Biomedical subjects
C Hershko
Publications and source records attributed to C Hershko.
Erythroid and myeloid maturation patterns related to progenitor assessment in the myelodysplastic syndromes.
Patterns of erythropoiesis and granulopoiesis were studied in 15 patients with myelodysplastic syndromes and in one with smouldering leukaemia by correlating CFU-C, BFU-E and CFU-E cloning efficiency with erythroid and myeloid maturation indices derived from quantitative 14C-autoradiography and with ferrokinetics. Maturation index of a cell lineage was defined as the ratio of cell production rate increase from the first to the last proliferative compartment over the corresponding normal value. The myeloid maturation index was reduced in all cases, but CFU-C progenitor frequency was increased by a factor of 3. Erythroid maturation index was also reduced in most cases, and BFU-E progenitor frequency was reduced by a factor of 2. Similarly, CFU-E cloning efficiency corrected for the erythroid maturation index was 2.5-10-fold lower than normal. Comparison of the erythroid maturation index with ferrokinetics revealed a constant ratio of ineffective erythropoiesis with a maturation disturbance in the proliferative pool twice that in the non-proliferative pool. These findings indicate basic qualitative and quantitative abnormalities and a difference in the patterns of production of erythroid and myeloid cells in the myelodysplastic syndromes: Myeloid progenitors are increased in number but their maturation is grossly abnormal. On the other hand, the apparent reduction in erythroid progenitors and the reduced erythroid maturation index are attributable to both premature cell death of the more mature erythroblasts and an increased proerythroblast proliferation, i.e. extra divisions in the proerythroblast compartment at the expense of maturation.
Myelodysplastic syndromes: evolution of overt leukaemia by one or several steps of transformation.
The evolution of leukaemia was studied prospectively in 29 patients with myelodysplastic syndrome (MDS) followed for 2-6 years by sequential blast counts, cell kinetics derived from quantitative 14C-autoradiography and karyotype analysis. Overt leukaemia developed in seven patients. Two distinct patterns of leukaemic evolution were identified. The first was characterized by a gradual increase in blast cell count and in the frequency of labelled blasts, and a corresponding reduction in myeloid maturation index indicating increased intracompartmental myeloblast divisions and premature myeloid cell death. A second pattern of leukaemic evolution was marked by a sudden rise in the blast cell population in a previously stable MDS. This rise was attributed both to an increased rate of blast proliferation, and the accumulation of non-proliferating blasts. In an additional patient with smouldering ANLL and multiple karyotype abnormalities, transient clinical remission took place following prednisone and oxymetholone therapy, characterized by a sideroblastic morphology, normal karyotype, and persistence of a highly abnormal myeloid maturation index. The sudden emergence of overt leukaemia in previously stable MDS in some of our patients and the temporary reversal of overt leukaemia into sideroblastic anaemia in one case, lend support to the notion of leukaemic evolution by several steps of transformation. On the other hand, the gradual transition of MDS into overt leukaemia in other patients is compatible with a single step leukaemia transformation, although the possibility of clonal disease prior to the development of MDS cannot be excluded with certainty.
Mechanisms and prognostic value of cell kinetics in the myelodysplastic syndromes.
Cell kinetics were studied by quantitative autoradiography in 29 patients with myelodysplastic syndromes (MDS) and in four with smouldering leukaemia (SML) in a prospective 6-year study. Cellular turnover in all FAB groups was characterized by reduced labelling index and prolonged DNA synthesis time indicating reduced proliferative activity. Two more parameters were derived from the measurements. (1) The relative cell production rate, which is increased in proerythroblasts and myeloblasts in most cases. This could be attributed to an increased number of divisions in early recognizable precursors in the absence of maturation, and (or) an increased influx from the progenitor compartments. (2) The maturation index of a cell lineage was determined by the ratio of relative cell production rate increase from the first to the last proliferative compartment over the corresponding normal value. It showed a high degree of abnormality in all FAB subgroups, indicating premature cell death in the bone marrow. None of the kinetic parameters proved to be of value in predicting the evolution of leukaemia. In contrast, an excellent correlation was found between the myeloid maturation index and survival (P less than 0.0001). No correlation, however, was found between survival and the erythroid maturation index, which was relatively normal in the worst prognostic group. These findings indicate that although in vitro cell kinetic studies can not predict the evolution of overt leukaemia, the myeloid maturation index is a useful predictor of survival in patients with MDS and SML.
Iron loading and chelation as studied in a heart cell culture system.
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Modification of iron uptake and lipid peroxidation by hypoxia, ascorbic acid, and alpha-tocopherol in iron-loaded rat myocardial cell cultures.
