Les pathologies du système musculosquelettique concernant les déformations / anomalies osseuses et musculaires (e.g. paralysie cérébrale) ont un fort impact sur la qualité de vie des personnes concernées. Les objectifs de la thèse sont d’approfondir les études précédentes en intégrant la modélisation de l’incertitude des données biomécaniques et biomédicales dans les modèles de diagnostic prédictif des pathologies du système musculosquelettique. L’intervalle a été choisi pour représenter l’incertitude des données biomécaniques. Ce formalisme est simple et peu coûteux sur le plan du calcul. Les données (physiologiques, morphologiques, mécaniques et analyse du mouvement) ont été recueillies à partir de la littérature en utilisant les moteurs de recherche des articles scientifiques fiables pour établir un espace d’incertitude. La nouvelle méthode de classement (nommée US-ECM) proposée est une méthode de classement semi-supervisé qui utilise la partition crédale pour représenter les connaissances partielles sur les clusters. L’utilisation de la fonction de croyance pour représenter ces éléments de connaissance permet de les combiner d’une manière souple et robuste. De plus, l’extension de cette méthode avec un espace d’incertitude multidimensionnelle a montré la meilleure performance par rapport à la version originale. L’analyse des avis d’expert permettra d’inclure ou d’exclure les sources de données selon leurs niveaux de fiabilité. Ensuite, le modèle de regroupement (US-ECM) développé sera appliqué sur une nouvelle base de données pour évaluer l’impact de la fiabilité des données sur la performance de diagnostic. / The aim of the project is to investigate the modeling of the reliability/incertitude/imprecision of biomedical and biomechanics data (medical images, kinematics/kinetics/EMG data, etc.) and its propagation in the predictive diagnosls models of the disorders of musculoskeletal systems. These diagnosis models will be based on multimodal and multidimensional patient data (3D medical imaging, mechanical data,dinical data,etc.). The literature-based data have been collected to estabish an uncertainty space, which represents fused data from multiple sources, of morphological, mechanical, and movement analysis properties of the musculoskeletal system from multiple sources (i.e. research papers from Science Direct and Pubmed). After that,a new clustering method (US-ECM) is proposed for integrating fused data from multiple sources ln form of a multidimensional uncertainty space (US). Reliability of biomechanical data was evaluated by a fusion approach expert opinion. Reliability criteria of a data source (ie scientific paper published) focus on the technique used the acquisition protocol and measurement and the number of data. A system of questionnaires was developed to co!lect expert opinion. Then, the theory of beliet functions has been applied to merge these opinion to establish a confidence level each data source.

Despite extensive research into musculoskeletal disorders (MSDs) they continue to plague workers. Manual materials handling (MMH), in particular the concurrence of load manipulation and awkward body posture, has been identified as a key factor in the onset of MSDs. Only a few studies have looked at the interaction between manipulation tasks and working posture during assembly tasks and as a result their relationship has not been widely explored. Assessing the stresses resulting from individual task factors and body posture in isolation and adding them together may be too simplified to estimate an overall risk profile, since this does not take into account that there may be a non-linear interaction in strain responses when manipulation task and body posture interact. Therefore, the present study investigated biophysical, physiological and psychophysical responses to combined tasks, rather than individual tasks of body posture and manipulative tasks. The objective of the research was to establish the interactive effects of constrained body postures and manipulative tasks and to identify whether a cumulative or compensatory reaction occurs during this interaction. Nine conditions were assessed in a laboratory setting, which included combinations of three working postures (standing, sitting and stooping) and three assembly tasks (torque wrenching, precision and no task). Thirty-six subjects were required to complete all nine conditions, with each condition lasting ninety seconds. Muscle activity was recorded for seven muscles from the upper extremity, trunk and lower extremity regions and was complemented by physiological (heart rate, tidal volume, minute ventilation, oxygen consumption, energy expenditure and breathing frequency) and psychophysical (body discomfort) data. At the completion of all nine conditions subjects completed a retrospective psychophysical rating questionnaire pertaining to discomfort felt during the conditions. Responses obtained for the different task and posture combinations revealed compensatory reactions (additive > combined) for most of the conditions assessed for the biomechanical and physiological responses. In the majority of cases for muscle activity, no significant differences were found between the combined and the additive effects (p < 0.05), while for the physiological responses there were mostly significant differences observed. Psychophysical responses indicated that there was a significant difference overall between the additive and combined effects. The results of this study demonstrate that in order to identify risk areas, manipulation tasks and constrained working postures may be considered either in isolation and added together (additive) or as a combined task, since there were very few significant differences observed between these two effects. Further studies are required, however, to provide conclusive evidence.

