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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 145 records · Page 8Linked to original sources
PubMed1981

Intracellular univalent cations and the regulation of the BALB/c-3T3 cell cycle.

Addition of serum to density-arrested BALB/c-3T3 cells causes a rapid increase in uptake of Na+ and K+, followed 12 h later by the onset of DNA synthesis. We explored the role of intracellular univalent cation concentrations in the regulation of BALB/c-3T3 cell growth by serum growth factors. As cells grew to confluence, intracellular Na+ and K+ concentrations ([Na+]i and [K+]i) fell from 40 and 180 to 15 and 90 mmol/liter, respectively. Stimulation of growth of density-inhibited cells by the addition of serum growth factors increased [Na]i by 30% and [K+]i by 13-25% in early G0/G1, resulting in an increase in total univalent cation concentration. Addition of ouabain to stimulated cells resulted in a concentration-dependent steady decrease in [K+]i and increase in [Na+]i. Ouabain (100 microM) decreased [K+]i to approximately 60 mmol/liter by 12 h, and also prevented the serum-stimulated increase in 86Rb+ uptake. However, 100 microM ouabain did not inhibit DNA synthesis. A time-course experiment was done to determine the effect of 100 microM ouabain on [K+]i throughout G0/G1 and S phase. The addition of serum growth factors to density-inhibited cells stimulated equal rates of entry into the S phase in the presence or absence of 100 microM ouabain. However, in the presence of ouabain, there was a decrease in [K+]i. Therefore, an increase in [K+]i is not required for entry into S phase; serum growth factors do not regulate cell growth by altering [K+]i. The significance of increased total univalent cation concentration is discussed.

Animals↗
PubMed1981

Control of the simian fetal hemoglobin switch at the progenitor cell level.

This investigation was designed to define the cellular level at which the gamma to beta globin switch is established in the developing simian fetus in order to determine whether the switch is controlled by environmental influences within differentiating erythroid precursors or predetermined by the genetic program of erythroid progenitors. Samples of marrow and liver were obtained from rhesus fetuses throughout the switch period, and marrow was obtained from adult rhesus monkeys. Globin chain synthesis was then measured in differentiated erythroblasts and in erythroid progenitor-derived colonies grown in semisolid media. The relative rates of synthesis of gamma and beta chains were determined by the uptake of [(3)H]leucine into the respective chains separated by Triton gel electrophoresis and in some cases by urea carboxymethyl cellulose chromatography. Four periods of the switch were defined during fetal development. In the preswitch period both erythroblasts and progenitor-derived colonies produced <5% beta globin. In the early switch erythroblasts produced 5-15% beta globin, while progenitor-derived colonies produced 10-35% beta globin. In mid-switch erythroblasts synthesized 50% beta globin, whereas progenitor-derived colonies produced only 15-35% beta. At the completion of the switch erythroblasts produced 100% beta globin, while progenitor-derived colonies produced as little as 40% beta chains. We conclude that the program of globin synthesis that characterizes the fetal switch is established at the level of erythroid progenitors. Fetal erythroid burst-forming units (BFU-E) dominate the marrow prior to the switch. The early switch period is heralded by the appearances of adult erythroid burst-forming units programmed to express increasing beta chain synthesis in colonies. By mid-switch a second class of adult erythroid progenitors capable of giving rise to fetal and adult hemoglobin synthesis in in vitro colonies becomes apparent. These shifting populations of erythroid progenitors with unique globin synthesis programs give rise to the erythroblasts that create the sigmoid pattern of the fetal to adult hemoglobin switch in the developing simian fetus.

Age Factors↗
PubMed1981

Heterogeneity of DNA deletion in gamma delta beta-thalassemia.

By restriction endonuclease mapping, gene cloning, and DNA sequencing we have determined the region of DNA that is deleted in a family with gamma delta beta-thalassemia. The deletion removes the linked epsilon, gamma-, and delta-globin structural genes and terminates within the coding portion of the beta-globin gene. Since the extent of DNA deletion in this family differs from that reported in another family, we conclude that gamma delta beta-thalassemia is heterogeneous at the molecular level.

Base Sequence↗
PubMed1981

Exercise-induced hemolysis in xerocytosis. Erythrocyte dehydration and shear sensitivity.

A patient with xerocytosis was found to have swimming-induced intravascular hemolysis and shortening of erythrocyte life-span. In a microviscometer, xerocytes were more susceptible than normal erythrocytes to hemolysis by shear stress. Fractionation of normal and abnormal cells on discontinuous Stractan density gradients revealed that increasingly dehydrated cells were increasingly more shear sensitive. This sensitivity was partially corrected by rehydrating xerocytic erythrocytes by means of the cation-ionophore nystatin in a high potassium buffer. Conversely, normal erythrocytes were rendered shear sensitive by dehydrating them with nystatin in a low potassium buffer. This effect of dehydration was entirely reversible if normal cells were dehydrated for less than 4 h but was only partially reversed after more prolonged dehydration. It is likely that dehydration of erythrocytes results in shear sensitivity primarily because of concentration of cell contents and reduced cellular deformability. With prolonged dehydration, secondary membrane changes may potentiate the primary effect. This increased shear sensitivity of dehydrated cells may explain atraumatic exercise-induced hemolysis in xerocytosis as cardiac output is shifted to vessels of exercising muscles with small diameters and high shear rates.

Adult↗
PubMed1981

Response of three classes of human erythroid progenitors to the absence of erythropoietin in vitro as a measure of progenitor maturity.

