UMLS:C0036690 - FACTA Search

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Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis and secretion of proinflammatory mediators like tumor necrosis factor-alpha and neopterin are common events in severe systemic inflammatory disorders, e.g. sepsis and septic shock. Recent data suggest that both substances show similarities with respect to their bioactivities. In the present study we investigated the potential interactions of neopterin and tumor necrosis factor-alpha on inducible nitric oxide synthase gene expression and nitric oxide generation in rat vascular smooth muscle cells. In addition, we studied the influence of neopterin on tumor necrosis factor-alpha synthesis in this cell type. Single stimulation of smooth muscle cells with either neopterin or tumor necrosis factor-alpha caused inducible nitric oxide synthase gene expression and nitric oxide production. Coincubation of cells with both compounds resulted in at least additive effects on nitric oxide synthesis. Quantification of tumor necrosis factor-alpha cDNA revealed a dose-dependent effect of neopterin on tumor necrosis factor-alpha gene expression. Similar results were obtained concerning the detection of tumor necrosis factor-alpha protein and the assessment of tumor necrosis factor-alpha bioactivity. These data suggest that neopterin and tumor necrosis factor-alpha are closely associated with regard to synthesis and effects, respectively. The interactions of both inflammatory mediators in vascular smooth muscle cells might contribute to the excessive release of nitric oxide observed during sepsis, thus triggering cellular destruction and multiple organ failure.
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PMID:Neopterin-induced tumor necrosis factor-alpha synthesis in vascular smooth muscle cells in vitro. 969 72

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
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PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

The present study was performed to determine the kinetics of serum neopterin levels after major thermal injury and their relationship to endotoxemia and sepsis. This prospective study included 35 patients (32 males and three females) with total burn surface area (TBSA) greater than 30% (30%-98%), and 22 healthy volunteers who served as normal controls. The results showed that neopterin levels increased in most patients on day 3 postburn, but they were not significantly correlated with the extent of the burn surface (P > 0.05). Patients with endotoxemia had much higher neopterin values than those who showed no endotoxemia from the second week onward (P < 0.05-0.01), and circulating endotoxin and neopterin levels were positively correlated in patients who developed endotoxemia on day 14 (r = 0.368, P < 0.05) and day 21 (r = 0.439, P < 0.01) after major burns. Moreover, a high serum neopterin level was found in patients with sepsis (n = 15), and the marked elevation persisted throughout the observation period. The difference between septic and non-septic patients (n = 20) became significant on 14 and 28 days postburn. These data suggest that extensive burns can lead to an elevation of serum neopterin independent of TBSA. The endotoxin release in the circulation may be involved in the continuous formation of neopterin during the late postburn stage. In addition, the presence of a constant high neopterin level is associated with a critical event in the development of burn sepsis.
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PMID:[Serum neopterin levels after extensive burns and their relationship to endotoxemia and sepsis]. 1045 47

Production and release of proinflammatory mediators such as tumour necrosis factor-alpha and neopterin are common events following the activation of the cellular immune system. Concerning inflammatory disorders of the lung, e.g. sepsis or sarcoidosis, high serum neopterin levels have been reported to correlate well with the severity of the disease. These situations are often associated with an increased expression of ICAM-1 reported to be induced in type II alveolar epithelial cells. In our study we investigated the potential effects of neopterin on ICAM-1 synthesis in the type II-like pneumocyte cell line L2. Detection of ICAM-1 gene expression by reverse transcriptase-polymerase chain reaction revealed a dose-dependent effect of neopterin, with maximum impact following 12-h incubations. Comparable results were obtained when ICAM-1 protein synthesis was measured via a cell-based ELISA. In a second set of experiments we were able to show that coincubation of L2 cells with pyrrolidine dithiocarbamate (PDTC) significantly suppressed neopterin-induced ICAM-1 synthesis. Since PDTC is known to be a potent inhibitor of NF-kappaB, the stimulating effects of neopterin on ICAM-1 gene expression and protein generation may be mediated by activation of this transcription factor. From these data we conclude that neopterin stimulates ICAM-1 production in L2 cells. In vivo, these effects may contribute to the prolongation of the inflammatory response, including cytotoxic cell host defence mechanisms that impair the functions of the airway epithelium.
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PMID:Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in type II-like alveolar epithelial cells. 1059 64

