Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the considerable advances made in understanding the pathophysiology of systemic inflammation during critical illness, clinical progress has been elusive as it remains a very deadly condition. Cortisol and thyroid hormone levels can be as predictive of outcome as the commonly used severity parameters (i.e. APACHE). Indeed, levels of endocrine humoral substances such as arachidonic acids, nitric oxide, endothelin, calcitonin precursors, leptin and adenosine correlate with the severity and outcome of critical illness. Furthermore, calcitonin precursors represent a potentially new hormokine paradigm, being transcriptionally activated in all cells in response to infection. The cytokines are immune markers that often correlate with severity and outcome, but their release is transient. In contrast, the so-called acute phase proteins, such as C-reactive protein and serum amyloid A, are highly sensitive to inflammatory activity and can be important markers of severity and outcome. Leukocyte esterase, adhesion molecules, platelet activating factor and activated protein C are additional humoral immune markers; the replacement of the latter has been shown to be a promising therapeutic option. Natriuretic peptides are neurocrine humoral markers that have important cardiovascular implications. The level of macrophage migrating inhibitory factor, released by the pituitary, is elevated in sepsis and counteracts glucocorticoid action. Cellular markers to severe stress include the enhanced expression of protective substances in the form of heat shock proteins. High mobility group-1 is a DNA-binding protein and a late mediator of the inflammatory response. Apoptotic markers such as the soluble fas ligand are also elevated in inflammation. In summary, during critical illness, the endocrine, immune and nervous systems elaborate a multitude of humoral markers, the roles of which merit further scrutiny in order to improve therapeutic outcome.
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PMID:Humoral markers of severity and prognosis of critical illness. 1180 May 23

Sixty coagulase-negative staphylococcus (CNS) isolates were recovered from the blood cultures or peritoneal dialysate effluent of 43 patients on renal dialysis. The patients had either renal dialysis catheter-related sepsis (CRS) or continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis. Isolates were characterized by biotyping, and genotyped by pulsed-field gel electrophoresis (PFGE). Phenotypic properties of the strains were also investigated. Several genotypes were identified with no one specific strain of CNS being associated with CRS. However, closely related strains were isolated from several patients within the units studied, suggesting horizontal transfer of micro-organisms. Genotypic macro-restriction profiles did not concur with phenotypic profiles or biotypes, confirming that genotyping is required for epidemiological studies. All staphylococcal strains were investigated for the production of phenotypic characteristics. Significant differences were predominantly seen in the production of lipase, esterase and elastase in strains isolated from the renal patients with CRS and CAPD-associated peritonitis, compared with a non-septic control group. These phenotypic characteristics may therefore have a role in the maintenance of CRS in renal patients.
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PMID:Genotypic and phenotypic properties of coagulase-negative staphylococci causing dialysis catheter-related sepsis. 1291 57

Neutrophil-specific granule deficiency (SGD) is a rare, congenital disease characterized by atypical neutrophil structure and function, resulting in recurrent bacterial infections from early infancy. Homozygous recessive mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) gene were described in two of five SGD patients, indicating loss of C/EBPepsilon function as the primary genetic defect in this disease. C/EBPepsilon is expressed in murine and human macrophages. Macrophages from the C/EBPepsilon-deficient mice show impaired differentiation, phagocytic activity, and transcription of macrophage-specific genes. To determine if monocyte/macrophage cells are impacted in SGD, we analyzed phenotypic features of peripheral blood (PB) monocytes in a SGD individual lacking functional C/EBPepsilon. Flow cytometric analysis of PB leukocytes revealed aberrant expression of CD45, CD11b, CD14, CD15, and CD16 on cells from the SGD individual. Also, the PB CD14(+) cells from this individual, weakly stained for the monocyte-specific enzyme, nonspecific esterase, and electron microscopic examination, indicated morphologic differences between the SGD cells and those from normal controls. Serum interleukin (IL)-6 levels in the SGD individual during a severe bacterial infection were lower compared with levels in other non-SGD individuals with sepsis. In contrast, serum IL-8 levels were markedly elevated in the SGD individual compared with those of non-SGD individuals in sepsis. PB CD14(+) cells from the SGD individual expressed higher IL-8 mRNA levels compared with normal controls in response to lipopolysaccharide and interferon-gamma. These phenotypic and functional alterations of PB monocytes in the SGD individual suggest that C/EBPepsilon plays a critical role in monocyte/macrophage development of humans and is consistent with observations in the murine system. This study implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of SGD.
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PMID:Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency. 1457 62

