Rapayan : une culture tardive du Haut Marañón dans les Andes centrales du Pérou

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Recherche de marqueurs de la dyskinésie tardive provoquée par les antidépresseurs à l'aide de l'imagerie quantitative par résonnance magnétique

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Diagnosing primary ciliary dyskinesia: an international patient perspective

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sinopulmonary disease, with symptoms starting soon after birth. A European Respiratory Society (ERS) Task Force aims to address disparities in diagnostics across Europe by providing evidence-based clinical practice guidelines. We aimed to identify challenges faced by patients when referred for PCD diagnostic testing. A patient survey was developed by patient representatives and healthcare specialists to capture experience. Online versions of the survey were translated into nine languages and completed in 25 countries. Of the respondents (n=365), 74% were PCD-positive, 5% PCD-negative and 21% PCD-uncertain/inconclusive. We then interviewed 20 parents/patients. Transcripts were analysed thematically. 35% of respondents visited their doctor more than 40 times with PCD-related symptoms prior to diagnostic referral. Furthermore, the most prominent theme among interviewees was a lack of PCD awareness among medical practitioners and failure to take past history into account, leading to delayed diagnosis. Patients also highlighted the need for improved reporting of results and a solution to the “inconclusive” diagnostic status. These findings will be used to advise the ERS Task Force guidelines for diagnosing PCD, and should help stakeholders responsible for improving existing services and expanding provision for diagnosis of this rare disease.

Rapayan : une culture tardive du Haut Marañón dans les Andes centrales du Pérou

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Recherche de marqueurs de la dyskinésie tardive provoquée par les antidépresseurs à l'aide de l'imagerie quantitative par résonnance magnétique

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Tyran et magicien ? Représentation de la figure de l’empereur Julien dans les sources littéraires grecques, latines et syriaques de l’Antiquité tardive

Même si les Humanistes et les Lumières tentèrent de réhabiliter le personnage de Julien l’Apostat, leurs tentatives furent somme toute vaines. En effet, encore au début du siècle dernier on parlait de l’Apostat sans même qu’il soit nécessaire de nommer Julien. Systématiquement, il était qualifié de suppôt de Satan, de magicien, d’impie pratiquant des sacrifices humains. Le présent travail se propose d’analyser l’évolution de la figure de l’empereur Julien durant les deux siècles qui suivirent sa mort, en 363, et se divise en trois chapitres. Le premier se concentre sur les faits historiquement attestés dans les différentes sources (épigraphiques, numismatiques, littéraires) au sujet de l’homme et traite des épisodes principaux de sa vie - sa naissance, son césarat, sa proclamation - sous la forme d’une analyse historique. Le deuxième étudie l’évolution de son image à travers les sources littéraires païennes et chrétiennes du IVe au VIe siècle, en analysant, dans un premier lieu, le portrait-bilan que les auteurs ont peint (portrait de Julien par lui-même ; portrait physique ; portrait psychologique). Le troisième chapitre est consacré au Roman syriaque de Julien l’Apostat et à l’étude du personnage désormais légendaire, où des extraits illustrant les thèmes du deuxième chapitre sont analysés. Le mémoire sert principalement à mettre en place le contexte des siècles précédant la mise par écrit du Roman.

Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability

International audience

Endoplasmic reticulum stress and cell death mechanisms in the cell model of Huntington’s disease

