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)

Sepsis increases phosphocreatine (PCr) breakdown and reduces PCr stores in skeletal muscle. To determine if systemic infection impairs mitochondrial function, in vivo 13P magnetic resonance spectroscopy (31P MRS) studies of the gastrocnemius muscle were performed in virus-free male Wistar rats 24 or 48 hr after cecal ligation and 18-gauge needle single puncture (24 degrees CLP, n = 16; 48 degrees CLP, n = 15) or sham operation (24 degrees SHAM, n = 18; 48 degrees SHAM, n = 13). Physiologic saline (6 ml/100 g body wt) was injected intraperitoneally for fluid resuscitation. Water but no food was allowed in all animals. High resolution (8.45 Tesla) 31P MRS spectra, obtained at rest and during exercise using a 1.4-cm surface coil, were used to calculate PCr/ATP, PCr/P(i) ratios, and intracellular pH. Steady-state muscle exercise was induced by supramaximal sciatic nerve stimulation at 10 Hz for 10 min. Recovery of PCr/(PCr + P(i)) ratios after exercise was fitted to a monoexponential curve. The resultant function was used to calculate the half time for PCr recovery, the initial PCr resynthesis rate, and the maximal oxidative ATP synthesis rate, which reflect the rephosphorylation of ADP and are therefore measures of mitochondrial oxidative capacity. PCr/ATP ratios decreased by 12 and 11%, 24 and 48 hr after CLP, respectively. The PCr/P(i) ratios decreased incrementally (7% in 24 degrees CLP vs 23% in 48 degrees CLP animals). Twenty-four hours after operation the half time for PCr recovery was shortened while the initial PCr resynthesis rate and maximal oxidative ATP synthesis rate were accelerated in CLP animals compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The duration of infection modifies mitochondrial oxidative capacity in rat skeletal muscle. 763 Jan 22

The authors studied 37 term neonates (38-42 gestational weeks) at 1-11 days after central nervous system insult to determine whether proton magnetic resonance spectroscopy (1H-MRS) of the occipital gray/parietal white matter was useful in predicting outcomes. Etiologies included asphyxia, 18; sepsis/meningitis, 8; metabolic disorders, 5; stroke, 4; and trauma, 2. 1H-MRS data (1.5T; 8 cm3 vol, stimulated echo acquisition mode sequence, TE = 20 ms, TR = 3000 ms) were expressed as metabolite peak area ratios (NAA/Cr, NAA/Cho, Cho/Cr) and the presence or absence of lactate. Outcomes were assessed at 6 to 12 months post-insult using the Pediatric Cerebral Performance Scale and were dichotomized as follows: good/moderate outcome (good, mild or moderate disability) or poor outcome (severe disability, persistent vegetative state, death). Neonates with poor outcomes had significantly lower NAA/Cho and significantly higher Cho/Cr ratios in the occipital region, as compared with patients with good/moderate outcomes. No neonates with good/moderate outcomes had metabolite ratios that exceeded 2 standard deviations from the mean. In addition, the absence of lactate on 1H-MRS correlated with a good/moderate outcome. The study also showed that 1H-MRS metabolite ratio data, added to either the Sarnat or EEG scores, enhanced the correlation between these prognostic factors and outcomes. 1H-MRS provides additional objective data early after a wide variety of perinatal neurologic insults to enhance outcome prediction.
 ...
PMID:Prognostic value of 1H-MRS in perinatal CNS insults. 943 94

