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

Serum opsonic activity for E. coli 075, conversion of C3 by inulin, total hemolytic complement (CH(50)), levels of native C3, factor B, C3b inactivator (KAF), properdin (P), and immunoglobulins (Ig) were determined in 14 patients with burns involving 13% to 91% body surface during 6 to 8 weeks postburn. In the 12 uninfected patients, levels of IgG and IgA were reduced during the first 10 days postburn, and decreased concentrations of P and IgM were demonstrated from three to 6 weeks postburn. C3 conversion was reduced from 10 days to 6 weeks postburn. Levels of C3, factor B, and KAF were normal or elevated for the entire study period. No difference in the occurrence of humoral abnormalities was noted in patients with burns caused by flame, immersion scald, or acid contact. Reduction in C3 conversion and P concentration were the only abnormalities which correlated with increasing burn size. Bacteremia and/or fungemia was documented in the other two patients. In one of these patients, reduction in CH(50) occurred during septicemia due to S. aureus, and in the other, reduction in all measurements of complement was associated with candidemia and Pseudomonas septicemia and occurred prior to the development of shock. Serum opsonic activity was only reduced significantly during sepsis, suggesting that this abnormality occurred as a result rather than a cause of infection. These results indicate that consumption of components of the classical and/or alternative pathways of complement activation may be an important mechanism by which infection is perpetuated in the burn patient. They also emphasize the importance of the clinical management of the burn patient in preventing the development of septic complications.
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PMID:Changes in humoral components of host defense following burn trauma. 87 73

Persistent pulmonary hypertension of the newborn (PPHN), initially described by Gersony et al as persistent foetal circulation (PFC syndrome), results from a flawed transition from foetal to extrauterine pulmonary circulation. It is characterised by the maintenance of a high pulmonary vascular resistance and right-to-left shunting through the ductus arteriosus and foramen ovale. Infants with a wide variety of underlying clinical conditions develop PPHN. According to Rudolph three main anatomic types of PPHN can be identified: normal pulmonary vascular development increased pulmonary vascular smooth muscle development decreased cross-sectional area of pulmonary vascular bed. It is important to realize that several pathophysiologic mechanisms may coexist and interact. Besides metabolic and respiratory acidosis, hypercapnia and hypoxaemia some other factors induce pulmonary vasoconstriction. Thromboxane, leukotrienes and prostaglandins play a decisive role. Since PPHN can be associated with a broad spectrum of clinical conditions, a specific clinical picture is lacking. The baby is usually term or post-term, cyanotic immediately after birth or some hours later. Birth asphyxia, hyperviscosity, sepsis and aspiration of meconium have been recognized as predisposing factors. The diagnosis can be confirmed by echocardiography. Contrast echo will indicate right-to-left shunting with normal anatomy. Currently hyperventilation, tolazolin, chlorpromazin and dopamine/dobutamine have been advocated as central foci for clinical therapy. Recently prostacyclin was introduced as a specific pulmonary vasodilatator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Persistent pulmonary hypertension of newborn. The PFC syndrome]. 229 36

Splenectomy continues to be the most commonly chosen method of management of traumatic injury to the spleen. However, patients of all age groups who have undergone splenectomy have significant impairment of immune functions as demonstrated by decreased production of IGM, tufsin, and properdin. This immune deficiency has been clinically manifested by an increased incidence of postsplenectomy pneumonia and sepsis which is reduced but not eliminated by the use of pneumococcal vaccine and/or prophylactic antibiotics. This paper presents the results of a study of the feasibility of repair and replantation of injured spleens using microsurgical techniques. Twenty cats had their spleens removed, finger-fractured, and debrided. The cats were then assigned to one of four groups. Group I had the entire spleen replanted but only 75% of the parenchyma revascularized. Group II had 75% of the parenchyma revascularized and replanted. Group III had 50% revascularized and replanted, and Group IV 25% revascularized and replanted. Patency of the anastomoses was assessed by postoperative arteriography. Restoration of reticuloendothelial (filter) function was assessed by the use of technetium sulphur colloid scans which showed preservation of reticuloendothelial function of the revascularized segments but absence of function in nonrevascularized segments which had been replanted. Histologic examination of replanted spleens harvested at 8 weeks showed normal architecture of red and white pulp in all areas that had been revascularized. However, in those spleens where the entire spleen had been replanted but only partially revascularized, the nonrevascularized segments were degenerated and atrophic.
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PMID:Debridement and replantation of the spleen with microsurgical restoration of blood flow. 402 93

