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Biomedical subjects

E Shinar

Publications and source records attributed to E Shinar.

At least 19 recordsLinked to original sources
PubMed1995

The instability of the membrane skeleton in thalassemic red blood cells.

The thalassemias are a heterogeneous group of disorders characterized by accumulation either of unmatched alpha or beta globin chains. These in turn cause the intramedullary and peripheral hemolysis that leads to varying anemia. A partial explanation for the hemolysis came our of our studies on material properties that showed that beta-thalassemia (beta-thal) intermedia ghosts were very rigid but unstable. A clue to this instability came from the observation that the spectrin/band 3 ratio was low in red blood cells (RBCs) of splenectomized beta-thal intermedia patients. The possible explanations for the apparent decrease in spectrin content included deficient or defective spectrin synthesis in thalassemic erythroid precursors or globin chain-induced membrane changes that lead to spectrin dissociation from the membrane during ghost preparation. To explore the latter alternative, samples from different thalassemic variants were obtained, ie, beta-thal intermedia, HbE/beta-thal, HbH (alpha-thal-1/alpha-thal-2), HbH/Constant Spring (CS), and homozygous HbCS/CS. We searched for the presence of spectrin in the first lysate of the standard ghost preparation. Normal individuals and patients with autoimmune hemolytic anemia, sickle cell anemia, and anemia due to chemotherapy served as controls. Using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, no spectrin was detected in identical aliquots of the supernatants of normals and these control samples. Varying amounts of spectrin were detected in the first lysate supernatants of almost all thalassemic patients. The identification of spectrin was confirmed by Western blotting using an affinity-purified, monospecific, rabbit polyclonal antispectrin antibody. Relative amounts of spectrin detected were as follows in decreasing order: splenectomized beta-thal intermedia including HbE/beta-thal; HbCS/CS; nonsplenectomized beta-thal intermedia, HbH/CS; and, lastly, HbH. These findings were generally confirmed when we used an enzyme-linked immunosorbent assay technique to measure spectrin in the first lysate. Subsequent analyses showed that small amounts of actin and band 4.1 also appeared in lysates of thalassemic RBCs. Therefore, the three major membrane skeletal proteins are, to a varying degree, unstably attached in severe thalassemia. From these studies we could postulate that membrane association of abnormal or partially oxidized alpha-globin chains has a more deleterious effect on the membrane skeleton than do beta-globin chains.

Actins↗
PubMed1995

Aprotinin improves hemostasis after cardiopulmonary bypass better than single-donor platelet concentrate.

Platelet transfusion and aprotinin administration improve platelet function and clinical hemostasis after extracorporeal circulation. To compare two methods of improving postoperative hemostasis, we preoperatively randomized 40 patients undergoing various open heart procedures into two groups. Group A included 20 patients who, immediately after bypass, received single-donor plateletpheresis concentrates collected from ABO-compatible donors (Baxter Autopheresis-C System). They were compared with 20 patients who received high-dose aprotinin (6 x 10(6) KIU) before and during cardiopulmonary bypass (group B). Group A patients showed significantly higher platelet count after single-donor plateletpheresis concentrate transfusion (157 +/- 36 x 10(9)/L compared with 118 +/- 42 x 10(9)/L (p < 0.05). However, platelet aggregation on extracellular matrix was better in group B (3.4 +/- 0.7 versus 2.8 +/- 0.9; p < 0.05). Total 24-hour blood loss and exposure to homologous blood products were significantly less in group B (396 +/- 125 mL and 1.1 +/- 1.6 units compared with 617 +/- 233 mL and 5.4 +/- 3.4 units; p < 0.01). Despite higher platelet count in patients after single-donor plateletpheresis concentrates transfusion, hemostasis in patients receiving aprotinin is better due to improved platelet function.

Aprotinin↗
PubMed1995

Ethnic differences in the prevalence of anti-hepatitis C antibodies and hepatitis B surface antigen in Israeli blood donors by age, sex, country of birth and origin.

