Use of biochemical markers (Lipoprotein phospholipase A2 and hyaluronic acid) for laboratory diagnosis of metabolic and degenerative diseases of the musculoskeletal system Abstract Musculoskeketal disorders currently belong to the most common diseases. The presented work describes the use of biochemical markers (Lipoprotein phospholipase A2 and hyaluronic acid) for laboratory diagnosis of metabolic and degenerative diseases of the musculoskeletal system. Concentrations of LP-PLA2 were significantly elevated in the patients with bone resorption compared to the control group of healthy individuals. Serum levels of Lp-PLA2 also negatively correlated with decreased levels of serum osteocalcin in patients. HA concentrations in synovial fluid did not differ from published reference values in synovial fluid. Patients who underwent arthroscopy had significantly elevated synovial HA concentration than patients who underwent total knee endoprosthesis. HA positively correlates with osmotic pressure determined by examination of osmolality in synovial fluid. Lipoprotein phospholipase A2 concentrations are elevated in patients with bone density impairment. LpPLA2 concentrations correlate with the severity of bone density impairment expressed by the T score. Hyaluronic acid concentrations in patients with knee...

Einleitung: Degenerativ-entzündliche Gelenkerkrankungen und insbesondere die Osteoarthritis (OA) gehören zu den häufigsten orthopädischen Erkrankungen beim Pferd und führen in vielen Fällen zu langfristigen und teilweise dauerhaften Leistungseinschränkungen. Ätiologisch ist die OA bei jungen Pferden hauptsächlich auf ein akutes oder repetitives Trauma zurückzuführen, während bei älteren Pferden von einem chronisch-degenerativen Krankheitsprozess ausgegangen werden kann. Zahlreiche klinische Studien konnten vielversprechende Therapieerfolge mit der intraartikulären Anwendung von potenziell regenerativ wirkenden Therapeutika aus autologen und allogenen Blutprodukten oder mesenchymalen Stromazellen (MSC) in unterschiedlichen OA-Modellen darlegen. Allerdings besteht aufgrund der heterogenen Studienlage bisher weitgehend Unklarheit über den Langzeiterfolg dieser sogenannten Orthobiologika bei Pferden mit natürlich auftretender OA. Zielsetzung: Die Zielsetzung dieser Arbeit war es, über eine statistische Aufarbeitung der Studienlage aus den Jahren 2007-2020 eine fundierte Aussage zu Langzeiterfolgen und zur Anwendungssicherheit von intraartikulär applizierten Orthobiologika bei natürlich auftretender OA beim Pferd zu treffen. Es wurde die Hypothese aufgestellt, dass die Anwendung von Orthobiologika eine sichere und effektive Therapieoption bei Pferden mit natürlich auftretender OA ist. Methoden: Für die Beurteilung wurde ein systematisches Review der aktuell publizierten Literatur in englischer und deutscher Sprache der Jahre 2007 bis 2020 mit anschließender Meta-Analyse angefertigt und ausgewertet. Die Literaturrecherche erfolgte über öffentlich zugängliche, anerkannte Wissenschaftsplattformen unter Nutzung definierter Schlüsselwörter. Es wurden zunächst alle klinischen Studien, die sich mit der Anwendung von Orthobiologika bei natürlich entstandener OA beim Pferd auseinandersetzen gesammelt und entsprechend festgelegter Ein- und Ausschlusskriterien selektiert. Für das systematische Review wurden klinische Studien, die eine intraartikuläre Behandlung mit MSC und/oder autologen Blutprodukten mit einer sechsmonatigen oder längeren Nachuntersuchungszeit der Pferde erfasst. Verglichen wurde der Lahmheitsgrad, gemessen an den Erfolgen in Wettkämpfen, Rückkehr in den Turniersport oder der Nutzung auf dem ursprünglichen Leistungsniveau, vor und nach der intraartikulären Behandlung. Zudem wurden auftretende Nebenwirkungen nach der Behandlung dokumentiert. Für die Meta-Analyse wurden ausschließlich randomisierte und kontrollierte Studien (RCTs) genutzt. Exkludiert wurden in-vivo-Studien mit induzierter OA, invitro- Studien oder Studien mit konventionellen Behandlungsmethoden. Jede Studie des systematischen Reviews wurde auf systematische Fehler untersucht und auf das Biasrisiko gemäß den „Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)“-Leitlinien getestet. Um die Ergebnisse mittels der Methodik der Meta-Analyse zu vergleichen, wurde das Quotenverhältnis (Odds Ratio) mit einem 95 % Konfidenzintervall berechnet. In einem random-effects Modell wurde jede Studie mit ihrer geschätzten Effektgröße und dem entsprechenden Konfidenzintervall im Forest Plot grafisch dargestellt. Die Heterogenität wurde