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M S Currie

Publications and source records attributed to M S Currie.

35 records · Page 2Linked to original sources
PubMed1990

Correlation between erythrocyte CR1 reduction and other blood proteinase markers in patients with malignant and inflammatory disorders.

Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma-crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.

Adult↗
PubMed1990

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production.

The effects of pentoxifylline (Trental) on human neutrophil CR3 up-modulation, degranulation, and superoxide production were studied. We used the chemotactic peptide fMLP and the phorbol ester PMA as soluble stimuli, and beta-glucan particles as a CR3-specific solid phase stimulus of neutrophil superoxide production. Since neutrophils have adenosine A2 receptors, we compared effects of pentoxifylline to effects of adenosine, and we also looked at the effect of cytochalasin B, which breaks up actin filaments. Pentoxifylline inhibited both CR3 up-modulation and degranulation of myeloperoxidase and lysozyme. Pentoxifylline is a more potent inhibitor of fMLP- compared to PMA-induced degranulation, and is especially potent against superoxide production. While pentoxifylline is less potent than adenosine in its inhibition of fMLP-induced superoxide production, it is more potent in its inhibition of PMA- and beta-glucan particle-stimulated superoxide production. Cytochalasin B, which enhances degranulation and fMLP-stimulated superoxide production, was found to inhibit beta-glucan particle-stimulated superoxide production. These findings are consistent with the hypothesis that pentoxifylline can affect both the cytoskeletal architecture of unstimulated neutrophils and the activation and responses of neutrophils which involve actin polymerization and receptor-cytoskeletal interactions.

Adenosine↗
PubMed1990

Effects of pentoxifylline administration on blood viscosity and leukocyte cytoskeletal function in patients with intermittent claudication.

We have previously shown that pentoxifylline, a drug used in intermittent claudication, causes depolymerization of actin in leukocytes in vitro. In this study we evaluated several parameters in peripheral blood obtained from 17 patients receiving pentoxifylline, before therapy and at 1 and 2 months after initiation of drug therapy. Total blood viscosity decreased at 1 month and was further reduced at 2 months. The plasma viscosity remained unchanged during the course of the therapy (1.770 +/- 0.147, 1.776 +/- 0.162, and 1.772 +/- 0.164 centipoise at 0, 1, and 2 months, respectively; mean +/- SD, n = 14 to 17). No changes were observed in stimulus-induced actin polymerization in granulocytes, concanavalin A-induced capping in granulocytes and lymphocytes, and anti-IgG-induced caps in lymphocytes, before and after therapy. Similarly, there was no difference in the magnitude of depolymerization caused by pentoxifylline when added in vitro. Thus none of the parameters altered by pentoxifylline treatment in vitro have been observed ex vivo in patients receiving this drug. However, the decrease in total blood viscosity along with unaltered plasma viscosity suggests that the rheology of the cellular elements is being affected by the administered drug. In addition to the direct effects on the cell membrane and the cytoskeleton, pentoxifylline may exert indirect effects through its inhibitory action on cytokine production. Subtle changes in a number of parameters in leukocytes, which taken alone fail to show demonstrable changes, might ultimately be responsible for the therapeutic benefit noted with pentoxifylline.

Actins↗
PubMed1989

Chemotactic peptide receptor-cytoskeletal interactions and functional correlations in differentiated HL-60 cells and human polymorphonuclear leukocytes.