The ability of ascorbic acid, alpha-tocopherol, and hypoxia to modify iron uptake, chelation, and toxicity as manifested by the generation of malonyldialdehyde (MDA) was studied in myocardial cell cultures obtained from newborn rats. Exposure to 20 micrograms/ml iron provided as 59Fe-ferric ammonium citrate in serum-free Ham F-10 culture medium resulted in the accumulation of 39% of the iron within 24 hours and a 10- to 12-fold increase in cellular MDA. Hypoxia (1% oxygen) resulted in a more than twofold increase in iron uptake but only minor changes in cellular MDA concentrations. Ascorbic acid and alpha-tocopherol (1 mg/ml) had opposing effects on iron uptake and MDA production. Ascorbic acid reduced 24-hour iron uptake by 73% (P less than 0.001) whereas alpha-tocopherol increased iron uptake by 19% (P less than 0.025). In contrast, cellular MDA after iron loading increased by 86% with the addition of ascorbate, and was reduced by 75% with alpha-tocopherol (P less than 0.001). The ratio of increase in cellular MDA relative to percent iron uptake (lipid peroxidation ratio) was 7.29 with iron loading plus ascorbate vs. 0.13 with iron loading plus alpha-tocopherol, a 56-fold difference between the two extremes. In vitro deferoxamine treatment for 3 hours resulted in a 53% reduction in the radioactive iron content of iron-loaded heart cells and a 40% reduction in MDA. Simultaneous deferoxamine and ascorbate or alpha-tocopherol treatment did not affect iron mobilization, but had a profound effect on MDA concentrations. Ascorbic acid prevented entirely the beneficial effect of deferoxamine on MDA concentrations in iron-loaded cells, whereas alpha-tocopherol potentiated the effect of deferoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Ultrastructural pathology of iron-loaded rat myocardial cells in culture.
The pathological changes induced by in-vitro iron-loading or cultured rat myocardial cells were studied. Cells were exposed to 59Fe-labelled ferric ammonium citrate for up to 24 h followed by 24-72 h chase experiment. After 24 h exposure 29% of the total cellular radioactivity was found in ferritin, 10% in non-ferritin heat supernatant and 61% in an insoluble heat-precipitable form. Mössbauer spectroscopy showed a gradual shift from intracellular iron particles less than 1.8 nm in diameter, through particles of intermediate size, to ferritin-like aggregates over 3.0 nm in diameter, reaching about 20% of total iron by 24 h. Ultrastructural studies showed premature damage such as mitochondrial abnormalities and excessive autophagocytosis. Small, 2.0-5.0 nm electron-dense cytosolic particles were noticed at 3 h of iron loading and reached maximal concentrations at 6 h. This was followed by accumulation of the small particles and of typical iron-rich ferritin cores within siderosomes. Because of the limited duration of iron loading and the high concentrations of non-transferrin inorganic iron employed, the present model is more relevant to acute than chronic iron overload. The efficient incorporation of large amounts of iron within ferritin molecules and its subsequent segregation, together with other smaller particles, within membrane-bound bodies, may represent a defence mechanism limiting iron toxicity in the face of advanced cytosiderosis.
[Hemochromatosis and iron chelating therapy].
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[Lead poisoning in West Bank Arabs caused by contaminated flour].
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Cerebrospinal fluid ferritin in malignant CNS involvement.
Cerebrospinal fluid (CSF) ferritin was measured in patients with benign inflammatory and noninflammatory neurologic disorders and in patients with malignant disease with and without documented central nervous system (CNS) involvement. CSF ferritin levels were increased in the majority of patients with inflammatory neurologic disease and in patients with malignant involvement of the CNS. In contrast, in patients with noninflammatory neurologic disorders and in malignant disease without CNS involvement, CSF ferritin levels were normal. These findings indicate that although the specificity of CSF ferritin measurement is limited, it is a highly sensitive test that may be useful in the initial evaluation of patients with malignant CNS involvement, and in assessing their response to therapy.
[Remission of severe aplastic anemia following antithymocyte globulin therapy].
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Severe reversible autoimmune haemolytic anaemia and thrombocytopenia associated with diclofenac therapy.
Severe immune haemolytic anaemia and thrombocytopenia developed in a 71-year-old female within 10 d of starting diclofenac (Voltarol) therapy. These complications resolved within 3 weeks of discontinuation of the drug and corticosteroid therapy. A warm autoantibody of the IgG type together with C3 was found in the direct antiglobulin test of the patient's RBC. The patient's serum and RBC eluate contained a warm autoantibody which reacted with all commercial panel cells without the addition of diclofenac, and gave a negative reaction with Rh null and -D- RBC. This pattern of interactions is similar to haemolysis associated with alpha-methyldopa, indicating the presence of autoantibodies directed against structural components common to all Rh antigens. The coexistence of immune thrombocytopenia and immune haemolytic anaemia is suggestive of an autoimmune disease caused by modified T-cell regulation. Although immune haemolytic anaemia is a rare complication of diclofenac therapy, our observations illustrate the severity of haemolytic anaemia in the occasional patient and stress the need for increased awareness of such a development.
