Angiopoietine-like 2 : un facteur circulant pro-oxydant et pro-inflammatoire qui contribue au développement de l’athérosclérose

L’athérosclérose est une maladie vasculaire inflammatoire chronique qui se développe progressivement au cours de la vie. Les mécanismes impliqués sont complexes et la recherche de nouveaux candidats impliqués dans l'athérogénèse est toujours d'actualité. L’Angiopoietine-like 2 (Angptl2) est une protéine relativement peu connue, aux propriétés pro-angiogéniques et pro-inflammatoires, qui appartient par homologie à la grande famille des angiopoietines, mais dont le récepteur n'est pas encore clairement identifié. Les situations pathologiques dans lesquelles l’Angptl2 jouerait un rôle crucial sont diverses, mais sa contribution moléculaire dans le développement de l’athérosclérose est inconnue. Par differential display, nous avons initialement identifié l'Angptl2 comme étant surexprimée dans des cellules endothéliales sénescentes, isolées et cultivées à partir d'artères mammaires internes de patients athérosclérotiques ayant subi un pontage coronarien. Cette découverte a été la à base de mon projet, et mes objectifs ont été 1) de déterminer l'implication de l’Angptl2 vasculaire en présence de facteurs de risques tels que le tabagisme et la dyslipidémie, 2) de produire et de purifier une protéine recombinante fonctionnelle de l’Angptl2 afin d'identifier in vitro de nouvelles propriétés cellulaires de l'Angptl2 et 3) d'étudier in vivo le potentiel pro-athérogénique de l'Angptl2 recombinante dans un modèle murin de dyslipidémie sévère. Nous avons montré que l’Angptl2 est sécrétée préférentiellement dans des conditions pro-oxydantes et pro-inflammatoires, avec une augmentation de son expression endothéliale de l’ordre de 6 fois chez des patients coronariens fumeurs atteints de maladie pulmonaire obstructive chronique. Suite à ces résultats, nous avons émis l’hypothèse que l’Angptl2, en plus de ses fonctions pro-inflammatoires connues, possède des propriétés pro-oxydantes. Nous avons démontré que l’Angptl2 recombinante stimule en effet la production de radicaux libres dans des HUVEC en culture, via l’inhibition partielle de la voie cytoprotectrice antioxydante Nrf2/HO-1 et potentiellement via l'activation de kinase intracellulaire de type p38. A l'aide de souris dyslipidémiques LDLr-/-; hApoB-100+/+, nous avons démontré que le niveau d’Angptl2 plasmatique, vasculaire et dans les plaques athéromateuses, augmente parallèlement avec le développement de l’athérosclérose. De plus, une stimulation avec l’Angptl2 recombinante engendre chez ces souris une réponse inflammatoire évaluée par l’expression endothéliale de cytokines et de molécules d'adhésion et par l’infiltration de leucocytes sur l’endothélium vasculaire. Finalement, l’administration intraveineuse de la protéine recombinante d’Angptl2 pendant quatre semaines à des souris LDLr-/-; hApoB-100+/+ augmente de 10 fois l'expansion de la plaque athérosclérotique et double leur taux de cholestérol circulant. Nous avons aussi montré que chez des patients athérosclérotiques, l'Angptl2 plasmatique est 6 fois plus élevée que chez des sujets sains du même âge. Nos études semblent donc définir l’Angptl2 comme un facteur contribuant directement au développement de l'athérosclérose en favorisant la sénescence, l’inflammation et l’oxydation des cellules endothéliales. Ces propriétés pourraient globalement définir l'Angptl2, non seulement comme un nouveau biomarqueur circulant de l’athérosclérose, mais également comme l'un de ses promoteurs.Atherosclerosis is a chronic vascular inflammatory disease that develops gradually during life. While the control mechanisms of this disease are complex and variable, research continues to identify new protein candidates involved in atherogenesis. Angiopoietin-like2 (Angptl2) is a relatively unknown protein, recently shown to display angiogenic and pro-inflammatory properties. Based upon structural homology, Angptl2 is a member of the angiopoietin family; however, the Angptl2 receptor has not yet been clearly identified. The reported pathological situations in which Angptl2 may play a crucial role are multiple, but its molecular contribution in the development of atherosclerosis remains unknown. By differential display, we initially identified Angptl2 as being overexpressed in senescent endothelial cells, isolated and cultivated from internal mammary arteries of atherosclerotic patients undergoing coronary bypass. This observation was at the basis of my project. My specific objectives were 1) to determine the abundance of vascular Angptl2 in the presence of risk factors such as smoking and dyslipidemia, 2) to produce and purify a functional recombinant human Angptl2 protein in order to examine its effects on cellular function in vitro, and 3) to study the pro-atherogenic potential of Angptl2 in vivo using a mouse model of severe dyslipidemia. We showed that Angptl2 is preferentially secreted under pro-oxidant and pro-inflammatory conditions, with a 6-fold increase in endothelial Angptl2 expression in smoker coronary patients with chronic obstructive pulmonary disease. Based on these results, we hypothesized that, in addition to its known pro-inflammatory functions, Angptl2 has pro-oxidant properties. Accordingly, we demonstrated that recombinant Angptl2 stimulates the production of free radicals by HUVEC, an action exerted, at least in part, by the inhibition of the cytoprotective antioxidant pathway, Nrf2/HO-1, and potentially via the activation of the intracellular p38 MAPK pathway. In dyslipidemic LDLr-/-; hApoB-100+/+ mice, we showed that the levels of endogenous Angptl2 in plasma, vascular tissue and atherosclerotic lesions increase in parallel with the development of atherosclerosis. In addition, stimulation with recombinant Angptl2 induces an inflammatory response, as assessed by the expression of cytokines and adhesion molecules and by infiltration of leukocytes into the vascular endothelium. Furthermore, intravenous infusion of purified recombinant Angptl2 for four weeks promoted a 10-fold increase in the formation of atherosclerotic plaques in LDLr-/-; hApoB-100+/+ mice and doubled their circulating cholesterol levels. Finally, we also demonstrated that plasma Angptl2 is 6-fold higher in atherosclerotic patients than in age-matched healthy subjects. These studies therefore strongly suggest that Angptl2 could directly contribute to the development of atherosclerosis by promoting senescence, inflammation and oxidation in endothelial cells. Such properties indicate that Angptl2 may be both a new biomarker of atherosclerosis, as well as one of its contributors