We studied the chemotactic peptide receptor/cytoskeletal interactions in HL-60 cells induced to differentiate with different agents and attempted to correlate these observations with the acquisition of different functional responses. Dibutyryl cyclic AMP-treated cells showed rapid superoxide anion production in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and slow, sustained response to phorbol myristate acetate (PMA). Retinoic acid-induced cells showed a slow, sustained response to both FMLP and PMA. Interferon-gamma-treated cells produced no superoxide anion on stimulation with FMLP, whereas tumor necrosis factor (TNF)-treated cells showed a slight response. Chemotactic peptide receptor association was the same in the HL-60 cells treated with different agents, despite marked differences in the superoxide anion generation and actin polymerization responses to FMLP and PMA in these cells. In mature neutrophils chemotactic peptide receptor association with the cytoskeleton was not affected by either pertussis or cholera toxin. However, both toxins inhibited FMLP-induced actin polymerization and superoxide anion generation. This suggested involvement of a G-protein similar to Gt, rather than Gi or Gs. Neither toxin had any effect on PMA-induced superoxide anion generation. These observations indicate that receptor association with the cytoskeleton may not have a significant role in affecting signal recognition and response. Among the several possible roles suggested, clearance of the occupied receptors may be the most important role of the cytoskeletal association. HL-60 cells induced to differentiate with different agents (because of their varied functional responses) might prove very useful in dissecting the molecular mechanisms regulating stimulus-induced activation of neutrophils.

Bucladesine↗
PubMed1988

Lack of correlation between induction of chemotactic peptide receptors and stimulus-induced actin polymerization in HL-60 cells treated with dibutyryl cyclic adenosine monophosphate or retinoic acid.

We used the promyelocytic leukemic cell line HL-60 to explore the molecular mechanisms regulating stimulus-induced actin polymerization in myeloid cells. HL-60 cells express very few chemotactic peptide receptors in their undifferentiated state and fail to undergo actin polymerization when stimulated with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP). However, when the cells were induced to differentiate with dibutyryl cyclic AMP (dbcAMP) or retinoic acid, they acquired the ability to undergo actin polymerization on stimulation with FMLP or phorbol myristate acetate. Kinetic experiments revealed that in the first 48 h of retinoic acid treatment there was no increase in the chemotactic peptide receptors on HL-60 cells, but the cells were capable of undergoing actin polymerization on stimulation with FMLP. Similarly, treatment with dbcAMP showed no increase in chemotactic peptide receptors until 24 h but stimulus-induced actin polymerization was demonstrable as early as 4 h after the treatment. In addition, with dbcAMP-treated cells the magnitude of stimulus-induced actin polymerization showed large variation depending on the duration of exposure to the drug. Dual-label studies using propidium iodide to measure DNA content and NBD-phallacidin to measure the F-actin content revealed that these variations were not related to the stages of cell cycle. Cells in all stages of the cell cycle responded to stimulus-induced actin polymerization, but the magnitude of the response appeared to be more in cells in G2/M phase. The observations reported here indicate that the small number of chemotactic peptide receptors present on HL-60 cells are adequate to mount an actin polymerization response, provided the required intracellular mechanisms exist. Differentiation-inducing agents, therefore, must cause changes within the cell, such as induction of actin-binding proteins, to cause actin polymerization following FMLP stimulation. The HL-60 system serves as a useful model for studying the molecular mechanisms regulating stimulus-induced actin polymerization in human neutrophils.

Actins↗
PubMed1988

Actin depolymerization and inhibition of capping induced by pentoxifylline in human lymphocytes and neutrophils.

Pentoxifylline is used clinically for the treatment of intermittent claudication. It is believed to exert its effect by altering the rheologic properties of blood. The cytoskeleton plays an important role in the maintenance of cell structure and function. In particular, alterations in the state of actin seem to play an important role in cell motility. Therefore, we examined the effect of pentoxifylline on the actin state in human polymorphonuclear leukocytes (PMN) and mononuclear cells. Pentoxifylline (10 mM final concentration) decreased F-actin content in both PMN and mononuclear cells. Pentoxifylline also inhibited concanavalin A-induced capping in PMN and mononuclear cells. Similarly, surface immunoglobulin capping in B lymphocytes was also inhibited. Pretreatment of cells with pertussis toxin did not inhibit pentoxifylline-induced decrease in F-actin, suggesting pentoxifylline does not act through pertussis toxin-sensitive G-proteins. Dibutyryl cyclic AMP failed to show any significant effect on the F-actin content in PMN. Therefore, the effect of pentoxifylline cannot be attributed to changes in cyclic AMP levels. Chemotactic peptide-induced actin polymerization was unaffected in PMN when expressed as percent changes in F-actin. The observations reported here suggest that the rheological effects of pentoxifylline might be due to its effects on the actin state in the cellular elements of the blood. Further studies on the mechanism of action of pentoxifylline on actin state in leukocytes will prove useful in delineating the physiological mechanisms regulating actin state in leukocytes.

