that found in beta-thalassemia heterozygotes. Thus Negro HPFH appears to be a well-compensated form of delta beta thalassaemia.

Adolescent↗
PubMed1976

Evaluation of extracorporeal alkylation of red cells as a potential treatment for sickle cell anemia.

Nitrogen mustard and nor-nitrogen mustard inhibit sickling, but the concentrations required would be associated with unacceptable toxicity if these agents were administered to patients. Red cells could be treated extracorporeally and infused back into donors, if the alkylating agent could be removed or inactivated, if the treatment per se did not significantly shorten red cell survival, and if viable alkylated lymphocytes could be eliminated from the treated blood. To estimate whether these conditions could be met in a clinical trial, red cells from four dogs were alkylated at 6-wk intervals. No toxic reactions were observed, although not all nor-nitrogen mustard was removed by the washing procedure. Red cell survival was shortened to about half that of control cells, using concentrations of alkylating agent which reduce sickling by 50%. Lymphocytes from treated blood could still exclude trypan blue, but could not be shown to circulate after reinfusion into donor dogs. If alkylating agents are used to treat patients' cells, inhibition of sickling may outweigh the shortening of red cell life span induced by the treatment; blood should probably be irradiated before infusion to avoid administration of alkylated and potentially mutated, but viable, lymphocytes.

Alkylating Agents↗
PubMed1975

Hemoglobin Richmond. Subunit dissociation and oxygen equilibrium properties.

In hemoglobin Richmond (beta102 leads to Lys), amino acid substitution has occurred at the same site as the mutation in hemoglobin Kansas (beta102 Asn leads to Thr), a variant with very low oxygen affinity. Although hemoglobin Richmond has been shown to have increased tetramer-dimer dissociation, its oxygen affinity has been inferred to be normal from studies on hemolysates of carriers. We have isolated hemoglobin Richmond and have further studied its properties. We confirm that the oxygen affinity of pure hemoglobin Richmond under conditions similar to those found in vivo is normal. However, the Bohr effect of the variant hemoglobin is markedly abnormal. Its oxygen affinity is low at high pH and high at low pH, relative to hemoglobin A. The tetramer-dimer equilibrium displays a strong pH dependence such that protons promote dissociation. A model is presented in which the structural change in hemoglobin Richmond results in low oxygen affinity, like hemoglobin Kansas. However, the close linkage between tetramer-dimer dissociation and proton concentration seen with hemoglobin Richmond results in normal oxygen affinity at intracellular pH and hemoglobin concentration, and carriers display no hematological abnormalities.

Amino Acid Sequence↗
PubMed1975

Polycythemia produced by hemoglobin Osler (beta-145 (HC2) Tyr yields Asp).

Polycythemia in a black woman was associated with hemoglobin Osler. In this hemoglobin the tyrosine at the penultimate position of the beta chain is replaced by aspartic acid. As a result oxygen affinity of the hemoglobin is very high, heme-heme interaction is absent, and the influence of hydrogen ion and 2,3 diphosphoglycerate on oxygen affinity is attenuated.

Adult↗
PubMed1975

Toxic-therapeutic ratio of sodium cyanate.

Six patients with sickle cell anemia were treated with sodium cyanate (30 mg/kg/day). In four, treatment was stopped because of definite or suspected toxicity, and no improvement was seen in the other two. Most alarming was the sudden development of peripheral motor neuropathy in a patient whose red blood cells contained less than 0.6 mols NCO-/mol of hemoglobin: six months after treatment was stopped, function had not completely returned in this patient. Safe oral dosage regimens may not be effective, but extra-corporeal treatment of sickle cells with cyanate, or other compounds, might circumvent that problem.

Adult↗
PubMed1973

Hemoglobin Okaloosa (beta 48 (CD7) leucine leads to arginine). An unstable variant with low oxygen affinity.

A slow-moving hemoglobin with electrophoretic mobility similar to that of hemoglobin S was discovered in a white laboratory technologist. She had an elevated reticulocyte count, as did several members of her family. Her red cell survival was shortened. Amino acid analysis indicated that leucine at position beta48 (CD7) had been replaced by arginine. The abnormal hemoglobin, called Okaloosa, was heat-precipitable and had decreased oxygen affinity. It exhibited a greater change in oxygen affinity than hemoglobin A when 2,3 DPG was added to "stripped" hemolysates. These findings cannot be readily explained by current views of structure-function relationships in the hemoglobin molecule. However, it is of interest that the amino acid in position CD7 is normally leucine in the alpha, beta, delta, and gamma-hemoglobin chains and in the myoglobin chain of man and a wide variety of other vertebrates.

Amino Acids↗
PubMed1973

Life span of carbamylated red cells in sickle cell anemia.

By using three isotopes of diisopropyl-phosphofluoridate ([(3)H]-, [(14)C]-, and [(32)P]DFP) simultaneously, the life span of red cells from 20 patients with sickle cell anemia (Hb SS) has been studied after varying degrees of carbamylation in vitro with cyanate (NCO) and carbamyl phosphate (CP). The results are expressed in terms of the red cell mean life span (MLS). The MLS of red cells in the patients studied averaged 15.2+/-6.3 (SD) days. After carbamylation the increase in red cell life span was linearly proportional to the concentration of cyanate used, so that at 0.01. 0.02, and 0.3 M NCO (approximately 1, 1.6, and 2 mol NCO/mol Hb) the average increase in MLS was 8.14+/-4.9 days, 14.7+/-4.1 days, and 18.4+/-8.8 days, respectively. Analysis of survival curves and the results of an experiment using a population of Hb SS cells separated by centrifugation indicated that carbamylation had a disproportionate effect on the survival of the youngest cells in the population. Improvement in MLS correlated with the reticulocyte count of the cells carbamylated. This finding is explained on the hypothesis that the life span of irreversibly sickled and other damaged cells is not improved by carbamylation but that carbamylation greatly improves the life span of the young, and as yet undamaged, cells. For this reason extracorporeal carbamylation is not favored as a form of therapy. At the level of carbamylation attainable by oral therapy, however, it would appear likely that only a modest increase in red cell life span will be achieved.

Adolescent↗