Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B19 parvovirus, the cause of fifth disease and transient aplastic crisis, has been successfully propagated in suspension cultures of human erythroid bone marrow cells obtained from patients with sickle cell disease and stimulated by erythropoietin. B19 inoculation in vitro resulted in a marked decline in identifiable erythroid cells over seven to nine days of incubation. Characteristic giant early erythroid cells were seen on Wright's-Giemsa stain of infected cultures. By in situ hybridization, 30% to 40% of erythroblasts were infected at 48 hours; a similar proportion of cells showed B19 capsid protein by immunofluorescence. B19 DNA was present in erythroblasts but not in the leukocyte fraction of bone marrow. B19 replication, as determined by Southern analysis, and B19 encapsidation, as determined by sensitivity of isolated cell fractions to DNase I, were restricted to the nuclei. B19 DNA was detectable in the nuclei from infected cultures beginning at 18 hours and in the supernatant at 32 hours; B19 genome copy number was estimated at about 25,000 to 30,000/infected cell at 48 hours. Recovery of virus depended on the multiplicity of infection (moi); at low moi, approximately 200x input virus was recovered from total cultures and 50x from the culture supernatants. Virus released into the supernatant was as infectious or more infectious than virus obtained from sera of infected patients. Human erythroid bone marrow culture represents a safe in vitro system for the elucidation of the cellular and molecular biology of the pathogenic B19 parvovirus.
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PMID:Productive infection by B19 parvovirus of human erythroid bone marrow cells in vitro. 303 11

Erythropoietin titers when related to the hematocrit percentage and measured by bioassay in 33 normal volunteers and in 61 patients with anemias not complicated by renal or chronic disease were found to overlap with titers measured by radioimmunoassay in 20 normals and 28 patients with similar anemias. Erythropoietin titers measured by radioimmunoassay in 34 patients with rheumatoid arthritis, 25 patients with sickle cell anemia (58 separate samples), and 28 patients with erythroid hypoplasia caused by hematologic malignancies were compared with those in the control group of patients with uncomplicated anemias and found not to differ significantly from titers in this group. Erythropoietin titers measured by bioassay in 12 patients with aplastic anemia also fell within the range of those in the control group. Consequently, erythropoietin titers in these anemias appear to be determined primarily by the degree of anemia and not by any specific effect of these illnesses on the production of erythropoietin.
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PMID:Erythropoietin titers in anemic, nonuremic patients. 310 59

Circulating 14-day erythroid progenitors (BFU-E) from sickle cell anemia (SS) patients were studied in culture to determine their frequency and their sensitivity to erythropoietin (Epo). Increased numbers of circulating BFU-E were found in half of the patients studied, whereas the remainder had a normal count. Patients with high circulating BFU-E counts had lower fetal hemoglobin (HbF) percentages (congruent to 4.5%) than patients with low circulating BFU-E counts (HbF congruent to 13%). This difference was highly significant (p less than 0.0001). In addition, SS circulating BFU-E expressed increased sensitivity to Epo due, at least partially, to an increased production of burst-promoting activity-like factor(s) generated by light-density mononuclear cells. These findings emphasize the possible role of the HbF level (and the extent of sickling) in BFU-E regulation under the continuous hemopoietic stress of SS disease.
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PMID:Circulating BFU-E in sickle cell anemia: relationship to percent fetal hemoglobin and BPA-like activity. 318 45

We have examined the possibility that permanent "stress" hemopoiesis in sickle cell anemia (SS) patients leads to the modification of the behavior of circulating 14 day erythroid progenitor cells (BFU-E). In these patients we find that peripheral blood BFU-E are increased in number and have high sensitivity to erythropoietin (Epo). Maximal number of BFU-E are generated from peripheral blood of SS patients at 0.3-0.75 Epo/ml of culture compared to 1.5-2.0 U Epo/ml of culture in normals. Peripheral blood adherent cells depletion leads to the shift of Epo dose response curve, so that the Epo sensitivity of BFU-E significantly decreases. This result suggests that apparent Epo hypersensitivity reflects, in fact, an increased production of a burst promoting activity (BPA) by SS peripheral blood light density adherent (PB-LDA) cells. Experiments with conditioned medium by SS PB-LDA cells confirmed this interpretation. When peripheral blood light density non-adherent (PB-LDNA) cells of SS patients or normal individuals were plated in the presence of various concentrations of SS PB-LD cells conditioned medium and constant amounts of Epo, a dose dependent increase of the number of BFU-E was observed. When the same target cells were plated in the presence of PB-LD cells conditioned medium from normal individuals, such effect does not occur. We conclude that increased BPA production may play a role in the erythropoietic regulation during constant hemopoietic stress in sickle cell anemia and might partially explain the lower than expected Epo levels in these patients.
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PMID:Increased BPA production modulates Epo sensitivity of circulating BFU-E in sickle cell anemia. 322 9