Destructive bone lesions in primary amyloidosis.
We describe a patient with primary amyloidosis in whom multiple osteolytic lesions caused by amyloid bone tumours developed, and review the clinical features of the 18 cases with primary amyloidosis in whom destructive bone lesions have been reported. In contrast to amyloidosis associated with multiple myeloma, destructive lesions in the primary disease are mainly located to long bones; joint involvement is common, and radionuclide bone scan shows pronounced uptake of 99mTc-PP by the destructive bone lesions. Despite the superficial similarity between the destructive bone lesions associated with primary amyloidosis and multiple myeloma, distinction between these entities on clinical grounds is possible and may be easily confirmed by direct aspiration of the osteolytic infiltrates.
Corticosteroid responsive immune thrombocytopenia in Hodgkin's disease.
A 72-year-old female is described in whom immune thrombocytopenia (ITP) and fever were the presenting features of stage IIB Hodgkin's disease (HD) of the nodular sclerosis type. Thrombocytopenia resolved following steroid therapy, and after having received MOPP chemotherapy the patient is in sustained remission and with normal platelet counts 18 months later. Review of the 35 cases published to date with ITP in HD shows that of 20 patients treated with corticosteroids alone, 14 failed to respond, 2 had a partial response and only 4 patients had a good response. In contrast, of 29 splenectomised patients only 7 failed to respond, 2 had a partial response, and 20 had a good response. The state of activity of HD was closely correlated with the response of thrombocytopenia to treatment by either corticosteroids or splenectomy: only 7 of 17 patients with active HD achieved a resolution of thrombocytopenia as compared to 15 of 17 patients with HD in remission. Thus, control of thrombocytopenia is easier in patients in remission than in patients with active HD, and splenectomy is more efficient in controlling thrombocytopenia than corticosteroids.
Disseminated intravascular coagulation and hypopotassemia associated with blast lung injury.
Forty six people were injured by a large explosive charge detonated in a Jerusalem bus. Four were killed instantaneously and 22 needed hospital care. We describe our experience in five patients with blast lung injury (BLI), all of whom survived in spite of severe respiratory failure requiring mechanical ventilation. Disseminated intravascular clotting (DIC) developed in three of the five patients and significant hypopotassemia ranging from 2.2 to 2.9 mEq/L in four. These two complications have not been previously described in association with BLI. Both DIC and hypopotassemia responded to replacement therapy. Vigorous treatment of respiratory failure, early recognition, and prompt correction of hemostatic and electrolyte abnormalities may have contributed to the avoidance of fatalities among the five patients with severe blast injury.
Medical problems in Ethiopian refugees airlifted to Israel: experience in 131 patients admitted to a general hospital.
Within a 2 month period 131 Ethiopian immigrants were admitted for treatment at a general hospital in Jerusalem. There were 52 patients with malaria, 13 with typhoid fever, 24 with pneumonia, seven with tuberculosis, nine with shigella and 11 with campylobacter. Over three-quarters of these patients were anaemic. In the majority of cases anaemia was normocytic and was most probably secondary to malaria and other intercurrent infections. The prevalence of diffuse non-toxic goitre was 7% in children and 19% in adults with a male to female ratio of 4:13. A positive rapid plasma reagin (RPR) test was found in 4% of sera tested and a positive HBsAg in 13%. IgG antibodies to HBc antigen were found in 75% of subjects. All patients with infectious diseases responded to therapy and, despite their poor condition at arrival, there were no fatalities and no late sequelae. The high HBsAg carrier state calls attention to the risk of vertical transmission by infected mothers and underlines the need for active immunization of infants at risk. The high prevalence of untreated tuberculosis and malaria poses a potential public health hazard, but with the current systematic screening of this population leading to identification and effective treatment of affected subjects, chances for the practical eradication of malaria and tuberculosis are excellent. Finally, the large scale transfer of a population from rural Africa to a modern and largely urban society presents a unique opportunity for a prospective study of the impact of environment on the emergence of diseases which plague modern society such as diabetes, atherosclerotic cardiovascular disease, hypertension and cancer.
Hyperkalemia associated with sulindac therapy.
Hyperkalemia has recently been recognized as a complication of nonsteroidal antiinflammatory agents (NSAID) such as indomethacin. Several recent studies have stressed the renal sparing features of sulindac, owing to its lack of interference with renal prostacyclin synthesis. We describe 4 patients in whom hyperkalemia ranging from 6.1 to 6.9 mEq/l developed within 3 to 8 days of sulindac administration. In all of them normal serum potassium levels reached within 2 to 4 days of stopping sulindac. As no other medications known to effect serum potassium had been given concomitantly, this course of events is suggestive of a cause-and-effect relationship between sulindac and hyperkalemia. These observations indicate that initial hopes that sulindac may not be associated with the adverse renal effects of other NSAID are probably not justified.
Acute renal failure associated with non-fulminant type-A viral hepatitis.
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