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Biomedical subjects

D G Nathan

Publications and source records attributed to D G Nathan.

At least 253 records · Page 14Linked to original sources
PubMed1971

Beta thalassemia and translation of globin messenger RNA.

To define the quality and relative quantity of beta and alpha messenger RNA in human nonthalassemic and thalassemic reticulocytes, intact cells were incubated with [(35)S]methionine. The relative amounts of beta- and alpha-nascent chains on polysomes of different sizes were measured by tryptic digestion of pooled polysomes and by determination of the specific activities of beta and alpha peptides that contain methionine. Betachain synthesis predominated on heavy polysomes in nonthalassemic, as well as in thalassemic cells. Since beta chains in thalassemia are made on normal-size polyribosomes, we conclude that the defect in thalassemia does not involve reduction in the rate of initiation of translation due to the production of an abnormal beta message. Such would lead to beta-chain synthesis on very small polysomes. We therefore suggest that the decreased production of beta-globin chains results from a decreased amount of functional beta-globin messenger RNA.

Anemia, Hemolytic↗
PubMed1971

Endogenous production of carbon monoxide in normal and erythroblastotic newborn infants.

The endogenous production of carbon monoxide ( V(CO)) in newborn infants was measured by serial determinations of blood carboxyhemoglobin during rebreathing in a closed system. Mean V(CO) in nine full-term infants was 13.7 +/-3.6 mul CO/kg per hr (SD), and in four erythroblastotic infants V(CO) ranged from 37 to 154 mul CO/kg per hr preceding exchange transfusion. Mean red cell life-span (MLS) and total bilirubin production were calculated from V(CO). MLS in normal newborns was 88 +/-15 days (SD), and bilirubin production was 8.5 +/-2.3 mg/kg per 24 hr. This is more than twice the amount of bilirubin normally produced in the adult per kilogram of body weight. Normal infants achieved a net excretion of bilirubin of at least 5.6 +/-2.3 mg/kg per 24 hr (SD) as calculated from the bilirubin production and the measured rise in serum bilirubin concentration.The measurement of V(CO) should prove valuable in the study of red blood cell survival and bilirubin metabolism in the newborn infant.

Bilirubin↗
PubMed1971

Selective reticulocyte destruction in erythrocyte pyruvate kinase deficiency.

Radioisotope studies of bilirubin turnover, ferrokinetics, and red cell survival ((51)Cr) in a patient with erythrocyte PK deficiency have provided evidence for prompt reticulocyte sequestration and destruction by the reticuloendothelial system. More mature erythrocytes appeared to survive well despite their deficiency of PK. PK-deficient reticulocytes, dependent upon oxidative phosphorylation for ATP production, are exquisitely sensitive to cyanide- or nitrogen-induced mitochondrial inhibition. If oxidative phosphorylation is unavailable, ATP levels decline rapidly, producing alterations in the cell membrane which allow massive losses of potassium and water. The result is a shrunken, spiculated, viscous cell whose rheologic properties would favor its sequestration by the reticuloendothelial system. Those reticulocytes with particularly low levels of PK exhibit very low glycolytic rates and thus are uniquely reliant upon oxidative phosphorylation. Other reticulocytes, better endowed with PK activity, can meet the increased ATP requirements of young erythrocytes. Upon reaching maturity, such cells have diminished ATP needs and can, therefore, survive despite their enzyme deficiency.

Adenosine Triphosphate↗
PubMed1971

Energy metabolism in human erythrocytes. I. Effects of sodium fluoride.

