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Biomedical subjects

R Hoffman

Publications and source records attributed to R Hoffman.

At least 343 records · Page 19Linked to original sources
PubMed1984

Sideroblastic anemia: differences in bone marrow erythroid colony (CFUE) growth responses to erythropoietin in plasma clot and methylcellulose cultures.

Bone marrow cells from three patients with idiopathic acquired sideroblastic anemia and one with X-linked sideroblastic anemia were simultaneously cultured in plasma clot and methylcellulose cultures in order to evaluate their erythroid colony (CFUE) cloning potential in these two systems. In contrast to normals, sideroblastic anemia bone marrow cells demonstrated a marked ability to form erythropoietin (Epo)-independent CFUE in methylcellulose culture, and were inhibited in their ability to generate CFUE in plasma clot culture even in the presence of Epo. Addition of citrated plasma to methylcellulose cultures inhibited Epo-independent CFUE growth, but not Epo-dependent growth, by both a normal and patients' bone marrow cells. These results demonstrate that bone marrow cells from some patients with sideroblastic anemia can undergo Epo-independent and Epo-dependent CFUE growth in vitro, and that there is a marked difference in CFUE growth depending on the type of clonal culture method used. It is suggested that the culture microenvironment, plasma, and sensitivity to Epo may be contributing factors which allow specific clones of sideroblastic anemia CFUE-forming cells to proliferate in vitro.

Anemia, Sideroblastic↗
PubMed1984

A microgenetic model of paragrammatisms produced by a schizophrenic speaker.

A series of papers appearing in Brain and Language ask whether schizophrenic language irregularities can be understood in linguistic terms. This literature is reviewed and the contrary positions of different authors are highlighted. The clinical presentation of a schizophrenic male is described. In a single interview he produced a set of paragrammatical errors which are noteworthy insofar as they indicate sustained epochs of diminished expressivity. In this sense, they differ from schizophasic deviance, which is described by Lecours and Vanier-Clement (Brain and Language, 3, 516-565, 1976) as an enhanced expressivity cooccurring with intact language competence. They are also partially decodable, which distinguishes them from the schizophrenic segments discussed by Chaika. Analyses of the paragrammatisms indicate disruptions at three discrete representational levels. One involves the formation of abstract speaker intentions, while the second organizes syntagms into some serial form, and the third level takes content words belonging to a particular syntagm and positions them in a syntactic frame. A microgenic model of these representational planes is proposed that is based on the theoretical perspective of Brown, as well as Garrett's investigations of normal speech errors. The model is justified insofar as the paragrammatisms indicate "linguistic regressions" back to more "thought-like" linguistic representations. Moreover, a recapitulation of specific linguistic mappings is demonstrated to occur between processing levels. This microgenetic model represents an extension of previous work in aphasiology insofar as it targets combinatorial rather than selectional processes as primary planes of disruption.

Adult↗
PubMed1984

Evidence for the clonal origin of acquired hypomegakaryocytic thrombocytopenic purpura from a sex chromosome mosaic.

Cytogenetic studies performed on a 79-year-old female presenting with clinical and hematologic features of acquired hypomegakaryocytic thrombocytopenic purpura revealed sex chromosome mosaicism in blood lymphocytes (45,X/46,XX/47,XXX). The presence of only 45,X cells in the bone marrow is consistent with a unicellular origin of acquired hypomegakaryocytic thrombocytopenia in this patient. These studies also suggest that, in some instances, this disorder may originate at the level of the pluripotent hematopoietic stem cell.

Aged↗
PubMed1984

Chloride transport properties of human leukemic cell lines K562 and HL60.

The Cl- transport characteristics of the human leukemic cell lines K562 and HL60, with erythroid and granulocytic phenotypic features, respectively, were investigated. Cl- effluxes were measured with 36Cl- under equilibrium conditions in both cell lines and were found to be three orders of magnitude slower than the unidirectional efflux of Cl- in normal erythrocytes. Induction of differentiation of the K562 cell line with hemin does not affect the rate of Cl- transport, while induction of the HL60 cell line with dimethyl sulfoxide results in a small decrease in the rate of Cl- transport. Cl- transport in both cell lines could be divided into two components. One component is inhibited by treatment with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), displays counter-transport characteristics, and has a high energy of activation--all properties characteristic of the human erythrocyte-facilitated anion exchange system. The second component is insensitive to DIDS, is partially inhibited by furosemide, and has a low energy of activation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1984

Blastic transformation of essential thrombocythemia: dual expression of myelomonoblastic/megakaryoblastic phenotypes.

