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Biomedical subjects

A Eldor

Publications and source records attributed to A Eldor.

At least 109 records · Page 6Linked to original sources
PubMed1994

Inhibition of tissue plasminogen activators and urokinase by human saliva.

The fibrinolytic activity found in body fluids is mediated through the generation of plasmin from plasminogen by plasminogen activator. Mixed fresh human saliva was found to have plasminogen activator inhibitory activity that has not yet been characterized. In the present study, mixed fresh human saliva was found to contain an inhibitor for tissue plasminogen activator and for urokinase. The plasminogen activator inhibitory activity was mainly found in the mixed fresh human saliva cellular pellet containing buccal epithelial cells and not in the supernatant salivary fluid. Saliva collected by Stenson's duct cannulation does not have any PA-inhibitor activity, although saliva collected from submandibular glands contains small amounts of such activity. The salivary plasminogen activator inhibitor is unstable, and its activity is lost during storage.

Adult↗
PubMed1994

Clinical and therapeutic experience in 712 Israeli patients with idiopathic thrombocytopenic purpura. Israeli ITP Study Group.

Idiopathic thrombocytopenic purpura (ITP) is a relatively common hematologic disorder. Steroids and splenectomy constitute the main modalities of treatment. Although the indications for these therapies are well established in the literature, the timing of splenectomy remains controversial. This report retrospectively reviews 712 consecutive patients with ITP hospitalised in 9 medical centers in Israel between the years 1977 and 1987. The clinical presentations, the time required for a response to steroids and the remission rate following splenectomy were all similar in children with ITP who were hospitalised and adults. There were however marked differences in associated conditions, predominantly viral infections in children, and autoimmune disorders, neoplasia or infections in adults. The overall response to initial steroid therapy was 82% in children and 74% in adults. Ninety-three percent of those responding did so within 60 days of starting treatment. One hundred and seventy-three patients underwent splenectomy; 123 (71%) achieved a prolonged complete remission. We recommend early splenectomy in patients not responding rapidly to corticosteroid treatment. This study demonstrates that chronic, more severe ITP in children requiring hospitalisation has a marked similarity to the disease in adults. Many children, however, present with mild transient thrombocytopenia that does not necessitate hospitalisation or a specific therapy.

Adolescent↗
PubMed1993

Effects of ionizing irradiation on endothelial cell transglutaminase.

The activity of transglutaminase (TG) was measured in cultures of bovine aortic and capillary endothelial cells (EC) following exposure to gamma-irradiation. Resting confluent EC express significant TG activity which fluctuates in growing cells. This activity was increased by 2-fold following non-lethal irradiation. The increase in TG activity was dose dependent up to 20 Gy and reached a plateau at 24-36 h after irradiation. Immunohistochemical studies showed a prominent increase in cytoplasmic TG following irradiation. Western blot analysis of whole cell extracts showed no increase in total cellular TG. Kinetic studies demonstrated that the affinity of the enzyme to its substrate was not altered, but the Vmax was increased. TG has previously been shown to be stored in an inactive form in EC membranes. This activity could be recovered in normal EC, but not in irradiated EC, by the addition of potassium thiocyanate and dithiothreitol or 0.8 M NaCl. An inhibitor of TG was previously demonstrated in the 100,000 x g particulate fraction of EC. Following irradiation, a significant decrease in this inhibitory activity was demonstrated. These results imply that the post-irradiation enhancement of TG activity may be caused by activation of a latent cellular enzyme. This elevated TG activity may cross-link adjacent cytoplasmic and membrane proteins and may thus play an active role in the enhanced apoptosis observed following irradiation of EC.

Animals↗
PubMed1993

Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes.

Investigation of red blood cells from beta-thalassemia patients by means of prothrombinase assay reveals phosphatidylserine in the outer leaflet of the plasma membrane. This might explain their elevated susceptibility to phagocytosis by macrophages and the chronic hypercoagulable state, frequent thrombotic events, and life-long platelet activation that are found in thalassemic patients.

Blood Coagulation Disorders↗
PubMed1993

Studies on fibronectin and its domains. I. Novel recombinant cell-binding domain of fibronectin--a modulator of human platelet functions.