Le système musculo-squelettique permet la mobilité. Le développement des muscles, du tissu conjonctif (TC) et des os est coordonné de manière très précise. Osr1 encode pour un facteur de transcription qui est exprimé au niveau du TC musculaire au cours du développement. Le but de cette thèse est d'élucider la fonction d’Osr1 dans la régulation cellulaire non-autonome de la formation des muscles au niveau des membres dans le modèle murin. Le traçage génétique a révélé que les cellules Osr1+ sont à l’origine de plusieurs TC, y compris musculaire, cutané et pulmonaire, mais aussi à l’origine du muscle lisse et des adipocytes bruns. L’analyse phénotypique des embryons de souris Osr1GCE/GCE à E13.5 a révélé des défauts dans l’organisation des muscles. L’analyse transcriptomique montre deux caractéristiques moléculaires causées par le manque d'activité d’Osr1. Tout d'abord, Osr1 réprime l'expression de gènes associés au développement du cartilage et du tendon, ce qui suggère qu’Osr1 confère une identité «tissu conjonctif musculaire». Ensuite, Osr1 régule positivement l'expression des composants de la matrice extracellulaire (MEC). De plus, l’expression de nombreuses molécules de signalisation est diminuée dans les cellules déficientes pour Osr1. Ces résultats montrent l’importance des cellules Osr1+ du TC dans la formation des muscles des membres. Ces résultats montrent également qu’Osr1 régule la transcription des composants de la MEC au niveau du tissu conjonctif musculaire. Enfin, ils suggèrent qu’Osr1 exerce sa fonction par l'intermédiaire de facteurs sécrétés pour assurer le bon développement musculaire. / The musculoskeletal system allows body motion. Despite the distinct mesodermal origins of its components, the development of muscle, connective tissue (CT) and bone is highly coordinated. Osr1 encodes a zinc-finger transcription factor expressed in muscle CT in limbs. The aim of the PhD was to elucidate Osr1 function in the non-cell autonomous regulation of mouse limb muscle formation. Genetic lineage tracing revealed that Osr1+ cells are progenitors for several CTs, including muscle, dermal and lung CTs, but also for smooth muscle and brown adipocytes. Comprehensive phenotypic analysis of skeletal muscles in E13.5 Osr1GCE/GCE mouse embryos revealed impaired muscle formation. Transcriptomic analysis highlighted two major molecular characteristics caused by the lack of Osr1 activity. First, Osr1 actively repressed the expression of genes associated with cartilage and tendon development, suggesting that Osr1 confers a muscle connective tissue identity. Second, Osr1 positively regulated the expression of components of the extracellular matrix (ECM). In addition to the decrease of ECM components, numerous signaling molecules were significantly down-regulated in Osr1-deficient cells of mutant embryos. This highlights the function of Osr1+ resident connective tissue cells in limb muscle formation. It also establishes that Osr1 regulates the transcription of ECM components in limb muscle CT. Lastly, it suggests that Osr1 exerts its function via chemokines and secreted factors to ensure proper muscle development.