The effect of erythropoietin (Ep) deprivation (epoprival state) on plasma clot cultures of human bone marrow and peripheral blood erythroid progenitors was examined. In normal individuals, there was a marked reduction of CFUE derived colony expression if Ep was withheld from the culture for even one day. Peripheral blood BFUE retained substantial function during the epoprival state for up to 2 to 5 days while bone marrow-derived BFUE had intermediate sensitivity. Thus the capacity of erythroid progenitors to withstand incubation in semi-solid media in the absence of Ep is a characteristic of immature, rather than mature, erythroid progenitors.

Bone Marrow Cells↗
PubMed1980

Treatment of acute myelogenous leukemia in children and adults.

We designed a protocol to address the problem of relapse from complete remission in acute myelogenous leukemia. Patients in remission were treated for 14 months; early and later intensification of chemotherapy, sequential drug combinations, and high-dose continuous infusions of cytarabine were included. Eighty-three consecutive patients under 50 years of age were entered into this study from February 1976 to October 1979. The rate of complete remission is 70 per cent. A Kaplan-Meier analysis predicts that 49 +/- 17 per cent of patients (mean +/- 2 S.D.) who entered complete remission will remain free of disease at two years. Durations of complete remission for patients in the 0 to 17-year and 18 to 50-year age groups are comparable.

Adolescent↗
PubMed1980

Mature bone marrow erythroid burst-forming units do not require T cells for induction of erythropoietin-dependent differentiation.

Cell-cell interactions between mature T cells and peripheral blood null cells induce erythropoietin-stimulated differentiation of peripheral blood-derived erythroid progenitors. By the use of complement-fixing cytolytic murine hybridoma and antibody uniquely reactive with mature T lymphocytes, this dependence of immature peripheral blood erythroid burst-forming unit (BFU-E) differentiation upon mature T cells or a T cell conditioned medium is confirmed. By using the same antibody, it is demonstrated that the differentiation of mature bone marrow BFU-E does not require either mature T cells or lymphocyte mitogenic factor. These findings do not preclude the presence in the bone marrow of other cells, perhaps even immature T cells, that influence erythropoietin-dependent erythroid differentiation of mature marrow BFU-E.

Bone Marrow Cells↗
PubMed1980

Aplastic and hypoplastic anemia.

Aplastic anemia is an acquired or constitutional trilineage bone marrow failure with peripheral pancytopenia, evidence of cellular hypoplasia of marrow, and replacement of normal cellular elements by fat. In some cases the marrow may be hypoplastic and the peripheral cytopenia relatively mild. The condition may persist for years and result in acute leukemia. In other cases, hypoplasia may involve only a single cell line. Basic research is directed toward understanding the multitude of cells, with a view toward selective manipulation of the cells themselves, interacting hormones, or cellular regulators. Early bone marrow transplantation presently offers the most hope when compatible donors are available.

Adolescent↗
PubMed1980

F-cell regulation.

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Anemia, Dyserythropoietic, Congenital↗
PubMed1980

Monocytes do not inhibit peripheral blood erythroid burst forming unit colony formation.

To determine a possible role of peripheral blood monocytes in erythroid differentiation, various fractions of peripheral blood mononuclear cells were prepared from normal volunteers. The fractions contained 3-95% monocytes. These freshly prepared monocytes did not inhibit erythroid burst forming unit expression in plasma clot erythroid colony culture. Null cell preparations contaminated by up to 84% monocytes expressed erythroid burst forming unit colony formation when either T lymphocytes or T-cell conditioned medium was added. These results indicate that certain peripheral blood null cells engage the program of erythroid differentiation in the presence of T cells and erythropoietin. Monocytes do not inhibit this engagement.

Adult↗
PubMed1980

Cell-cell interactions in in vitro erythropoiesis.

Cell-cell interactions between T and null lymphocytes induce erythropoietin-stimulated differentiation of peripheral blood-derived erythroid progenitors. Monocytes do not inhibit the engagement of this differentiation. By the use of murine hybridoma antibodies, which are uniquely reactive with mature T lymphocytes, the dependence of immature peripheral blood BFU-E differentiation on mature T lymphocytes, or a T cell-conditioned medium is confirmed. Studies with the same antibody show that the more mature and numerous BFU-E found in marrow have no requirement for mature T cells or T cell-conditioned medium. These findings do not preclude the presence in bone marrow of immature T or even non-T cells which may serve as inducers of erythropoietin-dependent erythroid differentiation of mature marrow BFU-E.

Cell Communication↗
PubMed1980

New approaches to the transfusion management of thalassemia.

Recent advances in the treatment of patients with thalassemia major have centered around the removal of iron from individuals already overloaded due to repeated transfusions. In this report we present therapeutic maneuvers designed to decrease the rate of iron accumulation. We demonstrate that the persistent maintenance of hematocrits above 35% ("supertransfusion") is not associated with an increased transfusion requirement because it produces a decrease in whole blood volume (21% +/- 2%). Supertransfusion is also associated with normalization or even prolongation of plasma iron turnover. In addition, we describe a method for obtaining units of blood from normal donors that contain primarily young red cells ("neocytes"). These cells have prolonged in vivo survival as measured by the interval between transfusions (30 +/- 2.5 days to 43 +/- 4.5 days) and 51Cr red cell survival (43.8 days versus 27.8 days). Supertransfusion with neocytes is effective in decreasing the rate of iron accumulation in thalassemia.

Adolescent↗