Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Pertussis toxin, and also cholera toxin are capable of inhibiting the effects of LPS in the elicitation of the generalized Schwartzman reaction. This is a potentially lethal generalized thrombo-haemorrhagic hypersensitivity and inflammatory-type response that occurs after two consecutive injections of LPS. The two exotoxins furnish significant protection against the lethal outcome of this reaction. It is known that the acute haematological and haemodynamic changes are accompanied by alterations in the levels of various endogenous mediators: glucocorticoid hormones, prostaglandins, arachidonic acid metabolites, cytokines and proteases. In vitro effects of LPS on murine leukocyte cell lines can be antagonized by pertussis toxin, implicating a Gi-like regulatory protein in the mediation of these effects. Experiments designed to study the involvement of particular second messenger systems (cAMP and phosphatidylinositol) used by LPS in vivo, revealed that the protective effects conferred by these exotoxins are associated with the antagonization of alterations caused by LPS. No correlation was found between the levels of IL-6 and the mortality rate in this experimental mouse model. The results indicate that G proteins play a role in the generation of the Schwartzman reaction and open a new approach for pharmacological intervention in endotoxemia and in clinical settings with Gram-negative sepsis.
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PMID:Cholera and pertussis exotoxins protect mice against the lethal Schwartzman reaction and antagonize the effects of lipopolysaccharide on second messenger systems. 216 28

Despite numerous reports, the role of tumor necrosis factor (TNF) in polymorphonuclear leukocyte (PMN) function remains controversial. We found TNF to be a potent, pertussis toxin-independent stimulator of PMN adhesion (ED50 2.6 pM). TNF-stimulated PMN under adherent conditions released up to 65% of their transcobalamine content (ED50 3.9 pM) and increased their burst activity 10-fold (ED50 3.2 pM) as measured by the hexose monophosphate shunt, whereas PMN held in suspension hardly degranulated at all and only little burst activity was demonstrable. However, preincubation of PMN with TNF in suspension led to a decrease in cellular adhesiveness, degranulation, and burst activity in response to a secondary stimulus of TNF under adherent conditions, although cells remained fully responsive toward phorbol myristate acetate. A concomitant dose-dependent decline of TNF receptor numbers that correlated well with the inhibition of PMN function (r = 0.91) suggests receptor down-regulation as the mechanism of functional PMN deactivation. Remarkably, preincubation with other PMN stimuli such as N-formyl-methionyl-leucyl-phenylalanine, platelet-activating factor, leukotriene B4, complement component fragment 5a (C5a)/C5a (desarginated), and endotoxin also led to a reduction of TNF-specific PMN responses (cross-deactivation) from 35% (LTB4) to 90% (endotoxin), corresponding with the down-regulation of TNF receptors. Deactivation and receptor down-regulation are independent of pertussis toxin-sensitive G proteins and protein kinase C but seemed to depend on changes in calcium metabolism. Granulocyte hyporesponsiveness towards TNF in sepsis (with elevated blood levels of endotoxin and TNF) might be a mechanism of self-protection or, to the contrary, might impair a possibly central mode of host defense.
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PMID:The tumor necrosis factor receptor and human neutrophil function. Deactivation and cross-deactivation of tumor necrosis factor-induced neutrophil responses by receptor down-regulation. 216 42

Endothelium is an important target of tumor necrosis factor/cachectin (TNF), a central mediator of the host response in endotoxemia and Gram-negative sepsis. In this report, TNF is shown to increase the permeability of endothelial cell monolayers to macromolecules and lower molecular weight solutes by a mechanism involving a pertussis toxin-sensitive regulatory G protein. Within 1-3 h of exposure to TNF (5 nM), changes in cell shape/cytoskeleton occurred that led to disruption of monolayer continuity with the formation of intercellular gaps. Correlated with these structural changes was an increase in endothelial permeability to macromolecular and lower molecular weight tracers; time-dependent, reversible increases in passage of these tracers, evident by 1-3 h, were observed after addition of TNF to cultures. Perturbation of barrier function by TNF also depended on the dose of TNF added being half-maximal by approximately 0.4 nM. Only a brief exposure (15 min) of TNF to endothelium was required to induce an increase in permeability, and this was not prevented by the presence of cycloheximide or actinomycin D. Preincubation of monolayers with pertussis toxin blocked in parallel TNF-induced increased passage of solutes and cell shape/cytoskeletal perturbation, indicating the close correlation between these changes in endothelial cell function. In contrast, pertussis toxin did not alter TNF-induced modulation of two endothelial cell coagulant properties. These data provide evidence for two intracellular pathways of TNF action that are distinguishable by pertussis toxin and provide insight into a mechanism underlying loss of solute from the intravascular space mediated by TNF: alteration in endothelial cell barrier function.
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PMID:Tumor necrosis factor/cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G proteins. 249 53

