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Berg, N. J. "Characterisation of axon degeneration in a model of Tau pathology." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596584.
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In disorders known as ‘dying-back’ neuropathies, the distal nerves appear to degenerate first and this form of degeneration has many similarities to Wallerian degeneration. In the slow Wallerian degeneration (Wlds) mouse there is a 85kb tandem triplication resulting in the expression of a chimeric protein, consisting of the first 70 amino acids of Ube4B and the full sequence of the Nmnat1 protein. In the Wlds mouse Wallerian degeneration appears to be slowed approximately ten fold. The aim of the present study was to determine whether the Wlds gene has a protective effect in neurodegeneration caused by tau pathology. In order to visualise in vivo axonal degeneration and a possible protective effect of the Wlds gene, P301S tau transgenic mice were crossed with TFP-H mice expressing yellow fluorescent protein in a subset of neurons. First it was determined whether the expression of YFP is harmful to axons, and then YFP expression was used to follow the progression of axonal pathology in the P301S mouse. The results indicate that expression of the YFP protein leads to an increase in axonal swellings in some brain regions of aged mice, older than the P301S tau used in this study. YFP expression allows visualisation of abundant broken and abnormal axons in the peripheral and central nervous systems of P301S tau transgenic, but not control mice. The Wlds gene does not rescue the axonal degeneration observed in P301S tau transgenic mice. These results indicate that YFP expression can be used for investigation in young mice, but possible pathological effects can be present in aged mice. Furthermore, the apparent lack of protection of the Wlds gene on P301S axonal pathology suggests that Wallerian degeneration is not a major player in tau-related neurodegeneration.
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Huseynova, Gunel. "Novel autophagy regulators that affect polyglutamine pathology in Drosophila." Thesis, University of Cambridge, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709531.
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Granner, Tamara. "Investigation of anti-angiogenic effects of 3,4 dihydroxyphenyl ethanol in macular degeneration." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114432.
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Age Related Macular Degeneration (AMD) is the most common cause of vision loss among the elderly in developed countries. It occurs primarily in individuals over the age of 50. Currently, 1.75 million people in the US suffer from the advanced form of AMD. AMD is characterised as an abnormality of retinal pigment epithelium (RPE) and/or choroid leading to photoreceptor degeneration of central retina (macula). There are two forms of AMD: Dry AMD (characterized by the build-up of drusen between the choroid and RPE layer resulting in RPE and photoreceptor cell death) and Wet AMD (characterized by abnormal blood vessel growth from the choroid into the retinal pigment epithelium). Current pharmacotherapies in AMD include anti-angiogenics (anti-VEGF) such as Macugen, Avastin, and Lucentis. Thus current research is focusing on trying to form combination therapies (such as anti-VEGF and other agents) to achieve better clinical efficacy. We will be investigating the compound 3,4 dihydroxyphenyl ethanol (DPE), which is a polyphenol present in virgin olive oil known to have antioxidant, anti-angiogenic, anti-inflammatory, and antithrombotic properties. Previous studies have investigated DPE and its ability to prevent cardiovascular diseases and treat different types of cancer. We believe that DPE can reduce angiogenic signalling in the macula. Our objective is to assess the potential utility of DPE as a therapeutic agent in combination with anti-VEGF drugs. ARPE-19 cells were treated with 0.25 mg/ml bevacizumab to study the effects of bevacizumab on the secretion of pro-angiogenic cytokines. The cells were then treated with 100M DPE for 24 hours in culture in both normoxic and CoCl₂-simulated hypoxic conditions. RPE cells were also treated with the combination of DPE and bevacizumab in order to determine the effectiveness of the combination therapy on RPE cells. Media was then harvested after 24 hours for sandwich ELISA-based angiogenesis arrays. The secretion of the following 10 pro-angiogenic cytokines was measured: Angiogenin, ANG-2, EGF, bFGF, HB-EGF, PDGF-BB, Leptin, PlGF, HGF, and VEGF-A. The secretion of three (Angiogenin, ANG-2, and EGF) was increased following treatment with bevacizumab, however only Angiogenin was significant. Angiogenin and VEGF-A were secreted under normoxia, and significantly increased under CoCl₂-simulated hypoxia, whereas ANG-2, HB-EGF, and PlGF were increased under hypoxia. Following treatment with DPE, levels of Angiogenin and VEGF-A were significantly reduced under normoxia, whereas secretion of all 5 secreted cytokines were significantly decreased under hypoxia. The combination of DPE and bevacizumab significantly reduced the secretion of Angiogenin under both normoxic and hypoxic conditions compared to bevacizumab alone. Considering the implications of angiogenesis in AMD, these studies could provide the framework for future studies to further investigate a potential therapeutic role for DPE. DPE may reduce the secretion of pro-angiogenic cytokines, such as Angiogenin, that are up-regulated following treatment with bevacizumab as a possible compensatory mechanism. Therefore, the combination of DPE and bevacizumab may represent a valuable therapeutic option for the wet form of AMD.La dégénérescence maculaire liée à l'âge (DMLA) est la cause la plus fréquente de la perte de la vision chez les personnes âgées dans les pays développés. Il survient principalement chez les personnes âgées de plus de 50 ans. Actuellement, 1,75 millions de personnes aux États-Unis souffrent de la forme avancée de la DMLA. La DMLA se caractérise par une anomalie de l'épithélium pigmentaire rétinien (EPR) et / ou de la choroïde, conduisant à la dégénérescence des photorécepteurs de la rétine centrale (macula). Il existe deux formes de DMLA: la DMLA de type sèche (caractérisée par l'accumulation de petites taches blanches sous la rétine (drusen) entre la choroïde et l'EPR résultant en la mort des cellules photoréceptrices) et la DMLA de type humide (caractérisée par une croissance anormale de néovaisseaux choroïdiens (NVC) sous l'épithélium pigmentaire de la rétine). Les pharmacothérapies actuelles pour traiter la DMLA comprennent les anti-angiogéniques (anti-VEGF), tels que Macugen, Avastin et Lucentis. Ainsi la recherche actuelle se concentre à essayer de former des combinaisons thérapeutiques (tels que des agents anti-VEGF et d'autres) pour parvenir à une meilleure efficacité clinique. Nous examinerons le 3,4 dihydroxyphenyl ethanol (DPE), qui est un polyphénol présent dans l'huile d'olive vierge connu pour avoir des propriétés antioxydantes, anti-angiogéniques, anti-inflammatoire, et des propriétés antithrombotiques. Des études antérieures sur le DPE ont démontré sa capacité à prévenir les maladies cardio-vasculaires et traiter les différents types de cancer. Nous croyons que le DPE peut réduire la signalisation angiogénique dans la macula. Notre objectif est d'évaluer la potentielle utilité de DPE comme agent thérapeutique en combinaison avec des médicaments anti-VEGF. Les cellules ARPE-19 ont été traitées avec 0,25 mg/ml de bevacizumab pour étudier les effets du bevacizumab sur la sécrétion de cytokines pro-angiogéniques. Ces cellules ont ensuite été traitées avec 100µM de DPE en culture pendant 24 heures à la fois dans des conditions normoxiques et des conditions simulé hypoxiques (CoCl₂). Les cellules de l'EPR ont également été traitées avec la combinaison de DPE et de bevacizumab en vue de déterminer l'efficacité de la thérapie avec cette combinaison sur les cellules de l'EPR. Le milieu de culture a ensuite été récolté après 24 heures pour proceder au sandwich ELISA pour tester l'angiogenèse. La sécrétion des 10 suivants cytokines pro-angiogéniques a été mesurée: Angiogenin, ANG-2, EGF, bFGF, HB-EGF, PDGF-BB, Leptin, PlGF, HGF, and VEGF-A. La sécrétion de trois d'entre eux (Angiogenin, ANG-2, et EGF) a été augmentée à la suite du traitement par bevacizumab, mais seulement celle de l'Angiogenin a été significative. L'Angiogenin et le VEGF-A ont été sécrétés sous normoxie, et ont considérablement augmenté en vertu de l'hypoxie simulée par CoCl₂, alors que le ANG-2, le HB-EGF et le PlGF ont été augmentée en vertu de l'hypoxie. Après le traitement avec DPE, les niveaux de Angiogenin et le VEGF-A ont été considérablement réduits en normoxie, tandis que la sécrétion de toutes les 5 cytokines sécrétées a été significativement diminuée sous l'hypoxie. La combinaison de la DPE et du bevacizumab a considérablement réduit la sécrétion de l'Angiogenin dans des conditions à la fois normoxiques et hypoxiques en comparaison avec le bevacizumab utilisé seul. Considérant les implications de l'angiogenèse dans la DMLA, ces études pourraient servir de base pour de futures études pour pousuivre les recherches sur le rôle thérapeutique potentiel du DPE. Le DPE peut réduire la sécrétion de cytokines pro-angiogéniques, comme celle de l'Angiogenin, qui augmentent après un traitement par le bevacizumab comme un possible mécanisme compensatoire. Par conséquent, la combinaison du DPE et du bevacizumab peut représenter une option thérapeutique valable pour la forme humide de la DMLA.
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Shih, Ann Yu-Jung. "Wallerian Degeneration Slow mutation does not alter the amyloid pathology of Alzheimer's disease." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1453673.
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Thesis (M.S.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed July 25, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 43-45).
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Schofield, Emma Medical Sciences Faculty of Medicine UNSW. "Characterisation of cortical pathology and clinicopathological correlates in progressive supranuclear palsy." Awarded by:University of New South Wales. School of Medical Sciences, 2006. http://handle.unsw.edu.au/1959.4/27326.
