Treatment of pernicious anemia: a 1931 advertisement.
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Biomedical subjects
Publications and source records attributed to L Kass.
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Using the ammoniacal silver stain, Cabot rings were identified in peripheral blood erythrocytes from patients with severe untreated pernicious anemia. Ultrastructural studies of these erythrocytes showed silver deposits in partial loops and figure-eight forms, indicating that arginine rich histone may be a prominent component of the Cabot ring.
The state of differentiation of the lymphocytes in chronic lymphocytic leukemia is a factor that appears to correlate with the presence and severity of clinical manifestations of the disease and with the incidence of complications. Among drug regimens proposed to date, the most efficacious in poorly differentiated disease appear to be the three- and four-drug combinations.
Three types of morphologic abnormalities of megaloblasts in the bone marrows of eight patients with severe untreated pernicious anemia and two patients with folate deficiency are described. A fourth type of abnormality, probably indicating disturbances in hemoglobin synthesis, was also observed in megaloblasts from patients with these conditons. In addition to the phenomenon of erythrophagocytosis in these disorders, the degenerating megaloblasts and those showing disturbances of hemoglobinization may constitute additional cytologic evidence for intramedullary destruction of erythroid precursors contributing to ineffective erythropoiesis in these disorders.
Utilizing a bacterial-agar overlay technic incorporating the methionine-requiring bacterium Leukonostoc mesenteroides, little or no bacterial growth was seen surrounding the megaloblasts and proerythroblasts of eight patients who had severe untreated pernicious anemia. Similarly, scant bacterial growth was observed in five cases of chronic erythremic myelosis (DiGuglielmo syndrome). Heavy bacterial growth, indicating ample amounts of methionine, was seen in two cases of autoimmune hemolytic anemia, and in two cases of severe untreated folate-deficiency anemia. The results are consistent with the "methyltetrahydrofolate trap" hypothesis in pernicious anemia, in which a defect in the methylcobalamin-dependent methyltransferase leads to reduced amounts of methionine. These studies also suggest that a similar methyltransferase defect does not occur in folate deficiency or autoimmune hemolytic anemia. The generation of methionine, as estimated by the present technic, may also be defective in chronic erythremic myelosis.
Chronic erythremic myelosis is a myeloproliferative disorder of unknown etiology that is characterized by refractory macrocytic anemia and marked megaloblastoid erythroid hyperplasia of the bone marrow. Ferrokinetic and cytologic evidence indicates that the disorder demonstrates ineffective erythropoiesis. Certain cytochemical tests may help both to substantiate the diagnosis and to provide insight into some of the biochemical abnormalities in the erythroid precursors. Therapeutic trials of androgen or pyridoxine (vitamin B6) or both may be of value in some cases but ineffective in others, and some patients may require administration of blood transfusions. Why an erythroid disorder characterized by a uniquetype of megaloblastoid erythropoiesis should be the forerunner of acute leukemia is one of the many unanswered questions in this often therapeutically frustrating disorder.
Cytochemical studies were performed on erythrocytes containing Cabot rings from the peripheral blood of two patients with severe untreated pernicious anemia. These studies demonstrated that the Cabot ring contained arginine-rich histone and non-hemoglobin iron. Structures that may represent precursors of Cabot rings were found in stippled late intermediate marrow megaloblasts. The Cabot ring may result in part from abnormalities in metabolism of both iron and arginine-rich histone that are known to occur in pernicious anemia.
Eosinophilia and plasmacytosis of the bone marrow were found in a group of patients with newly diagnosed Hodgkin's disease. An attempt was made to correlate these cytologic findings with other modalities used in the staging of patients with Hodgkin's disease and believed to have prognostic importance, such as age, sex, histologic type of Hodgkin's disease, presence or absence of bone marrow involvement, and pathologic stage. Statistical analyses of these finding s indicated that eosinophilia and plasmacytosis occur frequently but to date appear to be nonspecific findings. Whether the occurrence of eosinophilia and plasmacytosis is related to an immune response in unknown.
