Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Background: Patients with Panic Disorder (PD) direct their attention towards potential threat, followed by panic attacks, and increased sweat production. Onés own anxiety sweat odor influences the attentional focus, and discrimination of threat or non-threat. Since olfactory projection areas overlap with neuronal areas of a panic-specific fear network, the present study investigated the neuronal processing of odors in general and of stress-related sweat odors in particular in patients with PD. Methods: A sample of 13 patients with PD with/ without agoraphobia and 13 age- and gender-matched healthy controls underwent an fMRI investigation during olfactory stimulation with their stress-related sweat odors (TSST, ergometry) as well as artificial odors (peach, artificial sweat) as non-fearful non-body odors. Principal Findings: The two groups did not differ with respect to their olfactory identification ability. Independent of the kind of odor, the patients with PD showed activations in fronto-cortical areas in contrast to the healthy controls who showed activations in olfaction-related areas such as the amygdalae and the hippocampus. For artificial odors, the patients with PD showed a decreased neuronal activation of the thalamus, the posterior cingulate cortex and the anterior cingulate cortex. Under the presentation of sweat odor caused by ergometric exercise, the patients with PD showed an increased activation in the superior temporal gyrus, the supramarginal gyrus, and the cingulate cortex which was positively correlated with the severity of the psychopathology. For the sweat odor from the anxiety condition, the patients with PD showed an increased activation in the gyrus frontalis inferior, which was positively correlated with the severity of the psychopathology. Conclusions: The results suggest altered neuronal processing of olfactory stimuli in PD. Both artificial odors and stress-related body odors activate specific parts of a fear-network which is associated with an increased severity of the psychopathology.

The capacity of the olfactory neuraxis to undergo neuronal replacement and axon targeting following injury, has led to scrutiny concerning the molecular and physical determinants of this growth capacity. This is because injury to the central nervous system, in contrast, leads to permanent disconnection of neurons with targets. Olfactory ensheathing cells (OECs), a specialized glial cell, may contribute to olfactory repair, and have been used to promote recovery from spinal cord injury. However, there mechanisms underlying OEC-induced regeneration are poorly appreciated. To understand these mechanisms, OECs from the lamina propria (LP OECs) or olfactory bulb (OB OECs) were transplanted into a lesion of the dorsolateral funiculus. While both cells demonstrated reparative capacities, LP and OB OECs differentially promoted spinal fibre growth; large-diameter neurofilament-positive, CGRP-positive, and serotonergic fibres sprouted in response to both LP and OB OEC transplantation, whereas substance-P and tyrosine hydroxylase-positive neurons grew more extensively following OB or LP OEC transplantation, respectively. To further understand the growth of spinal cord neurons in response to OECs, a proteomic analysis of OEC secreted factors was performed, identifying secreted protein acidic and rich in cysteines (SPARC) as a mediator of OEC-induced outgrowth in vitro. To test the contributions of SPARC to spinal cord repair after OEC transplantation, cultures of LP OECs from SPARC null and wildtype (WT) mice were transplanted into a crush of the dorsolateral funiculus. Substance P and tyrosine hydroxylase positive axon sprouting was significantly reduced in SPARC null OEC-treated animals, suggesting that individual factors may contribute to OEC-promoted regeneration. To investigate the effect of OECs on corticospinal (CST) neurons, an in vitro assay was developed using postnatal day 8 CST neurons. Coculture of CST neurons with OB OECs produced extensive axon elongation. Application of OB OEC secreted factors increased CST neurite branching, but did not increase axon elongation. In contrast, plating of CST neurons on OB OEC plasma membrane resulted in extensive axon elongation. Furthermore, the OB OEC plasma membrane could overcome CST neurite outgrowth inhibition induced by an outgrowth inhibitor. Together these findings provide insight into OEC mechanisms of neurite outgrowth and axon regeneration.

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in English While axon fasciculation plays a key role in the development of neural networks, very lit- tle is known about its dynamics and the underlying biophysical mechanisms. In a model system composed of neurons grown ex vivo from explants of embryonic mouse olfactory epithelia, we observed that axons dynamically interact with each other through their shafts, leading to zippering and unzippering behaviour that regulates their fasciculation. Taking advantage of this new preparation suitable for studying such interactions, we carried out a detailed biophysical analysis of zippering, occurring either spontaneously or induced by micromanipulations and pharmacological treatments. We show that zippering arises from the competition of axon-axon adhesion and me- chanical tension in the axons. This is upheld on quantitative level by conforming change of network global structure in response to various pharmacological treatments, without active involvement of growth cones. The calibrated manipulations of interacting shafts provide qualitative support for the hypothesis, and also allow us to quantify the mechan- ical tension of axons in our system. Furthermore, we introduce a biophysical model of the zippering dynamics, which efficiently serves the purpose of estimating the magnitude of remaining involved...

