Brain oscillatory activity in adolescent idiopathic scoliosis

Pathophysiology of Adolescent Idiopathic Scoliosis (AIS) is not yet completely understood. This exploratory study aims to investigate two aspects neglected in clinical practice: a defective postural central nervous system control in AIS, and alterations of body schema due to scoliosis spinal deformities. We recorded EEG data and balance data in four different standing positions in 14 adolescents with AIS and in 14 controls. A re-adaptation of the Image Marking Procedure (IMP) assessed body schema alterations on the horizontal (Body Perception Indices (BPIs)) and vertical direction (interacromial and bisiliac axes inclinations). Our results revealed no differences in balance control between groups; higher EEG alpha relative power over sensorimotor areas ipsilateral to the side of the curve and a significant increase of theta relative power localized over the central areas in adolescents with AIS. The difference in BPI shoulder and BPI waist significantly differed between the two groups. The inclinations of the perceived interacromial axes in adolescents with AIS was opposite to the real inclination. Increased theta activity and alpha lateralization observed may be a compensatory strategy to overcome sensorimotor dysfunction mirrored by altered body schema. Scoliosis onset might be preceded by sensorimotor control impairments that last during curve progression

Dynamic surface topography and its application to the evaluation of adolescent idiopathic scoliosis

Dynamic surface topography is a method to quantify the surface and locations of features acquired from moving and distorting shapes against time. This thesis describes the application of the technique to the potential evaluation of adolescent idiopathic scoliosis patients. Scoliosis or curvature of the spine is one of the major skeletal diseases in adolescents where in the majority of cases the cause is unknown or idiopathic. The progression of the disease occurs in three dimensions with the spine simultaneously curving towards the arms and rotating as it collapses with the first indications usually being changes in body symmetry and back surface shape. Following diagnosis, most children do not exhibit any significant worsening of their condition and are routinely monitored using radiography as frequently as every three months whilst vertebral growth potential remains. In a small number of patients, the lateral curvature can unpredictably worsen requiring, in some cases, surgical intervention to prevent further deterioration and to diminish the deformity. Earlier work by many researchers concentrated on attempting to reduce patient exposure to ionizing radiation by investigating if there was a reliable correlation between progression of the scoliosis and changes in surface topography. The techniques have not gained acceptance as the relational algorithms were found to be insufficiently robust in all cases and measurements acquired from available technologies were prone to artefacts introduced by stance, breathing, 'posture and sway. For many patients the motivation in seeking treatment is for the improvement of their appearance rather than to correct the underlying deformity, so cosmetic concerns and an understanding of the psychosocial and physical impacts of the disease and treatments remain important factors in the clinical decision-making process. In the current environment of evidence based medicine there is a growing need to quantify back surface shape, general body asymmetry and patient capability with the objective of producing an agreed scoring to be used in developing treatment plans and assessing outcomes but to date many clinics continue to rely on qualitative methods to describe cosmetic deformity and ability. The aim of the research was to develop an original, low cost and inherently safe apparatus using well understood video based motion capture technology that overcame the disadvantages of earlier work by simultaneously acquiring multiple samples of back surface shape and the locations of bony landmarks to provide averaged results for a quantitative and reliable analysis of cosmetic defect and physical impairment. 