Myoclonus-Dystonia (MD) is an inherited, rare, autosomal dominant movement disorder characterized by quick, involuntary muscle jerking or twitching (myoclonus) and involuntary muscle contractions that cause twisting and pulling movements, resulting in abnormal postures (dystonia). The first MD locus was mapped to 7q21-q31 and called DYT11; this locus corresponds to the SGCE gene. Our group previously identified a second MD locus (DYT15) which maps to a 3.18 Mb region on 18p11. Two patients were chosen to undergo next-generation sequencing, which identified 2,292 shared novel variants within the critical region. Analysis of these variants revealed a 3 bp duplication in a transcript referred to as CD108131, which is believed to be a long non-coding RNA. Characterization of this transcript determined that it is 863 bp in size, it is ubiquitously expressed, with high expression in the cerebellum, and it accounts for ~3% of MD cases.

Dissertation zu Expressionsmustern von muskarinergen Acetylcholin-Rezeptoren des Subtypen 1,2,3 und 4 im Gehirn von DYT1 knock-in Mäusen.

Botulinum neurotoxin (BoNT), for more than a hundred years, has been a recognized poisonous principle in spoiled food. As its chemical structure became unraveled, and as more knowledge was gained over its mechanism of toxicity, it became clear that BoNT had the potential to act therapeutically as a targeted toxin that could inactivate specific nerve populations, and thus achieve a therapeutic goal. BoNT has evolved over the past 25 years into a viable therapeutic, now being a first line treatment for dystonia, overtly altering the course of progression of this disorder. BoNT is used for hyperhidrosis and gustatory sweating syndrome, alleviation of pain, as a treatment for overactive bladder, achalasia and anal fissure; and it has gained popularity as a cosmetic aid. Many other possible uses are being explored. The greatest potential for BoNT may lie in its being a molecular Trojan Horse - able to carry a specific enzyme or specific drug to the inside of a cancer or other type of cell while bypassing other cells and thereby having little or no ill effect. BoNTs pharmaceutical potential is boundless.

Musicians tend to suffer from a broad range of problematics related to their playing, from muscle/tendon injuries, to joint injuries, nerve compression disorders and central nervous system disorders. The purpose of this essay was therefore to explore methods used for health and wellbeing of guitarists. The research question was: Which actions are described to support guitarists to recover from injuries and/or maintain health? A qualitative approach was used to collect and analyse the data that were acquired through in-depth interviews and analysis of annotations of musicians who have been patients or were at the time of the interview been following a rehabilitation program in those centres. The analysis of the data produced eight common actions used by both the institutes. The result showed that there is a common ground between the two schools which could be a start for the development of further treatment strategies.

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals.

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This thesis examines the experiences of people living with dystonia1 and the ways these are represented by people living with dystonia, the Dystonia Society, neurologists, quality of life (QOL) researchers and pharmaceutical companies. Drawing on ethnographic fieldwork conducted within the Dystonia Society and on projects developing a disease-specific QOL measure, and investigating the impact of dystonia on people’s QOL, the thesis explores a series of questions about the conceptual and practical problems inherent in such measures. It asks: • How dystonia is defined and represented and its impact on people’s lives • Whether people’s experiences of living with dystonia can be adequately mapped by generic or disease-specific QOL measures and how the methodology used in their creation might affect such representations • How QOL measures are used to classify and compare and why it is now deemed necessary to represent people’s experiences in this form The thesis is contextualised within a historical account of the origins of QOL measurement and the social and economic context to its rapid expansion, including the pharmaceutical industry’s use of QOL to bring together diverse groups of actors. I address traditional anthropological questions about measuring and creating universal systems of classification and valuation, but go beyond this to link QOL measurement to the classification and hierarchisation of “audit culture”. I describe how attempts to articulate “the patient’s voice” through measures of QOL can silence the voices of people with limiting conditions and suggest we approach their experiences through narratives that embed their conditions in their lives and give them a meaning that is not wholly negative. I argue that even though the phrase “quality of life” promises an empowering and holistic vision of health, there are two main reasons why QOL measurement cannot fulfil this promise. Firstly, it is primarily a tool for audit, and secondly, new measures reproduce the assumptions of existing measures or clinical models and exclude the elements that people consider most important in maintaining quality of life. Paradoxically, the discourse can reduce people’s QOL when it is used to justify rationing in the UK and redirection of resources internationally. However, despite my criticisms of QOL, I conclude that it has benefited people living with dystonia by creating a discursive space for the discussion of health in non-clinical terms and a language to make claims for resources and the acknowledgement of their experiences. 1A chronic neurological condition involving involuntary muscle spasms in one or more body parts.

