bluuebunny/crossref_metadata_2025 huggingface dataset:
Anabolic Androgenic Steroids in the Treatment of Acquired Aplastic Anemia
Authors: SANCHEZ-MEDAL L. , GOMEZ-LEAL A. , DUARTE LORENZO , RICO MARIA GUADALUPE
Published: October 2019

The results of the oral administration of high doses of anabolic hormones (oxymetholone, metholone or dromostanolone and methenolone) in the treatment of 69 patients (14 children and 55 adults) with aplastic anemia are presented. Remission rates were 48 per cent for the whole group and 70 per cent for those treated for more than two months. Twenty-two cases have been in remission for 1 to 5 years without maintenance therapy. Eight others relapsed 2 to 4 months after stopping therapy, but responded to the reinstitution of medication. However, four of them have had several relapses and appear to require permanent therapy. In the other four, the second remission has continued for 6 to 40 months. Clinical response was first noted after 0.6 to 6 months of therapy and was characterized by a rise of hemoglobin to normal levels with a variable degree of improvement in the leukopenia and thrombocytopenia. The number of neutrophils and platelets rose to normal levels in over a third of the cases which responded. Response to therapy was not related to age, sex, etiology, degree of pancytopenia or bone marrow cellularity. The three anabolic hormones seemed equally effective.

Nine patients became clinically jaundiced during therapy; four recovered and five died. Abnormalities in liver function existed before treatment in three of those who died. In four of these five cases, the liver lesion was due to an independent cause: viral hepatitis in one, gram negative septicemia and necrotic colitis in two and thiazide toxicity in the fourth. No autopsy was performed in the other case and the etiology of his liver damage could not be determined. Three of the fatal cases were taking a non-17-alkylated steroid. Other patients presented mild, subclinical and nonprogressive rises in serum direct bilirubin and in BSP retention. The frequency of liver function changes was greater (80 per cent) with oxymetholone than with the other two non-17-alkylated steroids (26 per cent). The changes induced with the former drug regressed completely when metholone or methenolone was substituted. Other side effects were amenorrhea and mild virilization; no growth retardation or changes in bone maturation were observed.

Our results suggest that some anabolic adrogenic steroids may be more useful than testosterone in the treatment of aplastic anemia.
Clinical Investigations in the Treatment of Meningeal Leukemia: Radiation Therapy Regimens vs. Conventional Intrathecal Methotrexate
Authors: SULLIVAN MARGARET P. , VIETTI TERESA J. , FERNBACH DONALD J. , GRIFFITH KENNETH M. , HADDY THERESA B. , WATKINS W. LORRAINE
Published: October 2019

1. Using IT MTX as standard therapy for CNS leukemia, the comparative effectiveness of three radiation therapy regimens and a combination radiation-IT MTX regimen was determined by the Pediatric Division of the Southwest Cancer Chemotherapy Study Group.

2. IT MTX, 0.5 mg./Kg. every 2-3 days until the spinal fluid mononuclear cell count decreased to 10/mm3 or less, produced spinal fluid remissions in 78 per cent of 51 children experiencing their first episode of CNS leukemia. The duration of remission ranged from 6-414 days (median 87 days). These figures are comparable to those previously reported for IT antifol therapy.

3. Radiation therapy to the entire cranium using tumor doses of 500 rads and 1000 rads was ineffective in normalizing the CSF, although symptomatic relief was often obtained.

4. Radiation of the entire cerebrospinal axis using a tumor dose of 1000 rads resulted in a spinal fluid remission rate of 92 per cent. Remissions persisted for 13-527 days (median 52 days). Six of seven children in marrow remission when radiation therapy was administered showed evidence of myelosuppression.

5. A combination therapy regimen with two injections of MTX preceding radiation of the entire cerebrospinal axis (750-1000 rads tumor dose for children in marrow remission and 250-500 rads tumor dose for children in marrow relapse) and one injection of MTX intrathecally following radiation resulted in spinal fluid remission in 100 per cent of the evaluable children in the treatment group. Symptomatic remissions occurred in 94 per cent of the children. The duration of remission, however, was similar to that obtained with conventional IT MTX therapy. Evidence of myelosuppression appeared in half of the children in bone marrow remission.

6. None of the radiation regimens was superior to IT MTX when the following parameters were considered: (1) duration of CNS remission; (2) duration of existing bone marrow remission; (3) survival from onset of meningeal leukemia; and (4) number of CNS relapses.
The Eosinophil Response to Toxoids and its Inhibition by Antitoxin
Authors: SPEIRS R. S. , TURNER M. X.
Published: October 2019

Intraperitoneal injections of specific toxoid induce a prolonged eosinophilia in the peritoneal exudate of BDF1 mice previously immunized with tetanus toxoid combined with an adjuvant of pertussis vaccine. An injection of diphtheria toxoid into tetanus-primed mice induces a transient local eosinophilia which peaks at 24 hours. A challenging injection of tetanus toxoid produced a greater 24 hour eosinophil response and, in addition, a persisting accumulation of eosinophils peaking at 3 days and still evident at days 5 and 7. Injections of heterologous antitetanus globulins or isologous immune serum did not affect the transient eosinophilia, but did suppress the accumulation of eosinophils during the second or prolonged phase of the response to challenge.