To focus attention on the problem of infant mortality in Lebanon, data were compiled on infant mortality from 1978 to 1986 at the American University of Beirut Medical Center. Causes of death are analyzed for 602 males and 398 females. 54.9% deaths occurred at 1 month of age and 77.4% died within the 1st year. Autopsies were performed on .7%. 37.7% of all neonatal deaths were due to neonatal diseases such as hyaline membrane disease, asphyxia neonatorum, immaturity, necrotizing enterocolitis, hemorrhage, hemolysis, meconium aspiration, and kernicterus. Better prenatal care would reduce this group, or the administration of corticosteroids to the mother 24-48 hours prior to delivery, as well as rapid resuscitation at birth and prevention of the 5 curses: hypoxemia, hypoglycemia, hypothermia, hypotension, and acidosis. Although unavailable in Lebanon, administration of surfactants through an endotracheal tube would also help. Infections constitute 25.1% of deaths; many are preventable through adequate public health measures and strict personal hygiene, i.e., diseases such as sepsis, pneumonia, meningitis, gastroenteritis, hepatitis, encephalitis, and 1-2 cases of the following: diphtheria, measles, peritonitis, tetanus, tuberculosis, cytomegalis inclusion, herpes, parathyphoid, pertussis, poliomyelitis, and shigellosis. Congenital diseases were 21.6%. In utero diagnosis could prevent some diseases and in utero treatment is possible for hydrocephalus and hydronephrosis. Screening programs postnatally could lead to treatment. 5.9% were malignancies such as leukemia, lymphoma, brain tumors, histocytosis, Wilm's tumor, Ewing sarcoma, and Hodgkin's disease. Early diagnosis is critical if mortality is to be reduced in this group, but medical advances are still needed. 2.9% are miscellaneous diseases such as poisoning, rheumatic diseases, marasmus, Reye's syndrome, nephrosis, rickets, and epilepsy. Most of these diseases are preventable, except for rheumatic inflammation of the heart. Recommended necessary steps to reduce infant mortality are: prenatal care, diagnosis and screening, intrauterine surgery; resuscitation and intensive care centers with modern equipment and trained personnel; national vaccination and screening programs; adequate public health measures and hygiene; parental education; and well-equipped hospitals to serve all regardless of income level.
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PMID:Pediatric mortality: an avoidable tragedy. 251 28

Ceftazidime (CAZ) intravenous injection was evaluated from fundamental and clinical aspects in neonates, and the results obtained are summarized below. Following a 60-minute intravenous drip infusion of CAZ at 10 mg/kg, the peak serum level was 19.8 micrograms/ml at 30 minutes after the completion of the infusion(half-life: 2.75 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 20 mg/kg, the mean peak serum levels of CAZ were 33.1-33.0 micrograms/ml. Mean levels at 6 hours were 5.2-6.7 micrograms/ml (half-life: 1.6-4.1 hours). Following 30 to 60-minute intravenous drip infusions of CAZ at 25-30 mg/kg, peak serum levels were 51.7-64.6 micrograms/ml (half-life: 1.6-2.05 hours). Dose response relationship was clearly observed in peak serum levels after intravenous drip infusion, and half-lives of serum CAZ levels in neonates aged 0-10 days tended to be longer than those in infants. Following intravenous administration of CAZ at 20-30 mg/kg, urinary excretion rates during the first 6 hours were 18.7-66.5%, and the rates were low in neonates compared to those in infants and children. Following a 60-minute intravenous drip infusion of CAZ at 28.7 mg/kg, the cerebrospinal fluid level was 5.0 micrograms/ml at 3 hours, the ratio of cerebrospinal fluid level to serum level was 22.5%. Eleven neonates were subjected to the present study. Clinical efficacy of CAZ was excellent in sepsis caused by A. anitratus, which showed higher sensitivity to CAZ compared with other cephem antibiotics of the third generation. In all of the other cases, including those of pertussis and acute urinary tract infections and in the prophylaxis of amniotic infection, clinical efficacy of CAZ was excellent or good. S. epidermidis, E. coli and A. anitratus, identified from cultures of pharynx, urine or blood, were rapidly eliminated during the CAZ treatment. Doses of CAZ used in the present study were 29-133 mg/kg/day, mostly in the range of 40-60 mg/kg/day. Durations of treatment ranged from 3 to 10 days. Neither systemic nor local adverse effect was observed, nor was any abnormality observed in laboratory findings.
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PMID:[Fundamental and clinical evaluations of ceftazidime in neonates]. 354 Mar 44