The normal response to anemic or hypoxic hypoxia is synthesis and release of erythropoietin in accord with the concept that erythropoietin production is controlled by a renal oxygen sensor. In this study, erythropoietin production, as predicted, was abrogated in patients with renal impairment (55 cases), but normal in nonuremic individuals. Specifically, patients with rheumatoid arthritis (34 cases), sickle cell anemia (25 cases), aregenerative anemia (27 cases), and aplastic anemia (13 cases) had erythropoietin titers overlapping with those observed in simple anemia (61 cases) at corresponding hematocrits. The response of polycythemic laboratory animals to hypoxia is more difficult to fit within the concept of an oxygen sensor responsive both to anemic and hypoxic hypoxia. If the polycythemia was induced by hypertransfusion, erythropoietin production in response to hypoxia was, as predicted, less than that observed in normal animals. If, however the polycythemia was induced by previous exposure to hypoxia, the animals responded to hypoxia as though they were not polycythemic. An explanation for this challenging observation may provide a clue as to the operation of the oxygen sensor.
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PMID:Erythropoietin titers in response to anemia or hypoxia. 366 51

We have studied serum immunoreactive erythropoietin (SIE) levels in 28 patients with sickle cell anemia (SCA) without renal insufficiency and in 17 patients with nonhemoglobinopathy anemias of comparable severity using a sensitive radioimmunoassay procedure. An exponential relationship between SIE level and degree of anemia was noted in all patients. However, in nonhemoglobinopathy anemia, a sharp rise in the SIE level occurred as hemoglobin (Hb) levels fell below about 12 g/dL, whereas in sickle cell patients the increase was not marked until hemoglobin fell to about 9 g/dL. The response was more blunted in older SCA patients than in younger ones. A linear regression model relating SIE level to Hb level, presence/absence of SCA, and age explained 63% of the variation in SIE. We conclude that the serum erythropoietin levels in SCA increased at a lower hemoglobin concentration and are of a lower magnitude than that of the other anemias.
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PMID:Sickle cell anemia patients have low erythropoietin levels for their degree of anemia. 394 May 52

Colonies derived from erythroid burst-forming units (BFU-E) synthesize fetal hemoglobin (HbF) in amounts that far exceed in vivo levels. There is some evidence that HbF synthesis is controlled at the level of a primitive erythroid precursor cell. Dexamethasone may potentiate the development of BFU-E. Since a means of augmenting HbF production in sickle cell anemia or severe beta-thalassemia would be of great therapeutic value, we studied the effects of dexamethasone on HbF and gamma-globin chain synthesis in BFU-E from patients with sickle cell anemia and controls. HbF was measured by radioimmunoassay of BFU-E lysate and gamma-chain synthesis by the incorporation of 3H-leucine into globin, which was then purified by gel filtration and column chromatography. Dexamethasone (10(-9) M) produced an increase in the number of BFU-E in 16 of 19 subjects when compared with numbers of BFU-E cultured with only erythropoietin. The individual BFU-E were larger and contained more subcolonies. Dexamethasone did not increase HbF or gamma-chain synthesis, and there was no relationship between proliferation of BFU-E and augmented HbF production. Thus, although dexamethasone augmented the development of erythroid bursts, there was no increment in HbF.
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PMID:Effects of dexamethasone on fetal hemoglobin synthesis in peripheral blood erythroid burst-forming units. 616 63