Introduction First described in 2002, osteonecrosis of the jaw (ONJ, or avascular necrosis of the jaw) is an uncommon but potentially serious side effect of treatment with bisphosphonates. Although typically identified in patients with multiple myeloma and other malignancies, a few cases have been reported in patients taking bisphosphonates - a potent drug class used in the treatment of osteoclast-mediated bone resorption issues, including postmenopausal osteoporosis, Paget's disease, multiple myeloma, and malignant hypercalcemia. The clinical diagnosis of ONJ can be obscured by jaw pain, abscess, swelling, and fistulas, but exposed bone is a distinctive sign. This reports a case of ONJ secondary to bisphosphonate use in a 65-year-old woman and clinical management complications. Case Presentation A 65-year-old lady with history of age-related osteoporosis and compression fractures on alendronate for 4 years, squamous cell carcinoma of neck status post excision and radiotherapy 11-years prior, Sjogren's syndrome and discoid lupus on hydroxychloroquine, diabetes, hypertension, stroke and multiple dental abscesses presents with persistent neck pain. Initial CT neck with contrast showed diffuse fat stranding. Subsequently, alendronate was discontinued due to jaw necrosis suspicion. Eight months later, repeat CT scan showed new non-mass-like soft tissue thickening in the subcutaneous fat abutting the right anterior mandible with mandibular teeth cavities and periapical lucencies, likely to be periodontal cellulitis versus radiation osteonecrosis. Later, patient complained of a piece of bone penetrating the skin of her chin and presented with continuous drainage from sinus tract in her mandible, which was diagnosed as osteonecrosis attributed to bisphosphonates, previous radiation therapy, and dental abscesses. Patient was started on abaloparatide, an osteo-anabolic medication for osteoporosis and enrolled in hyperbaric oxygen therapy which immensely helped in controlling sinus drainage. Patient is currently awaiting mandibular reconstruction surgery. Discussion ONJ, often associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw, is a rare complication of bisphosphonate therapy. Currently, no prospective data exists to advise the benefits of therapy discontinuation however most clinical practices tend to discontinue at least temporarily. The incidence increases with longer treatment duration, particularly when therapy exceeds four years. Risk factors for developing ONJ while taking bisphosphonates include IV administration, anticancer therapy, dose and duration of exposure, dental extractions/implants, glucocorticoids, smoking, diabetes, and preexisting dental disease. Case reports and series suggest benefit from hyperbaric oxygen therapy in wound healing, pain, and quality of life at three months, however no significant differences exist with outcomes beyond three months. Patients being considered for therapy with a bisphosphonate should be thoroughly evaluated for dental issues, prior to initiating therapy. Conservative management with limited debridement, antibiotic therapy as needed, and topical mouth rinses rather than aggressive surgical resection are recommended. Conservative therapy may result in healing in a significant proportion of patients. Surgical resection of necrotic bone should be reserved for refractory or advanced cases. Providers should remain cautious while prescribing high doses of bisphosphonates in patients with increased risk factors to prevent, timely diagnose and treat this condition. References Edwards BJ, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 2008; 9:1166. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479. Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008; 23:826.

Skeletal muscle differentiation requires synergy between tissue-specific transcription factors, chromatin remodeling enzymes and the general transcription machinery. Here we demonstrate that two distinct protein arginine methyltransferases are required to complete the differentiation program. Prmt5 is a type II methyltransferase, symmetrically dimethylates histones H3 and H4 and has been shown to play a role in transcriptional repression. An additional member of the Prmt family, Carm1 is a type I methyltransferase, and asymmetrically methylates histone H3 and its substrate proteins. MyoD regulates the activation of the early class of skeletal muscle genes, which includes myogenin. Prmt5 was bound to and dimethylates H3R8 at the myogenin promoter in a differentiation-dependent fashion. When proteins levels of Prmt5 were reduced by antisense, disappearance of H3R8 dimethylation and Prmt5 binding was observed. Furthermore, binding of Brg1 to regulatory sequences of the myogenin promoter was abolished. All subsequent events relying on Brg1 function, such as chromatin remodeling and stable binding by muscle specific transcription factors such as MyoD, were eliminated. Robust association of Prmt5 and dimethylation of H3R8 at myogenin promoter sequences was observed in mouse satellite cells, the precursors of mature myofibers. Prmt5 binding and histone modification were observed to a lesser degree in mature myofibers. Therefore, these results indicate that Prmt5 is required for dimethylating histone at the myogenin locus during skeletal muscle differentiation in order to facilitate the binding of Brg1, the ATPase subunit of the chromatin remodeling complex SWI/SNF. Further exploration of the role of Prmt5 during the activation of the late class of muscle genes