mit I² für die Studien berechnet und mit einem Ergebnis von I² > 50 % als signifikant eingestuft. Ein Ergebnis wurde als signifikant angesehen, wenn sich p < 0,05 darstellte. Ergebnisse: Die elektronische und manuelle Recherche ergab insgesamt 271 Studien. Davon erfüllten 13 Studien die Einschlusskriterien für das systematische Review, wobei in fünf Studien die OA mit MSC behandeltet wurde. In acht der 13 Studien wurden autologe Blutprodukte verabreicht, davon wurde in drei Studien autologes konditioniertes Serum (ACS) angewandt. In den verbleibenden fünf Studien wurden zelluläre Eigenblutprodukte mit einer erhöhten Thrombozytenkonzentration verwendet. Insgesamt wurden bei zwei der 13 Studien ein geringes Risiko für eine statistische Verzerrung festgestellt. Nach der intraartikulären Behandlung mit orthobiologischen Therapeutika wurde eine durchschnittliche Verbesserung des Lahmheitsgrades um 65 % erreicht, unabhängig von der Art des verwendeten Orthobiologikums. Elf der 13 Studien zeigten einen generellen positiven Effekt nach der Behandlung, mit Pferden die auf ihr ursprüngliches Leistungsniveau zurückkehrten. Vier der 13 Studien erwiesen sich geeignet für die Meta-Analyse und wurden mittels Forest Plot exprimiert. Hier wurde die Reduktion des Lahmheitsgrades der Behandlungs- und der Kontrollgruppe verglichen. Die Heterogenität der Langzeitstudien mit einem Beobachtungszeitraum von mindestens sechs Monaten war moderat mit einem Heterogenitätsindex von I² = 55 %. Alle Studien mit einem OR-Wert > 1 begünstigen die experimentelle Gruppe, was hier zutreffend war (OR 17,02; 95 % CI: 8,5474 bis 33,8849 p < 0,0001). In keiner Studie wurde die Grenze zur Unwirksamkeit überschritten, was darauf hindeutet, dass der Behandlungseffekt in allen Studien als ähnlich eingeschätzt wurde. In der Langzeitbeobachtung führte die Anwendung von intraartikulär verabreichten orthobiologischen Therapeutika zu einer Verringerung der Lahmheit bei 73 %, während die Lahmheit in der Kontrollgruppe bei 17 % reduziert wurde. Transiente Nebenwirkungen im Sinne eines sogenannten „joint flare“, einer aseptischen, entzündlichen Gelenkreaktion, waren in allen dokumentierten Fällen (n = 15, 3 %) der insgesamt 518 ausgewerteten Pferde überwiegend selbstlimitierend und führten in nur einem Fall aufgrund fehlender Aufrechterhaltung der Verblindung zu einem Studienausschluss. Schlussfolgerung: Den eingeschlossenen Studien zufolge zeigten Pferde mit natürlich auftretender OA nach einer intraartikulären Behandlung mit orthobiologischen Therapeutika im Vergleich zur Kontrollgruppe im Langzeit-Follow-up einen signifikant geringeren Grad an Lahmheit bei hoher Anwendungssicherheit. Keines der Pferde zeigte nach Behandlung signifikante Nebenwirkungen.:Inhaltsverzeichnis Abbildungsverzeichnis Abkürzungsverzeichnis Tabellenverzeichnis 1. Einleitung 2. Literaturübersicht 2.1 Die Osteoarthritis beim Pferd 2.1.1 Ätiologie beim Pferd 2.1.2 Pathomechanismus der Osteoarthritis 2.1.3 Osteoarthritis auf zellulärer Ebene 2.1.4 Histologische Studien zur Osteoarthritis beim Pferd 2.2 Regenerative/-Orthobiologische Therapien bei Osteoarthritis 2.2.1 Das therapeutische Konzept orthobiologischer Therapieansätze 2.2.2 Behandlungsoptionen der Osteoarthritis beim Pferd 2.2.3 Osteoarthritis: Das Pferd als Modelltier 2.3 Evidenzbasierte Medizin 2.3.1 Definition der evidenzbasierten Medizin 2.3.2 Das Systematische Review 2.3.3 Risk of bias 2.3.4 Die Meta-Analyse 3. Publikation 4. Diskussion 4.1 Methodische Diskussion der Studienauswertung 4.2 Kritische Begutachtung verschiedener OA-Modelle 4.3 Heterogenität der Studien 4.3.1 Diversität der Behandlungsmethoden 4.3.2 Uneinheitliche Definition des Erfolgsmerkmals und der Untersuchung 4.4 Kritik an randomisierten, kontrollierten Studien 4.5 Kritik an der Meta-Analyse 4.6 Schlussfolgerung 5. Zusammenfassung 6. Summary Literaturverzeichnis Danksagung / Introduction: Degenerative-inflammatory joint diseases, specifically osteoarthritis (OA), are among the most common orthopedic diseases in horses and usually lead to long-term and even permanent performance limitations. Etiologically, OA in young horses is mainly caused by an acute or repetitive joint trauma, whereas chronic degenerative process is stated in older horses. Numerous clinical studies have been demonstrated promising therapeutic success by intra-articular application of potentially regenerative therapeutics derived from autologous and allogeneic blood products or mesenchymal stromal cells (MSCs) in different OA models. However, the long-term success