No description available.

No description available.

La sclérose en plaques est une maladie chronique, auto-immune et neurodégénérative qui se traduit par l’apparition de plaques inflammatoires démyélinisantes dans le système nerveux central. Pour caractériser la réponse immunitaire innée, j’ai développé des outils d’imagerie optique non linéaire multispectrale intravitale, et des solutions semi automatisées d’analyse d’images. J’ai participé à la mise au point d’un protocole d’identification des phénotypes immunitaires en cytométrie. Ces outils appliqués à l’étude de l’encéphalomyélite auto-immune expérimentale, un modèle murin de SEP, ont permis d’analyser la cascade immunitaire par immunomarquages et marquages fluorescents transgéniques, de décrire les distributions des populations cellulaires dans le SNC, et de les associer à la dégradation axonale sur des échelles de temps de la seconde à la semaine. Sur une lignée de souris transgénique, Thy1-CFP/Cd11c-EYFP/LysM-EGFP, j’ai suivi en microscopie biphotonique l’évolution des densités de cellules fluorescentes dans la moelle épinière pendant plusieurs semaines. J’ai conclu que la dégénération axonale et les déficits moteurs sont corrélés avec l’infiltration par les méninges de neutrophiles et monocytes. Les monocytes se différencient in situ en cellules dendritiques d’origine monocytaire (moDCs) parallèlement à l'activation de la microglie. Ces événements cellulaires, dont la maturation des moDCs sont corrélés avec la résorption de l’inflammation. La méthodologie est en place pour poursuivre ces investigations sur d’autres modèles. L’optimisation du microscope m’a aussi permis d’accéder simultanément au contraste endogène CARS pour visualiser la gaine de myéline. / Multiple sclerosis is a chronic auto-immune neurodegenerative disease characterized by the appearance of inflammatory plaques in the central nervous system. To characterize the innate immune response I have developed nonlinear optical tools for intravital multispectral imaging as well as semi-automated image processing solutions. I also contributed to the development of a flow cytometry protocol allowing the identification of immune cell phenotypes. Applied to study of Experimental Autoimmune Encephalomyelitis, a mouse model of MS, these tools have allowed to analyze the immune cascade thanks to immunolabelings and transgenic expression of fluorescence, describe the distributions of cell populations in the CNS with regard to neuron degeneration on time scales ranging from seconds to weeks. On a transgenic mouse line Thy1-CFP/Cd11c-EYFP/LysM-EGFP, I have followed by two-photon microscopy the evolution of fluorescent cells densities in the same area of the spinal cord for several weeks. I conclude that axonal degeneration and motor deficits are correlated with neutrophils and monocytes infiltration from the meninges. The monocytes differentiate in situ in monocyte-derived dendritic cells (moDCs) along with the recruitment of activated microglia. These cellular events correlated with a stabilization/remission phase of the disease. MoDCS maturation thus seems involved in the dampening of inflammation. Methodology and tools are now set for further investigations with other models. The microscope optimization for multicolor excitation allowed me to access simultaneously to the endogenous CARS contrast to visualize the myelin sheath.

