Étude des conséquences fonctionnelles de la mutation SGO1 K23E sur la voie de signalisation TGF-β

Nous avons identifié un nouveau syndrome d’arythmie généralisée rare dans la population franco-canadienne, CAID syndrome (Chronic Atrial and Intestinal Dysrhythmia) causé par une mutation fondatrice récessive dans le gène Shugoshin-like 1 (SGO1). La mutation change une lysine par un acide glutamique à la position 23. Les patients affectés souffrent d'une maladie du nœud sinusal et d'une pseudo-obstruction intestinale chronique. À ce jour, c’est la seule pathologie affectant à la fois le pacemaker cardiaque et le pacemaker intestinal. Nous avons montré que la mutation SGO1 K23E stimule la voie de signalisation TGF-β, qui est impliquée dans de très nombreux processus biologiques, et dont le rôle de SGO1 dans celle-ci reste inconnu. Une étude a identifié la protéine BUB1, impliquée dans la localisation centromérique de SGO1, comme régulatrice de la voie TGF-β (2015). Ce qui suggère une implication possible de SGO1 dans ce processus. L’objectif de ce projet de Maîtrise est de caractériser ce nouveau rôle de SGO1 lors du développement du nœud sinusal, ainsi que l’impact de la mutation K23E. L’état de phosphorylation de protéines impliquées dans cette voie TGF-β a été quantifié dans des fibroblastes de peau de patients et de sujets témoins, par la technologie ALPHA (Amplified Luminescence Proximity Homogenous Assay), et les résultats révèlent que la mutation K23E engendre une augmentation de la voie canonique et une inhibition de la voie non-canonique de TGF-β.We recently identified a novel generalized dysrhythmia syndrome in the French-Canadian population that we termed CAID syndrome (Chronic Atrial and Intestinal Dysrhythmia), caused by a recessive homozygous mutation in the gene Shugoshin-like 1 (SGO1). The mutation changes a lysine by a glutamic acid at the position 23. All patients have sick sinus syndrome as well as chronic intestinal pseudo-obstruction, making it the first generalized pace making syndrome affecting both the cardiac and the intestinal pacemaker. We previously have shown that the SGO1 K23E mutation affect the TGF-ß signaling pathway, which is involved in many crucial biological process, although the role of SGO1 in this pathway has not been well characterized. A study identified the BUB1 protein involved in the centromeric localization of SGO1, as regulator of this pathway (2015). This suggests a possible implication of SGO1 in this process. The objective of this Master project is to characterize this new role of SGO1 during the sinus node development, and the impact of the K23E mutation. The phosphorylation state of some proteins involved in this TGF-β pathway has been quantified in skin fibroblasts of both patients and controls, by using the ALPHA technology (Amplified Luminescence Proximity Homogenous Assay), and the results reveal that the K23E mutation induces an increase of the canonical TGF-β pathway and also, an inhibition of the non-canonical pathway

Intérêt de l'échographie dans la maladie du Dupuytren.

info:eu-repo/semantics/publishe

Intérêt de l’échographie dans la maladie de Dupuytren

info:eu-repo/semantics/nonPublishe

Non-invasive navigation in total knee arthroplasty: a validation study

The purpose of this study was to evaluate intraoperative alignment during total knee arthroplasty using a handheldnavigation system, iAssist, in comparison with conventional optical surgical navigation. Sixty-two consecutive patients were enrolled in this prospective study. iAssist was used to determine implantcomponent positioning. Orientation of the cuts were verified using a conventional optical surgical navigation system. We compared the iAssist system with the conventional system in terms of accuracy, percentage of outliers, bias, and precision.The occurrence of component malalignment was low. Taking standard radiography as the reference, there were no relevantdifferences between the handheld device and optical navigation in terms of measurement of accuracy or in outlier occurrence. Bias was small for both technologies, and precision was comparable. The study provides preliminary evidence that the use of iAssist leads to satisfactory implant alignment. The results from this study imply that iAssist could be a viable alternative to conventional optical navigation

Disc herniation with radiculopathy: epidemiologic and economic indicators of compensation in the Pays de la Loire region

International audienc

Role of A Disintegrin and Metalloprotease-12 in Neutrophil Recruitment Induced by Airway Epithelium.

