UMLS:C0036690 - FACTA Search

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

Despite intensive efforts to increase our knowledge of the inflammatory pathways involved in the pathogenesis of sepsis, several clinical trials of agents aimed at modulating the immune response of the host, such as anti-endotoxin antibodies, anti-tumour necrosis factor (TNF) antibodies and soluble TNF receptors, have failed to disclose any definite clinical benefit. The same applies to the administration of low-dose hydrocortisone as well as intense glucose control by continuous insulin infusion. Macrolides are a traditional class of antimicrobials proven to act as modulators of the host's response in chronic lung disorders such as diffuse panbronchiolitis and cystic fibrosis. The favourable outcome of community-acquired pneumonia treated with the combination of a beta-lactam and a macrolide is partly attributed to their immunomodulatory properties. Based on favourable responses to intravenous administration of clarithromycin in experimental models of sepsis by susceptible and multidrug-resistant Gram-negative isolates, a randomised clinical trial was conducted in 200 patients with ventilator-associated pneumonia (VAP) and sepsis (http://www.clinicaltrials.gov; NCT00297674). Clarithromycin was administered at a dose of 1g within 1h of infusion for three consecutive days. Analysis revealed a considerable benefit of clarithromycin in shortening the time to resolution of VAP and to de-intubation from mechanical ventilation. The relative risk of death by septic shock and multiple organ dysfunction was 19.00 among placebo-treated patients; it was reduced to 3.78 among clarithromycin-treated patients. These results render new perspectives for the future application of clarithromycin as an immunomodulatory therapy of sepsis.
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PMID:Immunomodulatory therapies for sepsis: unexpected effects with macrolides. 1870 49

Sphingolipids such as sphingosine-1-phosphate (S1P), ceramide, or sphingomyelin are essential constituents of plasma membranes and regulate many (patho)physiological cellular responses inducing apoptosis and cell survival, vascular permeability, mast cell activation, and airway smooth muscle functions. The complexity of sphingolipid biology is generated by a great variety of compounds, diverse receptors, and often antagonistic functions of different sphingolipids. For instance, apoptosis is promoted by ceramide and prevented by S1P, and pulmonary vascular permeability is increased by S1P2/3 receptors and by ceramide, whereas S1P1 receptors stabilize barrier integrity. Several enzymes of the sphingolipid metabolism respond to external stimuli such as sphingomyelinase isoenzymes that are activated by many stress stimuli and the sphingosine kinase isoenzymes that are activated by allergens. The past years have provided increasing evidence that these processes contribute to pulmonary disorders including asthma, chronic obstructive pulmonary disease, acute lung injury, and cystic fibrosis. Sphingolipid metabolism offers several novel therapeutic targets for the treatment of lung diseases such as emphysema, asthma, cystic fibrosis, respiratory tract infection, sepsis, and acute lung injury.
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PMID:Sphingolipids in the lungs. 1875 26

Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical to resolution of inflammation. Impaired efferocytosis is associated with an unfavorable outcome from inflammatory diseases, including acute lung injury and pulmonary manifestations of cystic fibrosis. High mobility group protein-1 (HMGB1), a nuclear nonhistone DNA-binding protein, has recently been found to be secreted by immune cells upon stimulation with LPS and cytokines. Plasma and tissue levels of HMGB1 are elevated for prolonged periods in chronic and acute inflammatory conditions, including sepsis, rheumatoid arthritis, acute lung injury, burns, and hemorrhage. In this study, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phosphatidylserine (PS) is directly involved in the inhibition of phagocytosis by HMGB1, as blockade of HMGB1 by PS eliminates the effects of HMGB1 on efferocytosis. Confocal and fluorescence resonance energy transfer demonstrate that HMGB1 interacts with PS on the neutrophil surface. However, HMGB1 does not inhibit PS-independent phagocytosis of viable neutrophils. Bronchoalveolar lavage fluid from Scnn(+) mice, a murine model of cystic fibrosis lung disease which contains elevated concentrations of HMGB1, inhibits neutrophil efferocytosis. Anti-HMGB1 Abs reverse the inhibitory effect of Scnn(+) bronchoalveolar lavage on efferocytosis, showing that this effect is due to HMGB1. These findings demonstrate that HMGB1 can modulate phagocytosis of apoptotic neutrophils and suggest an alternative mechanism by which HMGB1 is involved in enhancing inflammatory responses.
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PMID:High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. 1876 81

The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.
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PMID:Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. 1897