Cette thèse propose d'explorer les capacités en mémoire épisodique de patients atteints de sclérose en plaques (sep). A notre connaissance, l'analyse des processus touchés et préservés a fait l'objet de peu de travaux. L'une des raisons historiques semble être la création, dès les années 1980, de batteries d'évaluation rapide destinées aux neurologues. Ainsi, le golden standard de l'évaluation mnésique dans cette affection est le srt (dujardin et al., 2004) qui permet difficilement de contrôler les troubles d'encodage et de récupération. L'objectif de cette thèse sera dans un premier temps de documenter à l'aide d'épreuves permettant une analyse des processus mnésiques, les capacités de mémoire épisodique verbale dans la sep. Les performances de trois groupes de patients (sep, maladies d'Alzheimer et de Parkinson) seront comparées dans l'épreuve rl/ri-16 items. Cette étude sera destinée à vérifier si une majorité de patients sep présente une amélioration du rappel libre après délai contrairement aux deux autres affections testées. Si tel est le cas, l'hypothèse d'un temps de traitement, insuffisamment long pour les patients sep entre les rappels immédiats, mériterait d'être testée. Pour cela, une version parallèle du cvlt sera créée. Ainsi, les performances des patients seront comparées intra-individuellement lors de l'administration de l'épreuve dans sa version originale et lors d'une version où les temps entre les présentations de la liste de courses seront allongés. Un troisième volet sera destiné à tester les capacités de consolidation à long terme (une étude dans ce domaine pour la sep). Une analyse anatomo-fonctionnelle sera conduite en éprouvant l'hypothèse d'un lien entre les performances de rappel à une semaine et la volumétrie hippocampique des patients sep. / This thesis suggests exploring capacities in memory episodic of patients reached by multiple sclerosis. To our knowledge, the analysis of the affected and protected processes was the object of few works. One of the historic reasons seems to be the creation, from the 1980s, of batteries of fast evaluation intended for the neurologists. So, standard Golden of the mnesic evaluation in this affection is the srt (dujardin and al ., on 2004) which allows with difficulty to check) the disorders of encoding and recovery. The objective of this thesis will at first be to document by means of tests allowing an analysis of the mnesic processes, capacities of verbal episodic memory in frog. The performances of three groups of patients (frog, Alzheimer's diseases and of Parkinson) will be compared in the test rl / ri-16 items. This study will be intended to verify if a majority of patients frog presents an improvement of the free reminder after deadline contrary to two other tested affections. If that was the case, the hypothesis of a processing time, insufficiently long for the patients frog between the immediate reminders), would deserve to be tested. For that purpose, a parallel version of the cvlt will be created. So, the performances of the patients will be compared intra - individually during the administration of the test in its original version and during the version where the times between the presentations of the shopping list will be lengthened. The third shutter will be intended to test the capacities of long-term consolidation (a study in this domain for frog). An anatomo-functional analysis will be led by feeling the hypothesis of a link between the performances of reminder in a week and the hippocampal volumetry of the patients frog.

Systems biologists use interaction graphs to model the behaviour of biological systems at the molecular level. In an iterative process, such biologists observe the reactions of living cells under various experimental conditions, view the results in the context of the interaction graph, and then propose changes to the graph model. These graphs represent dynamic knowledge of the biological system being studied and evolve as new insight is gained from the experimental data. While numerous graph layout and drawing packages are available, these tools did not fully meet the needs of our immunologist collaborators. In this thesis, we describe the data display needs of these immunologists and translate these needs into visual encoding decisions. These decisions led us to create Cerebral, a system that uses a biologically guided graph layout and incorporates experimental data directly into the graph display. Our graph layout algorithm uses simulated annealing with constraints, optimized with a uniform grid to have an expected runtime of o(E/V). Small multiple views of different experimental conditions and a measurement-driven parallel coordinates view enable correlations between experimental conditions to be analyzed at the same time that the measurements are viewed in the graph context. This combination of coordinated views allows the biologist to view the data from many different perspectives simultaneously. To illustrate the typical analysis tasks performed, we analyze two datasets using Cerebral. Based on feedback from our collaborators, we conclude that Cerebral is a valuable tool for analyzing experimental data in the context of an interaction graph model. / Science, Faculty of / Computer Science, Department of / Graduate

