Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular and molecular mechanisms responsible for hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM) into peripheral blood after administration of cytokines such as granulocyte colony-stimulating factor (G-CSF) are still unknown. In this study we show that high concentrations of soluble calcium induce the detachment of BM CD34(+) HPC adherent on fibronectin, a major component of BM extracellular matrix. Because G-CSF has been shown to induce osteoporosis in patients with congenital neutropenia and in G-CSF-overexpressing transgenic mice, we hypothesized that short-term G-CSF administration may be sufficient to induce bone resorption, resulting in the release of soluble calcium in the endosteum leading in turn to the inhibition of attachment to fibronectin and the egress of HPC from the BM. We show herein that in humans, serum osteocalcin concentration, a specific marker of bone formation, is strongly reduced after 3 days of G-CSF administration. Furthermore, in patients mobilized with G-CSF either alone or in association with stem cell factor or interleukin-3, the reduction of serum osteocalcin is significantly correlated with the number of HPC mobilized in peripheral blood. Urine levels of deoxypyridinoline (DPyr), a specific marker of bone resorption, gradually elevated during the time course of G-CSF administration until day 7 after cessation of G-CSF, showing a simultaneous stimulation of bone degradation during G-CSF-induced HPC mobilization. In an in vivo murine model, we found that the number of osteoclasts was dramatically increased paralleling the elevation of DPyr after G-CSF administration. When pamidronate, an inhibitor of osteoclast-mediated bone resorption, was administered together with G-CSF in mice, the G-CSF-induced increase of DPyr levels was completely abolished whereas the numbers of colony-forming cells mobilized in peripheral blood were not decreased, but unexpectedly increased relative to the numbers elicited by G-CSF alone. Collectively, our data therefore show that short-term administration of G-CSF induces bone degradation by a simultaneous inhibition of bone formation and an enhanced osteoclast-mediated bone resorption. This increased bone resorption is inhibited by pamidronate without reducing G-CSF-induced HPC mobilization, suggesting that the activation of bone resorption after G-CSF administration is not the direct cause of HPC mobilization as initially hypothesized, but a parallel event.
...
PMID:Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. 978 89

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor that is widely used to treat neutropenia. In addition to stimulating polymorphonuclear neutrophil (PMN) production, G-CSF may have significant effects on PMN function. Because G-CSF receptor (G-CSFR)-deficient mice do not have the expected neutrophilia after administration of human interleukin-8 (IL-8), we examined the effect of the loss of G-CSFR on IL-8-stimulated PMN function. Compared with wild-type PMNs, PMNs isolated from G-CSFR-deficient mice demonstrated markedly decreased chemotaxis to IL-8. PMN emigration into the skin of G-CSFR-deficient mice in response to IL-8 was also impaired. Significant chemotaxis defects were also seen in response to N-formyl-methionyl-leucyl-phenylalanine, zymosan-activated serum, or macrophage inflammatory protein-2. The defective chemotactic response to IL-8 does not appear to be due to impaired chemoattractant receptor function, as the number of IL-8 receptors and chemoattractant-induced calcium influx, actin polymerization, and release of gelatinase B were comparable to those of wild-type PMNs. Chemoattractant-induced adhesion of G-CSFR-deficient PMNs was significantly impaired, suggesting a defect in beta2-integrin activation. Collectively, these data demonstrate that selective defects in PMN activation are present in G-CSFR-deficient mice and indicate that G-CSF plays an important role in regulating PMN chemokine responsiveness.
...
PMID:A functional granulocyte colony-stimulating factor receptor is required for normal chemoattractant-induced neutrophil activation. 1007 3

