Abstract Modic changes are vertebral bone marrow signal intensity changes adjacent to the endplates of the degenerated intervertebral discs in magnetic resonance imaging (MRI). This study evaluated the prevalence and the determinants of Modic changes and their association with low back pain symptoms in an occupational cohort of middle-aged Finnish men. The prevalence and the natural course of Modic changes were assessed over a 3-year follow-up period among sciatica patients. Finally, in a patient population, the characteristics of bone marrow changes in MRI were compared to the imaging findings in CT. The prevalence of Modic changes was 56% in an occupational cohort of middle-aged males. Besides age, the determinants of Modic changes and disc degeneration were different. Weight-related factors, which add to the load of the lumbar spine, were associated with Modic changes, whereas whole-body vibration was associated with severe disc degeneration. The prevalence of Modic changes among sciatica patients was 65%, type II change being the most frequent. During the 3-year follow-up, 14% of changes converted to another type, while the incidence of new Modic changes was 6%. Among middle-aged working males, Modic changes located at L5–S1 and type I Modic changes were more likely to be associated with pain symptoms than other types of Modic changes or changes located at other lumbar levels. Thirty-eight percent of the endplates with Modic changes had sclerosis in CT. Of specific Modic types, mixed I/II and II/III associated significantly with endplate sclerosis. Endplate sclerosis was not detected in MRI. In conclusion, Modic changes are a common MRI finding both among patients and middle-aged working males. In addition to age, weight-related factors seem to be important in the pathogenesis of Modic changes. Modic changes can convert from one type to another and type II changes may be less stable than previously assumed. A considerable proportion of Modic changes are sclerotic as observed in CT. Modic changes were always found in combination with a degenerative intervertebral disc and thus they are assumed to be a specific phenotype of degenerative disc disease. Finally, Modic changes may be painful – especially when located at L5–S1 and type I changes.

La dégénérescence maculaire liée à l’âge (DMLA) est la première cause de cécité chez les sujets âgés dans les pays industrialisés. Les questionnaires sur la qualité de vie suggèrent que les patients rencontrent des difficultés dans la recherche d’objets et dans leurs déplacements. En effet, les objets apparaissent rarement isolés dans leur environnement naturel. Ils apparaissent dans un contexte spatial qui peut les masquer en partie et le contraste d’une scène naturelle peut varier au cours de la journée. Nous étudions la capacité de reconnaissance des objets et des scènes naturelles chez les patients DMLA en utilisant des photographies de scènes naturelles. Nous nous sommes intéressés à la reconnaissance des scènes naturelles, puis à la capacité de discrimination figure/fond, à l’effet du contraste sur la reconnaissance des objets, et à la navigation spatiale dans un environnement virtuel. Nous avons comparé la performance de patients avec une DMLA à celle de sujets avec vision normale appariés en âge aux patients. Nos résultats montrent que les patients DMLA sont capables de catégoriser des scènes naturelle ou urbaine, et de discriminer une scène d’intérieur d’une scène extérieur avec un niveau de précision élevé, ce qui est en faveur des modèles centrés sur la scène. Ils détectent mieux un objet lorsque celui-ci était séparé du fond par un espace blanc et lorsque l’objet est présenté dans son contexte naturel que lorsqu’il est présenté sur un fond non structuré et non significatif ; ce qui indique que le fond est traité normalement en vision périphérique. Ils présentent plus de difficultés que les sujets avec vision normale pour détecter un objet dans une scène achromatique dont le contraste est réduit. Une étude sur la navigation spatiale met en évidence une compression de la représentation de l’espace: les sujets avec une DMLA sous-estiment plus la distance virtuelle que les sujets avec vision normale dans la tâche de navigation spatiale. Ces résultats peuvent avoir des applications pratiques dans la rééducation, dans la mise en page des textes et des magazines et dans l’agencement de l’environnement spatial des personnes âgés souffrant de DMLA afin d’améliorer la recherche d’objets, la mobilité et diminuer le risque de chute. / AMD (Age Related Macular Degeneration) is the leading cause of blindness in western countries. Quality of life Questionnaires indicate that people with AMD exhibit difficulties in finding objects and in mobility. In the natural environment, objects seldom appear in isolation. They appear in their natural setting in which they can be masked by other objects. The contrast of a scene may also change, as light varies as a function of the hour in the day and the light source. The objective of the study was to access objects and scene recognition impairments in people with AMD. We studied the perception of natural scenes, figure/ground discrimination, the effect of contrast on object recognition in achromatic scenes, and then navigation and spatial memory in a virtual environment. Performance was compared for people with AMD and age matched normally sighted controls. The results show that scene gist recognition can be accomplished with high accuracy with the low spatial resolution of peripheral vision, which supports the “scene centered approach” in scene recognition. Figure/ground discrimination is impaired in AMD. A white space surrounding the object is sufficient to improve its recognition and to facilitate figure/ground segregation. Performance is also improved when the object is displayed on its natural setting than when it appears on a non structured, non significant background. Sensitivity for the detection of a target object in achromatic scenes is impaired in AMD patients, who are more affected by contrast reductions than normally sighted people. A study on spatial nagigation showed a compression of space representation. People with AMD underestimate the virtual distance in a spatial navigation task. The results of our studies have implications for rehabilitation, for improving texts and magazines destined to people with low vision and for the improvement of the spatial environment of people suffering from AMD in order to facilitate mobility, object search and reduce the risk of falls.