Three patients with end-stage cystic fibrosis (CF) underwent single lung transplantation (SLT) with contralateral pneumonectomy. In the first case, contralateral pneumonectomy (CP) was performed before SLT. The patient is alive with no signs of infection or rejection. For the other 2 cases, CP was performed after SLT. One patient died 8 months later with septicemia; the other patient died after 10 days because of complicated bronchopleural fistula and infection of the pneumonectomy space. SLT can be a good option for some patients with CF. The outcome is good when CP is done before SLT. However, CP must be done simultaneously with SLTX.
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PMID:Single-lung transplantation for cystic fibrosis and metachronus pneumonectomy: case reports. 1910 Apr 46

P. aeruginosa is part of a large group of free-living bacteria that are ubiquitous in the environment. This organism is often found in natural waters such as lakes and rivers in concentrations of 10/100 mL to >1,000/100 mL. However, it is not often found in drinking water. Usually it is found in 2% of samples, or less, and at concentrations up to 2,300 mL(-1) (Allen and Geldreich 1975) or more often at 3-4 CFU/mL. Its occurrence in drinking water is probably related more to its ability to colonize biofilms in plumbing fixtures (i.e., faucets, showerheads, etc.) than its presence in the distribution system or treated drinking water. P. aeruginosa can survive in deionized or distilled water (van der Jooij et al. 1982; Warburton et al. 1994). Hence, it may be found in low nutrient or oligotrophic environments, as well as in high nutrient environments such as in sewage and in the human body. P. aeruginosa can cause a wide range of infections, and is a leading cause of illness in immunocompromised individuals. In particular, it can be a serious pathogen in hospitals (Dembry et al. 1998). It can cause endocarditis, osteomyelitis, pneumonia, urinary tract infections, gastrointestinal infections, and meningitis, and is a leading cause of septicemia. P. aeruginosa is also a major cause of folliculitis and ear infections acquired by exposure to recreational waters containing the bacterium. In addition, it has been recognized as a serious cause of keratitis, especially in patients wearing contact lenses. P. aeruginosa is also a major pathogen in burn and cystic fibrosis (CF) patients and causes a high mortality rate in both populations (MOlina et al. 1991; Pollack 1995). P. aeruginosa is frequently found in whirlpools and hot tubs, sometimes in 94-100% of those tested at concenrations of <1 to 2,400 CFU/mL. The high concentrations found probably result from the relatively high temperatures of whirlpools, which favor the growth of P. aeruginosa, and the aeration which also enhances its growth. The organism is usually found in whirlpools when the chlorine concentrations are low, but it has been isolated even in the presence of 3.00 ppm residual free chlorine (Price and Ahearn 1988). Many outbreaks of folliculitis and ear infections have been reportedly associated with the use of whirlpools and hot tubs that contain P. aeruginosa (Ratnam et al. 1986). Outbreaks have also been reported from exposure to P. aeruginosa in swimming pools and water slides. Although P. aeruginosa has a reputation for being resistant to disinfection, most studies show that it does not exhibit any marked resistance to the disinfectants used to treat drinking water such as chlorine, chloramines, ozone, or iodine. One author, however, did find it to be slightly more resistant to UV disinfection than most other bacteria (Wolfe 1990). Although much has been written about biofilms in the drinking water industry, very little has been reported regarding the role of P. aeruginosa in biofilms. Tap water appears to be a significant route of transmission in hospitals, from colonization of plumbing fixtures. It is still not clear if the colonization results from the water in the distribution system, or personnel use within the hospital. Infections and colonization can be significantly reduced by placement of filters on the water taps. The oral dose of P. aeruginosa required to establish colonization in a healthy subject is high (George et al. 1989a). During dose-response studies, even when subjects (mice or humans) were colonized via ingestion, there was no evidence of disease. P. aeruginosa administered by the aerosol route at levels of 10(7) cells did cause disease symptoms in mice, and was lethal in aerosolized doses of 10(9) cells. Aerosol dose-response studies have not been undertaken with human subjects. Human health risks associated with exposure to P. aeruginosa via drinking water ingestion were estimated using a four-step risk assessment approach. The risk of colonization from ingesting P. aeruginosa in drinking water is low. The risk is slightly higher if the subject is taking an antibiotic resisted by P. aeruginosa. The fact that individuals on ampicillin are more susceptible to Pseudomonas gastrointestinal infection probably results from suppression of normal intestinal flora, which would allow Pseudomonas to colonize. The process of estimating risk was significantly constrained because of the absence of specific (quantitative) occurrence data for Pseudomonas. Sensitivity analysis shows that the greatest source of variability/uncertainty in the risk assessment is from the density distribution in the exposure rather than the dose-response or water consumption distributions. In summary, two routes appear to carry the greatest health risks from contacting water contaminated with P. aeruginosa (1) skin exposure in hot tubs and (2) lung exposure from inhaling aerosols.
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PMID:Risk assessment of Pseudomonas aeruginosa in water. 1948 89