A diferença da percepção álgica entre homens e mulheres é, há muito, conhecida e documentada na literatura. Sabe-se também que a sensibilidade feminina varia durante o ciclo menstrual, o que levou à hipótese de que os hormônios ovarianos poderiam estar envolvidosnesse processo. Assim, este estudo teve como objetivo investigar os limiares de sensibilidade somestésica (térmica, dolorosa, tátil, vibratória e elétrica), gustativa e olfativa durante o ciclo menstrual de mulheres saudáveis e a sua relação com as concentrações dos hormônios estrógeno e progesterona na saliva. Foram avaliadas 39 mulheres com idade entre 19 e 47 anos, com ciclos menstruais regulares e sem morbidades associadas à dor. Todas as mulheres foram orientadas quanto aos propósitos desta pesquisa, e somente participaram do estudo aquelas que preencheram os critérios de inclusão e assinaram o termo de consentimento livre e esclarecido. A avaliação foi realizada em três momentos do ciclo menstrual: fase menstrual, fase folicular e fase lútea. Em cada uma dessas fases foram utilizados os seguintes métodos: coleta da saliva no início de cada sessão, para avaliação dos níveis hormonais; avaliação de fluxo salivar; avaliação sensitiva superficial (dor, tato - IITC Woodland Hills, EUA; frio, calor - MSA II e vibratórios - Somedic, Suécia) aplicada na região do ramo maxilar do nervo trigêmeo e na região do antebraço, ambas no lado direito da paciente; e avaliação das sensibilidades gustativa (doce - glicose, salgado - cloreto de sódio, azedo - ácido cítrico e amargo - ureia) e olfativa (isopropanol em diferentes concentrações). Foram observadas oscilações sensitivas em todas as modalidades de acordo com o momento do ciclo menstrual das mulheres avaliadas, sendo que níveis baixos de estrógeno se associaram a altos limiares de dor de profundidade no braço (p=0,008) e na face (p=0,041), altos limiares táteis (p=0,001) e álgicos superficiais (p=0,006) na face. Em contrapartida, altos níveis de progesterona se associaram a altos limiares de dor de profundidade na face (p=0,033) e altos limiares do sabor salgado (p < 0,001). Concluímos que o estrógeno e a progesterona estão envolvidos na neuromodulação da sensibilidade somestésica, gustativa e olfativa de mulheres, durante o ciclo menstrual / There is a sexual difference on pain perception that is supported by the scientific literature. Moreover, sexual hormones seem to be involved in the modulation of sensory detection and there is evidence of sensory variation during the menstrual cycle. Thus, the aim of this study was to investigate the somatosensory (thermal, painful, tactile, vibratory and electric), gustatory (salty, bitter, sweet, sour) and olfactory thresholds during the menstrual cycle in healthy women and verify association with saliva concentration of estradiol and progesterone. We evaluated 39 women aged between 19 and 47 years, with regular menstrual cycles and with no comorbidities related to pain.All women were instructed about the purposes of the study and only those that signed the informed consent were included. The evaluation wasperformed in three moments of the cycle: menstrual phase, follicular phase and luteal phase. In each of these stages, the following methods were used: saliva collection at the beginning of each session, to assess hormone levels; salivary flow measurement; somatosensory evaluation with quantitative sensory testing (pain, tactile - IITC Woodland Hills, USA; cold and warm - MSA II; and vibration - Somedic, Sweden) applied to the right maxillary branch region of the trigeminal nerve and right forearm region; and gustative (sweet - glucose, salt - sodium chloride, sour - citric acid and bitter - urea) and olfactory (isopropanol at different concentrations) thresholds. All sensory thresholds showed fluctuation during the menstrual cycle. Lower estrogen levels were correlated tohigher deep pain thresholds at the forearm (p=0.008) and face (p=0.041); they were also associated with higher tactile thresholds (p=0.001) and higher superficial pain (p=0.006) thresholds at face.High levels of progesterone were associated with high deep pain threshold at the face and high salty threshold (p < 0.001). In conclusion, estrogen and progesterone seems to be involved in sensory neuromodulation in women, during the menstrual cycle

