UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide anion (O2-) production and expression of cytochrome b 558 by neutrophils were determined in 20 patients with myelodysplastic syndrome (MDS). The reduction of O2- production was noted in eight of the 20 patients and an increase was noted in four patients when neutrophils were stimulated by n-formyl-methionyl-leucyl-phenylalanine (FMLP), while a low level of O2- production was found in 11 and an increase in six MDS patients when they were stimulated by phorbol myristate acetate (PMA). Among them, seven patients showed a decrease and four an increase in O2- production on stimulation with either FMLP or PMA. Expression of cytochrome b 558 was found to be at low levels in patients who had neutrophils showing decreased O2- production when stimulated with FMLP, indicating that decreased expression of cytochrome b 558 might contribute to the impairment of O2- production in some MDS patients. In this study, no significant differences in O2- production were noted among subtypes of MDS; however, the patients who had received prednisolone showed lower levels of O2- production than those who had not received prednisolone. Patients manifesting episodes of infection had reduced levels of O2- production compared with those without infection. Furthermore, the fact that one patient who exhibited a marked reduction in neutrophil counts together with reduced O2- production died of fatal infection, suggests that the determination of O2- production, in combination with hematological features, may be of some help in predicting severe infection.
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PMID:Superoxide anion production and expression of cytochrome b 558 by neutrophils are impaired in some patients with myelodysplastic syndrome. 165 16

We studied the long-term in vivo effects of recombinant granulocyte-macrophage colony stimulating factor (rhGM-CSF) on granulocyte functions in nine patients with myelodysplastic syndrome (MDS). The treatment schedule consisted of a 14 d course of rhGM-CSF (250 micrograms/m2/d s.c.) for patients with refractory anaemia (RA) and refractory anaemia with ringed sideroblasts (RARS), while patients with refractory anaemia with excess of blasts (RAEB) and refractory anaemia with excess blasts in transformation (RAEBt) received a 14 d combination course of rhGM-CSF (250 micrograms/m2 s.c.) and low dose cytosine arabinoside (20 mg/m2 s.c.). rhGM-CSF increased the mean neutrophil count from 3.9 x 10(9)/l to 44 x 10(9)/l. Significant increases of myeloperoxidase content in granulocytes occurred during treatment (P = 0.003). Phagocytosis and killing of Staph. aureus by granulocytes was markedly enhanced during treatment. Microbicidal capacity normalized in four out of six patients during GM-CSF therapy. However, chemotaxis in response to zymosan-activated serum (ZAS) and f-Met-Leu-Phe (f-MLP), was further impaired on the last day of treatment, which was associated with a marked increase in the expression of the granulocyte adhesion receptors CD11a (P = 0.01), CD11b (P = 0.002), CD11c (P = 0.00015) and CD18 (P = 0.0014). GM-CSF therapy did not cause significant changes in hexose monophosphate (HMP)-shunt activity, chemiluminescence, nor superoxide production. The present results show that in vivo administration of GM-CSF is able to repair at least in part the neutrophil anomalies in patients with myelodysplastic syndrome (MDS), which might be useful in modulating host response to infections. However, increased adherence and impaired chemotaxis may explain some toxicities observed during treatment with GM-CSF.
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PMID:In vivo administration of granulocyte-macrophage colony stimulating factor enhances neutrophil function in patients with myelodysplastic syndromes. 195 74