Among proteases, metalloproteases are implicated in tissue remodeling, as shown in numerous diseases including allergy. ADAMs (A Disintegrin And Metalloprotease) metalloproteases are implicated in physiologic processes such as cytokine and growth factor shedding, cell migration, adhesion, or repulsion. Our aim was to measure ADAM-12 expression in airway epithelium and to define its role during the allergic response. To raise this question, we analyzed the ADAM-12 expression ex vivo after allergen exposure in patients with allergic rhinitis and in vitro in cultured primary human airway epithelial cells (AEC). Clones of BEAS-2B cells transfected with the full-length form of ADAM-12 were generated to study the consequences of ADAM-12 up-regulation on AEC function. After allergen challenge, a strong increase of ADAM-12 expression was observed in airway epithelium from patients with allergic rhinitis but not from control subjects. In contrast with the other HB-epidermal growth factor sheddases, ADAM-10 and -17, TNF-alpha in vitro increased the expression of ADAM-12 by AEC, an effect amplified by IL-4 and IL-13. Up-regulation of ADAM-12 in AEC increased the expression of alpha3 and alpha4 integrins and to the modulation of cell migration on fibronectin but not on collagen. Moreover, overexpression of ADAM-12 in BEAS-2B enhanced the secretion of CXCL1 and CXCL8 and their capacity to recruit neutrophils. CD47 was strongly decreased by ADAM-12 overexpression, a process associated with a reduced adhesion of neutrophils. These effects were mainly dependent on epidermal growth factor receptor activation. In summary, ADAM-12 is produced during allergic reaction by AEC and might increase neutrophil recruitment within airway mucosa

Comparison of four software packages for CT lung volumetry in healthy individuals

Objectives: To compare CT lung volumetry (CTLV) measurements provided by different software packages, and to provide normative data for lung densitometric measurements in healthy individuals. Methods: This retrospective study included 51 chest CTs of 17 volunteers (eight men and nine women; mean age, 30 ± 6 years), who underwent spirometrically monitored CT at total lung capacity (TLC), functional residual capacity (FRC), and mean inspiratory capacity (MIC). Volumetric differences assessed by four commercial software packages were compared with analysis of variance (ANOVA) for repeated measurements and benchmarked against the threshold for acceptable variability between spirometric measurements. Mean lung density (MLD) and parenchymal heterogeneity (MLD-SD) were also compared with ANOVA. Results: Volumetric differences ranged from 12 to 213 ml (0.20 % to 6.45 %). Although 16/18 comparisons (among four software packages at TLC, MIC, and FRC) were statistically significant (P < 0.001 to P = 0.004), only 3/18 comparisons, one at MIC and two at FRC, exceeded the spirometry variability threshold. MLD and MLD-SD significantly increased with decreasing volumes, and were significantly larger in lower compared to upper lobes (P < 0.001). Conclusions: Lung volumetric differences provided by different software packages are small. These differences should not be interpreted based on statistical significance alone, but together with absolute volumetric differences. Key Points: • Volumetric differences, assessed by different CTLV software, are small but statistically significant. • Volumetric differences are smaller at TLC than at MIC and FRC. • Volumetric differences rarely exceed spirometric repeatability thresholds at MIC and FRC. • Differences between CTLV measurements should be interpreted based on comparison of absolute differences. • MLD increases with decreasing volumes, and is larger in lower compared to upper lobes

A new series of trivalent lanthanide (Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy) coordination polymers with a 1,2-cyclohexanedicarboxylate ligand: synthesis, crystal structure, luminescence and catalytic properties

International audienc

Matrix metalloproteinase-8 deficiency promotes granulocytic allergen-induced airway inflammation

Matrix metalloproteinases (MMPs) are involved in inflammatory reaction, including asthma-related airway inflammation. MMP-8, mainly produced by neutrophils, has recently been reported to be increased in the bronchoalveolar lavage fluid (BALF) from asthmatic patients. To evaluate the role of MMP-8 in asthma, we measured MMP-8 expression in lung tissue in an OVAsensitized mouse model of asthma and addressed the effect of MMP-8 deletion on allergen-induced bronchial inflammation. MMP-8 production was increased in lungs from C57BL/6 mice exposed to allergens. After allergen exposure, MMP-8-1-mice developed an airway inflammation characterized by an increased neutrophilic inflammation in BALF and an increased neutrophilic and eosinophilic infiltration in the airway walls. MMP-8 deficiency was associated with increased levels of IL-4 and antiOVA IgE and IgG1 in BALF and serum, respectively. Although allergen exposure induced an enhancement of LPS-induced CXC chemokine, KC, and MIP-2 levels in BALF and lung parenchyma, no difference was observed between the two genotypes. Inflammatory cell apoptosis was reduced in the lungs from MMP-8(-/-) mice. For the first time, our study evidences an important role of MMP-8 in the control of neutrophilic and eosinophilic infiltration during allergen-induced lung inflammation, and demonstrates that the anti-inflammatory effect of MMP-8 is partly due to a regulation of inflammatory cell apoptosis