Outer membrane protein A inhibits the degradation of caspase-1 to regulate NLRP3 inflammasome activation and exacerbate the Acinetobacter baumannii pulmonary inflammation.

Acinetobacter baumannii (A. baumannii), one of the major pathogens that causes severe nosocomial infections, is characterised by a high prevalence of drug resistance. It has been reported that A. baumannii triggers the NOD-like receptor 3 (NLRP3) inflammasome, but the role of its virulence-related outer membrane protein A (ompA) remains unclear. Therefore, this study aimed to explore the effects of ompA on the NLRP3 inflammasome and its underlying molecular mechanisms. Results showed that ompA enhanced inflammatory damage, which was reduced as a result of knockout of the ompA gene. Additionally, ompA-stimulated expression of NLRP3 inflammasome was significantly blocked by silencing caspase-1, but activation of NLRP3 inflammasome was not altered after silencing ASC; this indicated that ompA was dependent on the caspase-1 pathway to activate the inflammatory response. Simultaneously, the wild-type (WT) strains triggered NLRP3 inflammasome after inhibition of caspase-1 degradation by proteasome inhibitor MG-132, aggravating tissue damage. These findings indicated that ompA may be dependent on the caspase-1 pathway to enhance inflammation and exacerbate tissue damage. Taken together, these results confirmed a novel capsase-1-modulated mechanism underpinning ompA activity, which further reveals the NLRP3 inflammasome pathway as a potential immunomodulatory target against A. baumannii infections.

The -159C/T polymorphism in the CD14 gene and the risk of asthma: a meta-analysis.

The -159C/T polymorphism in the CD14 gene has been implicated in susceptibility to asthma, but a large number of studies have reported inconclusive results. The aim of this study is to investigate the association between the -159C/T polymorphism in the CD14 gene and the risk of asthma by meta-analysis. We searched Pubmed, Embase, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on April 20, 2010). Statistical analysis was performed by using the softwares Revman 4.2 and STATA 10.0. A total of 17 case-control studies in 17 articles (4,246 cases and 3,631 controls) were included in this meta-analysis. There was no association between this polymorphism and asthma risk in combined analyses (odds ratio (OR) = 0.86 and 95% confidence interval (95% CI) = 0.72-1.02, P = 0.09 for TC + TT vs. CC). In the subgroup analysis by age, ethnicity, and atopic status, no significant associations of asthma risks were obtained from age groups, ethnic groups, and atopic groups for TC + TT vs. CC comparison. For atopic population, significant decreased atopic asthma risks were found among Asian population (OR = 0.69, 95% CI 0.52-0.92, P = 0.01) and children population (OR = 0.69, 95% CI 0.54-0.89, P = 0.0004) for TC + TT vs. CC comparison. This meta-analysis suggests that CD14 is a candidate gene for atopic asthma susceptibility. The -159C/T polymorphism may be a protective factor for atopic asthma in Asian and children. More studies are needed to validate these associations.

Outer membrane protein a in Acinetobacter baumannii induces autophagy through mTOR signalling pathways in the lung of SD rats.

Outer membrane protein A (OmpA) of Acinetobacter baumannii (A. baumannii) is associated with autophagy, which plays an important role in its pathogenicity. However, its exact pathophysiological role in the process of lung tissue cell autophagy remains unclear. In this study, animal and cell infection models were established by wild A. baumannii strain and An OmpA knockout mutant (OmpA-/- A. baumannii) strain. The expression levels of markers autophagy, histological change, cell viability and protein expression levels of inflammatory cytokines were examined. OmpA-/-A. baumannii was successfully constructed. The capacities of bacterial adhesion and invasion to host cells increased more obviously in the AB group and the AB + Rapa group than in the OmpA-/- AB group and AB + CQ group. The AB group and AB + Rapa group could produce double membrane vacuoles, endoplasmic reticulum dilation, mitochondrial ridge rupture, and mitochondrial vacuoles. OmpA could lead to increased LC3, AMPK, and PAMPK protein release, and decreased levels of P62, mTOR and pmTOR proteins in vivo and in vitro. OmpA caused lung pathology and the release of inflammatory cytokines. A. baumannii OmpA promotes autophagy in lung cells through the mTOR signalling pathway, which increases the bacterial colonization ability in the double-layer membrane autophagosome formed by the autophagy reaction to escape the clearance of bacteria by the host, promote the release of inflammatory mediators and aggravate the damage to the host.

Polymorphisms in the transforming growth factor-beta1 gene and the risk of asthma: A meta-analysis.