Because qualitative neutrophil and platelet dysfunction is an important concomitant of the myelodysplastic syndrome, functional studies were performed prospectively of cells from eight patients with myelodysplastic syndrome undergoing treatment with recombinant alpha 2 interferon. Neutrophil studies performed included myeloperoxidase release and superoxide anion generation, measured spectrophotometrically, in response to stimulation by phorbol-12-myristate-13-acetate, opsonized zymosan, and the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP), respectively. The most consistently abnormal of these tests was the fMLP-stimulated superoxide anion generation, which was low in six of seven patients tested. Mean results with this test were significantly lower than controls (mean +/- SD = 5.11 +/- 2.41 nmol/10(6) patient cells vs. 10.14 +/- 3.02 with normal cells, p less than 0.001). No significant change was noted following 2 or 8 weeks of interferon therapy. Because of the severe thrombocytopenia prevalent in myelodysplastic syndrome, fewer platelet studies were feasible. One patient, however, exhibited normal platelet numbers but markedly decreased aggregation in response to arachidonic acid, epinephrine, and collagen. After 4 weeks of treatment, this patient's platelet aggregation was noted to be normal. Platelets from two patients were purified by gel filtration, and the ATP/ADP ratios were determined by HPLC. Pretreatment ATP/ADP ratio of one patient was 4.85 (normal = 1.85 +/- 0.28) which declined to 3.27 on treatment and then returned to 4.80 following a 14-day period off treatment. Another patient, also with elevated ATP/ADP, exhibited a smaller decline during a treatment cycle. From these studies it was concluded that fMLP-stimulated superoxide generation may be a sensitive marker for neutrophil dysfunction in the myelodysplastic syndrome. No evidence was found for improvement of neutrophil dysfunction following alpha 2 interferon treatment. alpha 2 interferon, however, may sometimes have beneficial effects upon platelet dysfunction.
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PMID:A trial of recombinant alpha 2 interferon in the myelodysplastic syndrome: II. Characterization and response of granulocyte and platelet dysfunction. 282 14

We examined the in vitro effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutrophil anomalies in 20 patients with myelodysplastic syndromes (MDS) and eight patients with chronic myelogenous leukemia (CML). Neutrophil alkaline phosphatase (NAP) activity was determined in nine MDS patients and eight CML patients by a scoring method. NAP scores were decreased in six of the nine patients with MDS and in all of the patients with CML. In all patients with these diseases, NAP scores increased by incubating the blood with rhG-CSF. An increase in NAP scores by rhG-CSF was observed even at a concentration of 1 U/mL in patients with MDS but was observed only at higher concentrations (1,000 to 10,000 U/mL) in patients with CML. Significant increases in NAP scores occurred at 12 hours' incubation in patients with MDS, whereas the increase was more gradual in patients with CML. This time course difference was thought to be due mainly to the difference in cell populations of circulating myeloid cells between MDS patients and CML patients. Induction of NAP activity by rhG-CSF in patients with both these diseases was suppressed by the addition of inhibitors of RNA or protein synthesis. Neutrophil superoxide anion (O2-) production induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was determined in the other 11 patients with MDS. This neutrophil function was decreased in seven of the 11 patients with MDS, normal in two patients, and increased in two patients. Preincubation with rhG-CSF caused a significant increase in fMLP-induced O2- production in nine of the 11 patients with MDS. rhG-CSF enhanced this neutrophil function in a time- and dose-dependent manner, and maximal stimulation was observed at 2,000 to 4,000 U/mL of rhG-CSF and at five to ten minutes' incubation. The present results show that rhG-CSF is able to repair at least in part the neutrophil anomalies in these patients, and our data, especially for patients with MDS, suggest the clinical usefulness of rhG-CSF for this preleukemic disorder.
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PMID:Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia. 303 12

Recently, a novel approach has been used in the treatment of leukemia: induction of the leukemic cells to undergo terminal differentiation. Based on its in vitro ability to induce differentiation in several myeloid leukemic cell lines, retinoic acid (RA) has been applied clinically in cases of myelodysplastic syndromes and acute myeloid and promyelocytic leukemia. In the present study we have determined in detail the ability of RA to induce expression of granulocytic functions in a human promyelocytic leukemia cell line (HL-60) and compared it with that of dimethylsulfoxide (DMSO). Several granulocytic characteristics (phagocytosis, surface adherence and generation of free radicals in response to phorbol-ester) were induced to the same degree by both agents. Other normal neutrophil functions, including lysozyme accumulation, spontaneous migration, chemotactic activity toward zymosan-activated serum (containing C5a), the peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and spontaneous motility in semi-solid medium were induced by DMSO, but they were absent or incompletely expressed in RA-induced cells. In contrast, only RA induced migration toward leukotriene B4 (LTB4). Simultaneous treatment with RA and DMSO proved synergistic with respect to morphological maturation and several functions (e.g. NBT reduction), but complementary stimulation of other activities (e.g. chemotaxis, lysozyme content) could not be demonstrated. Furthermore, characteristics induced by DMSO (i.e., expression of C5a and FMLP receptors and accumulation of lysozyme) were inhibited by the addition of RA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of granulocytic functions by leukemic promyelocytic HL-60 cells: differential induction by dimethylsulfoxide and retinoic acid. 347 6

