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

The type VIII capsular polysaccharide has been isolated and purified from a newly described strain of group B Streptococcus which is a leading cause of sepsis and neonatal meningitis in Japan. The polysaccharide contains D-glucose, D-galactose, L-rhamnose, and sialic acid in the molar ratio 1:1:1:1. By means of high resolution 1H nuclear magnetic resonance (1H NMR), 13C NMR, and homo- and heterocorrelated NMR, the repeating unit structure of the type VIII polysaccharide was delineated as the following, [formula: see text] Enzymatic studies established this polysaccharide as the first from which sialic acid, linked to a branched beta-D-galactopyranosyl residue, is known to be removed by bacterial neuraminidase.
 ...
PMID:Structural and immunochemical characterization of the type VIII group B Streptococcus capsular polysaccharide. 862 15

Streptococcus pneumoniae is an uncommon etiological organism in hemolytic uremic syndrome (HUS). Production of neuraminidase by S. pneumoniae results in exposure of red blood cell T-antigen, resulting in hemolysis, thrombocytopenia, and acute renal failure. Hepatic involvement in this form of HUS has not been described in the literature. We report in three children with S. pneumoniae-associated HUS the presence of severely elevated transaminases and conjugated hyperbilirubinemia. Increases in asparagine transaminase ranged from 11 to 46 times normal values and an increase in alanine transaminase ranged from 1.6 to 8 times normal. In all patients the rise in total bilirubin was 7-15 times normal. Biliary tree obstruction and viral causes for liver dysfunction were absent. Hepatocellular injury in S. pneumoniae-associated HUS likely results from mechanisms involved in sepsis and pneumonia-induced jaundice, combined with severely increased bilirubin production following massive hemolysis. The hepatic injury in all three patients resolved within 9, 5, and 10 days. Our experience suggests that an extensive evaluation including liver biopsy is not indicated.
 ...
PMID:Hepatocellular injury in Streptococcus pneumoniae-associated hemolytic uremic syndrome in children. 874 6

The Thomsen-Friedenreich cryptantigen (TCA) is located on the surface of all red cells, but is concealed by a layer of neuraminic acid. When bacteria that produce neuraminidase disrupt this coating, the TCA can be exposed and activated. If blood products containing antibody to the TCA are subsequently administered, haemolysis can result. While the relationship between TCA and necrotising enterocolitis (NEC) is well described, the incidence of TCA activation in other forms of sepsis in surgical neonates is not known. In a prospective study, 117 patients admitted to the Surgical Neonatal Nursery were examined for evidence of TCA activation. Of the 117 babies, 69 were clinically non-septic and only 1 had weak TCA activation (1.4%). Forty-eight were clinically or bacteriologically septic; 8 of these demonstrated TCA activation (17%), 3 of whom died. Forty of the septic group showed no evidence of TCA activation although 27 grew organisms on culture; 17 in this group died. Two of the TCA-activated babies received unwashed red cells, and both haemolysed; 4 TCA-activated babies received washed red cells and none haemolysed. Although 1 of the well babies in this study demonstrated TCA activation, we would not recommend routine TCA testing on clinically well babies. We would, however, recommend routine testing in all clinically septic infants, as 17% showed signs of TCA activation in this study. We would also suggest the adoption of a selective transfusion policy in TCA-activated patients to avoid the risk of haemolysis. This may help to reduce unnecessary morbidity and mortality in a high-risk group of neonates.
 ...
PMID:T-cryptantigen (TCA) activation in surgical neonates: a hidden problem. 988 Jul 50