Phosphorylase activity was detected in the cytoplasm of erythroid precursors of 6 of 7 patients with chronic erythremic myelosis (Di Guglielmo syndrome), in proerythroblasts and megaloblasts from 3 patients with pernicious anemia and in 2 patients with severe folate deficiency in neoplastic lymphocytes from 2 patients with acute lymphoblastic leukemia, and in 1 patient with leukemic lymphosarcoma. In all of these patients, most of the erythroid precursors and/or neoplastic lymphocytes contained increased amounts of glycogen when stained with the PAS reagent. Phosphorylase activity was not detected in erythroid precursors obtained from 6 presumed normal individuals or from 3 of 7 patients with a variety of other types of anemia in which the erythroid precursors were PAS-negative. Similarly, phosphorylase activity was absent in lymphocytes obtained from presumed normal individuals. Although the mechanisms responsible for the pathogenesis of PAS positivity are unclear, it is possible that the increased phosphorylase activity found in cells that are PAS-positive may reflect a disorder in the biosynthetic pathway of glycogen.
Cytochemical properties of atypical erythroblasts and 'histioid' cells from the bone marrows of two patients with acute erythremic myelosis (Di Guglielmo's disease) were studied. In addition to strong PAS and strong nonspecific esterase positivity, intense specific esterase positivity was also detected in the majority of the erythroid precursors. Since specific esterase activity is considered to be a feature of granulocytic cells, its presence in erythroid precursors raises the possibility that the atypical erythroblasts of acute erythremic myelosis may share close metabolic relationships with granulocytic cells.
Arginine-rich and lysine-rich histones were extracted from various cytologic types of leukemic blasts and from preparations rich in normal monocytes. On polyacrylamide disc electrophoresis, the patterns of normal monocyte histones closely resembled those found in acute histiomonocytic leukemia (Schilling type). The electrophoretic patterns of histones obtained from leukemic blasts in acute myelomonocytic leukemia (Naegeli type) were similar to those found in both acute myelobastic leukemia and chronic granulocytic leukemia. The results support the concept that acute myelomonocytic leukemia may be closely related to, or a variant of, acute myeloblastic leukemia, and that acute histiomonocytic leukemia is most probably a monocytic rather than a myeloblastic disorder. In addition to accepted morphologic and enzymatic criteria, the present studies suggest that differences in histone patterns might be useful in further distinguishing between histiomonocytic, myeloblastic, and myelomonocytic leukemias.
When normoblasts from patients with chronic erythremic myelosis were stained with the anthraquinone dye, alizarine red S, a purple perinuclear halo appeared. This halo corresponded in location to siderotic granules stained with a conventional iron stain. The rapidity of the alizarine red S stain makes it potentially useful for the detection of pathological sideroblasts in certain refractory anemias.
The localization of histones was studied ultrastructurally with the use of the ammoniacal silver stain in erythroid precursors from 6 patients with chronic erythremic myelosis (Di Guglielmo syndrome), 3 patients with severe untreated pernicious anemia, 2 patients with untreated autoimmune hemolytic anemia, and 4 presumedly normal individuals. Silver deposits, indicative of sites of arginine-rich histone within nuclei, were not observed in proerythroblasts from any of the individuals. Small deposits of silver were seen in the heterochromatin in very early intermediate normoblasts. Differences in the amount and distribution of the silver deposits in the various types of erythroid precursors first became recognizable in the intermediate normoblast stage. In all of the individuals, the silver deposits were localized predominantly in the heterochromatic regions of the nucleus. In 6 patients with chronic erythremic myelosis, unusually, dense deposits of silver were observed in erythroid precursors having amounts of heterochromatin comparable to that found in intermediate normoblasts of intermediate megaloblasts in other conditions. In these chronic erythremic myelosis erythroid precursors, the silver deposits were larger and, in many instances, appeared to be more aggregated than in erythroid precursors obtained from 3 patients with untreated pernicious anemia, 2 patients with autoimmune hemolytic anemia, and 4 presumedly normal persons. It is possible that the findings described in this study are involved in the pathogenesis of megaloblastoid erythropoiesis as found in chronic erythremic myelosis.
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