Evaluation de l'usure de la glène avant implantation de prothèses d'épaule

Question de recherche : Les prothèses d'épaule sont devenues au cours des années un traitement courant pour différentes affections de l'épaule, notamment l'arthrose gléno-humérale. L'évaluation de l'usure de la glène est un élément important pour le chirurgien, car la durée de vie des implants dépendra en effet d'un bon alignement de la tête humérale prothétique et de l'axe de la scapula. Dans le cas contraire, la glène prothétique peut s'user ou se desceller précocément. Il existe aujourd'hui une méthode de classification de l'usure ; elle a été étudiée par Walch grâce à l'utilisation du CT-Scan en 2 dimensions. L'usure de la glène a été classifiée en 3 types (A,B,C dépendant de la localisation présumée de l'usure). Cependant, cette méthode a montré ses limites face aux reconstructions en 3 dimensions. Ceci est notamment dû au fait de l'incidence des coupes de CT-Scan qui sont perpendiculaires au corps du patient et non pas alignées avec le corps de la scapula. De plus, l'usure se trouve dans une grande partie des cas dans la partie postéro-inférieure de la glène. Il est donc évident que la reconstruction en 3 dimensions d'images de CT-Scan permettrait d'obtenir de meilleures informations concernant l'usure de la glène. Objectifs : Mesurer les types d'usure de la glène en 3D dans un collectif de CT. Méthode : - Reconstruction en 3 dimensions (3D) d'images de CT-Scan de l'épaule en utilisant le logiciel Amira. La scapula entière sera reconstruite puis la surface articulaire glénoïdale sera sélectionnée manuellement. - Analyse de l'usure de la glène à partir des données récoltées lors de la reconstruction. L'analyse sera effectuée par un algorithme exécuté par le logiciel Matlab. Pour cela, il faudra déterminer le centre de la glène. Il sera également possible d'estimer l'angle de rétroversion. Ceci se déroulera au laboratoire d'orthopédie biomécanique (LBO) de l'Ecole Polytechnique Fédérale de Lausanne (EPFL). - Classification en différents groupes de types d'usure de la glène. Résultats attendus : Obtenir une classification 3 dimensions des différentes usures de la glène

On Guichard's nets and Cyclic systems

In the first part, we give a self contained introduction to the theory of cyclic systems in n-dimensional space which can be considered as immersions into certain Grassmannians. We show how the (metric) geometries on spaces of constant curvature arise as subgeometries of Moebius geometry which provides a slightly new viewpoint. In the second part we characterize Guichard nets which are given by cyclic systems as being Moebius equivalent to 1-parameter families of linear Weingarten surfaces. This provides a new method to study families of parallel Weingarten surfaces in space forms. In particular, analogs of Bonnet's theorem on parallel constant mean curvature surfaces can be easily obtained in this setting.Comment: 25 pages, plain Te

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

Interdisziplinäres Schockraum-Management unfallchirurgischer Patienten aus der Sicht der Mitarbeitenden

Zusammenfassung: Einleitung: Wir untersuchten, ob die Mitarbeiterbefragung in der Qualitätskontrolle des Schockraum-Managements von Nutzen sein kann. Methode: Konsekutive anonyme schriftliche Befragung (15Fragen, Likert-Skala 1-5) der klinisch Mitarbeitenden aller Schockraumeinsätze mit Verdacht auf Mehrfachverletzung von Juli 2002 bis Dezember 2003 (Anova; p<0,05). Ergebnisse: Bei 171 unfallchirurgischen Einsätzen retournierten 884Beteiligte den Antwortbogen. Die Beobachtungen der Mitarbeitenden hingen signifikant von der jeweiligen Schockraumsituation ab. Am meisten kritisiert wurden das Zeitmanagement und die eigene Ausbildung (Likert-Skala <4). Leitende- und Oberärzte bewerteten ihren Ausbildungsstand besser als Assistenzärzte und hatten häufiger einen ATLS®-Kurs absolviert (p<0,001). Es fanden sich signifikante systematische Unterschiede in den Beurteilungen, z.B. je nach Fachdisziplin der Antwortenden. Schlussfolgerung: Unser Fragebogen erwies sich als gut diskriminierendes Instrument und kann somit die Erfassung klinischer Parameter im Qualitätsmanagement der Schockraumphase sinnvoll ergänzen. Vor einer breiteren Anwendung werden allerdings zusätzliche Validierungs- und Korrelationsuntersuchungen benötig