Quelque soit le type de dégénérescences rétiniennes, les cellules photoréceptrices à l'origine de la genèse du signal lumineux, meurent par un mécanisme commun : l'apoptose. Au laboratoire, nous avons mis en évidence que l'inhibition de la caspase-3, une caspase effectrice de l'apoptose, permet de réduire l'apoptose des cellules photoréceptrices (Perche et al. 2007). Dans la continuité de ces résultats, le but de nos travaux de thèse est d'identifier les molécules impliquées en amont de la caspase-3. Pour mener à bien notre projet, nous avons utilisées un modèle expérimentale de dégénérescence rétinienne induite par une exposition à la lumière (modèle de photodégénérescence rétinienne). Les atteintes rétiniennes sont quantifiées par : l'électrorétinographie in-vivo permettant d'évaluer la fonction rétinienne, l'histologie pour l'analyse morphométrique de la rétine aux quelles sont associés des dosages enzymatiques. Ainsi, nous avons montré que l'injection d'un inhibiteur de la caspase-12 à 0,4 ou à 0,8 mM, de la caspase-9 à 0,2 ou à 0,4 mM, ou de la caspase-8 à 0,2 mM, injecté dans le vitré n'a aucun effet toxique sur la rétine et n'a aucun effet protecteur contre l'apoptose des cellules photoréceptrices induites par la lumière. Ces résultats suggèrent que les caspases-8, 9 et 12 ne sont pas impliquées dans l'activation de la caspase-3 et donc dans l'initiation de l'apoptose des photorécepteurs induite par la lumière. Toutefois, après injection dans le vitré, les inhibiteurs inhibent leur cible respective uniquement transitoirement. Par conséquent, pour pouvoir conclure sur le rôle de ces caspases dans le processus dégénératif, il faudrait pouvoir inhiber les caspases de façon plus persistante. Il serait donc intéressant de reproduire des expérimentations similaires en augmentant la concentration de l'inhibiteur injecté ou en réduisant le délai entre l'injection de l'inhibiteur et l'induction du stress. De plus, la caspase-3 peut être activée indépendamment des caspases initiatrices, comme par exemple : les céramides, les cathepsines et les calpaïnes. / No abstract available