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This thesis characterises the cortical pattern of degeneration in progressive supranuclear palsy (PSP) and its consequences. Global atrophy was first examined using a recently developed staging scheme in pathologically-proven PSP cases compared with other tauopathies: gross atrophy was not observed in PSP. Quantification of regional volume loss throughout the brain was then used to determine the magnitude of more focal tissue atrophy in PSP, cortical dysfunction was investigated by measuring cerebral blood flow (CBF) changes, and several cortical cellular pathologies were analysed. Any changes observed were related to each other and clinical assessments of motor, cognitive and behavioural abnormalities. At mid-stage PSP, frontal and subcortical atrophy related to decreased CBF in the frontal cortex and cognitive decline. Parietocerebellar CBF increases were also identified (related to frontal CBF deficits) and related to motor and non-motor deficits. By end-stage PSP, focal atrophy had advanced from frontal and subcortical structures to include atrophy in the parietal lobe. Parietal lobe atrophy related to behavioural abnormalities. Histopathological analysis at end-stage revealed that the cortical atrophy and cell loss does not relate to tau deposition. The focal cortical cell loss related exclusively to motor deficits whilst the more widespread cortical tau deposition related to cognitive and behavioural impairments. Both the tau deposition and these non-motor impairments increased in severity over time. The results show that frontal atrophy and dysfunction occurs rapidly and early in PSP and relate to increasing cognitive deficits. Such deficits appear to cause compensatory CBF enhancement in parietocerebellar regions which then also undergo rapid and severe neurodegeneration. These later changes occur in concert with the more classic PSP symptoms, such as oculomotor features. Throughout the disease, the progressive increase in frontotemporal tau deposition contributes to cognitive and behavioural deficits which become most marked late in the disease. The findings strongly suggest that progressive clinical dysfunction in PSP is directly related to progressive cortical degeneration. Cortical degeneration appears to occur in two independent functional networks. Increased CBF in PSP may be a useful early indicator for future neurodegeneration, although the cellular mechanism leading to cell death requires further investigation.
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Kouri, Naomi. "Advances in clinical, neuropathologic, and genetic features of corticobasal degeneration." Thesis, College of Medicine - Mayo Clinic, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=3702551.
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This is a dissertation on the neurodegenerative tauopathy corticobasal degeneration (CBD). Because CBD is a rare disorder and has <50% antemortem diagnostic accuracy, we sought to learn as much as possible from our invaluable resource, having the largest, single neuropathologically-confirmed CBD cohort in the world. This is a culmination of several different projects, all focused on neuropathologic, genetic, and clinical features of CBD, with the overall intent being to help patients who will suffer from this devastating disorder. Each study/chapter had a specific hypothesis, aimed to elucidate various unanswered questions about CBD. Essentially, the only possible approach to further our understanding of CBD is what we have done here: use patient tissue and DNA samples who have donated their brains to research.
Richardson syndrome is one of the most common clinical presentations of CBD: Clinicopathologic assessment of CBD patients presenting with Richardson syndrome (CBD-RS) (i.e. patients misdiagnosed as progressive supranuclear palsy), identified neuropathologic and clinical signs and symptoms that were able to differentiate CBD-RS from PSP patients. Digital microscopy and image analysis were used to quantify tau pathology in multiple brain regions and found CBD-CBS (corticobasal syndrome) cases had greater peri-Rolandic tau burden and CBD-RS had greater hindbrain and limbic tau pathology. CBD-RS patients exhibited a frontal/dysexecutive syndrome and urinary incontinence more often than PSP patients. We also describe an unusual variant of CBD with olivopontocerebellar atrophy, of which two of the patients presented with Richardson syndrome and had greater hindbrain tau pathology than CBD-CBS, and interestingly had significant TDP-43 (protein inclusions found in FTLD and ALS) pathology in affected regions. Regarding TDP-43 pathology in CBD, we found that >25% of cases have TDP-43 immunoreactive neuronal and glial cytoplasmic inclusions and threads, and the greatest burden was in the basal ganglia. With these studies we were able to show that Richardson syndrome is one of the most common clinical presentations of CBD.
Identification of a novel MAPT mutation (p.N410H) in a CBD case that is neuropathologically indistinguishable from sporadic CBD: We screened our autopsy-confirmed CBD cohort for MAPT mutations and identified a novel mutation in MAPT exon 13 (p.N410H) in a case that is neuropathologically indistinguishable from sporadic CBD. This is not only the first MAPT mutation identified to cause CBD, but it is also the first mutation to cause CBD. Functional studies with this mutation showed that there was decreased ability for mutant tau to promote microtubule assembly and exhibited a marked increase in filament formation in vitro. In this study we also identified two rare variants in the 3' untranslated regulatory region of MAPT that associate with CBD, and one of these variants also associated with PSP. CBD and PSP have shared and unique genetic risk factors: Our last study as part of my dissertation, is the first ever CBD genome-wide association study. We performed a discovery stage, replication stage, and meta-analysis in 152 CBD cases versus 3,111 control individuals (discovery), with 67 CBD cases versus 457 controls (replication). This identified two genome genome-wide significant associations with CBD at MAPT and KIF13B/DUSP4. Using a candidate gene approach, we tested for CBD association with the top progressive supranuclear palsy GWAS SNPs. This identified strong associations at MOBP and MAPT H1c haplotype. Another novel genetic association for CBD patients was identified at SOS1. Expression/SNP associations were tested from ~400 brain samples of cerebellum and temporal cortex and found significant associations at MAPT, MOBP, and SOS1. The genome-wide significant association at KIF13B/DUSP4 with CBD will require additional studies to determine which gene is responsible for the association signal. In summary, these findings show for the first time, that CBD and PSP share common genetic variation, other than MAPT, at MOBP which confers disease risk. Together, warranting future studies to understand the mechanism by which MOBP contributes to the CBD and PSP disease processes.
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Al-Malki, Hussain D. "Synaptic degeneration : a morphological study in a mouse model of prion disease." Thesis, University of Southampton, 2012. https://eprints.soton.ac.uk/334054/.
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Early synaptic degeneration in prion disease has developed into a subject of interest, because it is thought that it may allow therapeutic intervention to prevent the neuronal death which is often observed at the late stage of the disease. However, the events behind the synaptic degeneration in prion disease, that may ultimately lead to neuronal death, are still unclear. Studying the morphology of neuronal components, namely synaptic boutons, axons, spines, dendrites and cell bodies, of the population of origin may help in understanding the neuropathology of prion disease. Intrahippocampal injection of murine modified scrapie (ME7 homogenate) provides a model of prion disease in vivo. Animals injected with ME7 were compared to control animals (injected with normal brain homogenate, NBH) and both groups were killed at 13, 16 and 19 weeks. At each time point, Biotinylated Dextran Amine (BDA) tracer was injected into the CA3 area of the hippocampus to reveal the morphology of neurons and their components during the disease progression, using both light and electron microscopy. The results showed that at 13 weeks, the number of synaptic boutons, which are distributed along the axons in the CA1 stratum radiatum, was significantly reduced, while most of the remainder were hypertrophied. This correlated with an increase in both the synaptic spacing along the axonal segments and the presence of abnormal swellings on the axons throughout the stratum radiatum. At 13 weeks, electron microscopic studies revealed vacuole-like structures in the synaptic boutons, which differed from actual autophagic or spongiform vacuoles. The results also showed a significant reduction in the number of dendritic spines on CA3 neurons, associated with a reduction in dendritic arborizations and length. Abnormal swellings were also seen in dendrites and occasionally in the cell bodies. Changes in CA3 cell body size were not observed until 16 weeks, when the soma area had reduced. The results indicate that changes in the morphology of synaptic boutons and dendritic spines were observed at an early time point, 13 weeks the fist observation time, and progressed with time. These results showed for the first time that there is a correlation between both synaptic bouton and spine loss in the neuron of origin, which may suggest that there is continual, simultaneous degeneration between the efferent and afferent components of neuron, leading to an early impairment of the neuronal communication within the brain. This suggests the notion that the loss of communication of the neuron at the early stage may lead to neuronal dysfunction and degeneration at the late stage of the disease. The results also suggest that the synaptic vacuoles may play a crucial role in the hypertrophy or degeneration of the remaining synapses. Additionally, it has been shown for the first time that astrocytes in ME7-animals express features of pathology and degeneration, suggesting that the astrocytes may be another target of PrPSc in prion disease. The combination of these findings has opened new avenues in the field of prion studies. The possible mechanisms behind these results are discussed.
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Williams, J. F. "Enzyme and metabolic studies of growth and degenerative processes in animal systems with emphasis on pentose pathway reactions." Thesis, Canberra, ACT : The Australian National University, 1987. http://hdl.handle.net/1885/143755.
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Aladin, Kaderbatcha Darwesh Mohideen. "A macro, nano level study to evaluate the impact of Trp2 allele in the [alpha] 2 chain of collagen IX on the biomechanics of human intervertebral discs and disc collagens." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634425.
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Aladin, Kaderbatcha Darwesh Mohideen. "A macro, nano level study to evaluate the impact of Trp2 allele in theα 2 chain of collagen IX on the biomechanics of human intervertebraldiscs and disc collagens." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634425.
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Poirier, Julie. "Time course of neuronal degeneration in the pilocarpine model of epileptogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0017/MQ55087.pdf.
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Chen, Jacqueline T. 1973. "Image-processing of MRI for measuring brain injury, repair and degeneration in patients with multiple sclerosis." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=113848.