of these so named orthobiologics in horses with naturally occurring OA is controversially discussed due to the heterogeneity of studies. Objectives: The objective of this study was a statistical analysis of published literature between the years 2007-2020 regarding long-term success and safety of intraarticular orthobiologics in naturally occurring OA in horses. It was hypothesized that the use of orthobiologics is a safe and effective therapeutic option in horses with naturally occurring OA. Material and Methods: For assessment, a systematic review of the currently published literature in English and German from 2007-2020 with subsequent meta-analysis was performed and evaluated. The literature search was conducted via publicly available, recognized scientific platforms using defined keywords. First, all clinical studies dealing with the use of orthobiologics in naturally occurring OA in horses were reviewed and selected according to defined inclusion and exclusion criteria. All clinical trials that included intraarticular treatment with MSCs and/or autologous blood products with an at least six-month follow-up were included in the systematic review. The degree of lameness prior and after intraarticular treatment was evaluated (comparison of the success rate, horses working on competition, horses working at trainings level, lame free horses). In addition, any adverse effects that occurred after treatment were documented. For meta-analysis only randomized controlled trials (RCTs) were included. In vivo studies with chemically or experimentally induced OA, in vitro studies or studies used conventional treatments were excluded. Each study included in the systematic review was examined to the risk of bias according to the „preferred reporting items for systematic reviews and meta-analyses (PRISMA)” guidelines. To compare dichotomous outcomes via meta-analysis, an odds ratio (OR) with 95 % confidence interval (CI) was calculated. A random-effects model was used describing the overall outcome in a forest plot. The I² statistic was used to assess heterogeneity with a result of I² > 50 % classified as significant. Overall, a result was considered significant with p < 0,05. Results: The initial electronic and manual research resulted in a total of 271 studies. Of these, 13 studies met the inclusion criteria for the systematic review, whereof five studies used MSCs as an orthobiologic treatment option. In three of the 13 studies administered autologous conditioned serum (ACS) and the remaining five studies used cellular autologous blood products with an increased platelet concentrate. Overall, two studies considered to be at a low risk of bias. After intra-articular treatment with orthobiologic therapeutics, an average improvement of 65 % in lameness was achieved, regardless the type of orthobiologic agent used. Eleven of the 13 studies showed a general positive effect after treatment with horses returning to their original performance level. Four of the 13 studies proved suitable for metaanalysis and were expressed using forest plot. The reduction in the degree of lameness between the treatment and control groups was compared. There was moderate heterogeneity in the long-term studies with an observation period of at least six months, I² = 55 %. All studies with an OR value > 1 favor the experimental group, which was appropriate here (OR 17,02; 95 % CI: 8,5474 to 33,8849 p < 0,0001). No study crossed the line into ineffectiveness, indicating that the treatment effect was considered similar among the studies. In the long-term follow-up, the use of intraarticularly administered orthobiologics led to a reduction in lameness in 73 % reduction in lameness, while lameness was reduced in 17 % in the control group. All documented cases (n = 15, 3 %) of the total 518 horses evaluated experienced transient adverse effects, also referred to as “joint flare”, an aseptic, inflammatory, and in most cases self-limiting joint reaction. One case resulted in exclusion from the study because blinding could not be maintained. Conclusion: According to the included studies, horses with naturally occurring OA after intraarticular treatment with orthobiologic therapeutics demonstrated a significantly lower degree of lameness at long-term follow-up compared to the control group, with a high level of safety of use. None of the horses showed significant side effects after treatment.:Inhaltsverzeichnis Abbildungsverzeichnis Abkürzungsverzeichnis Tabellenverzeichnis 1. Einleitung 2. Literaturübersicht 2.1 Die Osteoarthritis