Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated polymorphonuclear granulocyte (PMN) function in polycythemia vera (PV) in relation to healthy controls. PMN oxidative metabolism, assessed by chemiluminescence (CL), was significantly lower in PV patients after stimulation with leukotriene B4 (LTB4) and f-Met-Leu Phe (fMLP) (60% of control), whereas no difference in CL was seen after stimulation with phorbol myristate acetate (PMA) (120% of controls). Spontaneous and fMLP-induced PMN adherence to an albumin-coated plastic surface, as well as spontaneous migration and LTB4 - and fMLP-induced chemotaxis, were similar to controls. This suggests the presence of a stimulus-specific defect in PMN oxidative metabolism in PV.
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PMID:Stimulus-specific defect in oxidative metabolism of polymorphonuclear granulocytes in polycythemia vera. 285 Feb 16

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

We have previously reported that polymorphonuclear granulocyte (PMN) and monocyte oxidative metabolism is reduced in polycythemia vera (PV) patients compared to healthy control subjects, after stimulation with cell surface receptor-dependent stimuli such as n-formyl-methionyl-leucyl-phenylalanine, leukotriene B4 and platelet-activating factor (PAF). In contrast, the oxidative response to phorbol myristate acetate (PMA) is normal. We now show that, in PV patients exhibiting significantly reduced PMN chemiluminescence after PAF stimulation, PAF induced platelet aggregation was also reduced--40 +/- 3% compared to 50 +/- 2% in controls (p < 0.01). The defective aggregatory response to PAF in PV remained over a wide range of stimuli concentrations. Platelet aggregation induced by PMA and ADP, however, was similar in PV and controls. In contrast, platelet aggregation induced by PAF (or by ADP and PMA) was not significantly reduced in patients with chronic myeloid leukemia, essential thrombocythemia and multiple myeloma. Furthermore, the release of beta-thromboglobulin was slightly but not significantly higher after PAF stimulation in PV and this argues against an abnormal PAF receptor as the cause of the defective function. Thus, not only PV neutrophils, but also PV platelets show a discrete defect of the stimulus response coupling for PAF, indicating a disease-specific abnormality that appears to be of clonal origin.
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PMID:Stimulus-specific defect in platelet aggregation in polycythemia vera. 792 57

We previously described a marked increase in the pathogenicity of a cell culture grown porcine rotavirus, PRV 4F, during serial passage in gnotobiotic piglets (Bridger et al., 1992). Here we report close temporal correlation between this change in pathogenicity and an amino acid change within a highly conserved hydrophobic domain of VP4 at position 469. Cell culture grown PRV 4F is unique in having a hydrophilic residue, glutamine, at amino acid 469; all previously sequenced VP4s have hydrophobic leucine or phenylalanine residues at the corresponding position. The detection of a point mutation causing a deduced amino acid change from glutamine to leucine at amino acid 469 of PRV 4F VP4 in virus obtained from one piglet at the second serial passage correlated exactly with the emergence of viral pathogenicity. However, given the multifactorial nature of virus pathogenicity, genetic studies are required to ascertain the degree to which this mutation is responsible for the observed change in pathogenicity.
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PMID:Temporal correlation between a single amino acid change in the VP4 of a porcine rotavirus and a marked change in pathogenicity. 803 Feb 38

We have assessed aspects of the stimulus response coupling for generation of superoxide anions (O2-) in polymorphonuclear granulocytes (PMNs) from patients with polycythemia vera (PV). Those cells exhibited less than half of the O2- secretion that PMNs from healthy controls did, when that response was initiated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), 0.35 +/- 0.38 nmol O2-/10(6) PMNs/min and 0.83 +/- 0.45 nmol O2-/10(6) PMNs/min, respectively (p < 0.02). In contrast, when induced by phorbol myristate acetate (PMA), O2- production in PV PMNs was normal (6.9 +/- 1.1 nmol O2-/10(6) PMNs/min vs 6.9 +/- 0.6 nmol O2-/10(6) PMNs/min for control cells). In an attempt to dissect this stimulus-specific dichotomy of the oxidative responsiveness of PV PMNs, we analyzed the number of and ligand affinity for fMLP surface receptors, fMLP-induced membrane potential changes, phospholipase C-dependent production of inositol-1,4,5-trisphosphate, and the subsequent rise of cytosolic calcium concentrations. All these variables and responses were normal in PV PMNs. However, on fMLP stimulation of PV PMNs, we observed a significantly lower diacylglycerol (DAG) generation than in control cells (1.4% +/- 0.9% and 2.2% +/- 1.2% DAG of total phospholipid, respectively; p < 0.05). Furthermore, the activation of phospholipase D, measured as the formation of phosphatidylethanol (PET) in the presence of 0.5% ethanol, was impaired in PV PMNs with a similar stimulus-specific dichotomy as observed for O2- generation. Thus PET generation was significantly lower in PV cells after fMLP stimulation in relation to control cells (1.7% +/- 0.8% and 2.7% +/- 0.8% PET of total phospholipid, respectively; p < 0.01), whereas PET formation after PMA stimulation did not differ. We suggest that the impairment of phospholipase D-mediated metabolism of phosphatidylcholine in response to fMLP stimulation of polycythemia vera granulocytes may be of significance for the reduced superoxide anion formation induced by fMLP in those cells.
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PMID:Superoxide anion production and phospholipase D-mediated generation of diacylglycerol are subnormal after N-formyl-methionyl-leucyl-phenylalanine stimulation of polymorphonuclear granulocytes in polycythemia vera. 838 48

