ABSTRACT
OBJECTIVES: Burkholderia pseudomallei, Yersinia pestis and Francisella tularensis are facultative intracellular bacteria causing life-threatening infections. We have (a) compared the activity of finafloxacin (a fluoroquinolone in development showing improved activity at acidic pH) with that of ciprofloxacin, levofloxacin and imipenem against the extracellular and intracellular (THP-1 monocytes) forms of infection by attenuated surrogates of these species (B. thailandensis, Y. pseudotuberculosis, F. philomiragia) and (b) assessed finafloxacin cellular pharmacokinetics (accumulation, distribution, efflux). METHODS: Bacteria in broth or in infected monocytes were exposed to antibiotics at pH 7.4 or 5.5 for 24 hr. Maximal relative efficacies (Emax) and static concentrations (Cs) were calculated using the Hill equation (concentration-response curves). Finafloxacin pharmacokinetics in cells at pH 7.4 or 5.5 was investigated using 14C-labelled drug. RESULTS: Extracellularly, all drugs sterilized the cultures, with finafloxacin being two to six times more potent at acidic pH. Intracellularly, Emax reached the limit of detection (4-5 log10 cfu decrease) for finafloxacin against all species, but only against B. thailandensis and F. philomiragia for ciprofloxacin and levofloxacin, while imipenem caused less than 2 log10 cfu decrease for all species. At acid pH, Cs shifted to two to five times lower values for finafloxacin and to one to four times higher values for the other drugs. Finafloxacin accumulated in THP-1 cells by approximately fivefold at pH 7.4 but up to 20-fold at pH 5.5, and distributed in the cytosol. CONCLUSIONS: Fluoroquinolones have proven to be effective in reducing the intracellular reservoirs of B. thailandensis, Y. pseudotuberculosis and F. philomiragia, with finafloxacin demonstrating an additional advantage in acidic environments.
Subject(s)
Anti-Bacterial Agents/pharmacology , Burkholderia/drug effects , Fluoroquinolones/pharmacology , Francisella/drug effects , Yersinia pseudotuberculosis/drug effects , Humans , Hydrogen-Ion Concentration , Imipenem/pharmacology , Levofloxacin/pharmacology , Microbial Sensitivity Tests , Monocytes , THP-1 CellsABSTRACT
Diabetic nephropathy (DN) is the main cause of morbidity and mortality in diabetes and is characterized by mesangial matrix deposition and podocytopathy, including podocyte loss. The risk factors and mechanisms involved in the pathogenesis of DN are still not completely defined. In the present study, we aimed to understand the cellular mechanisms through which activation of B2 kinin receptors contribute to the initiation and progression of DN. Stimulation of cultured rat podocytes with bradykinin (BK) resulted in a significant increase in ROS generation, and this was associated with a significant increase in NADPH oxidase (NOX)1 and NOX4 protein and mRNA levels. BK stimulation also resulted in a signicant increase in the phosphorylation of ERK1/2 and Akt, and this effect was inhibited in the presence of NOX1 and Nox4 small interfering (si)RNA. Furthermore, podocytes stimulated with BK resulted in a significant increase in protein and mRNA levels of connective tissue growth factor (CTGF) and, at the same time, a significant decrease in protein and mRNA levels of nephrin. siRNA targeted against NOX1 and NOX4 significantly inhibited the BK-induced increase in CTGF. Nephrin expression was increased in response to BK in the presence of NOX1 and NOX4 siRNA, thus implicating a role for NOXs in modulating the BK response in podocytes. Moreover, nephrin expression in response to BK was also significantly increased in the presence of siRNA targeted against CTGF. These findings provide novel aspects of BK signal transduction pathways in pathogenesis of DN and identify novel targets for interventional strategies.
Subject(s)
Bradykinin/pharmacology , Connective Tissue Growth Factor/metabolism , Membrane Proteins/metabolism , Podocytes/drug effects , Animals , Cells, Cultured , Connective Tissue Growth Factor/genetics , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Membrane Proteins/genetics , NADH, NADPH Oxidoreductases/genetics , NADH, NADPH Oxidoreductases/metabolism , NADPH Oxidase 1 , NADPH Oxidase 4 , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , Oxidative Stress/drug effects , Phosphorylation , Podocytes/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Messenger/metabolism , Rats , Receptor, Bradykinin B2/agonists , Receptor, Bradykinin B2/metabolism , Signal Transduction/drug effects , Time Factors , Transfection , Up-RegulationABSTRACT
L'etude retrospective; prospective et comparative de la survie au cours du myelome multiple chez les patients de moins de 60 ans (les cas) et les patients de 60 ans et plus (les temoins) portant sur respectivement 30 et 14 patients colliges de 1991 a 2005 dans le service d'hematologie clinique du CHU de Yopougon; a permis de retenir les resultats suivants: *La survie globale au cours du rnyelome multiple de l'adulte de moins de 60 ans est de 5;625 mois. *La mediane de survie des patients de moins de 60 ans etait plus importante que celle des patients de 60 ans et plus. Cette difference n'etait pas statistiquement significative (p=0;993). Cependant; l'etude de la survie moyenne montre que celle ci etait plus importante chez les patients de 60 ans et plus avec une difference statistiquement significative (p=0;024). Toutes les variables epidemiologiques; biologiques et evolutives prises en compte dans notre etude n'avaient pas d'influence statistiquement significative sur la survie chez le sujet de moins de 60 ans
