The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Pierre C Dagher - One of the best experts on this subject based on the ideXlab platform.
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pathways of renal injury in systemic Gram Negative Sepsis
European Journal of Clinical Investigation, 2008Co-Authors: Tarek M Elachkar, M Hosein, Pierre C DagherAbstract:Acute renal failure is a grave complication of systemic Gram-Negative Sepsis. The pathophysiological mechanisms of Sepsis leading to kidney injury result in part from systemic inflammatory and haemodynamic alterations. These are triggered by the interaction of endotoxin with Toll-like receptor 4 (TLR4) on cells of the immune system. Recently, TLR4 and other co-effector molecules were identified on renal tubular and vascular cells. Furthermore, it was demonstrated that systemic endotoxin has direct access to renal sites where these receptors are expressed. Therefore, we review data in support of this novel pathway of renal injury in Sepsis, whereby systemic endotoxin causes direct injury through interactions with local epithelial and endothelial TLR4.
Jeffrey A Norton - One of the best experts on this subject based on the ideXlab platform.
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treatment with recombinant human tumor necrosis factor alpha protects rats against the lethality hypotension and hypothermia of Gram Negative Sepsis
Journal of Clinical Investigation, 1991Co-Authors: H R Alexander, Brett C Sheppard, J C Jensen, Howard N Langstein, C M Buresh, David Venzon, E Walker, Douglas L Fraker, Mark C Stovroff, Jeffrey A NortonAbstract:Abstract Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-Negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 microGrams/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-Negative Sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-Negative Sepsis.
Michael A Martin - One of the best experts on this subject based on the ideXlab platform.
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Gram Negative Sepsis and the adult respiratory distress syndrome
Clinical Infectious Diseases, 1992Co-Authors: Michael A Martin, Henry J SilvermanAbstract:: Gram-Negative Sepsis has dramatically increased in frequency throughout the twentieth century in the United States. Currently, approximately 200,000 patients develop Gram-Negative Sepsis each year in this country. Of these, about one-quarter develop the adult respiratory distress syndrome (ARDS). Among these critically ill patients, mortality is estimated at 60%-90%. In the complex series of events leading to acute lung injury in Gram-Negative Sepsis, endotoxin is the proximal mediator. Although endotoxin may be capable of causing direct injury to the pulmonary endothelium, its primary role is as a trigger activating inflammatory agents, including complement, neutrophils, and platelets, and inducing the production of cytokines and arachidonic acid metabolites. The end results are impairment of the endothelial barrier, diffusely increased capillary permeability, and adherence of neutrophils to the endothelium with subsequent migration into the tissues. The consequent clinical syndrome is one of acute respiratory distress with pulmonary edema, poorly compliant lungs, and refractory hypoxemia. Endothelial injury often becomes widespread, leading to the failure of multiple organs, including the kidneys, brain, intestine, and liver. Conventional therapy consists of supplemental oxygen, positive end-expiratory pressure, inotropic agents, fluid management, and antibiotics aimed at the offending pathogen. Recent discoveries regarding the mediators of Sepsis as well as the expansion of the biotechnological armamentarium have provided clinicians with a plethora of new tools with which to manipulate the host's inflammatory response. The challenge for the next decade will be to ensure the safety, efficacy, and cost-effective use of these expensive but potentially lifesaving immunomodulators, singly or in combination, as adjuvant therapy.
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a controlled clinical trial of e5 murine monoclonal igm antibody to endotoxin in the treatment of Gram Negative Sepsis
JAMA, 1991Co-Authors: R. L. Greenman, Neil R. Maclntyre, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Richard P. Wenzel, Mary C Mccarthy, Joseph PlouffeAbstract:Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group ( P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated. ( JAMA . 1991;266:1097-1102)
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a controlled clinical trial of e5 murine monoclonal igm antibody to endotoxin in the treatment of Gram Negative Sepsis the xoma Sepsis study group
JAMA, 1991Co-Authors: R. L. Greenman, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Mary Mccarthy, Richard P. Wenzel, Neil R. Macintyre, Joseph PlouffeAbstract:OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated.