172,650 data samples were acquired from thirty skeletally mature subjects not exhibiting any musculoskeletal disease to define normality limits for Page 2 established morphological measurements and to compare the specificity of the approach with existing single sample techniques. Three novel calculations of back paraspinous volumetric asymmetry were tested of which two were found to be potentially useful clinical indicators of deformity and an index was proposed and tested using simulated data that could offer a single value to describe patient back shape asymmetry. Previous research has found that there is a loss of trunk ranges of motion among postoperative patients that has a direct impact on their quality of life, function and physical capability. Data were acquired from the mature subjects and similar results were observed when compared with published data for preoperative scoliosis patients. This thesis has shown that using averaged tri-dimensional morphological and back shape data combined with measurement of dynamic capability acquired using an inherently safe apparatus have the potential to be clinically useful. The opportunity to routinely and safely quantify the cosmetic defect and trunk ranges of motion of adolescent idiopathic scoliosis patients should stimulate more important research to help improve the quality of life of many affected children throughout the world

Dynamic surface topography and its application to the evaluation of adolescent idiopathic scoliosis

Dynamic surface topography is a method to quantify the surface and locations of features acquired from moving and distorting shapes against time. This thesis describes the application of the technique to the potential evaluation of adolescent idiopathic scoliosis patients. Scoliosis or curvature of the spine is one of the major skeletal diseases in adolescents where in the majority of cases the cause is unknown or idiopathic. The progression of the disease occurs in three dimensions with the spine simultaneously curving towards the arms and rotating as it collapses with the first indications usually being changes in body symmetry and back surface shape. Following diagnosis, most children do not exhibit any significant worsening of their condition and are routinely monitored using radiography as frequently as every three months whilst vertebral growth potential remains. In a small number of patients, the lateral curvature can unpredictably worsen requiring, in some cases, surgical intervention to prevent further deterioration and to diminish the deformity. Earlier work by many researchers concentrated on attempting to reduce patient exposure to ionizing radiation by investigating if there was a reliable correlation between progression of the scoliosis and changes in surface topography. The techniques have not gained acceptance as the relational algorithms were found to be insufficiently robust in all cases and measurements acquired from available technologies were prone to artefacts introduced by stance, breathing, 'posture and sway. For many patients the motivation in seeking treatment is for the improvement of their appearance rather than to correct the underlying deformity, so cosmetic concerns and an understanding of the psychosocial and physical impacts of the disease and treatments remain important factors in the clinical decision-making process. In the current environment of evidence based medicine there is a growing need to quantify back surface shape, general body asymmetry and patient capability with the objective of producing an agreed scoring to be used in developing treatment plans and assessing outcomes but to date many clinics continue to rely on qualitative methods to describe cosmetic deformity and ability. The aim of the research was to develop an original, low cost and inherently safe apparatus using well understood video based motion capture technology that overcame the disadvantages of earlier work by simultaneously acquiring multiple samples of back surface shape and the locations of bony landmarks to provide averaged results for a quantitative and reliable analysis of cosmetic defect and physical impairment. 172,650 data samples were acquired from thirty skeletally mature subjects not exhibiting any musculoskeletal disease to define normality limits for Page 2 established morphological measurements and to compare the specificity of the approach with existing single sample techniques. Three novel calculations of back paraspinous volumetric asymmetry were tested of which two were found to be potentially useful clinical indicators of deformity and an index was proposed and tested using simulated data that could offer a single value to describe patient back shape asymmetry. Previous research has found that there is a loss of trunk ranges of motion among postoperative patients that has a direct impact on their quality of life, function and physical capability. Data were acquired from the mature subjects and similar results were observed when compared with published data for preoperative scoliosis patients. This thesis has shown that using averaged tri-dimensional morphological and back shape data combined with measurement of dynamic capability acquired using an inherently safe apparatus have the potential to be clinically useful. The opportunity to routinely and safely quantify the cosmetic defect and trunk ranges of motion of adolescent idiopathic scoliosis patients should stimulate more important research to help improve the quality of life of many affected children throughout the world.