Modulation of monocytes matrix metalloproteinase-2, MT1-MMP and TIMP-2 by interferon-gamma and -beta: implications to multiple sclerosis

Recent findings have implicated the activity of matrix metalloproteinases (MMPs) in the pathogenesis of multiple sclerosis (MS), while in vivo interferon (IFN)-beta treatment was demonstrated to suppress MMPs. In the present study, the effects mediated by IFN-gamma and IFN-beta on the mRNA and protein expression of MMP-2, its physiological activator, MT1-MMP and its endogenous inhibitor, TIMP-2, by monocytes were evaluated in vitro. The results point to the significance of IFNs in modulating MMPs/tissue inhibitors of MMPs (TIMPs) expression, and support the possibility that the therapeutic effects of IFN-beta may be, in part, due to induction of a shift from "pro-" to "anti-proteolytic" pattern of MMPs and TIMPs expression.     

Cholesterol-rich domains are involved in Bordetella pertussis phagocytosis and intracellular survival in neutrophils

Bordetella pertussis-specific antibodies protect against whooping cough by facilitating host defense mechanisms such as phagocytosis. However, the mechanism involved in the phagocytosis of the bacteria under non-opsonic conditions is still poorly characterized. We report here that B. pertussis binding and internalization is cholesterol dependent. Furthermore, we found cholesterol to be implicated in B. pertussis survival upon interaction with human neutrophils. Pre-treatment of PMN with cholesterol sequestering drugs like nystatin or methyl-β-cyclodextrin (MβCD) resulted in a drastic decrease of uptake of non-opsonized B. pertussis. Conversely, phagocytosis of opsonized bacteria was not affected by these drugs, showing that cholesterol depletion affects neither the viability of PMN nor the route of entry of opsonized B. pertussis. Additionally, intracellular survival rate of non-opsonized bacteria was significantly decreased in cholesterol-depleted PMN. Accordingly, confocal laser microscopy studies showed that non-opsonized B. pertussis co-localized with lysosomal markers only in cholesterol-depleted PMN but not in normal PMN. Our results indicate that B. pertussis docks to molecules that eventually prevent cellular bactericidal activity.     

Effects of intra-aortic counterpulsation on aortic wall energetics and damping: in vivo experiments

Intra-aortic balloon pumping (IABP) could modify the arterial biomechanics; however, its effects on arterial wall properties have not been fully explored. This dynamical study was designed to characterize the pressure-dependent and smooth muscle-dependent effects of IABP on aortic wall energetics in an in vivo animal model. Intra-aortic balloon pumping (1:2) was performed in six anesthetized sheep in which aortic pressure and diameter signals were measured in basal, augmented (during balloon inflation), and assisted (postaugmented) beats. Energy dissipation values in augmented and assisted beats were significantly higher than those observed in basal state (p < 0.05). Assisted beats showed a significant increase of wall damping with respect to basal and augmented beats (p < 0.05). Intra-aortic balloon pumping resulted in a significant increase of pulse wave velocity (p < 0.05) in augmented beats with respect to basal state (6.3 +/- 0.8 vs. 5.2 +/- 0.5 m x s(-1)); whereas values observed in assisted beats were significantly (p < 0.05) lower than those observed in augmented beats (4.9 +/- 0.5 vs. 6.3 +/- 0.8 m x s(-1)). Our findings show that IABP determined the pressure and smooth muscle-dependent changes in arterial wall energetics and damping properties in this animal model.     

Extended-Infusion versus Standard-Infusion Piperacillin-Tazobactam for Sepsis Syndromes at a Tertiary Medical Center

Piperacillin-tazobactam (PTZ) is frequently used as empirical and targeted therapy for Gram-negative sepsis. Time-dependent killing properties of PTZ support the use of extended-infusion (EI) dosing; however, studies have shown inconsistent benefits of EI PTZ treatment on clinical outcomes. We performed a retrospective cohort study of adult patients who received EI PTZ treatment and historical controls who received standard-infusion (SI) PTZ treatment for presumed sepsis syndromes. Data on mortality rates, clinical outcomes, length of stay (LOS), and disease severity were obtained. A total of 843 patients (662 with EI treatment and 181 with SI treatment) were available for analysis. Baseline characteristics of the two groups were similar, except for fewer female patients receiving EI treatment. No significant differences between the EI and SI groups in inpatient mortality rates (10.9% versus 13.8%; P = 0.282), overall LOS (10 versus 12 days; P = 0.171), intensive care unit (ICU) LOS (7 versus 6 days; P = 0.061), or clinical failure rates (18.4% versus 19.9%; P = 0.756) were observed. However, the duration of PTZ therapy was shorter in the EI group (5 versus 6 days; P < 0.001). Among ICU patients, no significant differences in outcomes between the EI and SI groups were observed. Patients with urinary or intra-abdominal infections had lower mortality and clinical failure rates when receiving EI PTZ treatment. We did not observe significant differences in inpatient mortality rates, overall LOS, ICU LOS, or clinical failure rates between patients receiving EI PTZ treatment and patients receiving SI PTZ treatment. Patients receiving EI PTZ treatment had a shorter duration of PTZ therapy than did patients receiving SI treatment, and EI dosing may provide cost savings to hospitals.     

Analysis of genome sequence and trehalose lipid production peculiarities of the thermotolerant Gordonia strain

Gordoniae are one of the most promising hydrocarbon-oxidizing actinobacteria. Here we present the genome sequence analysis of thermotolerant strain Gordonia sp. 1D isolated from oil-refinery soil. It is capable of alkane consumption and biosurfactant production at temperatures of up to 50°C. Gordonia sp. 1D demonstrates maximum biosurfactant production when grown on hexadecane, and at 40°C it was slightly higher than at 27°C: 35 and 39 mN/m, respectively. For the first time, it was experimentally confirmed that the carbohydrate component of extracellular biosurfactants produced by strain 1D is trehalose. In addition, genes for the production of trehalose lipid biosurfactants were identified. The genetic determinants for two different pathways for trehalose synthesis were found. The strain carries genes otsA and otsB involved in de novo trehalose biosynthesis. Moreover, the genes treY and treZ responsible for trehalose biosynthesis from maltooligosaccharides and starch or glycogen were identified.