This thesis, entitled "The effect of physiotherapy on the function of postural motorics in competitive sportsmen (tennis players)", deals with how the activation of the deep stabilizing muscles affects postural functions in adolescent tennis players. A group of 13 competitive tennis players, aged between 10 and 17 years, were used as our probands. These subjects were examined with a bespoke set of tests of functions and then they were individually educated to train with a set of stabilization functions. After the therapy, they were re-examined with this set of tests again and the results of both sets of tests were compared and evaluated. In particular, we evaluated the changes in reactions of individual players, the changes in separate tests and in groups of tests, and the position of players in match rankings. Powered by TCPDF (www.tcpdf.org)

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Indiana University-Purdue University Indianapolis (IUPUI) / Skeletal manifestations including short stature, osteoporosis, kyphoscoliosis, and tibial dysplasia cumulatively affect approximately 70% of patients with neurofibromatosis type 1 (NF1). Tibial pseudarthrosis, the chronic non-union of a spontaneous fracture, is a debilitating skeletal malady affecting young children with NF1. These non-healing fractures respond poorly to treatment and often require amputation of the affected limb due to limited understanding of the causative mechanisms. To better understand the cellular and molecular pathogenesis of these osseous defects, we have established a new mouse model which recapitulates a spectrum of skeletal pathologies frequently observed in patients with NF1. Nf1flox/-;Col2.3Cre mice, harboring Nf1 nullizygous osteoblasts on a Nf1+/- background, exhibit multiple osseous defects which are closely reminiscent of those found in NF1 patients, including runting (short stature), bone mass deficits, spinal deformities, and tibial fracture non-union. Through adoptive bone marrow transfer studies, we have demonstrated that the Nf1 haploinsufficient hematopoietic system pivotally mediates the pathogenesis of bone loss and fracture non-union in Nf1flox/-;Col2.3Cre mice. By genetic ablation of a single Nf1 allele in early myeloid development, under the control of LysMCre, we have further delineated that Nf1 haploinsufficient myeloid progenitors and osteoclasts are the culprit lineages mediating accelerated bone loss. Interestingly, conditional Nf1 haploinsufficiency in mature osteoclasts, induced by CtskCre, was insufficient to trigger enhanced lytic activity. These data provide direct genetic evidence for Nf1’s temporal significance as a gatekeeper of the osteoclast progenitor pool in primitive myelopoiesis. On the molecular level, we found that transforming growth factor-beta1 (TGF-β1), a primary mediator in the spatiotemporal coupling of bone remodeling, is pathologically overexpressed by five- to six- fold in both NF1 patients and in mice. Nf1 deficient osteoblasts, the principal source of TGF-β1 in the bone matrix, overexpress TGF-β1 in a gene dosage dependent fashion. Moreover, p21Ras dependent hyperactivation of the Smad pathway accentuates responses to pathological TGF-β1 signals in Nf1 deficient bone cells. As a proof of concept, we demonstrate that pharmacologic TβRI kinase inhibition can rescue bone mass defects and prevent tibial fracture non-union in Nf1flox/-;Col2.3Cre mice, suggesting that targeting TGF-β1 signaling in myeloid lineages may provide therapeutic benefit for treating NF1 skeletal defects.

Les lésions traumatiques de la moelle épinière entraînent de graves conséquences d’un point de vue personnel, physique et social chez les individus qui en sont victimes. La prise en charge médicale et chirurgicale de ces patients évolue au fil de l’amélioration des connaissances sur ce qui favorise la récupération neurologique et la qualité de vie à long terme. Pour le chirurgien du rachis, les facteurs modifiables qui influencent de façon significative l’issue neurologique à long terme chez les blessés médullaires thoraco-lombaires sont peu explorés dans la littérature. Le délai entre le trauma et l’exécution du geste chirurgical est un de ces facteurs, mais la définition de chirurgie précoce chez cette population spécifique demeure à être objectivée. De plus, il n’y a pas de paramètres sur le scan préopératoire ayant été décrit pour aider la prise en charge en fonction de l’issue neurologique à long-terme. L’objectif général de ces travaux est de préciser ce qui influence la récupération neurologique chez les patients paraplégiques ayant subi une fracture dans la région thoraco-lombaire et évaluer l’impact de la morphologie de la fracture sur l’effet du délai entre le traumatisme et la chirurgie de décompression et de stabilisation de la colonne vertébrale. Le premier volet de ce mémoire concerne l’étude du seuil de délai chirurgical associé à une récupération neurologique optimale. Pour ce faire, une étude clinique rétrospective a été menée en évaluant plusieurs issues neurologiques à long terme chez une cohorte prospective de 35 patients blessés médullaires secondairement à un traumatisme vertébral de la région thoraco-lombaire. Déterminer de façon objective le seuil de délai optimal pour la récupération neurologique a été possible en utilisant une méthode statistique faisant intervenir des modèles de prédiction sous la forme d’arbres décisionnels élaborés par partition objective récursive. Cette méthode a démontré que la chirurgie de décompression et de stabilisation entreprise dans les 21 heures suivant le moment du traumatisme augmente la probabilité d’améliorer l’état neurologique 12 mois après le traumatisme, en termes de sévérité (grade) de la lésion et du niveau neurologique. Le deuxième volet du mémoire concerne l’étude de la morphologie de la fracture la plus commune de la région thoraco-lombaire, la fracture de type « burst ». De nombreux paramètres radiologiques sont connus et définissent ce type de fracture mais aucun n’a été bien évalué en