beim Pferd 2.1.1 Ätiologie beim Pferd 2.1.2 Pathomechanismus der Osteoarthritis 2.1.3 Osteoarthritis auf zellulärer Ebene 2.1.4 Histologische Studien zur Osteoarthritis beim Pferd 2.2 Regenerative/-Orthobiologische Therapien bei Osteoarthritis 2.2.1 Das therapeutische Konzept orthobiologischer Therapieansätze 2.2.2 Behandlungsoptionen der Osteoarthritis beim Pferd 2.2.3 Osteoarthritis: Das Pferd als Modelltier 2.3 Evidenzbasierte Medizin 2.3.1 Definition der evidenzbasierten Medizin 2.3.2 Das Systematische Review 2.3.3 Risk of bias 2.3.4 Die Meta-Analyse 3. Publikation 4. Diskussion 4.1 Methodische Diskussion der Studienauswertung 4.2 Kritische Begutachtung verschiedener OA-Modelle 4.3 Heterogenität der Studien 4.3.1 Diversität der Behandlungsmethoden 4.3.2 Uneinheitliche Definition des Erfolgsmerkmals und der Untersuchung 4.4 Kritik an randomisierten, kontrollierten Studien 4.5 Kritik an der Meta-Analyse 4.6 Schlussfolgerung 5. Zusammenfassung 6. Summary Literaturverzeichnis Danksagung

No / Starting from the premise that people are essentially narrative beings, I argue that the onset of severe mental illness compromises the narrative enterprise of being able to construct one's Self and one's relationships inmeaningful and coherent ways. This is due to both the curtailment of opportunities for narrative engagement and the dispossession of those whose narratives do not conform to the current conceptualization of narrative and narrativity. In these circumstances, supporting the narrative enterprise is an ethical endeavour that requires that we examine not only which narratives we construct, but also how we construct them. This requires a re-thinking of what might constitute narrative and how we might facilitate or enhance the narrativity of people with severe mental illness. Following this, I suggest four means to support the narrativity of people with severe mental illness: through maintaining narrative continuity, maintaining narrative agency, countering master narratives and attention to small stories.

Submitted to the Faculty of Health Sciences at the Durban University of Technology in partial compliance with the requirements for a Master’s Degree in Technology: Chiropractic, Department of Chiropractic, Durban University of Technology, Durban, South Africa, 2016. / Background: Neck pain is an extremely common condition and the treatment of neck pain forms an integral part of chiropractic practice. The optimal treatment of neck pain is provided when practitioners incorporate available evidence, experience, and knowledge regarding the clinical presentation of the patient into their treatment regimes. Current evidence suggests that a combination of manual therapy, specifically manipulation and/or mobilization, and rehabilitation may offer the optimum treatment for mechanical neck pain. However, numerous factors other than available evidence, experience and clinical presentation may influence treatment choices made by practitioners. Through the assessment of practice patterns, one may asses if the optimal treatment for a neck pain is being provided by practitioners and assess if factors specific to a practitioner may influence the treatment of neck pain. Objectives: The aim of this study is to determine the chiropractic treatment and management of mechanical neck pain, to compare this to evidence based recommendations for the conservative treatment of mechanical neck pain and to assess if factors other than the available evidence may influence the treatment of mechanical neck pain. Method: A quantitative, cross-sectional descriptive survey compiled using available literature and validated by means of a focus group and pilot testing, was administered to chiropractors practicing in KwaZulu-Natal. Upon completion of the questionnaire, the data was coded into an Excel spread sheet and imported into IBM SPSS version 20 for statistical analysis. This research protocol was approved by the Durban University of Technology Institutional Research Ethics Committee (REC 82/13) and the study took place from March to July 2014. Results: Ninety-six practitioners responded to the study which is a response rate of greater than 70%. Practitioners favoured the use of spinal manipulation, auxiliary therapeutic techniques (specifically those which were manual in nature), rehabilitation, and numerous forms of education. Specific variations in treatment pattern existed when comparing various patient presentations indicating that practitioner based factors impacted on treatment choices made by practitioners. The