Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microvascular endothelial cells (mECs) circulate at higher numbers in patients with severe sepsis and hemophagocytic syndromes. Although these blood mECs might stem from damaged microvasculature, they are perfectly viable and lead to the establishment of cell lines. Such mECs were cultured in low-dose human serum pools (0.5%) and MEM-alpha medium. Antigenic profiling revealed the expression of CD36, factor VIIIa, CD95-ligand, and CD44, but also CD146. We studied the antioxidative effect of the hematopoietic growth factor G-CSF(1) after in vitro stimulation with LPS from E. coli 0111:B4; the growth factor appeared to exhibit a protective effect on organ function in patients with SIRS. mECs were stimulated with 1 micro g/mL of LPS for 24 h and 48 h with and without G-CSF (3x10(3) U/mL) preincubation. After 24 h, supernatants of the stimulated mEC were tested for IL-8 by ELISA, and cells were tested for hemoxygenase-1 (HO-1, Hsp32) by immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene). Stimulation with LPS upregulated IL-8 by a factor of 2 to 10 in mEC. Preincubation with G-CSF markedly downregulated the LPS-induced IL-8 secretion (20-50%), but IL-6 production was not affected. Upon 48 h of LPS stimulation, mECs developed massive signs of apoptosis and concomitant caspase 3 activation. Caspase 3 activity induced by LPS (24 h) or by staurosporin (6 h) was found to be dramatically downregulated by the G-CSF preincubation protocol.
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PMID:G-CSF modulates LPS-induced apoptosis and IL-8 in human microvascular endothelial cells: involvement of calcium signaling. 1503 98

In addition to the ability of G-CSF to stimulate the maturation and function of granulocytes, experimental and clinical evidence suggests that induction of leukemia cell differentiation may also be possible. This critical effect has received little attention with respect to its potential therapeutic application in myeloid malignancies. We describe the clinical course of a 62-year-old patient with atypical AML1/ETO-positive AML-M2 who repeatedly displayed a marked, dose-dependent response to G-CSF. He was originally investigated for neutropenia, but declined chemotherapy at diagnosis of AML (40% bone marrow blasts) and commenced G-CSF therapy when a life-threatening chest infection occurred. The bone marrow infiltration regressed and his blood counts normalized after 20 days. A slow relapse occurred over the next 3 months but a second hematological remission was achieved upon reintroduction of G-CSF. He remained well and free of transfusions for 2.5 years, receiving only maintenance G-CSF. Despite the presence of the AML1/ETO transcript, his leukemic blasts always failed to demonstrate the typical morphological, immunological and cytogenetic characteristics of AML1/ETO-AML of M2 subtype. He eventually developed resistance to G-CSF and died from sepsis after cytotoxic therapy. In selected AML cases differentiation therapy with growth factors may emerge as a useful antileukemic strategy, either alone or as an adjunct to established treatment modalities.
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PMID:Dose dependent long-term in vivo remission of AML1/ETO positive acute myeloid leukemia with G-CSF. 1520 65

Bacterial factors stimulate the release of tissue factor as well as proinflammatory and antiinflammatory cytokines. TNF augments inflammation, TNF and IFN-gamma induce coagulation, and IL-1beta induces coagulation and fibrinolysis. IL-8 augments synergistic inflammation and coagulation. IL-6 augments coagulation and inhibits fibrinolysis. IL-10 inhibits inflammatory process and inhibits fibrinolysis. IL-4, IL-13, and TGF-beta act for anticoagulation. Administration of IL-2, G-CSF or IFN-gamma has been reported to have side effect of induction of coagulation. IL-12 induces coagulation first and fibrinolysis later. On the other, tissue factor induces proinflammatory (except TNF) and antiinflammatory cytokines, and thrombin enhances inflammation. Patients who died of SIRS/sepsis have been complicated with hypercoagulopathy and impaired fibrinolysis correlated with increased IL-10 production. Inhibition of IL-10 production or administration of fiblynolitic agents may be useful. Recently, activated protein C (APC) which has antiinflammatory effect has been paid attention in the treatment of SIRS/sepsis.
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PMID:[Correlation between intravascular coagulation/fibrinolysis system and cytokines]. 1559 92

Newer immunosuppressive agents have dramatically reduced the rates of acute graft rejection over the last decade but may have exacerbated the problem of post-transplant infections. Causes of early mortality include graft dysfunction and sepsis. Late mortality occurs mainly due to sepsis. An excessive inflammatory response followed with a dramatic paralysis of cell-mediated immunity has been documented in septic patients. In transplanted individuals the pathophysiological changes of the immune response are further complicated by immunosuppressive agents. This article will focus on the effect of immunosuppressive agents and sepsis on cell-mediated immune responses. Moreover, potentially promising immunomodulatory approaches, i.e. human activated protein C, immunomodulatory diets containing L-arginine and fish oil, selective cytokine blockade, platelet-activating factor receptor antagonist, LPS receptor CD14 blockade and G-CSF, for the treatment of immunodysfunction in septic patients will be outlined in this review article. Most of them, however, have not been tested in the clinical arena in transplanted patients. Thus, the main part of the article, immunomodulation during sepsis in organ transplanted children is quite speculative and based on immunomodulatory strategies in other non-transplanted septic patients.
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PMID:Immunomodulation during sepsis in organ transplanted children. 1620 9

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.
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PMID:Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. 1706 11