To investigate the cellular events that accompany erythroid hyperplasia, we studied several effects of erythropoietin (Epo) on marrow CFU-E in sickle cell anemia (SCA). We measured CFU-E number, CFU-E growth as a function both of Epo exposure time and of Epo concentration, and suppression of Epo-induced CFU-E formation by anti-Epo antiserum. With 0.5 U Epo/ml, the number of CFU-E was elevated in SCA (1,087 +/- 520) compared to normal (430 +/- 130). CFU-E were formed even when Epo was immediately neutralized by a 1/150 dilution of anti-Epo. After 40 hr of Epo exposure, only 2% of total CFU-E were expressed in normal marrow, whereas 12%-40% of CFU-E were expressed in SCA. Inhibition of CFU-E growth required at least 1/50 dilution of anti-Epo in SCA and a 1/300 dilution in normal marrow. In contrast to normal, a small number (5%-20%) of CFU-E were expressed in the absence of added Epo in SCA, and this pool required a 1/150 dilution of anti-Epo for inhibition. The Epo dose-response curve in SCA revealed a peak in colony formation around 0.1 U Epo/ml and 0.5 U Epo/ml, whereas only one peak at 0.5 U Epo/ml was seen in normals. These data strongly suggest that, in response to the demands of chronic erythroid hyperplasia in SCA, a pool of CFU-E is present characterized by increased in vitro sensitivity to Epo.
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PMID:Evidence for the presence of CFU-E with increased in vitro sensitivity to erythropoietin in sickle cell anemia. 671 94

Erythropoietin responsible for the hormonal regulation of red blood cell production. Its formation is largely controlled by the kidneys. A number of assay methods for erythropoietin are available. Asymptomatic patients with sickle cell disease have elevated erythropoietin levels, as expected with chronic hemolysis. When complicated by chronic renal failure, erythropoietin levels do not rise appropriately. Chronic infection has not been studied, but the erythropoietin response in acute infection does not seem to conform to a pattern. Aplastic crises are characterized by very high levels of erythropoietin, suggesting bone marrow suppression, but events that trigger the crises remain obscure. In vaso-occlusive crises, there is also some suggestion of mild and transient lack of bone marrow response. Patients with sickle cell disease, with their chronic high erythropoietin anemia and susceptibility to altered states, are uniquely suited for investigating the physiology of erythropoietin, especially under the constraints of present assay methods.
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PMID:Erythropoietin in sickle cell disease: relation of erythropoietin levels to crisis and other complications. 711

Seven sickle cell disease (SCD) patients [sickle cell anaemia = 4 (males 2, females 2, age range 18-40 years), and sickle cell beta (0)-thalassaemia = 3 (all females, age range 20-47 years)], suffering from a severe form of the disease were enrolled in a treatment protocol using hydroxyurea (HU) for up to 12 months followed by a combination therapy with HU and human recombinant erythropoietin (rHuEpo; using 400 U/kg/week i.v.) for 3-4 weeks. Following the withdrawal of rHuEpo the patients were maintained on HU alone. The patients were characterised on the basis of the 'severity index' prior to the initiation of the therapy. Haematological and relevant biochemical parameters, Hb A2 fetal haemoglobin (HbF), HbF cells, reticulocytes and platelet counts were estimated at least at three occasions to determine the mean and range of the parameters. During the treatment period the patients were followed every 2-4 weeks where the haematological and biochemical parameters were assessed. The results were separately analysed and mean +/- SD were obtained for each parameter at the end of each protocol. The statistical significance of the difference in the results obtained on treatment and the baseline results was examined using the paired t test. No toxic side effects of HU and rHuEpo (as judged from reduction in platelet and white blood cell count) were documented during and after the whole period of treatment. The patients showed a significant clinical improvement. Total haemoglobin, haematocrit, red cell count, HbF and HbF cells increased, while white blood cells, reticulocyte counts and bilirubin level decreased. Platelet count decreased but remained within the normal range. The results revealed that 5 of the patients on HU treatment showed a significant increase in the HbF level and HbF cells, while 2 patients (1 sickle cell anaemia and 1 Hb S/beta(0)-thalassaemia patient) did not and were considered as 'non-responders'. The rHuEpo and HU combination therapy elevated the HbF level, with a varying degree, in all patients except 2, who had already reached a high HbF level and showed a decrease in HbF during the rHuEpo protocol. Variable individual response to both HU and rHuEpo therapy was a common feature. We recommend the use of HU for the treatment of SCD and a combination therapy using HU and rHuEpo for the non-responders.
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PMID:On the use of hydroxyurea/erythropoietin combination therapy for sickle cell disease. 750 28


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