Streptococcus pneumoniae infection and disease have been modeled in several animal species including infant and adult mice, infant and adult rats, infant Rhesus monkeys, and adolescent and adult chinchillas. Most are models of sepsis arising from intravenous or intraperitoneal inoculation of bacteria, and a few were designed to study disease arising from intranasal infection. Chinchillas provide the only animal model of middle ear pneumococcal infection in which the disease can be produced by very small inocula injected into the middle ear (ME) or intranasally, and in which the disease remains localized to the ME in most cases. This model, developed at the University of Minnesota in 1975, has been used to study pneumococcal pathogenesis at a mucosal site, immunogenicity and efficacy of pneumococcal capsular polysaccharide (PS) vaccine antigens, and the kinetics and efficacy of antimicrobial drugs. Pathogenesis experiments in the chinchilla model have revealed variation in ME virulence among different pneumococcal serotypes, enhancement of ME infection during concurrent intranasal influenza A virus infections, and natural resolution of pneumococcal otitis media (OM) without intervention. Research has explored the relative contribution of pneumococcal and host products to ME inflammation. Pneumococcal cell wall components and pneumolysin have been studied in the model. Host inflammatory responses studied in the chinchilla ME include polymorphonuclear leukocyte oxidative products, hydrolytic enzymes, cytokine and eicosanoid metabolites, and ME epithelial cell adhesion and mucous glycoprotein production. Both clinical (tympanic membrane appearance) and histopathology (ME, Eustachian tube, inner ear) endpoints can be quantified. Immunologic and inflammatory studies have been facilitated by the production of affinity-purified antichinchilla immunoglobulin G (IgG), IgM, and secretory IgA polyclonal antibody reagents, and the identification of cross-reactivity between human and chinchilla cytokines, and between guinea pig and chinchilla C3. Alteration of ME mucosa by pneumococcal neuraminidase and alteration of ME epithelial cell (MEEC) surface carbohydrates during intranasal pneumococcal infection have been demonstrated. Pathogenesis studies have been aided by cultured chinchilla MEEC systems, in which the ability of platelet activating factor and interleukin (IL)-1 beta to stimulate epithelial mucous glycoprotein synthesis has recently been demonstrated. Because chronic OM with effusion is characterized by presence of large amounts of mucous glycoprotein in the ME, pneumococcus may have an important role in both acute and chronic ME disease. Both unconjugated PS and PS-protein-conjugated vaccines are immunogenic after intramuscular administration without adjuvant in chinchillas. Passive protection studies with human hyperimmune immunoglobulin demonstrated that anti-PS IgG alone is capable of protecting the chinchilla ME from direct ME challenge with pneumococci. Active PS immunization studies demonstrated protection following direct ME and intranasal pneumococcal challenge with and without concurrent influenza A virus infection. An attenuated influenza A virus vaccine also showed protection for pneumococcal OM. Antimicrobial treatment of acute OM has been based almost exclusively on empirical drug use and clinical trials without a foundation of ME pharmacokinetics. Studies in the chinchilla model have started to bring a rational basis to drug selection and dosing. Microassays have been developed using high-pressure liquid chromatography for many relevant drugs. Studies have explored the in vivo ME response in pneumococcal OM to antimicrobial drugs at supra- and sub-minimum inhibitory concentration (MIC), the effect of concurrent influenza A virus infection on ME drug penetration, and the effect of treatment on sensorineural hearing loss produced by pneumococcal OM.
 ...
PMID:Otitis media: the chinchilla model. 1033 23

The inflammatory process is associated with alterations in iron metabolism. Transferrin, an acute-phase N-glycosylated glycoprotein, plays an important role in iron transport. Human serum transferrin contains two biantennary glycans, each consisting of 0 to 4 molecules of sialic acid (SA); its SA content is heterogeneous with high concentration of tetrasialotransferrin (4SA) and low amounts of disialo-, trisialo-, penta-, and hexasialotransferrin. The hepatic uptake of iron is greater for desialylated transferrin isoforms (disialotransferrin) than for the other forms. We hypothesized that serum levels of carbohydrate-deficient transferrin (CDT, disialotransferrin) may increase rapidly in septic patients. Blood samples were obtained from critically ill patients with (n = 15) and without (n = 14) documented sepsis and compared with healthy volunteers. The different forms of transferrin were studied by capillary zone electrophoresis; SA concentrations were measured by enzymatic colorimetric assay. There was a significant increase in the proportion of CDT in septic compared with nonseptic patients and volunteers (18.3% [1.3-30.5] vs. 0.7% [0.5-0.9]; P < 0.01 and 0.9% [0.5-1.1]; P < 0.05). Conversely, tri- and tetrasialotransferrin levels were lower in septic patients. Total and free SA concentrations were significantly higher in septic patients than in healthy volunteers. In a sheep model of septic shock secondary to peritonitis, serum free SA was already increased after 15 h. Sepsis is associated with decreased SA content on circulating transferrin and with an increase in blood free SA concentrations. In view of these rapid modifications and the long half-life of transferrin, the most likely explanation is degradation of transferrin by neuraminidase. Further studies including measurement of blood neuraminidase concentration and activity are needed to understand the process and exact role of SA decrease in septic patients.
 ...
PMID:Rapid alterations in transferrin sialylation during sepsis. 1598 20