most significant findings included the increased utilisation of auxiliary therapeutic techniques by female practitioners, the increased utilisation of traction by practitioners identifying with the straight philosophy of chiropractic. Other significant findings included the increased utilisation of cervical collars by practitioners of increased age and experience and the increased utilisation of auxiliary therapeutic techniques by practitioners who did not attend health related conferences at least once every second year or did not attend short courses or subscribe to journals or magazines since qualification. Conclusions: This study indicates that treatment for mechanical neck pain offered by chiropractors in KwaZulu-Natal is in line with current evidence based recommendations for the treatment of mechanical neck pain, with practitioners commonly using modalities which were recommended, whilst rarely using modalities which were not recommended. The use of rehabilitation was, however, slightly lower than expected. Patient presentation and practitioner based factors were found to influence the treatment of mechanical neck pain; however, as a whole these variations were small with the majority of practitioners favouring the use of modalities which were recommended within the literature. Future studies should address the gap in the literature regarding the conservative treatment of cervical radiculopathy. / M

Submitted to the Faculty of Health Sciences at the Durban University of Technology in partial compliance with the requirements for a Master’s Degree in Technology: Chiropractic, Department of Chiropractic, Durban University of Technology, Durban, South Africa, 2016. / Background: Neck pain is an extremely common condition and the treatment of neck pain forms an integral part of chiropractic practice. The optimal treatment of neck pain is provided when practitioners incorporate available evidence, experience, and knowledge regarding the clinical presentation of the patient into their treatment regimes. Current evidence suggests that a combination of manual therapy, specifically manipulation and/or mobilization, and rehabilitation may offer the optimum treatment for mechanical neck pain. However, numerous factors other than available evidence, experience and clinical presentation may influence treatment choices made by practitioners. Through the assessment of practice patterns, one may asses if the optimal treatment for a neck pain is being provided by practitioners and assess if factors specific to a practitioner may influence the treatment of neck pain. Objectives: The aim of this study is to determine the chiropractic treatment and management of mechanical neck pain, to compare this to evidence based recommendations for the conservative treatment of mechanical neck pain and to assess if factors other than the available evidence may influence the treatment of mechanical neck pain. Method: A quantitative, cross-sectional descriptive survey compiled using available literature and validated by means of a focus group and pilot testing, was administered to chiropractors practicing in KwaZulu-Natal. Upon completion of the questionnaire, the data was coded into an Excel spread sheet and imported into IBM SPSS version 20 for statistical analysis. This research protocol was approved by the Durban University of Technology Institutional Research Ethics Committee (REC 82/13) and the study took place from March to July 2014. Results: Ninety-six practitioners responded to the study which is a response rate of greater than 70%. Practitioners favoured the use of spinal manipulation, auxiliary therapeutic techniques (specifically those which were manual in nature), rehabilitation, and numerous forms of education. Specific variations in treatment pattern existed when comparing various patient presentations indicating that practitioner based factors impacted on treatment choices made by practitioners. The most significant findings included the increased utilisation of auxiliary therapeutic techniques by female practitioners, the increased utilisation of traction by practitioners identifying with the straight philosophy of chiropractic. Other significant findings included the increased utilisation of cervical collars by practitioners of increased age and experience and the increased utilisation of auxiliary therapeutic techniques by practitioners who did not attend health related conferences at least once every second year or did not attend short courses or subscribe to journals or magazines