revealed that though Prmt5 is associated with and dimethylates histones at the regulatory elements of late muscle genes in tissue and in culture, it was dispensable for late gene activation. Previous reports had indicated that Carm1 was involved during late gene activation. We observed that Carm1 was bound to and responsible for dimethylating histones at late muscle gene promoters in tissue and in culture. In contrast to Prmt5, a complete knockout of Carm1 resulted in abrogation of late muscle gene activation. Furthermore, loss of Carm1 binding and dimethylated histones resulted in a disappearance of Brg1 binding and chromatin remodeling at late muscle gene loci. Time course chromatin immunoprecipitations revealed that Carm1 binding and histone dimethylation occurred concurrently with the onset of late gene activation. In vitro binding assays revealed that an interaction between Carm1, myogenin and Mef2D exists. These results demonstrate that Carm1 is recruited to the regulatory sequences of late muscle genes via its interaction with either myogenin or Mef2D and is responsible for dimethylates histones in order to facilitate the binding of Brg1. Therefore, these results indicate that during skeletal muscle differentiation, distinct roles exist for these Prmts such that Prmt5 is required for activation of early genes while Carm1 is essential for late gene induction.

The Runx family of transcription factors supports cell fate determination, cell cycle regulation, global protein synthesis control, and genetic as well as epigenetic regulation of target genes. Runx1, which is essential for hematopoiesis; Runx2, which is required for osteoblast differentiation; and Runx3, which is involved in neurologic and gut development; are expressed in the growth plate during chondrocyte maturation, and in the chondrocytes of permanent cartilage structures. While Runx2 is known to control genes that contribute to chondrocyte hypertrophy, the functions of Runx1 and Runx3 during chondrogenesis and in cartilage tissue have been less well studied. The goals of this project were to characterize expression of Runx proteins in articular cartilage and differentiating chondrocytes and to determine the contribution of Runx1 to osteoarthritis (OA). Here, the expression pattern of Runx1 and Runx2 was characterized in normal bovine articular cartilage. Runx2 is expressed at higher levels in deep zone chondrocytes, while Runx1 is primarily expressed in superficial zone chondrocytes, which is the single cell layer that lines the surface of articular cartilage. Based on this finding, the hypothesis was tested that Runx1 is involved in osteoarthritis, which is a disease characterized by degradation of articular cartilage and changes in chondrocytes. These studies showed that Runx1 is upregulated in articular cartilage explants in response to mechanical compression. Runx1 was also expressed in chondrocytes found at the periphery of OA lesions in the articular cartilage of mice that underwent an OA-inducing surgery. Runx1 was also upregulated in cartilage explants of human osteoarthritic knees, and IHC data showed that Runx1 is mainly expressed in chondrocyte “clones” characteristic of OA. To ascertain the potential function of the upregulation of Runx1 in these cartilage stress conditions and disease states, the hypothesis was tested that Runx1 is upregulated in very specific chondrocyte populations in response to the cartilage damage in osteoarthritis. These studies addressed the properties of these cells that related to functions in cell growth and differentiation. In both the surface layer of normal articular cartilage, and in OA cartilage, Runx1 expression by IF co-localized with markers of mesenchymal progenitor cells, as well as markers of proliferation Ki-67 and PCNA. This finding indicated that Runx1 is found in a population of cells that represent a proliferative population of mesenchymal progenitor cells in osteoarthritis. To further address Runx1 function and identify downstream targets of Runx proteins, a promoter analysis of genes that are known to be either downregulated or upregulated during chondrocyte maturation was done. These studies found that many of these genes have 1 or more Runx binding sites within 2kb of their transcription start site, indicating that they are potential downstream Runx target genes. Lastly, some preliminary experiments were done to characterize novel roles of Runx proteins in the chondrocyte. Runx proteins have been shown to epigenetically regulate their target genes by remaining bound to them throughout mitosis, “poising” them for transcription upon exit from mitosis. The hypothesis that Runx proteins also function by remaining bound to their target genes throughout mitosis in chondrocytes was tested. It was demonstrated by immunofluorescense imaging of Runx proteins on metaphase chromosomes of ATDC5 cells, that Runx2 remains bound to chromosomes during mitosis. Cell proliferation and hypertrophy are both linked to increases in protein synthesis. Runx factors, which regulate rates of global protein synthesis, are expressed in both proliferating and hypertrophic chondrocytes. Thus, it was hypothesized that Runx proteins regulate rates of global protein synthesis during chondrocyte maturation. These studies showed that the overexpression of Runx proteins in a chondrocyte cell line (ATDC5) did not affect protein synthesis rates or levels of protein synthesis machinery. Additionally, Runx proteins did not affect proliferation rates in this chondrocyte cell line.