The presence of anti-hepatitis C virus (HCV) antibodies frequently indicates both persistent infection and infectivity. Consequently, blood donors found to be anti-HCV positive, are excluded from the donor pool. The aim of this study was to compare age, sex and ethnic differences in the prevalence of anti-HCV antibodies with that of hepatitis B surface antigen (HBsAg) among immigrant and Israeli-born blood donors. Anti-HCV antibodies were assayed by a second-generation enzyme-immunoassay (EIA) and HBsAg by a standard EIA in a sample of 136,977 blood donors in Israel during 1992. The overall age-adjusted prevalence of anti-HCV antibodies was 0.66% in men and 0.55% in women, and for HBsAg, 0.85% and 0.44%, respectively. There was a significant increase in the prevalence of anti-HCV antibody with age, and significant differences by country of birth, with the highest prevalence found among those born in the former USSR and eastern Europe. This contrasted with the findings for the prevalence of HBsAg, where the highest rates were among those born in northern Africa. Among Israeli-born donors, differences in the prevalence of anti-HCV antibodies by parental country of origin were minimal and much less than for HBsAg. Hence the prevalence of anti-HCV antibodies in Israel is strongly associated with age and country of birth but not with country of origin. There is little evidence of substantial vertical or intrafamilial transmission of HCV infection in Israel.

Adolescent↗
PubMed1993

HIV/AIDS among Palestinian Arabs.

We studied 24 HIV-positive Palestinians who presented for medical care in the West Bank, Jerusalem and the Gaza Strip between 1987 and 1992. Three individuals, all males, were detected by blood bank screening. An additional 21 individuals (12 males, 7 females, 2 infants) were diagnosed as having HIV infection. Fifteen of 24 had full-blown AIDS--11/24 (46%) were expatriates; there were 4 heterosexuals, 5 transfusion recipients and 6 homosexuals, together comprising 79% of the individuals whose risk group was known. As compared with Israelis, Palestinians presented for medical treatment at a later stage of HIV infection. We also studied the incidence of HIV infection among Palestinian blood donors between 1987 and 1992. The incidence analysis was based on HIV screening at seven blood banks of major hospitals in the West Bank, at the Makassed Hospital in East Jerusalem, at Hadassah University Hospital (Palestinian blood donors only) and at two blood banks in the Gaza Strip. Demographic features were derived from the health department of the West Bank and from the AIDS clinic at Hadassah Hospital. Approximately 50,000 Palestinians were screened at the blood banks. Only three, all males, were detected as HIV seropositive, giving an HIV overall cumulative incidence of 0.006%. This figure was similar to the incidence among 500,000 Israeli donors (0.008%; NS) during that period. Although the low HIV incidence at the blood banks is encouraging, the negligible number of HIV seropositives and the presentation at a late clinical stage points to a deficiency in AIDS tracing and in access to specialized AIDS care in the West Bank and the Gaza Strip. The small overall number of cases precludes any definite conclusion as to trends in the epidemiology of AIDS in the West Bank and Gaza. However, the receipt of contaminated transfusions and the return of infected expatriates seem to be important features of AIDS in the West Bank and Gaza.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Isolation, characterization, and immunoprecipitation studies of immune complexes from membranes of beta-thalassemic erythrocytes.

beta-Thalassemia, a hemoglobinopathy that results in the precipitation of denatured alpha-globin chains on the membrane, is characterized by erythrocytes with significantly reduced lifespans. We have demonstrated previously that hemoglobin denaturation on the membrane can promote clustering of integral membrane proteins, and that this clustering in turn leads to autologous antibody binding, complement fixation, and rapid removal of the cell by macrophages. To evaluate whether this pathway also occurs in beta-thalassemic cells, we have isolated and characterized the immune complexes from the membranes of these cells. We observe that autologous IgG-containing complexes obtained by either immunoprecipitation or simple centrifugation of nondenaturing detergent extracts of beta-thalassemic cell membranes contain globin, band 3, IgG, and complement as major components. Absorption spectra of these complexes demonstrate that the globin is, indeed, mainly in the form of hemichromes. Immunoblotting studies further show that much of the band 3 protein in the aggregates is covalently cross-linked to a dimeric or tetrameric form, consistent with the preference of the autologous IgG for clustered band 3. Although the insoluble aggregates constitute only approximately 1.6% of the total membrane protein, they still contain 27% of the total IgG and 35% of the total complement C3 on the thalassemic cell surface. Because cell surface IgG and complement component C3 are thought to trigger removal of erythrocytes from circulation, the hemichrome-induced clustering of band 3 may contribute to the beta-thalassemic cell's shortened lifespan.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1992

Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia.

