28 research outputs found
ï»żDĂ©veloppement de nouvelles formulations dâantifongiques et Ă©valuation de lâactivitĂ© sur Candida spp. et Aspergillus spp.
Les travaux effectuĂ©s dans le cadre de cette thĂšse de doctorat avaient pour but de mettre au point des nouvelles formulations dâantifongiques sous forme de nanoparticules polymĂ©riques (NP) en vue dâamĂ©liorer lâefficacitĂ© et la spĂ©cificitĂ© des traitements antifongiques sur des souches sensibles ou rĂ©sistantes de Candida spp, dâAspergillus spp et des souches de Candida albicans formant du biofilm.
Dans la premiĂšre partie de ce travail, nous avons synthĂ©tisĂ© et caractĂ©risĂ© un polymĂšre Ă base de polyester-co-polyĂ©ther branchĂ© avec du poly(Ă©thylĂšne glycol) (PEG-g-PLA). En plus dâĂȘtre original et innovant, ce co-polymĂšre a lâavantage dâĂȘtre non-toxique et de possĂ©der des caractĂ©ristiques de libĂ©ration prolongĂ©e. Trois antifongiques couramment utilisĂ©s en clinique et prĂ©sentant une biodisponibilitĂ© non optimale ont Ă©tĂ© choisis, soient deux azolĂ©s, le voriconazole (VRZ) et lâitraconazole (ITZ) et un polyĂšne, lâamphotĂ©ricine B (AMB). Ces principes actifs (PA), en plus des problĂšmes dâadministration, prĂ©sentent aussi dâimportants problĂšmes de toxicitĂ©. Des NP polymĂ©riques encapsulant ces PA ont Ă©tĂ© prĂ©parĂ©es par une technique dâĂ©mulsion huile-dans-lâeau (H/E) suivie dâĂ©vaporation de solvant. Une fois fabriquĂ©es, les NP ont Ă©tĂ© caractĂ©risĂ©es et des particules de dâenviron 200 nm de diamĂštre ont Ă©tĂ© obtenues. Les NP ont Ă©tĂ© conçues pour avoir une structure coeur/couronne avec un coeur constituĂ© de polymĂšre hydrophobe (PLA) et une couronne hydrophile de PEG. Une faible efficacitĂ© de chargement (1,3% m/m) a Ă©tĂ© obtenue pour la formulation VRZ encapsulĂ© dans des NP (NP/VRZ). Toutefois, la formulation AMB encapsulĂ©e dans des NP (NP/AMB) a montrĂ© des taux de chargement satisfaisants (25,3% m/m). En effet, le caractĂšre hydrophobe du PLA a assurĂ© une bonne affinitĂ© avec les PA hydrophobes, particuliĂšrement lâAMB qui est le plus hydrophobe des agents sĂ©lectionnĂ©s. Les Ă©tudes de libĂ©ration contrĂŽlĂ©e ont montrĂ© un relargage des PA sur plusieurs jours. La formulation NP/AMB a Ă©tĂ© testĂ©e sur un impacteur en cascade, un modĂšle in vitro de poumon et a permis de dĂ©montrer le potentiel de cette formulation Ă ĂȘtre administrĂ©e efficacement par voie pulmonaire. En effet, les rĂ©sultats sur lâimpacteur en cascade ont montrĂ© que la majoritĂ© de la formulation sâest retrouvĂ©e Ă lâĂ©tage de collecte correspondant au niveau bronchique, endroit oĂč se situent majoritairement les infections fongiques pulmonaires.
Dans la deuxiĂšme partie de ces travaux, nous avons testĂ© les nouvelles formulations dâantifongiques sur des souches planctoniques de Candida spp., dâAspergillus spp. et des souches de Candida albicans formant du biofilm selon les procĂ©dures standardisĂ©es du National Committee for Clinical Laboratory Standards (NCCLS). Les souches choisies ont dĂ©montrĂ© des rĂ©sistances aux azolĂ©s et aux polyĂšnes. Les Ă©tudes dâefficacitĂ© in vitro ont permis de prouver hors de tout doute que les nouvelles formulations offrent une efficacitĂ© nettement amĂ©liorĂ©e comparĂ©e Ă lâagent antifongique libre.