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This thesis presents methods for quantitative MRI analysis of brain injury, repair and degeneration in multiple sclerosis (MS) that provide new insights into disease pathogenesis and evolution.Demyelinated and inflammatory white-matter lesions are hallmark features of MS. A methodology is described to detect regions of acute white-matter lesions that undergo myelin destruction and repair based on analysis of magnetization transfer ratio (MTR) images. Validation is performed based on histopathology and error is assessed based on same-day scans. To quantify the spatial extent and temporal evolution of myelin destruction and repair, data from a 3-year clinical trial is analyzed using this method. Approximately 20% of acute lesion voxels show some repair over the initial 7 months. In subsequent months, there is little further repair, but some increases in the lesion volume undergoing demyelination.
Although less conspicuous on conventional MRI, there is considerable MS pathology in the brain tissue outside of white-matter lesions. An image-processing methodology was developed to obtain accurate metrics that quantify change over time in whole-brain MTR (associated with changes in myelin-density) and in T2 relaxation time (associated with changes in inflammatory edema). These metrics, in addition to metrics of brain atrophy and axonal integrity, were used to quantify brain injury and degeneration following immunoablation and autologous hematopoietic stem cell transplantation therapy for MS. Pronounced brain volume loss was detected immediately following therapy, associated with decreased myelin density and not resolution of edema.
Post-mortem histopathology has revealed abnormalities in the cortical grey-matter of MS patients that appear to be independent of white-matter lesions. A methodology to quantify neocortical injury and degeneration that yields cross-sectional and longitudinal metrics of cortical thickness and grey-matter/white-matter interface integrity both globally and regionally is presented and validated. MS patients with progressive disability showed greater decreases in cortical metrics compared to MS patients with stable disability.
The quantitative MRI analysis methods presented in this thesis are applicable to MRI data obtained in clinical trials of therapies for MS, have the necessary sensitivity and specificity to assess therapeutic efficacy, and provide new insights into disease pathogenesis and evolution.
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Maloney, Shawn. "Dual role of SIRT1 as a regulator of retinal development and a therapeutic target in age-related macular degeneration." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104689.
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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in developed countries. Aggressive research is underway to elucidate putative molecular targets for therapy for both the atrophic and neovascular forms of this disease. Current pharmacotherapy is effective in some patients but not sufficient to halt disease progression or repair damage that has already occurred. Drug intervention and retinal cell replacement represent the two most promising potential treatment avenues. The purpose of this thesis was to investigate the role of a recently identified regulator of neural development, SIRT1, in retinogenesis and to further investigate whether pharmacological inhibition of this protein represents a possible treatment option in neovascular AMD. Via immunohistochemistry and immunocytochemistry we evaluated the expression and subcellular localization of SIRT1 and its innate inhibitor, DBC1, in mouse and human fetal and adult retinas. We further studied SIRT1 in mouse- and human-derived retinal progenitor cells, the former being using in small interfering RNA studies. We found SIRT1 to be widely expressed in developing and adult retinas and to be a regulator of key retinal development genes, namely PAX6, Nestin and CRX. Moreover, we found that photoreceptor precursor cells were among the smallest cells in the heterogeneous population of mouse retinal progenitors. Collectively, these results provide the foundation for manipulating SIRT1 expression in small retinal progenitors as a means of increasing the yield of photoreceptors for transplantation in models of retinal degeneration.We further found SIRT1 to be highly expressed in human-derived choroidal neovascular membranes and sought to pharmacologically inhibit its activity via the drug Nicotinamide. We found Nicotinamide to be a potent regulator of angiogenic and hypoxic signaling in a human retinal pigment epithelial cell line at both the protein level using angiogenesis arrays and at the RNA level using whole genome microarrays. These results point to the SIRT1 inhibitor, Nicotinamide, as a possible agent for treatment of neovascular AMD. Further studies of Nicotinamide are warranted in animal models of AMD. To the best of our knowledge, this is the first time that a detailed analysis of SIRT1 as a regulator of both retinal development and choroidal neovascularization has been reported.La dégénérescence maculaire liée à l'âge (DMLA) est la principale cause de cécité chez les personnes âgées dans les pays développés. Une recherche dynamique est en cours pour élucider des cibles moléculaires potentiels pour le traitement de la dégénérescence à la fois pour la forme atrophique et la forme néovasculaire de cette maladie. L'actuelle pharmacothérapie est efficace chez certains patients mais pas suffisante pour arrêter la progression de la maladie ou la réparation des dommages qui ont déjà eu lieu. La decouverte de nouveaux medicaments et le remplacement de cellules rétiniennes représentent les deux avenues les plus prometteuses de traitements possibles. Le but de cette thèse est d'étudier le rôle d'un régulateur récemment identifié du développement neuronal, SIRT1, dans le developpement de la retine et de rechercher si l'inhibition pharmacologique de cette protéine représente une option de traitement possible dans la DMLA. Via l'immunohistochimie et l'immunocytochimie, nous avons évalué l'expression et la localisation subcellulaire de SIRT1 et de son inhibiteur inné, DBC1, chez la souris et les humains dans les retines fœtales et adultes. Nous avons également étudié SIRT1 dans les cellules souches de la rétine chez la souris et l'homme. Nous avons trouvé SIRT1 largement exprimé dans la rétine en développement et des adultes et à un régulateur de gènes clés du développement de la rétine, à savoir PAX6, Nestin et CRX. En outre, nous avons constaté que les cellules précurseurs des photorécepteurs ont été parmi les plus petites cellules dans la population hétérogène de cellules progénitrices. Collectivement, ces résultats fournissent la base pour la manipulation de l'expression SIRT1 dans les petits progéniteurs rétiniens comme un moyen d'augmenter le rendement des photorécepteurs à la transplantation dans les modèles de dégénérescence rétinienne. Nous avons en outre constaté que SIRT1 est fortement exprimé dans les membranes néovasculaires humaines et avons cherché à inhiber son activité pharmacologique par le nicotinamide. Nous avons trouvé que Nicotinamide est un puissant régulateur de l'hypoxie et de l'angiogenèse au niveau de la protéine et de l'ARN. Ces résultats indiquent que l'inhibiteur de SIRT1, Nicotinamide est un agent possible pour le traitement de la DMLA néovasculaire. D'autres études de la nicotinamide devraient être poursuivit dans des modèles animaux de la DMLA. Au meilleur de notre connaissance, c'est la première fois qu'une analyse détaillée de SIRT1 l'identifie comme un régulateur du développement tant de la rétine et de la néovascularisation choroïdienne.
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NI, JIAQIAN. "Plasma Biomarkers for Age-Related Macular Degeneration." Cleveland State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=csu1236700270.
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Petrin, Dino P. "Using the X-linked inhibitor of apoptosis (XIAP) as a therapeutic agent in rodent models of retinal degeneration." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/29249.
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Retinitis Pigmentosa (RP) is the leading cause of hereditary blindness. The clinical manifestations of RP are night blindness, loss of peripheral vision leading to tunnel vision and a decreased electroretinogram (ERG) amplitude. There are numerous genes that when mutated cause RP. Regardless of the causative mutation, the end point is the same, photoreceptor cell death by apoptosis or programmed cell death (PCD). Interestingly, though all photoreceptors in an affected individual would have a mutation, disease progresses at a relatively slow rate indicating the affected cells can function. It is unclear as to why completely unrelated mutations would cause photoreceptors to die via the same mechanism. Somatic gene replacement studies using viral vectors in animal models have been successful in slowing down disease. However, attempting to cure all retinal degeneration mutations by this approach would be costly and difficult for two reasons. First, there are some mutations that comprise a small percentage of all RP cases and the cost/benefit ratio to develop a therapeutic agent for a few people would be enormous. Secondly, a number of genes that cause retinal degenerations have not been cloned. A more practical approach involves preventing apoptosis of the photoreceptor cell. The advantage of this approach is that the causative mutation does not need to be known. Developing a single therapeutic agent to target RP would also be economically more favourable than developing multiple therapeutic agents.
The X-linked Inhibitor of Apoptosis (XIAP) can inhibit cell death from numerous triggers both in vitro and in vivo. XIAP prevents apoptosis by binding to and inhibiting caspase-3, -7 and -9. Work presented here shows that adeno-associated virus (AAV) encoding XIAP is neuroprotective when injected sub-retinally in an acute retinal degeneration model in Sprague Dawley rats. In addition, transgenic mice overexpressing XIAP throughout the neural retina have normal retinal morphology and their ERGs appear normal. These findings suggest that XIAP holds promise as a therapeutic agent in the treatment of hereditary retinal diseases such as retinitis pigmentosa.
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Maloney, Shawn C. "Histopathology of human age-related macular degeneration and the development of a novel animal model." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112539.
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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly worldwide. Due to the inadequacy of current pharmacotherapies, novel molecular targets must be sought as potential therapeutic candidates. Furthermore, there is a need for more efficient and cost-effective animal models of this pathology in order to accelerate in vivo investigations.Our laboratory is in possession of human choroidal neovascular membranes which we examined for expression of cyclooxygenase (COX)-2. This expression was characterized in retinal pigment epithelial, vascular endothelial, and fibroblast cells and correlated with patient age. We also looked at the feasibility of creating a rabbit laser-injury model to adequately mimic human neovascular AMD.
Our results suggest that anti-COX-2 therapies may be beneficial to some patients with neovascular AMD. Moreover, there is strong potential for the development of clinically relevant choroidal neovascularization in rabbits using the laser-injury technique. This approach may yield a novel, cost-effective AMD model.
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Holmes, Toby M. "A study of the retinal vascular pathology in the Royal College of Surgeons rat : a model of human retinal degeneration." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444441/.