Actins↗
PubMed1988

Procainamide-induced lupus anticoagulants and thrombosis.

The specific factors predisposing to thrombosis in patients with LAs have not been resolved. With extensive cross-reactivity, and several proposed sites of action, LAs and their effects may be heterogeneous. While the risk of thrombosis with phenothiazine-induced LAs is probably low, the incidence of thrombosis in association with procainamide-induced LAs is uncertain. Procainamide is a commonly used antiarrhythmic drug associated with the induction of autoantibodies, and occasionally with a lupus-like syndrome. Serologic and coagulation profile monitoring may be required to detect patients in whom LAs develop since these individuals may be at increased risk for thrombosis. Monitoring may be especially important in patients who are receiving procainamide and who have atherosclerosis and cardiac disease, since they may be at increased risk for thrombosis of coronary and other arteries. Future prospective studies are needed to investigate whether the development of lupus anticoagulants during procainamide therapy increases the risk of thrombosis.

Aged↗
PubMed1988

Effect of antigen site and complement receptor status on the rate of cleavage of C3c antigen from red cell bound C3b.

C3b was bound to human red cells when serum complement was activated by addition of antibodies directed against different red cell antigens, and the rate of cleavage to C3dg was determined by assay for loss of bound C3c antigens using radiolabeled monoclonal anti-C3c. When C3b was bound by antibodies to antigens on branched-chain glycoproteins, cleavage to C3dg occurred more rapidly than when C3b was bound by antibodies to antigens closer to the red cell lipid bilayer. The rate of cleavage to C3dg also correlated directly with the number of complement receptors (CR1) per red cell, reflecting their role as cofactors in the cleavage of iC3b by factor I. Thus, the life span of C3b/iC3b on human red cells, which may be important for determining the rate and mechanism of clearance of C3-coated red cells, appears to depend on the CR1 status of the red cells and the characteristics of the antigen sites around which complement is bound.

Antigens↗
PubMed1987

Granulocyte antibodies in leukaemic chronic lymphoproliferative disorders.

The anti-granulocyte activity of serum from patients with B-cell chronic lymphocytic leukaemia (CLL) and other lymphoproliferative disorders was investigated. Granulocyte-binding IgG was measured in 34 patients with CLL, 13 patients with hairy cell leukaemia, one patient with prolymphocytic leukaemia, two patients with Sézary cell leukaemia, and seven patients with chronic T-cell lymphocytosis who had a predominance of circulating large granular lymphocytes. Anti-granulocyte activity was absent in CLL and its variants, but present in the majority of granulocytopenic patients with chronic T-cell lymphocytosis. In one of these patients, granulocytopenia was associated with complement-activating IgG granulocyte antibody. Thus, antibody-mediated granulocyte injury appears to be an unusual occurrence in chronic lymphocytic leukaemia, but is a frequent complication of chronic T-cell lymphocytosis.

Adult↗
PubMed1987

Pseudo-Bernard-Soulier syndrome: thrombocytopenia caused by autoantibody to platelet glycoprotein Ib.