Three patients developed blastic transformation of essential thrombocythemia (tET). Morphological studies in all patients showed that the majority of blasts had either myeloblastic or myelomonoblastic differentiation. Immunologic assays of hematopoietic cells were performed in two patients. In patient 1, 86% of peripheral blood mononuclear cells (predominantly blasts) reacted with a monoclonal antibody specific for granulocytes and monocytes (MMA), and 15% of mononuclear cells reacted with Tab, a monoclonal antibody specific for megakaryocyte-platelet glycoproteins (PGP) IIb and IIIa. In patient 2, 41.5% of peripheral blood mononuclear cells (predominantly blasts) were MMA-positive, 22.5% were Tab-positive, and 40% reacted with rabbit anti-human PGP. These results suggest either that two subpopulations of blast cells exist in tET, or that blast cells simultaneously express surface markers of myeloblastic/monoblastic and megakaryoblastic differentiation. In these three and in nine previously reported cases of tET, neither age, sex, nor previous therapy were obvious etiologic factors. tET occurred 24.2 +/- 14.4 mo after diagnosis of essential thrombocythemia, and a majority of patients had hepatomegaly and/or splenomegaly, anemia, leukocytosis, and thrombocytopenia. Leukemic cell morphology was myeloblastic and/or monoblastic in 12/12 patients, 5/12 had marrow fibrosis. Despite various treatments, death occurred in 3.6 +/- 2.7 mo; one patient had a brief complete remission.

Aged↗
PubMed1984

Isolation of human megakaryocytes by density centrifugation and counterflow centrigual elutriation.

Density centrifugation and counterflow centrifugal elutriation were utilized to prepare enriched fractions of megakaryocytes from human bone marrow aspirates. This separation method enriched megakaryocytes in initial marrow aspirates by 116- to 463-fold. Approximately 63% of megakaryocytes were recovered from the initial samples, composing 18.7% of the nucleated cells in the final preparations. Mean megakaryocyte diameters of 51.6 micron and 33.8 micron were obtained from fixed and unfixed cellular specimens, respectively. Smaller platelet glycoprotein-positive mononuclear cells with a mean diameter of 20.5 micron were found in the highest concentrations in this final fraction. These cells presumably represent immature megakaryocytic forms. Counterflow centrifugal elutriation provides a means of isolating enriched populations of marrow megakaryocytes. This accessibility to viable populations of human megakaryocytes will allow additional investigation of the terminal events of megakaryocyte development.

Bone Marrow↗
PubMed1983

Mechanisms of abnormal erythropoiesis in malignancy.

In order the investigate mechanisms of diminished red cell production in malignancy, we assayed erythroid progenitor cell proliferative responses to erythropoietin in plasma clot cultures of bone marrow cells from 34 cancer patients. Erythroid colony growth by marrow cells of 11 healthy donors (means of 58 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) was similar to that in cultures of cells from patients either with (means of 44 CFU-E and 22 BFU-E derived colonies/6 X 10(4) cells) or without (means of 50 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) myelophthisis. Colony formation was normal at all erythropoietin concentrations tested, indicating that both the CFU-E and BFU-E retain normal erythropoietin sensitivity in vitro. CFU-E proliferation correlated negatively (r = -0.56; P less than 0.001) with the level of hemoglobin. In contrast to marrow cell proliferative responses to erythropoietin, serum erythropoietin levels were inappropriately reduced in all 19 patients in whom they were measured, a finding which may be important in the pathogenesis of anemia in patients with cancer.

Carcinoma, Squamous Cell↗
PubMed1983

Hypercalcaemia complicating acute myelogenous leukaemia: a syndrome of multiple aetiologies.

Hypercalcaemia complicating acute myelogenous leukaemia is a rare but well-recognized phenomenon. In most cases the pathogenetic mechanism causing the hypercalcaemia remains poorly understood. We recently studied in detail two patients with acute myelogenous leukaemia who developed hypercalcaemia during the course of their illness. The results of these studies conclusively excluded primary hyperparathyroidism or ectopic parathyroid hormone production as causes of the patients' hypercalcaemia. In vitro studies carried out on short-term suspension cultures of one patient's peripheral blood blast cells demonstrated production of a factor with potent bone resorbing activity, distinct from parathyroid hormone (iPTH) and prostaglandin E2 (PGE2). Further characterization of the bone resorbing factor suggested that it bore some similarity to osteoclast activating factor (OAF). Hypercalcaemia in the other case appeared to be due to a combination of skeletal invasion by malignant cells, and to ectopic secretion of an unidentified humoral factor with bone resorbing activity. These two cases demonstrate that the hypercalcaemia complicating acute myelogenous leukaemia may be due to a variety of mechanisms distinct from parathyroid hormone production.

Aged↗
PubMed1983

Studies of BFU-E in flask cultures of human peripheral and cord blood cells.

