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

Gram-negative bacterial sepsis remains a major cause of lethality in hospitalized patients, despite routine therapy consisting of antimicrobial agents, hemodynamic monitoring and fluid resuscitation, and metabolic support. Because a large body of evidence supports the concept that Gram-negative bacterial lipopolysaccharide (endotoxin, LPS) is responsible for many of the direct and host mediator-induced deleterious effects, recent work has been centered on the development and use of anti-LPS antibody preparations in order to ameliorate lethality. Both polyclonal and monoclonal antibody preparations directed against the common deep core/lipid A region of LPS are cross-reactive in vitro and cross-protective in vivo against a wide range of challenge organisms and LPS, and preliminary clinical trials indicate that a reduction in lethality may be possible. The precise endotoxin epitope against which antibody should be directed in order to maximize protection, however, has not been established. This modality most probably will become a standard form of adjunctive therapy within the next several years for the treatment of Gram-negative bacterial sepsis.
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PMID:Development and potential use of antibody directed against lipopolysaccharide for the treatment of gram-negative bacterial sepsis. 225 68

An overview of gram-negative sepsis is presented, and the need for improved treatment for this condition is emphasized. The availability of new and more potent antimicrobial agents has not substantially altered the mortality from sepsis and septic shock. Gram-negative infection, bacteremia, sepsis, and septic shock remain major clinical problems, particularly among hospitalized patients. The estimated incidence of gram-negative sepsis in the United States alone is 200,000 cases annually. The predominant pathogens are Escherichia coli, Klebsiella, and Pseudomonas aeruginosa. Mortality is strongly influenced by the host's clinical status and age and the development of shock; it may reach 90% in patients with rapidly fatal disease. Analysis of risk factors and use of criteria for categorizing severity of disease can be helpful in designing new treatments, identifying potential recipients of such agents, and evaluating outcome of therapy. Because bacterial endotoxin plays a pivotal role in triggering the biological cascade of mediators in the septic process, a new therapy has been developed, immunotherapy with monoclonal antibodies that neutralize lipopolysaccharide by binding to lipid A. Successful treatment of gram-negative sepsis requires appropriate patient identification and timely intervention. While antimicrobial agents remain important, monoclonal antibodies hold promise as a new therapeutic intervention.
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PMID:Overview of gram-negative sepsis. 227 77

The pathogenesis, clinical presentation, and complications of gram-negative bacterial sepsis are described, and the implications for therapy are reviewed. The sepsis syndrome is a clinically defined condition that involves the physiologic alterations and clinical consequences of the presence of microorganisms or their toxins in the bloodstream or tissues. Gram-negative bacteria produce sepsis and septic shock via the release of the cell-wall component known as endotoxin (lipopolysaccharide). The lipid A moiety, common to gram-negative bacteria, is immunogenic and appears to account for many of the biologic effects of endotoxin. A variety of mediators, including tumor-necrosis factor, are released in response to endotoxin, with resultant diverse effects on host tissues, including organ dysfunction and shock. Adequate treatment requires prompt recognition of infection, especially endotoxemia and sepsis, and the early institution of appropriate therapy. Corticosteroids offer little benefit, and the efficacy of naloxone and nonsteroidal anti-inflammatory drugs has not been determined. Although suitable antimicrobial therapy is necessary to eliminate the offending organisms, antimicrobial agents do not inhibit the effects of the bacterial toxins that are present in sepsis. The outcome of sepsis may be favorably influenced in the future by the use of newer methods of detection and newer treatment modalities, including monoclonal antibodies directed against endotoxin or inhibitors of inflammatory mediators.
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PMID:Pathophysiology and treatment of gram-negative sepsis. 227 78