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A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis
JAMA: The Journal of the American Medical Association, 1991Co-Authors: Richard L. Greenman, Neil R. Maclntyre, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Mary Mccarthy, Richard P. Wenzel, Joseph PlouffeAbstract:OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated.
Tom Van Der Poll - One of the best experts on this subject based on the ideXlab platform.
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endogenous tissue type plasminogen activator impairs host defense during severe experimental Gram Negative Sepsis melioidosis
Critical Care Medicine, 2012Co-Authors: Liesbeth M Kager, Joris J T H Roelofs, Joost C M Meijers, M Levi, Joost W Wiersinga, Cornelis Van T Veer, Tom Van Der PollAbstract:OBJECTIVE: Melioidosis is a frequent cause of severe Sepsis in Southeast Asia caused by the Gram-Negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of tissue-type plasminogen activator, an important regulator of fibrinolysis. In this study, we aimed to investigate the role of tissue-type plasminogen activator during melioidosis. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: Wild-type and tissue-type plasminogen activator-deficient C57BL/6 mice. INTERVENTIONS: Mice were intranasally infected with viable Burkholderia pseudomallei and killed after 24, 48, or 72 hrs for harvesting of lungs, liver, and blood. Additionally, survival studies were performed. MEASUREMENTS AND MAIN RESULTS: Experimentally induced melioidosis was associated with elevated levels of tissue-type plasminogen activator in lungs of infected wild-type mice. During infection with Burkholderia pseudomallei, tissue-type plasminogen activator-deficient mice were protected when compared to wild-type mice as demonstrated by a strongly decreased mortality (62% vs. 100% amongst wild-type mice, p < .0001), together with decreased pulmonary bacterial loads, less severe histopathological scores, and decreased fibrinolysis. These results were accompanied with an early increase in cytokine levels in tissue-type plasminogen activator-deficient mice. CONCLUSIONS: During severe Gram-Negative Sepsis caused by Burkholderia pseudomallei, endogenous tissue-type plasminogen activator has harmful effects with respect to survival and pulmonary bacterial growth. These effects are related to tissue-type plasminogen activator-associated plasmin-induced fibrinolysis and/or a tissue-type plasminogen activator-associated decrease in proinflammatory cytokine production.
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oxidized phospholipids inhibit phagocytosis and impair outcome in Gram Negative Sepsis in vivo
Journal of Immunology, 2007Co-Authors: Sylvia Knapp, Ulrich Matt, Norbert Leitinger, Tom Van Der PollAbstract:Oxidized phospholipids that are generated during inflammation exert anti-inflammatory properties and prevent death during murine endotoxemia. Oxidized 1-palmitoyl-2-arachidonoyl- sn -glycero-3-phosphorylcholine (OxPAPC) inhibits the interaction of LPS with LPS-binding protein and CD14. In this study, we determined the functional properties of OxPAPC and potential interference with CD14 during abdominal Sepsis caused by Escherichia coli . Administration of OxPAPC rendered mice highly susceptible to E. coli peritonitis, as indicated by an accelerated mortality and enhanced bacterial outgrowth and dissemination. CD14 −/− mice also displayed increased mortality and bacterial outgrowth and OxPAPC did not further impair host defense in these animals. The mechanisms by which OxPAPC and CD14 deficiency impaired the immune response differed: whereas CD14 −/− mice demonstrated a strongly reduced recruitment of phagocytes to the site of the infection, OxPAPC did not influence the influx of inflammatory cells but strongly diminished the phagocytosing capacity of neutrophils and macrophages by a CD14-independent mechanism. Furthermore, OxPAPC potently inhibited uptake of fluorospheres as well as receptor-mediated endocytosis and fluid-phase pinocytosis. These data suggest that oxidized phospholipids such as produced during inflammatory reactions may contribute to mortality during Gram-Negative Sepsis in vivo via impairment of the phagocytic properties of professional phagocytes.
Richard P. Wenzel - One of the best experts on this subject based on the ideXlab platform.