The DNA sequences encoding for two proteins of the cell-binding domain (CBD) of human fibronectin (FN), namely a 33-kDa protein (aa 1329-1722) and a 40-kDa (aa 1380-1851) protein, were cloned and expressed in Escherichia coli. The interactions of the resulting rCBD proteins, refolded and purified to homogeneity, with human platelets were studied in comparison with those of the pentapeptide GRGDS. The binding of both the 33-kDa and the 40-kDa proteins to washed platelets appeared to be dependent upon platelet activation. In the case of the 33-kDa protein, binding to stimulated platelets was shown to be saturable, with Kd = 2 microM (thrombin as agonist). Moreover, both the 33-kDa and the 40-kDa proteins inhibited fibrinogen binding (at 0.1 microM) to ADP- or thrombin-stimulated platelets with IC50 values in the same concentration range. Binding seemed therefore to occur mainly at the GPIIb/IIIa receptor, and accordingly monoclonal antibodies against this receptor prevented up to 85% of the binding of the 33-kDa protein to platelets. With most stimuli the 33-kDa and the 40-kDa proteins inhibited platelet aggregation at concentrations 15- to 25-fold lower than those required by GRGDS and, in the case of the 33-kDa protein, this was shown to occur in either platelet-rich plasma, washed platelets, or whole blood. The 33-kDa protein also inhibited platelet aggregation and thromboxane A2 (TXA2) generation on the subendothelial extracellular matrix, whereas the GRGDS peptide inhibited only matrix-induced platelet aggregation, but not TXA2 formation. Furthermore, the 33-kDa protein, which is derived from the human FN CBD, seemed to be highly selective, since it inhibited the aggregation of platelets from primates only, and not from other animals tested. Finally, the 33-kDa protein did not promote fibroblast cell attachment, as was observed for both whole FN and the 40-kDa protein, thus displaying a selectivity toward platelets. In conclusion, the unique properties of the 33-kDa protein, and, in particular, its special affinity directed only toward activated primate platelets, seem to hold a promising potential for the further development of an antithrombotic agent.

3T3 Cells↗
PubMed1993

Treatment of the hematological manifestations of dyskeratosis congenita.

Dyskeratosis congenita is a congenital multisystem disorder, characterized by skin pigmentation, dystrophic nails, and leukoplakia. Hematologic abnormalities progressing to severe pancytopenia play a significant role in the poor prognosis of afflicted patients. We report on a patient with dyskeratosis congenita and severe aplastic anemia, complicated by life threatening infection. The patient was treated with recombinant granulocyte-macrophage colony-stimulating factor. This therapy resulted in a moderate and transient improvement in absolute neutrophil counts. Current concepts regarding the pathogenesis and etiology of dyskeratosis congenita are discussed, while reviewing the available therapeutic options.

Anemia, Aplastic↗
PubMed1993

The changing course of thrombotic thrombocytopenic purpura and modern therapy.

Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder of unknown etiology. Pathologically, there appears to be an abnormal interaction between the vascular endothelium and platelets, but the primary event remains uncertain. While historically, TTP was a fatal disease, dramatic improvement in its outcome has occurred over the past two decades with the development of effective therapy. Plasma infusion or exchange remains the cornerstone of the treatment of TTP, along with corticosteroids, platelet inhibitor drugs, vincristine and splenectomy. This review summarizes the clinical findings, what is known of the pathogenesis and the available therapeutic modalities for TTP. In most cases, remissions can be attained and cures are now common. However, approximately half the patients will relapse. The clinical course at relapse is usually milder than the disease at presentation and less aggressive therapy may be needed. However, relapsing TTP still carries a significant mortality and preventive therapies are not always effective. Further progress may have to await an understanding of the fundamental etiology of this disease.

Adult↗
PubMed1993

Circulating megakaryocytes: delivery of large numbers of intact, mature megakaryocytes to the lungs.

To determine the locus of platelet production, we sought to determine if sufficient megakaryocytes reach the lungs in a state that could produce platelets. Elutriation was used to isolate megakaryocytes from blood reaching and leaving the lungs of 20 patients undergoing routine cardiac catheterizations. A mean of 5.0 intact megakaryocytes/ml were found in pulmonary artery blood, compared to only 0.5 megakaryocytes/ml, with partial cytoplasmic content, in aortic samples. The megakaryocytes in central venous and aortic samples were all mature. The identity of these cells as megakaryocytes, their maturity and normal morphology were confirmed by standard and immunoelectron microscopy. Cardiac outputs were obtained for each patient at the time of blood sampling, allowing an extrapolation that 40 x 10(6) intact, mature megakaryocytes were being delivered to the lungs every day in the average patient, compared to only 4.0 x 10(6) partially spent megakaryocytes exiting the lungs daily. About 98% of megakaryocyte cytoplasm reaching the lungs did not exit as recognizable megakaryocytes or fragments. The number and state of the megakaryocytes apparently filtered in the lungs is consistent with the hypothesis that megakaryocytes may shed platelets within the pulmonary microvasculature, which may be the primary site of platelet production.

Adult↗
PubMed1993

Disseminated intravascular coagulopathy caused by acetic acid ingestion.

A case of disseminated intravascular coagulopathy following ingestion of 100% acetic acid is presented. The patient was successfully treated with fresh frozen plasma and cryoprecipitate. Complete resolution of the bleeding diathesis and the disturbed coagulation tests was achieved.