Background: At present, it is unclear whether in experimental endotoxemia, the pro-inflammatory response observed in healthy volunteers is followed by an anti-inflammatory response, as observed in patients with sepsis. We studied the evolution of a number of inflammatory parameters during a prolonged period (24 h) after infusion of endotoxin in healthy subjects. Methods: Six healthy male subjects received an infusion of endotoxin (4 ng/kg body weight). Blood was drawn before, and at various intervals up to and including 24 h after, endotoxin infusion. Circulating cytokine levels, leukocyte activation surface markers, plasma lactoferrin, and neopterin levels were measured, and clinical signs and symptoms were noted during a 24-h period. Monocyte and neutrophil activation after endotoxin infusion is investigated in relation to the inflammatory response. The extent of neutrophil and monocyte activation was correlated to clinical markers and blood levels of inflammatory mediators and cytokines. Results: Tumor necrosis factor-alpha appeared 30 min after infusion in the circulation, peaking (5665+/-1910 pg/ml) at 2 h. Interleukin-10 appeared 60 min after infusion, peaking (427+/-348 pg/ml) at 3 h. The expression of leukocyte activation markers increased significantly after infusion. Expression of HLA-DR on monocytes decreased significantly after 3 h (P=0.03). There was a correlation between the TNF-alpha:IL-10 ratio and the CD11b:HLA-DR ratio (P=0.03). Conclusions: During experimental human endotoxemia, an initial pro-inflammatory response is successfully compensated by an anti-inflammatory response, leading to homeostasis. This is in contrast to what happens in septic patients with compensatory anti-inflammatory response syndrome. The inflammatory balance, expressed as the cytokine pro:anti-inflammatory ratio, is reflected at a cellular level.
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PMID:Leukocyte activation and cytokine production during experimental human endotoxemia. 1074 52

Cardiopulmonary bypass increases the blood levels of various immune mediators, thereby leading to a systemic inflammatory response syndrome, e.g. sepsis, with some hemodynamic alterations, such as vasodilatation, tachycardia, and a decrease in systemic vascular resistance. Perioperative hemofiltration is one of the treatment modalities proposed to prevent this syndrome. Modified hemofiltration has been introduced recently by investigators who recommend that the former standard techniques are ineffective in eliminating the inflammatory mediators. The purpose of this study was to determine the effects of the modified technique on these mediators and on hemodynamic parameters. Forty patients undergoing coronary artery bypass grafting were randomized into equal control and hemofiltered groups. The hemodynamic parameters, as well as blood samples, were taken before and after hemofiltration to assess blood concentrations of interleukin-6, interleukin-8 and neopterin. The hemodynamic parameters and immune mediator levels did not differ between the two groups during the course of the study, except in the immediate postoperative periods, where cardiac output, cardiac index, and systemic vascular resistance values were significantly greater in the hemofiltered group while there were no differences in the immune mediators. The results of our study suggest that the effects of modified hemofiltration on immune mediators are still debatable. The improvement found in cardiac performance could be attributed to the prevention of hemodilution and hypervolemia.
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PMID:The effects of modified hemofiltration on inflammatory mediators and cardiac performance in coronary artery bypass grafting. 1078 69

Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.
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PMID:alpha-MSH in systemic inflammation. Central and peripheral actions. 1081 51