Exposure of red cells to fluoride produces a variety of metabolic alterations, most of which are based upon the secondary effects of enolase inhibition, which reduces pyruvate synthesis and interferes with the regeneration of diphosphopyridine nucleotide (NAD). Adenosine triphosphate (ATP) is consumed in the hexokinase and phosphofructokinase reactions but is not regenerated since the deficiency of NAD limits glyceraldehyde phosphate dehydrogenase. ATP depletion in the presence of fluoride and calcium induces a massive loss of cations and water. Of the other known sites of ATP utilization, membrane-bound ATPase is inhibited by fluoride, but the incorporation of fatty acids into membrane phospholipids is unaffected until ATP is depleted. The addition of methylene blue to fluoride-treated red cells regenerates NAD, permitting triose oxidation and the generation of 3-phosphoglycerate and 2,3-diphosphoglycerate. Enolase inhibition is then partially overcome by mass action, and sufficient glycolysis proceeds to maintain the concentration of ATP. This in turn prevents the massive cation and water loss, and permits membrane phospholipid renewal to proceed. Membrane ATPase activity is not restored by the oxidant so that normal cation leakage remains unopposed by cation pumping in red cells exposed to the combination of fluoride and methylene blue.

Adenosine Triphosphatases↗
PubMed1971

Amino acid oxidase of leukocytes in relation to H 2 O 2 -mediated bacterial killing.

D-Amino acid oxidase and L-amino acid oxidase have been measured in sucrose homogenates of polymorphonuclear leukocytes (PMN) obtained from guinea pigs and humans. Subcellular distribution patterns and studies on latency indicate that these oxidases are soluble enzymes. Their hydrogen peroxide-generating capacity was verified. Chronic granulomatous disease PMN, which lack a respiratory burst and fail to generate H(2)O(2) during phagocytosis and do not kill catalase positive bacteria, had peroxide-generating amino acid oxidase activity equal to that found in PMN homogenates from patients with bacterial infections. The precise metabolic and bactericidal role of amino acid oxidases in PMN remains uncertain.

Amino Acid Oxidoreductases↗
PubMed1971

Oxidant injury of caucasian glucose-6-phosphate dehydrogenase-deficient red blood cells by phagocytosing leukocytes during infection.

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency of red blood cells (RBC) may develop sudden hemolytic anemia during infection. Since phagocytizing polymorphonuclear leukocytes (PMN) are known to generate hydrogen peroxide, we explored the influence of this oxidant product of PMN on juxtaposed G6PD-deficient and normal RBC. The oxidant stress induced by phagocytosis depleted G6PD-deficient RBC of reduced glutathione (GSH) and this was associated with rapid removal of these cells from the circulation by the liver and spleen. No such effect was observed on normal RBC. Phagocytizing chronic granulomatous disease (CGD) PMN which lack hydrogen peroxide generation, failed to diminish GSH level in G6PD-deficient RBC. Thus, PMN can pose as a source of oxidant damage to G6PD-deficient RBC due to hydrogen peroxide generated during phagocytosis.

Anemia, Hemolytic↗
PubMed1970

Mild thalassemia: the result of interactions of alpha and beta thalassemia genes.

Homozygous thalassemia is due to inherited unbalanced synthesis of the alpha- or beta-chains of hemoglobin. Clinical severity may be in part related to the extent of alpha:beta imbalance. Two families are presented that illustrate this concept. Thalassemia in these individuals was evaluated by clinical and genetic criteria. The relative rates of alpha- and beta-chain synthesis in their reticulocytes were estimated by the extent of incorporation of 1-leucine-U-(14)C into the chains. Unusual combinations of clinical and hematological data and biosynthetic ratios were obtained in certain individuals which indicated the presence of combinations of alpha- and beta-thalassemia genes. The propositus of the first family had mild Cooley's anemia and was believed to have one alpha- as well as two beta-thalassemia genes. Presumably the alpha-thalassemia gene interfered with alpha-chain production which lead to less accumulation of alpha-chains and a reduced rate of intramedullary and peripheral hemolysis. In the second family two individuals were believed to have an alpha-thalassemia, a "silent carrier," and a beta-thalassemia gene. Despite the fact that they appeared to have the genotype of hemoglobin H disease, their cells contained no hemoglobin H and had a normal lifespan presumably because excess beta-chain production was inhibited by the beta-thalessemia gene. These family studies suggest that the alpha:beta imbalance observed in thalassemia may be favorably influenced by combinations of alpha- and beta-thalassemia genes.

Adult↗