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Book of Abstracts 15th International Symposium on Computer Methods in Biomechanics and Biomedical Engineering and 3rd Conference on Imaging and Visualization

In this edition, the two events will run together as a single conference, highlighting the strong connection with the Taylor & Francis journals: Computer Methods in Biomechanics and Biomedical Engineering (John Middleton and Christopher Jacobs, Eds.) and Computer Methods in Biomechanics and Biomedical Engineering: Imaging and Visualization (JoãoManuel R.S. Tavares, Ed.). The conference has become a major international meeting on computational biomechanics, imaging andvisualization. In this edition, the main program includes 212 presentations. In addition, sixteen renowned researchers will give plenary keynotes, addressing current challenges in computational biomechanics and biomedical imaging. In Lisbon, for the first time, a session dedicated to award the winner of the Best Paper in CMBBE Journal will take place. We believe that CMBBE2018 will have a strong impact on the development of computational biomechanics and biomedical imaging and visualization, identifying emerging areas of research and promoting the collaboration and networking between participants. This impact is evidenced through the well-known research groups, commercial companies and scientific organizations, who continue to support and sponsor the CMBBE meeting series. In fact, the conference is enriched with five workshops on specific scientific topics and commercial software.info:eu-repo/semantics/draf

Reconstruction 3D personnalisée de la colonne vertébrale à partir d'images radiographiques non-calibrées

Les systèmes de reconstruction stéréo-radiographique 3D -- La colonne vertébrale -- La scoliose idiopathique adolescente -- Évolution des systèmes de reconstruction 3D -- Filtres de rehaussement d'images -- Techniques de segmentation -- Les méthodes de calibrage -- Les méthodes de reconstruction 3D -- Problématique, hypothèses, objectifs et méthode générale -- Three-dimensional reconstruction of the scoliotic spine and pelvis from uncalibrated biplanar X-ray images -- A versatile 3D reconstruction system of the spine and pelvis for clinical assessment of spinal deformities -- Simulation experiments -- Clinical validation -- A three-dimensional retrospective analysis of the evolution of spinal instrumentation for the correction of adolescent idiopathic scoliosis -- Auto-calibrage d'un système à rayons-X à partir de primitives de haut niveau -- Segmentation de la colonne vertébrale -- Approche hiérarchique d'auto-calibrage d'un système d'acquisition à rayons-X -- Personalized 3D reconstruction of the scoliotic spine from hybrid statistical and X-ray image-based models -- Validation protocol

Effets de l'estradiol et du chargement mécanique sur la régulation de la POC5 et du récepteur ADGRG7 dans la scoliose idiopathique

La scoliose est une déformation complexe en 3D de la colonne vertébrale ayant une prévalence de 1.5-3% dans la population générale. La forme la plus commune est la scoliose idiopathique (SI) qui inclue la scoliose idiopathique de l’adolescent (SIA) affectant principalement les filles au cours de la puberté. L’étiologie est largement inconnue, mais les observations cliniques révèlent un rôle de l’hérédité ainsi que d’une croissance rapide dans le développement de la SIA. Il existe une forte évidence qu’une composante génétique entre en jeu dans cette pathologie. Récemment, de nombreux gènes ont été suspectés d’être responsables ou de contribuer à la SI. Notre équipe a identifié des variantes du gène POC5, codant pour une protéine centriolaire, dans une large famille française dont plusieurs membres sont atteints de SI. Dans cette même famille, nous avons suspecté l’implication d’une mutation du gène ADGRG7 (récepteur orphelin appartenant aux récepteurs d’adhésion couplés aux protéines G) dans la pathogénicité de la SI. Au travers de nos travaux, nous nous sommes concentrés sur l’élucidation du rôle des protéines POC5 sauvages et