The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha-thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.

Blotting, Western↗
PubMed1990

Citrate-induced impairment of neuromuscular transmission in human and experimental autoimmune myasthenia gravis.

Two patients who underwent plasmapheresis for severe myasthenia gravis showed marked exacerbation of myasthenic weakness at the end of exchange sessions, in which citrate was used for anticoagulation. In one patient, improvement occurred after the administration of calcium but not after edrophonium. In rabbits and in rats with experimental autoimmune myasthenia gravis, decremental muscle response to 3 Hz repetitive nerve stimulation worsened significantly after injection of the citrate anticoagulant. The worsened neuromuscular transmission defect was reversed by the administration of calcium. When used for anticoagulation, citrate reduces serum ionized calcium levels and thus may aggravate myasthenic weakness and endanger patients during or immediately after plasmapheresis.

Adult↗
PubMed1990

Differences in the pathophysiology of hemolysis of alpha- and beta-thalassemic red blood cells.

The basic pathology in all forms of thalassemia results from the presence of excess unstable globin chains within the pathological RBC, but the pattern and rate of their precipitation is different. Consequently, their effects on the RBC membrane components are not the same and may account for the different rheological properties that have been found. It is possible that the damage incurred by excess beta chains in Hb H disease is primarily due to the direct interaction of the large inclusions with some cytoskeletal proteins such as spectrin, ankyrin, and band 3. In beta-thalassemia, where excess unstable alpha chains have already precipitated in young erythroblasts, the main damage might be caused by an excess of free oxygen radicals, which affect in particular protein 4.1. A search for additional changes and for potential differences in the membrane and cellular properties between the different thalassemic syndromes is warranted in order to understand better the different clinical expression in the various types of the disease. Moreover, when there is a better elucidation of the mechanisms by which the RBC are destroyed, one may look for possible ways and means to prevent these changes, with a consequent extension of the current short life span of the affected RBC.

Erythrocyte Membrane↗
PubMed1990

Oxidative denaturation of red blood cells in thalassemia.

We believe that on the basis of all available data, severe oxidative damage occurs in alpha- and beta-thalassemic RBCs, as depicted schematically in Fig 6. The differences in the severity and pattern of the oxidative damage may be related to the type and, perhaps, quantity of precipitated globin chains. The detrimental effect of the excess chains is multifold. In the process of globin-chain precipitation, free radicals are generated. The end product of the precipitated hemoglobin chains is heme, from which eventually iron and globin are liberated. Globin chains have been found to interact and disrupt the RBC membrane, damaging the cytoskeleton. The role of heme has not yet been studied in detail in thalassemic RBCs. However, there is some evidence that it participates in damaging RBCs in other types of hemoglobinopathies. Excess of iron is known to be a catalyst of peroxidation via the Fenton reaction, causing damage to the various RBC membrane components (lipids, proteins, etc). The denatured hemaglobin, in the form of hemichromes, aggregates with protein 3, forming Actual proof of excessive free radical production in thalassemia is still warranted. It will not be easy to document since the amount of superoxide dismutase in RBCs is above and beyond that required for neutralizing excess amount of superoxide. The more active radicals, particularly hydroxyl free radical, are difficult to measure because they are so active an interact immediately with any given substrate in their vicinity. In addition, we have to better understand the finding of excess membrane lipids in thalassemic RBCs and whether there are changes in the formation and propagation of lipid peroxidation in these cells compared with normal RBCs. Regarding the proteins, further understanding is required concerning the exact type and sites of oxidation that occurs in the beta-thalassemia 4.1 protein, and whether the damage found in alpha-thalassemia is due to oxidation of ankyrin itself or its entrapment within the complex of the precipitated hemichromes of beta chains. What is the role of the different globin chain oxidation and precipitation in generating such different cytoskeletal protein alterations? Another point that needs to be elucidated is the role of different kinds of antibodies that are attached to the newly exposed antigenic sites on the thalassemic RBC membranes.(ABSTRACT TRUNCATED AT 400 WORDS)

Erythrocytes↗
PubMed1989

Oxidative damage to human red cells induced by copper and iron complexes in the presence of ascorbate.