Since humoral antibody prevented the antigen from inititating the eosinophil response in animals primed to respond to a challenging injection, it was concluded that antigen-antibody reactions per se could not be responsible for the prolonged phase of the eosinophil response. It was suggested that antibody may block the antigen from complexing with sensitized cells, thereby preventing the release of eosinophilotactic factors.
Protein Synthesis in Human Leukocytes and Lymphocytes: 1. Effect of Steroids and Sterols
Authors: WERTHAMER SEYMOUR , HICKS CARL , AMARAL LEONARD
Published: October 2019

The in vitro effects of sterols, cholesterol and 3-methyl cholanthrene and steroids, cortisol, prednisolone and testosterone on protein synthesis in separate popultions of human lymphocytes and leukocytes has been investigated. It has been shown that all agents used result in the inhibition of protein synthesis under these conditions. It has also been shown that the inhibitory mechanism of the steroid hormones requires the presence of plasma, presumably as a protein binding factor in order to achieve its effect. The sterol, cholesterol and 3-methyl cholanthrene, in the absence of plasma, still inhibit amino acid incorporation. However, in the case of cholesterol, the magnitude of inhibition is lower than that observed in the presence of plasma, perhaps indicating a partial plasma dependence. The results presented therefore support the hypothesis that the inhibition of lymphocyte protein synthesis by steroid hormones occurs only when the steroid is bound to a plasma protein. The physiologic role of the plasma protein-cortisol complex and its relation to the condition of lymphopenia in man is discussed.
Diisopropylfluorophosphate Is Not a Specific Label for the Red Cell Membrane
Authors: SEARS DAVID A. , WEED ROBERT I.
Published: October 2019

When red cells were labeled either in vitro or in vivo with DF32P, the label was attached primarily at intracellular, not membrane, sites. Thus, despite the fact that it binds to and inactivates the red cell membrane enzyme, acetylcholinesterate, DF32P is not a specific label for the red cell membrane.
Brief Report: Hemoglobin-Coated Charcoal Radioassay for Serum Vitamin B12. A Simple Modification To Improve Intrinsic Factor Reliability
Authors: HILLMAN R. S. , OAKES M. , FINHOLT C.
Published: October 2019

Reliable binding of vitamin B12 by intrinsic factor (IF) is essential in the hemoglobin-coated charcoal radioassay for serum vitamin B12 as described by Lau et al.4 The fact that some IF preparations bind less B12 in the saline IF control tube than in those tubes containing serum can result in a falsely low measurement of unknown sera. This may be avoided by the simple substitution of 0.5 ml. of 5 per cent human albumin solution for the saline in the IF control tube.
Elevated Serum Iron, Low Unbound Transferrin and Candidiasis in Acute Leukemia
Authors: CAROLINE LEONA , ROSNER FRED , KOZINN PHILIP J.
Published: October 2019

Patients with acute leukemia have been shown to have elevated serum iron levels and markedly diminished or absent unbound iron binding capacity (21 of 34 patients with myeloblastic and 2 of 6 patients with lymphoblastic leukemia). Four patients (2 myeloblastic and 2 lymphoblastic) developed systemic candidiasis with elevated Candida agglutination titers and positive precipitin tests against a somatic antigen of Candida albicans. It is postulated that high serum iron and/or low unbound transferrin predispose patients with acute leukemia to candidal infection by enhancing growth of this fungus. In vitro studies support this hypothesis.
Regulation of Erythropoiesis (XXIV). Studies on the Post-Hypoxic "Rebound" Phase
Authors: SHADDUCK RICHARD K. , KUBANEK BERNHARD , PORCELLINI ADOLFO , FERRARI LUIGI , TYLER WILLIAM S. , HOWARD DONALD , STOHLMAN FREDERICK
Published: October 2019

After exposure to hypoxia there was only a moderate stimulation of erythropoiesis in a strain of mouse which produces minimal amounts of erythropoietin in response to such a stimulus. This was associated with minimal changes in bone marrow CFU’s, but there was a striking decrease in splenic CFU’s. This splenic depopulation seemed related to a specific effect of hypoxia rather than stem cell depletion secondary to erythroid differentiation. On return to ambient pressure there was a prompt onset of splenic red cell aplasia, but only a gradual decrease in marrow erythropoiesis. Despite the prompt splenic red cell aplasia, there was only a slow return to splenic CFU’s to normal levels during the first 4-5 days. Thereafter a slight rebound or overshoot was noted. Although differentiated erythroid elements were still present in the marrow on the fourth post-hypoxic day, a moderate rebound in marrow CFU’s to 150 per cent of control was evident. These findings might best be explained by a migration of stem cells during the post-hypoxic interval. Marrow lymphocytes decreased during hypoxia and rose gradually there-after following, rather than preceeding, the increase in bone marrow CFU’s.
The Monovalent Cation Content and Adenosine Triphosphatase Activity of Human Normal and Leukemic Granulocytes and Lymphocytes: Relationship to Cell Volume and Morphologic Age
Authors: LICHTMAN MARSHALL A. , WEED ROBERT I.
Published: October 2019

Differences in volume, water content and weight of leukocytes of different morphologic type are described. These differences make it mandatory that the influence of those factors which contribute to the denominator in comparative studies of leukocyte characteristics be considered if different cell types are being compared. The influence of cell isolation on monovalent cation content is emphasized. Restoration of a high potassium, low sodium steady-state occurred at 37 C. after incubation in physiologic solutions. Inhibition of this cation restoration by ouabain, or deviations from optimal extracellular pH, optimal ambient temperature and optimal extracellular potassium concentration coupled with the presence of ouabain inhibitable monovalent cation activated adenosine triphosphate hydrolysis in vitro support the presence of active cation transport in all types of human leukocytes studied. It is likely that discrepant values for leukocyte cation content and absence of monovalent cation activated ATPase previously reported are related to technical factors.