since qualification. Conclusions: This study indicates that treatment for mechanical neck pain offered by chiropractors in KwaZulu-Natal is in line with current evidence based recommendations for the treatment of mechanical neck pain, with practitioners commonly using modalities which were recommended, whilst rarely using modalities which were not recommended. The use of rehabilitation was, however, slightly lower than expected. Patient presentation and practitioner based factors were found to influence the treatment of mechanical neck pain; however, as a whole these variations were small with the majority of practitioners favouring the use of modalities which were recommended within the literature. Future studies should address the gap in the literature regarding the conservative treatment of cervical radiculopathy. / M

RNA interference (RNAi) is a post transcriptional gene silencing mechanism that allows potent and specific silencing of cognate mRNA transcripts. Selective silencing can be used to dissect complex polygenic diseases, elucidate the function of known genes and provide a tool for genetic therapy. Its use in the case of dominant inherited disorders including disorders of the central nervous system, depends on its ability to confer single nucleotide discrimination between normal and mutant gene alleles. In this thesis the ability of RNAi effector molecules to provide single nucleotide specificity was examined by targeting two dominant inherited mutations of the acetylcholine receptor that cause slow-channel syndrome. Allele-specific silencing was achieved for one mutation. The other mutation was also silenced but not in an allele specific way despite employing known techniques for increasing single-nucleotide specificity. The model used in this thesis is the congenital myasthenia slow-channel syndrome. This is a dominant inherited disorder of the neuromuscular junction which is both well-characterised and more readily accessible compared to the central nervous system, thus provides a prototype for development of allele-specific RNAi therapeutics. Here we describe a new transgenic animal model of the slow-channel syndrome and show good representation of the human disorder. The need for defining the characteristics that determine the effectiveness and the specificity of RNAi effectors at single-nucleotide level, along with the future uses of the newly described animal model are discussed.

By 2040, the World Health Organization expects neurodegenerative diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease, to surpass cancer as the second most common cause of death worldwide. Currently, only treatments for symptoms of these diseases are available. Thus, research is critical to alleviate this public health burden by elucidating the pathogenic processes and developing novel therapies. While exact mechanisms by which these heterogeneous neuropathological conditions become manifest in patients remain unclear, growing evidence suggests that oxidative stress (OS) makes a significant contribution to neuronal dysfunction and apoptosis in all major neurodegenerative diseases. Recently, the gene oxidation resistance 1 (Oxr1) has emerged as a critical regulator of neuronal survival in response to OS. Oxr1 is expressed throughout the central nervous system, and its highly conserved TLDc domain protects neurons from oxidative damage through an unknown mechanism. This thesis aimed to define mechanisms by which Oxr1 confers neuronal sensitivity to OS, and to determine its role in neurodegenerative diseases. I found that Oxr1 mediates cytoplasmic localization of ALS-associated proteins Fused in Sarcoma (FUS) and transactive response DNA binding protein 43 kDa (TDP-43) through a TLDc domain- and arginine methylation-dependent pathway. Next, I investigated in vivo neuroprotective functions of Oxr1, and demonstrated that neuronal Oxr1 over-expression extends survival and ameliorates behavioural dysfunction and pathology of an ALS mouse model. In particular, neuronal Oxr1 over-expression strikingly delays neuroinflammation during ALS pathogenesis. Finally, I characterised a mouse model that specifically deletes Oxr1 from motor neurons. While loss of Oxr1 in ChAT-positive motor neurons does not cause overt neurodegeneration in the spinal cord, constitutive loss of Oxr1 leads to neuroinflammation in the cerebellum and spinal cord. Taken together, these studies illuminate functions of Oxr1 in the complex antioxidant defence network and present implications for future therapeutic strategies.