Load-velocity relationships may vary between people of different strength levels and across different loads. The purpose of this dissertation was to investigate how external loads influence the velocity characteristics of the back squat exercise, and the influence of strength on these variables. Healthy male students with a history of resistance training completed repetitions at specified intensities of their estimated one-repetition maximum (1RM) until they reached 1RM. Back squat 3D motion analysis was captured using four Vicon T010 cameras (Vicon Motion Systems Ltd.; Oxford, UK) and Vicon Nexus 1.8.5 software. Data were transported into R custom coding statistical analysis software (version 3.5.2; The R Foundation) to calculate velocity analyses which determined mean and peak concentric (MCV, PCV) and eccentric (MEV, PEV) values. Participants were grouped by their relative strength (body mass/1RM) in the back squat, as well as their ability to move often prescribed loads with greater speed (63-70%1RM, 83-87%1RM). Between-groups comparisons were made for MCV at all loading conditions, and correlational relationships between all velocity measures (MEV, PEV, MCV, PCV) were examined for each group. For all subjects, there was a significant effect for relative intensity (%1RM) on MCV, but only for the groups organized by MCV at 63-70%1RM and 83-87%1RM was there a between-subjects effect for group. Correlational analyses between velocity measurements during concentric and eccentric phase of the back squat showed a tendency for high relationships (r = 0.5-0.69) between all phases that weakened as the relative intensity increased. These differences were illustrated uniquely between subject grouping conditions. These results indicate that load-velocity characteristics of the back squat cannot necessarily be positively related to strength level in the movement, and that profiling athletes by their velocities at specific relative intensities could be an effective means of organization.

The aim of this study was to investigate the relationship between thigh intramuscular fat (intraMF) and intermuscular fat (IMF) with quadriceps and hamstrings power and physical performance in women (n=20) with clinical, radiographic knee osteoarthritis (OA). Secondarily, we investigated the correlation between thigh and calf fat volumes, and the agreement between 3.0T and 1.0T MRI for quantifying fat. The thigh and calf of the symptomatic leg were scanned using 3.0T MRI with the IDEAL sequence, and fat separated images were analyzed using semi-automated software to quantify intraMF, IMF and muscle. The calf was also scanned using 1.0T MRI with a Fast Spin Echo (FSE) sequence. Knee extensor and flexor isokinetic power was measured at 20% and 40% of individuals’ maximum voluntary isometric contraction (MVIC) torque, and surface electromyography (EMG) measured activation. We found no relationship between quadriceps or hamstrings intraMF and knee extensor or flexor power, respectively. In addition, there were no relationships between intraMF and performance-based tests. There was a correlation between thigh and calf intraMF (r=0.759; p=0.001) and a trend toward a correlation in IMF (r=0.436; p=0.055). There was agreement and a correlation between calf intraMF (r=0.779; p=0.001) and IMF (r=0.956; p=0.001) using 3.0T and 1.0T MRI. There is disagreement about the relationship of intraMF and quadriceps strength, although studies have found that intraMF is related to decreased physical performance. The importance of calf fat subsets in physical performance of individuals with OA should be further investigated. Power analysis demonstrated a sample size (n=91) is recommended for future investigations of intraMF and power in OA. / Thesis / Master of Science in Medical Sciences (MSMS)