The purpose of the present study was to examine whether or not luminance thresholds through static, chromatic perimetry could be used to distinguish visual threshold losses in multiple sclerosis from that of normal functioning. It was proposed that threshold losses would be greater at both the fovea and near foveal eccentricities due to the assumption that the cone system, unlike the rods, would be the most effected by MS. Twenty-two MS patients and thirty age matched normals were tested on an extensively modified version of the Fieldmaster F225 Automatic Perimeter. Thresholds were established for an achromatic, red, and blue stimulus along a 195 - 15 degree meridian. Testing was done using a 45 apostilb background, to which the subjects were preadapted prior to testing. Results indicated that there was extensive cone involvement (loss in chromatic thresholds) for the MS subjects. Significant differences existed at the fovea between normal and clinically definite subjects but not between normal and probable. Correlational analyses indicated great functional changes in retinal sensitivity for the MS patients. Similar results were obtained between MS patients with and without optic neuritis. Discriminant analyses indicated that the red filter could correctly classify 86.27% of the normals and MS patients with few false positives or negatives. Log threshold difference values between the fovea and 30 degree nasal eccentricity were used to determine a threshold value which could separate normal profiles from MS profiles. The typical "swiss cheese" defects reported in the clinical literature were found only for the achromatic and blue filters. No irregular profiles were found for the red filter. A possible theoretical model based on the results was discussed. Limitations of the study as well as possible future research were also discussed. / Arts, Faculty of / Psychology, Department of / Graduate

Thesis (M.D.)--Boston University

Eine ernstzunehmende Nebenwirkung der anti-resorptiven Therapie (AR-Therapie) beim Multiplem Myelom ist die Medikamenten-assoziierten Kiefernekrose. Für die vorliegende Arbeit wurden 50 Patienten mit Medikamenten-assoziierter Kiefernekrose (MRONJ-Gruppe) einer gleich großen Kontrollgruppe ohne Medikamenten- assoziierter Kiefernekrose (KTRL-Gruppe) gegenübergestellt. In der MRONJ-Gruppe dauerte die AR-Therapie signifikant länger als in der KTRL-Gruppe (p < 0,001). Die MRONJ-Patienten erhielten die AR-Therapie im Schnitt knapp 4 Jahre, die KTRL- Patienten 2,5 Jahre. Zudem wurde den MRONJ-Patienten die AR-Therapie signifikant häufiger im 4-wöchentlichen Intervall verabreicht als den KTRL-Patienten (n = 49 vs. n = 36, p = 0,003). Das mediane Gesamtüberleben der MRONJ-Gruppe lag signifikant über dem Gesamtüberleben der KTRL-Gruppe (126 vs. 86 Monate, p = 0,013). Das mediane Gesamtüberleben des gesamten Patientenkollektivs lag bei 111 Monaten. Zudem korrelierte das Gesamtüberleben aller Patienten dieser Arbeit signifikant mit der kumulativen Zoledronatdosis (p < 0,001, r = 0,557). Die Stadieneinteilung und die CRAB-Kriterien zeigten bei Erstdiagnose keine signifikanten Unterschiede zwischen den Gruppen. Die Gründe für das längere Gesamtüberleben der MRONJ-Gruppe können auf die Unterschiede in der AR-Therapie zurückgeführt werden. Es bestand ein signifikanter Unterschied in der Therapiedauer, dem verabreichten Intervall und der kumulativen Zoledronatdosis zwischen den beiden Gruppen. Die Sinnhaftigkeit der Fortführung der AR-Therapie muss regelmäßig evaluiert werden und eine engmaschige Untersuchung des stomatognathen Systems ist von höchster Relevanz, um ein längeres Überleben bei guter Lebensqualität zu ermöglichen. / A serious side effect of anti-resorptive therapy (AR therapy) in multiple myeloma is medication-related osteonecrosis of the jaw. In this study, 50 patients with medication- related osteonecrosis of the jaw (MRONJ group) were compared to an equally sized control group without medication-related osteonecrosis of the jaw (KTRL group). In the MRONJ group, AR therapy lasted significantly longer than in the KTRL group (p < 0.001). MRONJ patients received AR therapy for an average of nearly 4 years, whereas KTRL patients received AR therapy for 2.5 years. In addition, the MRONJ patients were significantly more likely to receive AR therapy at a 4 week interval than the KTRL patients were (n = 49 vs. n = 36, p = 0.003). The median overall survival of the MRONJ group was significantly higher than the overall survival of the KTRL group (126 vs. 86 months, p = 0.013). The median overall survival of the entire patient population was 111 months. In addition, overall survival of all patients in this work correlated significantly with cumulative zoledronate dose (p < 0.001, r = 0.557). Classification into different stages and CRAB criteria showed no significant differences between groups at initial diagnosis. The reasons for the longer overall survival of the MRONJ group may be attributed to the differences in AR therapy. There was a significant difference in the duration of therapy, intervals administered, and cumulative zoledronate dose between the two groups. The usefulness of continuing AR therapy must be evaluated regularly, and close examination of the stomatognathic system is of paramount relevance to facilitate prolonged survival with good quality of life.