We examined the role of the neuraminidases NanA and NanB in colonization and infection in the upper and lower respiratory tract by Streptococcus pneumoniae, as well as the role of these neuraminidases in the onset and development of septicemia following both intranasal and intravenous infection. We demonstrated for the first time using outbred MF1 mouse models of infection that both NanA and NanB were essential for the successful colonization and infection of the upper and lower respiratory tract, respectively, as well as pneumococcal survival in nonmucosal sites, such as the blood. Our studies have shown that in vivo a neuraminidase A mutant is cleared from the nasopharynx, trachea, and lungs within 12 h postinfection, while a neuraminidase B mutant persists but does not increase in either the nasopharynx, trachea, or lungs. We also demonstrated both neuraminidase mutants were unable to cause sepsis following intranasal infections. When administered intravenously, however, both mutants survived initially but were unable to persist in the blood beyond 48 h postinfection and were progressively cleared. The work presented here demonstrates the importance of pneumococcal neuraminidase A and for the first time neuraminidase B in the development of upper and lower respiratory tract infection and sepsis.
 ...
PMID:Pneumococcal neuraminidases A and B both have essential roles during infection of the respiratory tract and sepsis. 1679 Jul 74

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia and gram-positive sepsis. While multiple virulence determinants have been identified, the combination of features that determines the propensity of an isolate to cause invasive pneumococcal disease (IPD) remains unknown. In this study, we determined the genetic composition of 42 invasive and 30 noninvasive clinical isolates of serotypes 6A, 6B, and 14 by comparative genomic hybridization. Comparison of the present/absent gene matrix (i.e., comparative genomic analysis [CGA]) identified a candidate core genome consisting of 1,553 genes (73% of the TIGR4 genome), 154 genes whose presence correlated with the ability to cause IPD, and 176 genes whose presence correlated with the noninvasive phenotype. Genes identified by CGA were cross-referenced with the published signature-tagged mutagenesis studies, which served to identify core and IPD-correlated genes required for in vivo passage. Among these, two pathogenicity islands, region of diversity 8a (RD8a), which encodes a neuraminidase and V-type sodium synthase, and RD10, which encodes PsrP, a protein homologous to the platelet adhesin GspB in Streptococcus gordonii, were identified. Mice infected with a PsrP mutant were delayed in the development of bacteremia and demonstrated reduced mortality versus wild-type-infected controls. Finally, the presence of seven RDs was determined to correlate with the noninvasive phenotype, a finding that suggests some RDs may contribute to asymptomatic colonization. In conclusion, RDs are unequally distributed between invasive and noninvasive isolates, RD8a and RD10 are correlated with the propensity of an isolate to cause IPD, and PsrP is required for full virulence in mice.
 ...
PMID:Identification of a Candidate Streptococcus pneumoniae core genome and regions of diversity correlated with invasive pneumococcal disease. 1686 65