L'Économie de communion : devoirs moraux et responsabilité sociale axée sur le relationnel dans l'entreprise

Au sein de l’économie libérale, est né un modèle d’entreprise conjuguant altruisme et recherche du profit : l’Économie de Communion. À travers sa responsabilité sociale, cette entreprise adopte des stratégies particulières de gestion qui tentent de replacer l’homme au centre de l’activité de l’entreprise. L’objectif du mémoire est de présenter l’Économie de Communion, son but et les différents axes qui la soutiennent, ainsi que sa compréhension de l’interaction du monde des affaires avec l’éthique, la morale et le droit. À la lumière des expériences vécues par 811 entreprises, cet agir économique rend compte de l’efficacité de son mode de gestion au niveau de l’optimisation de la performance entrepreneuriale. L’Économie de Communion met en exergue notamment une approche où la dynamique économique repose sur la solidarité et la fraternité.Within the liberal economy, a business model was born combining altruism and profit-seeking: the Economy of Communion. Through its social responsibility, this model adopts specific management strategies that try to put people at the center of the firm's activities. The aim of the paper is to present the Economy of Communion, its purpose and the various axes that support it, as well as its understanding of the interaction of the business world with ethics, values and law. In the light of the experience of 811 firms, the Economic of Communion acknowledges the efficiency of its management mode in terms of optimizing entrepreneurial performance. It emphasizes in particular an approach where economic dynamics are based on solidarity and fraternity

Trueness of milled zirconia versus milled hybrid composite crowns designed for primary teeth restoration compared to the digitally designed file: an in vitro study.