Leukemic and normal granulocytes and lymphocytes of similar morphologic type do not differ in their monovalent cation content or in sodium-potassium ATPase activity. Cell volume of leukemic and normal small lymphocytes and PMNG’s parallels their cation content. Immature granulocytes and small lymphocytes have higher sodium-potassium ATPase activities than mature granulocytes. Sodium concentration and water content were also slightly higher in immature granulocytes and lymphocytes as compared to PMNG’s. The data are consistent with the hypothesis that increased sodium-potassium ATPase activity is a biochemical feature of leukocytes with the potential to divide and differentiate. The impaired mitotic capacity of human leukemic blast cells does not appear to be related to a deficiency in sodium-potassium ATPase activity or a resultant alteration in intracellular monovalent cation content.
Determinants of Erythrocyte Size in Chronic Liver Disease
Authors: KILBRIDGE THOMAS M. , HELLER PAUL
Published: October 2019

Serial determinations of red cell volumes were made with an electronic sizing device in 30 patients with hepatic cirrhosis. Variations in red cell volumes were correlated with other hematologic and clinical findings. The results of these studies suggest that volume macrocytosis in patients with alcoholic cirrhosis is either due to megaloblastosis of the bone marrow or to an accelerated influx of young red cells into the peripheral blood.
Chlorambucil Treatment of Patients With Cold Agglutinin Syndrome
Authors: HIPPE E. , JENSEN K. B. , OLESEN H. , LIND K. , THOMSEN P. E. B.
Published: October 2019

Four patients aged 62 to 78 years with the cold agglutinin syndrome have been treated intermittently or continuously with chlorambucil for one to seven years. This resulted in a decreased susceptibility to the cold so that Raynaud phenomena and hemoglobinuria were avoided in the winter. The hemoglobin value increased, the concentration of IgM-globulin in serum was nearly normalized, and the cold agglutinin titre decreased by a factor 3-30. The thermal amplitude was lowered by 2.2-7.2°C.
Erythrocyte Vitamin B12 Activity in Health, Polycythemia, and in Deficiency of Vitamin B12 and Folate
Authors: OMER A. , FINLAYSON N. D. C. , SHEARMAN D. J. C. , SAMSON R. R. , GIRDWOOD R. H.
Published: October 2019

A method for the estimation of vitamin B12 in erythrocytes using E. gracilis is described. In 29 normal subjects the mean value was 158 pg./ml. (S.D. 31 pg.) packed cells.

Five of 14 patients with untreated primary polycythemia had very low erythrocyte vitamin B12 levels, and in the group as a whole the value was significantly less than normal. In eight patients with secondary polycythemia the erythrocyte vitamin B12 did not differ from normal, though two patients had values below the normal range.

In 19 cases of pernicious anemia the mean erythrocyte vitamin B12 level was 53 pg./ml. (S.D. 32 pg.) packed cells which was significantly reduced. There was no constant relation between the erythrocyte and plasma levels. In eight cases of folate deficiency the erythrocyte vitamin B12 level was significantly reduced, with a mean value of 95 pg./ml. (S.D. 57 pg.) packed cells.
Prophylactic Treatment of Factor VIII Deficiency
Authors: HIRSCHMAN RICHARD J. , ITSCOITZ SAMUEL B. , SHULMAN N. RAPHAEL
Published: October 2019

Two patients with classical hemophilia, and twins with a combination of classical hemophilia and von Willebrand’s disease, were treated prophylactically with cryopercipitate for periods up to two years. All had significantly fewer spontaneous hemorrhages during therapy. The prophylactic regimen required to prevent spontaneous hemorrhage was different in each case. Progressive enlargement of an inoperable hemophilic pseudotumor was arrested in one. Complications encountered included hepatitis in one case and occasional urticaria in another. Prophylactic treatment appears to be practical and indicated in selected cases.
DNA Metabolism and Development of Organelles in Guinea-Pig Megakaryocytes: A Combined Ultrastructural, Autoradiographic and Cytophotometric Study
Authors: PAULUS JEAN-MICHEL
Published: October 2019

The thick and thin section technique was used to study guinea-pig megakaryocytes by electron microscopy, combined with either autoradiography or cytophotometric determination of DNA. Megakaryocytes engaged in polyploidization already showed granule formation, which began in the Golgi apparatus partially encircled by the nucleus. The ploidization phase stopped at the 8N, 16N or 32N level, after an average of 3 ± 0.5 (1 S.D.) genome duplications. Microtubules, myofibrils and demarcation membranes were also present in the immature megakaryocytes but organelles were formed in increasing amounts in non DNA-synthesizing cells. Platelet liberation, possible at the 8N, 16N or 32N stage, occurred in non DNA-synthesizing cells, principally at the 16N level.
Studies on the Regulation of Granulopoiesis. I. The Response to Neutropenia
Authors: MORLEY ALEC , STOHLMAN FREDERICK
Published: October 2019

Mice were irradiated with one leg shielded in order to study the response of the protected marrow to neutropenia. The findings suggested that neutropenia increases the rate of release of segmented neutrophils from the marrow and also increases the rate of production of neutrophil precursors, possibly by increasing the rate of flux from a committed granulocytic stem cell compartment into the myeloblast-promyelocyte compartment. A humoral mechanism may be involved.
Evidence for Abnormal Red Cell Population in Refractory Sideroblastic Anemia
Authors: BEN-BASSAT ISAAC , SIMONI FRIDA BROK , RAMOT BRACHA
Published: October 2019

Red cell enzymes were studied in 11 patients with refractory sideroblastic anemia. Eight of the cases were of the primary idiopathic type while three had an underlying (?) disease. The red cells were separated into several density groups by different flotation with phthalate ester mixtures. The glucose-6-phosphate dehydrogenase, 6-phosphogluconic dehydrogenase, hexokinase and pyruvate kinase activities and adenosine triphosphate contents were determined in each fraction, with special attention to the lightest and densest fractions.