Pour mettre en lumiĂšre si lâamĂ©lioration de lâefficacitĂ© antifongique Ă©tait due Ă une internalisation des NP, nous avons Ă©valuĂ© le comportement des NP avec les cellules de champignons. Nous avons procĂ©dĂ© Ă des Ă©tudes qualitatives de microscopie de fluorescence sur des NP marquĂ©es avec de la rhodamine (Rh). Tel quâattendu, les NP ont montrĂ© une localisation intracellulaire. Pour exclure la possibilitĂ© dâune simple adhĂ©sion des NP Ă la surface des levures, nous avons aussi confirmĂ© leur internalisation en microscopie confocale de fluorescence.
Il est important de noter que peu dâĂ©tudes Ă ce jour ont mis lâaccent sur lâĂ©laboration de nouvelles formulations dâantifongiques Ă base de polymĂšres non toxiques destinĂ©es aux traitements des mycoses, donnant ainsi une grande valeur et originalitĂ© aux travaux effectuĂ©s dans cette thĂšse. Les rĂ©sultats probants obtenus ouvrent la voie vers une nouvelle approche pour contourner les problĂšmes de rĂ©sistances fongiques, un problĂšme de plus en plus important dans le domaine de lâinfectiologie.The work done presented in this thesis was aimed to develop new formulations of antifungal drugs in order to improve the effectiveness and specificity of treatments. The formulations of polymeric NP encapsulated antifungals were tested on sensitive or resistant strains of Candida spp, Aspergillus spp and strains of Candida albicans that are able to develop biofilm structure.
The first part of this work focussed on the synthesis and characterizations of a polyester-co-polyether polymer grafted with poly(ethylene glycol) (PEG-g-PLA). Besides being original and innovative, polymeric nanoparticles composed of PEG-g-PLA co-polymers have been used as drug delivery devices due to their biodegradable and biocompatible nature and controllable release characteristics. Three antifungal drugs (voriconazole, itraconazole and amphotericin B) commonly administered have been selected due to physicochemical properties and pharmacokinetics problems. In fact, these drugs are known to have significant delivery and toxicity issues. Polymeric nanoparticles were prepared by a high pressure homogenization oil-in-water emulsion method. Nanoparticles were designed in order to have an hydrophobic core (PLA) and a hydrophilic corona (PEG). Antifungal drugs were successfully incorporated into nanoparticles with appropiate mean diameters (~ 200 nm). Drug loading efficiency for VRZ was the lowest with 1,3% w/w of loading. A fraction of the VRZ was lost during the manufacturing process because of its solubility in water. However, AMB encapsulated in NP showed better loading efficiency (25,3% w/w). Indeed, the hydrophobic nature of PLA ensured a good affinity with the hydrophobic drugs, particularly for AMB who is the most hydrophobic of the selected drugs. Drug release study from new formulations showed a burst effet during 24 h followed by a prolonged release over several days. Furthermore, new formulation of AMB was tested on a cascade impactor, an in vitro lung model and successfully demonstrated the potential of this formulation to be administered effectively by the pulmonary route. Indeed, the results obtained showed that the majority of the formulation was found on the collection stage corresponding to the bronchial region, where is located predominantly pulmonary fungal infections.
The second part of the thesis was aimed at testing the new formulations on planktonic strains of Candida spp and Aspergillus spp. and biofilm structure of Candida albicans according to NCCLS standardized procedures. The selected strains have demonstrated resistance to azoles and polyenes. Studies in vitro have proven that the new formulations offer significantly improved effictiveness compared to free antifungal agent.