Secretion of tumor necrosis factor (TNF)/cachectin occurs during gram-negative bacterial sepsis in response to macrophage stimulation by lipopolysaccharide (endotoxin) and may play an early pivotal role in the subsequent host response. We sought to determine whether administration of: (1) murine monoclonal antibody directed against endotoxin, (2) steroids, or (3) antimicrobial agents would abrogate TNF production and whether the protective capacity would correlate with TNF levels in an experimental model of murine gram-negative bacterial sepsis. Mice were pretreated with anti-lipopolysaccharide monoclonal antibody, gentamicin sulfate, hydrocortisone, or saline and were then challenged with a lethal dose of intraperitoneal Salmonella minnesota. Murine serum TNF levels were measured by the L929 fibroblast cytotoxicity assay. Both gentamicin and anti-lipopolysaccharide monoclonal antibody significantly enhanced survival, and TNF activity at 1.5 and 3 hours was significantly suppressed in animals receiving these agents compared with animals that received either steroids or saline. We conclude that agents such as gentamicin, which inhibits bacterial replication, or monoclonal antibodies, which may neutralize lipopolysaccharide, indeed enhance survival, and survival was correlated with a significant reduction in circulating TNF during the early stages of infection.
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PMID:Decreased tumor necrosis factor production during the initial stages of infection correlates with survival during murine gram-negative sepsis. 229 80

Immunological assessment is important to characterize the host defence response of trauma patients as infection is the most common cause of severe morbidity and late death. Sixty trauma patients were followed serially and divided into three groups: those with an uneventful recovery (n = 17), those with recovery after major sepsis (n = 27) and those who died (n = 16). The ability of peripheral blood monocytes to express the antigen HLA-DR was measured and compared to the results from 77 asymptomatic volunteers. After initial injury, there was a significant reduction from normal in the three trauma groups. It took one week for HLA-DR antigen expression to return to the normal range in the first group, three weeks in the second group, and in the third group it never returned to normal. Monocyte HLA-DR antigen expression, after incubation with lipopolysaccharide, distinguished those patients who survived from those who died. There was no difference in HLA-DR antigen expression between a high transfusion group of 31 patients who received 10 or more units of blood and a low transfusion group of 29 patients who received less than 10 units. The ability of monocytes to express HLA-DR antigen correlated directly with the clinical course in these patients and its measurement identified a group of patients at high risk of infection and death following trauma.
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PMID:Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patient. 231 82

Fibrin formation plays an important role in glomerular injury. We therefore examined the procoagulant signal produced by cultured rat mesangial cells. Actively growing mesangial cells produced procoagulant activity (PCA) that was present in intact cells (surface-associated), was inhibitable by cyclohexamide and which, by clotting assay, had the characteristics of tissue factor. This PCA decreased with incubation of cells in serum-deprived medium. Incubation with bacterial lipopolysaccharide (LPS) and tumor necrosis factor (TNF alpha) induced increased detectable tissue factor by mesangial cells within two hours which was maximal by four hours. We conclude that quiescent mesangial cells produce a small amount of tissue factor-like procoagulant activity, and that this PCA can be stimulated by incubation with TNF alpha, LPS or when cells are actively growing in high serum medium. Therefore mesangial cells have the capability of contributing to fibrin formation during inflammatory glomerular injury or sepsis.
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PMID:Tissue factor production by cultured rat mesangial cells. Stimulation by TNF alpha and lipopolysaccharide. 234 26

The effects of immunization in modulating the pathogenesis of Bacteroides (Porphyromonas) gingivalis infection in a murine model system were examined. BALB/c mice were immunized by intraperitoneal injection with B. gingivalis ATCC 53977 (one injection per week for 3 weeks), or with a lithium diiodosalicylate (LIS) extract (one injection per week for 3 weeks), or with lipopolysaccharide (LPS; one intravenous or intraperitoneal injection) from this same strain. Two weeks after the final immunization, the mice were challenged by subcutaneous injection of B. gingivalis ATCC 53977. Mice immunized with bacteria had no secondary lesions and no septicemia, whereas mice immunized with LIS extract had few secondary lesions and no septicemia. Mice immunized with LPS and nonimmunized mice demonstrated secondary abdominal lesions and septicemia after challenge. Bacterial cells and LIS extract, but not LPS, induced serum antibody and antigen reactive lymphocytes, as measured by enzyme-linked immunosorbent assay, immunoblot, Western immunoblot transfer, and in vitro lymphoproliferative responses. The present study suggests that immunization with a LIS extract or whole cells may induce a protective response against experimental B. gingivalis infection.
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PMID:Protective immunization against experimental Bacteroides (Porphyromonas) gingivalis infection. 240 68

The primary structure of lipopolysaccharide binding protein (LBP), a trace plasma protein that binds to the lipid A moiety of bacterial lipopolysaccharides (LPSs), was deduced by sequencing cloned complementary DNA. LBP shares sequence identity with another LPS binding protein found in granulocytes, bactericidal/permeability-increasing protein, and with cholesterol ester transport protein of the plasma. LBP may control the response to LPS under physiologic conditions by forming high-affinity complexes with LPS that bind to monocytes and macrophages, which then secrete tumor necrosis factor. The identification of this pathway for LPS-induced monocyte stimulation may aid in the development of treatments for diseases in which Gram-negative sepsis or endotoxemia are involved.
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PMID:Structure and function of lipopolysaccharide binding protein. 240 37

We compared the ability of 13 materials, all with known affinity for lipopolysaccharide (LPS), to remove LPS from water, pooled normal human plasma, and plasma from a patient with Gram-negative bacterial sepsis. Escherichia coli O111:B4 LPS was added to water and pooled normal human plasma to a concentration of 200 ng/ml and aliquots were adsorbed in parallel with each of the materials. Plasma containing 25 ng/ml of LPS was obtained by plasmapheresis from a patient with fatal Klebsiella pneumoniae sepsis and was similarly adsorbed. Ethanolamine bound to Sepharose 4B served as a control adsorbent. LPS was most readily removed from water and least readily removed from plasma obtained from the patient with sepsis. Nonetheless, some materials removed substantial quantities of LPS from the patient's plasma. Upon ip injection of control-adsorbed patient's plasma into LPS-sensitized mice, death occurred in 13 of 13 mice within 12 h. In contrast, when this plasma was first adsorbed with activated charcoal, Kaopectate, or polymyxin B bound to Sepharose 4B, death occurred 12 h after challenge in 0/13, 0/13, and 2/13 mice, respectively (p less than .0001 by actuarial life table analysis of survival distributions). Thus, plasma that contains bacterial toxins produced during Gram-negative bacterial sepsis can be detoxified by adsorption.
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PMID:Detoxification of plasma containing lipopolysaccharide by adsorption. 199 16

The immunophysical characteristics of 29 Serratia marcescens strains isolated from hospitalized patients in three different cities were studied. Their outer membrane antigens were compared by solid-phase radioimmunoassay inhibition, and their proteinase K-treated, whole-cell lysates were compared by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis. The strains had a limited number of unique outer membrane lipopolysaccharide (LPS) and capsular polysaccharide (K) antigens. By solid-phase radioimmunoassay inhibition, these strains could be divided into four distinct LPS and five K antigenic groups. By SDS-PAGE, the LPS groups could be further divided into three distinct SDS-PAGE core polysaccharide profiles and five distinct O-side-chain polysaccharide profiles. Immunoblot analysis with rabbit antiserum confirmed the limited heterogeneity of these isolates. Of the strains tested, no PAGE profile was unique to blood or nonblood isolates or to organisms collected from a given hospital. Variability of O and core PAGE profiles was not a function of organism growth cycle. Five representative Serratia strains were tested by SDS-PAGE and immunoblot analysis and in a bactericidal assay with normal human serum. We found that (i) the normal human serum had antibodies to the LPS of each of the strains, (ii) the anti-LPS antibody measured by immunoblot did not correlate with the level of bactericidal activity in the normal human serum, (iii) three of four sepsis isolates were serum sensitive, (iv) two Serratia strains serum sensitive in log-phase growth became serum resistant in late stationary-phase growth and under limiting nutrient conditions, and (v) no LPS PAGE profile distinguished serum-sensitive from serum-resistant strains.
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PMID:Immunophysical characterization of human isolates of Serratia marcescens. 240 11


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