The superoxide (O2-)-releasing capacity in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the priming effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on FMLP-induced O2- release were investigated in neutrophils from 14 patients with myelodysplastic syndromes (MDS). The O2(-)-releasing capacity in MDS neutrophils varied from patient to patient. As compared with normal neutrophils, the O2(-)-releasing capacity in MDS neutrophils was increased in 9/14 patients, normal in three patients and decreased in two patients. There was no close relationship between the O2(-)-releasing capacity and the peripheral blood neutrophil count or the plasma concentration of C-reactive protein. The priming of neutrophils by rhG-CSF was not observed in five patients, whereas rhGM-CSF primed neutrophils from all patients. The priming effect of rhGM-CSF was consistently greater than that of rhG-CSF in each patient. The intravenous administration of rhG-CSF (300 micrograms/body) to two MDS patients showed an increase in the peripheral blood neutrophil count and enhancement of neutrophil O2- release. These findings demonstrate that the neutrophil O2(-)-releasing capacity in MDS varies from patient to patient and is not always impaired, and that rhGM-CSF is able to prime neutrophils which never respond to rhG-CSF.
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PMID:Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on respiratory burst activity of neutrophils in patients with myelodysplastic syndromes. 767 62

In hematological diseases such as myeloproliferative disorders (MPD) or myelodysplastic syndromes (MDS), some abnormalities in the chemiluminescence of neutrophils are observed. There are two groups; one includes chronic myelogenous leukemia (CML), essential thrombocythemia (ET) and MDS, which all have decreased chemiluminescence of neutrophils. The other group includes polycythemia vera (PV) which has increased neutrophil chemiluminescence. We studied the neutrophil function by analyzing the chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were correlated with those in response to phorbol 12-myristate 13-acetate (PMA). But there were exceptional cases in which the maximal light emission of chemiluminescence (Max CL) in response to FMLP was obviously lower than controls despite the fact that the Max CL in response to PMA was the same as the controls. These facts suggest a heterogenicity of the defect site in these diseases. There was a correlation between the level of chemiluminescence and the neutrophil alkaline phosphatase (NAP) activity in these patients. In vitro culture of CML neutrophils with granulocyte colony-stimulating factor (G-CSF) showed a correlation between the increase in the level of chemiluminescence and NAP activity. These results suggest that NAP may take part in the control of neutrophil function.
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PMID:Chemiluminescence of neutrophils in patients with myeloproliferative or myelodysplastic hematologic diseases--relation to neutrophil alkaline phosphatase activity. 768 68

f-Met-Leu-Phe-stimulated luminol-enhanced chemiluminescence was found to be repeatedly defective in some MDS patients. This defect was not attributed to myeloperoxidase deficiency, nor to a defect in NADPH oxidase function, because PMA chemiluminescence was found to be normal in these individuals. An arbitrary value of 7 mV (half the mean control value) was chosen to subdivide the group: MDS patients with values < 7 mV had a mean f-Met-Leu-Phe chemiluminescence response of 2.5 +/- 0.5 compared to MDS patients with values > 7 mV who had a mean response of 15.6 +/- 1.6 mV, P < 0.01 (healthy controls 14 +/- 2 mV). The characteristics of the f-Met-Leu-Phe receptor and initial calcium flux results suggested that the receptor itself was normal in number and function in low f-Met-Leu-Phe responders. The rate of superoxide generation, which is calcium-dependent, was also found to be in the normal range in low f-Met-Leu-Phe responders, although total superoxide production was reduced in some of these patients. When MDS neutrophils with a low f-Met-Leu-Phe response were stimulated with PMA, chemiluminescence was normal, suggesting normal activity of the NADPH-oxidase complex. Furthermore, myeloperoxidase activity was reduced in only three out of the 11 low f-Met-Leu-Phe responders. Following priming with GM-CSF, f-Met-Leu-Phe chemiluminescence was 27 +/- 1.6 mV in low f-Met-Leu-Phe responders compared to controls (87.7 +/- 11 mV, P < 0.005). Thus, although responses were improved, they were not as marked as in control neutrophils. These data suggest that a subgroup of MDS patients have a low f-Met-Leu-Phe chemiluminescence response which is not due to a defect in the f-Met-Leu-Phe receptor or oxidase activity, and in the majority of cases MPO activity is normal. Initial patient survival data suggest that these patients may have an increased risk of infective mortality. It is proposed that defective f-Met-Leu-Phe chemiluminescence results from a putative defect in cell-signalling mechanism upstream of PKC, and GM-CSF priming only partially improves responsiveness.
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PMID:Identification of a subgroup of myelodysplastic patients with a neutrophil stimulation-signalling defect. 791 69

