Carl V. Moore

Immunologic mechanisms in idiopathic and neonatal thrombocytopenic purpura.

Excerpt The mechanisms responsible for the low platelet count in idiopathic thrombocytopenic purpura are not well understood despite the careful studies by many competent investigators. The thrombo...

Characterization of the anemia associated with chronic renal insufficiency

Abstract The anemia occurring with chronic renal insufficiency was studied in twenty-six patients. From this study it is possible to draw the following conclusions: 1.1. The anemia is usually normocytic and normochromic although an occasional patient has a consistently macrocytic mean corpuscular volume. 2.2. Serum iron and free erythrocyte protoporphyrin values follow no consistent pattern. 3.3. There is an invariable depression of erythropoiesis, demonstrated in these patients by poor utilization of radioiron. This constitutes the prominent mechanism responsible for the anemia. 4.4. Erythrocytes formed under conditions of severe renal insufficiency and azotemia are normal as measured by their ability to survive normally in healthy recipients. 5.5. Occasionally the anemia becomes rapidly progressive in the absence of detectible blood loss. At these times an unidentified extracorpuscular hemolytic factor is present and presumably is responsible for the increased breakdown of red cells. Thus the anemia must at times be due to a combined disorder of depressed erythropoiesis and increased red cell destruction. 6.6. Blood loss infrequently accounts for a significant part of the anemia, but in individual cases may be a third responsible factor.

Hemoglobin metabolism in thalassemia: In vivo studies

Abstract 1.1. C 14 -labeling of heme and globin was measured in three patients with thalassemia major and in two normal subjects after the oral administration of 100 μc. of glycine-2-C 14 . The labeling of stercobilin also was measured in one patient with thalassemia. 2.2. In the patients with thalassemia, the apparent utilization of glycine for hemoglobin synthesis was decreased, and the appearance of radioactivity in circulating hemoglobin was relatively delayed. In contrast, radioactivity appeared extremely rapidly in the fecal stercobilin, reaching a maximum on the third day, when it was over 100 times greater than the maximum radioactivity found in heme. 3.3. The 50 per cent red cell survival was estimated in two patients with thalassemia as thirty-six and twenty-eight days, and in two normal subjects as 118 and 128 days. 4.4. The relative labeling of heme and globin was expressed as the heme:globin ratio, which had a mean value of 0.784 in both normal subjects, and fell after the 100th day; it is suggested that the fall may be due to preferential reutilization of C 14 for globin synthesis. The ratio was significantly lower than normal in two of the three patients with thalassemia. 5.5. These results are compatible with the concept that there is a defect in hemoglobin synthesis as well as an abnormality of erythrocyte production in thalassemia major. The enhanced early labeling of stercobilin implies an abnormal degree of premature destruction of red cells or hemoglobin within the bone marrow, or an anabolic pathway for the production of stercobilin. The basic abnormality would seem to be in the erythroblast, a genetic biochemical lesion, it is suggested, not yet identified.

The physiologic evaluation and management of chronic bone marrow failure.

Abstract 1.1. Physiologic technics are available which permit evaluation of the relative importance of inadequate production and increased destruction of red blood cells in the pathogenesis of a given anemia. 2.2. Data derived from these technics have been applied to the clinical management of ten patients with chronic bone marrow failure. 3.3. The anemia of chronic bone marrow failure is due to decreased production of red blood cells and may be associated with a hemolytic component. 4.4. Erythropoiesis in some patients may be stimulated by the administration of adrenocorticotrophic hormone or cortisone. Evidence is presented to suggest that it is these patients who are most likely to respond favorably to splenectomy. If a hemolytic component is also present, splenectomy tends to correct the abnormal red cell destruction. 5.5. The anemia of chronic bone marrow failure should not be considered entirely refractory to therapy.

Haemoglobin Synthesis in Thalassaemia; In-Vitro Studies.

IN thalassaemia, hypochromia of the red blood cells, in the presence of an abundance of iron, suggests that there is a defect in haemoglobin synthesis. As part of an attempt to elucidate the nature of the defect, the irz-vitro biosynthetic activity of blood samples from patients with thalassaemia major has been investigated. The peripheral blood of many of these patients contains appreciable numbers of normoblasts and reticulocytes which retain some capacity to synthesize haemoglobin in vitro. The use of peripheral blood containing nucleated red cells or reticulocytes as a system for the in-vitro study of haemoglobin biosynthesis was first reported by Shemin and his collaborators (London, Shemin and Rittenberg, 1948, 1950; Shemin, London and Rittenberg, 1948,1950); they and other groups of investigators have employed the system most productively to work out many of the steps in the process (Shemin, 1955; Dresel and Falk, 1954; Kruh and Borsook, 1956; Goldberg, Ashenbrucker, Cartwright and Wintrobe, 1956). In their first report London, Shemin and Rittenberg (1948) described the incorporation of 15N-glycine into haem by blood from patients with sickle-cell anaemia; later they showed that this activity could also be demonstrated in blood samples from patients with other diseases (London et al., 1950). The incorporation of 59Fe into haem by human blood in vitro has also been reported (Walsh, Thomas, Chow, Fluharty and Finch, 1949; Schapira, Dreyfus and Kruh, 1953; Goldberg et al., 1956). 59Fe and glycine-2-14C ([2-l4CC] glycine) incorporation into haemoglobin by human cord blood in vitro have been measured simultaneously (Schapira, Dreyfus, Kruh, Paoletti and Boiron, 1955). In the reports mentioned above, estimates of the actual amount of haem synthesized were not made, and data on the absolute numbers of nucleated red cells and reticulocytes participating in the process were not provided. Thus it was impossible to make more than a very rough comparison between the biosynthetic capacities of different blood samples. We have attempted to estimate the amount of haemoglobin synthesized by human blood samples containing immature red cells from patients with thalassaemia major and other diseases. The incorporation of glycine-2-14C into protoporphyrin and globin, and the incorporation of 59Fe and of 14Gtagged protoporphyrin into haem were measured. Investigations on the utilization of 14C-tagged protoporphyrin for haem synthesis have been reported in detail elsewhere (Grinstein, Bannerman and Moore, in press, a). We have related haem synthesis to the absolute number of immature red cells present in the in-vitro system in order to be able to compare the biosynthetic activity of different samples. We have found a wide variation in biosynthetic activity, but the results inhcate that the method may be of use in studying pathological alterations of haemoglobin synthesis and confirm that there is a quantitative impairment of this process in thalassaemia major. * Radcliffe Travelling Fellow of the University of Oxford; Dazian Foundation Fellow; on leave &om St. Thomas’s Hospital, t Present address: Facultad de Ciencias Exactas y Naturales, University of Buenos Aires, Argentina. London. Present address: The Moore Clinic, Johns Hopkins Hospital, Baltimore, U.S.A.