It was found that the refractory anemia patients have a population of abnormal light red cells with a very high enzymatic activity, especially of hexokinase, a normal adenosine triphosphate content but relatively reduced surface charge. This abnormal population which so far seems typical to this disease, is probably another reflection of the disordered red cell proliferation and maturation seen in refractory anemia.
A Philippino Glucose-6-Phosphate Dehydrogenase Variant (G6PD Union) With Enzyme Deficiency and Altered Substrate Specificity
Authors: YOSHIDA AKIRA , BAUR ERNST W. , MOUTLSKY ARNO G.
Published: October 2019

A variant of glucose-6-phosphate dehydrogenase (G6PD) associated with altered substrate specificity and severe deficiency of red cell enzyme activity was found in a Philippino male and in his relatives. The genetic pattern was consistent with X-linked inheritance. α-Thalassemia was found in the propositus and in several family members, but there was no interaction between G6PD deficiency and α-thalassemia. This G6PD variant has two pH optima, at pH 5.5 and pH 9.0, while the normal enzyme is inactive at pH 5.5. The substrate specificity of the variant enzyme is different from any known G6PD variant: 2-deoxyglucose-6-phosphate and galactose-6-phosphate are good substrates and deamino-NADP is a better coenzyme than NADP. Although G6PD activity in the variant red cells was only three per cent of normal, quantitative immunologic neutralization suggested that the specific activity of the variant enzyme might be at least ten per cent of that of the normal enzyme. This variant is named after the place of origin, Gd Union.
Genetic and Biological Aspects of the HL-A System of Human Histocompatibility
Authors: DAUSSET J. , COLOMBANI J. , LEGRAND L. , FEINGOLD N. , RAPAPORT F. T.
Published: October 2019

The HL-A system of leukocyte group antigens is a system of great complexity and polymorphism, governed by an autosomal region which includes a number of subunits or subloci. It constitutes the principal system of histo-compatibility in man.

Extensive population and family studies have resulted in the identification of two HL-A subloci. The first sublocus determines antigens HL-A 1, 2, 3, 9, Da 15 and Da 17 as alternative alleles. Antigens HL-A 5, 7, 8, Da 4, Da 6, HN, and probably Da 9 and Da 18 are determined in similar fashion at a second sublocus. The products of 20 per cent of the genes of the first sublocus, and of 29 per cent of the genes of the second sublocus are still unknown.

Study of 113 families has documented 226 human HL-A genotypes and 452 haplotypes. The observed gene and haplotype frequencies were in close agreement with the anticipated values calculated on the basis of Mendelian laws. This result supports the concept that the HL-A system is in equilibrium.

Although the HL-A system plays a major role as a determinant of human allograft responses, its primordial function may be of relevance to other fundamental biological problems, with particular reference to host defenses against microorganisms, viruses and neoplastic cells.
Cyclic Leukocyte Oscillations in Chronic Myelogenous Leukemia During Hydroxyurea Therapy
Authors: KENNEDY B. J.
Published: October 2019

Cyclic fluctuations of the leukocyte and platelet counts were observed in five patients with chronic myelogenous leukemia during treatment with hydroxyurea. The cyclic periods ranged from 30 to 50 days, were similar in each individual, but the peak-to-trough values of single cycles varied in magnitude. A second biorhythm was a cyclic undulation of the leukocyte count with heights of the peaks at nine-to-20-month intervals. Rhythmic variations of the platelet counts were also observed; the period and phase of the cycle being the same as that of the leukocyte cycle. No cyclic oscillations were noted in the hemoglobin or reticulocyte counts. The recognition of the phenomenon may aid in the use of hydroxyurea or other chemotherapeutic agents in the control of myelogenous leukemia. Chronopharmacology may more accurately develop the use of antitumor agents by its investigation of drug effects on biologic characteristics as a function of biologic timing.
Relationship of Erythropoietin Effectiveness to the Generative Cycle of Erythroid Precursor Cell
Authors: MORSE BERNARD S. , RENCRICCA NICHOLAS J. , STOHLMAN FREDERICK
Published: October 2019

Hydroxyurea, a cytotoxic agent that kills cells in DNA synthesis, was used to study the relationship between erythropoietin and the generative cycle of the immediate erythroid precursor cell. When OHU and EP were administered simultaneously to hypertransfused mice, the resultant erythroid response was diminished relative to EP treated controls. OHU given at intervals after EP resulted in a progressively greater diminution of erythroid response.