The five-part "Pointers in Practical Pharmacology" immunomodulation series has presented some of the agents researchers are investigating in hopes of finding the means to effectively prevent and treat infectious processes in neonates. The phosphodiesterase inhibitor pentoxifylline appears promising, but large, randomized, clinical trials are still lacking. So far, there is no clear evidence to support the use of G-CSF for either the prevention or the treatment of sepsis. The results of a large, randomized, clinical trial of G-CSF in the United Kingdom are pending. Although intravenous immunoglobulin (IVIG) therapy does not appear to be useful in the prevention of sepsis, its effectiveness in the treatment of sepsis is uncertain. It is hoped that the results of the International Neonatal Immunotherapy Study will provide definitive answers regarding treatment of sepsis with IVIG. The "conditionally essential" amino acid glutamine administered either enterally or parenterally does not make a difference in the rate of systemic infection or NEC in very low birth weight infants. Finally, probiotics appear promising as documented by at least two of the three randomized, clinical trials described here. As the search continues for agents to enhance the neonate's immune system and prevent and treat infectious diseases, remember that our best prevention tool is excellent and consistent hand hygiene.
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PMID:Immunomodulation, Part V: probiotics. 1728 88

The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide. Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients.
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PMID:G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms. 1788 43

It has recently been appreciated that patients with severe sepsis and septic shock suffer from altered innate and adaptive immune responses, leading to an impaired clearance of microorganisms. This explains their difficulty to fight their primary bacterial infection and their propensity to develop superinfections. A depressed immunological surveillance in some of these patients is also responsible for a reactivation of dormant viruses, such as cytomegalovirus. Leukocyte functions are profoundly affected during sepsis. Circulating phagocytes show a marked decrease in their capacity to mount a pro-inflammatory reaction in response to microorganisms. Monocytes express low levels of major histocompatibility class II molecules. These phenotypic changes are known as 'immune paralysis'. Massive lymphocyte and dendritic cell apoptosis has also been reported in patients dying of sepsis, responsible, at least in part, for the impairment of adaptive responses. This was highlighted by the defective skin tests to common antigens documented already three decades ago in patients with sepsis. Patients with severe sepsis and septic shock may therefore benefit from treatments aimed at stimulating innate and adaptive immune responses. The aims of immune stimulation are: (1) to help bacterial killing at the primary focus of infection; (2) to prevent the development of nosocomial infections; and (3) to prevent the reactivation of dormant viruses. Therapeutic strategies based on 'boosting' immune responses with interferon gamma, G-CSF, and more recently with GM-CSF have been initiated. Although results of pilot studies are encouraging, these will need to be confirmed in larger clinical studies. As a word of caution, one should not induce deleterious overwhelming inflammatory reactions, and therefore close monitoring of immune and inflammatory responses during immune stimulation therapy is necessary.
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PMID:Immunostimulation is a rational therapeutic strategy in sepsis. 1738 Jul 86

A 45-year-old homosexual man with pneumocystis pneumonia and esophageal candidiasis tested positive in ELISA and Western blot analysis for HIV-1. His CD4+ T cell count was 43/microL and his HIV-RNA load was 250,000 copies/mL. He was treated with Trimetoprim-Sulfamethoxazole, Prednisolone and Fluconazole. Valganciclovir was added to treat CMV retinitis. During the clinical course, 21 days after admission, the patient presented with a temperature of 39 degrees C and blood analysis showed neutropenia. Cefepime and G-CSF were initiated, but new consolidation was observed in the upper left lobe in chest radiography. He underwent bronchoscopy and lavage culture was positive for Aspergillus fumigatus. Serum testing of galactomannan was also positive and pulmonary aspergillosis was diagnosed. The patient was initially treated with Micafungin but switched to Voriconazole when clinical symptoms worsened. An eventual clinical response was observed and pulmonary aspergillosis was controlled. Unfortunately, he died of sepsis due to MRSA 2 months later. Pulmonary aspergillosis is a devastating complication with poor prognosis in patients with HIV infection. Amphotericin-B has been the mainstay of pulmonary aspergillosis treatment, but reports indicate mortality exceeding 80%. Use of Voriconazole, a relatively new antifungal agent, may lower mortality with fewer adverse effects than conventional antifungal therapy.
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PMID:[Voriconazole as an effective therapy against pulmonary aspergillosis in a man with immunodeficiency virus-infection: a case report]. 1744 80

First line treatment of patients pts with poor-prognosis GCT, using BEP, is unsatisfactory. T-BEP (paclitaxel followed by BEP) demonstrated promising efficacy in the group of pts with intermediate and poor prognosis GCT. We present the results achieved with 1st line T-BEP in pts with poor-prognosis CGT. Twenty-four pts received T-BEP as initial therapy. Three pts (12.5%) had primary mediastinal GCT. Four cycles of T-BEP were given 21 days apart. Paclitaxel 175 mg/m2 was administered on day 1 before administration of BEP. The administration of G-CSF was not scheduled. Surgical resection of all radiographic residua was considered. All pts were assessable for response. Complete or partial response with negative tumor markers was achieved in 13 pts (54.2%; CI 95%: 34.3-74.1%). Median follow-up is 35.6 months. Median survival was not achieved and median time-to-progression is 9.5 months. Myelosuppression was the major toxicity with Gr3-4 granulocytopenia experienced in 52.1% of all courses. There were two treatment-related deaths due to sepsis. Patients treated with 1st line T-BEP didn't achieve higher response rate or time to progression. However, the overall survival observed in our study is surprisingly long. We do not recommend using this regimen without G-CSF support due to substantial toxicity.
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PMID:Paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) as initial treatment in patients with poor-prognosis germ cell tumors (GCT): a phase II study. 1744 57


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