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long term survival and function after suspected Gram Negative Sepsis
JAMA, 1995Co-Authors: Trish M Perl, Luann Dvorak, Taekyu Hwang, Richard P. WenzelAbstract:Objective. —To determine the long-term (>3 months) survival of septic patients, to develop mathematical models that predict patients likely to survive long-term, and to measure the health and functional status of surviving patients. Setting. —A large tertiary care university hospital and an associated Veterans Affairs Medical Center. Design. —From December 1986 to December 1990, a total of 103 patients with suspected Gram-Negative Sepsis entered a double-blind, placebo-controlled efficacy trial of monoclonal antiendotoxin antibody. Of these, we followed up 100 patients for 7667 patient-months. Beginning in May 1992, we reviewed hospital records and contacted all known survivors. We measured the health status of all surviving patients. Main Outcome Measures. —The determinants of long-term survival (up to 6 years) were identified through two Cox proportional hazard regression models: one that included patient characteristics identified at the time of Sepsis (bedside model) and another that included bedside, infection-related, and treatment characteristics (overall model). Results. —Of the 60 patients in the cohort who died at a median interval of 30.5 days after Sepsis, 32 died within the first month of the septic episode, seven died within 3 months, and four more died within 6 months. In the bedside multivariate model constructed to predict long-term survival, large hazard ratios (HRs) were associated with severity of underlying illness as classified by McCabe and Jackson criteria (for rapidly fatal disease, HR=30.4, P P P =.001). In the overall model for long-term survival, severity of underlying illness (rapidly fatal disease, HR=23.7, P P P =.04), use of vasopressors at the time of Sepsis (HR=2.0; P =.02), and development of adult respiratory distress syndrome (HR=2.3; P =.02) predicted patients most likely to die. The Acute Physiology and Chronic Health Evaluation II score was not a significant predictor of outcome when either model included the simpler McCabe and Jackson classification of underlying disease severity. We compared the health status scores with norms for the general population and found that patients with resolved Sepsis reported more physical dysfunction ( P P =.02), and more poorly perceived general health ( P P =.004). The mean Barthel score of our patients was 85 (100=total independence) and the mean Eastern Cooperative Oncology Group score was 0.7 (0=normal, 4=100% bedridden), suggesting that the patient's physical function was not normal. Conclusions. —At the onset of suspected Gram-Negative Sepsis, severity of underlying illness and in-hospital use of vasopressors are strong and consistent predictors of short- and long-term survival. Our data validate the McCabe and Jackson severity of illness scoring system for predicting long-term survival after Sepsis. Physical dysfunction and more poorly perceived general health occur commonly after Sepsis. ( JAMA . 1995;274:338-345)
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a controlled clinical trial of e5 murine monoclonal igm antibody to endotoxin in the treatment of Gram Negative Sepsis the xoma Sepsis study group
JAMA, 1991Co-Authors: R. L. Greenman, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Mary Mccarthy, Richard P. Wenzel, Neil R. Macintyre, Joseph PlouffeAbstract:OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated.
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a controlled clinical trial of e5 murine monoclonal igm antibody to endotoxin in the treatment of Gram Negative Sepsis
JAMA, 1991Co-Authors: R. L. Greenman, Neil R. Maclntyre, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Richard P. Wenzel, Mary C Mccarthy, Joseph PlouffeAbstract:Objective. —To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. Design. —Double-blind, randomized, placebo-controlled trial. Setting. —Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. Patients. —Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. Intervention. —Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. Main Outcome Measures. —Mortality over the 30-day study period, resolution of organ failures, and safety. Results. —Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P =.01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group ( P =.05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. Conclusions. —Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated. ( JAMA . 1991;266:1097-1102)
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A Controlled Clinical Trial of E5 Murine Monoclonal IgM Antibody to Endotoxin in the Treatment of Gram-Negative Sepsis
JAMA: The Journal of the American Medical Association, 1991Co-Authors: Richard L. Greenman, Neil R. Maclntyre, George Emmanuel, Richard B. Kohler, Michael A Martin, Roland M. H. Schein, Herman Chmel, Mary Mccarthy, Richard P. Wenzel, Joseph PlouffeAbstract:OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with Gram-Negative Sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of Gram-Negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against Gram-Negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed Gram-Negative Sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with Gram-Negative Sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with Gram-Negative Sepsis who are not in shock when treated.