Kostmann's syndrome is a congenital disorder that causes an impairment of myeloid differentiation in the bone marrow characterized by severe neutropenia, which can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We present the case of a 13-year-old boy with Kostmann's syndrome who was treated with recombinant human G-CSF from age 3.5 years. His growth and development was normal, although complicated by intermittent infections. Bone mineral density (BMD) measurement revealed severe osteopenia at the spine and hips (lumbar spine BMD 0.486 g/cm(2); Z score -3.6), and he was referred to the Endocrine Service. Relevant laboratory evaluation showed a pretreatment ionized calcium level at the upper limit of normal (1.28 mmol/L; range: 1.13-1.32 mmol/L), suppressed intact parathyroid hormone (iPTH) level (12 pg/mL; range: 10-65 pg/mL), and a low 1,25-dihydroxy vitamin D level (21 pg/mL; range: 24-65 pg/mL). He had evidence of increased bone turnover evidenced by elevated urinary deoxypyridinoline (DPD) cross-links (46.9 nmol/mmol creatinine; range: 2-34 nmol/mmol creatinine) and a simultaneous increase in markers of bone formation with elevated osteocalcin level (200 ng/mL; normal: 20-80 ng/mL) and alkaline phosphatase level (236 IU/mL; normal: 38-126 IU/mL). Because of clinical concern for his skeletal health, bisphosphonate therapy with intravenous pamidronate was initiated. One month after treatment, the iPTH and DPD cross-links were in the normal range (54 pg/mL and 17.7 nmol/mmol creatinine, respectively) and the 1,25-dihydroxy vitamin D level was elevated (111 pg/mL). Four months after treatment, there was a striking increase in BMD at the lumbar spine (+30.86%), femoral necks (left, +20.02%; right, +17.98%), and total hips (left, +18.40%; right, +15.94%). Seven months after bisphosphonate therapy, his biochemical parameters showed a return toward pretreatment levels with increasing urinary DPD cross-links (28.7 nmol/mmol creatinine) and decreasing iPTH (26 pg/mL). However, the BMD continued to increase (8 months posttreatment), but the magnitude of the increment was attenuated (lumbar-spine, +4.8%; left total hip, +1.2% and right total hip +2.4%), relative to BMD at 4 months. Eight months after the initial treatment, his iPTH was suppressed at 14 pg/mL and he again received pamidronate (at a lower dose); 3 months later, he had an additional increase in BMD (lumbar spine +7.4%, left total hip +3.9%, right total hip +2.7%), relative to the previous study. We hypothesize that prolonged administration of G-CSF as treatment for Kostmann's syndrome is associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. In children, the resulting osteopenia can be successfully managed with antisreorptive bisphosphonate therapy with significant improvement in bone density. Measurements of biochemical parameters of bone turnover can be used to monitor the magnitude and duration of the therapeutic response and the need for BMD reassessment and, perhaps, retreatment.
...
PMID:Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach. 1153 72

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions, suggesting that the product of the affected gene may be important in the natural control of this infection. We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4). Haplotype and mutation analyses in a pedigree transmitting myelokathexis as an apparently autosomal recessive trait support genetic heterogeneity for this aspect of the WHIM syndrome phenotype. Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor. The identification of mutations in CXCR4 in individuals with WHIM syndrome represents the first example of aberrant chemokine receptor function causing human disease and suggests that the receptor may be important in cell-mediated immunity to HPV infection.
...
PMID:Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. 1269 54

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
...
PMID:Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter. 1292 67

The value of thalidomide-dexamethasone was assessed in 26 consecutive, previously untreated patients with multiple myeloma of high tumor mass. All showed Hgb < 8.5 g/dL, serum calcium > 11.5 mg/dL, or both. The response rate was 73%, frequency of early death < 3 months was 5%, projected median survival was 30 months, and projected median remission time was 25 months. There were no occurrences of grade 3 or 4 neutropenia or thrombocytopenia, so that serious infection occurred in only 12% of patients. Thalidomide-dexamethasone was useful for these patients with advanced disease because of the high response rate and acceptable survival, with a low frequency of serious complications.
...
PMID:Thalidomide-dexamethasone as primary therapy for advanced multiple myeloma. 1662 15

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). Glc-6-PT activity has been shown to be critical in the liver and kidney where a deficiency disrupts glucose homeostasis. GSD-Ib patients also have defects in the neutrophil respiratory burst, chemotaxis, and calcium flux. They also manifest neutropenia, but whether Glc-6-PT deficiency in the bone marrow underlies myeloid dysfunctions in GSD-Ib remains controversial. To address this, we transferred bone marrow from Glc-6-PT-deficient (Glc-6-PT(-/-)) mice to wild-type mice to generate chimeric mice (BM-Glc-6-PT(-/-)). As a control, we also transferred bone marrow between wild-type mice (BM-Glc-6-PT(+/+)). While BM-Glc-6-PT(+/+) mice have normal myeloid functions, BM-Glc-6-PT(-/-) mice manifest myeloid abnormalities characteristic of Glc-6-PT(-/-) mice. Both have impairments in their neutrophil respiratory burst, chemotaxis response, and calcium flux activities and exhibit neutropenia. In the bone marrow of BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice, the numbers of myeloid progenitor cells are increased, while in the serum there is an increase in granulocyte colony-stimulating factor and chemokine KC levels. Moreover, in an experimental model of peritoneal inflammation, local production of KC and the related chemokine macrophage inflammatory protein-2 is decreased in both BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice along with depressed peritoneal neutrophil accumulation. The neutrophil recruitment defect was less severe in BM-Glc-6-PT(-/-) mice than in Glc-6-PT(-/-) mice. These findings demonstrate that Glc-6-PT expression in bone marrow and neutrophils is required for normal myeloid functions and that non-marrow Glc-6-PT activity also influences some myeloid functions.
...
PMID:Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions. 1689 6