The double-edged sword of antibiotic use in the fight against disease has saved countless lives at the cost of an escalation in pathogenic bacteria with increased resistance to multiple antibiotic classes. Reduction of resistance is a complicated multi-step endeavor that requires a sustained international effort of reduced utilization, infection control and development of effective and economical antimicrobial agents. The carbapenems are beta-lactam antibiotics that are stable to most beta-lactamases. They have potent bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic bacteria as well as against anaerobic bacteria, while being safe, efficacious and tolerable. The use of carbapenems in hospitals has therefore been restricted to the empirical treatment of critical patients with a variety of serious infections, e.g., nosocomial pneumonia, septicemia, meningitis and cystic fibrosis. This article reviews patents claiming carbapenem antibacterial agents published from 2004-2008.
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PMID:An update on the synthesis and antibacterial effects of carbapenems. 1992 40

Linezolid is the first oxazolidinone agent introduced into clinical practice for use against Gram-positive bacteria that are resistant to beta-lactams and glycopeptides, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). An optimal antibacterial effect is achieved when plasma drug concentrations are above the minimum inhibitory concentration (MIC) [T>MIC] for the entire length of treatment and the ratio between the area under the plasma concentration-time curve (AUC) and the MIC (AUC/MIC) is greater than 100, as is most commonly obtained with administration of the standard dosage of linezolid 600 mg twice daily. A wide tissue distribution, including the CNS and respiratory tract, nearly linear pharmacokinetics and good tolerability are additional characteristics of linezolid. However, variability in the drug pharmacokinetics associated with clinical conditions (e.g. sepsis, burn injuries, end-stage renal disease, cystic fibrosis), haemodialysis and/or young age may lower the T>MIC and the AUC/MIC ratio, thus impairing both antibacterial activity and prevention of mutants. In most cases, changes in the dosage or in the schedule of administration (e.g. an additional [third] daily dose) may improve the effectiveness of linezolid. It is worth noting that linezolid could affect its own metabolism as a result of protein synthesis inhibition in mitochondria, and this could lead to high plasma concentrations and an increased risk of non-negligible toxicities. The latter may be reported during long-term administration of linezolid or in the presence of some pathological conditions (e.g. renal disease or kidney transplantation) associated with high plasma drug concentrations. Therefore, treatment optimization should be considered a requirement for more effective and tolerable use of the drug, particularly in special populations.
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PMID:Pharmacological issues of linezolid: an updated critical review. 2052 4

Cystic fibrosis (CF) lung transplant recipients infected with Burkholderia cenocepacia have a worse survival rate after lung transplantation than those who are not infected with this organism. The decreased survival is predominantly due to recurrent B. cenocepacia infection, with the majority of affected recipients succumbing within 3 months after transplant. B. cepacia complex (BCC) sepsis is one of the defining criteria for cepacia syndrome, an almost universally fatal necrotizing pneumonic illness. We report 2 CF patients who were long-term survivors of B. cenocepacia sepsis after lung transplantation. The aim of this report is to demonstrate that, although survival of B. cenocepacia sepsis after lung transplantation is extremely uncommon, with aggressive multidisciplinary management, long-term survival remains a realistic objective.
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PMID:Survival of Burkholderia cepacia sepsis following lung transplantation in recipients with cystic fibrosis. 2055 38

Exopolysaccharides (EPSs) from the Burkholderia genus are proposed to be involved in pathological conditions in humans, such as cystic fibrosis and septicemia, as well as in the stability of soil aggregates. Hence, considering that the conformational and dynamic aspects of such EPSs may influence their biological activity, the current work employs a series of molecular dynamics simulations on di-, oligo-, and polysaccharide fragments of three EPSs, from Burkholderia caribensis, Burkholderia cepacia, and Burkholderia pseudomallei, with previously determined NOE data, to obtain a conformational description of such EPSs at the atomic level. As the obtained results show good agreement with the experimental data, pointing to the adequacy of the employed methodology to accurately describe the dynamics of polysaccharides, the strategy was also employed to predict the conformational behavior of an additional compound, from Burkholderia tropica, for which NOE signals are not available. Taking into account the potential importance of EPSs on the interaction of Burkholderia bacteria with distinct environments, it may be expected that a greater understanding of their structural aspects may contribute to controlling their pathological roles and potential agricultural applications.
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PMID:Solution conformation and dynamics of exopolysaccharides from Burkholderia species. 2063 74

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