La gravité du traumatisme crânien (TC) dépend de la sévérité immédiate des lésions primaires mais également de leur aggravation dans les heures et les jours qui suivent le TC, avec l’apparition de lésions secondaires. La neuro-inflammation constitue l’une des cascades physiopathologiques post-TC dont le contrôle a été décrit comme une stratégie neuroprotectrice potentielle. Elle compromet le taux de la forme soluble α du précurseur du peptide ß amyloÏde, sAPPα, un neuroprotecteur endogène issu de l’action des enzymes α-sécrétases (ADAMs). Dans ce contexte, mon travail de thèse a eu pour but d’étudier l’intérêt thérapeutique des composés pharmacologiques modulant le taux de sAPPα post-TC sur les conséquences biochimiques, histopathologiques et fonctionnelles, à court et à long terme, dans un modèle de TC par percussion mécanique chez la souris. Parmi les différents composés, la minocycline, une tetracycline de 2e génération aux effets anti-inflammatoires, et l’étazolate, une pyrazolopyridine récemment décrite comme activateur des α-sécrétases, ont été sélectionnés. Le traitement anti-inflammatoire par la minocycline permet de restaurer le taux de la sAPPα, et cet effet dans la phase précoce est accompagné d’une réduction des conséquences histopathologiques (atrophie callosale et striatale, lésion des bulbes olfactifs et ventriculomégalie) à 3 mois post-TC. Sur le plan fonctionnel, le test d’aversion olfactive a été pour la première fois mis au point sur un modèle expérimental de TC et a permis de révéler un déficit olfactif persistant dans notre modèle. De plus, un déficit cognitif persistant a été également mis en évidence par le test NORT « Novel Object Recognition Test ». Le même traitement par la minocycline a permis de corriger ces déficits olfactif et cognitif à court et à long terme (3 mois) post-TC. Les résultats obtenus sur l’étazolate (étude de fenêtre thérapeutique, étude d’effet-dose) ont montré, pour la première fois dans un modèle de lésion cérébrale, son potentiel anti-inflammatoire et anti-œdémateux, associé à la restauration du taux de la sAPPα, avec une fenêtre thérapeutique d’au moins de 2h. Le même traitement réduit les conséquences histopathologiques (activation microgliale, ventriculomégalie, lésion des bulbes olfactives) et fonctionnelles (hyperactivité locomotrice, déficit cognitif), à court à long terme (3 mois) post-TC. En conclusion, l’ensemble de ce travail a permis d’établir les bénéfices d’une stratégie pharmacologique s’opposant à la fois à la neuro-inflammation et à la chute du taux de la sAPPα dans la phase précoce de TC avec une amélioration histologique et fonctionnelle à long terme, soulignant son intérêt thérapeutique. Il est important de souligner que la minocycline est déjà entrée en essai clinique pour le traitement de TC, et que malgré le peu de données précliniques, l’étazolate (EHT-0202) est tout récemment entré en phase II pour le traitement de la maladie d’Alzheimer. / The severity of the sequelae of traumatic brain injury (TBI) depends on the extent of primary damage as well as the implication of secondary injury cascades that are triggered within the hours and days post- insult. Neuroinflammation is an important post-TBI cascade whose inhibition has been described as a potential neuroprotective strategy. Neuroinflammation has been associated to the decrease of an endogenous neuroprotector, the soluble form α of the amyloid precursor protein (sAPPα), generated by the activity of the enzymes α-secretases or ADAMs. The aim of this work was to evaluate the therapeutic interest of pharmacological compounds that restore sAPPα levels on short- and long-term biochemical, histological and functional outcome in a mouse model of TBI by mechanical percussion. Among the potential candidates, the compounds selected were minocycline, a tetracycline that exerts anti-inflammatory activity, and etazolate, a pyrazolopyridine that activates α-secretases. The anti-inflammatory treatment with minocycline was able to restore post-TBI sAPPα levels, and this acute effect was accompanied by lasting neuroprotection, namely reduction of lesion size (corpus callosum, striatum and olfactory bulbs) and ventriculomegaly and attenuation of glial reactivity. The olfactory aversion test, developped for the first time in experimental TBI, unraveled a persistant olfactory deficit. Moreover, a durable cognitive deficit was revealed by the Novel Object Recognition Task (NORT). Treatment with minocycline was able to attenuate both the olfactory and cognitive deficits in an effective manner. Moreover, the results obtained in the pharmacological study with etazolate (therapeutic window, dose-response) demonstrated, for the very first time, the anti-inflammatory and anti-oedematous efficacy of etazolate, when administered at least 2 hours post-TBI. The same treatment protocol was also able to attenuate sAPPα levels and offered persistent neuroprotection, namely reduction of lesion size (ventriculomegaly, olfactory bulb lesion) and microglial activation, and attenuation of functional deficits (hyperactivity, cognitive deficit). In conclusion, the findings of this work highlight the therapeutic efficacy of compounds that attenuate neuroinflammation and restore sAPPa levels within the acute and critical post-TBI aftermath, on histological and functional outcome. It is worth noting that minocycline is actually in a clinical trial for the treatment of traumatic brain injury and etazolate (EHT 0202), despite the poor experimental data available, has managed to enter a clinical trial for the treatment of Alzheimer’s disease.