Submitted in fulfilllment of the requirements for the Masters in Nursing degree, Durban University of Technology, 2014. / Introduction Work-related musculoskeletal disorders are the most commonly reported work-related illnesses impacting on the quality of life of nurses. Absenteeism, work restriction, loss of income and disability are related outcomes. Nurses are at a higher risk of work-related musculoskeletal disorders (WMSD) compared to other healthcare professionals because of the nature of their duties. Problem statement The relationship between work-related musculoskeletal disorders, absenteeism and visits to the staff clinic by nurses has not been established in South Africa. Purpose The purpose of this study was to determine the prevalence of WMSD in nurses and its relationship to absenteeism and visits to the staff clinic by nurses in a selected eThekwini District hospital. Research method A cross-sectional quantitative descriptive survey was conducted in two stages namely the prospective cross-sectional survey of nurses and the retrospective review of records. A random sample of 231 nurses was selected, proportionally, from all nursing ranks and invited to fill in the self-administered musculoskeletal questionnaire. Results The lifetime prevalence of WMSD in nurses in this study was 77% with the twelve months prevalence of 67% and the seven days prevalence of 43%. The prevalence of low back pain was higher (21% for twelve months and 47% for seven days) than that of other body regions with a higher tendency (65%) of WMSD affecting more than two body regions. Although the prevalence and patterns of WMSD was almost the same across all nursing ranks, nurses working in the Out Patients Department reported the highest prevalence (22%). There was no significant relationship between age, gender and smoking; however, a strong correlation between WMSD and participation in physical exercise, work task and workload was noted. No relationship could be established between WMSD and staff visits to the staff clinic as well as amount of sick leave taken. Conclusion This study showed that WMSD is high in the selected hospital. Nurses working in the Outpatients department reported the most WMSD; body parts affected was not related to age, gender, nurse rank or unit in which the nurse worked. There is a problem of under- reporting of WMSD. Nurses working in this hospital have an option of attending their private health service providers even following a WMSD. In these cases the staff clinic is unable to keep accurate statistics of WMSD, conduct reviews and proper management of the WMSD.

Dissertation submitted in compliance with the requirements for the Masters Degree in Chiropractic at the Durban University of Technology, 2009 / Occupational injuries sustained by Emergency Rescue Care workers have been well documented. However, despite their high rates of injury, the literature regarding the risk factors for work-related musculoskeletal injuries (WRMSIs) in the fire service has not been well-established, especially in South Africa. Objectives: To determine the prevalence and risk factors for musculoskeletal injuries in the Durban Metropolitan Fire Department and to evaluate the relationship between selected risk factors and the prevalence of musculoskeletal injuries. Methods: This was a descriptive study from a large urban Fire Department employing 350 active firefighters. Using a cross sectional study design, a retrospective analysis investigated the musculoskeletal injury prevalence from 2006-2008 by means of a questionnaire. Individuals reported on demographics, injury location, injury etiology, injury nature, extent of treatment rendered and time lost from work. Additionally, data was obtained regarding smoking, occupational stress, fitness, protective gear and injury prevention advice given by the Durban Metropolitan Fire Department. A 41% response rate was achieved. Results: The point prevalence of WRMSIs was 33.6% and the period prevalence was 81.1% of the sample. Low back injuries (47.9%) and strain injuries (40.8%) were the most common, followed by knee (22.5%), shoulder (19.7%) and ankle injuries (19%). The most common causes included lifting heavy objects, working in awkward postures and running. Weight, ethnic group, stress, lack of nutritional advice and alcohol consumption were all significantly associated with the prevalence of injuries. Ex-smoking was significant in the prevalence of low back injuries, stress was significant in the prevalence of knee injuries and alcohol consumption was associated with the prevalence of shoulder injuries. Conclusion: WRMSIs are of great concern in the fire service as their prevalence is substantial. Evaluation and implementation of further preventative measures and advice based on the results of this study can be effective in reducing WRMSIs.