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Biomedical subjects

S Charache

Publications and source records attributed to S Charache.

At least 19 recordsLinked to original sources
PubMed1992

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Adult↗
PubMed1992

Hydroxyurea induction of fetal hemoglobin synthesis in sickle-cell disease.

In the past 8 years, it has become apparent that some cytotoxic drugs that interfere with DNA replication can reprogram erythroid progenitors to switch from adult hemoglobin to fetal hemoglobin (HbF) production. Hydroxyurea has now been shown to substantially increase HbF in patients with sickle cell anemia. Since HbF interferes with sickle hemoglobin polymerization, hydroxyurea may become an important therapeutic agent for patients with sickle cell anemia.

Anemia, Sickle Cell↗
PubMed1979

Conformation in solution of hemoglobin Osler (alpha 2 A beta 2 145 Tyr replaced by Asp).

Computer simulations of Gelin and Karplus ((1977) Proc. Natl. Acad. Sci. U.S.A. 74, 801-805) suggest that in hemoglobin upon ligation the penultimate tyrosyl residues of the subunits are not expelled from the hydrophobic pockets described in the crystals between the helices E and F (Perutz, M.F. (1970) Nature 228, 726-737). This implies that both the liganded and unliganded conformations of hemoglobin may be affected by mutations involving such residues. Investigation of the conformational behavior of liganded and unliganded hemoglobin Osler was conducted measuring the functional properties, the subunits dissociation, the CD and electronic spectra, the protons absorption upon interaction with polyanions, and the reactivity of the -SH groups of the protein. The results suggest that both the liganded and unliganded conformations of the system are affected by the mutation, confirming the anticipations of Gelin and Karplus on the relevance of tyrosine at beta 145 for both allosteric states of hemoglobin.

Alkylation↗
PubMed1979

Comparison of microchromatography and electrophoresis with elution for hemoglobin A2 (Hb A2) quantitation.

Microcolumns prepared in the authors' laboratory, two commercial microchromatography kits, and electrophoresis with elution were compared for Hb A2 quantitation. Day-to-day imprecision of microchromatographic methods was similar (CV 4.7--6.6%) and somewhat less than electrophoresis with elution (CV 8.0--9.1%). Both commercial kits showed variable imprecision in different lots; one lot of Kit B gave erratic results due to resin leakage. From 49 patient specimens, Kit A microcolumns and those of the authors identified the same 14 patients with an elevated percentage of Hb A2 and showed good correlation (P = 0.90), although Kit A showed constant bias toward higher values. Electrophoresis with elution resulted in a false-positive and a false-negative value, did not correlate well with microcolumns (P = 0.78 and 0.76), and showed proportional bias toward lower values for an elevated percentage of Hb A2. Commercial kits were convenient, relatively quick, and cost-effective. Frozen, stabilized hemolysates performed well for quality control.

Blood Protein Electrophoresis↗
PubMed1979

The effect of hemoglobin F-Chesapeake (alpha 2 92 Arg. leads to Leu gamma 2) on fetal oxygen affinity and erythropoiesis.

A carrier of hemoglobin Chesapeake, born of a normal mother, had a cord-blood hematocrit of 60%. The oxygen affinity of his blood was increased. Hemoglobin F-Chesapeake (alpha 2 Ches gamma 2), partially purified from the infant's blood, had oxygen affinity greater than that of hemoglobin A, but less than that of the adult form of the abnormal hemoglobin (alpha 2 Ches beta 2). These findings suggest that the conformation of that part of the gamma chain which contacts the site of amino acid substitution in Hb F-Chesapeake is similar to the analogous region of hemoglobin F. They also support the hypothesis that regulation of erythropoiesis in late fetal life is similar to that of the adult, and is under fetal control.

Erythropoiesis↗
PubMed1979

"Acute chest syndrome" in adults with sickle cell anemia. Microbiology, treatment, and prevention.

Fifty-two episodes of fever, chest pain, increased leukocytosis, and pulmonary infiltrate ("acute chest syndrome") were studied in 28 adults with sickle cell anemia. Possible bacterial pathogens were identified in sputum cultures from less than half of the episodes; no pneumococci were found, and Staphylocococcus aureus was the only bacterium associated with a longer illness than that seen when only normal flora were recovered. Much disease diagnosed as "pneumonia" in adults with sickle cell anemia is probably pulmonary infarction. Many of these patients will recover with no more than modest supportive care; if antibiotics are used they should be directed against S aureus (and possibly Hemophilus species). Pneumococcal polysaccharide vaccine has great potential for preventing life-threatening infection in children with sickle cell anemia, but may not change the incidence or severity of the acute chest syndrome in adults.