mutantes (in vitro et in vivo) ainsi que sur la régulation de l’expression de POC5 et ADGRG7 par l’estradiol (E2), dans le but de tester si ces gènes pourraient être fonctionnellement liés à la scoliose. Afin d’investiguer le rôle du gène POC5 dans la SI, nous avons surexprimé la protéine POC5 mutante dans des lignées cellulaires par transfection transitoire (in vitro) et nous avons induit une perte de fonction du gène POC5 dans un modèle animal, le poisson zèbre (in vivo). Le rôle de POC5 a été étudié par : 1) Analyses de spectroscopie de masse et co-immunoprécipitation afin d’identifier les différents partenaires de liaisons entre la protéine sauvage (wt POC5) et mutante (mut POC5); 2) immunolocalisation de la protéine sauvage et mutante au niveau cellulaire; 3) histologie et immunohistochimie réalisés sur des tissus issus de poissons zèbres contrôles (wt POC5) et scoliotiques (mut POC5). Notre travail a permis d’identifier plusieurs protéines partenaires de la POC5, et nous avons trouvé des interactions fonctionnelles entre ces protéines et la POC5 reliées aux cils et centrosome. Un certain nombre de protéines ciliaires ont été identifiées comme interagissant avec wt POC5 et non avec mut POC5 comme CEP290, RAB11, CKAP5, Annexine 2 et Septine 9. Au niveau cellulaire, la localisation et la colocalisation des protéines wt POC5 et POC5 mutée avec la tubuline alpha acétylée (marqueur ciliaire), confirme la conséquence de la mutation sur la localisation subcellulaire en relation avec la longueur et l’intensité de la coloration du cil. In vivo, nous avons identifié de nombreux défauts de la rétine et de l’oreille interne chez le poisson zèbre POC5 mutant par rapport au contrôle. Enfin, en utilisant différents marqueurs des couches rétiniennes et la tubuline acétylée, nous avons localisé ces défauts dans le segment externe et les cônes de la rétine. Afin d’étudier le rôle possible de POC5 et ADGRG7 dans la SI, nous avons examiné comment POC5 et ADGRG7 est régulé au niveau transcriptionnel. Nous avons utilisé des modèles cellulaires, des ostéoblastes humains dérivées de contrôles et de SIA patient, et nous avons étudié l’expression de la protéine POC5 et ADGRG7 en réponse à une stimulation par l’E2. La région promotrice du gène ADGRG7 a été clonée et analysée pour les éléments cis médiant les effets de l’E2. Les analyses de délétion du promoteur indiquent que le site SP1 dans le fragment 474bp est requis pour une activité basale ainsi que pour une activation hormone-dépendante, et des mutations dans les sites de liaison au sein de cette région résultent en la perte de transactivation. Les résultats d’immunoprécipitation de la chromatine (ChIP) ont montré que le site SP1 ESRα lie le promoteur d’ADGRG7. Nos résultats suggèrent que la régulation de l’expression d’ADGRG7 par l’E2 est due à l’association des protéines ESRα et SP1 au promoteur d’ADGRG7. La même stratégie expérimentale a été appliquée pour l'étude de la régulation de POC5 par E2. L'analyse de délétion et ChIP ont confirmé la régulation de POC5 à travers ESRα. Basé sur des études de promoteur, qPCR, Western blot et ChIP, cette étude clarifie comment POC5 et ADGRG7 sont régulées par l’E2. Un autre aspect de ce projet était d’étudier les différents effets du chargement mécanique sur des cellules, incluant des ostéoblastes humains, exprimant POC5 sauvage ou mutée. Les cellules ont été soumises à un stress mécanique à différents temps, et différentes voies de signalisations (incluant ERK, p38, NFκB) ont été testées. Nos résultats montrent une différence dans la réponse des cellules surexprimant POC5 mutée par rapport aux cellules contrôles. Les effets du chargement comprenant les différentes voies de signalisations ont été montrés comme étant initiés via TRPV4, un canal calcique perméable activé par l’étirement localisé dans le cil primaire et la membrane plasmique.Scoliosis is a complex three-dimensional deformity of the spine, with 1.5–3% prevalence in the general population. The most commonly known type of scoliosis is idiopathic scoliosis (IS), including adolescent idiopathic scoliosis (AIS) affecting principally girls during puberty. The etiology is largely unknown, but clinical observations revealed the role of hereditary and rapid growth in the development of this condition. There exists strong evidence that there is a genetic component to the disease. More recently, several genes were suspected to cause or contribute to IS. Our group identified gene variants of POC5 centriolar protein in a large French family with multiple members affected with IS. In the same family, we suspected the involvement