As current treatments for multiple sclerosis (MS) do not prevent the accumulation of long-term disability, researchers and persons with MS are interested in wellness behaviours and how they may be used to manage MS. This thesis includes a review of the literature on wellness-based interventions in persons with progressive MS. Following this review, a cross-sectional study was conducted to characterize dietary intake by disability status in this population, and to examine the functional and symptomatic correlates of dietary behaviours. Participants with MS and matched controls completed questionnaires and a three-day food intake record. There were significant differences in dietary intake with and without supplements between the MS and control groups. Correlates of dietary behaviours were also examined. Further research examining dietary intake in MS is necessary to understand how disability and other factors impact dietary intake behaviours, and which other correlates may be useful targets for future nutrition interventions.

Fatigue als ein „überwältigendes Gefühl von Müdigkeit, Energielosigkeit und Erschöpfung” stellt bei Patienten mit MS ein häufig auftretendes und oft im Alltag beeinträchtigendes Symptom dar, das sowohl mit körperlichen als auch mit kognitiven Erschöpfungssymptomen einhergeht. Die objektive Erfassung des Schweregrades der Fatigue beim einzelnen Patienten stellt ein Problem dar, da bisher keine objektiven Messverfahren zur Erfassung der Fatigue existieren. Im klinischen Alltag kommen meist Fragebögen zum Einsatz, die das Ausmaß der subjektiven Beeinträchtigung durch Fatigue im Alltag quantifizieren sollen. Ziel dieser Arbeit war es, zu untersuchen, inwieweit bestimmte im klinischen Alltag erhobene Parameter Rückschlüsse auf die subjektive Fatigue bei Patienten mit MS erlauben, auch im Hinblick darauf, ob sich einzelne Parameter besonders zur Einschätzung der körperlichen bzw. kognitiven Fatigue eignen. Zudem sollte untersucht werden, ob die untersuchten klinischen Parameter bei bestimmten Patientengruppen besser als bei anderen Rückschlüsse auf die subjektive Fatigue erlauben. Erfasst wurde die subjektive Fatigue durch das Würzburger Erschöpfungsinventar bei Multipler Sklerose (WEIMuS), einer Serie von Fragen, die zwischen körperlicher und kognitiver Fatigue unterscheiden. Dazu wurden Korrelationsanalysen zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und EDSS-Wert, MSFC Z-Score einschließlich dessen Subscores und der Zeit des 50-Meter-Gehversuchs durchgeführt. Bezüglich der körperlichen Fatigue ergaben sich zwischen der WEIMuS-Subskala für körperliche Fatigue und dem EDSS sowie der Zeit des 50-Meter-Gehversuchs im Vergleich die stärksten, absolut gesehen als mittelstark zu wertende, Korrelationen. Bezüglich der kognitiven Fatigue ergab sich die stärkste Korrelation zwischen der WEIMuS-Subskala für kognitive Fatigue und dem PASAT3, die allerdings trotzdem als gering zu werten ist. Mit EDSS und 50-Meter-Gehversuch scheinen also zwei objektive klinische Parameter zu existieren, die in einem gewissen Maß auf die subjektive Fatigue rückschließen lassen. Ziel weiterer Untersuchungen wird es sein müssen, einen geeigneten klinischen Parameter zu finden, der bessere Rückschlüsse auf die subjektive kognitive Fatigue erlaubt als der PASAT3. Zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und Alter, Geschlecht und Erkrankungsdauer fanden sich bestenfalls geringe Korrelationen, weshalb diese Parameter ungeeignet erscheinen, Aussagen über die subjektive Fatigue zu machen. Durch die Einteilung der Patienten nach Alter und Geschlecht konnte untersucht werden, inwieweit diese Parameter Einfluss auf die untersuchten Zusammenhänge zwischen klinischen Parametern und subjektiver Fatigue haben. Die