M.A. (Psychology) / Please refer to full text to view abstract

D.Litt. et Phil. (Psychology) / The aim of this study was to investigate the effect that hypertension has on brain function. A neuropsychological test battery comprising of the following tests was employed as a multivariate measure of brain dysfunction in a quasiexperimental, matched group design: a) The Complex Figure Test of Rey (copy, immediate recall and delayed recall), b) the Logical Memory Test, c) the Digits Span Test, d) the Verbal Paired Associate Learning Subtest, e) the Controlled Oral Word Generation Test, fr the Trail Making Test, and the Digit Symbol Substitution Subtest, This permitted a comparison in brain functioning between a group of hypertensive and a group of normotensive participants that were matched according to age, handedness, level of education and sex. The matching of variables increased the sensitivity of the study by controlling extraneous variables and ensured that the groups were compatible on the paired variables. The results were statistically analyzed by employing the Mann-Whitney U statistic for small groups and the Chi-square statistic on the measured variables. Further, content analysis was employed to test for significant differences in strategies of coping, immediate recall and delayed recall of the Complex Figure of Rey. The results indicated that: 1. there were significant differences in attention and concentration, motor functioning, perceptual abilities, information processing, memory, and planning and organisation between the two groups, with the hypertensive group obtaininq significantly lower scores on test measuring these variables; and 2. there were no significant differences in the verbal abilities (word fluency) of the two groups. The results support previous research, finding indications of vocal lesions located across the brains of people suffering from hypertension. Practical implications of the results are discussed and recommendations for future research have been made...

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a profound loss of dopaminergic neurons from the substantia nigra (SN). Among the many pathogenic mechanisms thought to be responsible for the demise of these cells, dopamine (DA)-dependent oxidative stress and oxidative damage has taken center stage due to extensive experimental evidence showing that DA-derived reactive oxygen species (ROS) and oxidized DA metabolites are toxic to SN neurons. Despite its being the most efficacious drug for symptom reversal in PD, there is concern that levodopa (LD) may contribute to the neuronal degeneration and progression of PD by enhancing DA concentrations and turnover in surviving dopaminergic neurons. The present study investigates the potential neurotoxic and neuroprotective effects of DA in vitro. These effects are compared to the toxicity and neuroprotective effects observed in the rat striatum after the administration of LD and selegiline (SEL), both of which increase striatal DA levels. The effects of exogenous LD and/or SEL administration on both the oxidative stress caused by increased striatal iron (II) levels and its consequences have also been investigated. 6-Hydroxydopamine (6-OHDA) is a potent neurotoxin used to mimic dopaminergic degeneration in animal models of PD. The formation of 6-OHDA in vivo could destroy central dopaminergic nerve terminals and enhance the progression of PD. Inorganic studies using high performance liquid chromatography with electrochemical detection (HPLC-ECD) show that hydroxyl radicals can react with DA to form 6-OHDA in vitro. SEL results in a significant decrease in the formation of 6-OHDA in vitro, probably as a result of its antioxidant properties. However, the exogenous administration of LD, with or without SEL, either does not lead to the formation of striatal 6-OHDA in vivo or produces concentrations below the detection limit of the assay. This is despite the fact that striatal DA levels in these rats are significantly elevated (two-fold) compared to the control group. The auto-oxidation and monoamine oxidase (MAO)-mediated metabolism of DA causes an increase in the production of superoxide anions in whole rat brain homogenate in vitro. In addition to this, DA is able to enhance the production of hydroxyl radicals by Fenton chemistry (Fe(III)-EDTA/H2O2) in a cell free environment. Treatment with systemic LD elevates the production of striatal superoxide anions, but does not lead to a detectable increase in striatal hydroxyl radical production in vivo. The co-adminstration of SEL with LD is able to prevent the LD induced rise in striatal superoxide levels. It has been found that the presence of DA or 6-OHDA is able to reduce lipid peroxidation in whole rat brain homogenate induced by Fe(II)-EDTA/H2O2 and ascorbate (Fenton system). However, DA and 6-OHDA increase protein oxidation in rat brain homogenate, which is further increased in the presence of the Fenton system. In addition to this, the incubation of rat brain homogenate with DA or 6-OHDA is also accompanied by a significant reduction in the total GSH content of the homogenate. The exogenous administration of LD and/or SEL was found to have no detrimental effects on striatal lipids, proteins or total GSH levels. Systemic LD administration actually had a neuroprotective effect in the striatum by inhibiting iron (II) induced lipid peroxidation. Inorganic studies, including electrochemistry and the ferrozine assay show that DA and 6-OHDA are able to release iron from ferritin, as iron (II), and that DA can bind iron (III), a fact that may easily impede the availability of this metal ion for participation in the Fenton reaction. The binding of iron (III) by DA appears to discard the involvement of the Fenton reaction in the increased production of hydroxyl radicals induced by the addition of DA to mixtures containing Fe(II)-EDTA and hydrogen peroxide. 6-OHDA did not form a metal-ligand complex with iron (II) or iron (III). In addition to the antioxidant activity and MAO-B inhibitory activity of SEL, the iron binding studies show that SEL has weak iron (II) chelating activity and that it can also form complexes with iron (III). This may therefore be another mechanism involved in the neuroprotective action of SEL. The results of the pineal indole metabolism study show that the systemic administration of SEL increases the production of N-acetylserotonin (NAS) by the pineal gland. NAS has been demonstrated to be a potent antioxidant in the brain and protects against 6-OHDA induced toxicity. The results of this study show that DA displays antioxidant properties in relation to lipid eroxidation and exhibits pro-oxidant properties by causing an increase in the production of hydroxyl radicals and superoxide anions, as well as protein oxidation and a loss of total GSH content. Despite the toxic effects of DA in vitro, the treatment of rats with exogenous LD does not cause oxidative stress or oxidative damage. The results also show that LD and SEL have some neuroprotective properties which make these agents useful in the treatment of PD.

Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.

Ces travaux entendent soumettre à l’épreuve des textes fin-de-siècle d’Arthur Machen (1863-1947) deux hypothèses : celle d’une appartenance au décadentisme et au symbolisme, d’une part, et celle d’un principe de consistance régulant les tensions qui sous-tendent son œuvre mineure, d’autre part, celle-ci mêlant les pratiques issues des corpus sapientiaux de la Bible et des récits intertestamentaires aux rites thérianthropiques du totémisme primitif. Le syncrétisme entre christianisme et paganisme ainsi que l’oscillation entre ascétisme apollonien et esthétisme dionysiaque reflètent aussi bien la résilience que les pathologies de l’artiste, qui façonne à la manière d’un homo faber des Künstlerromane et des autoportraits révélant sa nature protéenne. Inspirés des multiples courants artistiques jalonnant l’époque victorienne, les textes de Machen composés au tournant du siècle font de lui un auteur difficile à classer et trop souvent étiqueté parmi les écrivains gothiques et fantastiques – indétermination générique notamment due à l’anthologisation de son œuvre et nécessitant un travail de fouille dans des domaines variés tels que l’archéologie, l’anthropologie et l’ethnologie. La nouvelle, le roman par épisodes, le conte et le poème en prose en particulier deviennent des formes expérimentales où les diaristes établissent les prémices de l’écriture automatique des surréalistes. Perçu tantôt comme l’emblème de la contagion héréditaire, tantôt comme le héraut d’une civilisation décadente, l’artiste porte plusieurs masques que parasitent les fausses pistes laissées par l’auteur. Ayant exploré l’hypothèse d’un Machen poète, théologien, puis essayiste et théoricien du Beau, il sera possible, dès lors, de comprendre le décalage qui oppose la fiction et la vie de ce fervent anglican de la Haute Église, de cet époux fidèle qui cultive néanmoins, dans ses textes, des fantasmes paraphiliques, des rêves de l’Orient et de la Grèce ou, au contraire, des itinéraires pénitentiels douloureux régis par une tradition galloise médiévale supposant autoflagellation et jeûnes anorexiques. Loin de représenter un « calice vide », la liturgie devient chez Machen un pouvoir sacré, comme l’atteste la corrélation entre l’humiliation du corps et l’élévation de l’esprit dans The Hill of Dreams. En revendiquant également la richesse d’une culture galloise minoritaire, Machen participe au « Celtic Revival » et compose des chroniques du Gallois déraciné, exilé à Londres, tentant de survivre à un environnement urbain hostile en le reterritorialisant, spatialement et temporellement. / The present study sustains an analogy between the fin-de-siècle texts of Arthur Machen and the aesthetics of Decadence and Symbolism, first, and a principle of consistency regulating the tensions that underlie his minor works – id est, the customs originating from the sapiential corpus of the Bible and the intertestamental narratives being blended with the therianthropic rites of primitive totemism. The syncretism between Christian and Pagan rites and the oscillation between Apollonian ascesis and Dionysiac aestheticism mirror the resilience as well as the pathologies of the artist in his Protean Künstlerromane and self-portraits. Inspired by the numerous artistic currents of the Victorian age, Machen’s turn-of-the-century texts are quite complex to classify and account for the too frequent association made between his style and that of Gothic or Fantastic authors. This generic indetermination, notably triggered by the anthologization of Machen’s texts, requires a work of investigation in diverse domains such as archaeology, anthropology and ethnology. Episodic novels, short stories, tales, and prose poems, in particular, become experimental diaries foreshadowing the Surrealists’ automatic writing. Deemed to be either the emblem of hereditary contagion or the herald of a decadent civilization, the artist wears several masks which are further distorted by the author’s misleading autobiographical hints. After showing that Machen is not only a poet but also a theologian and an essayist and a theorician on aesthetics, it will be possible to understand the discrepancy between the fiction and the life of a fervent High-Branch Anglican, a faithful husband who nevertheless cultivated, in his texts, paraphilic fantasies, dreams of a new Orient and an Ancient Greece, or quite the contrary, extreme penitential itineraries grounded in a Medieval Welsh tradition requiring self-flagellation and anorexic fasting. Far from representing a “chalice empty of wine”, liturgy becomes a sacred power as the correlation between physical losses and spiritual gains in The Hill of Dreams shows. By championing the beauty of a minor Welsh culture, Machen partook in the “Celtic Revival” and wrote the chronicles of uprooted Welsh subjects exiled in the hostile environment of fin-de-siècle London and striving to reterritorialize its spatial and temporal constitution.

