249 research outputs found
Administration of liposomal agents and blood clearance capacity of the mononuclear phagocyte system
As liposomes are cleared from the circulation to a substantial extent by
the phagocytic cells of the mononuclear phagocyte system (MPS), there is a
question whether administration of liposome-based therapeutic agents
interferes with clearance of infectious organisms by the MPS from blood.
In the present study, at first the effect of administration of three types
of empty liposomes (devoid of drug), differing in blood residence time, on
carbon clearance and bacterial clearance from blood was studied with mice.
Classical liposomes (LIP A) and placebo liposomes with lipid composition
as in AmBisome (LIP B) or as in Doxil (LIP C) were used. Liposomes were
administered intravenously as a single dose. Second, the effect of
multiple-dose administration of AmBisome on bacterial blood clearance was
studied with rats. AmBisome was administered with two different dosage
schedules. The blood clearance capacity of the MPS was monitored at
different time points after the last liposome injection. It was shown that
the carbon blood clearance capacity of the MPS was impaired only at a high
lipid dose of empty classical liposomes. The bacterial blood clearance
capacity was never impaired, not even after prolonged treatment with
AmBisome administered in a clinically relevant regimen
Liposomal amphotericin B (AmBisome) reduces dissemination of infection as compared with amphotericin B deoxycholate (Fungizone) in a rate model of pulmonary aspergillosis
The efficacy of AmBisome, a liposomal formulation of amphotericin B, was
compared with that of Fungizone (amphotericin B desoxycholate), in a rat
model of unilateral, pulmonary aspergillosis. Repeated administration of
cyclophosphamide resulted in persistent, severe granulocytopenia. The left
lung was inoculated with a conidial suspension of Aspergillus fumigatus,
thus establishing an unilateral infection. Antifungal treatment was
started 40 h after fungal inoculation, at which time mycelial disease was
confirmed by histological examination. Both Fungizone 1 mg/kg and AmBisome
10 mg/kg resulted in increased survival in terms of delayed as well as
reduced mortality. Quantitative cultures of lung tissue showed that only
AmBisome 10 mg/kg resulted in reduction of the number of fungal cfus in
the inoculated left lung. Compared with Fungizone, both AmBisome 1
mg/kg/day and AmBisome 10 mg/kg/day significantly prevented dissemination
from the infected left lung to the right lung. In addition, both AmBisome
regimens reduced hepatosplenic dissemination, and the 10 m/kg dosage fully
prevented this complication. In conclusion, when compared with Fungizone,
in this model AmBisome is more effective in reducing dissemination of
unilateral, pulmonary aspergillosis, even when given in relatively low
dosage. Such low dosages may have a place in prophylactic settings
Addition of 17-(allylamino)-17-demethoxy-geldanamycin to a suboptimal caspofungin treatment regimen in neutropenic rats with invasive pulmonary aspergillosis delays the time to death but does not enhance the overall therapeutic efficacy
Caspofungin (CAS) which is used as salvage therapy in patients with invasive pulmonary aspergillosis (IPA) inhibits the 1,3-ÎČ-D-glucan synthesis in Aspergillus fumigatus. Inhibiting 1,3-ÎČ-D-glucan synthesis induces a stress response and in an invertebrate model it was demonstrated that inhibiting this response with geldamycin enhanced the therapeutic efficacy of CAS. Since geldamycin itself is toxic to mammalians, the therapeutic efficacy of combining geldamycin with CAS was not studied in rodent models. Therefore in this study we investigated if the geldamycin derivate 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was able to enhance the therapeutic efficacy of CAS in vitro and in our IPA model in transiently neutropenic rats. In vitro we confirmed the earlier demonstrated synergy between 17-AAG and CAS in ten A. fumigatus isolates. In vivo we treated A. fumigatus infected neutropenic rats with a sub-optimal dose of 0.75 mg/kg/day CAS and 1 mg/kg/day 17-AAG for ten days. Survival was monitored for 21 days after fungal inoculation. It appeared that the addition 17-AAG delayed death but did not improve overall survival of rats with IPA. Incre
Evidence Supporting a Role for Mammalian Chitinases in Efficacy of Caspofungin against Experimental Aspergillosis in Immunocompromised Rats
Objectives:Caspofungin, currently used as salvage therapy for invasive pulmonary aspergillosis (IPA), strangely only causes morphological changes in fungal growth in vitro but does not inhibit the growth. In vivo it has good efficacy. Therefore the question arises how this in vivo activity is reached. Caspofungin is known to increase the amount of chitin in the fungal cell wall. Mammals produce two chitinases, chitotriosidase and AMCase, which can hydrolyse chitin. We hypothesized that the mammalian chitinases play a role in the in vivo efficacy of caspofungin.Methods:In order to determine the role of chitotriosidase and AMCase in IPA, both chitinases were measured in rats which did or did not receive caspofungin treatment. In order to understand the role of each chitinase in the breakdown of the caspofungin-exposed cells, we also exposed caspofungin treated fungi to recombinant enzymes in vitro.Results:IPA in immunocompromised rats caused a dramatic increase in chitinase activity. This increase in chitinase activity was still noted when rats were treated with caspofungin. In vitro, it was demonstrated that the action of both chitinases were needed to lyse the f
Successful high-dosage monotherapy of tigecycline in a multidrug-resistant Klebsiella pneumoniae pneumonia-septicemia model in rats