Acute hypercytokinaemia represents an imbalance of pro-inflammatory and anti-inflammatory cytokines, and is believed to be responsible for the development of acute respiratory distress syndrome and multiple organ failure in severe cases of avian (H5N1) influenza. Although neuraminidase inhibitors are effective in treating avian influenza, especially if given within 48 h of infection, it is harder to prevent the resultant hypercytokinaemia from developing if the patient does not seek timely medical assistance. Steroids have been used for many decades in a wide variety of inflammatory conditions in which hypercytokinaemia plays a role, such as sepsis and viral infections, including severe acquired respiratory syndromes and avian influenza. However, to date, the results have been mixed. Part of the reason for the discrepancies might be the lack of understanding that low doses are required to prevent mortality in cases of adrenal insufficiency. Adrenal insufficiency, as defined in the sepsis/shock literature, is a plasma cortisol rise of at least 9 microg dl(-1) following a 250 microg dose of adrenocorticotropin hormone (ACTH), or reaching a plasma cortisol concentration of >25 microg dl(-1) following a 1-2 microg dose of ACTH. In addition, in the case of hypercytokinaemia induced by potent viruses, such as H5N1, systemic inflammation-induced, acquired glucocorticoid resistance is likely to be present. Adrenal insufficiency can be overcome, however, with prolonged (7-10 or more days) supraphysiological steroid treatment at a sufficiently high dose to address the excess activation of NF-kappaB, but low enough to avoid immune suppression. This is a much lower dose than has been typically used to treat avian influenza patients. Although steroids cannot be used as a monotherapy in the treatment of avian influenza, there might be a potential role for their use as an adjunct treatment to antiviral therapy if appropriate dosages can be determined. In this paper, likely mechanisms of adrenal insufficiency are discussed, drawing from a broad background of literature sources.
 ...
PMID:A rationale for using steroids in the treatment of severe cases of H5N1 avian influenza. 1757 50

Group B streptococci (GBS) are the most common cause of neonatal sepsis and meningitis. Most infants who are colonized with GBS at birth do not develop invasive disease, although many of these uninfected infants lack protective levels of capsular polysaccharide (CPS)-specific antibody. The lectin pathway of complement is a potential mechanism for initiating opsonization of GBS with CPS-specific antibody-deficient serum. In this study, we determined whether mannose-binding lectin (MBL)/MBL-associated serine protease (MASP) complexes and L-ficolin/MASP complexes bind to different strains of GBS to activate the lectin pathway, and we identified the molecules recognized by lectins on the GBS surface. We found that MBL did not bind to any GBS examined, whereas L-ficolin bound to GBS cells of many serotypes. L-ficolin binding to GBS cells correlated with the CPS content in serotypes Ib, III (restriction digestion pattern types III-2 and III-3), and V but not with the group B-specific polysaccharide (GBPS) content or with the lipoteichoic acid (LTA) content. L-ficolin bound to purified CPS and GBPS in a concentration-dependent manner but not to purified LTA. All strains to which L-ficolin/MASP complexes bound consumed C4. When N-acetylneuraminic acid (NeuNAc) was selectively removed from GBS cells by treatment with neuraminidase, the reduction in L-ficolin binding was correlated with the amount of NeuNAc removed. Additionally, L-ficolin was able to bind to wild-type strains but was able to bind only weakly to unencapsulated mutants and a mutant strain in which the CPS lacks NeuNAc. We concluded that L-ficolin/MASP complexes bind to GBS primarily through an interaction with NeuNAc of CPS.
 ...
PMID:L-Ficolin/mannose-binding lectin-associated serine protease complexes bind to group B streptococci primarily through N-acetylneuraminic acid of capsular polysaccharide and activate the complement pathway. 1793 15

The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood circulation glycoproteins bearing glycan ligands that include galactose and N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key factor in the development and administration of glycoprotein pharmaceuticals, yet a biological purpose of the Ashwell receptor has remained elusive. We have identified endogenous ligands of the Ashwell receptor as glycoproteins and regulatory components in blood coagulation and thrombosis that include von Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates vWF homeostasis and is responsible for thrombocytopenia during systemic Streptococcus pneumoniae infection by eliminating platelets desialylated by the bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor moderates the onset and severity of disseminated intravascular coagulation during sepsis and improves the probability of host survival.
 ...
PMID:The Ashwell receptor mitigates the lethal coagulopathy of sepsis. 1932 79


<< Previous 1 2 3 4 Next >>