Early erythroid progenitors (the burst-forming units-erythroid or BFU-E) from human peripheral and cord blood mononuclear cells were maintained in flask culture for 2 weeks without added erythropoietin (Epo) or erythroid potentiating activity (EPA). These cultures did not develop adherent cell layers and did not support the more mature erythroid colony-forming unit (CFU-E). Samples removed at intervals from these flask cultures were assayed for BFU-E recovery in a plasma clot system in response to a range of Epo doses and to added EPA with time in flask culture. The BFU-E recovered showed increased proliferative capacity and decreased responsiveness to Epo and EPA. These results indicate selection of more primitive erythroid progenitor cells under the conditions described. Peripheral and cord blood mononuclear cell cultures provide a flexible and accessible approach to in vitro studies of human erythropoiesis. Comparative studies with long-term marrow cultures should help to elucidate the role of adherent cells and humoral factors in erythroid differentiation.

Cell Division↗
PubMed1983

In vitro studies of megakaryocytopoiesis in thrombocytotic disorders of man.

Increased numbers of bone marrow megakaryocytes and thrombocytosis are frequently observed in patients with myeloproliferative disorders (MPD). Increased marrow megakaryocytes and thrombocytosis are also noted in a variety of inflammatory and neoplastic disease leading to the phenomenon of reactive thrombocytosis (RT). The pathogenesis of this finding remains incompletely understood. Using methodology developed in our laboratory, we investigated the causative role of megakaryocyte colony-stimulating activity (Meg-CSA) in generating this phenomenon. We also examined the cloning efficiency of colony-forming units-megakaryocyte (CFU-M) and their responsiveness to an exogenous source of Meg-CSA in patients with these diseases. The results of our investigations suggest that: (1) increased production of Meg-CSA is not responsible for the megakaryocyte hyperplasia and thrombocytosis noted in these patients; (2) the intrinsic stem cell defect described in MPD appears to affect the CFU-M of these patients as well, resulting in an effective expansion of the CFU-M pool with consequent megakaryocyte hyperplasia and thrombocytosis; (3) the CFU-M of patients with MPD remain responsive to an exogenous source of Meg-CSA, suggesting that this megakaryocyte hyperplasia may not be entirely autonomous of its effects; and (4) the CFU-M pool in RT is normal both in size and responsiveness to Meg-CSA, suggesting that in these disorders, the stimulus leading to megakaryocyte hyperplasia and thrombocytosis is active at the post-CFU-M level of megakaryocyte differentiation.

Cells, Cultured↗
PubMed1983

Cyclosporine suppression of lymphocyte recruitment, regional blood flow, and vascular permeability at sites of allogeneic cellular interactions.

Although cyclosporine (CsA) has been thought to act primarily on the afferent phase of the immune response, we can demonstrate that it also acts at the efferent phase. The effect of CsA on lymphocyte recruitment (LR), regional blood flow (RBF), and vascular permeability (VP) was studied in paired, healed, subcutaneously placed urethane sponge grafts inoculated with specifically sensitized lymphocytes (SSLs) and allogeneic target cells. Intravenous injection of 111In-labelled unsensitized lymphocytes, 86RbCl and 125I-labelled albumin were used to assess LR, RBF, and VP, respectively. Suspensions of SSL and targets in CsA at 10 and 1 microgram/ml prior to graft inoculation markedly reduce the preferential increase in LR to the site of interaction between SSLs and targets bearing the sensitizing alloantigen (P less than 0.002 for both). Similarly, CsA blocks the preferential increase in RBF (P = 0.017) and VP (P less than 0.002) to the graft site. These effects persist for at least 24 hours. If SSLs and targets are washed after incubation with CsA, LR is still reduced. These results are consistent with the idea that cell-bound CsA blocks the elaboration of lymphokines which results from the interaction between SSLs and specific alloantigen in vivo. These lymphokines increase RBF and VP and are accompanied by an increase in LR. Inhibition of these vascular effects may prevent the recruitment of additional lymphocytes to the graft site. CsA may, therefore, prevent or interrupt allograft rejection by blocking amplification of the rejection mechanism at the graft site.

Animals↗
PubMed1982

Recruitment of unsensitized circulating lymphocytes to sites of allogeneic cellular interactions.