Studies on T-1982 (cefbuperazone), a new cephamycin antibiotic, were carried out in the field of pediatrics, and the following results were obtained. 1. Peak MIC of T-1982 against S. pyogenes (group A) lately isolated was 0.39 micrograms/ml, and the drug was active even against highly resistant strains of macrolides, lincomycin, tetracycline and chloramphenicol. 2. Peak MICs of T-1982 were 0.78 microgram/ml against B. pertussis, 0.2 microgram/ml against E. coli and less than or equal to 0.05 microgram/ml against K. oxytoca, and the drug was also active against ampicillin-resistant bacteria. 3. Serum levels and urinary excretions of T-1982 were investigated in 6 cases. When given at a dose of 20-28 mg/kg by 1 hour intravenous drip infusion, serum concentrations of T-1982 attained the peak level of 63.5-75.9 micrograms/ml at the end of administration and sustained the level of 0.9-2.6 micrograms/ml at 6 hours, the serum half-life (T 1/2) ranging 70-82 minutes. Approximately 20-72% of the dose were excreted in the active form into urine within 6 hours. 4. Twenty-seven cases of acute pediatric infections were treated with T-1982 mainly by intravenous drip infusion, and satisfactory clinical results were obtained in all the cases of angina lacunaris, bronchitis, bronchopneumonia, pertussis, sepsis caused by Serratia and acute urinary tract infections caused by ampicillin-resistant E. coli. The efficacy rate was 96.3%. In this study the drug was administered chiefly at a daily dose of 50-70 mg/kg 2-3 times a day for 2-12 days. 5. Gram-positive cocci (S. aureus, S. pneumoniae, S. pyogenes) and Gram-negative rods (H. influenzae, H. parainfluenzae P. vulgaris, B. pertussis, S. marcescens, E. coli) were eradicated by the treatment with T-1982. 6. No noticeable side effects were observed, except for temporary increase of eosinophil in 2 cases and slight elevation of GOT in 1 case.
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PMID:[Fundamental and clinical studies on T-1982 (cefbuperzone), a new cephamycin antibiotic, in the field of pediatrics]. 630 96

In the present study, auditory brainstem responses (ABR) were recorded in 60 high-risk neonates in the intensive care unit selected by the following criteria: Birth-weight less than 2000 g, hyperbilirubinemia requiring phototherapy or exchange transfusion, idiopathic respiratory distress syndrome, artificial ventilation, asphyxia, sepsis or meningitis, intracranial haemorrhage, neurological symptoms and potential ototoxic medication (aminoglycoides, furosemide). The infants tested ranged in gestational age from 27-44 weeks. The ABR testing was performed in a sound-proof room using the Madsen (ERA-74) equipment. Four infants did not reveal responses to 70 dB HL ("nonresponders"), and the total of 10 neonates (16.6%) had abnormal ABR-tests, when the physiological changes related to gestational age and conceptional age (gestational age plus the age after birth) were taken into account. The 10 neonates with abnormal tests were reexamined after discharge, and in six there were no improvement of threshold sensitivity. three of the "nonresponders" were retested several times within the two years after birth (one died at age 18 months of pertussis), and none of them revealed ABR at stimulus intensity of 70 dB HL. They all attend an audiological training program started at age of six months as a consequence of the early diagnosis of impaired auditory function. It is our opinion that a routine ABR-evaluation should be performed on high risk neonates (criteria mentioned above) in the newborn intensive care unit. Retesting of infants with abnormal responses within three months, and several times within the next two years if abnormal responses persist, is important. Transient impairment of auditory functions is not uncommon in these infants. However, the children with persisting hearing impairment should be discovered early to attend an early audiological training program.
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PMID:Auditory brainstem responses (ABR) in high-risk neonates. 718 Apr 39