BACKGROUND AND OBJECTIVE: Polymorphisms in the transforming growth factor-beta1 (TGF-beta1) gene have been implicated in susceptibility to asthma, but a large number of studies have reported inconclusive results. A meta-analysis was performed to investigate the association between polymorphisms in the TGF-beta1 gene and asthma susceptibility. METHODS: Searches were performed of Medline (Ovid), PubMed, the Chinese Biological Medicine Database (CBM), the Chinese Journals Full-text Database (CNKI), the Cochrane Library Database and the Web of Science, covering all papers published up to 30 April 2009. Statistical analysis was performed using Revman4.2.8 and STATA10.0 software. RESULTS: Two polymorphisms (-509C/T and 915G/C(G25C)) were investigated in 14 studies, involving 2979 asthma patients and 4941 control subjects. The results showed that individuals carrying the -509T allele (TT+TC) had a 36% increased risk of asthma, when compared with homozygotes (-509CC) (OR 1.36, 95% CI: 1.12-1.65). However, there was no significant association with risk of asthma in carriers of the 915C allele (GC+CC) compared with 915GG homozygotes (OR 1.05, 95% CI: 0.65-1.70). In a subgroup analysis by ethnicity, the risk of asthma associated with the -509T allele was significantly elevated among Asians (OR 1.50, 95% CI: 1.04-2.17) but not Caucasians (OR 1.16, 95% CI: 1.00-1.36). In a subgroup analysis by age, the -509T allele was associated with a significantly elevated risk of asthma among adults (OR 1.45, 95% CI: 1.09-1.92) but not children (OR 1.19, 95% CI: 0.96-1.46). CONCLUSIONS: This meta-analysis suggested that the -509C/T polymorphism in the TGF-beta1 gene may be a risk factor for asthma. To further evaluate gene-gene and gene-environment interactions between polymorphisms in the TGF-beta1 gene and asthma susceptibility, more studies involving thousands of patients are required.

IL-33 Treatment Attenuates the Systemic Inflammation Reaction in Acinetobacter baumannii Pneumonia by Suppressing TLR4/NF-κB Signaling.

Interleukin (IL)-33 treatment has been reported to reduce mortality in a rat model of sepsis, and the present study aimed to determine whether this effect of IL-33 is achieved through a reduction in the systemic inflammatory response in Acinetobacter baumannii pneumonia. After induction of pneumonia, rats were treated with normal saline or IL-33, and mortality over 5 days was recorded. Inflammation within lung tissues was evaluated by hematoxylin and eosin staining as well as measurement of the concentrations of IL-8 and tumor necrosis factor alpha (TNF-α) in the bronchoalveolar lavage fluid (BALF) and plasma by enzyme-linked immunosorbent assay. In addition, the expression of Toll-like receptor 4 (TLR4), ST2, and nuclear factor kappa B (NF-κB) in rat lung tissues was assessed by western blotting. The result showed that the mortality rate and systemic inflammation were significantly increased in rats upon infection with A. baumannii, as evidenced by significant increases in the IL-8 and TNF-α levels in BALF and plasma as well as increased NF-κB activity and TLR4 expression in rat lung tissues. Importantly, IL-33 (1 µg/kg) treatment significantly decreased mortality and pulmonary inflammation in A. baumannii-infected rats. Moreover, IL-33 treatment suppressed the elevation of IL-8 and TNF-α levels and inhibited TLR4 expression and NF-κB activation. Overall, these results suggest that IL-33 may decrease the mortality and inhibit the systematic inflammatory response associated with A. baumannii pneumonia by suppressing TLR4/NF-κB signaling.

Endobronchial anthracofibrosis: possibly a new indication of aggressive treatment for active endobronchial tuberculosis.

Anthracofibrosis, which was defined as a luminal narrowing associated with overlying anthracotic mucosa on bronchoscopy, has been infrequently reported. Recently, we have identified a case of patient who had a history of pulmonary tuberculosis (TB), manifested left main bronchial stenosis and hyperpigmentation. Despite repeated and multiple cryotherapy, the condition was still progressing. Given to the potential relationship between active endobronchial tuberculosis (EBTB) and anthracofibrosis, the patient received a diagnostic anti-tuberculosis (anti-TB) treatment due to initial failed cryotherapy, resulting in improvement of hyperpigmentation and stenosis of the left main bronchus. Eventually, the patient recovered well with regular anti-TB combined with intermittent cryotherapy. Our study suggests that even without etiological evidence, there might be an indication of therapeutic trial of anti-TB medication in case of repeated bronchial stenosis due to anthracofibrosis in patients with past history of TB and other causes are excluded. Yet, the recommendation of aggressive treatment should reply on the effect of diagnostic treatment and further research.

[Comparison of value of GRACE, APACHEII and REMS for early prognosis of death in patients with acute myocardial infarction].

