Problem-based learning: cognitive retention and cohort traits of randomly selected participants and decliners.
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Biomedical subjects
Publications and source records attributed to W E Barry.
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An unusually high level of expression of the c-myc protooncogene was observed in peripheral blood lymphocytes of a patient with prolymphocytic leukemia (atypical chronic lymphocytic leukemia). The overexpression of c-myc could not be attributed to a high level of proliferating activity of the leukemic cells in the blood. Treatment with cytosine-arabinoside at high doses abolished this altered expression of c-myc and resulted in a twofold increase in the expression of a gene sequence encoding the invariant gamma-chain of class II histocompatibility antigens, preferentially expressed in resting B lymphocytes. These observations suggest that the leukemic cells may have been arrested in the cell cycle outside the G0 phase. Our findings demonstrate that growth-regulated genes can be useful molecular markers of diseases with altered mechanisms of cellular proliferation.
Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a disorder of hematopoiesis characterized by severe thrombocytopenia due to a selective reduction or total absence of megakaryocytes in an otherwise normal-appearing bone marrow. Although the development of autoantibodies directed against cells in the megakaryocyte progenitor cell pool has been implicated in the pathogenesis of this disorder, cell-mediated suppression of megakaryocytopoiesis has not been described. Accordingly, we report two cases of AATP in which in vitro suppression of megakaryocyte colony formation by autologous ancillary marrow cells was demonstrable. Light-density bone marrow mononuclear cells (MNCs) obtained from both patients were either plated directly into plasma clot cultures, or after first being depleted by adherent monocytes (M phi) or T lymphocytes using standard methodologies. In some experiments, the depleted ancillary marrow cells were recovered for autologous co-culture studies with the MNCs from which they had been depleted. Megakaryocyte colony formation was detected in the cultures using an indirect immunofluorescence assay with a rabbit anti-human platelet glycoprotein antiserum. Removal of M phi (n = 6), or T lymphocytes (n = 4) from normal marrow MNCs had no apparent effect on colony formation. In contrast, depleting T lymphocytes from the MNCs of patient 1 significantly augmented megakaryocyte colony formation; a similar effect was observed after depleting M phi from the MNCs of patient 2. This observed augmentation in colony formation could be abrogated by autologous co-culture with the putative suppressor cell at effector cell/target cell ratios of 1:10 in the case of T lymphocytes or 1:5 in the case of M phi. Neither suppression nor stimulation of megakaryocyte colony formation was observed after culturing normal MNCs with autologous T cells (n = 4) or M phi (n = 3) at similar or greater ratios. We also observed inhibition of megakaryocyte colony formation after culturing normal MNCs in the presence of tissue culture medium conditioned by the M phi of patient 2. This effect was shown to be specific for megakaryocytes since this same conditioned medium had no significant effect on BFU-E and CFU-E-derived colony formation by autologous marrow mononuclear cells. These results suggest that: both T cells and M phi are capable of exerting a regulatory effect on the proliferation of human megakaryocyte progenitor cells (CFU-Meg); in the case of M phi, a soluble factor elaborated by these cells may be responsible for suppressing CFU-Meg growth; and aberrant ancillary cell-megakaryocyte progenitor cell interactions may lead to clinically significant disease.
Attempts were made to establish lymphoid cell lines from the cultured peripheral blood lymphocytes of six patients with chronic lymphocytic leukemia. In only one case was cell growth obtained following the addition of exogenous transforming Epstein-Barr virus, and those cell cultures proved not to have acquired the ability to proliferate permanently. In the same case, cell lines were established spontaneously from the peripheral blood without addition of Epstein-Barr virus. The cells which grew spontaneously were large, were occasionally weakly surface adherent, and grew in suspension as loose clumps or as single cells. They were negative for surface immunoglobulins and spontaneous rosette formation with sheep erythrocytes and positive for intracytoplasmic immunoglobulins (Fc and C3 receptors). At an early passage, the spontaneous lines had an aneuploid karyotype with some triploid and some tetraploid cells. Structural chromosomal aberrations include a 14q+. Electron microscopy of the chronic lymphocytic leukemia lines revealed relatively smooth surfaces with numerous mitochondria, widespread vacuolization, and numerous unusual "myelin" figures. Five to 10% of the cells were phagocytic as detected by internalization of latex particles; however, they were Epstein-Barr nuclear antigen positive. The nature of these cells and their possible relationship to the etiology of chronic lymphocytic leukemia are discussed.
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Some patients with thrombocytosis due to myeloproliferative diseases or other etiologies experience thromboembolic complications and others may bleed excessively. It seems unlikely that elevations in platelet count per se are a direct cause either of thrombosis or of hemorrhage. In an effort to ascertain whether variations in platelet function might determine whether an individual patient experiences thrombotic or hemorrhagic complications we have evaluated platelet function in 22 patients with thrombocytosis due to a variety of etiologies. The results of platelet counts, bleeding time determinations, and studies of platelet aggregation were similar in patients with thrombosis, in patients with bleeding and in patients with neither complication. Therefore, detailed studies of platelet coagulant activities were carried out in 8 patients. The results of platelet coagulant activity assays were normal in all 3 patients with thrombocytosis and neither thrombotic nor bleeding complications and an additional 3 patients with myeloproliferative diseases, normal platelet counts and no thrombohemorrhagic complications. In 2 patients with thrombotic complications significant elevation of platelet coagulant activities concerned with the early phases of intrinsic coagulation were observed whereas in 2 patients with severe hemorrhagic complications deficiencies of either contact forming activity or collagen-induced coagulant activities were evident. This preliminary study suggests the possibility that variations in platelet coagulant activities concerned with the early stages of intrinsic coagulation may determine whether patients with thrombocytosis will experience bleeding or thrombotic complications.
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Ninety-two courses of daily low-dose intravenous nitrogen mustard were administered to 46 patients with advanced cutaneous lymphomas (mycosis fungoides, Sezary syndrome and lymphoma cutis). Seventy-eight % of patients showed objective clinical remission, and 35% reached a clinically disease-free state following 1 or more courses. The response rate was greater in patients with the plaque-tumor type of mycosis fungoides than in those with erythrodermic variants. Therapy was free of significant side effects.
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