To evaluate if improved antifungal effectiveness was due to internalization of NP, we evaluated the behavior of NP with fungal cells. We conducted qualitative studies in fluorescence microscopy on NP labeled with rhodamine. As expected, the NP showed intracellular localization. To exclude the possibility of NP absorption on the surface of yeast cells, we also confirmed internalization by confocal fluorescence microscopy.
Noteworthy, only a few studies have focused on the development of new formulations of antifungal drug, giving great value and originality of this work. Encouraging results pave the way to a new approach to overcome fungal resistance issues, a problem more acute in the field of fungal diseases
Drug-loaded nanocarriers : passive targeting and crossing of biological barriers
Poor bioavailability and poor pharmacokinetic characteristics are some of the leading causes of drug development failure. Therefore, poorly-soluble drugs, fragile proteins or nucleic acid products may benefit from their encapsulation in nanosized vehicles, providing enhanced solubilisation, protection against degradation, and increased access to pathological compartments. A key element for the success of drug-loaded nanocarriers (NC) is their ability to either cross biological barriers themselves or allow loaded drugs to traverse them to achieve optimal pharmacological action at pathological sites. Depending on the mode of administration, NC may have to cross different physiological barriers in their journey towards their target.
In this review, the crossing of biological barriers by passive targeting strategies will be presented for intravenous delivery (vascular endothelial lining, particularly for tumour vasculature and blood-brain barrier targeting), oral administration (gastrointestinal lining) and upper airway administration (pulmonary epithelium). For each specific barrier, background information will be provided on the structure and biology of the tissues involved as well as available pathways for nano-objects or loaded drugs (diffusion and convection through fenestration, transcytosis, tight junction crossing, etc.). The determinants of passive targeting â size, shape, surface chemistry, surface patterning of nanovectors â will be discussed in light of current results. Perspectives on each mode of administration will be presented. The focus will be on polymeric nanoparticles and dendrimers although advances in liposome technology will be also reported as they represent the largest body in the drug delivery literature
Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector
A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or Ï lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, Ï, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan ÎČ in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN
Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey
Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020
Tailored Nanocarriers for the Pulmonary Delivery of Levofloxacin against Pseudomonas aeruginosa: A Comparative Study
International audienceCystic fibrosis (CF) patients are faced with chronic bacterial infections displaying persistent resistance if not eradicated during the first stage of the disease. Nanoantibiotics for pulmonary administration, such as liposomal ciprofloxacin or amikacin, have progressed through clinics thanks to their sustained release, prolonged lung residence time, and low systemic absorption. In this work, we sought a nanoformulation of levofloxacin for the treatment of Pseudomonas aeruginosa. We prepared and compared poly(lactic acid)-grafted-poly(ethylene glycol) nanoparticles, as well as anionic and cationic liposomes for their size, charge, and encapsulation efficiency. Cationic liposomes were unable to encapsulate any drug and were subsequently considered as a control formulation. Regarding the efficiency of the nanocarrier, anionic liposomes exhibited a prolonged release over 72 h and preserved the antibacterial activity of levofloxacin against five strains of P. aeruginosa, whereas polymeric nanoparticles quickly released their entire payload and increased the minimum inhibitory concentration of levofloxacin. Thus, only anionic liposomes were considered for further preclinical development. Anionic liposomes exhibited a suitable colloidal stability in Turbiscan analysis and crossed a layer of artificial mucus in under 1 h in a Transwell setup. Despite their negative surface charge, liposomes still interacted with the P. aeruginosa membrane in a doseâresponse manner, as demonstrated by flow cytometry. Viability assays confirmed that anionic liposomes, loaded or not, exhibited a good safety profile on A549 epithelial cells, even at high concentrations. Finally, nebulization of anionic liposomes containing levofloxacin did not impact their colloidal stability, and the droplet size distribution was suitable for deep lung deposition, where the P. aeruginosa infection lies. Therefore, levofloxacin-loaded anionic liposomes exhibited suitable properties for the pulmonary treatment of P. aeruginosa in CF. This step-by-step study confirms the promising role of liposomes for lung administration of antibiotics, as recently seen in clinics, and fosters their development for several types of antibiotics
Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root âs = 7 TeV with the ATLAS detector
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Measurement of the cross-section for W boson production in association with b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector
See paper for full list of authors - 31 pages plus author list (53 pages total), 9 figures, 10 tables, submitted to JHEP. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2012-11/This paper reports a measurement of the W+b-jets production cross-section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC. These results are based on data corresponding to an integrated luminosity of 4.6 fb-1, collected with the ATLAS detector. Cross-sections are presented as a function of jet multiplicity and of the transverse momentum of the leading b-jet for both the muon and electron decay modes of the W boson. The W+b-jets cross-section, corrected for all known detector effects, is quoted in a limited kinematic range, using jets reconstructed with the anti-k_t clustering algorithm with transverse momentum above 25 GeV and rapidity within +/- 2.1. Combining the muon and electron channels, the fiducial cross-section for W+b-jets is measured to be 7.1 +/- 0.5 (stat) +/- 1.4 (syst) pb, consistent with next-to-leading order QCD calculations within 1.5 standard deviations
Measurements of Wgamma and Zgamma production in pp collisions at sqrt{s}= 7 TeV with the ATLAS detector at the LHC
see paper for full list of authors ; 28 pages plus author list (40 pages total), 13 figures, 15 tables, submitted to PRD. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2012-07/The integrated and differential fiducial cross sections for the production of a W or Z boson in association with a high-energy photon are measured using pp collisions at sqrt{s} = 7 TeV. The analyses use a data sample with an integrated luminosity of 4.6 fb^{-1} collected by the ATLAS detector during the 2011 LHC data-taking period. Events are selected using leptonic decays of the W and Z bosons (W(e nu,mu nu) and Z(e+ e-, mu+ mu-, nu nubar)) with the requirement of an associated isolated photon. The data are used to test the electroweak sector of the Standard Model and search for evidence for new phenomena. The measurements are used to probe the anomalous WWgamma, ZZgamma and Zgammagamma triple-gauge-boson couplings and to search for the production of vector resonances decaying to Zgamma and Wgamma. No deviations from Standard Model predictions are observed and limits are placed on anomalous triple-gauge-boson couplings and on the production of new vector meson resonances
Search for the neutral Higgs bosons of the Minimal Supersymmetric Standard Model in pp collisions at sqrt(s)=7 TeV with the ATLAS detector
See paper for full list of authors - 30 pages plus author list (53 pages total), 7 figures, 6 tables, submitted to JHEP, All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HIGG-2012-11A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7 TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or tau lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, phi, as a function of the Higgs boson mass and for h/H/A production in the MSSM as a function of the parameters mA and tanbeta in the mh-max scenario for mA in the range of 90 GeV to 500 GeV
Measurement of angular correlations in Drell-Yan lepton pairs to probe Z/gamma* boson transverse momentum at sqrt(s)=7 TeV with the ATLAS detector
10 pages plus author list (22 pages total), 3 figures, 3 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at this http URL, See paper for full list of authorsA measurement of angular correlations in Drell-Yan lepton pairs via the phistar observable is presented. This variable probes the same physics as the Z/gamma* boson transverse momentum with a better experimental resolution. The Z/gamma*->e+e- and Z/gamma*->mu+mu- decays produced in proton--proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV are used. The data were collected with the ATLAS detector at the LHC and correspond to an integrated luminosity of 4.6 fb-1. Normalised differential cross sections as a function of phistar are measured separately for electron and muon decay channels. These channels are then combined for improved accuracy. The cross section is also measured double differentially as a function of phistar for three independent bins of the Z boson rapidity. The results are compared to QCD calculations and to predictions from different Monte Carlo event generators. The data are reasonably well described, in all measured Z boson rapidity regions, by resummed QCD predictions combined with fixed-order perturbative QCD calculations. Some of the Monte Carlo event generators are also able to describe the data. The measurement precision is typically better by one order of magnitude than present theoretical uncertainties