PubMed Health⌕ Search

Biomedical subjects

J DeSimone

Publications and source records attributed to J DeSimone.

52 records · Page 3Linked to original sources
PubMed1981

Genetic relationship between fetal Hb levels in normal and erythropoietically stressed baboons.

Previous studies have shown that the magnitude of the fetal haemoglobin (Hb F) response to haemolytic anaemia and hypobaric hypoxia in the baboon is specific to an animal ('high and low Hb F responders'), suggesting that the Hb F response is under genetic control. In this study Hb F levels in 55 adult (over 8 years old) and 23 juvenile unstressed baboons varied between 0.02% and 0.6% ('resting Hb F levels'). Twenty-nine of these animals were subjected to haemolytic stress and the magnitude of their Hb F response was positively correlated with the resting Hb F levels. In addition, the resting levels of Hb F in parents were positively correlated with those of their offspring. In 11 animals, seven adults and four juveniles, subjected to haemopoietic stress the Hb F levels were increased proportionally to the number of F-cells. In juvenile animals the calculated concentration of Hb F per F-cell was markedly higher than in adult animals. These data demonstrate that the resting level of Hb F is predictive of the magnitude of the Hb F response to stress erythropoiesis. The number of F-cells and the concentration of Hb F per cell in erythropoietic stress appear to be modulated by different mechanisms.

Anemia, Hemolytic↗
PubMed1980

Magnitude of the fetal hemoglobin response to acute hemolytic anemia in baboons is controlled by genetic factors.

When hemolytic anemia was induced in 26 baboons (Papio cynocephalus), aged 7-22 mo, they increased their production of fetal hemoglobin (HbF). Although the resulting reduction in hematocrits and increases of reticulocyte counts were similar in all stressed animals there was marked variability in the maximal rates of HbF synthesis. The maximal levels of HbF attained appeared to fall into three separate groups: low, intermediate, and high. These differences were not related to sex or several measures of erythrocyte metabolism. Animals exposed to repeated episodes of erythropoietic stress after full hematologic recovery demonstrated some variability in their maximal HbF levels attained from one episode to another, but these variations never extended to adjacent classes. The described biochemical and mating data suggest that the magnitude of the HbF response to hemolytic anemia is controlled by genetic factors.

Anemia, Hemolytic↗
PubMed1979

Hemopoietic stress and fetal hemoglobin synthesis: comparative studies in vivo and in vitro.

Baboons exposed to acute hemolytic stres increase their production of fetal hemoglobin (HbF). Although the maximal in vivo HbF levels attained in 5 treated animals varied from 6.4% to 34.8%, their cultured bone marrow erythroid cells reverted to the fetal pattern of hemoglobin synthesis. These data suggest that HbF synthesis is modulated by the interaction of inhibiting and promoting factors, which is different among animals in vivo but equal in the cultures of their bone marrow erythroid cells.

Animals↗
PubMed1978

Stimulation of fetal hemoglobin synthesis in baboons by hemolysis and hypoxia.

Fetal hemoglobin (Hb F) levels in the peripheral blood of baboons (Papio cynocephalus) increased from an average value of 0.78% to 18.1% during the recovery phase from phenylhydrazine-induced hemolytic anemia. A similar increase was observed in animals exposed to hypobaric hypoxia. Large individual variations in the maximal Hb F levels were observed which could not be correlated with the ages of the animals. Reinduction of hemolysis in two fully recovered animals resulted in Hb F levels that were of similar magnitude as in the preceding episode, suggesting the possibility of genetically determined individual variations in the rate of Hb F synthesis under the same conditions of erythropoietic stimulation. Reticulocytes from the animals subjected to hemolysis of hypobaric hypoxia synthesized similar absolute quantities of Hb F in vitro. The results of the present studies indicate that the physiological switch from the synthesis of Hb F to that of Hb A during ontogeny can be reversed in adult nonhuman primates by conditions of erythropoietic stress known to be associated with high erythropoietin levels. These findings open the possibility that Hb F synthesis in adult humans may be therapeutically modulated in individuals who might benefit from increased levels of Hb F, such as patients with sickle cell anemia.

Anemia, Hemolytic↗
PubMed1977

Evidence for rapid loss of newly synthesized haemoglobin S molecules in sickle cell anaemia and sickle cell trait.

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.

Anemia, Sickle Cell↗
PubMed1976

betaS Chain turnover in reticulocytes of sickle trait individuals with high or low concentrations of haemoglobin S.