Neurodegeneration is a progressive loss of neuron function or structure, including death of neurons, and occurs at many different levels of neuronal circuitry. In this thesis I discuss Parkinson’s Disease (PD), the second most common neurodegenerative disease (NDD). PD is a devastating progressive NDD often with delayed diagnosis due to detection methods that depend on the appearance of visible motor symptoms. By the time cardinal symptoms manifest, 60 to 80 percent or more of the dopamine-producing cells in the substantia nigra are irreversibly lost. Although there is currently no cure, earlier detection would be highly beneficial to manage treatment and track disease progression. However, today’s clinical diagnosis methods are limited to subjective evaluations and observation. Onset, symptoms and progression significantly vary from patient to patient across stages and subtypes that exceed the scope of a standardized diagnosis. The goal of this thesis is to provide the basis of a more general approach to study the brain, investigating early detection method for NDD with focus on PD. It details the preliminary development, testing and validation of tools and methods to objectively quantify and extrapolate motor and non-motor features of PD from behavioral and cognitive output during everyday life. Measures of interest are categorized within three domains: the motor system, cognitive function, and brain activity. This thesis describes the initial development of non-intrusive tools and methods to obtain high-resolution movement and speech data from everyday life and feasibility analysis of facial feature extraction and EEG for future integration. I tested and validated a body sensor system and wavelet analysis to measure complex movements and object interaction in everyday living situations. The sensor system was also tested for differentiating between healthy and impaired movements. Engineering and design criteria of the sensor system were tested for usability during everyday life. Cognitive processing was quantified during everyday living tasks with varying loaded conditions to test methods for measuring cognitive function. Everyday speech was analyzed for motor and non-motor correlations related to the severity of the disease. A neural oscillation detection (NOD) algorithm was tested in pain patients and facial expression was analyzed to measure both motor and non-motor aspects of PD. Results showed that the wearable sensor system can measure complex movements during everyday living tasks and demonstrates sensitivity to detect physiological differences between patients and controls. Preliminary engineering design supports clothing integration and development of a smartphone sensor platform for everyday use. Early results from loaded conditions suggest that attentional processing is most affected by cognitive demands and could be developed as a method to detect cognitive decline. Analysis of speech symptoms demonstrates a need to collect higher resolution spontaneous speech from everyday living to measure speech motor and non-motor speech features such as language content. Facial expression classifiers and the NOD algorithm indicated feasibility for future integration with additional validation in PD patients. Thus this thesis describes the initial development of tools and methods towards a more general approach to detecting PD. Measuring speech and movement during everyday life could provide a link between motor and cognitive domains to characterize the earliest detectable features of PD. The approach represents a departure from the current state of detection methods that use single data entities (e.g.one-off imaging procedures), which cannot be easily integrated with other data streams, are time consuming and economically costly. The long-term vision is to develop a non-invasive system to measure and integrate behavioral and cognitive features enabling early detection and progression tracking of degenerative disease.

La proprioception cervicale joue un rôle important dans le contrôle postural, mais la nature exacte de sa contribution est controversée. Dans certains cas de « coup du lapin », une atteinte posturale a été démontrée, sans que l'atteinte du rachis cervical puisse être tenue pour seule responsable. Malgré la forte prévalence des pathologies cervicales dégénératives, leurs conséquences posturales ont été peu étudiées dans la littérature scientifique. Il n'existe aucune publication centrée sur les deux types de pathologie responsables de névralgies cervicobrachiales : les hernies discales cervicales et l'arthrose cervicale. Cette étude a eu pour but d'évaluer le contrôle postural de deux groupes de patients présentant une pathologie cervicale dégénérative avec et sans stimulation optocinétique avant et après traitement chirurgical. Dix-sept patients présentant une radiculalgie ont été inclus dans cette étude et répartis en deux groupes selon l'origine arthrosique ou discale de la compression neurologique. Tous les patients ainsi que 31 témoins ont été soumis à un examen de posturographie statique comprenant 12 enregistrements : les quatre premiers enregistrements ont été réalisés la tête dans l'axe (à 0°) : yeux fermés, yeux ouverts sans stimulation optocinétique, yeux ouverts avec stimulation optocinétique dans le sens horaire, puis antihoraire. Ces quatre situations sensorielles ont été répétées tête tournée 30° à gauche, puis 30° à droite. Les patients ont à nouveau été soumis à ces 12 enregistrements six semaines après l'intervention. Aucun patient ne s'est plaint de sensations vertigineuses que ce soit en pré ou en postopératoire. Avant intervention, les yeux fermés, le groupe hernie discale était plus stable que le groupe arthrose. Après intervention, la contribution