From these studies, then, we would suggest that in the suppressed animal the committed stem cell compartment is in cycle but with a prolonged G1. After EP there is a shortening of the generation time and an increase in the rate of turnover of the committed stem cells. The data also indicate that cells in cycle are differentiated into the pronormoblast compartment. It further may be suggested that erythropoietin is effective throughout the bulk of the generative cycle although it seems unlikely that differentiation is accomplished during the mitotic phase. Whether erythropoietin must be present in both G1 and S as suggested by Kretchmar cannot be answered by the present studies. The data also indicate that cells of the pluripotential compartment are normally in G0 or perhaps a prolonged G1. Damage to the committed compartment appears to be in part repaired by the influx of cells from the pluripotential compartment.
Stimulation of Thrombocytopoiesis in Irradiated Mice
Authors: EBBE SHIRLEY , STOHLMAN FREDERICK
Published: October 2019

Platelet depletion in mice, by injection of heterologous anti-platelet serum (APS), resulted in apparent stimulation of megakaryocytopoiesis as evidenced by a subsequent over-compensation of the level of circulating platelets. Injection of APS immediately before or after exposure to sublethal radiation or a day after exposure appeared to modify the response to radiation. Radiation-induced thrombocytopenia was neither as severe nor as prolonged in animals so treated as in irradiated controls. More chronic thrombocytopenia at the time of irradiation, however, appeared to increase the radiosensitivity of the megakaryocytic system.
Immunologic Studies of Antihemophilic Factor (AHF, Factor VIII) II. Properties of Cross-reacting Material
Authors: HOYER LEON W. , BRECKENRIDGE ROBERT T.
Published: October 2019

Patients with a genetic variant of hemophilia A have in their plasmas material which has antigenic characteristics similar to those of antihemophilic factor (AHF). The physical properties of the biologically inactive cross-reacting material (CRM) are like those of AHF from normal plasma. The CRM is concentrated in Cohn fraction I and in cryoprecipitates and is not adsorbed from plasma by calcium phosphate or barium sulfate. It is inactivated by heating to 56° for 30 minutes. The CRM is less sensitive to thrombin inactivation than AHF and is recovered in serum. The similar properties of AHF and CRM support the hypothesis that patients with this genetic variant of hemophilia A synthesize a material similar to AHF but lacking procoagulant activity.
Hemorrhagic Thrombocythemia; Control of Postsplenectomy Thrombocytosis with Melphalan
Authors: BENSINGER THOMAS A. , LOGUE GERALD L. , RUNDLES R. WAYNE
Published: October 2019

Hemorrhagic thrombocythemia is a relatively well-defined myeloproliferative disease in which the major abnormality is the excessive production of megakaryocytes and platelets. In its natural evolution acute and chronic bleeding from the gastrointestinal tract, thromboembolic phenomena, gastric and esophageal varices, and infarction atrophy of the spleen are the important clinical features. Disastrous complications may follow splenectomy. Removal of the spleen by surgery, or infarction and atrophy allows masses of platelets to circulate which produce thrombi or emboli in small vessels and ultimately hemorrhage. Effective treatment requires the suppression of megakaryocyte growth and thrombopoiesis. In four patients who developed severe postsplenectomy hemorrhagic thrombocythemia, melphalan (L-phenylalanine mustard) therapy effectively controlled the abnormal thrombocytosis and clinical evidence of disease.
Transmural Cellular Passage in Vascular Sinuses of Rat Bone Marrow
Authors: WEISS LEON
Published: October 2019

The structure of vascular sinuses in rat bone marrow is modified as cells cross their wall. Endotoxin, by causing withdrawal of granulocytes from the circulation, induces a compensatory discharge of fresh granulocytes through the wall of sinuses. As a result the sinus wall becomes infiltrated by clusters of late-stage hematopoietic cells which appear in transmural passage. Two correlates of such infiltration are elevation of adventitial cells from the wall and the creation of adventitial spurs extending into perisinusal hematopoietic spaces. In untreated rats adventitial cells cover, on the average, about 65 per cent of the sinus wall. After 0.04 µg. endotoxin the cover is reduced, fitting a slope regressing at the rate of 0.22 per cent/min. (t = 3.1038, p = < 0.003), the last determinations made at 120 minutes. Values for the percentage of adventitial cover calculated from observations after endotoxin are 52.5 per cent in 90 minutes and 32 per cent in 120 minutes. Even after endotoxin, a number of sinuses retain full cover while a number of control sinuses, likely reflecting normal cell passages, have little adventitial cover. Endothelial cells form a continuous layer. Apertures occur in the wall normally and increase in number after endotoxin. These apertures may contain cells, apparently in passage, or may be free of cells. Lysosomal disruption occurs in mural cells, particularly in segments of wall associated with cellular passage and with gelatinous change.
Pulmonary Bed Sequestration of Neutrophils During Hemodialysis
Authors: TOREN MICHAEL , GOFFINET JOHN A. , KAPLOW LEONARD S.
Published: October 2019

A severe, transient granulocytopenia occurs shortly after the beginning of hemodialysis in the dog, as has been previously shown in man. Simultaneous blood sampling across the pulmonary vascular bed indicates that the process of granulocyte removal begins almost instantaneously and that the pulmonary vascular bed is a major site of granulocyte sequestration.
Patterns of Granulocyte Kinetics in Acute Myelogenous and Myelomonocytic Leukemia
Authors: GALBRAITH PETER R. , CHIKKAPPA GUNDABHAKTHA , ABU-ZAHRA HAKAM T.
Published: October 2019

Granulocyte kinetic studies, using radioactive diisopropylfluorophosphate (DF32P), were performed in 15 patients with acute myelogenous leukemia (AML) and 10 patients with the myelomonocytic variety (AMML). Attention was focused upon the more differentiated cells present in the blood of the leukemic patients. The patterns of disappearance of in vitro labeled leukocytes from the blood, and the patterns of emergence of in vivo labeled leukocytes from the bone marrow were variable. Nonuniformity in the results suggests that the terms AML and AMML cover a spectrum of disorders, and that broad generalizations concerning their kinetics cannot be made. The implications of these findings are discussed, and new evidence suggesting that the mature neutrophils in the blood of leukemic patients may arise from abnormal or leukemic precursors is presented.
Endogenous Production of 14CO: A Method for Calculation of RBC Life-span In Vivo
Authors: LANDAW STEPHEN A. , WINCHELL H. SAUL
Published: October 2019