This thesis clarifies important molecular pathways that are activated during the cell death observed in Huntington’s disease. Huntington’s disease is one of the most common inherited neurodegenerative diseases, which is primarily inherited in an autosomal dominant manner. HD is caused by an expansion of CAG repeats in the first exon of the IT15 gene. IT15 encodes the production of a Huntington’s disease protein huntingtin. Mutation of the IT15 gene results in a long stretch of polyQ residues close to the amino-terminal region of huntingtin. Huntington’s disease is a fatal autosomal neurodegenerative disorder. Despite the current knowledge of HD, the precise mechanism behind the selective neuronal death, and how the disease propagates, still remains an enigma. The studies mainly focused on the control of endoplasmic reticulum (ER) stress triggered by the mutant huntingtin proteins. The ER is a delicate organelle having essential roles in protein folding and calcium regulation. Even the slightest perturbations on ER homeostasis are effective enough to trigger ER stress and its adaptation pathways, called unfolded protein response (UPR). UPR is essential for cellular homeostasis and it adapts ER to the changing environment and decreases ER stress. If adaptation processes fail and stress is excessive and prolonged; irreversible cell death pathways are engaged. The results showed that inhibition of ER stress with chemical agents are able to decrease cell death and formation of toxic cell aggregates caused by mutant huntingtin proteins. The study concentrated also to the NF-κB (nuclear factor-kappaB) pathway, which is activated during ER stress. NF-κB pathway is capable to regulate the levels of important cellular antioxidants. Cellular antioxidants provide a first line of defence against excess reactive oxygen species. Excess accumulation of reactive oxygen species and subsequent activation of oxidative stress damages motley of vital cellular processes and induce cell degeneration. Data showed that mutant huntingtin proteins downregulate the expression levels of NF-κB and vital antioxidants, which was followed by increased oxidative stress and cell death. Treatment with antioxidants and inhibition of oxidative stress were able to counteract these adverse effects. In addition, thesis connects ER stress caused by mutant huntingtin to the cytoprotective autophagy. Autophagy sustains cellular balance by degrading potentially toxic cell proteins and components observed in Huntington’s disease. The results revealed that cytoprotective autophagy is active at the early points (24h) of ER stress after expression of mutant huntingtin proteins. GADD34 (growth arrest and DNA damage-inducible gene 34), which is previously connected to the regulation of translation during cell stress, was shown to control the stimulation of autophagy. However, GADD34 and autophagy were downregulated at later time points (48h) during mutant huntingtin proteins induced ER stress, and subsequently cell survival decreased. Overexpression GADD34 enhanced autophagy and decreased cell death, indicating that GADD34 plays a critical role in cell protection. The thesis reveales new interesting data about the neuronal cell death pathways seen in Huntington’s disease, and how cell degeneration is partly counteracted by various therapeutic agents. Expression of mutant huntingtin proteins is shown to alter signaling events that control ER stress, oxidative stress and autophagy. Despite that Huntington’s disease is mainly an untreatable disorder; these findings offer potential targets and neuroprotective strategies in designing novel therapies for Huntington’s disease.

The effects of entacapone on cardiorespiratory, autonomic, and clinical responses in L-dopa-treated patients with Parkinson's disease

Rest tremor, rigidity, and slowness of movements-considered to be mainly due to markedly reduced levels of dopamine (DA) in the basal ganglia-are characteristic motor symptoms of Parkinson's disease (PD). Although there is yet no cure for this illness, several drugs can alleviate the motor symptoms. Among these symptomatic therapies, L-dopa is the most effective. As a precursor to DA, it is able to replace the loss of DA in the basal ganglia. In the long run L-dopa has, however, disadvantages. Motor response complications, such as shortening of the duration of drug effect ("wearing-off"), develop in many patients. In addition, extensive peripheral metabolism of L-dopa by aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT) results in its short half-life, low bioavailability, and reduced efficacy. Entacapone, a nitrocatechol-structured compound, is a highly selective, reversible, and orally active inhibitor of COMT. It increases the bioavailability of L-dopa by reducing its peripheral elimination rate. Entacapone extends the duration of clinical response to each L-dopa dose in PD patients with wearing-off fluctuations. COMT is important in the metabolism of catecholamines. Its inhibition could, therefore, theoretically lead to adverse cardiovascular reactions, especially in circumstances of enhanced sympathetic activity (physical exercise). PD patients may be particularly vulnerable to such effects due to high prevalence of cardiovascular autonomic dysfunction, and the common use of monoamine oxidase B inhibitor selegiline, another drug with effects on catecholamine metabolism. Both entacapone and selegiline enhance L-dopa's clinical effect. Their co-administration may therefore lead to pharmacodynamic interactions, either beneficial (improved L-dopa efficacy) or harmful (increased dyskinesia). We investigated the effects of repeated dosing (3-5 daily doses for 1-2 weeks) of entacapone 200 mg administered either with or without selegiline (10 mg once daily), on several safety and efficacy parameters in 39 L-dopa-treated patients with mild to moderate PD in three double-blind placebo-controlled, crossover studies. In the first two, the cardiovascular, clinical, and biochemical responses were assessed repeatedly for 6 hours after drug intake, first with L-dopa only (control), and then after a 2 weeks on study drugs (entacapone vs. entacapone plus selegiline in one; entacapone vs. selegiline vs. entacapone plus selegiline in the other). The third study included cardiovascular reflex and spiroergometric exercise testing, first after overnight L-dopa withdrawal (control), and then after 1 week on entacapone plus selegiline as adjuncts to L-dopa. Ambulatory ECG was recorded in two of the studies. Blood pressure, heart rate, ECG, cardiovascular autonomic function, cardiorespiratory exercise responses, and the resting/exercise levels of circulating catecholamines remained unaffected by entacapone, irrespective of selegiline. Entacapone significantly enhanced both L-dopa bioavailability and its clinical response, the latter being more pronounced with the co-administration of selegiline. Dyskinesias were also increased during simultaneous use of both entacapone and selegiline as L-dopa adjuncts. Entacapone had no effect on either work capacity or work efficiency. The drug was well tolerated, both with and without selegiline. Conclusions: the use of entacapone-either alone or combined with selegiline-seems to be hemodynamically safe in L-dopa-treated PD patients, also during maximal physical effort. This is in line with the safety experience from larger phase III studies. Entacapone had no effect on cardiovascular autonomic function. Concomitant administration of entacapone and selegiline may enhance L-dopa's clinical efficacy but may also lead to increased dyskinesia.

Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

Governo, resistência e práticas de subjetivação em Michel Foucault

O presente trabalho é resultado de uma pesquisa no campo da ética e da filosofia política contemporâneas cujo objetivo geral consiste em analisar o modo pelo qual se articulam, no pensamento tardio de Michel Foucault (1926-1984), as noções de governo, resistência e práticas de subjetivação. A questão que o conduz é a do papel das práticas de subjetivação na constituição de novas formas de resistência às práticas de governo da vida humana na atualidade. Procurando respondê-la a partir do pensamento foucaultiano, desenvolvemos a seguinte hipótese: em Foucault, as práticas de constituição dos sujeitos teriam papel de fundamental importância para a elaboração de novas formas de resistência política às diferentes técnicas de governo e condução da vida humana na atualidade, isto é, a importância conferida às formas de subjetivação ética ou às práticas de governo de si, não implica num individualismo ético ou numa redução da política à esfera da ética. Trata-se, ao contrário, de uma investigação acerca do modo pelo qual as práticas de si se encontram inseridas num contexto mais amplo de práticas sociais e de lutas, podendo se constituir como pontos de resistência aos tipos de governamentalidade que, ao longo dos séculos, impuseram aos indivíduos determinadas formas de existência. Trata-se, em todo o trabalho, de uma possível articulação entre ética e política a partir da noção foucaultiana de governamentalidade, que concerne ao par governo dos outros/governo de si, e que é também o fio condutor desta investigação. Método: para verificar nossa hipótese, julgamos necessário articular elementos da trajetória filosófica tardia de Foucault presentes em seus últimos cursos e livros, que permitissem compreender mais apropriadamente a relação que há entre: as formas históricas de governar os indivíduos e as populações nas sociedades ocidentais modernas; as formas de resistência possível a essas formas de governar; e as práticas de subjetivação. Com a pesquisa, verificamos o caráter estratégico e móvel tanto das práticas de governar a si mesmo e aos outros quanto das formas de resistência expressas nas lutas da atualidade e nos modos de subjetivação elaborados por indivíduos e grupos.

Depression of Serotonin Synaptic Transmission by the Dopamine Precursor L-DOPA

Imbalance between the dopamine and serotonin (5-HT) neurotransmitter systems has been implicated in the comorbidity of Parkinson's disease (PD) and psychiatric disorders. L-DOPA, the leading treatment of PD, facilitates the production and release of dopamine. This study assessed the action of L-DOPA on monoamine synaptic transmission in mouse brain slices. Application of L-DOPA augmented the D2-receptor-mediated inhibitory postsynaptic current (IPSC) in dopamine neurons of the substantia nigra. This augmentation was largely due to dopamine release from 5-HT terminals. Selective optogenetic stimulation of 5-HT terminals evoked dopamine release, producing D2-receptor-mediated IPSCs following treatment with L-DOPA. In the dorsal raphe, L-DOPA produced a long-lasting depression of the 5-HT1A-receptor-mediated IPSC in 5-HT neurons. When D2 receptors were expressed in the dorsal raphe, application of L-DOPA resulted in a D2-receptor-mediated IPSC. Thus, treatment with L-DOPA caused ectopic dopamine release from 5-HT terminals and a loss of 5-HT-mediated synaptic transmission.