Introduction : La dystonie est définie comme un syndrome de cocontractions musculaires soutenues aboutissant à des mouvements répétitifs et des postures anormales. Cependant la physiopathologie des dystonies reste mal comprise. Les études menées chez l’homme soulignent le rôle crucial des ganglions de la base dans la physiopathologie des dystonies. Des données récentes obtenues chez le rongeur suggèrent l’implication d’un désordre de la transmission cholinergique striatale mais es modèles qu’ils soient génétiques ou pharmacologiques n’aboutissent pas toujours à un phénotype de dystonie. C’est pourquoi il était important de proposer une étude chez le primate non humain, visant à vérifier notre hypothèse de travail, à savoir : est-ce qu’une augmentation de la transmission cholinergique dans le putamen est capable d’induire un phénotype clinique de dystonie similaire à celui rencontré chez l’homme.Méthodes : Nous avons réalisé des infusions chroniques d’un agoniste muscarinique non sélectif (Oxotremorine) au sein du territoire sensori-moteur du striatum chez le primate non-humain. Les symptômes cliniques induits par ce produit ont été évalués à l’aide de l’échelle de Burke-Fahn-Marsden (BFM) adaptée à l’animal. Nous avons également utilisé une approche électromyographique pour caractériser l’activité musculaire en lien avec la clinique ainsi que des enregistrements de l’activité Multi-Unitaire et Unitaire au sein des ganglions de la base afin d’établir des corrélations électro-cliniques.Résultats : Les infusions d’Oxotremorine nous ont permis d’observer : (i) des postures et des mouvements anormaux similaires aux mouvements dystoniques rencontrés en pathologie humaine ; (ii) une fréquence de décharge neuronale anormalement basse dans le GPi (13,5Hz) et un pattern de décharge de type « bursty » principalement lorsque les symptômes sont sévères ; (iii) une activité oscillatoire (28-30Hz) au sein du putamen, du GPe et du GPi; (iv) l’absence de cohérence de l’activité oscillatoire entre ces structures ; (v) que le GPi est la seule structure à présenter une cohérence de l’activité oscillatoire.Conclusion : Nos travaux démontrent pour la première fois qu’un modèle de dystonie chronique peut être obtenu chez le primate non humain par augmentation du tonus cholinergique dans le putamen. Ce travail valide l’hypothèse de l’implication des interneurones cholinergiques dans la physiopathologie des dystonies. Ils confortent l’idée qu’une augmentation du tonus cholinergique peu à elle seule induire un phénotype de dystonie. / Introduction: Dystonia is defined as a syndrome of sustained muscular cocontractions leading to repetitive movements and abnormal postures. However, the pathophysiology of dystonia remains poorly understood. Studies in humans emphasize the crucial role of basal ganglia in the pathophysiology of dystonia. Recent data in rodents suggest the involvement of a disorder in the striatal cholinergic transmission. But these genetic or pharmacological rodent models do not always express the phenotype of dystonia. Therefore, it was important to propose a primate study to test whether an increase of cholinergic transmission within the putamen is able to induce a clinical phenotype of dystonia similar to that seen in humans.Methods: To verify our hypothesis, we chronically infused non-selective muscarinic agonist (Oxotremorine) in the sensory-motor striatum in non-human primates. Dystonic clinical symptoms induced by this drug were assessed using the Burke-Fahn-Marsden (BFM) scale adapted to animals. We used electromyographic approach to characterize muscular activity linked to clinical symptoms, and we recorded Multi-Unit and Single-Unit neuronal activity in basal ganglia to establish electro-clinical correlations.Results: The infusions of Oxotremorine allowed us to observe: (i) abnormal postures and movements similar to the dystonic movements encountered in human pathology; (ii) an abnormally low neuronal firing frequency in the GPi (13.5Hz) and a bursty firing pattern mainly when the symptoms where severe; (iii) oscillatory activity (28-30Hz) within the putamen, GPe and GPi; (iv) the lack of coherence of the oscillatory activity between these structures; (v) that the GPi is the only structure to present a coherence of the oscillatory activity.Conclusion: We have demonstrated for the first time that a model of chronic dystonia can be obtained in non-human primates by increasing cholinergic tone in the putamen. This work validates the hypothesis of an involvement of cholinergic interneurons and striatal acetylcholine levels in the pathophysiology of dystonia.