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The leading causes of loss of vision in the developed world are the degenerative diseases of photoreceptors in particular, age-related macular degeneration (AMD) and retinitis pigmentosa (RP). A common characteristic of these diseases is secondary damage affecting the vascular network, which is apparently initiated by photoreceptor loss. One problem with investigating the vascular consequences of these diseases has been the lack of a suitable animal model that can be used to investigate various potential treatments. This study has developed methods of quantifying retinal vascular damage in the pigmented Royal College of Surgeons (RCS) rat, which is characterised by the formation of vascular complexes and these methods have been used to explore strategies to retard or reverse this damage. This was done with the view to improving the retinal environment, thereby assisting other therapeutic strategies that target the primary defect causing the loss of photoreceptors. The work was divided into three areas: 1) investigation of the vascular effects of progressive photoreceptor loss and development of computerised image analysis to quantify changes, 2) pharmaceutical intervention to modify the normal sequence of events, 3) examination of the effects of RPE sub-retinal transplantation on the vascular network to determine how the retinal vasculature would react to the presence of transplanted human RPE cells at different time-points. These three areas of study validate the use of naturally occurring events in the RCS rat to provide a model of vascular pathology in human retinal degenerative diseases. This contrasts with previous models, which have relied on creating wounds to simulate conditions that occurring in the diseased human retina.
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Funk, Kristen E. "Alzheimer’s Disease Pathology as a Clue to Pathogenesis." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343231184.
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Tan, Celia I. C. "A radiological and biochemical perspective on ageing and degeneration of the human thoracic intervertebral disc." University of Western Australia. School of Surgery and Pathology, 2004. http://theses.library.uwa.edu.au/adt-WU2004.0059.
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Disc degenerative changes are directly or indirectly associated with spinal pain and disability. Literature revealed a high prevalence of disc degeneration in the thoracic region, however thoracic MRI degeneration trends and information on disc biochemical matrix constituents are limited for thoracic discs compared to lumbar and cervical discs. The objective of this thesis was to use MRI to investigate the prevalence of disc degenerative changes affecting the human thoracic spine, and to determine the factors affecting spinal disc biochemical matrix. A 3-point subjective MRI grading scale was used to grade the films. The feasibility of using archived formalin-fixed cadaver material was investigated to analyse collagen and elastin crosslinks. The prevalence of degenerative changes in human thoracic discs and vertebrae (T1 to T12) was determined retrospectively from an audit of 216 MRI cases, using sagittal T1- and T2-weighted MR images. In a subsequent series of ex-vivo studies, human thoracic discs and LF from 26 formalin-fixed and two fresh spines, involving all thoracic levels, were examined macroscopically to determine the degeneration status. Subsequently, disc and ligament tissues were analysed biochemically for collagen (pyridinoline and deoxypyridinoline) and elastin (desmosine and isodesmosine) crosslinks. These crosslinks were extracted from hydrolysed samples by cellulose partition chromatography, and analysed by reverse-phase HPLC. Collagen content was determined using its hydroxyproline content, and proteoglycan content was assayed using a modified DMB assay for chondroitin sulphate. Finally the MRI and macroscopic assessments of thoracic discs, were compared with the biochemical data from two fresh cadaver thoracic spines. The 3-point MRI grading scale had a high inter- (k = 0.57 to 0.78) and intra-rater (k = 0.71 to 0.87) reliability. There were no significant differences in the collagen and elastin content and extent of collagen crosslinks between formalin fixed and unfixed ligament and disc tissues, after 25 weeks of formalin fixation. From the in-vivo MRI series of investigations (n = 216 MRI films), the prevalence of thoracic disc degenerative and vertebral morphological changes revealed significant age, gender and spinal level trends (p < 0.05).Generally, males had a higher propensity for disc degeneration in contrast to females, especially older females, where the trend showed a higher prevalence of osteophytes and vertebral body changes. In particular, the mid and lower thoracic levels have a higher prevalence of degenerative changes, except for osteophytes and anterior vertebral wedging. With increased age, there was a concomitant increase in anterior wedging and bi-concavity and disc degenerative changes except for end-plates. The biochemical investigations on the ex-vivo series of formalin-fixed thoracic discs (n = 303) also revealed significant changes in the disc matrix due to degeneration status, age, gender and spinal regional factors. With increased age, normal disc matrices have significantly lower collagen content and extent of pyridinoline (p < 0.001). In contrast, the degenerated disc matrix revealed significantly higher collagen content and extent of deoxypyridinoline (p < 0.05). These findings suggest that an altered matrix existed in normal ageing discs, which render the disc prone to injury and degeneration over the life span. The higher collagen and deoxypyridinoline in degenerated disc matrices reflects an increase in chondrocyte synthesis, and is also a novel finding, suggesting that they may be used as markers of ageing and degeneration processes. The biochemical investigations on another series of ex-vivo spinal LF tissues (n = 364), revealed that this had a lower collagen and pyridinoline, but significantly higher elastin and deoxypyridinoline compared to spinal discs (p < 0.05). Elastin crosslinks however were difficult to detect in spinal discs, being present in negligible amounts in a few lumbar discs. The elastin crosslinks in the LF were not significantly affected by age, but were significantly higher in calcified, and female ligamentum tissues, and also in the lumbar region (p < 0.05). These MRI prevalence findings enhanced our knowledge of vertebral body and disc degeneration trends in the thoracic region and contributed to the interpretation of MR images for pathology in the human thoracic spine. Information on the associated collagenous and elastic changes in the disc and ligamentum matrices provide original data and insight on the pathogenesis of degeneration in the disc matrix from a biochemical perspective, highlighting gender, age and spinal level influences on the matrix tensile strength and cellular synthetic activities.
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DeLaurier, April. "The effects of habitual biomechanical stress, trauma, and pathology on the development and age-related degeneration of the male pubic symphysis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq30710.pdf.
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Hu, Quan. "The molecular pathology, genetic involvement and biochemical characteristics of fused in sarcoma (FUS) protein and chromosome 9p-linked frontotemporal lobar degeneration." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/the-molecular-pathology-genetic-involvement-and-biochemical-characteristics-of-fused-in-sarcoma-fus-protein-and-chromosome-9plinked-frontotemporal-lobar-degeneration(4ac87100-f73a-41c9-a921-f6af5d54dd27).html.
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The fused in sarcoma (FUS) protein has been shown to be a significant disease protein in a subgroup of patients with frontotemporal lobar degeneration (FTLD). Nevertheless, the mechanism underlying FUS associated FTLD is only poorly understood. Recent research has identified a large hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72), reinforcing the association between C9orf72 and FTLD. Moreover, an unusual histopathological change has been observed within the granule cell layer of the cerebellum in chromosome 9p-linked frontotemporal dementia with motor neuron disease. Whether this type of cerebellar pathology is a pathological marker for chromosome 9p-linked families remains unknown. The purpose of this study was to genetically, neuropathologically and biochemically characterize FUS and C9orf72 in FTLD, and also to investigate the association between the cerebellar pathology and chromosome 9p-linked families. The genetic sequencing study searching for potential genetic factors of FUS in FTLD failed to detect any pathogenic mutations or variations. Immunohistochemical study for FUS pathology in FTLD provided strong evidence for FUS being the specific pathological protein in all forms of FTLD-FUS. Immunoblotting for FUS in FTLD detected one novel disease-associated FUS aggregate (~37 kDa) in the urea fraction of atypical FTLD with ubiquitinated inclusions (aFTLD-U) frontal cortical samples, suggesting this unique protein product might be more associated with disease than the full-length protein itself. Immunohistochemical study of C9orf72 in FTLD detected a 'synaptic' staining in CA sectors, as the most prominent histological feature identified. Immunoblotting for C9orf72 protein demonstrated no distinctive bands among different diagnostic groups, in frontal and cerebellar cortical regions. The present study also confirmed the presence of cerebellar p62 neuronal cytoplasmic inclusions (NCI) in a proportion of FTLD-TDP cases. Although most of these cases showed an autosomally dominant pattern of inheritance, not all of them shared a common C9orf72 haplotype, or mutation in C9orf72.Much work is still needed to investigate the underlying pathogenesis of FTLD-FUS. Attention should still be given to identifying possible genetic risk factors in FUS using a large series of FTLD samples and searching for other possible proteins within the FUS immunoreactive neuronal inclusions. Moreover, the target protein within the cerebellar p62 NCI remains unknown, but it is clear that it is not C9orf72 protein.
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Chen, Rebecca Y. "Attenuation of the Progression of Articular Cartilage Degeneration by Inhibition of Tgf-β1 Signaling in a Mouse Model of Osteoarthritis." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17331955.
Full textAbstract:
Background
The goal of this study is to understand role of transforming growth factor beta 1 (TGF-β1) in development of osteoarthritis (OA). Results from studies indicate that the genetic inactivation of Smad-3, or the disruption of the interaction of Tgf-β1 with its receptor Tgf-β type II receptor (Tgfbr2), in germline cells results in OA-like knee joints in mice at one month of age. However, other studies suggest that the increased expression of Tgf-β1 in mature knee joints causes OA in animal models. A human genetic study reports that a two-nucleotide deletion, 741-742del AT, and/or a nucleotide change, 859C>T or 782C>T in SMAD-3 are associated with early-onset OA. This observation is consistent with the finding that the lack of Tgf-β1 signaling in the germline cell results in OA in developing joints and that increased Tgf-β1 signaling causes OA in mature joints. The plausible explanation for this “conflicting” role of TGF-β1 in the pathogenesis of OA is that the effective TGF-β1 signaling acts in either a dose-dependent or a developmental stage-dependent manner. The present study addresses the question as to whether inhibition of Tgf-β1 signaling prevents mature knee joints from being degenerated in mouse models of OA.