A kinetic model is presented for estimation of the degradation rate of labeled heme by measurement of appearance of 14CO in the breath following injection of glycine-2-14C. This method does not require sampling of blood or other body fluids, is absolutely independent of circulating blood volume and relatively independent of erythropoietic rate, and estimates the relative contribution to 14CO production from destruction of circulating RBC hemoglobin heme and that arising from other heme sources. For circulating RBC, rate of random hemolysis, mean potential lifespan and spread of lifespans about this mean can be calculated. Mean overall RBC lifespan and the fraction of RBC dying of senescence can be derived from these calculations. In normal male buffalo rats, the average value for random hemolysis was 0.67 per cent per day, corrected mean potential lifespan 66.2 days and standard deviation about this mean of 7.6 days. For normal female LAF1 mice, the corresponding average values were 0.60, 51.8 and 9.1, respectively. Results in two other inbred mouse strains were similar save for a shorter mean potential lifespan of 47.1 days in SEC/1Re mice and a longer mean potential lifespan of 57.3 days in WC-B6 mice. Following splenectomy in the rat, an isolated significant increase in mean potential lifespan was seen. An isolated decrease in mean potential lifespan was seen in three rats recovering from phenylhydrazine-induced anemia. An example of markedly increased random hemolysis, together with shortened mean potential life-span, was seen in a gastrectomized rat with a severe hypochromic anemia. The present method is shown to simultaneously determine the major parameters defining RBC survival, and as such, should be quite useful in the study of red blood cell disorders in animals and man.
A Difference Between Spleen-derived and Bone Marrow-derived Colony-forming Units in Ability to Protect Lethally Irradiated Mice
Authors: KRETCHMAR A. L. , CONOVER W. R.
Published: October 2019

Suspensions of cells in the bone marrow and in the spleen of normal mice were prepared. Two groups of lethally irradiated mice were given cells from bone marrow and two groups of lethally irradiated mice were given cells from the spleen of the same donor mouse. One of the groups injected with bone marrow and one injected with spleen cells were killed at 9 days for determination of CFU. The remaining animals were followed for 100 days to determine the mortality statistics. The mortality among mice not given cells was 100 per cent; among mice injected with cells, the mortality was reduced. The data permit a comparison of the reduction in mortality (protection) following injection of bone marrow CFU with protection following injection of spleen CFU. Protection with CFU of bone marrow was different from protection with CFU of spleen. It seems possible that both hemopoietic pluripotent "stem cells" and "early differentiated progenitors" can form spleen colonies and that the ratio of these CFU may be different for bone marrow and spleen.
Colony Formation by Normal and Leukemic Human Marrow Cells in Culture: Effect of Conditioned Medium From Human Leukocytes
Authors: ISCOVE N. N. , SENN J. S. , TILL J. E. , MCCULLOCH E. A.
Published: October 2019

"Conditioned medium" obtained from cultures of human peripheral leukocytes promoted the growth of human marrow cells in cell culture. This material also permitted the growth of small colonies from the marrow of patients with acute myelogenous leukemia in relapse; in its absence, only occasional colonies were observed.
Surface Morphology of Human Leukocytes
Authors: MICHAELIS THOMAS W. , LARRIMER NYE R. , METZ EARL N. , BALCERZAK STANLEY P.
Published: October 2019

Surface morphology of individual leukocytes was correlated with their light microscopic appearance by a simple, direct technique. Circulating leukocytes of all types were roughened spheres with diameters similar to red cells, and leukocyte types could not be distinguished consistently by surface morphology. After surface contact, leukocytes increased in diameter and exhibited a variety of projections. Cells spread on surfaces could be identified by external morphology. Several stages in the phagocytosis of latex particles were demonstrated. The study of surface contours by scanning electron microscopy represents a new approach to morphology.
Serum Vitamin B12-Binding Capacity and Muramidase Changes With Cyclic Neutropenia Induced by Cytosine Arabinoside
Authors: CARMEL RALPH , COLTMAN CHARLES A.
Published: October 2019

A patient with acute leukemia in sustained complete remission was studied for 8 months. Periodic maintenance chemotherapy with cytosine arabinoside regularly induced granulocytopenia, with granulocytosis upon marrow recovery. Changes in serum unbound B12-binding capacity (UBBC) occurred simultaneously with peripheral granulocyte fluctuations. Both α- and β-globulin UBBC were affected. Serum muramidase rose and fell out of phase with the granulocyte and UBBC fluctuations, preceding them by several days. These data support the concept that serum UBBC and serum muramidase reflect different aspects of granulocyte activity.
Functional Studies of Young Versus Old Platelets in a Patient With Chronic Thrombocytopenia
Authors: JOHNSON CHRISTINE A. , ABILDGAARD CHARLES F. , SCHULMAN IRVING
Published: October 2019