An estimated 8 million infants and 2 million children and adults may die from tetanus during the 1990s despite efforts by the World Health Organization (WHO) to eliminate it by 1995. Vaccination to prevent postabortal and maternal tetanus has been neglected. The immunization of preschool children and of pregnant women has omitted adolescent girls, who are therefore at risk. Data collected on 1101 cases of maternal tetanus in developing countries between 1958 and 1990 indicated that 27% were attributed to postabortal and 67% to postpartum sepsis. In southeastern Nigeria where abortion rates are high, a high proportion of girls were also seronegative for tetanus antibodies. Many unvaccinated pregnant women cite the lack of money for obtaining vaccination when obtaining prenatal services. The WHO is promoting vaccination of women of reproductive age by screening their tetanus toxoid status, but adolescents are poorly covered because they are not regular attenders. Expressly targeting girls would be feasible, as it would require 5 injections providing protection for life. Even 4 injections may protect for 20 years if delivered at the end of primary school. Thus a school health service delivering tetanus vaccination may improve the vaccination of adolescent girls. This could be combined with distribution of vitamin A and antihelminthics whereby the response to the vaccine could be improved significantly. In addition, it has also been suggested that a late dose of an acellular pertussis vaccine and a second dose of measles vaccine given in adolescence would reduce the pool of susceptible girls, just as girls have been targeted for rubella vaccination. Implementation of tetanus vaccination would require local schools vaccination days, immunization cards, high potency primary vaccination, and tetanus boosters free of charge with a system to monitor antibody responses.
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PMID:Protecting adolescent girls against tetanus. 754 4

To estimate the incidence of Haemophilus influenzae type b (Hib) invasive disease in Italian infants we performed a prospective study in a cohort of newborns enrolled for a randomized trial on safety and efficacy of three pertussis vaccines and followed for onset of serious disease or pertussis. The overall cumulative incidence observed in 15,601 children was 51.3/100,000 for all invasive Hib infections and 38.4/100,000 for Hib meningitis, over 27 months of observation. The incidence density of all invasive Hib disease was 28.7/100,000 person-years, while meningitis occurred with an incidence of 21.5/100,000 person-years. Among the eight cases detected, six were meningitis, one sepsis, and one cellulitis. The child with sepsis died. The incidence and epidemiology of invasive Hib disease in Italy are comparable to those reported from other European countries. Cost-benefit analyses are needed for planning Italian vaccination policy.
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PMID:Incidence of invasive Haemophilus influenzae type b disease in Italian children. 906 83

Effects of GTP-binding proteins on the activation of secretory phospholipaseA2 (sPLA2) and cytosolic phospholipaseA2 (cPLA2) in rat liver during two different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. The results show that in the absence of G-protein modulator, hepatic sPLA2 and cPLA2 activities were activated by 40.8-46 and 91.6-105.8%, respectively, during early and late phases of sepsis. GTPgammaS and fluoroaluminate (AlF4-) stimulated sPLA2 and cPLA2 activities within each experimental group, i.e., control, early sepsis, and late sepsis. The GTPgammaS and AlF4(-)-stimulated sPLA2 and cPLA2 activities remained significantly elevated during early phase (22.3-65.6% increase) and late phase (32.5-109.1% increase) of sepsis. Further analyses demonstrate that cholera toxin significantly stimulated sPLA2 and cPLA2 activities within each experimental group, and that the cholera toxin stimulated sPLA2 and cPLA2 activities remained significantly higher during early phase (23.5-37% increase) and late phase (56.7-70% increase) of sepsis. In contrast, pertussis toxin significantly inhibited sPLA2 and cPLA2 activities within each experimental group, and that the pertussis toxin-inhibited sPLA2 and cPLA2 activities remained significantly higher in early septic (57-68.5% increase) and late septic (34.6-45.5% increase) experiments. These data demonstrate that cholera toxin-sensitive G alpha s and pertussis toxin-sensitive G alpha i were both involved in the activation of sPLA2 and cPLA2 activities in rat liver during the progression of sepsis.
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PMID:GTP-binding protein mediated phospholipase A2 activation in rat liver during the progression of sepsis. 987 54


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