Extrazelulläre Purine und Pyrimidine sind wichtige Signalmoleküle, die über membranständige Rezeptoren, so genannte purinerge Rezeptoren ihre biologischen Effekte vermitteln. In der vorliegenden Arbeit wurden ATP-induzierte Antworten in den Stützzellen des olfaktorischen Epithels mit Hilfe der Calcium-Imaging-Technik charakterisiert.Die Applikation von ATP induzierte Zunahmen der intrazellulären Kalziumkonzentration ([Ca2+]i) sowohl in Anwesenheit, als auch in Abwesenheit von extrazellulärem Kalzium. Anders bei Anwendung von CPA, einem spezifischen Hemmstoff der Ca2+-ATPase des sarkoplasmatischen bzw. endoplasmatischen Retikulums. In diesen Versuchen wurden die ATP-induzierten [Ca2+]i-Zunahmen komplett aufgehoben. Das zeigt, dass die ATP-induzierten [Ca2+]i-Zunahmen in Stützzellen größtenteils, wenn nicht vollständig, durch die Aktivierung von G-Protein gekoppelten P2Y-Rezeptoren ausgelöst werden. Die ermittelte Wirkpotenz purinerger Agonisten war UTP>ATP>ATPγS. Die ATP-induzierten [Ca2+]i-Zunahmen konnten durch die purinergen Antagonisten PPADS und RB2 reduziert werden. Die hemmende Wirkung des purinergen Antagonisten Suramin blieb aus. Zusammen weisen die oben genannten Ergebnisse dieser Arbeit darauf hin, dass extrazelluläre Nukleotide die Stützzellen des olfaktorischen Epithels über P2Y2 / P2Y4-artige Rezeptoren aktivieren. Zusätzlich zeigten die Versuche mit dem Ektonukleotidase-Hemmstoff ARL 67156, dass im olfaktorischen Epithel von larvalen Xenopus laevis eine hohe Ektonukleotidasenaktivität herrscht.

Abstract The aim of the study was to describe Finnish patients' experiences of the regulation of personal privacy in hospital with the concept 'personal space'. The central topics of interest included the personal space and it's preservation. The right of self-determination while inpatients in hospital enables the patient to preserve personal space. Patients' experiences of personal space and it's preservation were examined by describing the significance of the preservation of personal space, other factors connected with personal space preservation, patients' means to protect their personal space preservation in the interaction with nursing staff, and the tactile, auditory, visual, and olfactory failure of personal space preservation. Patients' personal space was observed from the point of view of triangulation, and quantitative and qualitative data were integrated in the research. The purpose was to provide fresh knowledge in Finnish nursing science on patients' personal space and it's preservation in hospital, as well as to introduce the factors and concepts connected with the phenomenon of personal space to a wider public. The research material was collected in the internal medicine wards of a university hospital. The collection of data was carried out by means of a structured interview (N = 250) and the observation (N = 25) of interactive situations between patients and nursing staff. The structured questions of the interviews were analysed in the software SPSS for Windows 10.1.2. The results were presented as frequency and percentage distributions. The averages used were the mean, the mode, and the median. Cross-tabulation and Spearman's correlation coefficient were used to find out the correlation between variables. The significance of sum variables measuring auditory, visual, and olfactory invasion was tested by means of the t-test on independent groups, the one-way variance analysis, Mann-Whitney's U-test, and χ2-independence test. The open questions of the interviews and the observations were analysed with deductive-inductive content analysis. Patients' right of self-determination in relation to the nursing procedures on their own body was best implemented among the young and more educated patients. The patients protected their personal space with verbal messages related to pain and the right of self-determination, and with non-verbal messages related to body positions, gestures, expressions, eye contact as well as its avoidance, and to the use of hospital screens. The screens were used for the protection of one's own privacy and intimacy, but also for the protection of co-patients' privacy and intimacy. For the majority of