The Utilization of Glycine in the Biosynthesis of Hemoglobin

Isotopic studies have demonstrated that glycine is used in the biosynthesis of hemoglobin. Glycine has been tagged in one of three ways: (a) with N’” in the amino group (l-3), (b) with Cl4 in the a-methylene carbon position (4), and (c) with Cl4 in the carboxyl group (5). When any of these three forms of glycine is fed to animals, the isotope is incorporated into hemoglobin, but interesting differences have been observed in the distribution of the isotope between the pigment and protein portions of the molecule. For instance, Shemin and Rittenberg, using glycine labeled with NIB, found greater concentrations of the heavy nitrogen in hemin than in red blood cell protein (2). Similarly, Altman and his associates observed that when the methylene carbon of glycine is tagged 7 to nearly 10 times as much Cl4 appear in hemoglobin protoporphyrin as in globin (4). On the other hand, recent observations in t,his laboratory have shown that when glycine containing Cl4 in the carboxyl group is administered the radioactive carbon is synthesized into globin but cannot be demonstrated in protoporphyrin (5). The experiments to be described in this report were designed (1) to confirm the demonstration that the carboxyl carbon of glycine is used for the biosynthesis of globin but not protoporphyrin, (2) to determine whether globin within the red cell participates in protein interchange, and (3) to discover whether coproporphyrin I isolated from the urine and feces after the tagged glycine was fed would contain Cl* even if the hemoglobin protoporphyrin did not.

Studies on Infectious Mononucleosis.

Excerpt Interest in the etiology of infectious mononucleosis was first aroused in this laboratory by the recovery1ofListerella monocytogenesfrom the blood of a patient with clinical, hematologic, a...

Whole Blood and Plasma Ascorbic Acid Concentrations in Patients with Pellagra and Associated Deficiency Diseases.

Summary and Conclusions Whole blood and plasma ascorbic acid determinations made on 70 patients in the nutrition clinic of the Hillman Hospital indicate that 55 of these persons had a whole blood concentration of ascorbic acid lower than in normal controls. In 8 of the 70 cases, the concentration was so low as to suggest that depletion may have been advanced. Most of these patients had clinical evidence of other deficiencies, such as pellagra, beriberi and riboflavin deficiency, but no significant correlation could be made between the blood ascorbic acid values and the symptoms of these deficiency states, nor indeed of scurvy itself. These observations seem pertinent in view of the fact that they were made in late June, at a period when leafy vegetables and berries had been available to the patients for some time, and probably indicate that ascorbic acid deficiency is still greater at other periods. These studies give strong support to the concept that natural-occurring deficiency diseases exist as complexities rather than as single entities.

Hemoglobin and Its Abnormalities

Several years ago, Ingram made the exciting discovery that substitution of one amino acid for another ( valine substituted for glutamic acid) in one of the peptide chains is apparently the only chemical difference between normal and sickle cell hemoglobin. The chemical nature of a gene mutation had thus been identified, and the strikingly different physical properties of sickle cell hemoglobin which are at least largely responsible for the clinical manifestations of sickle cell anemia were demonstrated to be the result of an amazingly small change in the molecule. Investigative interest in the electrophoretic recognition of abnormal hemoglobins and in the clinical study of the hemoglobinopathies was already intense, but additional groups of protein chemists and of biochemical geneticists now focused their research activities on hemoglobin. No one is more qualified than Ingram to review the resultant rapid accumulation of information. The book is divided into 2 parts. The first reviews

LONG-TERM PRESERVATION OF BLOOD

Medical scientists and physicians interested in transfusion problems have worked hard to find ways of storing blood for months or years rather than for the current three or four weeks. Effective stockpiling of the large amounts of blood needed for the armed forces and the general population in the event of a nuclear attack would then become possible. Blood banks could accumulate rare types of blood and improve their ability to meet special demands, like those of open heart surgery. To date, only minor improvements have resulted from changes in the composition of solutions of anticoagulants and preservatives. Freezing of red blood cells, which has seemed the most promising attack, has been studied on a limited scale by many workers. The technical difficulties, however, are formidable: Formation of ice crystals during freezing and thawing must be avoided or cells will be damaged; glycerolization of erythrocytes has been found to prevent