There are approximately 250,000 cases of acute pyelonephritis each year, resulting in more than 100,000 hospitalizations. The most common etiologic cause is infection with Escherichia coli. The combination of the leukocyte esterase test and the nitrite test (with either test proving positive) has a sensitivity of 75 to 84 percent and a specificity of 82 to 98 percent for urinary tract infection. Urine cultures are positive in 90 percent of patients with acute pyelonephritis, and cultures should be obtained before antibiotic therapy is initiated. The use of blood cultures should be reserved for patients with an uncertain diagnosis, those who are immunocompromised, and those who are suspected of having hematogenous infections. Outpatient oral antibiotic therapy with a fluoroquinolone is successful in most patients with mild uncomplicated pyelonephritis. Other effective alternatives include extended-spectrum penicillins, amoxicillin-clavulanate potassium, cephalosporins, and trimethoprim-sulfamethoxazole. Indications for inpatient treatment include complicated infections, sepsis, persistent vomiting, failed outpatient treatment, or extremes of age. In hospitalized patients, intravenous treatment is recommended with a fluoroquinolone, aminoglycoside with or without ampicillin, or a third-generation cephalosporin. The standard duration of therapy is seven to 14 days. Urine culture should be repeated one to two weeks after completion of antibiotic therapy. Treatment failure may be caused by resistant organisms, underlying anatomic/functional abnormalities, or immunosuppressed states. Lack of response should prompt repeat blood and urine cultures and, possibly, imaging studies. A change in antibiotics or surgical intervention may be required.
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PMID:Diagnosis and management of acute pyelonephritis in adults. 1634 41

Streptococcus pneumoniae is the worldwide leading cause of deaths from invasive infections such as pneumoniae, sepsis, and meningitidis in children and the elderly. Nasopharyngeal colonization, which plays a key role in the development of pneumococcal disease, is highly dependent on a family of surface-exposed proteins, the choline-binding proteins (CBPs). Here we report the crystal structure of phosphorylcholine esterase (Pce), the catalytic domain of choline-binding protein E (CBPE), which has been shown to be crucial for host/pathogen interaction processes. The unexpected features of the Pce active site reveal that this enzyme is unique among the large family of hydrolases harboring the metallo-beta-lactamase fold. The orientation and calcium stabilization features of an elongated loop, which lies on top of the active site, suggest that the cleft may be rearranged. Furthermore, the structure of Pce complexed with phosphorylcholine, together with the characterization of the enzymatic role played by two iron ions located in the active site allow us to propose a reaction mechanism reminiscent of that of purple acid phosphatase. This mechanism is supported by site-directed mutagenesis experiments. Finally, the interactions of the choline binding domain and the Pce region of CBPE with chains of teichoic acids have been modeled. The ensemble of our biochemical and structural results provide an initial understanding of the function of CBPE.
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PMID:Crystal structure of phosphorylcholine esterase domain of the virulence factor choline-binding protein e from streptococcus pneumoniae: new structural features among the metallo-beta-lactamase superfamily. 1590 36

Lipophilic Malassezia species may induce catheter-associated sepsis in premature neonates and immunocompromised patients receiving parenteral lipid emulsions. To assess the participation of lipolytic enzymes in the pathogenesis of this yeast, we cloned a gene encoding the enzyme. A lipolytic enzyme in the culture supernatant of Malassezia pachydermatis was purified 210-fold to homogeneity. The enzyme showed high esterase activity toward p-nitrophenyl octanoate. The cDNA encoding the enzyme was cloned using a degenerate oligonucleotide primer constructed from the N-terminal amino acid sequence. The cDNA consisted of 1582 bp, including an open reading frame encoding 470 amino acids. The first 19 amino acids and the following 13 amino-acid sequence were predicted to be the signal peptides for secretion and prosequence, respectively. The predicted molecular mass of the 438-amino acid mature protein was 48 kDa. Analysis of the deduced amino acid sequence revealed that it contains the consensus motif (Gly-X-Ser-X-Gly), which is conserved among lipolytic enzymes. Homology investigations showed that the enzyme has similarities principally with 11 lipases produced by Candida albicans (29-34% identity) and some other yeast lipases.
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PMID:Isolation, characterization and molecular cloning of a lipolytic enzyme secreted from Malassezia pachydermatis. 1648 31