Acetates↗
PubMed1993

Disseminated visceral fusariosis treated with amphotericin B-phospholipid complex.

Fusariosis, a rare infectious disease of the immunocompromised host, is relatively resistant to amphotericin B (AmB) or other antifungal agents. We describe a 5-year follow-up of a 40 year old woman with T-type acute lymphoblastic leukemia who following chemotherapy developed prolonged high fever, chills, night sweats, and severe weakness. Liver function tests were impaired and abdominal computerized tomography (CT) showed multiple lesions in the liver and abnormal structure of the spleen. A laparotomy revealed multiple granulomas containing Fusarium sp. in the liver, and the spleen was heavily infiltrated by the same fungus. The patient failed to respond to the conventional AmB dosage form (Fungizone) even after a total dose of 3.0 g was given, and developed significant renal impairment. AmB was complexed (in a mole ratio of 1:16) with a mixture of the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol (mixed in 7:3 mole ratio). The resulting drug complex, AmB-PLC, was then administered (1-4 mg/kg/day, total dose 4.2 g) and subsequently the patient was cured of all symptoms of fusariosis. There were only mild side effects and no nephrotoxicity was evident. On the contrary, marked improvement of the renal function tests occurred during AmB-PLC treatment. Eight months later, she developed a spinal lesion with dense consistency in L5 and S1, and after receiving another course of AmB-PLC (3.1 g) she recovered completely. In a 2 year follow-up period the patient had no further relapse of the fungal disease. Subsequent chemotherapy given for relapse of the leukemia was followed by a new fungal infection, which was treated with AmB-cholesteryl sulfate complex (Amphocil).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The response to treatment in chronic idiopathic thrombocytopenic purpura (ITP).

Immune thrombocytopenic purpura (ITP) is a relatively common illness. The initial recommended therapy is glucocorticoids, however due to low response rate and high rate of relapses, the second preferred line of therapy is splenectomy. About 60% of the patients respond to this therapy. A retrospective study performed in Israel in 226 children and 446 adults with ITP has evaluated the response to steroids and splenectomy. The response rates were similar to reported studies and no significant differences were observed between children and adults. The possibilities of treating patients who fail splenectomy and exhibit refractory disease are summarized.

Adolescent↗
PubMed1993

A chronic hypercoagulable state and life-long platelet activation in beta thalassemia major.

Increased frequency of thromboembolic events has been recently observed in patients with thalassemia major (TM), causing hypoxemia and cor pulmonale. Autopsy findings demonstrated "old" and recent pulmonary and renal infarcts as well as premature atherosclerosis. Studies to determine hypercoagulability showed: impaired platelet aggregation, increased circulating platelet aggregates, shortened platelet survival, enhanced excretion of urinary metabolites of thromboxane A2 (TXA2) and prostacyclin and decreased plasma levels of Protein C, Protein S or anti-thrombin III. Erythrocytes from TM patients enhanced thrombin formation in a "prothrombinase" assay (using a chromogenic substrate). Chronic anti-thrombotic therapy may be indicated in thalassemic patients to prevent the cardiac and pulmonary complications.

Blood Platelet Disorders↗
PubMed1993

Effect of bone marrow T lymphocytes treated with CAMPATH 1G on megakaryocyte colony formation.

Specific populations of lymphocytes play a significant role in the regulation of megakaryocyte (MK) development. CAMPATH 1G (C1G) and CAMPATH 1M (C1M) are T lymphocyte (TL)-specific monoclonal antibodies (MABs) that are routinely employed to reduce graft-vs.-host disease (GVHD) in allogeneic bone marrow transplantation (BMT). Following BMT, engraftment of the erythroid and myeloid lineages is prompt, but prolonged thrombocytopenia often prevails. We therefore studied the effect on MK colony formation of treating donor bone marrow (BM) with the CAMPATH MABs. MK colonies were grown in plasma clots using postirradiation aplastic canine serum (PICS-J) as MK colony-stimulating factor (MK-CSF). C1M, which causes TL destruction by complement-dependent lysis, had no effect on MK cloning efficiency. C1G is not lytic but causes the elimination of TL in the BMT recipients via antibody-dependent cell cytotoxicity (ADCC). Treatment of donor BM with C1G significantly enhanced the number of early burst-forming units (BFU-MK) and late colony-forming units (CFU-MK) and had no effect on granulocyte-macrophage (CFU-GM) or erythroid (BFU-E) colonies. Enhancement of MK cloning efficiency was concentration-dependent between 0.03 and 3 micrograms MAB/10(6) BM mononuclear cells (MNC). Similar results were observed when C1G-treated TL or purified CD4+ TL were co-cultured with untreated autologous BMMNC or peripheral blood (PB) MNC. Conditioned medium (CM) from C1G-treated TL and CD4+ TL contained soluble factors that, when combined with suboptimal doses of PICS-J, potentiated MK growth. C1G in combination with PICS-J also stimulated TL proliferation in a dose-dependent manner. The T cell CM did not contain elevated levels of interleukin-3 (IL-3), IL-6, IL-1 beta, or GM-CSF. Our data provide additional evidence for the involvement of activated TL, and perhaps novel soluble T cell products, in the immunomodulation of megakaryocytopoiesis.

