UMLS:C0027947 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A revision of the criteria of fever of unknown origin (FUO), established in 1961, is desirable because of important evolutions in medical practice and the emergence of new patient populations. The development of rapid laboratory tests and powerful diagnostic tools, such as ultrasonography, computed tomography and magnetic resonance imaging often makes hospitalization unnecessary and new categories of patients such as those with HIV infection, neutropenia, immunosuppression and nosocomial illness require an approach different from classical FUO. The more then 200 reported causes of FUO can be classified into four diagnostic categories; infections, tumours, noninfectious inflammatory diseases (NIID) and miscellaneous. A uniform classification system is highly wanted to allow comparison between different series. The reports of the 1990s show slight changes in the distribution of causes, namely less infections, less tumours, more NIID and more undiagnosed cases. A uniform diagnostic strategy cannot be determined. The initial investigation should be directed by potentially diagnostic clues revealed by extensive history, meticulous physical examination and a standard set of laboratory tests. 18Fluoro-deoxy-glucose-positron-emitted-tomography is a new valuable total body scintigraphy in the search for the site of origin of the fever. In view of the rather good long-term prognosis, a wait-and-see strategy may be more appropriate than a systematic staged approach. Elderly patients and patients with episodic fever represent two specific groups of classical FUO that require a distinct approach. HIV-associated, nosocomial and neutropenic FUO should be considered as separate clinical entities.
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PMID:Fever of unknown origin in adults: 40 years on. 1260 93

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.
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PMID:Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter. 1292 67

Malaria, caused mostly by Plasmodium falciparum and P. vivax, remains one of the most important infectious diseases in the world. Antimalarial drug toxicity is one side of the risk-benefit equation and is viewed differently depending upon whether the clinical indication for drug administration is malaria treatment or prophylaxis. Drug toxicity must be acceptable to patients and cause less harm than the disease itself. Research that leads to drug registration tends to omit two important groups who are particularly vulnerable to malaria--very young children and pregnant women. Prescribing in pregnancy is a particular problem for clinicians because the risk-benefit ratio is often very unclear. The number of antimalarial drugs in use is very small. Despite its decreasing efficacy against P. falciparum, chloroquine continues to be used widely because of its low cost and good tolerability. It remains the drug of first choice for treating P. vivax malaria. Pruritus is a common adverse effect in African patients. As prophylaxis, chloroquine is usually combined with proguanil. This combination has good overall tolerability but mouth ulcers and gastrointestinal upset are more common than with other prophylactic regimens. Sulfadoxine/pyrimethamine is well tolerated as treatment and when used as intermittent preventive treatment in pregnant African women. Sulfadoxine/pyrimethamine is no longer used as prophylaxis because it may cause toxic epidermal necrolysis and Stevens Johnson syndrome. Mefloquine remains a valuable drug for prophylaxis and treatment. Tolerability is acceptable to most patients and travellers despite the impression given by the lay press. Dose-related serious neuropsychiatric toxicity can occur; mefloquine is contraindicated in individuals with a history of epilepsy or psychiatric disease. Quinine is the mainstay for treating severe malaria in many countries. Cardiovascular or CNS toxicity is rare, but hypoglycaemia may be problematic and blood glucose levels should be monitored. Halofantrine is unsuitable for widespread use because of its potential for cardiotoxicity. There is renewed interest in two old drugs, primaquine and amodiaquine. Primaquine is being developed as prophylaxis, and amodiaquine, which was withdrawn from prophylactic use because of neutropenia and hepatitis, is a potentially good partner drug for artesunate against falciparum malaria. Atovaquone/proguanil is a new antimalarial combination with good efficacy and tolerability as prophylaxis and treatment. The most important class of drugs that could have a major impact on malaria control is the artemisinin derivatives. They have remarkable efficacy and an excellent safety record. They have no identifiable dose-related adverse effects in humans and only very rarely produce allergic reactions. Combining an artemisinin derivative with another efficacious antimalarial drug is increasingly being viewed as the optimal therapeutic strategy for malaria.
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PMID:Antimalarial drug toxicity: a review. 1472 85

We report herein the efficacy and feasibility of weekly administration of paclitaxel for advanced/recurrent gastric cancer retrospectively. Eleven patients with advanced or recurrent gastric cancer who had received prior chemotherapy were treated with this regimen. Seventy mg of paclitaxel per m2 dissolved in 250 ml 5% glucose was administered by 1-hour intravenous infusion once a week for 3 weeks followed by 1 week rest. To avoid hypersensitivity reactions, the following short premedication was given to all the patients 1 hour before paclitaxel treatment: Dexamethasone 20 mg intravenously (i.v.), diphenhydramine 50 mg i.v., and ranitidine 50 mg i.v. Treatment cycle was 1 to 23 with an average cycle of 5.4. The response rate was 33% (2/6 with measurable lesions), the median time to progression was 104 days, and the median survival time was 160 days. Grade 3 neutropenia occurred in 27.2% of the patients. Weekly paclitaxel may be a promising regimen as a second-line chemotherapy for advanced/recurrent gastric cancer. However, special attention needs to be paid to the neutropenic adverse effect in gastric cancer patients with poor performance status than 2 (greater).
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PMID:[Usefulness of weekly administration of paclitaxel for advanced or recurrent gastric cancer]. 1522 4