of ADGRG7 (an orphan receptor that belongs to the Adhesion G protein-coupled receptors) gene mutation in the pathogenicity of IS. In the present work, we focused on elucidating the role of wild type (wt) and mutant (mut) POC5 proteins (in vitro and in vivo) as well as the regulation of POC5 and ADGRG7 by estradiol (E2), with the goal to test whether these genes could be functionally connected with scoliosis. To investigate the role of POC5 gene in IS, we overexpressed mutant POC5 in cell lines by transient transfection (in vitro study) and created a loss-of-function model in zebrafish (in vivo study). The role of POC5 was investigated by: 1) mass spectroscopy analysis and co-immunoprecipitation to identify differences in binding partners between the wt POC5 and mut POC5 proteins; 2) immunolocalization of wt and mut POC5 proteins at the cellular level; 3) histology and immunohistochemistry performed on tissues from wt (control) and scoliotic (poc5 mut) zebrafish. Our work identified several interacting partners with POC5, and documented functional connections with respect to cilia and centrosome dysfunction. A number of ciliary proteins were identified to be interacting with wt POC5 but not mut POC5 like CEP290, RAB11, CKAP5, Annexin 2 and Septin 9. At the cellular level, localization and co-localisation of wt POC5 and mut POC5 protein with alpha acetylated tubulin (cilia marker), confirmed the consequence of the mutation on subcellular location with respect to cilium length and staining intensity. In vivo, several defects in the retina of zebrafish and inner ear were identified in mutpoc5 zebrafish compared to wt zebrafish. Finally, using different markers for retinal layers and alpha acetylated tubulin, the defects were localized in the outer segment layer and cones of the retina. To further investigate the possible roles of POC5 and ADGRG7 in IS, we examined how POC5 and ADGRG7 are regulated at the transcriptional level. Human osteoblasts derived from control and AIS patients were used as a cell model, and the expression of POC5 and ADGRG7 protein was monitored upon E2 stimulation. The promoter region of the human POC5 and ADGRG7 gene was then cloned and analyzed for functional cis-elements mediating effects of E2. Deletion analysis of the ADGRG7 promoter indicates that the SP1 site in the 474bp fragment is required for both basal activity and hormone-induced activation, and mutations of the binding sites within this region result in the loss of transactivation. Further results from chromatin immunoprecipitation (ChIP) assay showed that SP1 and ESRα bind to ADGRG7 promoter. Our results suggest that the regulation of ADGRG7 expression by E2 is due to the association of ESRα and SP1 proteins to ADGRG7 promoter. The same experimental strategy was applied for studying the POC5 regulation by E2. Deletion analysis and ChIP confirmed the regulation of POC5 through ESRα. Through promoter studies, qPCR, and western blot and (ChIP) assay, this study clarifies how POC5 and ADGRG7 are regulated by E2. Another aspect of this project was to study the differential effects of mechanical stress on wt and mut POC5 expressing cells, including human osteoblasts. Cells were exposed to mechanical stress for different time points and then different signalling pathways (including ERK, p38, NFκB) were tested. Our results show that there is difference in the response of control normal cells and cells overexpressing the mut POC5. The effects of loading including the signalling pathways were found to be initiated through TRPV4 which is a stretch-activated Ca2+- permeable channel and localizes to the primary cilium and plasma membrane. The importance of this work is that it covers several factors that contribute to the pathogenesis of AIS. Based on our findings, AIS is a complex multifactorial disease where POC5, cilia, E2 and mechanical load intreplay in the pathogenesis of the disease. The significance of this work is that it puts the basics for understanding the molecular mechanisms that are implicated in AIS

Étude de la mécanotransduction dans la scoliose idiopathique de l’adolescence (SIA)

