Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands

Toll-like receptor ligands (TLRLs) produced by various pathogens activate mitogen-activated protein kinases (MAPKs). While the dependence on p38 MAPK activation for the induction of inflammatory genes by the TLR4L, lipopolysaccharide (LPS), has been well documented, the importance of the p38 pathway in gene regulation by other TLRLs is less well understood. We have focused our analysis on two TLRLs with therapeutic potential, imidazoquinoline S28463 (TLR7L) and CpG DNA (TLR9L), to explore in detail their effects on the regulation of gene expression in macrophages. Here we report that activation of the p38 MAPK/MK2 pathway is crucial for both S28463- and CpG-induced cytokine and chemokine production. We show that the stability of TNF mRNA induced by CpG DNA and S28463 is not dependent on the p38 MAPK/MK2 pathway, in contrast to LPS-induced TNF mRNA. Using a GFP reporter construct under the control of the 3' untranslated region of the TNF gene, we demonstrate that S28463 and CpG DNA-induced MK2 signalling regulates TNF mRNA primarily at the translational level, whereas LPS-induced MK2 signalling regulates both the stability and translational efficiency of TNF mRNA. Overall, these data provide insight into distinct molecular mechanisms of gene expression regulation by different Toll-like receptor ligands.     

In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii

The activity of eravacycline was compared with that of anti-Acinetobacter reference antimicrobials against carbapenem non-susceptible Acinetobacter baumannii isolates associated with an acquired OXA or up-regulation of the intrinsic OXA-51-like enzyme. Antimicrobial susceptibility testing was performed by broth microdilution of 286 non–duplicate, carbapenem non-susceptible A. baumannii isolates to eravacycline, amikacin colistin, doxycycline, imipenem, levofloxacin, meropenem, minocycline, sulbactam, tigecycline and tobramycin.Eravacycline showed greater activity than the comparators of the tetracycline class, levofloxacin, amikacin, tobramycin and colistin. The eravacycline MIC_50/90 values were 0.5/1?mg/L and those for tigecycline, minocycline and doxycycline were 1/2, 4/8 and 32/?≥?64?mg/L, respectively. In conclusion, eravacycline was the most potent antibiotic of those tested against A. baumannii, including isolates that were resistant to sulbactam, imipenem/meropenem, levofloxacin and amikacin/tobramycin. Eravacycline has the potential to become a useful addition to the limited armamentarium of drugs that can be used to treat this problem pathogen.     

Pathobiology of Lomentospora prolificans: could this species serve as a model of primary antifungal resistance?

The number of fungal isolates resistant to antifungal drugs has increased dramatically over the last few years and has become an important concern for clinicians. Among these isolates, fungi showing multidrug resistance are particularly worrying because of the difficulties associated with their treatment. These factors hamper the successful recovery of patients and drastically raise mortality rates. Antifungal resistance is multifactorial and several mechanisms in different fungi have been described. There is a need to study these mechanisms in depth; however, the study of antifungal drug resistance separately for each individual species makes progress in the field very slow and tedious. The selection of a multiresistant microorganism as a model for understanding resistance mechanisms and extrapolating the results to other species could help in the search for a solution. In this mini-review, we describe the pathobiology of Lomentospora (Scedosporium) prolificans, paying special attention to its intrinsic resistance to all currently available antifungal agents. The characteristics of L. prolificans offer several advantages: the possibility of using a single microorganism for the study of resistance to different drugs, even cases of double and triple resistance; it is biologically safe for society in general as no new genetically–modified strains are needed for the experiments; it is homologous with other fungal species, and there is repetitiveness between different strains. In conclusion, we propose L. prolificans as a candidate for consideration as a fungal model for the study of resistance mechanisms against antifungal agents.     

Comorbid mental disorders among adults in the mental health surveillance survey

Purpose

To examine the prevalence and correlates of mental disorder comorbidity in the adult U.S. household population.

Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) often colonize the anterior nares, and nasal carriage remains the main source of bacterial dissemination. The aim of this study was to assess the in vivo activity of the lantibiotic mersacidin against MRSA colonizing nasal epithelia. METHODS: The efficiency of mersacidin in the eradication of MRSA was tested employing mice pre-treated with hydrocortisone and inoculated intranasally either three or six times with a bacterial suspension. RESULTS: In mersacidin-treated animals, pre-colonized with MRSA, bacteria could not be detected in blood, lungs, liver, kidney, spleen or nasal scrapings and there were no lesions manifested after intraperitoneal drug application. Blood samples from infected mice obtained 2 h after mersacidin therapy revealed anti-MRSA activity in a serum bactericidal test. Moreover, elevated interleukin-1beta and tumour necrosis factor-alpha titres were noticed in the pre-infected but not in cured animals. In contrast, mersacidin did not induce differences in the cytokine profiles of treated uninfected control mice. CONCLUSIONS: In the mouse rhinitis model, mersacidin was able to eradicate MRSA colonization. The site of action (epithelium versus blood) of mersacidin needs to be further explored.