Human diseases caused by species of Aeromonas have been classified into two major groups: septicemia and gastroenteritis. In this study, we reported the molecular and functional characterization of a new virulence factor, ToxR-regulated lipoprotein, or TagA, from a diarrheal isolate, SSU, of Aeromonas hydrophila. The tagA gene of A. hydrophila exhibited 60% identity with that of a recently identified stcE gene from Escherichia coli O157:H7, which encoded a protein (StcE) that provided serum resistance to the bacterium and prevented erythrocyte lysis by controlling classical pathway of complement activation by cleaving the complement C1-esterase inhibitor (C1-INH). We purified A. hydrophila TagA as a histidine-tagged fusion protein (rTagA) from E. coli DE3 strain using a T7 promoter-based pET30 expression vector and nickel affinity column chromatography. rTagA cleaved C1-INH in a time-dependent manner. The tagA isogenic mutant of A. hydrophila, unlike its corresponding wild-type (WT) or the complemented strain, was unable to cleave C1-INH, which is required to potentiate the C1-INH-mediated lysis of host and bacterial cells. We indeed demonstrated colocalization of C1-INH and TagA on the bacterial surface by confocal fluorescence microscopy, which ultimately resulted in increased serum resistance of the WT bacterium. Likewise, we delineated the role of TagA in contributing to the enhanced ability of C1-INH to inhibit the classical complement-mediated lysis of erythrocytes. Importantly, we provided evidence that the tagA mutant was significantly less virulent in a mouse model of infection (60%) than the WT bacterium at two 50% lethal doses, which resulted in 100% mortality within 48 h. Taken together, our data provided new information on the role of TagA as a virulence factor in bacterial pathogenesis. This is the first report of TagA characterization from any species of Aeromonas.
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PMID:Molecular and functional characterization of a ToxR-regulated lipoprotein from a clinical isolate of Aeromonas hydrophila. 1679 Jul 46

Group B Streptococcus (GBS) is a common cause of neonatal sepsis and meningitis. A major GBS virulence determinant is its sialic acid (Sia)-capped capsular polysaccharide. Recently, we discovered the presence and genetic basis of capsular Sia O-acetylation in GBS. We now characterize a GBS Sia O-acetylesterase that modulates the degree of GBS surface O-acetylation. The GBS Sia O-acetylesterase operates cooperatively with the GBS CMP-Sia synthetase, both part of a single polypeptide encoded by the neuA gene. NeuA de-O-acetylation of free 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac(2)) was enhanced by CTP and Mg(2+), the substrate and co-factor, respectively, of the N-terminal GBS CMP-Sia synthetase domain. In contrast, the homologous bifunctional NeuA esterase from Escherichia coli K1 did not display cofactor dependence. Further analyses showed that in vitro, GBS NeuA can operate via two alternate enzymatic pathways: de-O-acetylation of Neu5,9Ac(2) followed by CMP activation of Neu5Ac or activation of Neu5,9Ac(2) followed by de-O-acetylation of CMP-Neu5,9Ac(2). Consistent with in vitro esterase assays, genetic deletion of GBS neuA led to accumulation of intracellular O-acetylated Sias, and overexpression of GBS NeuA reduced O-acetylation of Sias on the bacterial surface. Site-directed mutagenesis of conserved asparagine residue 301 abolished esterase activity but preserved CMP-Sia synthetase activity, as evidenced by hyper-O-acetylation of capsular polysaccharide Sias on GBS expressing only the N301A NeuA allele. These studies demonstrate a novel mechanism regulating the extent of capsular Sia O-acetylation in intact bacteria and provide a genetic strategy for manipulating GBS O-acetylation in order to explore the role of this modification in GBS pathogenesis and immunogenicity.
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PMID:NeuA sialic acid O-acetylesterase activity modulates O-acetylation of capsular polysaccharide in group B Streptococcus. 1764 66

One of the new experimental trends in pharmacotherapy of sepsis is the use of C1-esterase inhibitor (C1I) from the group of immunobiological agents influencing the complement system. An open prospective study on the safety and efficacy of C1I revealed its positive effect on the death rate among the patients with sepsis. In a dose of 12000 IU, C1I had a significant inhibitory action on the complement system activity, as well as an antiinflammatory effect by blocking the complement-dependent link in the systemic inflammation. The adverse and significant adverse events were not associated with the use of C1I.
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PMID:[Safety and efficacy of purified human C1-esterase inhibitor in the treatment of patients with sepsis]. 1949 17

The risk of mortality is high in burn patients and correlates with age, burn area extent, and sepsis. Immunosuppression has been reported to occur after severe burn. Cytotoxic cells possess specialized granules containing perforin and a group of serine proteases (granzymes). Granzyme A is a serine protease constitutively expressed by gammadelta and NK cells, in agreement with their functional cytolytic potential. In vitro studies have shown that GrA may be released extracellularly during cytotoxic cell degranulation, indicating the activation of cytotoxic cells. The aim of our study was to determine plasma GrA activity in burned patients and to verify if decreased GrA levels were associated with poor prognosis. Specific GrA activity was tested in the plasma of burned and healthy subjects by esterase assay. Plasma GrA was significantly decreased in septic rather than in nonseptic burn patients and in healthy subjects (p < 0.05 and p < 0.001, respectively). At day 3 plasma GrA was significantly lower in nonsurvivor than in survivor septic patients (p < 0.05). The value of 91 mOD showed a sensitivity of 100% and a specificity of 84% in differentiating survivor from nonsurvivor septic patients. Because this is a retrospective study, Granzyme A is not a confirmed predictor of septic outcome after burn, but its determination could give useful information about the development and severity of sepsis.
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PMID:Reduction of plasma granzyme A correlates with severity of sepsis in burn patients. 2036 98


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