À ce jour, la scoliose idiopathique de l’adolescent (SIA) est la déformation rachidienne la plus commune parmi les enfants. Il est bien connu dans le domaine de recherche sur la SIA que les forces mécaniques, en particulier les forces biomécaniques internes dans le système musculosquelettique, pourraient jouer un rôle majeur dans l’initiation et le développement de la maladie. Cependant, les connaissances sur la transformation des forces et des stimulations mécaniques en activité biochimique sont peu abondantes. Cet axe de recherche est très prometteur et peut nous fournir de nouvelles idées dans le dépistage et le traitement de la SIA. Dans le cadre de cette étude, nous visons à caractériser la mécanotransduction chez les patients atteints de la SIA en employant des techniques novatrices aux niveaux in vivo et in vitro. Antérieurement dans notre laboratoire, nous avons démontré que les niveaux d’Ostéopontine (OPN) plasmatique chez l’humain corrèlent avec la progression et la sévérité de la maladie, et que ces changements sont observables avant le début de la scoliose. En plus, selon la littérature, l’OPN est une molécule sensible à la force mécanique, dont l’expression augmente en réponse dans de nombreux types de cellules chez plusieurs espèces. Toutefois, il n’existe aucune preuve que ce résultat soit valide in vivo chez l’humain. L’hétérogénéité physique et biochimique de la SIA pose un gros défi aux chercheurs. Souvent, il est très difficile de trouver des résultats ayant une grande applicabilité. Les études portant sur les facteurs biomécaniques ne font pas exception à cette tendance. En dépit de tout cela, nous croyons qu’une approche basée sur l’observation des contraintes de cisaillement présentes dans le système musculosquelettique pourrait aider à surmonter ces difficultés. Les contraintes de cisaillement physiologique sont générées par des courants de fluide en mouvement à l’intérieur des os. Aussi, elles sont omniprésentes et universelles chez l’humain, peu importe l’âge, le sexe, la condition physique, etc., ce qui veut dire que l’étudier pourrait fort bien avancer nos connaissances en formant une base fondamentale avec laquelle on pourra mieux comprendre les différences quant à la mécanotransduction chez les patients atteints de la SIA par rapport aux sujets sains. Pour ce projet, donc, nous proposons l’hypothèse que les sujets atteints de la SIA se différencient par leurs réponses respectives à la force mécanique au niveau cellulaire (en termes de l’expression génique) ainsi qu’au niveau in vivo (en termes du marqueur OPN et son récepteur, sCD44). Afin de vérifier la partie de notre hypothèse de recherche concernant l’aspect in vivo, nous avons recruté une cohorte de patients âgés de 9-17 ans, y compris i) des cas pré-chirurgicaux (angle de Cobb > 45°), ii) des cas modérément atteints (angle de Cobb 10-44°), iii) des témoins, et iv) des enfants asymptomatiques à risque de développer la scoliose (selon nos dépistages biochimiques et fonctionnels) d’âge et sexe appariés. Une pression pulsatile et dynamique avec une amplitude variant de 0-4 psi à 0.006 Hz a été appliquée à un des bras de chacun de nos sujets pour une durée de 90 minutes. Au tout début et à chaque intervalle de 30 minutes après l’initiation de la pression, un échantillon de sang a été prélevé, pour pouvoir surveiller les niveaux d’OPN et de sCD44 circulants chez les sujets. Nous avons découvert que le changement des niveaux d’OPN plasmatique, mais pas des niveaux de sCD44, corrélaient avec la sévérité de la difformité rachidienne chez les sujets, ceux ayant une courbe plus prononcée démontrant une ampleur de réponse moins élevée. Pour vérifier la partie de notre hypothèse de recherche concernant la réponse mécanotransductive cellulaire, des ostéoblastes prélevées à 12 sujets ont été mis en culture pour utilisation avec notre appareil (le soi-disant « parallel plate flow chamber »), qui sert à fournir aux ostéoblastes le niveau de contraintes de cisaillement désiré, de manière contrôlée et prévisible. Les sujets étaient tous femelles, âgées de 11-17 ans ; les patients ayant déjà une scoliose possédaient une courbe diagnostiquée comme « double courbe majeure ». Une contrainte fluidique de cisaillement à 2 Pa, 0.5 Hz a été appliquée à chaque échantillon ostéoblastique pour une durée de 90 minutes. Les changements apportés à l’expression génique ont été mesurés et quantifiés par micropuce et qRT-PCR. En réponse à notre stimulation, nous avons trouvé qu’il n’y avait que quelques gènes étant soit différentiellement exprimés, soit inchangés statistiquement dans tous les groupes expérimentaux atteints, en exhibant simultanément la condition contraire chez les témoins. Ces résultats mettent en évidence la grande diversité de la réponse mécanotransductive chez les patients comparés aux contrôles, ainsi qu’entre les sous-groupes fonctionnels de la SIA. Globalement, cette œuvre pourrait contribuer au développement d’outils diagnostiques innovateurs pour identifier les enfants asymptomatiques à risque de développer une scoliose, et évaluer le risque de progression