We have developed a new, specific, and highly sensitive enzyme-linked immunosorbent assay (ELISA) which quantitates activation of the alternative pathway in human serum, plasma, or on the surface of activators. The ELISA detects the third component of complement (C3b), proteolytic fragment of complement Factor B (Bb), and properdin (P) complex or its derivative product, C3b,P. In the method, activator-plasma mixtures, plasma containing an activated alternative pathway, or other samples are added to the wells of microtitration plates precoated with antibody to P. C3b, Bb,P or C3b,P complexes which become bound are quantitated by subsequently added, enzyme-labeled, anti-C3. The resulting hydrolysis of the chromogenic substrate is expressed as nanograms of C3b by reference to a C3 standard curve. In addition to absolute specificity for activation of the pathway because of the nature of the complex detected by the assay, the ELISA is highly sensitive and able to reproducibly detect 10-20 ng/ml of C3b,P complexes in serum. This value corresponds to 0.0015% of the C3 in serum. In a series of studies to validate the parameters of the ELISA, reactivity was found to be dependent on the presence of alternative pathway proteins, the functional integrity of the pathway, and on the presence of magnesium. Sheep erythrocytes were converted to activators by treatment with neuraminidase. By using a variety of activators, the kinetics of activation and the numbers of bound C3b molecules quantitated by the ELISA were very similar to those measured by C3b deposition. The ELISA also detected identical activation kinetics when MgEGTA-serum and a mixture of the purified alternative pathway proteins were used as sources of the pathway. ELISA reaction kinetics also correlated with the restriction index, a measure of alternative pathway-activating ability. These studies cumulatively validate the ELISA as a direct and quantitative assay for alternative pathway activation. The sensitivity of the ELISA has permitted its use to detect direct alternative pathway activation by several viruses. The ELISA has also shown that certain classical pathway activators trigger the amplification loop of the alternative pathway while others do not. In addition, stable ELISA reactive complexes appeared in the supernatant of mixtures of serum with certain, but not other activators. The ability of the ELISA to detect activation which has already occurred and the stability of the reactive complexes permits studies of clinical sera. Normal human sera (20) contained low levels (5-20 ng/ml) of ELISA-reactive complexes. A proportion of sera from individuals with the adult respiratory distress syndrome (9-10), typhoid fever (8-10), malaria (3-5), gram-negative sepsis (9 of 47), acute trauma and shock (6 f 25), and systemic lupus erythematosus (3 of 29) showed elevated levels of complexes reactive in the alternative pathway ELISA. In contrast, nine sera from patients with circulating C3 nephritic factor were not reactive in the ELISA.
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PMID:Development and application of an enzyme-linked immunosorbent assay for the quantitation of alternative complement pathway activation in human serum. 641 67

The bactericidal activities of human complement and human antibody directed against specific Haemophilus influenzae type b cell surface determinants were investigated. Strain Eagan, a laboratory isolate, and strain Kn, a clinical isolate, were used as the test organisms and gave qualitatively similar results. In the absence of antibody, both isolates were resistant to killing by 60% agammaglobulinemic serum (AGS) containing normal complement levels. The addition of affinity-purified immunoglobulin G anticapsular antibody was bactericidal with 15% AGS as the complement source. Bactericidal activity was also demonstrated with this antibody when the complement source was AGS-Mg-EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid], C2-deficient human serum (alternative complement pathway), or AGS in which factor D and properdin had been selectively inactivated (classical pathway). Immunoglobulin G fractions from a human serum pool or from serum from an adult who had recovered from H. influenzae type b (Kn) sepsis were absorbed to remove anticapsular antibody. The absorbed fractions containing noncapsular antibodies also activated complement-dependent bactericidal activity. But, in contrast to the results with anticapsular antibody, noncapsular antibodies did not elicit alternative pathway bactericidal activity. Incubation of cells of H. influenzae type b in C2-deficient serum or AGS-Mg-EGTA did not cause complement consumption (total hemolytic complement and C3). The addition of immunoglobulin G anticapsular antibody (but not noncapsular antibody) increased consumption of total complement and C3, paralleling the results of the bactericidal assays. These studies demonstrated an absolute requirement for anticapsular antibody in alternative pathway activation and killing of H. influenzae type b.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antibody-dependent alternative pathway killing of Haemophilus influenzae type b. 660 28

Factor I deficiency causes a permanent, uncontrolled activation of the alternative pathway resulting in an increased turnover of C3 and consumption of factor B, factor H and properdin. Factor I deficiency is clinically associated with recurrent bacterial infections already in early infancy, mainly affecting the upper and lower respiratory tract, or presenting as meningitis or septicemia. We here report on a Brazilian family (n = 9) with known consanguinity, where in 3/7 children, suffering from chronic otitis, meningitis, and respiratory infections, a complete factor I deficiency was recognized. One of the patients died after fulminant sepsis. Hemolytic activity of the alternative pathway was not detectable in the patients' sera due to decreased plasma concentrations of C3, factor B and properdin. As a consequence of factor I deficiency, C3b could not be metabolized with the result that no C3-derived split products (C3dg/C3d) were detectable in the patients' sera. In vitro reconstitution with purified factor I restored the regulatory function in the patients' sera with the subsequent cleavage of C3b to C3c and C3dg. Factor H levels were decreased in all patients' sera and found to be tightly complexed with C3b resulting in a modified electrophoretic mobility. Upon factor I reconstitution, factor H was released from C3b regaining its beta 1 electrophoretic mobility. Complement-mediated biological functions like opsonization of bacteria, chemotactic activity and phagocytosis in these patients were impaired. The parents (cousins, 2nd degree) and 3/4 siblings had significantly reduced factor I plasma levels without further alteration in their complement profile. 3 of these obviously heterozygously deficient family members suffered from recurrent bacterial infections of different frequency and severity.
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PMID:Complement factor I deficiency in a family with recurrent infections. 947 32