Methods
1) Using conditional knock out techniques with aggrecan-CreERt2 mice and floxed Tgfbr2 mice, Tgfbr2 was removed from articular cartilage of knee joints in 2-month-old mice. Mice without Tgfbr2 were kept for another 6 months or longer. Knee joints from the mice (n=8) and their corresponding control (n=4) were collected for morphological analysis.
2) Mice without Tgfbr2 at two months old were subjected to DMM to induce articular cartilage degeneration. Knee joints from the mice at 4 and 8 weeks post surgery (n=8 in each group) were collected for morphological analysis.
Results
1) We did not find the initiation and acceleration of articular cartilage degeneration by the genetic inactivation of Tgfbr2 in knee joints of mice at the age of 9 months or older. We also did not find hypertrophic chondrocytes in the articular cartilage of the mice.
2) We found that removal of Tgfbr2 in articular cartilage of knee joints delayed articular cartilage degeneration, at least 6 weeks, compared to that in wild-type littermates.
Conclusion
Inhibition of Tgf-β1 signaling attenuated articular cartilage degeneration in mature knee joints of mouse models of OA. Therefore, inhibition activity of TGF-β1, not application of TGF-β1, may be considered in treatment of OA in mature joints.
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Stevens, William Dale. "Visual system pathology caused by chronic cerebral hypoperfusion, loss of pupillary reflex, retinal and optic nerve degeneration, and the role of light toxicity." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ57781.pdf.
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Stevens, William Dale Carleton University Dissertation Psychology. "Visual system pathology caused by chronic cerebral hypoperfusion; loss of pupillary reflex, retinal and optic nerve degeneration, and the role of light toxicity." Ottawa, 2000.
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Muir, Eric R. "Magnetic resonance imaging of retinal physiology and anatomy in mice." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/37268.
Full textAbstract:
MRI can provide anatomical, functional, and physiological images at relatively high spatial resolution and is non-invasive and does not have depth limitation. However, the application of MRI to study the retina is difficult due to the very small size of the retina. This thesis details the development of MRI methods to image blood flow (BF), anatomy, and function of the retina and choroid, and their application to two diseases of the retina: diabetic retinopathy and retinal degeneration.
A unique continuous arterial spin labeling technique was developed to image BF in mice and tested by imaging cerebral BF. This method was then applied to image layer-specific BF of the retina and choroid in mice, and to acquire BF functional MRI of the retina and choroid in response to hypoxic challenge. Additionally blood oxygen level dependent functional MRI of the mouse retina and choroid in response to hypoxic challenge was obtained using a balanced steady state free precession sequence which provides fast acquisition, has high signal to noise ratio, and does not have geometric distortion or signal dropout artifacts.
In a mouse model of diabetic retinopathy, MRI detected reduced retinal BF in diabetic animals. Visual function in the diabetic mice, as determined by psychophysical tests, was also reduced. Finally, in a mouse model of retinal degeneration, BF and anatomical MRI detected reductions of retinal BF and the thickness of the retina. The studies detailed in this thesis demonstrate the feasibility of layer-specific MRI to study BF, anatomy, and function, in the mouse retina. Further, these methods were shown to provide a novel means of studying animal models of retinal disease in vivo.
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Navarrete, Ampuero Roberto Andrés [UNESP]. "Variabilidade da frequência cardíaca em cães com degeneração mixomatosa crônica da valva mitral." Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/108416.
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000735679.pdf: 1127906 bytes, checksum: 39d05c2b84cb87260be1e3e5ece89511 (MD5)Estudo da variabilidade da frequência cardíaca, no domínio do tempo, realizado em 48 cães de diferentes raças de pequeno a médio porte, com degeneração mixomatosa crônica da valva mitral, estadiados em classes de insuficiência cardíaca congestiva (ICC) proposta pela ISACHC. Os animais apresentaram sinais clínicos de: tosse, cansaço, dispneia no grupo classe 2, em ordem de prevalência. No exame eletrocardiográfico os cães perdem arritmia sinusal respiratória, passando para ritmo sinusal, junto podem apresentar: aumento da onda P em duração e amplitude, complexo QRS em duração e amplitude da onda R quando desenvolvem esta doença valvular e aumentam de classe. Os cães com DMVM em estádios de ICC moderados (classe 2) em comparação com estágios iniciais (classe 1a e classe 1b) da doença apresentaram maiores valores ecocardiográficos: relação AE/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. O presente estudo mostrou que a insuficiência cardíaca em cães com DMVM, tinha diminuído os valores de NN médio (NNm), SDNN, SDNNindex e pNN50%. Inferindo uma diminuição da participação do sistema nervoso parassimpático e um aumento da participação do sistema nervoso simpático. Além disso, foi observado um aumento da FC média e aumento número de complexos QRS (NQRS) que também são indicadores de maior participação do sistema simpático. Determinou-se um predomínio das arritmias ventriculares nos três grupos, com semelhante proporção das arritmias supraventricular no grupo clínico. As arritmias tanto ventriculares como as arritmias supraventriculares foram de caráter isolado nos grupos pré-clínicos e de caráter complexo no grupo clínico. As correlações obtidas no exame Holter foram correlação positiva entre: NNm v/s NQRS na classe 2, classe 1b e classe 1a (r= 0,978, r= 0,932, r= 0,962); NNm v/s pNN50% na classe 2 e classe ...
Study of heart rate variability in the time domain, performed in 48 dogs of different breeds of small to medium sized, with chronic myxomatous degeneration of the mitral valve, aged in heart failure classes (CHF) proposed by ISACHC. The animals showed clinical signs of: cough, fatigue, dyspnea group class 2, in order of prevalence. Electrocardiographic examination in dogs lose respiratory sinus arrhythmia, going to sinus rhythm, with display: increase in p wave duration and amplitude, QRS duration and in R wave amplitude when developing this valvular disease and increase class. Dogs with MMVD in stages of ICC moderate (class 2) compared with early stages (class 1a and class 1b) of the disease had higher echocardiographic values: Relations LA/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. The present study showed that heart failure in dogs with MMVD, had decreased values of NN medium (NNM), SDNN, SDNNindex and pNN50%. Implying a decrease in the participation of the parasympathetic nervous system and an increase in the participation of the sympathetic nervous system. Furthermore, we observed an increase in mean HR and increased QRS complexes (NQRS) which are also indicators of increased participation of the sympathetic system. We determined the prevalence of ventricular arrhythmias in the three groups, with a similar proportion of supraventricular arrhythmias in the clinical group. Both ventricular arrhythmias and supraventricular arrhythmias were isolated character in the pre-clinical and complex character in the clinical group. Especially supraventricular arrhythmias and ventricular arrhythmias may manifest themselves throughout the progression of the disease, initial ventricular arrhythmias, with further increase supraventricular arrhythmias as a consequence of atrial dilation. The correlations obtained in Holter examination were, positive correlation ...
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Navarrete, Ampuero Roberto Andrés. "Variabilidade da frequência cardíaca em cães com degeneração mixomatosa crônica da valva mitral /." Jaboticabal, 2013. http://hdl.handle.net/11449/108416.
Full textAbstract:
Orientador: Aparecido Antonio CamachoBanca: Marlos Gonçalves Sousa
Banca: Tatiana Champion
Resumo: Estudo da variabilidade da frequência cardíaca, no domínio do tempo, realizado em 48 cães de diferentes raças de pequeno a médio porte, com degeneração mixomatosa crônica da valva mitral, estadiados em classes de insuficiência cardíaca congestiva (ICC) proposta pela ISACHC. Os animais apresentaram sinais clínicos de: tosse, cansaço, dispneia no grupo classe 2, em ordem de prevalência. No exame eletrocardiográfico os cães perdem arritmia sinusal respiratória, passando para ritmo sinusal, junto podem apresentar: aumento da onda P em duração e amplitude, complexo QRS em duração e amplitude da onda R quando desenvolvem esta doença valvular e aumentam de classe. Os cães com DMVM em estádios de ICC moderados (classe 2) em comparação com estágios iniciais (classe 1a e classe 1b) da doença apresentaram maiores valores ecocardiográficos: relação AE/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. O presente estudo mostrou que a insuficiência cardíaca em cães com DMVM, tinha diminuído os valores de NN médio (NNm), SDNN, SDNNindex e pNN50%. Inferindo uma diminuição da participação do sistema nervoso parassimpático e um aumento da participação do sistema nervoso simpático. Além disso, foi observado um aumento da FC média e aumento número de complexos QRS (NQRS) que também são indicadores de maior participação do sistema simpático. Determinou-se um predomínio das arritmias ventriculares nos três grupos, com semelhante proporção das arritmias supraventricular no grupo clínico. As arritmias tanto ventriculares como as arritmias supraventriculares foram de caráter isolado nos grupos pré-clínicos e de caráter complexo no grupo clínico. As correlações obtidas no exame Holter foram correlação positiva entre: NNm v/s NQRS na classe 2, classe 1b e classe 1a (r= 0,978, r= 0,932, r= 0,962); NNm v/s pNN50% na classe 2 e classe ...