des patients en ayant une déjà. Aussi, dans les années à venir, les profils mécanotransductifs des patients pourraient s’avérer un facteur crucial à considérer cliniquement, particulièrement en concevant ou personnalisant des plans de traitements pour des personnes atteintes.Adolescent idiopathic scoliosis (AIS) is the most commonly occurring musculoskeletal deformity among children today. It is generally well accepted in scoliosis research that mechanical forces, especially the internal biomechanical forces of the musculoskeletal system, could well have a major role in the induction and pathogenesis of the disease. However, the process by which mechanical loads or stimuli are converted into biochemical activity (mechanotransduction) has not been explored so deeply. This emerging facet of research in AIS holds much promise for new insights into the disease. Here, we aim to characterize mechanotransduction in scoliosis patients using some novel techniques at both the in vivo and in vitro levels. Previously in our lab, we demonstrated that the level of plasma osteopontin (OPN) and sCD44 in the human body is a strong indicator of disease progression and severity, and that these changes are observable before scoliosis onset. In the literature, OPN in vitro is known to be mechanosensitive, showing upregulation in response to mechanical stress in a variety of cell types across many species. However, to the best of the author’s knowledge, no literature exists as to whether this behaviour carries over in vivo in humans. A major difficulty in AIS research is the heterogeneity of the disease, both physically and biochemically. Because of this, many times it is difficult to find results with wide applicability to patients. Study of biomechanical factors in AIS is no exception. We believe, however, that study of fluid shear stress in the musculoskeletal system may be able to solve this problem for mechanotransduction-related issues in AIS. Native physiological fluid shear stresses in humans are experienced in the musculoskeletal system, caused by fluid movement over cells therein. These fluid shear stresses are omnipresent and universal in all humans, regardless of age, gender, fitness level, etc., which means that studying it could very well go a long way towards establishing a fundamental basis of understanding the differences as to mechanotransduction in scoliosis patients as opposed to normal cases. In this project, then, we advanced the hypothesis that AIS patients are distinguishable in the way they respond to mechanical force at both the cellular level (in terms of gene expression) as well as globally at the in vivo level (in terms of the scoliosis marker OPN and its receptor sCD44). To test the in vivo portion of our hypothesis, we recruited a cohort of patients between the ages of 9-17, each one of which fell into one of 4 subject groups: i) surgical cases (pre-surgery, Cobb angle > 45°), ii) moderately affected cases (Cobb angle 10-44°), iii) controls, or iv) asymptomatic children at risk of developing scoliosis matched for age and gender against healthy controls. A dynamic, pulsatile, compressive pressure of variable amplitude from 0-4 psi at 0.006 Hz was applied to the arm of each subject for a period of 90 minutes. Initially and at intervals of 30 minutes after the start of force application, blood samples were taken in order to monitor circulating plasma OPN and sCD44 levels in subjects. We found that the change of circulating OPN levels, but not sCD44 levels, measured in vivo in response to our mechanical stimulation was statistically significantly correlated to status of spinal deformity severity, with more severely affected subjects demonstrating lower magnitudes of ΔOPN. To test the cellular portion of our hypothesis, osteoblasts from severely affected AIS patients and unaffected controls were cultured for use with our parallel plate flow chamber (PPFC) apparatus setup, which permits application of fluid shear stress patterns to cells in a predictable, controllable manner. Subjects were all females who fell into the 11-17 years age range, with scoliotic patients presenting with double major curves. A dynamic, sinusoidal and oscillatory fluid shear stress pattern was applied to osteoblasts at 2 Pa, 0.5 Hz for 90 minutes. Overall gene expression changes across RNA samples as a result of our stimulation were measured using microarray and qRT-PCR approaches. In response, only a very small number of genes are either mutually differentially expressed or statistically unchanged across all functional scoliotic subgroups while having the opposite condition in the control group, indicating a great degree of difference in terms of mechanotransductive response as compared internally between AIS functional subgroups, as well as between control and AIS patients. Globally, this project’s work may contribute to the development of innovative diagnostic tools to identify asymptomatic children at risk of developing scoliosis, and to assess the risk of curve progression at an early stage in those already affected. Also, in years to come, the mechanotransductive profile of a patient could be another integral factor to weigh, clinically, when considering or designing treatment plans for affected persons