Although people with bacterial meningitis lack adequate protective antibody against the invading pathogen, most do not have an underlying immunodeficiency. Certain comorbid conditions increase the risk for development of bacterial sepsis and meningitis. In addition, certain congenital complement deficiencies, defects of antibody production, or asplenia may be first recognized by the occurrence of bacterial meningitis, particularly when it occurs in infants or young children. Deficiencies of the terminal components of complement (C5-C9) or properdin have been associated with recurrent or invasive neisserial infections, and asplenia, agammaglobulinemia, and deficiencies of the early components of complement (e.g., C1-C3) are associated with risks of infections caused by Streptococcus pneumoniae, Haemophilus influenzae, and meningococci. The presence of congenital or acquired immunodeficiencies should be considered in persons who present with bacterial meningitis on the basis of the etiology, clinical epidemiology, and presence of other risk factors.
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PMID:Indications for the immunological evaluation of patients with meningitis. 1252 51

The clinical presentation of infections caused by Neisseria meningitidis is highly diverse. Some patients develop meningitis, and others present with sepsis or even septic shock. After invasion of the bloodstream by the bacteria, three main cascade pathways are activated. These are the complement system, the inflammatory response, and the coagulation and fibrinolysis pathway. These pathways do not act independently but are able to interact with each other. Genetic polymorphisms among components of these pathways have been shown to be involved in the susceptibility, severity, and outcome of meningococcal disease. We review knowledge of genetic variations associated with susceptibility to and severity of meningococcal infection. Complement deficiencies and defects in sensing or opsonophagocytic pathways, such as the rare Toll-like receptor 4 single nucleotide polymorphisms (SNPs) and combinations of inefficient variants of Fcgamma-receptors, seem to have the most important role in genetically established susceptibility. Effect on severity has repeatedly been reported for FcgammaRIIa and plasminogen activator inhibitor type 1 (PAI1) polymorphisms. Outcome effects have been confirmed for SNPs in properdin deficiencies, PAI1 and combination of the -511C/T SNP in interleukin 1beta, and the +2018C/T SNP in interleukin RN. Conflicting results are reported for the effect of the -308G/A promoter polymorphism in tumour necrosis factor (TNF) alpha. These differences may reflect discrepancies in group definitions between studies or the influence of additional SNPs in the TNFalpha promoter, which can form haplotypes representing different cytokine production capacity. For several SNPs, the potential effect on susceptibility, severity, or outcome has not yet been confirmed in an independent study.
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PMID:Host genetic determinants of Neisseria meningitidis infections. 1295 63

Neisseria meningitidis (meningococcus) is an important cause of meningitis and sepsis. Currently, there is no effective vaccine against serogroup B meningococcal infection. Host defense against neisseriae requires the complement system (C) as indicated by the fact that individuals deficient in properdin or late C components (C6-9) have an increased susceptibility to recurrent neisserial infections. Because the classical pathway (CP) is required to initiate efficient complement activation on neisseriae, meningococci should be able to evade it to cause disease. To test this hypothesis, we studied the interactions of meningococci with the major CP inhibitor C4b-binding protein (C4bp). We tested C4bp binding to wild-type group B meningococcus strain (H44/76) and to 11 isogenic mutants thereof that differed in capsule expression, lipo-oligosaccharide sialylation, and/or expression of either porin (Por) A or PorB3. All strains expressing PorA bound radiolabeled C4bp, whereas the strains lacking PorA bound significantly less C4bp. Increased binding was observed under hypotonic conditions. Deleting PorB3 did not influence C4bp binding, but the presence of polysialic acid capsule reduced C4bp binding by 50%. Bound C4bp remained functionally active in that it promoted the inactivation of C4b by factor I. PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation.
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PMID:Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis. 1587 29

Properdin is a positive regulator of complement activation so far known to be instrumental in the survival of infections with certain serotypes of Neisseria meningitidis. We have generated a fully backcrossed properdin-deficient mouse line by conventional gene-specific targeting. In vitro, properdin-deficient serum is impaired in alternative pathway-dependent generation of complement fragment C3b when activated by Escherichia coli DH5alpha. Properdin-deficient mice and wild-type littermates compare in their levels of C3 and IgM. In an in vivo model of polymicrobial septic peritonitis induced by sublethal cecal ligation and puncture, properdin-deficient mice appear immunocompromised, because they are significantly impaired in their survival compared with wild-type littermates. We further show that properdin localizes to mast cells and that properdin has the ability to directly associate with E. coli DH5alpha. We conclude that properdin plays a significant role in the outcome of polymicrobial sepsis.
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PMID:Properdin plays a protective role in polymicrobial septic peritonitis. 1829 56


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