Left ventricular global work index and prediction of cardiovascular mortality after transcatheter aortic valve implantation

INTRODUCTION Echocardiography is used for assessment of patients after transcatheter aortic valve implantation (TAVI). Global work index (GWI) integrates LV deformation throughout the cardiac cycle and LV afterload and may be advantageous for long-term follow-up. METHODS We analysed 144 patients with severe aortic stenosis who underwent TAVI and echocardiography within two weeks afterwards. GE EchoPAC v2.6 was applied for determining LV ejection fraction, global longitudinal strain (GLS), stroke work (SW), cardiac power output (CPO), and GWI. The endpoint was cardiovascular mortality. RESULTS During median follow-up of 625 [IQR: 511-770] days, 20 (14%) patients died. Clinical baseline characteristics were comparable between non-survivors and survivors. GWI (p = 0.003) and LVEF (p = 0.039) were lower in non-survivors, while GLS, SW, and CPO were not different. In Kaplan-Meier analysis patients with GWI ≤1234 mmHg% exhibited a lower survival probability (P = 0.006). In univariable Cox regression, a significant mortality association was identified for GWI (P = 0.004), weaker for LVEF (P = 0.014), but not for the other parameters. In multivariable Cox regression, GWI independently improved an LV systolic function model including LVEF and GLS. Similarly, GWI but not LVEF independently improved outcome association of different clinical models. CONCLUSIONS GWI was lower in non-survivors than survivors, differentiated non-survivors from survivors, was associated with mortality independent of clinical or LV parameters, and improved the fitness of clinical or LV prediction models. In contrast, GLS, SW, and CPO did not show any of these properties. GWI provides added value for follow-up after TAVI possibly by integrating LV deformation throughout the cardiac cycle

Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System

The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.Fil: Carabajal, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Asquith, Christopher R. M.. University of North Carolina; Estados UnidosFil: Laitinen, Tuomo. University of North Carolina; Estados UnidosFil: Tizzard, Graham J.. University of North Carolina; Estados UnidosFil: Yim, Lucía. Universidad de la República; UruguayFil: Rial, Analía. Universidad de la República; UruguayFil: Chabalgoity, José A.. Universidad de la República; UruguayFil: Zuercher, William J.. University of North Carolina; Estados UnidosFil: Garcia Vescovi, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentin

Non-surgical oncology – Guidelines on Parenteral Nutrition, Chapter 19

Reduced nutritional state is associated with unfavourable outcomes and a lower quality of life in patients with malignancies. Patients with active tumour disease frequently have insufficient food intake. The resting energy expenditure in cancer patients can be increased, decreased, or remain unchanged compared to predicted values. Tumours may result in varying degrees of systemic pro-inflammatory processes with secondary effects on all significant metabolic pathways. Therapeutic objectives are to stabilise nutritional state with oral/enteral nutrition and parenteral nutrition (PN) and thus to prevent or reduce progressive weight loss. The maintenance or improvement of quality of life, and the increase in the effectiveness and a reduction in the side-effects of antitumor therapy are further objectives. Indications for PN in tumour patients are essentially identical to those in patients with benign illnesses, with preference given to oral or enteral nutrition when feasible. A combined nutritional concept is preferred if oral or enteral nutrition are possible but not sufficient. There are generally no accepted standards for ideal energy and nutrient intakes in oncological patients, particularly when exclusive artificial nutrition is administered. The use of PN as a general accompaniment to radiotherapy or chemotherapy is not indicated, but PN is indicated in chronic severe radiogenic enteritis or after allogenic transplantation with pronounced mucositis or GvH-related gastrointestinal damage for prolonged periods, with particular attention to increased risk of bleeding and infection. No PN is necessary in the terminal phase

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well-characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth-inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4-position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft, SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland