Biomedical subjects
Publications and source records attributed to O Shalev.
We report the presence of sickle cell trait in several members of a white Jewish family. The trait was discovered when the propositus developed massive splenic infarction at high altitude. No erythrocyte markers characteristic of African ancestry were detected in any of the family members. This is the first bona fide documentation of sickle trait among white Jews.
We investigated physician awareness of the diagnosis of beta thalassemia minor as suggested by RBC indices obtained from routine electronic counts; and, the knowledge of the carriers of their genetic trait. Out of 17,000 counts, 324 were compatible with the diagnosis of beta thalassemia minor, but, only 175 (54 per cent) were identified by physicians as possibly thalassemic and in 47 of these (27 per cent) was the diagnosis verified. Twenty-four of 39 interviewed patients in whom the diagnosis of beta thalassemia minor was established knew about their carrier state.
Reported findings of elevated total calcium (Ca) contents in erythrocytes (RBCs) from patients with beta-thalassemia intermedia (beta-TI) prompted the question of whether the state and transport of Ca in these RBCs are similar to those in sickle cell anemia (SS) RBCs where the increased Ca is compartmentalized in endocytic inside-out vesicles and extracted by exposure of the cells to the Ca ionophore A23187 and a Ca chelator (ethylene glycol tetraacetic acid) and the levels of cytoplasmic free ionized Ca [( Ca2+]i) are normal. We confirmed a high total Ca content of 51 +/- 13 mumol/L RBCs in splenectomized (SPX) beta-TI and 24 +/- 1 mumol/L RBCs in non-SPX beta-TI. Unlike SS RBCs, however, most of the increased Ca was in the lighter, presumably younger beta-TI RBCs, and about half the Ca was not ionophore mobilizable but apparently firmly bound, possibly to remnants of organelles in nucleated and other young RBCs. In the denser RBCs from non-SPX beta-TI, total and extractable Ca amounts were normal. beta-TI RBCs loaded with the Ca chelator Benz 2 showed an initial influx of 45Ca in the normal range, which indicated normal Ca permeability, and near-steady-state levels of [Ca2+]i that were normal (22 +/- 7 nmol/L RBCs in non-SPX beta-TI) or minimally increased (40 +/- 19 nmol/L RBCs in SPX beta-TI). Serial-section electron microscopy of beta-TI ghosts from the denser cell fractions showed more fully enclosed vesicles in non-SPX ghosts than were seen in normal ghosts and many large vesicles and structured, electron-dense material in SPX ghosts. A delayed extrusion of ionophore-preloaded 45Ca only by the SPX beta-TI RBCs together with normal [Ca2+]i suggested compartmentalization of the loaded Ca in these RBCs, perhaps in endocytic inside-out vesicles, and normal Ca pumps. Since beta-TI RBCs show essentially normal levels of [Ca2+]i and normal Ca influx, their high total Ca content should not be associated with any of the deleterious effects observed in vitro with increased levels of [Ca2+]i.
The integrity of the erythrocyte (RBC) hexose monophosphate shunt was investigated in a group of 33 healthy elderly individuals by determining their RBC glutathione content, glucose-6-phosphate dehydrogenase activity and glutathione regeneration. When these parameters were compared with those of the controls, 44 young healthy adults, no significant differences were found. This study indicates that the RBC hexose monophosphate shunt in healthy elderly individuals is intact. Factors other than senescence per se should be sought in elderly individuals who exhibit dysfunction of this shunt.
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A 26-yr-old woman with chronic myeloid leukemia developed busulfan-induced ovarian failure. The ovarian failure was manifested by amenorrhea and climacteric symptoms and was verified by elevated plasma levels of luteinizing and follicle-stimulating hormones concomitant with low 17 beta-estradiol levels. The amenorrhea proved to be reversible when, during hematological relapse one year later, the patient was found to be four months pregnant. The busulfan which she was receiving at that time was stopped and amniocentesis revealed a normal karyotype. The remainder of the pregnancy was unremarkable and was terminated by the normal delivery of a healthy child.
Propranolol reduces left atrial pressure at rest and during exercise in patients with mitral stenosis by lowering cardiac output and heart rate. Ten patients (aged 19-56) with moderate to severe isolated mitral stenosis were studied to determine whether propranolol increased their exercise tolerance. All were in sinus rhythm and free of left or right ventricular failure. Patients were trained in an individually graded bicycle or treadmill exercise protocol that provoked a reproducible degree of near maximal dyspnoea during the second three minute stage of exercise. Propranolol (80 mg or 120 mg) or matching placebo in two or three divided daily doses was given for one week in random double blind fashion. Exercise testing and questioning about subjective clinical response were carried out at the end of each week by an investigator who was unaware of the patient's heart rate. During propranolol treatment the heart rate was 19 beats/minute slower at rest and 38 beats/minute slower at peak exercise, but there was no change in mean exercise time to dyspnoea (274 s during propranolol vs 283 s during placebo). Four patients felt worse during the propranolol week, one patient felt better during the propranolol week, and five patients felt no difference between the two weeks. Propranolol did not improve objective or subjective exercise tolerance in patients with isolated mitral stenosis in sinus rhythm.
We report the occurrence of megaloblastic hematopoiesis with peripheral microcytosis in a beta-thalassemic heterozygote who developed profound anemia secondary to folate deficiency. The folate deficiency was precipitated by prolonged therapy with diphenylhydantoin. In thalassemic heterozygotes who develop anemia, the possibility of a megaloblastic pathogenesis should be pursued even when the RBC indices maintain their microcytic-hypochromic expression.
The protein composition of ghosts, inside-out vesicles (IOV), and membrane skeletons (MS) of erythrocytes (RBC) from splenectomized (spx) and nonsplenectomized (non-spx) patients with beta-thalassemia major and beta-thalassemia intermedia was determined. Ghosts from spx thalassemia intermedia patients had a significant increase in their globin content (which was mostly heme reactive) and contained extra polypeptides in the protein 4.2 to 5 and 6-globin areas. The Triton-extracted MS from all of the thalassemic patients showed two major abnormalities: they retained up to twice the amount of protein 3 when compared with controls; they had a significant increase in their globin content, the concentration of which was independent of their protein 3 content. Analysis of the IOV revealed no differences between those prepared from normal controls and those of the patients. MS from spx thalassemia intermedia patients were grossly abnormal when examined by scanning electron microscopy and they exhibited aggregates of material that on transmission electron microscopy suggested the presence of globin precipitates. We propose that, although the integral protein composition, as reflected in the IOV, from severely affected beta-thalassemics is intact, their MS assembly is deranged. The altered skeletal structure of thalassemic RBC could result from attachment of denatured globin to the skeleton components. These abnormalities may contribute to the premature cell death seen in severe beta-thalassemia.
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We have studied erythrocyte Ca2+-ATPase as a model target for elucidating effects of activated oxygen on the erythrocyte membrane. Either intracellular or extracellular generation of activated oxygen causes parallel decrements in Ca2+-ATPase activity and cytoplasmic GSH, oxidation of membrane protein thiols, and lipid peroxidation. Subsequent incubation with either dithiothreitol or glucose allows only partial recovery of Ca2+-ATPase, indicating both reversible and irreversible components which are modeled herein using diamide and t-butyl hydroperoxide. The reversible component reflects thiol oxidation, and its recovery depends upon GSH restoration. The irreversible component is largely due to lipid peroxidation, which appears to act through mechanisms involving neither malondialdehyde nor secondary thiol oxidation. However, some portion of the irreversible component could also reflect oxidation of thiols which are inaccessible for reduction by GSH, since we demonstrate existence of different classes of thiols relevant to Ca2+-ATPase activity. Activated oxygen has an exaggerated effect on Ca2+-ATPase of GSH-depleted cells. Sickle erythrocytes treated with dithiothreitol show a heterogeneous response of Ca2+-ATPase activity. These findings are potentially relevant to oxidant-induced hemolysis. They also may be pertinent to oxidative alteration of functional or structural membrane components in general, since many components share with Ca2+-ATPase both free thiols and close proximity to unsaturated lipid.
The effect of the thiol-oxidizing agent diamide on erythrocyte (Ca+2 + Mg+2)-ATPase activity was measured in normal and glucose-6-phosphate-dehydrogenase-deficient (G6PD-) cells. Although the enzyme activity before the oxidative stress was similar in both groups, diamide induced a markedly greater inhibition in the enzyme activity in the G6PD- cells than in the normal controls. These data indicate dependence of erythrocyte (Ca+2 + Mg+2)-ATPase, in part, on the redox status of the cell. The increased vulnerability of (Ca+2 + Mg+2)-ATPase to oxidative stress in G6PD- may be of pathophysiological relevance to their premature destruction in oxidant-induced hemolysis.
We present a young man with Mediterranean type glucose-6-phosphate dehydrogenase (G6PD) deficiency and insulin-dependent diabetes mellitus whose brittle course was characterized by recurrent bouts of hypoglycemia and diabetic ketoacidosis (DKA). While neither of the episodes of DKA was complicated by hemolysis, hemolytic anemia consistently followed the recurrent attacks of hypoglycemia. Stringent control of the patient's blood glucose levels in the upper limit and slightly above the normal range successfully prevented recurrence of hypoglycemia and recrudescence of hemolytic anemia. Hypoglycemia is proposed as capable of inducing hemolysis in G6PD deficiency.
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Diabetic ketoacidosis is traditionally stated as being capable of precipitating haemolysis in patients deficient in glucose-6-phosphate dehydrogenase (G6PD). This, however, is based on only a few case reports with inadequate documentation. A study was therefore conducted to review the subject in people with the Mediterranean variant of G6PD deficiency. Perusal of the medical records for the years 1970-82 yielded 15 patients with G6PD deficiency who had been admitted to hospital for a total of 36 episodes of diabetic ketoacidosis. Ten of these episodes had been complicated by haemolytic anaemia, but in every one there was unequivocal evidence of either concurrent bacterial infection or inadvertent ingestion of drugs, either of which might induce haemolysis in G6PD deficient patients. In the remaining 26 episodes there was no evidence of developing or established haemolytic anaemia. From these findings diabetic ketoacidosis should not be regarded as a risk factor for haemolysis in the Mediterranean variant of G6PD deficiency.
Because the erythrocyte (RBC) in Duchenne's muscular dystrophy (DMD) is thought to be a suitable experimental paradigm for the sarcolemma, the RBC membrane-bound enzyme (Ca2+ + Mg2+)-ATPase has been investigated as to its relevance to abnormalities of calcium metabolism in DMD muscle. In this study, RBC (Ca2+ + Mg2+)-ATPase activity, intracellular calcium and potassium contents and complete hemogram were examined in 10 DMD patients and 16 age-matched controls. (Ca2+ + Mg2+)-ATPase activity was found elevated in the DMD RBC, consistent with reports from previous studies, but no abnormalities in intracellular calcium, potassium or hemograms were detected. It seems that although the (Ca2+ + Mg2+)-ATPase activity is changed, it bears no relevance to calcium homeostasis in DMD RBC. It is inferred that the increase in intramuscular calcium in DMD muscle, which is also found in other neuromuscular diseases, may be a non-specific finding in the diseased muscle and part of the final common pathway leading toward cellular degeneration and death.