PURPOSE. The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1(ki/ki) mice carrying this mutation or in Efemp1(-/-) mice. METHODS. Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (R-s) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. RESULTS. HSPGs and C/DSPGs were markedly increased in Efemp1(ki/ki) Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1(ki/ki) Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1(-/-) Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP-3 levels were similar to that of Efemp1(+/+) mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1(-/-) Bruch's membrane was enhanced. CONCLUSIONS. Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP-2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane.

L'Atrophie Musculaire spinale (SMA) est une maladie neurodégénérative causée par des mutations du gène SMN1 et caractérisée par la dégénérescence sélective des motoneurones alpha de la moelle épinière. les mécanismes moléculaires de la SMA ne sont aps clairs. cependant, deux hypothèses ont été retenues:D'une part, que la déficience en SMN entraine une perturbation de la biogenèse des snRNPs spliceosomales individuelles et par conséquent des défauts d'épissage. pendant ma thèse, nous avons montré que la déficience en SMN provoquait une diminution des particules tri-snRNPs majeures amis surtout mineures et que cela avait des conséquences sur l'épissage d'un sous-groupe de pré-ARNm contenant des introns mineurs.D'autre part, que la déficience en SMN entraine des altérations de transport d'ARN dans les axones, essentiels pour la survie des motoneurones. A part l'ARNm de la beta-actine et l'ARNm de cpg15 récemment identifié, ceux qui pourraient être transportés par SMN n'ont pas été décrits. nous avons donc identifié les ARN interagissant avec les isoformes a-SMN et SMN-fl dans des cellules neuronales, et montré que certains de ces ARN cibles colocalisent avec SMN dans les axones, suggérant qu'elle est impliquée dans leur transport. / Spinal Muscular Atrophy is a neurodegenerative disease caused by mutations in SMN1 gene. SMA is characterized by the loss of alpha-motoneurons of the spinal cord. However, the precise molecular mechanisms underlying the disease are still unkown. two hypotheses have been retained to explain SMA pathigenesis:In one hand, the fact that SMN deficiency leads to a perturbation of individual snRNPs biogenesis and consequently splicing defects. During my PhD, we have shown that SMN deficiency alters the levels of major, but mostly, minor tri-snRNPs. And that leads to splicing defects of a subset of pre-mRNA containing minor introns.In the other hand, that SMN deficiency causes alteration of axonal transport of RNAs crucial to motoneurons survival. Except beta-actin mRNA and the recently identified cpg mRNA, the RNA targets of SMN have not been described. We succeed to identify RNA targets of both a-SMN and SMN-fl isoformes in a neuronal cell line and colocalisation data of some of these targets suggested that SMN could be implicated in the transport of these RNAs.