Evidence for a Physiologic Role of Erythropoietin in Fetal Erythropoiesis

Administration of antibody prepared inrabbits against human urinary Ep to fetalsheep during the last third of the gestation period resulted in a suppression oferythropoiesis in the fetus. This wasevidenced by a sharp decrease in the numbers of circulating reticulocytes and a reduced rate of ⁵⁹Fe incorporation into RBC,spleen, and bone marrow, effects ascribable to a neutralization of endogenous Ep.In addition, there was a significant decrease in the numbers of nucleated erythroid cells in the bone marrows of thesefetuses. These results point to a physiologic role for Ep in fetal erythropoiesis.

Submitted on December 17, 1973 Revised on February 19, 1974 Accepted on February 20, 1974     

Hemopoietic effects in mice of a transplanted, granulocytosis-inducing tumor.

A transplanted tumor that induces granulocytosis and produces colony stimulating factor (CSF) was studied in mice during several passages. The sequence of events leading to granulocytosis was characterized. Band granulocytes were increased 3 days after tumor inoculation, while simultaneously CFU-s and CFU-c in bone marrow and spleen were transitorily low. This was followed by rapid accumulation of CFU-c and CFU-s in spleen, and by successive waves of increased mitotable and non-mitotable granulocytes in spleen and marrow. In contrast, marrow CFU-c and CFU-s remained normal or slightly decreased.     

Public Health Service study of Reye's syndrome and medications. Report of the main study

Between January 1985 and May 1986, following completion of a pilot study, a main study concerning the possible association between Reye's syndrome and salicylates was conducted. Twenty-seven patients with stage II or deeper Reye's syndrome whose diagnoses were confirmed by an expert panel and who had appropriate antecedent illnesses (chickenpox, respiratory illness, or gastrointestinal illness) prior to the onset of Reye's syndrome were compared with 140 controls matched for age, race (black or not black), and type and timing of onset of antecedent illness. Controls were selected from the same hospital, emergency room, or school as case-patients or were identified by random-digit telephone dialing. As in the pilot study, a strong statistical association with ingestion of salicylates during the antecedent illness and prior to the onset of Reye's syndrome was observed (odds ratio, 40; lower 95% confidence limit, 5.8). Analysis of the independent risk of aspirin and nonaspirin salicylates revealed a significant association with aspirin (odds ratio, 26; lower 95% confidence limit, 6.4); the independent risk of nonaspirin salicylates could not be assessed because only two cases were not exposed to aspirin. Assessment of epidemiologic issues of concern, including case-control differences in the severity of the antecedent illness, did not explain the high odds ratios that were observed. The high percentage of patients with Reye's syndrome exposed to salicylates (greater than or equal to 90%) in this and prior studies suggests that, though the reported incidence of Reye's syndrome has declined in recent years, concomitant with a decline in salicylate use among children, a majority of Reye's syndrome cases may be attributable to salicylate use.     

Periodic oscillation of blood leukocytes, platelets, and reticulocytes in a patient with chronic myelocytic leukemia.

A patient with chronic myelocytic leukemia had a cyclic oscillation of blood neutrophils, eosinophils, monocytes, platelets, normoblasts, and reticulocytes but not of lymphocytes. The cycle interval was 53--69 days. Except for reticulocytes all other cells cycled with neutrophils. Plasma colony-stimulating factor (CSF) oscillated out of phase with neutrophils, suggesting that granulocytopoiesis is regulated through CSF by a feed-back mechanism. Plasma erythropoiesis-stimulating factor (ESF) also oscillated. ESF crests preceded or coincided with reticulocyte crests, indicating that the ESF elevation may have been responsible for the reticulocyte peaks. The relationship between neutrophils and reticulocytes and their oscillations with plasma CSF and ESF suggests that there is a common stem cell which differentiates along one cell line or the other depending upon the balance of regulatory stimuli. The fraction of blood neutrophilic precursors (myeloblasts, promyelocytes, and myelocytes) in DNA synthesis fluctuated with neutrophil level. The calculated generation time was shorter at the crests than at the troughs of the neutrophil cycles. This finding suggested that the rate of proliferation of the neutrophils changed periodically. This observation, along with a periodic increase in differentiation of the stem cell toward the neutrophilic cells, is the probable explanation of oscillation of the neutrophil count in the blood.     

Selective damage to erythroblasts by 55-Fe

The low energy and short range of 55-Fe Auger electrons were utilized in mice to deliver lethal intracellular radiation to iron-incorporating erythropoietic precursors with minimal radiation damage to other bone marrow cells. The ensuing intramedullary, selective erythropoietic death was demonstrated by absolute and differential bone marrow cell counts and by decreased blood uptake of 59-Fe. The decreased number of colony-forming units in spleen colony assay and the decreased ability of tranplanted bone marrow to protect fatally irradiated mice shows that the bone marrow was partially depleted of pluripotent stem cells. These data are interpreted to indicate an increased pluripotent stem cell utilization in response to increased demand for differentiation of stem cells along the erythropoietic pathway.     

Erythropoietin Production in Cultures of Goat Renal Glomeruli

Cultures initiated with isolated goat-kidney glomeruli produce erythropoietin over periods of 7 months. Production seems dependent upon a minimum interval of about 30 days between changes of medium. Experiments distinguishing between erythropoietin, renal activator, and serum substrate support the conclusion that the factor released to the medium of long-term glomerular cultures is erythropoietin itself. The system offers promising opportunities for studying regulation of erythropoietin production, and possibly could be developed as a source of significant quantities of the hormone.