fonction de la récupération neurologique à long terme. Une deuxième étude clinique rétrospective implique l’étude du scan préopératoire à la recherche de paramètres reliés à l’issue neurologique chez les blessés médullaires avec atteinte motrice sévère. Trois caractéristiques morphologiques fortement associées à la récupération ont été identifiées : la présence d’une fracture complète de la lame, le recul de plus de 4 mm de la portion inférieure du mur postérieur du corps vertébral et la présence de comminution du fragment de corps vertébral rétropulsé dans le canal spinal. Ces paramètres sont des facteurs de pronostic défavorable de récupération neurologique plus importants que l’atteinte neurologique initiale ou l’estimation du degré d’énergie impliquée durant le traumatisme. Puisque ces paramètres décrivent la géométrie du canal spinal endommagé lors d’une fracture de type « burst », ils offrent un reflet de l’énergie locale dissipée dans le canal spinal et transmise aux éléments neuraux. Le troisième volet du mémoire implique l’intégration des nouvelles connaissances issues des deux articles présentés, à la recherche de l’influence de certains paramètres morphologiques sur l’effet de la chirurgie précoce sur la récupération neurologique. Les analyses complémentaires effectuées sur la cohorte de patients atteints de fracture de type « burst » n’ont pas démontré que l’avantage procuré par une chirurgie de décompression et stabilisation précoce était modifié ou altéré par la présence d’un des paramètres démontrés comme importants d’un point de vue neurologique. Ces travaux permettent de mieux guider le chirurgien du rachis dans la planification du geste chirurgical de par une meilleure compréhension des facteurs prédictifs de l’issue neurologique à long terme. En déterminant un seuil de délai objectif optimal de 21 heures, ils permettent d’établir une recommandation pour la définition même de la chirurgie précoce chez le blessé médullaire thoraco-lombaire. Ils proposent également une base pour l’étude subséquente de nouveaux paramètres clés quantifiables sur le scan préopératoire, un examen essentiel et disponible chez tous les patients, et de leur relation potentielle avec le choix de l’approche chirurgicale idéale ainsi qu’avec de multiples issues neurologiques et non-neurologiques. / Traumatic spinal cord injury (TSCI) is a debilitating condition that leads to many adverse consequences on a personal, physical and social standpoint for the injured victim. Medical and surgical care evolved along with the progression of understanding regarding what factors lead to better neurological recovery and overall quality of life in paralyzed patients. With respect to surgical care, modifiable factors significantly related to neurological recovery in thoracolumbar TSCI are not well known. In this regard, the optimal timing threshold for surgical spinal decompression and stabilization has not been demonstrated objectively. Moreover, there are no radiological parameter on the pre-operative computed tomography scan (CT scan) that have been shown to predict long term neurological outcome. The main goal of the presented work is to provide precise identification of such factors, and therefore evaluate the impact of the spine fracture specific morphological features on the effect of early surgical care. The first part involves the assessment of the optimal surgical timing threshold for neurological recovery. A retrospective clinical study was conducted to evaluate several neurological outcome measures in a prospective cohort of 35 thoracolumbar TSCI patients. Thresholds were obtained from the elaboration of prediction models with the use of Classification And Regression Tree (CART) statistical analysis. The first article demonstrated that for optimal recovery of the neurological level of injury, a timing threshold of a maximum of 21 hours should ideally be respected between the traumatic event and the beginning of the surgical intervention. The second part encompasses the study of the morphology of the fractured vertebrae in thoracolumbar burst fractures. Many radiological descriptors are used to describe these severe spine compression injuries but few have been evaluated with regards to neurological recovery. A second retrospective clinical study was conducted and associated a thorough examination of the preoperative CT scan reconstructions to the assessment of long term neurological outcome. Three morphologic parameters were found to be linked to poor prognostic of neurological recovery: complete lamina fracture, comminution of the posteriorly retropulsed fragment and vertebral body postero-inferior corner translation of 4 mm or more. Such features, all three describing the disrupted anatomy of the spinal canal, could be potential indicators of the amount of energy locally dissipated to the neural elements. These parameters were found to be more important to predict neurological outcome than the initial neurologic examination and global trauma energy indicators. The third part integrates the notions derived from the two presented studies and aims to assess for the influence of the presence of specific fracture parameters on the effect of early surgery regarding neurological outcome. Additional analyses did not show that the advantage of early surgery, defined in the first article, was influenced by the presence of any of the relevant fracture features demonstrated in the second article. Therefore, this work emphasizes on the importance of early surgery for better neurological recovery and serves to guide the surgeon in planning the timing of the intervention. Defining the concept of early surgery is key in implementing future retrospective or prospective research protocols. It also highlights the importance of new morphological features of the most common type of thoracolumbar fracture. It sets standards for further research involving preoperative CT scan parameters and their potential relationship with surgical approach, neurological and non-neurological outcomes.