Abstract: Study of heart rate variability in the time domain, performed in 48 dogs of different breeds of small to medium sized, with chronic myxomatous degeneration of the mitral valve, aged in heart failure classes (CHF) proposed by ISACHC. The animals showed clinical signs of: cough, fatigue, dyspnea group class 2, in order of prevalence. Electrocardiographic examination in dogs lose respiratory sinus arrhythmia, going to sinus rhythm, with display: increase in p wave duration and amplitude, QRS duration and in R wave amplitude when developing this valvular disease and increase class. Dogs with MMVD in stages of ICC moderate (class 2) compared with early stages (class 1a and class 1b) of the disease had higher echocardiographic values: Relations LA/Ao, DIVEd/Ao, DIVEs/Ao, ESIVs/Ao, EPPVEd/Ao, EPPVEs/Ao, FE%,FEC%, PVE e PVA mitral. The present study showed that heart failure in dogs with MMVD, had decreased values of NN medium (NNM), SDNN, SDNNindex and pNN50%. Implying a decrease in the participation of the parasympathetic nervous system and an increase in the participation of the sympathetic nervous system. Furthermore, we observed an increase in mean HR and increased QRS complexes (NQRS) which are also indicators of increased participation of the sympathetic system. We determined the prevalence of ventricular arrhythmias in the three groups, with a similar proportion of supraventricular arrhythmias in the clinical group. Both ventricular arrhythmias and supraventricular arrhythmias were isolated character in the pre-clinical and complex character in the clinical group. Especially supraventricular arrhythmias and ventricular arrhythmias may manifest themselves throughout the progression of the disease, initial ventricular arrhythmias, with further increase supraventricular arrhythmias as a consequence of atrial dilation. The correlations obtained in Holter examination were, positive correlation ...
Mestre
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Boluda, Casas Susana. "Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/399674.
Full textAbstract:
Filamentous tau pathologies are the hallmark lesions of several neurodegenerative tauopathies including Alzheimer’s disease (AD) and corticobasal degeneration (CBD). These diseases show cell type-specific and topographically distinct tau inclusions. Growing evidence supports templated transmission of tauopathies through functionally interconnected neuroanatomical pathways suggesting that different self-propagating strains of pathological tau could account for the diverse manifestations of neurodegenerative tauopathies.
In the study, the rapid induction of tau pathology and the distinct cell type-specific spread of pathological tau following intracerebral injections of CBD or AD brain extracts enriched in pathological tau in human mutant P301S tau transgenic (Tg) mice (line PS19) is analysed.
At 1 mo post-injection of extracts obtained from brains with CBD pathology (CBD-Tau), tau inclusions developed predominantly in oligodendrocytes of the fimbria and white matter near the injection sites with infrequent intraneuronal tau aggregates. In contrast, injections of enriched tau extracts from brains with AD pathology (AD-Tau) in young PS19 mice induced tau pathology predominantly in neuronal perikarya with little or no oligodendrocyte involvement 1 mo post-injection. With longer post-injection survival intervals of up to 6 mo, CBD-Tau and AD-Tau induced tau pathology spread to different brain regions distant from the injection sites while maintaining the cell type specific pattern noted above.
In conclusion, these experiments provide evidence for the prion-like hypothesis of disease spread and suggest that the tau pathology formed in vivo is dependent on the tau pathology in the preparation indicating that there are post-translational modifications or strains of tau protein that are responsible for the variation between diseases.La enfermedad de Alzheimer (AD) y la degeneración corticobasal (CBD) son enfermedades neurodegenerativas que pertenecen al grupo de las taupatías. Estas enfermedades se caracterizan por presentar agregados de proteína tau intracelulares. Cada una de estas enfermedades se manifiesta con unos síntomas clínicos propios, una determinada distribución de los agregados de tau y una afectación celular específica. Estudios recientes sugieren que la proteína tau se puede transmitir de una célula a otra por trayectos anatómicos determinados, a través de la conexión entre neuronas, de forma similar a lo que occurre con los priones. En el estudio se describe como tras la inyección de extractos enriquecidos con tau patológica obtenidos de tejido cerebral humano de donantes afectos de AD y CBD en ratones transgénicos que sobreexpresan la proteína tau con la mutación P301S (línea PS19) éstos desarrollan patología tau. Los agregados de tau aparecen rápidamente, a los 30 días posteriores a la inyección. Estos agregados presentan unas características similares a las inclusiones observadas en las enfermedades humanas correspondientes, de forma que los ratones inyectados con extractos protéicos obtenidos de casos afectos de CBD desarrollan patología predominantemente en células gliales mientras que los ratones inyectados con extractos obtenidos de casos afectos de AD desarrollan agregados en las neuronas. Asimismo, se observa un incremento de la patología tau con el aumento del tiempo transcurrido después de la inyección así como la propagación a regiones distantes a la zona de inyección que, en el caso de inyecciones con extractos de AD, se encuentran interconectadas mediante vías neuroanatómicas. En conclusión, estos experimentos proporcionan evidencia de la hipótesis de la transmisión “prion-like” de la enfermedad y sugieren que la patología tau generada in vivo depende de la patología tau en la preparación indicando que hay modificaciones postraduccionales o cepas de la proteína tau que son responsables de la variabilidad entre las enfermedades.
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Carpenedo, Richard L. "Microsphere-mediated control of embryoid body microenvironments." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33948.
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Embryonic stem cells (ESCs) hold great promise for treatment of degenerative disorders such as Parkinson's and Alzheimer's disease, diabetes, and cardiovascular disease. The ability of ESCs to differentiate to all somatic cell types suggests that they may serve as a robust cell source for production of differentiated cells for regenerative medicine and other cell-based therapeutics. In order for ESCs to be used effectively in clinical settings, efficient and reproducible differentiation to targeted cell types must be demonstrated. The overall objective of this project was to engineer microenvironmental control over differentiating ESCs through the formation of embryoid bodies (EBs) uniform in size and shape, and through the incorporation of morphogen-containing polymer microspheres within the interior of EBs. The central hypothesis was that morphogen delivery through incorporated polymer microspheres within a uniform population of EBs will induce controlled and uniform differentiation of ESCs.
Rotary suspension culture was developed in order to efficiently produce uniform EBs in high yield. Compared to static suspension culture, rotary suspension significantly improved the production of differentiating cells and EBs over the course of 7 days, while simultaneously improving the homogeneity of EB size and shape compared to both hanging drop and static EBs. The diffusive transport properties of EBs formed via rotary suspension were investigated using a fluorescent, cell permeable dye to model the movement of small morphogenic molecules within EBs. Confocal microscopy, cryosections and EB dissociation all demonstrated that the dye was not able to fully penetrate EB, and that the larger EBs at later time points (7 days) retarded dye movement to a greater extent than earlier EBs (days 2 and 4). Polymer microspheres capable of encapsulating morphogenic factors were incorporated into EBs in order to overcome the diffusional limitations of traditional soluble delivery. The size of microspheres, microsphere coating, microsphere to cell ratio, and rotary mixing speed were all observed to influence incorporation within EBs. The use of microsphere-mediated delivery within EBs to direct cell differentiation was examined. Microsphere-mediated delivery of retinoic acid (RA) induced formation of uniquely cystic spheroids with a visceral endoderm layer enveloping a pseudo-stratified columnar epithelium, and with spatial localization of transcriptional profiles similar to the early primitive streak stage of mouse development. Continued differentiation of RA MS EBs in defined media conditions was assessed. Gene expression demonstrated that regular serum enhanced endoderm induction, serum-free media supported ectoderm differentiation, while mesoderm was most prominent in untreated EBs in full serum.
In summary, this work has realized a unique approach for stem cell differentiation through modification of the internal microenvironment of ESC spheroids. This novel inside-out method toward engineering EBs demonstrated that the mode of morphogen delivery significantly affected the course of differentiation. These studies provide the basis for ongoing work, which will utilize the choice of microsphere material, coating, and morphogen in order to uniquely study mechanisms of ESC differentiation and achieve unparalleled engineering of the EB microenvironment.
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Garcia, Marcos F. "An Assessment of Cognitive and Sensorimotor Deficits Associated with APPsw and P301L Mouse Models of Alzheimer's Disease." Scholar Commons, 2003. https://scholarcommons.usf.edu/etd/1368.
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Behavioral characterization of animal models for Alzheimer's Disease is critical for the development of potential therapeutics and treatments against the disease. While there are several known animal models of AD, three current models--APPsw, P301L, and APPsw+P301L--have not been well characterized, if at all. This study, therefore, aimed to perform a full behavioral characterization of these three models in order to better understand the impairments associated with each one. Between 5 and 8.5 months of age, animals were behaviorally tested in a variety of sensorimotor, anxiety, and cognitive tasks. The number of tau+ neurons in the forebrains of P301L mice was then compared to their behavioral performance.
Results of this study indicate that retinal degeneration (rd) seriously impairs the performance of mice in behavioral tasks. Animals that carry the homozygous allele of this mutation must, therefore, be eliminated from any such study requiring visual acuity. After this elimination, my findings indicate that APP mice are impaired in several cognitive tasks (including platform recognition, Morris maze, Y-maze, and radial-arm water maze) at a young early age (5 to 8.5 months of age). These mice have fairly normal sensorimotor function, showing significant impairment only in balance beam performance starting at 5 months. Although P301L mutant Tau mice, as a group, did not have significant impairments in any sensorimotor or cognitive task, correlation analysis revealed that higher numbers of tau+ neurons in cortex and hippocampus were associated with poorer cognitive performance. Finally, discriminant function analysis (DFA) appears able to accurately discriminate between the three transgenic groups of mice using only an 8-measure data set.
In conclusion, this study provides the first comprehensive, multiple task behavioral assessment of the APPsw and P301L animal models of AD, indicating that APPsw mice are cognitively impaired at an early age while P301L mice are largely unimpaired through 8.5 months. Nonetheless, correlational analysis implicates the formation of neurofibrillary tangles in the onset of cognitive impairments. Finally, my findings recommend the continued use of DFA to determine if groups of animals, based on different transgenicity or therapeutic treatment, could be discriminated between from their behavior alone.
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Sargent, Carolyn Yeago. "Effects of hydrodynamic culture on embryonic stem cell differentiation: cardiogenic modulation." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/34710.