OBJECTIVE: To evaluate and compare the predictive value of short-term risk of death of global registry of acute coronary events (GRACE) risk scores, acute physiology and chronic health evaluation II (APACHEII) scores and rapid emergency medicine score (REMS) in patients with acute myocardial infarction (AMI). METHODS: A retrospective review of clinical data of 390 patients with AMI admitted from October 2012 to March 2013 in emergency department and cardiology care unit (CCU) in Guizhou People's Hospital were performed. The lowest scores within 24 hours of GRACE risk score, APACHEII risk score, and REMS risk score, respectively, for each patient were recorded. Mortality rate within 30 days after onset was calculated. Prediction of the mortality rate of AMI within 30 days as made in three scoring systems was compared. RESULTS: A total of 54 patients died from cardiovascular disease within 30 days. GRACE risk scores, APACHEII scores, and REMS risk scores were higher in non-survivors as compared with that of survivors (GRACE: 206.09±24.67 vs. 150.17±25.72, t=-4.349, P=0.000; APACHEII: 15.81±7.60 vs. 7.50±2.83, t=-4.182, P=0.000; REMS: 7.11±2.70 vs. 5.38±2.59, t=-2.345, P=0.020). Area under the receiver operator characteristic curve (ROC curve) for GRACE risk scores, APACHEII risk scores and REMS in patients with AMI died from cardiac vascular disease in 30 days were 0.862 [95% confidence interval (95%CI) 0.76-0.95, P=0.000], 0.825 (95%CI 0.71-0.93, P=0.002) and 0.615 (95%CI 0.46-0.77, P=0.192), sensitivity of three kinds of scoring system was 92.32%, 76.91%, 69.26%, respectively, with specificity of 66.23%, 77.84%, 54.02% respectively. CONCLUSIONS: GRACE and APACHEII scores for patients with AMI risk of short-term death showed more accurate in predicting early than GRACE scores, and REMS for AMI risk of short-term death did not have predictive value.

C-reactive protein levels predict bacterial exacerbation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) causes a high rate of morbidity worldwide and predicting a bacterial cause of an exacerbation of COPD is difficult. METHOD: In this study, patient serum was obtained and C-reactive protein (CRP) levels were measured using an automated latex-enhanced turbidimetric assay. Sputum samples were obtained and evaluated microscopically. The relationship between CRP and the bacterial colonies in sputum in 81 patients with an exacerbation of COPD was assessed. Receiver operating characteristic (ROC) curves and the respective areas under the curve (AUCs) were calculated. Data from 64 patients with bacterial acute exacerbation of COPD (AECOPD) were compared with those of 37 patients with no documented bacterial AECOPD. Results categorized according to the nature of sputum as mucoid or purulent were also compared. RESULTS: High median CRP levels were observed in bacterial AECOPD compared with nonbacterial AECOPD. The ideal cutoff point for distinguishing patients with bacterial AECOPD from those with nonbacterial AECOPD was 19.65 mg/L (sensitivity, 78.18%; specificity, 84.61%; AUC, 0.832). In patients with mucoid sputum, the cutoff point was 15.21 mg/L and the area under the ROC curve 0.86, with a sensitivity of 81.5% and a specificity of 77.8%. Purulent sputum had a significantly higher CRP level than mucoid sputum, but with an AUC of only 0.617 (95% confidence interval, 0.49-0.74) to diagnosis bacterial AECOPD. CONCLUSIONS: In adult patients with symptoms of AECOPD, an elevated serum CRP level of >19.6 mg/L indicates bacterial exacerbation. In patients with AECOPD with mucoid sputum, an elevated CRP level of >15.21 mg/L indicates bacterial infection, which may be a useful clinical marker for therapy of this disease.

Diversity of SCCmec elements in methicillin-resistant coagulase-negative staphylococci clinical isolates.

BACKGROUND: Methicillin-resistant coagulase-negative staphylococci (MR-CoNS) are opportunistic pathogens and serve as a large reservoir of staphylococcal cassette chromosome mec (SCCmec). Characterization of SCCmec in MR-CoNS can generate useful information on the mobilization and evolution of this element. METHODOLOGY/PRINCIPAL FINDINGS: Non-repetitive MR-CoNS clinical isolates (n = 84; 39 S. epidermidis, 19 S. haemolyticus, 9 S. hominis, 6 S. capitis, 4 S. warneri, 2 S. cohnii, 2 S. saprophyticus, 1 S. kloosii, 1 S. simulans and 1 S. massiliensis) were collected. All isolates could grow on plates with 4 mg/L cefoxitin and all had mecA as detected by PCR. Strain typing using RAPD and ERIC-PCR revealed that almost all isolates were of different strains. SCCmec typing was performed using multiplex PCR published previously. For isolates in which SCCmec could not be typed, the mec complex classes were determined by additional PCR and the ccr genes were amplified with published or newly-designed primers and then sequenced. SCCmec types were assigned for 63 isolates by multiplex PCR and were assigned for 14 other isolates by PCR targeting mec and ccr. Among 77 isolates with determined SCCmec types, 54 had a single type, including type III (n = 19), IV (n = 14), V (n = 10), II (n = 2), I (n = 1), VIII (n = 1) and five unnamed types (n = 7), while 23 isolates had two types, III+V (n = 12), II+V (n = 8), II+IV (n = 2) or IV+V (n = 1). The five unnamed types were assigned UT1 (class A mec, ccrA1/ccrB4), UT2 (class C1 mec, ccrA4/ccrB4), UT3 (class A mec, ccrA5/ccrB3), UT4 (class C2 mec, ccrA2/ccrB2 plus ccrC1) and UT5 (class A mec, ccrA1/ccrB1 plus ccrC1). CONCLUSIONS/SIGNIFICANCE: SCCmec types III, IV and V were prevalent in MR-CoNS and many isolates could harbor more than one type. Several new types of SCCmec were identified, highlighting the great genetic diversity and the need of developing classification schemes for SCCmec in MR-CoNS.