A retrospective analysis of the clinical and microbiological efficacy and safety of cefoperazone/sulbactam in the treatment of 39 cardiosurgical patients operated under the conditions of artificial circulation is presented. The age of the adult patients (n = 28) varied from 44 to 58 years and that of the pediatric patients varied from 4 months to 6 years. Antibacterial therapy of 26 patients was needed because of postoperative infectious complications, such as nosocomial pneumonia in 22 patients and sepsis in 4 patients. The antibacterial therapy with cefoperazone/sulbactam in 9 patients was performed during the operation because of active infectious endocarditis. In 4 patients there were observed clinical and laboratory signs of infection without the infection foci. The initial empirical therapy with cefoperazone/sulbactam was applied to 14 patients (group 1) and the target-aimed therapy based on the data of the pathogen susceptibility to cefoperazone/sulbactam was used in 6 patients (group 2). 19 patients (group 3) were treated with cefoperazone/sulbactam because of the fail of the previous antibacterial therapy, including the 4th generation cephalosporins and carbapenems as well. Cefoperazone/sulbactam was used in the monotherapy of 15 cases (38%). Cefoperazone/sulbactam showed high efficacy in the treatment of severe nosocomial infections and infectious endocarditis (in combination with vancomycin or linezolid). It amounted to 93, 100 and 79% in groups 1, 2 and 3 respectively, the total of 94%. The results of the microbiological assay were evident of the cefoperazone/sulbactam high activity against the problem gram nagative isolates of Klebsiella pneumoniae (n = 12), Acinetobacter baumanii (n = 4), Pseudomonas aeruginosa (n = 4) and Stenotrophomonas maltophilia (n = 5). Adverse reactions were stated in 2 patients (5%), 1 case of urticaria requiring discontinuation of the drug use. Many of the patients proved to be colonized by MRS before the therapy with cefoperazone/sulbactam. The high probability of staphylococcal superinfection required combination of cefoperazone/sulbactam with antistaphylococcal agents, such as rifampicin, fusidin, vancomycin, linezolid. The best results were provided by the target-aimed therapy based on the microbiological monitoring.
 ...
PMID:[Clinical experience with the treatment of severe nosocomial infections by inhibitor-protected 3rd generation cephalosporin cefoperazone/sulbactam]. 1639 38

The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-alpha 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5'N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
 ...
PMID:A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. 1677 64

We reported previously that hypertonic saline (HS) treatment can prevent or upregulate the function of polymorphonuclear neutrophils (PMNs) via A2a-type adenosine receptors or A3-type adenosine receptors (A3R), respectively. A3R translocate to the cell surface upon PMN stimulation, and thus, HS promotes PMN responses under conditions of delayed HS treatment. Here we investigated if inhibition of A3R improves the protective effects of HS resuscitation in a mouse sepsis model. We found that HS nearly triples extracellular adenosine concentrations in whole blood and that inhibition of A3R with the selective antagonist MRS-1191 dose dependently improves the inhibitory effect of HS. MRS-1191 at a concentration of 1 nM enhanced the inhibitory effect of HS and reduced stimulatory effects of delayed HS treatment. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that MRS-1191 reduces acute lung injury and PMN accumulation in lung tissue. Whereas delayed HS treatment (4 mL/kg of 7.5% NaCl) of mice 1 h after CLP aggravated PMN accumulation, lung tissue damage, and mortality 24 h after CLP, infusion of MRS-1191 (2 ng/kg body weight) combined with HS reduced these detrimental effects of delayed HS treatment. Our data thus show that A3 receptor antagonists can strengthen the beneficial effects of HS resuscitation by avoiding stimulatory adverse effects that result from delayed HS administration.
 ...
PMID:A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation. 2066 Nov 81

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections.
...
PMID:Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II. 2424 61

Bacteremia continues to result in significant morbidity and mortality, particularly among neonates. There is scarce data on neonatal bacteremia in among Iranian neonates. In this study, we determined neonatal bacteremia isolates and their antibiotic resistance pattern in neonatal insensitive care unit at Beasat hospital, Sanandaj, Iran. During one year, all neonates admitted to the NICU were evaluated. Staphylococcal isolates were subjected to determine the prevalence of MRS and mecA gene. A total of 355 blood cultures from suspected cases of sepsis were processed, of which 27 (7.6%) were positive for bacterial growth. Of the 27 isolates, 20 (74%) were Staphylococcus spp as the leading cause of bacteremia. The incidence of Gram negative bacteria was 04 (14.8%). The isolated bacteria were resistant to commonly used antibiotics. Maximum resistance among Staphylococcus spp was against Penicillin, and Ampicillin. In our study, the isolated bacteria were 7.5 % Vancomycin and Ciprofloxacin sensitive. Oxacillin disk diffusion and PCR screened 35% and 30% mec a positive Staphylococcus spp. The spectrum of neonatal bacteremia as seen in NICU at Beasat hospital confirmed the importance of pathogens such as Staphylococcus spp. Penicillin, Ampicillin and Cotrimoxazol resistance was high in theses isolates with high mecA gene carriage, probably due to antibiotic selection.
 ...
PMID:Neonatal bacteriemia isolates and their antibiotic resistance pattern in neonatal insensitive care unit (NICU) at Beasat Hospital, Sanandaj, Iran. 2490 12

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.
 ...
PMID:Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis. 3071 92