The Bernard-Soulier syndrome is an inherited bleeding disorder that is due to a deficiency in platelet glycoprotein Ib. Bernard-Soulier platelets fail to agglutinate in response to ristocetin despite normal levels of factor VIII:von Willebrand factor. We report a patient who developed severe refractory thrombocytopenia postsurgically while receiving procainamide therapy. Thrombocytopenia was immune mediated since the patient's platelets bore high levels of antiplatelet antibody. Radioimmunoprecipitation studies demonstrated that the autoantibodies had specificity for platelet glycoproteins Ib and V as well as platelet HLA. The patient's plasma as well as purified immunoglobulin G completely inhibited the ristocetin-induced aggregation of normal platelets but did not inhibit adenosine diphosphate-induced aggregation. The laboratory studies revealed that this patient suffered from antibody-mediated thrombocytopenia with unusual characteristics that we have called pseudo-Bernard-Soulier syndrome.

Aged↗
PubMed1987

Antibodies to granulocyte precursors in selective myeloid hypoplasia and other suspected autoimmune neutropenias: use of HL-60 cells as targets.

Patients with syndromes of autoantibody-mediated hematocytopenias may manifest signs of increased cell destruction and/or decreased cell production, depending on the maturity of the target cell and the effects of antibody binding. The purpose of this study was to use a cultured human cell line of hematopoietic origin for in vitro assays of antibody binding to overcome the relative inaccessibility of natural human marrow progenitor cells. This report describes the detection, using radioiodinated staphylococcal protein A (SPA), of antibodies binding to a human promyelocytic cell line (HL-60) in sera from three patients with chronic idiopathic granulocytic hypoplasia ("pure white cell aplasia," PWCA) and 22 patients with other syndromes of suspected immune neutropenia. Bone marrow from patients with increased IgG binding to HL-60 cells showed less than 15% granulocytic lineage cellularity in 11 of 17 cases. In vitro differentiation of HL-60 cells by retinoic acid resulted in increased IgG binding for sera that had shown increased IgG binding to mature granulocytes but not undifferentiated HL-60 cells; in contrast, for sera with antibodies to untreated HL-60 cells and for normal serum, in vitro differentiation had little effect on IgG binding. Antibodies eluted from mature granulocytes were similar to the parent serum regarding the ratio of IgG binding to mature cells v HL-60 cells. No sera from 19 patients with febrile transfusion reactions showed increased IgG binding to HL-60 cells in the absence of increased IgG binding to mature granulocytes, although two sera had antibodies to both cell types. The use of HL-60 cells as targets may permit measurement of serum antibodies associated with granulocytic hypoplasia. In combination with assays to detect antibody binding to mature granulocytes, these techniques may discriminate among autoantibody specificities for antigens that are gained, conserved, or lost during myeloid maturation.

Aged↗
PubMed1986

Teardrop-shaped red cells in autoimmune hemolytic anemia.

The presence of teardrop-shaped red cells in peripheral blood has traditionally been felt to reflect altered marrow architecture, namely myelofibrosis. We evaluated two patients with splenomegaly, moderately severe hemolytic anemia due to warm-reactive IgG anti-red cell autoantibody, and bone marrow erythroid hyperplasia without myelofibrosis. A striking predominance of teardrop-shaped red cells was noted upon examination of their blood films. Removal of a spleen containing extramedullary hematopoiesis in one and resolution of splenomegaly in the other were accompanied by disappearance of these cells. Our observations support a role for the spleen and for extramedullary hematopoiesis in the pathogenesis of this distinctive red cell morphologic abnormality.

Anemia, Hemolytic, Autoimmune↗
PubMed1985

Complement-activating antineutrophil antibody in systemic lupus erythematosus.