visuelle au contrôle postural avait diminué dans les deux groupes dans un environnement visuel dynamique, alors que dans un environnement visuel stable, elle n'avait diminué que dans le groupe arthrose. L'importance relative des informations visuelles et proprioceptives pour le contrôle postural varie selon le type de pathologie et la chirurgie tend à réduire la contribution visuelle surtout pour les patients présentant une arthrose cervicale / Cervical proprioception plays a key role in postural control, but its specific contribution is controversial. Postural impairment was shown in whiplash injuries without demonstrating the sole involvement of the cervical spine. The consequences of degenerative cervical spine diseases are underreported in posture-related scientific literature in spite of their high prevalence. No report has focused on the two different mechanisms underlying cervicobrachial pain: herniated discs and spondylosis. This study aimed to evaluate postural control of two groups of patients with degenerative cervical spine diseases with or without optokinetic stimulation before and after surgical treatment. Seventeen patients with radiculopathy were recruited and divided into two groups according to the spondylotic or discal origin of the nerve compression. All patients and a control population of 31 healthy individuals underwent a static posturographic test with 12 recordings; the first four recordings with the head in 0° position: eyes closed, eyes open without optokinetic stimulation, with clockwise and counter clockwise optokinetic stimulations. These four sensorial situations were repeated with the head rotated 30° to the left and to the right. Patients repeated these 12 recordings 6 weeks postoperatively. None of the patients reported vertigo or balance disorders before or after surgery. Prior to surgery, in the eyes closed condition, the herniated disc group was more stable than the spondylosis group. After surgery, the contribution of visual input to postural control in a dynamic visual environment was reduced in both cervical spine diseases whereas in a stable visual environment visual contribution was reduced only in the spondylosis group. The relative importance of visual and proprioceptive inputs to postural control varies according to the type of pathology and surgery tends to reduce visual contribution mostly in the spondylosis group

Made available in DSpace on 2016-01-26T12:51:47Z (GMT). No. of bitstreams: 1 fernandofilipe_dissert.pdf: 443784 bytes, checksum: bb6328cd8296f1c4b222d0c43cdafda1 (MD5) Previous issue date: 2006-02-13 / Adjacent segment disease is defined as an abnormal process developing in the adjacent level above and/or bellow the arthrodesis of the segment. It is considered a late complication of lumbar spine arthrodesis. It has been very important due to the procedures in the last years. Objective: To evaluate the risk factors associated with the disease at adjacent level as well as its relationship with the natural history of degenerative disease of the lumbar spine. Material and Methods: This was a retrospective study, from January 2000 to December 2002.Thirty-eight patients undergoing arthrodesis in the lumbosacral spine using the pedicle screw fixation participated in the study. Results: These patients had a mean follow-up of 30 months; 10 patients presented adjacent segment disease, 7 disc degeneration, 2 spinal stenosis and one discal spine hernia. The patients´ mean age was 48.5 years; female sex was the majority. Degeneration occurred in 4 patients with stenosis; 4 with spondylolisthesis, and 1 with post disc hernia; all these had been submitted to arthrodesis of lumbosacral spine. The majority was asymptomatic, after being treated by arthrodesis in multiple levels. There was no statistical difference when the above factors were related. Conclusion: Adjacent segment disease is a late complication in the arthrodesis of lumbosacral spine with no relationship of risk factors presented in this study. Therefore, its origin could be related with the natural history of the degenerative disease of lumbar spine. / A doença do nível adjacente é definida como um processo anormal que se desenvolve no nível adjacente, acima e/ou abaixo do segmento artrodesado. Considerada como uma complicação tardia da artrodese da coluna vertebral, tem-se tornado muito importante em decorrência do aumento dos procedimentos nos últimos anos. Objetivo: Avaliar os fatores de risco associados à ocorrência da doença do nível adjacente e sua relação com a história natural da doença degenerativa da coluna vertebral. Material e métodos: Análise retrospectiva de janeiro de 2000 a dezembro de 2002, realizada em 38 pacientes submetidos a artrodese de coluna lombosacra com a utilização de parafuso pedicular. Resultado: Os pacientes analisados apresentavam follow up médio de 30 meses, com a presença de 10 pacientes com doença do nível adjacente; sendo 7 com degeneração discal, 2 com estenose de canal vertebral e 1 com hérnia de disco. A idade média dos pacientes foi 48,5 anos, com predomínio no sexo feminino. A degeneração ocorreu em 4 pacientes com estenose de canal, em 4 pacientes com espondilolistese, em 1 paciente com escoliose e em 1 paciente pós hérnia de disco, os quais tinham sido submetidos a artrodese da coluna lombosacra. A maioria dos pacientes foram submetidos a artrodese em múltiplos níveis e apresentavam-se assintomáticos. Nenhuma diferença estatística foi evidenciada quando relacionados os fatores acima. Conclusão: A doença do nível adjacente é uma complicação tardia existente na artrodese de coluna lombosacra, não relacionada aos fatores de risco apresentados; portanto o seu aparecimento estaria relacionado à história natural da doença degenerativa da coluna lombar.