Reticulocytes, isolated from the blood of sickle cell trait donors with either low (25-30%) or high (40-42%) haemoglobin S(Hb S) concentrations, were incubated with [3H]leucine for various times from 1.25 to 60 min. Samples of the total soluble fractions of the cells were denatured with urea and mercaptoethanol. The mixtures were analysed by electrophoresis on cellulose acetate strips. The specific radioactivities (dpm/mg) of the separated betaS and betaA globin chains were determined. The betaS/betaA ratios of globin chain specific radio activities in the reticulocytes of the 'low Hb S' donors decreased gradually from initial values higher than 1.30 to values near unity. These data suggested that faster turnover of some of the soluble, newly synthesized betaS chains compared to the newly synthesized betaA chains could explain part, but not all, of the disparity in concentrations of Hbs S and A in these people. When reticulocytes from 'high Hb S' donors were 3H-labelled for times longer than 5 min, the betaS/betaA specific radioactivity ratios remained at or near unity. This result suggested that newly synthesized betaS chains were not turning over selectively in these cells. Instead, there was a relative decrease in betaS chain synthesis proportional to the difference in blood concentrations of Hb S and Hb A. Additional calculations suggested that the more rapid turnover of newly synthesized betaS chains in the 'low Hb S' reticulocytes could explain the difference in Hb S concentrations between 'high and low Hb S' people. These results are consistent with previous reports that an alpha-thalassaemia gene, present in 'low Hb S' but absent in 'high Hb S' donors, may be responsible for the selective turnover of betaS chains.

Anemia, Sickle Cell↗
PubMed1975

Patterns of hemoglobin assembly in reticulocytes of sickle cell trait individuals.

Venous blood was obtained from five sickle cell trait donors with relatively high hemoglobin S concentrations (40% of total hemoglobin) and five donors with unusually low hemoglobin S concentrations (25 to 30%). A fraction of cells with 15 to 20% reticulocytes was isolated from the blood and incubated with [3H]leucine in a medium supporting protein synthesis for various times from 1.25 to 60 min. Previous studies showed an imbalance in globin chain synthesis in reticulocytes of "low hemoglobin S" donors which suggested the presence of an alpha-thalassemia gene; reticulocytes of "high hemoglobin S" donors had balanced globin chain synthesis (DeSimone, J., Kleve, L., Longley, M.A., and Shaeffer, J. (1974) Biochem. Biophys. Res. Commun. 59, 564-569). In the present study the soluble phase of the 3H-labeled reticulocytes was examined by electrophoresis on strips of cellulose acetate. The tetramer hemoglobins A and S were separated from each other and from a small pool of free, newly synthesized alpha and beta chains. Kinetics of labeling studies showed that the free alpha and beta chains were intermediates in tetramer hemoglobin assembly. The distribution of radioactivity between the alpha and beta chains of each of the electrophoretically isolated components were determined by separation of their globin chains on CM-cellulose columns. After 5 min of 3H-labeling of the reticulocytes from donors with 40% hemoglobin S the ratio of newly synthesized alpha chains to beta chains in the tetramer hemoglobins A and S ranged from 0.37 to 0.58. This ratio increased with longer labeling times. Almost all of the radioactivity of the free chain intermediates was in the alpha chain. These results confirmed the presence of a significant pool of newly synthesized alpha chains and a normal pattern of hemoglobin assembly in which initially unlabeled alpha chains combined with labeled beta chains when the cells were exposed to [3H]leucine. Conversely, in the reticulocytes of donors with 25 to 30% hemoglobin S the ratio of newly synthesized alpha chains to beta chains in the completed hemoglobins A and S ranged from 0.96 to 1.37 and remained unchanged throughout the 3H-labelling period. The radioactivity of the free alpha chain pool was substantially less that the total radioactivity of the betaA and betaS chain pools. These results confirmed the existence of a decreased pool size of soluble alpha chain intermediates and a pattern of hemoglobin assembly consistent with the presence of the alpha-thalassemia gene.

Adult↗
PubMed1975

Hemoglobin synthesis studies of a family with alpha-thalassemia trait and sickle cell trait.

The ratio of total globin alpha to beta chain synthesis was determined in reticulocytes isolated from the blood of the members of a black family, some of whom had sickle cell trait with low blood HbS concentrations (25-30%). The results support the hypothesis that sickle cell trait individuals with low HbS concentrations also carry a gene for alpha-thalassemia.

Anemia, Sickle Cell↗