Orientador: Nereu Carlos Prestes / Coorientador: Maria Denise Lopes / Banca: Carla Fredrichsen Moya-Araujo / Banca: Maria Dalva Cesário / Resumo: A placentação e o desenvolvimento das membranas fetais na espécie canina atualmente são estudados de forma extensiva, já que o conhecimento da morfologia da placenta possibilita reconhecer corretamente alterações patológicas e sua possível correlação com a viabilidade neonatal. O presente estudo tem como objetivo a caracterização morfológica e imunohistoquímica de placentas de cadelas provenientes de eutocia e distocia. Para o desenvolvimento deste experimento foram coletadas 80 placentas, de acordo com o tipo de parto as placentas foram divididas em três grupos experimentais, GN (n=40) placentas obtidas de parto normal, GC (n=28) placentas obtidas de cesariana e GAUP (n=12) placentas obtidas de cadelas em atonia uterina primária. Fragmentos 1cm x 1cm foram seccionados da região próxima ao cordão umbilical e armazenados em formol tamponado 10% durante 48 horas, a seguir, foram transferidos para álcool 70%, no qual permaneceram até o processamento para o estudo histopatológico e imunohistoquímico. Foram reconhecidas áreas de hemorragia, necrose, inflamação e calcificação nas placentas dos três grupos estudados. A hemorragia no parênquima placentário foi identificada em todos os grupos experimentais, não apresentando diferença significativa. A necrose evidenciada junto a face materna foi uma constante nos grupos avaliados, entretanto foram observados na região lamelar focos e áreas de necrose no GC e GAUP, porém estes achados não foram estatisticamente relevantes quanto a comparação ao GN. A inflamação foi raramente observada no GN, esteve pouco presente no GC e predominou nas amostras placentárias do GAUP. Os focos de calcificação identificados foram mais notórios no GC e GAUP. Nos grupos estudados foram observadas alterações discretas quanto a integridade histológica dos hematomas marginais. Nas placentas GN a imunomarcação para vimentina mostrou-se intensa e homogênea em toda zona lamelar, fato... / Abstract: Placentation and the development of fetal membranes in dogs are currently studied extensively, since the knowledge of morphology of the placenta enables properly recognize pathological changes and its correlation with neonatal viability. We aimed to characterize morphologically and immunohistochemically placentas of bitches from eutocia and dystocia. For that 80 placentas were collected and classified according to the type of delivery into three experimental groups,GN (n = 40) placentas obtained from normal delivery, GC (n = 28) placentas obtained from cesarean section and GAUP (n = 12) placentas obtained from bitches with uterine atony. 1cm x 1cm pieces were cut from the region near the umbilical cord and stored in 10% buffered formalin for 48 hours following, were transferred to 70% alcohol, which remained until processing for histopathological and immunohistochemical study. In this research, areas of hemorrhage, necrosis, inflammation and calcification were observed in the placentas in all three groups. Hemorrhagic areas were identified in the placental parenchyma in all groups, without significant difference. The evident necrosis in the placenta maternal face was constant in the groups, we observe areas and spots of necrosis in the lamellar region in GC and GAUP, but those findings were not statistically significant when compared to GN. Inflammation was rarely observed in the GN and it was observed in a few samples in the GC, however it was predominant in samples from GAUP. Calcification spots were observed in GC and GAUP. In the studied groups, discrete alterations were observed when histological integrity of marginal hematomas was evaluated. In GN the immunostaining for vimentin proved to be intense and homogeneous throughout lamellar zone, however this was not observed in GC and GAUP, which presented immunostaining characterized by variation of intensity. For cytokeratin there was no difference between experimental groups. The RP... / Mestre

This thesis examines the experiences of people living with dystonia1 and the ways these are represented by people living with dystonia, the Dystonia Society, neurologists, quality of life (QOL) researchers and pharmaceutical companies. Drawing on ethnographic fieldwork conducted within the Dystonia Society and on projects developing a disease-specific QOL measure, and investigating the impact of dystonia on people’s QOL, the thesis explores a series of questions about the conceptual and practical problems inherent in such measures. It asks: • How dystonia is defined and represented and its impact on people’s lives • Whether people’s experiences of living with dystonia can be adequately mapped by generic or disease-specific QOL measures and how the methodology used in their creation might affect such representations • How QOL measures are used to classify and compare and why it is now deemed necessary to represent people’s experiences in this form The thesis is contextualised within a historical account of the origins of QOL measurement and the social and economic context to its rapid expansion, including the pharmaceutical industry’s use of QOL to bring together diverse groups of actors. I address traditional anthropological questions about measuring and creating universal systems of classification and valuation, but go beyond this to link QOL measurement to the classification and hierarchisation of “audit culture”. I describe how attempts to articulate “the patient’s voice” through measures of QOL can silence the voices of people with limiting conditions and suggest we approach their experiences through narratives that embed their conditions in their lives and give them a meaning that is not wholly negative. I argue that even though the phrase “quality of life” promises an empowering and holistic vision of health, there are two main reasons why QOL measurement cannot fulfil this promise. Firstly, it is primarily a tool for audit, and secondly, new measures reproduce the assumptions of existing measures or clinical models and exclude the elements that people consider most important in maintaining quality of life. Paradoxically, the discourse can reduce people’s QOL when it is used to justify rationing in the UK and redirection of resources internationally. However, despite my criticisms of QOL, I conclude that it has benefited people living with dystonia by creating a discursive space for the discussion of health in non-clinical terms and a language to make claims for resources and the acknowledgement of their experiences. 1A chronic neurological condition involving involuntary muscle spasms in one or more body parts.