Alemtuzumab↗
PubMed1992

Low molecular weight heparin for Hickman catheter--induced thrombosis in thrombocytopenic patients undergoing bone marrow transplantation.

BACKGROUND: Patients with an indwelling central venous catheter are prone to development of thrombotic complications. Thrombocytopenia in patients undergoing bone marrow transplantation (BMT) generally is protracted. The management of thrombosis in thrombocytopenic patients is difficult because heparin and warfarin are relatively contraindicated because of the high risk of major bleeding. Low molecular weight heparin (LMWH) is a new class of antithrombotic drug. Enoxaparin (Rhone Poulenc Rorer, Antony, France) is an LMWH that has been shown to be effective in the treatment and prophylaxis of venous thrombosis. Enoxaparin, with its high antithrombotic to anticoagulant ratio, may be safer than standard heparin in patients at high risk of hemorrhagic complications. METHODS: The authors report the cases of five thrombocytopenic patients, undergoing autologous BMT, in whom venous thrombosis developed related to a Hickman catheter. RESULTS: All the patients were treated with Enoxaparin and recovered promptly without hemorrhagic complications. CONCLUSIONS: The authors suggest that Enoxaparin is an effective drug in treating thrombocytopenic patients in whom acute venous thrombosis develops.

Adult↗
PubMed1992

Inhibition of platelet activation by tyrosine kinase inhibitors.

Protein tyrosine kinase (PTK) blockers (tyrphostins) inhibit in a dose-dependent fashion thrombin-induced aggregation and serotonin release with IC50 values in the 10-35 microM concentration range. The inhibition of thrombin-induced aggregation correlates with their potency in inhibiting phosphorylation of proteins on tyrosine residues. Using metabolically 32P-labelled human platelets, it was found that the tyrphostins have no effect on the decrease in [32P]phosphatidylinositol bisphosphate but prevent the replenishment of [32P]polyphosphoinositide. Tyrphostins decreased [32P]phosphatidic acid production induced by thrombin, although never by more than 50%, and only delayed the peak of diacylglycerol, suggesting that phospholipase C was still activated. Tyrphostins inhibited the thrombin-elicited early phosphorylation of p43 and p20, substrates for protein kinase C (PKC) and myosin light chain kinase, respectively, at short times of activation. This inhibition, however, was overcome after 1 min of stimulation with thrombin. Tyrphostin AG213 also inhibited platelet aggregation and tyrosine protein phosphorylation induced by phorbol myristate acetate (PMA), but did not inhibit pleckstrin phosphorylation. These results suggest that thrombin induces the phosphorylation of proteins on tyrosine residues which most probably results in the activation of phosphoinositide kinases. The ability of tyrphostins to inhibit phosphorylation of p43 and p20 when induced by thrombin but not when induced by PMA confirms that PTKs may be involved subsequent to PKC activation.

Catechols↗
PubMed1992

Inhibition of platelet-derived growth factor-induced mitogenesis and tyrosine kinase activity in cultured bone marrow fibroblasts by tyrphostins.

Tyrphostins, which block protein tyrosine kinase activity, were studied for their inhibitory action on platelet-derived growth factor (PDGF)-induced proliferation of human bone marrow fibroblasts. Of the seven tryphostins examined, tyrphostin AG370 was found to be the most potent blocker against PDGF-induced mitogenesis (IC50 = 20 microM). This PTK blocker also blocks mitogenesis induced by epidermal growth factor (IC50 = 50 microM) and human serum (IC50 = 50 microM), but with lower efficacy. In digitonin-permeabilized fibroblasts as well as in intact fibroblasts, tyrphostin AG370 inhibits PDGF receptor autophosphorylation and the tyrosine phosphorylation of intracellular protein substrates (pp120, pp85, and pp75) which coprecipitate with the PDGF receptor. In comparison to AG370, AG18, a potent EGF receptor blocker, was less efficient in inhibiting PDGF-induced proliferation of fibroblasts and phosphorylation of the intracellular protein substrates. Under the conditions in which AG370 inhibits PDGF-induced mitogenesis and phosphorylation, it does not affect [125I]PDGF internalization and enhance [125I]PDGF binding. These findings suggest that AG370, which is an indole tyrphostin, may serve as a model for developing analogues with a therapeutic potential for treatment of diseases which involve abnormal cellular proliferation induced by PDGF.

Blotting, Western↗