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Stem and progenitor cells are an attractive cell source for the treatment of degenerative diseases due to their potential to differentiate into multiple cell types and provide large cell yields. Thus far, however, clinical applications have been limited due to inefficient differentiation into desired cell types with sufficient yields for adequate tissue repair and regeneration. The ability to spontaneously aggregate in suspension makes embryonic stem cells (ESCs) amenable to large-scale culture techniques for the production of large yields of differentiating cell spheroids (termed embryoid bodies or EBs); however, the introduction of hydrodynamic conditions may alter differentiation profiles within EBs and should be methodically examined. The work presented here employs a novel, laboratory-scale hydrodynamic culture model to systematically interrogate the effects of ESC culture hydrodynamics on cardiomyocyte differentiation through the modulation of a developmentally-relevant signaling pathway. The fluidic environment was defined using computational fluid dynamic modeling, and the effects of hydrodynamic conditions on EB formation, morphology and structure were assessed. Additionally, EB differentiation was examined through gene and protein expression, and indicated that hydrodynamic conditions modulate differentiation patterns, particularly cardiogenic lineage development. This work illustrates that mixing conditions can modulate common signaling pathways active in ESC differentiation and suggests that differentiation may be regulated via bioprocessing parameters and bioreactor design.
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Scott, Adrian Phillip. "Investigation of major histocompatibility complex (MHC) associations in sporadic inclusion body myositis." University of Western Australia. School of Pathology and Laboratory Medicine, 2009. http://theses.library.uwa.edu.au/adt-WU2009.0153.
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[Truncated abstract] Sporadic inclusion body myositis (sIBM) is a chronic inflammatory disease that is the most common myopathy in individuals above the age of 50 in the Caucasian population. sIBM is characterised by cytotoxic immune infiltration of skeletal muscle, consisting primarily of CD8+ T-cells and macrophages, as well as a degenerative process, with muscle fibre vacuolation and intracellular filamentous inclusions. The pathogenesis of sIBM is likely to involve a complex interaction between genetic and environmental factors. Whilst the physiological and pathological characteristics of sIBM have been clearly identified, the exact origin and genetic basis of the disease remains unknown. A number of studies show that sIBM is associated with alleles of the major histocompatibility complex (MHC) on chromosome 6p21.3 and specifically with two ancestral haplotypes (AH) in Caucasians the 8.1AH, defined by HLA-B*0801, HLA-DRB1*0301 and the 35.2AH, defined by HLA-B*3501, HLA-DRB1*0101. Mapping studies subsequently showed that sIBM susceptibility likely originates from a 389kb region of the MHC, spanning from centromeric of PBX2 to telomeric of HLA-DRB1. The central hypothesis of this thesis was that susceptibility to sIBM is conferred by a single allele found within a region defined using the 8.1AH, which is also carried by other haplotypes associated with sIBM. Three patient cohorts from Australia, the U.S.A and Japan were studied. ... Of the 32 alleles genotyped, none were found in all susceptibility haplotypes and one was common, but not unique, to the 8.1AH, 7.2AH and 52.1AH. Five SNPs were also found in two of the three haplotypes, although none were specific to the sIBM susceptibility haplotypes. These data suggest that the 8.1AH is likely to carry an sIBM susceptibility allele independent of the 35.2AH, 7.2AH and 52.1AH. Based on the possible mechanism of action in cellular differentiation and its location within the 8.1AH-defined sIBM susceptibility region reported in 2004, NOTCH4 was a strong candidate for conferring sIBM susceptibility. NOTCH4 coding region polymorphisms were thus investigated in a Caucasian patient cohort to assess any possible role in sIBM susceptibility. While the frequency of some alleles were increased in sIBM patients, the strong linkage disequilibrium throughout the MHC prevented confirmation of any alleles as playing a direct role in sIBM. The 8.1AH-derived sIBM susceptibility region was further refined using recombination mapping. This approach used markers characterised against multiple haplotypes to genotype patients carrying part of the 8.1AH to locate a common, overlapping susceptibility region. Recombination mapping of patients revealed a common overlapping region of the 8.1AH, extending from BTNL2 to HLA-DRB3. The results of the study indicate that 8.1AH-derived susceptibility for sIBM is likely to originate from a 172kb region encompassing HLA-DRA, HLA-DRB3 and part of BTNL2. These genes warrant further investigation in future studies.
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Ajmo, Craig T. "Alternative targets for the treatment of stroke." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002114.
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Henninger, Nils. "Inhibiting Axon Degeneration in a Mouse Model of Acute Brain Injury Through Deletion of Sarm1." eScholarship@UMMS, 2017. http://escholarship.umassmed.edu/gsbs_diss/900.
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Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI.
Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause immediate disruption of axons (primary axotomy), it is now recognized that the most frequent form of traumatic axonal injury (TAI) is mediated by a cascade of events that ultimately result in secondary axonal disconnection (secondary axotomy) within hours to days.
Proposed mechanisms include immediate post-traumatic cytoskeletal destabilization as a direct result of mechanical breakage of microtubules, as well as catastrophic local calcium dysregulation resulting in microtubule depolymerization, impaired axonal transport, unmitigated accumulation of cargoes, local axonal swelling, and finally disconnection. The portion of the axon that is distal to the axotomy site remains initially morphologically intact. However, it undergoes sudden rapid fragmentation along its full distal length ~72 h after the original axotomy, a process termed Wallerian degeneration.
Remarkably, mice mutant for the Wallerian degeneration slow (Wlds) protein exhibit ~tenfold (for 2–3 weeks) suppressed Wallerian degeneration. Yet, pharmacological replication of the Wlds mechanism has proven difficult. Further, no one has studied whether Wlds protects from TAI. Lastly, owing to Wlds presumed gain-of-function and its absence in wild-type animals, direct evidence in support of a putative endogenous axon death signaling pathway is lacking, which is critical to identify original treatment targets and the development of viable therapeutic approaches.
Novel insight into the pathophysiology of Wallerian degeneration was gained by the discovery that mutant Drosophila flies lacking dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously recapitulated the Wlds phenotype. The pro-degenerative function of the dSarm gene (and its mouse homolog Sarm1) is widespread in mammals as shown by in vitro protection of superior cervical ganglion, dorsal root ganglion, and cortical neuron axons, as well as remarkable in-vivo long-term survival (>2 weeks) of transected sciatic mouse Sarm1 null axons. Although the molecular mechanism of function remains to be clarified, its discovery provides direct evidence that Sarm1 is the first endogenous gene required for Wallerian degeneration, driving a highly conserved genetic axon death program.
The central goals of this thesis were to determine (1) whether post-traumatic axonal integrity is preserved in mice lacking Sarm1, and (2) whether loss of Sarm1 is associated with improved functional outcome after TBI. I show that mice lacking the mouse Toll receptor adaptor Sarm1 gene demonstrate multiple improved TBI-associated phenotypes after injury in a closed-head mild TBI model. Sarm1-/- mice developed fewer beta amyloid precursor protein (βAPP) aggregates in axons of the corpus callosum after TBI as compared to Sarm1+/+ mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phosphorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after TBI. Strikingly, whereas wild type mice exhibited a number of behavioral deficits after TBI, I observed a strong, early preservation of neurological function in Sarm1-/- animals. Finally, using in vivo proton magnetic resonance spectroscopy, I found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1-/- mice compared to controls immediately following TBI. My results indicate that the Sarm1-mediated prodegenerative pathway promotes pathogenesis in TBI and suggest that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after TBI.
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Sargeant, Aaron Matthew. "Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.
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Kanyenda, Limbikani J. "Investigating the impact of CD147 and its expression on neurodegenaration and Alzheimer's disease (AD)." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2012. https://ro.ecu.edu.au/theses/499.
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CD147, also known as basigin, extracellular matrix metalloproteinase inducer, neurothelin, tumour cell-derived collagenase stimulatory factor, M6, HT7, OX47 or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues with high expression in the hippocampus, pre-frontal cortex, thyroid, heart, early erythroid, amygdala and placenta. This protein is involved in various cellular and biological functions such as lymphocyte migration and maturation, tissue repair, cancer progression, T and B lymphocyte activation and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with with cyclophilin A, cyclophilin B, sterol carrier protein, caveolin-1 and integrins, and can influence beta amyloid peptide levels, a protein that is central to Alzheimer’s disease pathology.
Mechanisms through which CD147 regulates bata amyloid levels still remain unclear, thus the current study investigated the impact of high cholesterol and beta amyloid 42 loading on CD147 expression in rat primary cortical neuronal cultures. Its expression in human brain tissue from Alzheimer’s disease and non-Alzheimer’s disease dementias and APPswe transgenic mice fed on a high fat/high cholesterol diet were also determined. CD147 over expression experiments in rat primary cortical neuronal and SH-SY5Y cultures using recombinant adenoviruses (AdRSV-CD147 and AdRSV-Empty) in the presence and/or absence of cyclophilin A were employed to determine level of proection against oxidative stress and toxicity. Finally sequencing of the CD147 promoter region (-392 to -242 nucleotides) was perfomed to identify possible single neucrotide polymorphysims that may be linked to Alzheimer’s disease pathology.
The in vitro experiments conducted in this study have shown that cholesterol and beta amyloid loading and oxidative stress result in increased CD147 expression in rat primary cortical neuronal cultures and that CD147 protects neuronal cultures from beta amyloid toxicity only in the presence of cylophilin A. However in vivo experiments in animal model have shown that a high fat/high cholesterol diet does not affect brain CD147 levels as evidenced by unchanged expression levels in APPswe mice.