Myelodysplastic syndromes (MDS) are clonal haematological disorders and MDS neutrophils have various abnormal functions which cause an increased risk of infective mortality. We examined luminol-dependent chemiluminescence and cytoplasmic Ca2+ increase in order to characterize the mechanisms of a signalling defect in MDS neutrophil respiratory burst. In MDS patients, chemiluminescence stimulated with N-formyl-L-methionyl-L-leucil-L-phenylalanine (FMLP) and calcium ionophore A23187 was defective (17.2 +/- 13.7 v 44.3 +/- 16.6, P = 0.001; 42.2 +/- 21.3 v 82.0 +/- 23.6, P < 0.05, respectively), but phorbol 12-myristate 13-acetate (PMA) chemiluminescence was normal (73.4 +/- 26.9 v 79.5 +/- 23.8, P = 0.52). There were no statistical significances in cytoplasmic Ca2+ increase stimulated with FMLP and recombinant human interleukin-8 (rhIL-8) compared with controls (251.1 +/- 104.3 v 272.7 +/- 41.2, P = 0.295; 238.6 +/- 65.0 v 253.9 +/- 38.3, P = 0.567, respectively). Flow cytometric analysis of MDS neutrophils disclosed that most MDS patients showed normal neutrophil cytoplasmic Ca2+ response to FMLP and rhIL-8. However, two patients with refractory anaemia with excess of blasts displayed a significant decrease of both chemiluminescence and cytoplasmic Ca2+ response to FMLP, and they also displayed low expression of FMLP receptor. These data suggest that most MDS patients have low FMLP chemiluminescence which is not due to a defect in the FMLP receptor. It is proposed that defective FMLP chemiluminescence in MDS results from a putative defect in protein kinase C- and Ca(2+)-independent cell-signalling mechanisms. Only a small group of patients have numerical or structural defects in the FMLP receptor, causing significant decrease of neutrophil respiratory burst.
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PMID:Signalling defect in FMLP-induced neutrophil respiratory burst in myelodysplastic syndromes. 894 88

The production of reactive oxygen species (ROS) by human neutrophils is imperative for their bactericidal activity. Proinflammatory agents such as granulocyte macrophage-colony stimulating factor (GM-CSF) can prime ROS production in response to chemoattractants such as N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). In neutrophils from patients suffering from Myelodysplastic syndromes (MDS), a clonal, hematological disorder characterized by recurrent bacterial infections, this GM-CSF priming is severely impaired. In this study, we set out to further delineate the defects in neutrophils from MDS patients. We examined the effect of GM-CSF priming on fMLP-triggered activation of Rac, a small GTPase implicated in neutrophil ROS production. In contrast to healthy neutrophils, activation of Rac in response to fMLP was not enhanced by GM-CSF pretreatment in MDS neutrophils. Furthermore, activation of Rac was attenuated by pretreatment of neutrophils with the phosphatidylinositol 3-kinase (PI-3K) inhibitor LY294002. Unlike healthy neutrophils, fMLP-induced accumulation of the PI-3K lipid product PI(3,4,5)trisphosphate was not increased by GM-CSF pretreatment in MDS neutrophils. The disturbed Rac and PI-3K activation observed in MDS neutrophils did not appear to reflect a general GM-CSF or fMLP receptor-signaling defect, as fMLP-triggered Ras activation could be primed by GM-CSF in MDS and healthy neutrophils. Moreover, fMLP-induced activation of the GTPase Ral was also normal in neutrophils from MDS patients. Taken together, our data suggest that in neutrophils from MDS patients, a defect in priming of the PI-3K-Rac signaling pathway, located at the level of PI-3K, results in a decreased GM-CSF priming of ROS production.
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PMID:Disturbed granulocyte macrophage-colony stimulating factor priming of phosphatidylinositol 3,4,5-trisphosphate accumulation and Rac activation in fMLP-stimulated neutrophils from patients with myelodysplasia. 1510 57

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