Étude de la symétrie de la réponse vestibulo-posturale chez des adolescentes ayant une scoliose idiopathique

La scoliose idiopathique de l’adolescence (SIA) est une déformation 3D de la colonne vertébrale, la plus fréquente en orthopédie pédiatrique. Elle peut créer de la douleur, une diminution de l’estime de soi et entraîner plusieurs complications comme des problèmes respiratoires et cardiaques. Si l’étiologie de la SIA est peu connue, il est admis qu’elle est multifactorielle et pourrait impliquer une asymétrie vestibulaire. L’objectif de ce mémoire était d’évaluer l’asymétrie de la voie vestibulospinale chez des adolescentes avec une SIA, par l’analyse spectrale entre l'activité vestibulaire évoquée et la réponse posturale. Méthode: 7 adolescentes avec une SIA et 15 sans SIA ont reçu une stimulation vestibulaire électrique de type stochastique tout en se tenant debout sur une plateforme de forces. Différentes configurations des électrodes ont permis d’induire des stimulations binaurales ou monaurales (gauche et droite), ce qui a induit des changements dans les forces de réaction au sol. La cohérence vestibulo-posturale, la phase et la corrélation croisée entre l’activité vestibulaire et les forces de réaction au sol ont été calculées. Afin de soutirer davantage d’information sur la transformation sensorimotrice, nous avons calculé la norme et l’orientation du vecteur postural résultant. Finalement, nous avons exploré la relation entre l’asymétrie vestibulo-posturale et la sévérité de la scoliose. Résultats: Les adolescentes avec une SIA ont montré une asymétrie dans la cohérence vestibulo-posturale, de même qu’une plus grande variabilité de la phase et un plus lent délai du pic de la corrélation croisée lors de la comparaison des conditions de stimulations monaurales droite et gauche. L’analyse du vecteur postural résultant a révélé une orientation déviée de l’espace intéraural lors des stimulations monaurales gauches. Toutefois, l’asymétrie observée semble être atténuée lors de stimulations binaurales. Conclusion : Les résultats suggèrent une asymétrie de la transformation vestibulo-posturale chez les adolescentes avec une scoliose idiopathique.Adolescence idiopathic scoliosis (AIS) is a 3D deformation of the spine, the most common in pediatric orthopedics. It can cause pain, lower self-esteem, and lead to several complications such as pulmonary and cardiac problems. The etiology of AISis little known, but it is believed to be multifactorial and could imply vestibular asymmetry. The objective of this dissertation was to assess the asymmetry of the vestibulospinal pathways in adolescent girls with AIS, using spectral analysis between the vestibular evoked activity and the postural response. Methods: 7 adolescent girls with AIS and 15 healthy controls received a stochastic electrical vestibular stimulation (SVS) while standing on a force platform. Different electrodes configurations were used to induce binaural or monaural stimulation (leftand right), which induced changes in ground reaction forces. Vestibulo-postural coherence, phase and cross-correlation between vestibular activity and ground reaction forces were calculated. To extract more information on sensorimotor transformation, we calculated the norm and the orientation of the resulting postural vector. Finally, we explored the relationship between vestibulo-postural asymmetry and the severity of scoliosis. Results: Adolescent girls with AIS showed asymmetrical vestibulo-postural coherence, greater phase variability and a delayed peak of the cross-correlation when comparing the right and left monaural stimulation. During left monaural stimulation, the resulting postural vector also deviated from the interaural axis in the AIS group. The asymmetry observed, however, seems to be reduced during binaural stimulation. Conclusion: The results suggest an asymmetry in the vestibulo-postural transformation in adolescent girls with idiopathic scoliosis