The recruitment of indium-111-labeled unsensitized lymphocytes (ULs) from the circulation into healed subcutaneous urethane sponge implants inoculated with specifically sensitized T lymphocytes (SSLs) and allogeneic target cells was studied in mice. Intravenously injected ULs were preferentially recruited to the site of specific effector-target interaction. Preferential recruitment was demonstrable within 1 hr of i.v. injection and was maximal at 4 hr. The recruitment of ULs was proportional to the number of SSLs or targets injected into the sponge. Effector cells capable of mediating the recruitment of ULs when presented with the sensitizing alloantigenic cells are detectable early in mixed lymphocyte culture (MLC) prior to the development of strong cytotoxicity. Furthermore, effector cells can be generated in MLC between H-2 identical but Mls-disparate strains in which a proliferative response occurs, but few cytotoxic cells develop. Depletion of Lyt-2+ cells from day 5 MLC abrogates cytotoxicity, but the capacity of the remaining cells to mediate recruitment is not changed. In contrast, depletion of Lyt-1+ cells does not alter cytotoxicity, but significantly reduces recruitment mediated by the remaining sensitized cells. These results suggest that recruitment of circulating lymphocytes to the site of an allograft response is mediated by an immunologicaly specific interaction between SSLs and alloantigen. These SSLs may be proliferating noncytotoxic lymphocytes or cytotoxic T lymphocytes. The capacity of a specific immune interaction at the allograft site to recruit circulating lymphocytes may be a rapid and potentially important mechanism of immune amplification in allograft rejection.

Animals↗
PubMed1982

Constitutive expression of platelet glycoproteins by the human leukemia cell line K562.

The human leukemia cell line K562 was derived from a patient with chronic granulocytic leukemia. This cell line has subsequently been shown to possess phenotypic markers typical of erythroid and myeloid cells. Using a rabbit antiserum directed against purified platelet glycoproteins (PGPs), we have obtained evidence for the constitutive expression of PGPs on the surface of K562 cells. PGPs expressed have been tentatively identified as IIa and III based on their apparent migration in a 7% sodium dodecylsulfate polyacrylamide gel. K562 may become an important tool for the study of early events involved in megakaryocytic differentiation.

Animals↗
PubMed1982

Eosinophilic fasciitis.

Eosinophilic fasciitis (EF, a diffuse fasciitis with eosinophilia) is a recently recognized connective tissue disorder. It consists of deeply indurated, bound-down plaques of skin and subcutaneous tissue, most commonly present on the extremities. It is associated with peripheral eosinophilia, hypergammaglobulinaemia and an elevated sedimentation rate. There is usually no evidence of Raynaud's phenomenon, acral sclerosis or visceral involvement. Antinuclear antibodies are usually absent. The abnormal histopathology primarily involves the lower subcutis and the fascia. The clinical and laboratory features usually improve following the administration of systemic corticosteroids. Serious haematological abnormalities have been associated with eosinophilic fasciitis (EF) and have been discussed in detail. The similarities and distinctions between eosinophilic fasciitis and scleroderma have been discussed.

Adrenal Cortex Hormones↗
PubMed1982

Acquired amegakaryocytic thrombocytopenic purpura: a syndrome of diverse etiologies.

The possible pathogenetic mechanisms responsible for the production of acquired amegakaryocytic thrombocytopenic purpura (AATP) were investigated in a group of patients with this disorder. Absence of megakaryocytes and small platelet glycoprotein-bearing mononuclear cells, as determined by immunochemical staining of patient marrows with an antisera to platelet glycoproteins, suggested that the defect in AATP occurs in an early progenitor cell of the megakaryocytic lineage. Using an in vitro clonal assay system for negakaryocytic progenitor cells or megakaryocyte colony-forming units (CFU-M), the proliferative capacity of AATP marrow cells was then assessed. Bone marrow cells from three of four patients formed virtually no megakaryocyte colonies, suggesting that in these individuals the AATP was due to an intrinsic defect in the CFU-M. Bone marrow cells from an additional patient, however, formed 12% of the normal numbers of colonies, providing evidence for at least partial integrity of the CFU-M compartment in this patient. Serum specimens from all six patients were screened for their capacity to alter in vitro megakaryocyte colony formation. Five of six sera enhanced colony formation in a stepwise fashion, demonstrating appropriately elevated levels of megakaryocyte colony-stimulating activity. The serum of the patient with partial integrity of the CFU-M compartment, however, stimulated colony formation only at low concentrations. At higher concentrations, this patient's serum actually inhibited the number of colonies cloned, suggesting the presence of a humoral inhibitor to CFU-M. Serum samples from all patients were further screened for such humoral inhibitors of megakaryocyte colony formation using a cytotoxicity assay. The patient whose serum was inhibitory to CFU-M at high concentrations was indeed found to have a complement-dependent serum IgG inhibitor that was cytotoxic to allogeneic and autologous marrow CFU-M but did not alter erythroid colony formation. These-studies suggest that AATP can be due to at least two mechanisms: either an intrinsic effect at the level of the CFU-M or a circulating cytotoxic autoantibody directed against the CFU-M.

Adult↗