The dopamine metabolite 3-methoxytyramine is a neuromodulator.

Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated cAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause cAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia.

Interobserver agreement of the Gross Motor Function Classification System in an ambulant population of children with cerebral palsy

Gross Motor Function Classification System (GMFCS) level was reported by three independent assessors in a population of children with cerebral palsy (CP) aged between 4 and 18 years (n=184; 112 males, 72 females; mean age 10y 10mo [SD 3y 7mo]). A software algorithm also provided a computed GMFCS level from a regional CP registry. Participants had clinical diagnoses of unilateral (n=94) and bilateral (n=84) spastic CP, ataxia (n=4), dyskinesia (n=1), and hypotonia (n=1), and could walk independently with or without the use of an aid (GMFCS Levels I-IV). Research physiotherapist (n=184) and parent/guardian data (n=178) were collected in a research environment. Data from the child's community physiotherapist (n=143) were obtained by postal questionnaire. Results, using the kappa statistic with linear weighting (?1w), showed good agreement between the parent/guardian and research physiotherapist (?1w=0.75) with more moderate levels of agreement between the clinical physiotherapist and researcher (?1w=0.64) and the clinical physiotherapist and parent/guardian (?1w=0.57). Agreement was consistently better for older children (>2y). This study has shown that agreement with parent report increases with therapists'experience of the GMFCS and knowledge of the child at the time of grading. Substantial agreement between a computed GMFCS and an experienced therapist (?1w=0.74) also demonstrates the potential for extrapolation of GMFCS rating from an existing CP registry, providing the latter has sufficient data on locomotor ability.

Comme un poème en plusieurs chambres : maisons d'écrivains en France et au Québec

Les plus récentes études sur l'auteur se sont intéressées à plusieurs aspects de sa figure. Elles ont questionné ses représentations dans la fiction. Elles l'ont étudiée comme une fabrication du champ littéraire. Elles ont réfléchi aux croyances et aux mythes dont cette image est porteuse. Elles se sont penchées sur le rapport que les lecteurs entretiennent avec la biographie de l'auteur. Elles ont même cherché à comprendre à quelles conditions un individu en arrive à se dire écrivain. Aucune étude ne s'est toutefois intéressée à la conservation posthume des figures d'auteur par ces fascinants musées que constitue leur maison personnelle, lorsqu'elle est ouverte au public.Dans une perspective chronologique, le premier objectif de la Thèse consiste à situer et à comparer les maisons d'écrivains en France et au Québec. Dans une perspective synchronique, le deuxième objectif est d'étudier les représentations des écrivains que les maisons-musées véhiculent.L'ouverture des premières maisons d'hommes célèbres en Europe à la fin du XIXe siècle est tributaire du culte des grands hommes. La première partie de la Thèse est consacrée à ce phénomène, notamment étudié par Jean-Claude Bonnet. En France, les maisons-musées gagnent en popularité tout au long du XXe siècle et connaissent un âge d'or dans les années 1980 et 1990, sous le coup de politiques gouvernementales qui témoignent désormais d'une conception élargie de la culture. Au Québec, l'émergence du phénomène n'est pas beaucoup plus tardive, mais connait une expansion beaucoup moins importante. La deuxième partie de la Thèse s'intéresse aux politiques culturelles qui favorisent l'ouverture au public de maisons d'écrivains dans ces pays de la Francophonie. Elle présente également les monographies des six maisons d'écrivains qui composent le corpus restreint de la Thèse : en France, la Maison de Balzac à Paris, la Maison de Tante Léonie-Musée Marcel-Proust à Illiers-Combray et la Maison Elsa-Triolet-Aragon à Saint-Amoult-en-Yvelines; au Québec, la Maison Samuel-Bédard-Musée Louis-Hémon à Péribonka, l'Espace Félix-Leclerc à l'île d'Orléans et l'Espace Claude-Henri-Grignon à Saint-Jérome. Enfin, la troisième partie de la Thèse porte sur les représentations des écrivains dans les maisons d'écrivains, en s'intéressant à une particularité importante de ces lieux semi-privés et semi-publics : l'opposition entre familiarité et grandeur sur laquelle ils reposent.