the patients, the inviolability of their tactile and olfactory space were particularly important. The personal space had been invaded tactily, auditorily, and olfactorily. Significant factors affecting the experience of personal space were the patient's sex and age, the size of the patient room, the patient's coping capability in hospital, the number of treatments, and mood during hospitalisation. The failure of personal space preservation made the patients feel, above all, hurt and treated as objects. The patients found it justified for the nursing staff to touch them when assisting, but also thought that unnecessary extra taction does not belong to nursing practice. Taction by the nursing staff was mainly experienced as gentle and pain-reactive, as well as respectful of the patient's body. / Tiivistelmä Tutkimuksen tarkoituksena oli kuvata suomalaisten potilaiden kokemuksia yksityisyyden säätelystä sairaalassa henkilökohtaisen tilan avulla. Mielenkiinnon kohteina olivat henkilökohtainen tila ja sen säilyminen. Potilaan itsemääräämisoikeuden toteutuminen hoidon aikana mahdollistaa henkilökohtaisen tilan säilymisen. Potilaiden kokemuksia henkilökohtaisesta tilastaan ja sen säilymisestä selvitettiin kuvaamalla henkilökohtaisen tilan säilymisen merkityksellisyyttä, henkilökohtaisen tilan säilymiseen yhteydessä olevia tekijöitä, potilaiden keinoja suojata henkilökohtaisen tilansa säilyminen ja henkilökohtaisen tilan säilymisen taktiilista, auditiivista, visuaalista ja olfaktorista epäonnistumista. Potilaan henkilökohtaista tilaa tarkasteltiin triangulaation näkökulmasta ja tutkimuksessa yhdistettiin kvantitatiivinen ja kvalitatiivinen aineisto. Tutkimuksen tavoitteena oli saada uutta suomalaista hoitotieteellistä tietoa potilaan henkilökohtaisesta tilasta ja sen säilymisestä sairaalassa sekä tehdä tunnetuksi henkilökohtaisen tilan ilmiöön liittyviä tekijöitä ja käsitteitä. Tutkimuksen aineisto kerättiin yliopistollisen sairaalan sisätautien klinikan vuodeosastoilla. Aineisto kerättiin strukturoidulla haastattelulla (N = 250) ja havainnoimalla (N = 25) potilaan ja hoitotyöntekijän välisiä vuorovaikutustilanteita. Haastattelujen strukturoidut kysymykset analysoitiin SPSS for Windows 10.1.2 -ohjelmalla. Tulokset esitettiin frekvenssi- ja prosenttijakaumina. Keskilukuina käytettiin keskiarvoa, moodia ja mediaania. Muuttujien välisten riippuvuuksien selvittämiseksi käytettiin ristiintaulukointia ja Spearmanin korrelaatiokerrointa. Auditiivista, visuaalista ja olfaktorista loukkaamista mittaavien summamuuttujien merkitsevyyden testaamiseksi käytettiin riippumattomien ryhmien t-testiä, yksisuuntaista varianssianalyysiä, Mann-Whitneyn U-testiä ja χ2-riippumattomuustestiä. Haastattelujen avoimet kysymykset ja havainnoinnit analysoitiin deduktiivis-induktiivisella sisällön analyysillä. Potilaiden itsemääräämisoikeus suhteessa omaa kehoa koskeviin hoitotoimenpiteisiin toteutui parhaiten nuorten ja enemmän koulutettujen potilaiden kohdalla. Potilaat käyttivät henkilökohtaisen tilansa suojaamiseksi erilaisia kipuun ja itsemääräämisoikeuteen liittyviä verbaalisia viestejä ja kehon asentoihin, eleisiin, ilmeisiin, katsekontaktiin ja sen välttämiseen sekä väliverhojen käyttämiseen liittyviä nonverbaalisia viestejä. Väliverhoja käytettiin suojaamaan omaa yksityisyyttä ja mahdollistamaan oma intimiteettisuoja, mutta myös suojaamaan potilastoverin yksityisyyttä ja mahdollistamaan hänelle intimiteettisuoja. Potilaat kokivat merkityksellisenä erityisesti taktiilisen ja olfaktorisen tilan säilymisen loukkaamattomana. Henkilökohtainen tila oli tullut loukatuksi taktiilisesti, auditiivisesti ja olfaktorisesti. Henkilökohtaisen tilan kokemiseen merkityksellisenä olivat yhteydessä potilaan sukupuoli, ikä, potilashuoneen koko, selviytymiskyky sairaalassa, hoitokertojen määrä ja mieliala sairaalassa. Henkilökohtaisen tilan säilymisen epäonnistuminen aiheutti potilaille etenkin pahaa mieltä ja itsen kokemista esineeksi. Potilaat oikeuttivat hoitotyöntekijän kosketuksen autettaessa, mutta turha ja ylimääräinen kosketus ei kuulu hoitotyöhön. Hoitotyöntekijän kosketus koettiin pääasiallisesti hellävaraiseksi, kivut huomioon ottavaksi ja kehoa kunnioittavaksi ja arvostavaksi.