Neutropenia and neutrophil dysfunction are common in many diseases, although their etiology is often unclear. Previous views held that there was a single ER enzyme, glucose-6-phosphatase-alpha (G6Pase-alpha), whose activity--limited to the liver, kidney, and intestine--was solely responsible for the final stages of gluconeogenesis and glycogenolysis, in which glucose-6-phosphate (G6P) is hydrolyzed to glucose for release to the blood. Recently, we characterized a second G6Pase activity, that of G6Pase-beta (also known as G6PC), which is also capable of hydrolyzing G6P to glucose but is ubiquitously expressed and not implicated in interprandial blood glucose homeostasis. We now report that the absence of G6Pase-beta led to neutropenia; defects in neutrophil respiratory burst, chemotaxis, and calcium flux; and increased susceptibility to bacterial infection. Consistent with this, G6Pase-beta-deficient (G6pc3-/-) mice with experimental peritonitis exhibited increased expression of the glucose-regulated proteins upregulated during ER stress in their neutrophils and bone marrow, and the G6pc3-/- neutrophils exhibited an enhanced rate of apoptosis. Our results define a molecular pathway to neutropenia and neutrophil dysfunction of previously unknown etiology, providing a potential model for the treatment of these conditions.
...
PMID:Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta. 1731 59

When the entire body of dogs was exposed to 450 units of Roentgen irradiation a hemorrhagic syndrome developed which was characterized by thrombo-cytopenia, prolonged clotting and bleeding times, and neutropenia. The prothrombin time remained normal until about 24 hours before death. The calcium, phosphorus, and magnesium levels were not altered. Fibrinogen was present but syneresis was poor. Toluidine blue and protamine sulfate, substances which can inhibit the biologic action of heparin, restored the clotting time to normal. The hemorrhagic state was not materially altered by transfusions, vitamin K, or vitamin C. Toluidine blue and protamine sulfate were ineffective in the control of hemorrhage produced by dicumarol. The defect responsible for bleeding after irradiation appeared to be the presence in the circulation of an anticoagulant whose properties, so far as tested, were indistinguishable from those of heparin.
...
PMID:HEPARINEMIA (?) : AN ANTICOAGULANT IN THE BLOOD OF DOGS WITH HEMORRHAGIC TENDENCY AFTER TOTAL BODY EXPOSURE TO ROENTGEN RAYS. 1987

We conducted a phase I/II trial of 5-fluorouracil (5-FU), calcium leucovorin (LV), zidovudine (AZT) and dipyridamole (DP), (FLAP) in patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. AZT and DP were given to enhance the biochemical modulation and antitumor activity of 5-FU and LV. All patients received 5-FU (370 mg/m(2) i.v. bolus day 0-4), LV (50 mg/m(2) p.o. every 4 h day 0-4) and DP (50 mg/m(2) p.o. every 6 h days 0-27). In the phase I portion of the study, AZT was dose escalated in cohorts of 5 patients each, from 50 mg p.o. every 6 h days 0-27 to the MTD of 200 mg p.o. every 6 h days 0-27. Thirty-three patients received 200 mg of AZT in the phase II portion of the trial. Eleven patients developed grade III and 5 patients developed grade IV leukopenia. Four patients developed grade III and 21 patients developed grade IV neutropenia, with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. Fifty-eight percent (19 of 33) of patients required dose reductions of AZT for hematologic toxicity (13 of 19 in the first treatment cycle). At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%), no objective responses in 14 patients with renal cell carcinoma or in 14 patients with melanoma. FLAP does not have significant activity in melanoma, renal cell carcinoma or 5-FU-treated colorectal cancer patients, although it may have activity in untreated colon cancer.
...
PMID:Phase i/ii trial of 5-Fluorouracil, leucovorin, Zidovudine and dipyridamole for patients with metastatic colorectal-cancer, renal-cell carcinoma and malignant-melanoma. 2155 74


<< Previous 1 2 3 4 5 6 Next >>

---