Acute Disease↗
PubMed1979

Oxygen transport in a woman with hemoglobin Hope/beta+ thalassemia.

Because their blood may "unload" oxygen more readily than normal, people with hemoglobin of low oxygen affinity might be expected to be anemic. We have studied a woman with hemoglobin Hope/beta+ thalassemia, whose hemoglobin level was 10.4 to 12.3 gm/dl (normal 14 +/- 2) despite a P50 of 41 mm Hg (normal 26). Her cardiac index was normal, yielding a calculated mixed venous PO2 of 51 mm Hg (normal 34 to 49). Oxygen transport in patients with low oxygen affinity can be maintained by a variety of homeostatic responses, only one of which is altered erythropoiesis.

Adult↗
PubMed1978

Individual variation in the production and survival of F cells in sickle-cell disease.

The protective role and underlying sources of the elevated levels of fetal hemoglobin associated with sickle-cell anemia were reassessed by microscopical immunodiffusion assays. Three variables that contribute to levels of fetal hemoglobin were examined: the percentage of fetal-hemoglobin-containing reticulocytes produced; the quantity of fetal hemoglobin synthesized within such cells; and the extent to which the fraction of fetal-hemoglobin-bearing erythrocytes is enriched beyond the level produced. Four general findings emerged from analysis of 29 patients: each variable is separately regulated; the expression of each is often distinctly different between individual patients; contrary to prior speculation, production of fetal hemoglobin may be as great in the absence of heterocellular hereditary persistence of the hemoglobin as in its presence; and fetal hemoglobin does not, as often supposed, guarantee preferential cell survival. We conclude that the differences encountered among patients must reflect heterogeneity among factors that modify production and survival of cells bearing fetal hemoglobin.

Adult↗
PubMed1978

The structure of hemoglobin Hopkins-2.

Hemoglobin Hopkins-2 was originally reported to contain two abnormal alpha chains. Both had aspartic acid instead of the normal histidine at position alpha 112; the second alpha chain also contained two additional amino acid substitutions. In subsequent reports of the structure of this hemoglobin, only the His replaced by Asp substitution was found. To determine whether the second abnormal alpha chain was limited to the original kindred, the structure of their hemoglobin was redetermined. Only the His replaced by Asp substitution was present.

Aspartic Acid↗
PubMed1978

Sickle cell anemia.

Explore the source record for details and available documents.

Anemia, Sickle Cell↗
PubMed1978

Hb Potomac (101 Glu replaced by Asp): speculations on placental oxygen transport in carriers of high-affinity hemoglobins.

Blood from a woman with unexplained erythrocytosis had increased oxygen affinity, but no abnormality could be detected by electrophoresis or chromatography of her hemolysate. Separation of the tryptic peptides of her beta chains disclosed two half-sized peaks in the regions of beta T-11. The faster of these was abnormal, with the structure beta 101 Glu replaced by Asp. The new hemoglobin was called "Potomac." Three of the proband's four surviving siblings and both of her children were carriers. Differences in the ratio of carrier: normal children born to male of female carriers of 23 other high-affinity hemoglobins were not significant. The high proportion of carriers in this kindred was probably due to chance alone, and not because high maternal oxygen affinity interfered with oxygen transport to fetuses with normal hemoglobin.

Adult↗
PubMed1978

Variability of the homeostatic response to altered p50.

Blood from carriers of hemoglobin Osler (Hb Osler) had almost the same oxygen affinity as that of carriers of Hb McKees Rocks (Hb MR) (P50 10-11 mm Hg), but Hb concentrations were higher in male carriers of the former (21.6 versus 17.2 g/dl). Two carriers of each Hb were studied to compare their adaptations to altered oxygen affinity and their responses to phlebotomy. All four were healthy, and all excreted normal amounts of erythropoietin. Carriers of Hb MR had somewhat lower mixed venous pO2 than carriers of Hb Osler. There was no suggestion that phlebotomy impaired ability to exercise in either group of patients.

Adolescent↗
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↗