Neutrophil granule subsets and dynamics were studied in 4 patients with polycythemia vera/myelofibrosis and 2 patients with chronic myelogenous leukemia. Alkaline phosphatase, a marker for the membrane of secretory vesicles (the most readily mobilizable pool of intracellular membranes in neutrophils) was highly elevated in the PV/MF patients and significantly reduced in the CML patients. In spite of this, the amount of secretory vesicles was normal as judged by the content of albumin, and of the membrane protein cytochrome b-245 and CD11b, both partially localized in secretory vesicles. Gelatinase granules were present in all patients. The azurophil granules were lighter than normal in both CML patients. SDS-PAGE protein profiles indicated absence of defensins from azurophil granules from 1 CML patient. In addition, a 41-42 kD doublet protein band was absent from 2 PV and 1 CML patient, and reduced in the other CML patient. No difference in mobilization of granules was observed between patient neutrophils and control neutrophils. Also, stimulation with 10(-8) mol/l N-formyl-methionyl-leucyl-phenylalanine induced normal increases in intracellular Ca2+ in patient neutrophils. These results indicate that stimulus-response coupling leading to granule exocytosis is intact in neutrophils from patients with myeloproliferative disorders.
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PMID:Mobilization of granules in neutrophils from patients with myeloproliferative disorders. 838 6

Activation of opioid receptors in the periphery and centrally in the brain results in inhibition of gastric and other vagally mediated functions. The aim of this study was to examine the role of the endogenous opioid agonist endomorphin 1 (EM-1) in regulating synaptic transmission within the nucleus tractus solitarius (NTS), an integration site for autonomic functions. We performed whole cell patch-clamp recordings from coronal brain slices of the rat medulla. A subset of the neurons studied was prelabeled with a stomach injection of the transsynaptic retrograde virus expressing EGFP, PRV-152. Solitary tract stimulation resulted in constant latency excitatory postsynaptic currents (EPSCs) that were decreased in amplitude by EM-1 (0.01-10 microM). The paired-pulse ratio was increased with little change in input resistance, suggesting a presynaptic mechanism. Spontaneous EPSCs were decreased in both frequency and amplitude by EM-1, and miniature EPSCs were reduced in frequency but not amplitude, suggesting a presynaptic mechanism for the effect. Spontaneous inhibitory postsynaptic currents (IPSCs) were also reduced in frequency by EM-1, but the effect was blocked by TTX, suggesting activity at receptors on the somata of local inhibitory neurons. Synaptic input arising from local NTS neurons, which were activated by focal photolysis of caged glutamate, was inhibited by EM-1. The actions of EM-1 were similar to those of D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) and were blocked by naltrexone, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). These results suggest that EM-1 acts at mu-opioid receptors to modulate viscerosensory input and specific components of local synaptic circuitry in the NTS.
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PMID:Modulation of synaptic transmission in the rat nucleus of the solitary tract by endomorphin-1. 1561 36

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.
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PMID:A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. 1579 61

Polycythemia vera (PV) is a human clonal hematological disorder. The molecular etiology of the disease has not been identified. PV hematopoietic progenitor cells exhibit hypersensitivity to growth factors and cytokines, suggesting possible abnormalities in protein-tyrosine kinases and phosphatases. By sequencing the entire coding regions of cDNAs of candidate enzymes, we identified a G:C--> T:A point mutation of the JAK2 tyrosine kinase in 20 of 24 PV blood samples but none in 12 normal samples. The mutation has varying degrees of heterozygosity and is apparently acquired. It changes conserved Val(617) to Phe in the pseudokinase domain of JAK2 that is known to have an inhibitory role. The mutant JAK2 has enhanced kinase activity, and when overexpressed together with the erythropoietin receptor in cells, it caused hyperactivation of erythropoietin-induced cell signaling. This gain-of-function mutation of JAK may explain the hypersensitivity of PV progenitor cells to growth factors and cytokines. Our study thus defines a molecular defect of PV.
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PMID:Identification of an acquired JAK2 mutation in polycythemia vera. 1586 14

The abnormal megakaryocytopoiesis associated with idiopathic myelofibrosis (IM) plays a role in its pathogenesis. Because mice with defective expression of transcription factor GATA-1 (GATA-1(low) mutants) eventually develop myelofibrosis, we investigated the occurrence of GATA-1 abnormalities in IM patients. CD 34(+) cells were purified from 12 IM patients and 8 controls; erythroblasts and megakaryocytes were then obtained from unilineage cultures of CD 34(+) cells. Purified CD 61(+), GPA(+), and CD 34(+) cells from IM patients contained levels of GATA-1, GATA-2, and FOG-1 mRNA, as well as of GATA-2 protein, that were similar to controls. In contrast, CD 61(+) cells from IM patients contained significantly reduced GATA-1 protein. Furthermore, 45% of megakaryocytes in biopsies from IM patients did not stain with anti-GATA-1 antibody, as compared to controls (2%), essential thrombocythemia (4%), or polycythemia vera (11%) patients. Abnormalities in immunoreactivity for FOG-1 were not found, and no mutations in GATA-1 coding sequences were found. The presence of GATA-1(neg) megakaryocytes in bone marrow biopsies was independent of the Val 617 Phe JAK 2 mutation, making it unlikely that a downstream functional relationship exists. We conclude that megakaryocytes from IM patients have reduced GATA-1 content, possibly contributing to disease pathogenesis as in the GATA-1(low) mice and also representing a novel IM-associated marker.
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PMID:Abnormalities of GATA-1 in megakaryocytes from patients with idiopathic myelofibrosis. 1612 62


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