Intra-abdominal infections: the role of different classifications on the selection of the best antibiotic treatment.

BACKGROUND: Intra-abdominal infections (IAIs) represent a most frequent gastrointestinal emergency and serious cause of morbimortality. A full classification, including all facets of IAIs, does not exist. Two classifications are used to subdivide IAIs: uncomplicated or complicated, considering infection extent; and community-acquired, healthcare-associated or hospital-acquired, regarding the place of acquisition. Adequacy of initial empirical antibiotic therapy prescribed is an essential need. Inadequate antibiotic therapy is associated with treatment failure and increased mortality. This study was designed to determine accuracy of different classifications of IAIs to identify infections by pathogens sensitive to current treatment guidelines helping the selection of the best antibiotic therapy. METHODS: A retrospective cohort study including all adult patients discharged from hospital with a diagnosis of IAI between 1st of January and 31st of October, 2016. All variables potentially associated with pre-defined outcomes: infection by a pathogen sensitive to non-pseudomonal cephalosporin or ciprofloxacin plus metronidazole (ATB 1, primary outcome), sensitive to piperacillin-tazobactam (ATB 2) and hospital mortality (secondary outcomes) were studied through logistic regression. Accuracy of the models was assessed by area under receiver operating characteristics (AUROC) curve and calibration was tested using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Of 1804 patients screened 154 met inclusion criteria. Sensitivity to ATB 1 was independently associated with male gender (adjusted OR = 2.612) and previous invasive procedures in the last year (adjusted OR = 0.424) (AUROC curve = 0,65). Sensitivity to ATB 2 was independently associated with liver disease (adjusted OR = 3.580) and post-operative infections (adjusted OR = 2.944) (AUROC curve = 0.604). Hospital mortality was independently associated with age ≥ 70 (adjusted OR = 4.677), solid tumour (adjusted OR = 3.127) and sensitivity to non-pseudomonal cephalosporin or ciprofloxacin plus metronidazole (adjusted OR = 0.368). The accuracy of pre-existing classifications to identify infection by a pathogen sensitive to ATB 1 was 0.59 considering place of acquisition, 0.61 infection extent and 0.57 local of infection, for ATB 2 it was 0.66, 0.50 and 0.57, respectively. CONCLUSION: None of existing classifications had a good discriminating power to identify IAIs caused by pathogens sensitive to current antibiotic treatment recommendations. A new classification, including patients' individual characteristics like those included in the current model, might have a higher potential to distinguish IAIs by resistant pathogens allowing a better choice of empiric antibiotic therapy.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Impairment of Multiple Mitochondrial Energy Metabolism Pathways in the Heart of Chagas Disease Cardiomyopathy Patients.

Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy occurring in 30% of the 6 million infected with the protozoan Trypanosoma cruzi in Latin America. Survival is significantly lower in CCC than ischemic (IC) and idiopathic dilated cardiomyopathy (DCM). Previous studies disclosed a selective decrease in mitochondrial ATP synthase alpha expression and creatine kinase activity in CCC myocardium as compared to IDC and IC, as well as decreased in vivo myocardial ATP production. Aiming to identify additional constraints in energy metabolism specific to CCC, we performed a proteomic study in myocardial tissue samples from CCC, IC and DCM obtained at transplantation, in comparison with control myocardial tissue samples from organ donors. Left ventricle free wall myocardial samples were subject to two-dimensional electrophoresis with fluorescent labeling (2D-DIGE) and protein identification by mass spectrometry. We found altered expression of proteins related to mitochondrial energy metabolism, cardiac remodeling, and oxidative stress in the 3 patient groups. Pathways analysis of proteins differentially expressed in CCC disclosed mitochondrial dysfunction, fatty acid metabolism and transmembrane potential of mitochondria. CCC patients' myocardium displayed reduced expression of 22 mitochondrial proteins belonging to energy metabolism pathways, as compared to 17 in DCM and 3 in IC. Significantly, 6 beta-oxidation enzymes were reduced in CCC, while only 2 of them were down-regulated in DCM and 1 in IC. We also observed that the cytokine IFN-gamma, previously described with increased levels in CCC, reduces mitochondrial membrane potential in cardiomyocytes. Results suggest a major reduction of mitochondrial energy metabolism and mitochondrial dysfunction in CCC myocardium which may be in part linked to IFN-gamma. This may partially explain the worse prognosis of CCC as compared to DCM or IC.

Long Pentraxin 3-Mediated Fibroblast Growth Factor Trapping Impairs Fibrosarcoma Growth.

Fibrosarcomas are soft tissue mesenchymal tumors originating from transformed fibroblasts. Fibroblast growth factor-2 (FGF2) and its tyrosine-kinase receptors (FGFRs) play pivotal roles in fibrosarcoma onset and progression, FGF2 being actively produced by fibroblasts in all stages along their malignant transformation to the fibrosarcoma stage. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is an extrinsic oncosuppressor whose expression is reduced in different tumor types, including soft tissue sarcomas, via hypermethylation of its gene promoter. PTX3 interacts with FGF2 and other FGF family members, thus acting as a multi-FGF antagonist able to inhibit FGF-dependent neovascularization and tumor growth. Here, PTX3 overexpression significantly reduced the proliferative and tumorigenic potential of fibrosarcoma cells in vitro and in vivo. In addition, systemic delivery of human PTX3 driven by the Tie2 promoter inhibited the growth of fibrosarcoma grafts in transgenic mice. In a translational perspective, the PTX3-derived small molecule FGF trap NSC12 prevented activation of the FGF/FGFR system in fibrosarcoma cells and reduced their tumorigenic activity in vivo. In conclusion, impairment of the FGF/FGFR system by FGF trap molecules may represent a novel therapeutic approach for the treatment of fibrosarcoma.