Results of a comparative study of the functional capacity of young versus old platelets are presented. A girl with thrombopoietin deficiency, who predictably produced platelets in response to plasma transfusion, was used as platelet donor. Her platelets obtained 4 days after infusion were used as young test cells. Platelets obtained at 18 or 21 days after infusion were used as old cells. Young platelets were found to be associated with normal bleeding times, normal clot retraction, normal or increased platelet adhesiveness, normal aggregation to ADP and collagen, and normal platelet factor 3 availability. Old platelets were found to be associated with long bleeding times, decreased platelet adhesiveness in vivo and in vitro, and deficient platelet factor 3 availability. The clot retraction and aggregation to ADP and collagen of old platelets, however, was normal. No differences between young and old platelets were observed by electron microscopy.
Evidence for a Circulating Stem Cell: Newly Formed Erythroblasts Found in Autologous Leukocyte-filled Diffusion Chambers Inserted into Bled Rabbits
Authors: GRIGORIU G. , ANTONESCU MONICA , IERCAN E.
Published: October 2019

Leukocytes from severely bled rabbits were sedimented and introduced in diffusion chambers that were implanted intraperitoneally into donor animals during the same day. Erythroblasts were found in the Millipore chambers on the fourth day culture. They were present in large numbers from the seventh to eighth day when they comprised 47.5 per cent of the nucleated cells present. Concomitantly, the young classes of reticulocytes, never found in controls, were detected in the diffusion chambers of bled animals, after more than 4 days of culture. It was assumed that: (1) Some circulating leukocytes may develop into erythroblasts under the influence of endogenous erythropoietin. (2) Under the experimental conditions employed, bleeding promoted only erythropoiesis within the implanted diffusion chambers containing leukocytes. There was no evidence of granulopoiesis and thrombopoiesis.
Accelerated Regeneration of Transplanted Hematopoietic Stem Cells in Irradiated Mice Pretreated With Cyclophosphamide
Authors: GREGORY S. A. , FRIED W. , KNOSPE W. H. , TROBAUGH F. E.
Published: October 2019

Results of experiments are reported which indicate that colony-forming units (CFU) regenerate more rapidly when transplanted into the marrow of lethally irradiated hosts pretreated with cyclophosphamide (CY) than when transplanted into those pretreated with saline. This effect is probably unrelated to the immunosuppressive properties of CY because it occurs in isogeneic strains as well as in randomly bred CF1 mice. It also does not result from an increase in the radioresistance of cells which survive after injection of CY. The data presented here are compatible with the concept that CY somehow improves the environment for hematopoietic stem cell (HSC) proliferation and thereby causes an increased rate of regeneration of transplanted HSC in the marrow cavity of the host. The possibility that this is caused by release of HSC from an inhibitory effect of cell-cell interactions on proliferation or by the release of a humoral stimulus to HSC regeneration is discussed.
Studies of Marrow Transplantation, Chemotherapy and Cross-circulation in Canine Lymphosarcoma
Authors: EPSTEIN ROBERT B. , GRAHAM THEODORE C. , STORB RAINER , THOMAS E. DONNALL
Published: October 2019

During a 4-year period 75 dogs with malignant neoplasms were referred by veterinarians to a medical research unit interested in the study of canine lymphoma and leukemia. Sixty dogs had lymphoblastic lymphosarcoma, six had leukemia, and nine had nonhemopoietic malignancies. Twenty-nine allogeneic marrow grafts were attempted following 1200 R of whole-body irradiation. Seven dogs with lymphosarcoma and one dog with anaplastic carcinoma survived beyond the first postirradiation week and demonstrated evidence of allogeneic marrow engraftment. All animals died, two following graft rejection, two with intercurrent sepsis and three of secondary disease. The two longest survivors, dying of secondary disease on days 46 and 60, were free of clinical or histologic evidence of tumor. Four dogs with lymphosarcoma were treated for 18 to 30 days with L-asparaginase. Rapid tumor regression was noted in all. Eleven dogs were treated with weekly intravenous cyclophosphamide. Moderate to marked node regression occurred in nine cases. Lymphocytes from normal dogs presensitized with tumor tissue were given by cross circulation to tumor-bearing hosts. Tumor regression occurred in two of five dogs. It was concluded that canine lymphosarcoma is a disease with uniform histologic and clinical features suitable for evaluation of therapeutic procedures in the treatment of a spontaneous malignancy in a randomly bred species.
Origin of Repopulating Cells in a Mechanically Depleted Medullary Cavity as Determined by Studies With Marrow Transplants
Authors: FONG PHILIP L. , MALONEY MARY A. , PATT HARVEY M.
Published: October 2019

The restoration of marrow in a mechanically depleted segment of rabbit femur has been reported to be a local phenomenon initiated by cells normally resident in bone. That marrow regeneration in an evacuated femur is independent of circulating stem cells has been confirmed in mice bearing a heterologous marrow transplant. Mice were given 800 R of whole-body X-radiation with experimental femur shielded. Rat marrow cells, histochemically distinguishable from those of the mouse by alkaline phosphatase staining, were then transplanted to the irradiated animals. The shielded femur diaphysis was evacuated by dextran perfusion, and 2 weeks later the animal was sacrificed. Imprints were made of the spleen and of the marrow in the contralateral limb, the epiphyseal ends of the depopulated femur, and the depopulated section of the femur. Alkaline phosphatase staining showed that all of the areas involved except the evacuated femur section had an abundance of alkaline-positive rat cells. The depopulated femur diaphysis showed a typical regenerating marrow tissue at 14 days and the cell constituents were of mouse cell origin.
Vinblastine: Colchicine-like Effects on Human Blood Leukocytes During Phagocytosis
Authors: MALAWISTA STEPHEN E.
Published: October 2019