Background: Recent scientific reports on the use of high dose tigecycline monotherapy as a âdrug of last resortâ warrant further research into the use of this regimen for the treatment of severe multidrug-resistant, Gram-negative bacterial infections. In the current study, the therapeutic efficacy of tigecycline monotherapy was investigated and compared to meropenem monotherapy in a newly developed rat model of fatal lobar pneumonia-septicemia. Methods: A Klebsiella pneumoniae producing extended-spectrum ÎČ-lactamase (ESBL) and an isogenic variant producing K. pneumoniae carbapenemase (KPC) were used in the study. Both strains were tested for their in vitro antibiotic susceptibility and used to induce pneumonia-septicemia in rats, which was characterized using disease progression parameters. Therapy with tigecycline or meropenem was initiated at the moment that rats suffered from progressive infection and was administered 12-hourly over 10 days. The pharmacokinetics of meropenem were determined in infected rats. Results: In rats with ESBL pneumonia-septicemia, the minimum dosage of meropenem achieving survival of all rats was 25 mg/kg/day. However, in rats with KPC pneumonia-septicemia, this meropenem dosage was unsuccessful. In contrast, all rats with KPC pneumonia-septicemia were successfully cured by administration of high-dose tigecycline monotherapy of 25 mg/kg/day (i.e., the minimum tigecycline dosage achieving 100% survival of rats with ESBL pneumonia-septicemia in a previous study). Conclusions: The current study supports recent literature recommending high-dose tigecycline as a last resort regimen for the treatment of severe multidrug-resistant bacterial infections. The use of ESBL- and KPC-producing K. pneumoniae strains in the current rat model of pneumonia-septicemia enables further investigation, helping provide supporting data for follow-up clinical trials in patients suffering from severe multidrug-resistant bacterial respiratory infections
A globally relevant change taxonomy and evidence-based change framework for land monitoring
A globally relevant and standardized taxonomy and framework for consistently describing land cover change based on evidence is presented, which makes use of structured land cover taxonomies and is underpinned by the Driver-Pressure-StateïżœImpact-Response (DPSIR) framework. The Global Change Taxonomy currently lists 246 classes based on the notation âimpact (pressure)â, with this encompassing the consequence of observed change and associated reason(s), and uses scale-independent terms that factor in time. Evidence for different impacts is gathered through temporal comparison (e.g., days, decades apart) of land cover classes constructed and described from Environmental Descriptors (EDs; state indicators) with pre-defined measurement units (e.g., m, %) or categories (e.g., species type). Evidence for pressures, whether abiotic, biotic or human-influenced, is similarly accumulated, but EDs often differ from those used to determine impacts. Each impact and pressure term
is defined separately, allowing flexible combination into âimpact (pressure)â categories, and all are listed in an openly accessible glossary to ensure consistent use and
common understanding. The taxonomy and framework are globally relevant and can reference EDs quantified on the ground, retrieved/classified remotely (from groundbased, airborne or spaceborne sensors) or predicted through modelling. By providing capacity to more consistently describe change processesâincluding land degradation,
desertification and ecosystem restorationâthe overall framework addresses a wide and diverse range of local to international needs including those relevant to policy,
socioeconomics and land management. Actions in response to impacts and pressures and monitoring towards targets are also supported to assist future planning, including
impact mitigation actions
Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in âs = 7 TeV pp collisions with the ATLAS detector
A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fbâ1 of protonâproton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results
Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC
Measurements of inclusive jet suppression in heavy ion collisions at the LHC
provide direct sensitivity to the physics of jet quenching. In a sample of
lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated
luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with
a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the
transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the
anti-kt algorithm with values for the distance parameter that determines the
nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of
the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp.
Jet production is found to be suppressed by approximately a factor of two in
the 10% most central collisions relative to peripheral collisions. Rcp varies
smoothly with centrality as characterized by the number of participating
nucleons. The observed suppression is only weakly dependent on jet radius and
transverse momentum. These results provide the first direct measurement of
inclusive jet suppression in heavy ion collisions and complement previous
measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables,
submitted to Physics Letters B. All figures including auxiliary figures are
available at
http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02
Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment
This paper describes an analysis of the angular distribution of W->enu and
W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with
the ATLAS detector at the LHC in 2010, corresponding to an integrated
luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and
the missing transverse energy, the W decay angular distribution projected onto
the transverse plane is obtained and analysed in terms of helicity fractions
f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV
and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw
> 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour,
are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017
+/- 0.030, where the first uncertainties are statistical, and the second
include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables,
revised author list, matches European Journal of Physics C versio
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