Serum samples from 18 patients with systemic lupus erythematosus (SLE) were tested for neutrophil C3-fixing ability and neutrophil-binding lgG by the binding of radioiodinated monoclonal anti-C3 antibody and staphylococcal protein A to paraformaldehyde-fixed allogeneic neutrophils sensitized with serum. Serum from patients with SLE resulted in the binding of significantly greater amounts of lgG to neutrophils than normal serum, but this lgG binding did not correlate with the degree of neutropenia. In contrast, serum samples from 10 neutropenic patients with SLE resulted in the binding of significantly greater amounts of C3 to neutrophils when compared with serum samples from eight non-neutropenic patients with SLE. Fixation of C3 to neutrophils by serum from patients with SLE appeared to be due to the binding of complement-activating monomeric antineutrophil lgG autoantibody. A significant negative correlation (r = -0.78) between the neutrophil count and the C3-fixing ability of serum from patients with SLE suggested that antineutrophil antibody-mediated activation of complement may be important in the pathophysiology of neutropenia in SLE.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1985

Clinical data quality: impact on revenue.

In large measure, individual hospitals' survival and growth in a prospective payment environment depend on management's abilities to develop both an aggressive strategic plan and short-term monitoring systems to ensure the quality of the clinical data. In general, managers should capitalize on factors favorable to the hospital, minimize the impact of unfavorable factors, and position the organization to respond favorably to expect future changes. To accomplish these three goals, the quality of the clinical data must be analyzed and linked to revenue expectations. Then, if needed, the next step is to implement short-term actions to improve any data deficiencies that are identified. In this way, the hospital's clinical data, which are an accurate reflection of services rendered, can be used with confidence for long-term strategic and financial planning.

Data Collection↗
PubMed1983

T-lymphocytes escape membrane defect in paroxysmal nocturnal haemoglobinuria.

Erythrocytes, granulocytes and platelets from patients with paroxysmal nocturnal haemoglobinuria (PNH) are abnormally sensitive to lysis by complement. We studied T-lymphocytes from PNH patients for abnormal complement lysis sensitivity. T-lymphocytes free of other contaminating blood cells were prepared by sedimentation, nylon wool filtration, and density gradient centrifugation. The lymphocytes were then labelled with 51Cr and lysis induced by antithymocyte globulin and rabbit complement. PNH lymphocytes were no more susceptible to complement-mediated lysis than lymphocytes from normal individuals. The unusual sensitivity of PNH erythrocytes could still be demonstrated when rabbit serum was a source of complement so the lack of any difference in the sensitivity of normal and PNH lymphocytes was probably not attributable to the inability of rabbit serum to elicit the membrane defect. PNH erythrocytes and granulocytes also acquire more membrane-bound C3 when human complement is activated. Therefore we also searched for increased membrane C3 binding on PNH lymphocytes using anti-I antibody and human serum as a complement source. C3 binding was measured using 125I labelled monoclonal mouse anti-human C3. While we verified increased membrane C3 binding on PNH granulocytes during complement activation we were unable to show similar differences between PNH and normal T-lymphocytes. Thus PNH T-lymphocytes do not share the membrane abnormalities of PNH-erythrocytes and granulocytes.

Aged↗
PubMed1982

Activation of human complement by immunoglobulin G antigranulocyte antibody.

The ability of antigranulocyte antibody to fix the third component of complement (C3) to the granulocyte surface was investigated by an assay that quantitates the binding of monoclonal anti-C3 antibody to paraformaldehyde-fixed cells preincubated with Felty's syndrome serum in the presence of human complement. The sera from 7 of 13 patients with Felty's syndrome bound two to three times as much C3 to granulocytes as sera from patients with uncomplicated rheumatoid arthritis. The complement-activating ability of Felty's syndrome serum seemed to reside in the monomeric IgG-containing serum fraction. For those sera capable of activating complement, the amount of C3 fixed to granulocytes was proportional to the amount of granulocyte-binding IgG present in the serum. Thus, complement fixation appeared to be a consequence of the binding of antigranulocyte antibody to the cell surface. These studies suggest a role for complement-mediated injury in the pathophysiology of immune granulocytopenia, as has been demonstrated for immune hemolytic anemia and immune thrombocytopenia.

Arthritis, Rheumatoid↗