Vinblastine and colchicine interfere with the normal organization of microtubules both in the mitotic spindle of dividing cells—causing metaphase arrest—and in the cytoplasm of nondividing cells such as polymorphonuclear leukocytes, with effects less well understood. In addition to this ultrastructural alteration, colchicine has other morphologic, enzymic, and metabolic effects on phagocytizing leukocytes, that may contribute to its anti-inflammatory properties in vivo. In the present work, effects of vinblastine were compared to those of colchicine. The effects of vinblastine 2.5 x 10-5 M were in all respects similar to those of colchicine and, on a molar basis, at least as strong. There was inhibition of the increased oxygen consumption and glucose-1-14C oxidation that normally accompany phagocytosis. There was also inhibition of lysosomal degranulation and the formation of digestive vacuoles, indicated both in morphologic studies and in measurements of granule-associated acid phosphatase activity after phagocytosis. In this system there was no demonstrable effect either on the ingestion process itself or on the intracellular killing of Staphylococcus aureus. If, however, leukocytes in buffer were incubated with preopsonized staphylococci, they ingested bacteria more rapidly than in the serum system. Under those circumstances, if the concentration of drug was doubled (to 5 x 10-5 M), there was still no difference in ingestion of bacteria between drug-treated and control leukocytes, but both vinblastine and colchicine inhibited intracellular killing of staphylococci. However, this inhibition, though statistically significant, was trivial compared to the percentages of the inocula ingested and killed by both treated and control leukocytes. These findings support the hypothesis that common structural and functional effects of vinblastine and colchicine may ultimately be traced to common ultrastructural effects on microtubules. Moreover, microtubules may facilitate the fusion of lysosomes with vacuoles containing ingested material.
Skin and Mucosal Hemorrhage of Prolonged Duration in Systemic Amyloidosis
Authors: AMIR JACOB , KESSLER ELENA , DE VRIES ANDRÉ
Published: October 2019

A patient with primary systemic amyloidosis is described in whom skin and mucosal hemorrhages constituted the sole clinical manifestation for a period of 3 yr. The cause of the hemorrhagic disorder was widespread vascular deposition of amyloid. Characteristic features of amyloid purpura are emphasized.
Further Studies on the Abnormal Factor X (Factor X Friuli) Coagulation Disorder: A Report of Another Family
Authors: GIROLAMI A. , LAZZARIN M. , SCARPA R. , BRUNETTI A.
Published: October 2019

Another patient with a congenital coagulation disorder due to the presence of an abnormal factor X (factor X Friuli) is presented. The proposita was a 43-yr-old white female who had a bleeding tendency from early childhood (epistaxes, monorrhagias, bleeding after tooth extractions and other surgical procedures, posttraumatic hemarthroses, bleeding from the gums and postpartum hemorrhages). The coagulation work-up demonstrated a prolonged prothrombin time, prolonged partial thromboplastin time, abnormal prothrombin consumption, and abnormal thromboplastin generation corrected by normal serum. Factors II, V, VII, IX, and XII were within normal limits. Platelets, vascular tests and fibrinolysis were normal. Mr. Stuart’s plasma failed to correct the defect of the proposita’s plasma, but a known factor VII deficient plasma was able to correct the abnormality. The factor X assay was low (6-9%) only when tissue thromboplastin, whole or partial, was used. When Factor X was assayed with a Stypven-cephalin mixture, normal or near normal values were observed. Likewise, the Stypven-cephalin clotting time, the Stypven clotting time and the factor II + factor X level using a Stypven-cephalin mixture were normal. The presence of the abnormal factor X was demonstrated immunologically. The defect, like classical factor X deficiency, is transmitted as an autosomal incompletely recessive trait. The mother and the two children of our proposita had factor X levels varying from 38 to 56% of normal and were considered to be heterozygotes.
Congenital Familial Megaloblastic Anemia
Authors: LAMPKIN BEATRICE C. , PYESMANY ALLAN , HYMAN CAROL B. , HAMMOND DENMAN
Published: October 2019

Two sisters with a previously unreported megaloblastic anemia unassociated with a deficiency of either folic acid or vitamin B12 are described. Deficiencies of these vitamins were ruled out by standard studies. All other previously reported forms of megaloblastic anemia not secondary to a vitamin deficiency, such as orotic aciduria, were also excluded by appropriate studies. Optimal hemoglobin responses were obtained after the administration of large amounts of both vitamin B12 and folic acid. Because of this hemoglobin response, the conversion of deoxyuridine-5-monophosphate to deoxythymidine-5-monophosphate in vitro was examined in bone marrow samples from both patients using a modification of a method described by Killmann.18 This preliminary step in DNA synthesis was found to be normal. The results of this test and the optimal hemoglobin response after administration of both vitamins suggest that both folic acid and vitamin B12 may be necessary at some other preliminary step in DNA synthesis.
Lysolecithin Metabolism by Human Platelets
Authors: ELSBACH PETER , PETTIS PENELOPE , MARCUS AARON
Published: October 2019

Human platelets incubated with 32P lysolecithin convert this compound to platelet lecithin and the water-soluble product glycerylphosphorylcholine. Lecithin synthesis from lysolecithin by intact platelets has a pH optimum of 9, whereas platelet homogenates show a pH optimum of 7.5 for the same reaction. Conversion of lysolecithin to platelet lecithin takes place by direct acylation of lysolecithin with free fatty acid. Addition of thrombin or ADP to the incubation medium has no effect on lysolecithin acylation or breakdown and does not affect the degradation of 14C choline-labeled platelet lecithin. Polystyrene particles stimulate lecithin synthesis and lysolecithin breakdown to glycerylphosphorylcholine by intact platelets but have no effect when added to platelet homogenates. By converting lysolecithin to lecithin, platelets add 2% to their lecithin content in 1 hr.