<p dir="ltr">People suffering from COPD are also known to suffer from other musculoskeletal issues like fracture risk, back pain, etc. Intervertebral disc degeneration (IVD) is a prominent cause of back pain and inflammation, influenced by factors such as aging, sudden loading, and genetics. <i>SERPINA1</i>, a common genetic variant in individuals with chronic obstructive pulmonary disease (COPD), encodes the alpha-antitrypsin protein (AAT). AAT deficiency is also associated with IVD degeneration, bone loss, and gait impairment. Currently, AAT-deficient individuals receive costly and short-lived weekly AAT injections, with no established guidelines for managing IVD degeneration and osteoporosis. Our primary research objective was to examine the effects of <i>serpinA1a/c</i> using a mouse model with global knockout (KO) of <i>serpinA1a/c</i>, generated through CRISPR technology, on intervertebral discs (IVD) and bone. We found that global deletion of <i>serpinA1a/c</i> was found to cause IVD elastin degradation, leading to a loss of mechanical properties. Moreover, <i>serpinA1</i> was associated with increased bone-resorbing cells (osteoclasts) and a reduction in bone-forming cells (osteoblasts). Notably, sexual dimorphism was observed, with female IVDs exhibiting less degeneration than male counterparts, and <i>serpinA1a/c</i> KO mice were protected from mechanically-induced tail compression. Even in human IVDs, males expressed more AAT-1 compared to female IVDs. There are no FDA-approved drugs currently existing for IVD degeneration. Since IVD degeneration frequently occurs in individuals with osteoporosis, it shows a probable cross-talk happening between IVD and bone. In our study, we found the association of <i>serpinA1 </i>with estrogen receptor alpha and osteoclasts. Hence, we investigated the potential of raloxifene, an FDA-approved selective estrogen receptor modulator (SERM) typically prescribed to post-menopausal women for osteoporosis treatment, in averting IVD degeneration and improving mechanical characteristics in IVD. Our findings suggest that raloxifene injection may retard IVD degeneration induced by AAT deficiency, particularly in male mice. Furthermore, the latter study touched upon a conditional <i>serpinA1a</i> mouse model crossed with aggrecan-cre, specifically targeting <i>serpinA1a</i>-expressing cells in the IVD while sparing bone. Conditional <i>serpinA1a</i> deletion induced mild IVD degeneration without affecting bone loss. In summary, this study serves as a foundation for testing potential treatments for AAT patients with IVD degeneration and osteoporosis. It also provides compelling evidence for considering raloxifene as a treatment option for IVD degeneration in AAT-deficient patients experiencing IVD-related pain.</p>

Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine and other affected joints, which is highly heritable, being strongly influenced by the HLA-B27 status, as well as hundreds of mostly unknown genetic variants of smaller effect. The aim of my research was to confirm some of the previously observed genetic associations and to identify new associations, many of which are in biological pathways relevant to AS pathogenesis, most notably the IL-23/T_H17 axis (IL23R) and antigen presentation (ERAP1 and ERAP2). Studies presented in this thesis include replication and refinement of several potential associations initially identified by earlier GWAS (WTCCC-TASC, 2007 and TASC, 2010). I conducted an extended study of IL23R association with AS and undertook a meta-analysis, confirming the association between AS and IL23R (non-synonymous SNP rs11209026, p=1.5 x 10-9, OR=0.61). An extensive re-sequencing and fine mapping project, including a meta-analysis, to replicate and refine the association of TNFRSF1A with AS was also undertaken; a novel variant in intron 6 was identified and a weak association with a low frequency variant, rs4149584 (p=0.01, OR=1.58), was detected. Somewhat stronger associations were seen with rs4149577 (p=0.002, OR=0.91) and rs4149578 (p=0.015, OR=1.14) in the meta-analysis. Associations at several additional loci had been identified by a more recent GWAS (WTCCC2-TASC, 2011). I used in silico techniques, including imputation using a denser panel of variants from the 1000 Genomes Project, conditional analysis and rare/low frequency variant analysis, to refine these associations. Imputation analysis (1782 cases/5167 controls) revealed novel associations with ERAP2 (rs4869313, p=7.3 x 10-8, OR=0.79) and several additional candidate loci including IL6R, UBE2L3 and 2p16.3. Ten SNPs were then directly typed in an independent sample (1804 cases/1848 controls) to replicate selected associations and to determine the imputation accuracy. I established that imputation using the 1000 Genomes Project pilot data was largely reliable, specifically for common variants (genotype concordence~97%). However, more accurate imputation of low frequency variants may require larger reference populations, like the most recent 1000 Genomes reference panels. The results of my research provide a better understanding of the complex genetics of AS, and help identify future targets for genetic and functional studies.