The role of trace metals in the generation of free radical mediated oxidative stress in normal human red cells was studied. Ascorbate and either soluble complexes of Cu(II) or Fe(III) provoked changes in red cell morphology, alteration in the polypeptide pattern of membrane proteins, and significant increases in methemoglobin. Neither ascorbate nor the metal complexes alone caused significant changes to the cells. The rate of methemoglobin formation was a function of ascorbate and metal concentrations, and the chemical nature of the chelate. Cu(II) was about 10-times more effective than Fe(III) in the formation of methemoglobin. Several metals were tested for their ability to compete with Cu(II) and Fe(III). Only zinc caused a significant inhibition of methemoglobin formation by Fe(III)-fructose. These observations suggest that site-specific as well as general free radical damage is induced by redox metals when the metals are either bound to membrane proteins or to macromolecules in the cytoplasm. The Cu(II) and Fe(III) function in two catalytic capacities: (1) oxidation of ascorbate by O2 to yield H2O2, and (2) generation of hydroxyl radicals from H2O2 in a Fenton reaction. These mechanisms are different from the known damage to red cells caused by the binding of Fe(III) or Cu(II) to the thiol groups of glucose-6-phosphate dehydrogenase. Our system may be a useful model for understanding the mechanisms for oxidative damage associated with thalassemia and other congenital hemolytic anemias.

Ascorbic Acid↗
PubMed1989

Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia.

Thalassemic red cells show irregular morphology and maldistribution of glycoproteins and sialic acids. These changes are compatible with damage to the red cell membrane skeleton. To test this possibility, we systematically studied the interconnections of skeletal proteins in patients with a form of alpha thalassemia (HbH disease), in patients with beta thalassemia intermedia, and in normal individuals. Alpha- and beta-thalassemic spectrin functions normally in spectrin self-association, binding to normal inside-out vesicles (IOVs), and binding to actin in the presence and absence of normal protein 4.1. Binding of normal spectrin to beta: thalassemic IOVs is normal but alpha-thalassemic IOVs are defective and bind only half the normal amount of spectrin (66 +/- 5 vs. 120 +/- 16 micrograms spectrin dimer/mg IOV protein, respectively). A different defect is detected in beta thalassemia, in which protein 4.1 shows markedly reduced ability (48 +/- 7% of normal) to enhance the binding of normal spectrin to actin and a decreased ability to bind normal spectrin in a binary interaction, compared with normal protein 4.1 (24 +/- 1 and 43 +/- 1 micrograms protein 4.1/mg spectrin, respectively). As no quantitative deficiency of beta-thalassemic protein 4.1 is detected, we assume an acquired lesion is present, which affects about half of the protein 4.1 molecules. These findings indicate that specific, localized, yet different defects exist in the skeletal proteins of alpha- and beta-thalassemic red cells. The different molecular lesions imply that the mechanism of hemolysis and probably the interaction of unpaired globin chains with the membrane differs in the two diseases.

Ankyrins↗
PubMed1989

Convulsions induced by aminocaproic acid infusion.

Aminocaproic acid is a widely used antifibrinolytic agent. Serious adverse effects associated with its use are rare, but we report on a patient with liver disease and cirrhosis who experienced a grand mal seizure during the intravenous administration of aminocaproic acid. Clinicians should be alert to the occurrence of this adverse effect in patients with no previous neurological problems.

Aminocaproates↗
PubMed1988

Generalized morphea and idiopathic thrombocytopenia.

A patient with generalized morphea and thrombocytopenia is reported. The thrombocytopenia responded promptly to corticosteroid and immunosuppressive therapy but recurred when the steroids were discontinued. The occurrence of thrombocytopenia in generalized morphea suggests a common immune mechanism and emphasizes the need to look for concomitant autoimmune hematologic disorders in patients with systemic, as well as localized, scleroderma.

Biopsy↗