Infectious complications are still a major cause of morbidity and mortality after organ transplantation, and early therapy would certainly reduce the risk associated with severe infections. We therefore investigated the significance of polymorphonuclear leukocyte (PMN) functional tests as predictive markers for infection in transplant patients under immunosuppressive therapy in a longitudinal study. In 41 patients, blood PMN migration and reactive oxygen species release, the blood levels of PMN elastase, malondialdehyde, neopterin, sICAM-1 and sVCAM-1, and urine neopterine were measured in 3- and 4-day intervals after liver-, kidney-, kidney-pancreas-, and heart and lung transplantation. PMN migration was determined in whole blood and estimated by the amount of PMNs to penetrate into a membrane filter upon FMLP stimulation. Three groups of patients were formed according to their postoperative course. Group I patients (n = 23) had no or only minor local infection, group II patients (n = 11) had infections with distinct systemic involvement, and group III patients (n = 7) developed sepsis. A first elastase-level of over 100 mg/L after surgery, followed by a drop in the amount of blood PMNs ready to migrate, on FMLP stimulation, to below 12 %, turned out to be a marker for impending infection, whereas all other parameters tested were not predictive. In six of seven group III patients, this marker became positive (sensitivity 85.7 %) up to 15 days before clinical manifestation of sepsis. In group I (largely uneventful recovery) only one of 23 patients was positive (specificity 95.6 % ), whereas group II patients were in between (4 of 11 positive). By this method it seems possible to diagnose severe infections in the pre-clinical phase, which may help prevent them if treatment is begun promptly.
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PMID:Polymorphonuclear leukocyte functions as predictive markers for infections after organ transplantation. 1083 47

We examined whether procalcitonin (PCT) or neopterin (NT) are useful in predicting sepsis, multiple organ failure (MOF), or death after multiple trauma (MT). In a prospective clinical study, a total of 137 consecutive trauma patients (mean age 39 years, median injury severity score [ISS] 27 points) and 34 healthy volunteers were enrolled. Blood samples were collected on arrival in the emergency room until day 28 after trauma. Plasma NT was detected by enzyme-linked immunoassay and PCT plasma levels were determined using an immunoluminometric assay. The incidence of sepsis was 65%, MOF 48%, and death in hospital within 28 days 11%. After adjustment for age, gender, and ISS, PCT and NT levels during the first 2 days after injury were unable to differentiate between patients who developed sepsis or not. On the contrary, patients who developed MOF had higher PCT plasma levels on day 0 (0.60 vs. 0.15 ng/mL), and on days 1 and 2 combined (1.95 vs. 0.32 ng/mL). This difference remained significant in multivariate logistic regression (P = 0.01) and additional subgroup analyses for early and late MOF (P = 0.048 and 0.002). For NT, smaller differences were observed (4.39 vs. 3.68 nmol/L, and 7.20 vs. 5.79 nmol/L), which lost significance in multivariate analysis. On the basis of PCT, ISS, and age, a MOF prediction rule was developed and had a good predictive power (area under the curve: 0.77; P < 0.001). These findings demonstrate that high plasma concentrations of PCT in the early posttraumatic phase are an independent predictor of MOF but not of sepsis.
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PMID:The clinical value of procalcitonin and neopterin in predicting sepsis and organ failure after major trauma. 1456 Jan 5

Neopterin released by monocytes/macrophages upon activation by interferon-gamma secreted from T-lymphocytes, is a sensitive indicator of cell-mediated immune activation. Chemically, neopterin is a pyrazino-pyrimidine derivative, namely, 2-amino-4 hydroxy-(1',2',3' trihydroxypropyl)-pteridine. Biosynthetically, neopterin derives from guanosine triphosphate (GTP), and is a biologically stable cytokine. Increased concentrations of neopterin in serum and urine have been found in various infections (especially viral), autoimmune diseases, malignant disorders, and during allograft rejection episodes. In addition, there is a close relationship between high neopterin levels and systemic inflammatory diseases, septicemia and surgical stress. Measurement of neopterin concentration in human body fluids such as serum, urine, cerebrospinal fluid and pleural fluid, allows insight into a cell-mediated immune response. In recent years neopterin becomes an important laboratory parameter for clinical and therapeutical follow-up of diseases involving the cellular immune system. In this review article, the clinical use of neopterin as a marker in the diagnosis and monitorization of the infectious diseases has been discussed.
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PMID:[Neopterin: a marker used for monitoring infections]. 1612 38

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