Recombinant granulocyte colony-stimulating factor (r-GCSF) is used in autologous bone marrow/peripheral blood progenitor cell transplantation (ABMT/PBPC) to shorten the period of neutropenia. As these patients require platelet transfusions, their sera may be monitored for the presence of platelet/human leukocyte antigen (HLA) antibodies. Sera of some patients on r-GCSF (16 microg/kg/day) became difficult to evaluate in vitro for the presence of HLA and platelet antibodies because of apparently anomalous reactions in solid phase red cell adherence (SPRCA) assays. SPRCA tests were positive only when platelets were adhered to the polystyrene plates in the presence of glucose; when other simple sugars were used, the patients' sera failed to react. HLA Bw6-positive platelets were more likely than HLA Bw6-negative platelets to be reactive (p <.001). The transfusion of HLA Bw6-positive platelets to patients displaying this in vitro reactivity (positive patients) resulted in a 50 percent lower corrected count increment (CCI) than those given to patients without it (negative patients; p = <.001). When all transfusions were considered, the CCI for those of the positive patients was decreased 73 percent when compared to the control patients (p =.0005). The presence of the antibody also was associated with a twofold increase in the number of platelet transfusions given (p =.0005). ABMT/PBPC patients receiving r-GCSF may develop unexpected reactions on SPRCA antibody screens and poor responses to transfusion of Bw-6-positive platelets.
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PMID:Development of anti-Bw6 reactivity in patients receiving r-GCSF: a preliminary report. 1537 81

Glycogen storage disease (GSD) 1b is a metabolic disorder characterized by a deficiency of glucose 6-phosphate transporter and neutrophil alterations, which are reduced in number and functionally impaired. The present study aimed at investigating neutrophil dysfunction correlating submembrane and cytoskeletal changes at different ages with or without granulocyte-colony stimulating factor (G-CSF) treatment. GSD1b neutrophils showed reduced expression and diffused localization of focal adhesion kinase (FAK) and actin. No abnormalities were observed in GSD1a patient neutrophils. Gelsolin was also slightly reduced in neutrophils of GSD1b patients. When patients were treated for at least 3 months with G-CSF, the neutrophil number and the expression of FAK and actin were significantly increased. Granulocyte colony-stimulating factor treatment was similarly effective when performed in 1 year old patients. FAK auto- and IL-8-mediated phosphorylations were already affected as early as 1 year of age. G-CSF treatment also improved this alteration. Our data suggest that neutrophil dysfunction in GSD1b patients might be related to functional impairment and disorganization of proteins of the sub-membrane apparatus, and that G-CSF treatment counteracts neutropenia and prevents the progressive alterations of neutrophil sub-membrane proteins.
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PMID:Amelioration of neutrophil membrane function underlies granulocyte-colony stimulating factor action in glycogen storage disease 1b. 1588 52

The oxazaphosphorines cyclophosphamide, ifosfamide and trofosfamide remain a clinically useful class of anticancer drugs with substantial antitumour activity against a variety of solid tumors and hematological malignancies. A major limitation to their use is tumour resistance, which is due to multiple mechanisms that include increased DNA repair, increased cellular thiol levels, glutathione S-transferase and aldehyde dehydrogenase activities, and altered cell-death response to DNA damage. These mechanisms have been recently re-examined with the aid of sensitive analytical techniques, high-throughput proteomic and genomic approaches, and powerful pharmacogenetic tools. Oxazaphosphorine resistance, together with dose-limiting toxicity (mainly neutropenia and neurotoxicity), significantly hinders chemotherapy in patients, and hence, there is compelling need to find ways to overcome it. Four major approaches are currently being explored in preclinical models, some also in patients: combination with agents that modulate cellular response and disposition of oxazaphosphorines; antisense oligonucleotides directed against specific target genes; introduction of an activating gene (CYP3A4) into tumor tissue; and modification of dosing regimens. Of these approaches, antisense oligonucleotides and gene therapy are perhaps more speculative, requiring detailed safety and efficacy studies in preclinical models and in patients. A fifth approach is the design of novel oxazaphosphorines that have favourable pharmacokinetic and pharmacodynamic properties and are less vulnerable to resistance. Oxazaphosphorines not requiring hepatic CYP-mediated activation (for example, NSC 613060 and mafosfamide) or having additional targets (for example, glufosfamide that also targets glucose transport) have been synthesized and are being evaluated for safety and efficacy. Characterization of the molecular targets associated with oxazaphosphorine resistance may lead to a deeper understanding of the factors critical to the optimal use of these agents in chemotherapy and may allow the development of strategies to overcome resistance.
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PMID:Insights into oxazaphosphorine resistance and possible approaches to its circumvention. 1615 99

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.
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PMID:Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions. 1689 6

Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), an endoplasmic reticulum-associated transmembrane protein that is ubiquitously expressed. GSD-Ib patients suffer from disturbed glucose homeostasis and myeloid dysfunctions. To evaluate the feasibility of gene replacement therapy for GSD-Ib, we have infused adenoviral (Ad) vector containing human G6PT (Ad-hG6PT) into G6PT-deficient (G6PT(-/-)) mice that manifest symptoms characteristics of the human disorder. Ad-hG6PT infusion restores significant levels of G6PT mRNA expression in the liver, bone marrow and spleen, and corrects metabolic as well as myeloid abnormalities in G6PT(-/-) mice. The G6PT(-/-) mice receiving gene therapy exhibit improved growth; normalized serum profiles for glucose, cholesterol, triglyceride, uric acid and lactic acid; and reduced hepatic glycogen deposition. The therapy also corrects neutropenia and lowers the elevated serum levels of granulocyte colony-stimulating factor. The development of bone and spleen in the infused G6PT(-/-) mice is improved and accompanied by increased cellularity and normalized myeloid progenitor cell frequencies in both tissues. This effective use of gene therapy to correct metabolic imbalances and myeloid dysfunctions in GSD-Ib mice holds promise for the future of gene therapy in humans.
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PMID:Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice. 1700 47

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.
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PMID:Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-beta. 1731 59

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