Purpose: Stainless Steel Crowns (SSC) are not easily replaced by Zirconia Prefabricated Crowns (ZPC) because of their adaptation problem and risk of fracture and loosening. This study aimed to assess and compare the trueness of milled zirconia and milled hybrid composite crowns designed for primary teeth restoration to a digitally designed file. Methods: Fourteen extracted primary molars were scanned using an intraoral scanner to obtain digital files of the teeth. The digital files were imported into the Design dental software (TDS) and used to design and mill zirconia and hybrid composite crowns using a 4-axis milling machine: 14 zirconia crowns and 14 hybrid composite crowns were milled. The milled crowns were fitted onto their corresponding primary molars and evaluated for trueness using Geomagic Control X Software (Control X®, Geomagic, Morrisville, NC, USA). The results were recorded in millimeters. Wilcoxon signed-rank test was used to evaluate the difference in trueness between the two groups of milled crowns, and the level of significance was set at 5%. Results: No significant difference was observed in terms of trueness between the milled zirconia crowns and the milled hybrid composite crowns (p\u3e0.05). Conclusion: CAD-CAM technology and zirconia/hybrid composite materials can be used effectively in the restoration of primary teeth. The use of the hybrid composite material in this technique, provides a highly accurate, quick and esthetic solution for pediatric patients, potentially improving their oral health and quality of life. Objectif: Les Couronnes Pédodontiques Préformées (CPP) ne sont pas facilement remplacées par les Couronnes Préfabriquées en Zircone (CPZ) en raison de problèmes d\u27adaptation et du risque de fracture et de descellement. Cette étude vise à évaluer et à comparer la précision des couronnes en zircone et des couronnes en composite hybrides confectionnées digitalement conçues pour la restauration des dents temporaires par rapport à un fichier conçu numériquement. Méthodes : Quatorze molaires temporaires extraites ont été préparées et scannées à l\u27aide d\u27un scanner intra-oral pour obtenir des fichiers numériques des dents. Ces derniers ont été importés dans le logiciel de conception dentaire (TDS) et utilisés pour concevoir et fabriquer des couronnes en zircone et en composite hybride à l\u27aide d\u27une fraiseuse 4 axes : 14 couronnes en zircone et 14 couronnes composite hybrides ont été usinées. Ces couronnes ont été adaptées sur leurs molaires correspondantes et évaluées pour leur précision à l\u27aide du logiciel Geomagic Control X (Control X®, Geomagic, Morrisville, NC, USA). Les résultats ont été enregistrés en millimètres. Le test de Wilcoxon signé a été utilisé pour évaluer la différence de précision entre les deux groupes de couronnes usinées, avec un niveau de signification fixé à 5 %. Résultats : Aucune différence significative n\u27a été observée en termes de précision entre les couronnes en zircone et les couronnes en composite hybrides confectionnées digitalement (p \u3e 0,05). Conclusion: La technologie de CFAO (Conception et Fabrication Assistées par Ordinateur) et les matériaux en zircone/composite hybride peuvent être tous les deux utilisés efficacement dans la restauration des dents temporaires. L\u27utilisation du matériau composite hybride dans cette technique offre une solution hautement précise, rapide et esthétique pour les patients pédiatriques, améliorant potentiellement leur santé bucco-dentaire et leur qualité de vie

Simulation of a Sensitive Mid-infrared (MIR) D-Shaped Optical Fiber Water Pollutant Sensor

In this work, an efficient optical sensor is proposed for the sensitive detection of various pollutants in water. The suggested optical sensor is based on an indium fluoride (InF3) glass fabricated as a D-shaped optical fiber. The polished surface of the D-shaped fiber is coated with a gold grating to induce the surface plasmon resonance (SPR). The SPR depends on the optical properties of the polluted water analyte in physical contact with the grating. The proposed optical SPR fiber sensor operates within the mid-infrared (MIR) range (3000–4500 nm) to detect any slight change in the water refractive index (RI) due to any pollutants. The full vectorial finite element method (FVFEM) is utilized to calculate the modal properties of the reported sensor. High sensor sensitivity of 17,834 nm/RIU (refractive index units) is achieved for the detection of dissolution of nitric acid (HNO3) in water at a concentration of 14% v/v (volume/volume). Additionally, the reported sensor detects the dissolution of hydrogen peroxide (H2O2) in water investigated at concentrations of 15% v/v and 30% v/v, with sensitivities of 12,308 nm/RIU and 17,143 nm/RIU, respectively. Further, suspending polystyrene beads of diameter 0.1 μm in the water at a concentration of 10% v/v gives a maximum sensitivity of 5333 nm/RIU. Therefore, the proposed sensor provides a promising approach for the detection of water pollutants in the MIR wavelength regime, rather than the weaker response in the near infrared

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Elevated International Normalized Ratio values in a patient receiving warfarin and ceftaroline

PURPOSE: The case of a patient whose International Normalized Ratio (INR) became elevated due to a probable interaction between ceftaroline and warfarin is reported. SUMMARY: A 65-year-old African-American man developed an INR of \u3e18.0 after completing 12 days of ceftaroline therapy for the treatment of cellulitis while taking warfarin therapy. The patient was on warfarin due to his history of deep vein thrombosis of a lower extremity and pulmonary embolism, and his INR was consistently therapeutic for approximately 2 years before ceftaroline therapy. The patient reported no known drug allergies, had no history of adverse drug reactions, and had no recent changes in medications or diet. Phytonadione was administered, and the patient\u27s INR began to decrease, returning to a therapeutic range of 2.30 after approximately 48 hours, at which time warfarin was restarted. After six days of hospitalization, the patient was discharged on his previous regimen of warfarin 7.5 mg orally once daily, with a therapeutic INR of 2.11. His cellulitis had resolved, so no further antibiotic therapy was warranted. To determine the likelihood of the drug interaction between warfarin and ceftaroline in this patient, the Drug Interaction Probability Scale of Horn and colleagues was applied and yielded a score of 6, indicating a probable likelihood of an interaction. Rechallenge was not attempted, as the patient\u27s cellulitis had resolved and there were no evident signs or symptoms of infection. CONCLUSION: A 65-year-old man experienced an increase in INR values after the addition of ceftaroline to his medication regimen