Korrelationen zwischen den WEIMuS-Subskalen für körperliche und kognitive Fatigue mit den untersuchten klinischen Parametern waren für junge Patienten überwiegend stärker als für ältere Patienten, insbesondere ältere Männer. Somit scheinen die untersuchten klinischen Parameter bei jüngeren Patienten besser geeignet, Aussagen über die subjektive Fatigue zu machen als bei älteren. Insgesamt ist festzuhalten, dass EDSS und 50-Meter-Gehversuch insbesondere bei jungen Patienten zu einer besseren objektiven Beurteilbarkeit vor allem der körperlichen Fatigue im klinischen Alltag beitragen können. / Fatigue as an "overwhelming feeling of tiredness, lack of energy and exhaustion" is a common and often disabling symptom in patients with MS, which is associated with both physical and cognitive symptoms of exhaustion. The objective assessment of the severity of fatigue in the individual patient is a problem, because so far no objective measurement methods exist for the assessment of fatigue. In clinical practice, questionnaires are usually used to quantify the extent of subjective impairment caused by fatigue in everyday life. The aim of this study was to investigate the extent to which certain parameters collected in everyday clinical practice allow conclusions to be drawn about subjective fatigue in patients with MS, also with regard to whether individual parameters are particularly suitable for assessing physical or cognitive fatigue. In addition, it should be investigated whether the examined clinical parameters allow better conclusions about the subjective fatigue in certain patient groups than in others. Subjective fatigue was assessed by the Würzburger Erschöpfungsinventar bei Multipler Sklerose (WEIMuS), a series of questions that distinguish between physical and cognitive fatigue. For this purpose, correlation analyses were performed between the WEIMuS total scale or its subscales for physical and cognitive fatigue and EDSS score, MSFC Z-score including its subscores, and the time of the 50-meter walk test. Regarding physical fatigue, the WEIMuS physical fatigue subscale and the EDSS and the time of the 50-meter walk test showed the strongest correlations in comparison, which could be considered medium in absolute terms. Regarding cognitive fatigue, the strongest correlation was found between the WEIMuS cognitive fatigue subscale and the PASAT3, which, however, should still be considered low. Thus, with EDSS and 50-meter walk test, two objective clinical parameters seem to exist that can be used to infer subjective fatigue to a certain extent. The aim of further investigations will have to be to find a suitable clinical parameter that allows better conclusions about subjective cognitive fatigue than the PASAT3. Between the WEIMuS total scale or its subscales for physical and cognitive fatigue and age, gender and duration of illness, at best only low correlations were found, which is why these parameters appear unsuitable for making statements about subjective fatigue. By classifying patients according to age and gender, it was possible to investigate the extent to which these parameters influence the correlations investigated between clinical parameters and subjective fatigue. The correlations between the WEIMuS physical and cognitive fatigue subscales with the clinical parameters studied were predominantly stronger for young patients than for older patients, especially older men. Thus, the clinical parameters studied appear to be better at providing information about subjective fatigue in younger patients than in older patients. Overall, it can be concluded that EDSS and 50-meter-walk test can contribute to a better objective assessability especially of physical fatigue in clinical practice, especially in young patients.