Human studies have revealed a correlation between CD147 and γ-secretase complex components (nicastrin and presenilin 1) in the hippocampus. However, there is no difference in CD147 protein expression between hippocampus and frontal cortex from Alzheimer’s disease patients. Sequencing of the CD147 promoter region, where sterol carrier protein binds to initiate CD147 transcription, has identified two novel single neucrotide polymorphysims (-61A>G and 37C>G). However, single neucrotide polymorphysims within this region are not associated with Alzheimer’s disease pathology.
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Rabaneda, Lombarte Neus. "Brain immune response as therapeutic target in the treatment of Parkinson’s disease." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668030.
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Neuroinflammation is present in practically all neurological disorders. Microglial cells, the main representatives of the endogenous immune system of the brain, play a key role in neuroinflammation, although peripheral immune cells can also be involved. In the last years, a considerable effort has been focused on the study of the modulation of the inflammatory response as a possible therapeutic strategy in neurological diseases. Parkinson’s disease (PD) is the second most common neurodegenerative disease and is mainly characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and an abnormal intracellular accumulation of α-synuclein protein, known as Lewy bodies. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. Activated microglia has been described in the post-mortem brains of PD patients; however, the pathogenic role of the immune system in PD remains enigmatic. In the present thesis, we have studied one of the inhibitory mechanisms suggested to be involved in the control of the inflammatory response in microglial cells: CD200 ligand (mainly expressed in neurons and astrocytes) - CD200R1 receptor (mainly microglial) interaction.
The aim of this thesis was to study the involvement of the microglial inhibitory immune receptor CD200R1 in the modulation of neuroinflammation and its potential as therapeutic target in PD.
In vitro, the disruption of the CD200-CD200R1 system potentiated the pro-inflammatory response of glial cells. Mesencephalic cultures from CD200-deficient mice showed a higher microglial proportion and increased sensitivity of dopaminergic neurons to the neurotoxin 1-methyl-4- phenylpyridinium (MPP+). The parkinsonian neurotoxins MPP+ and rotenone impaired the immune response of glial cells to pro- and anti-inflammatory stimuli and changed CD200 and CD200R1 expression.
In vivo, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) experimental mouse model of PD dopaminergic neurodegeneration and glial activation were associated to changes in CD200 and CD200R1 expression: mainly a transient increase in striatal CD200R1 and a sustained decrease in CD200full in the ventral midbrain. When we potentiated the CD200-CD200R1 system by administering a CD200R1 agonist, we observed partial protection in dopaminergic neurons of the SNpc, which was accompanied by an attenuated microglial activation. On the contrary, CD200-deficient mice showed a more reactive microglial phenotype at early stages after MPTP administration, although it was not associated to an exacerbated neurodegeneration.
Post-mortem brain samples from substantia nigra, frontal cortex and hippocampus of PD patients had particular changes in the expression of the mRNA variants and protein isoforms of the CD200-CD200R1 system.
In conclusion, these results suggest that the CD200-CD200R1 system is a potential target to control microglial activation in PD, and that the mechanisms of control of microglial activation may be used to modulate microglial activation and its potential neurotoxicity on neurodegenerative diseases.La neuroinflamació està present en pràcticament tots els desordres neurològics i la micròglia hi juga un paper clau. La malaltia de Parkinson (MP) és la segona malaltia neurodegenerativa més comú i està caracteritzada per la pèrdua de neurones dopaminèrgiques de la part compacta de la substancia negra (SNpc) i la presència de cossos de Lewy. Hi ha evidència de que la neurodegeneració dopaminèrgica està influenciada pel sistema immunitari innat. En aquesta tesi, hem estudiat un dels mecanismes inhibitoris suggerits d’estar involucrats en el control de la resposta inflamatòria de la micròglia: el lligand CD200 (principalment neuronal i astrocític) i el receptor CD200R1 (principalment microglial). La finalitat era estudiar el rol de CD200R1 en la modulació de la neuroinflamació i el seu potencial com a diana terapèutica en la MP. In vitro, la disrupció del sistema CD200-CD200R1 va potenciar la resposta pro-inflamatòria glial. Cultius mesencefàlics de ratolins deficients en CD200 van mostra una major proporció de micròglia i una sensibilitat incrementada de les neurones dopaminèrgiques al 1-metil-4- fenilpiridina (MPP+). Les neurotoxines parkinsonianes MPP+ i rotenona van alterar la resposta glial a estímuls inflamatoris i van modificar l’expressió de CD200 i CD200R1. In vivo, en el model de ratolí de la MP amb 1-metil-4-fenil,6-tetrahidropiridina (MPTP) la mort dopaminèrgica i l’activació glial es van associar a un increment transitori de CD200R1 estriatal i una disminució sostinguda de CD200full en el mesencèfal ventral. L’administració d’un agonista de CD200R1 va protegir parcialment les neurones dopaminèrgiques de la SNpc i va atenuar l’activació microglial. Contràriament, ratolins deficients en CD200 van mostrar un fenotip microglial més reactiu en estadis inicials després de l’administració del MPTP, encara que no es va associar a una neurodegeneració exacerbada. A mostres de cervell post-mortem de la SN, còrtex frontal i hipocamp de pacients amb MP es van observar canvis en l’expressió de les variants de RNA i les isoformes proteiques del sistema CD200-CD200R1. En conclusió, aquests resultats suggereixen que el sistema CD200-CD200R1 és una diana potencial pel control de l’activació microglial en la MP, i que els mecanismes de control de l’activació microglial podrien ser usats per modular l’activació microglial i el seu potencial neurotòxic en les malalties neurodegeneratives.
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Kennedy, Seamus. "Pathology of experimentally induced nutritional degenerative myopathy in ruminant cattle." Thesis, Queen's University Belfast, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484303.
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Vázquez, Jiménez Laura. "Studies on the Chemical Modulation of Neuroprotective Agents Related to CR-6 Addressed to Improve the Delivery through the Blood-Brain Barrier." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/285339.
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Oxidative stress is one of the most important factors in degenerative diseases like cancer, Alzheimer or in episodes like ischemia. During these processes, reactive species of oxygen (ROS) and nitrogen (RNS) are generated. This fact can cause the chemical modification of important biomolecules, in particular lipids and proteins. The strategy that involves the use of antioxidants and neuroprotective agents to fight against the lesive effects of these species stumbles over the blood-brain-barrier (BBB). This barrier protects the brain from the action of a wide variety of organic molecules and drugs. Thus, it is important to develop novel antioxidant agents with good delivery through the BBB.
In our group it was discovered the antioxidant agent 3,4-dihydro-2,2-dimethyl-7-metoxy-1-(2H)-benzopyran (CR-6), an analogue of alpha- and gamma-tocopherols (Figure 1), which is currently used in dermopharmacy and it is also in a phase II trials for anticancer treatment (combined with other drugs). In our present project, one of the main goals is the synthesis of a short library of CR-6 analogues that could improve the pass through the BBB.
Accordingly, fourteen novel CR-6 analogues have been synthesized introducing essential nutrients for brain that work as BBB-shuttles at C2 of CR-6 scaffold. The antioxidant activity was evaluated to assure that it does not change by the incorporation of variability at C2 position (the DPPH assay and the in vitro CAA were used). In addition, the BBB permeability was evaluated to compare the BBB bioavailability of these new antioxidant agents with the references CR-6 and Trolox (PAMPA, Caco-2 and BBCEC assays were used).El estrés oxidativo es uno de los factores etiológicos más importantes en las enfermedades degenerativas como el cáncer, el Alzheimer o en episodios de isquemia. Durante estos procesos, se generan especies reactivas de oxigeno (ROS) y de nitrógeno (RNS) que provocan modificaciones de las biomoléculas como los lípidos, las proteínas y el ADN. El uso de agentes antioxidantes y neuroprotectores ayudan a reducir los efectos lesivos que el estrés oxidativo tiene en el cerebro, por ejemplo. La barrera hematoencefálica o BBB protege al cerebro de la acción de una amplia variedad de moléculas orgánicas y fármacos. Por ello, existe un gran interés en el desarrollo de nuevos agentes antioxidantes con un buen transporte a través de la BBB. En nuestro grupo de investigación se ha desarrollado el agente antioxidante 3,4-dihidro-2,2-dimetil-7-metoxi-1-(2H)-benzopirano (CR-6), un análogo de alfa- y gamma-tocoferol, que en la actualidad se emplea en dermofarmacia y se encuentra en ensayos de fase II para el tratamiento del cáncer (combinado con otros fármacos). En este proyecto se persigue la síntesis de una colección de análogos del CR-6 que mejoren el paso a través de la BBB. De este modo, se han sintetizado catorce compuestos derivados del CR-6 introduciendo nutrientes esenciales del cerebro que actúan como transbordadores de la BBB. La actividad antioxidante de todos estos compuestos se ha evaluado para asegurar que ésta se mantiene al introducir variabilidad en la posición C2 mediante los ensayos del DPPH y el in vitro CAA. A su vez, la permeabilidad de la BBB se ha evaluado para compararla con los compuestos de referencia CR-6 y Trolox a partir de los ensayos in vitro Caco-2, PAMPA y BBCEC.
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Wagner, Gregory Randall. "Identification and characterization of altered mitochondrial protein acetylation in Friedreich's ataxia cardiomyopathy." Thesis, Hindawi Publishing Corporation and Oxford Journals and SAGE Journals, 2011. http://hdl.handle.net/1805/4209.
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Indiana University-Purdue University Indianapolis (IUPUI)Friedreich’s Ataxia (FRDA) is a rare and poorly understood autosomal recessive disease caused by a pathological deficiency of the mitochondrial protein frataxin. Patients suffer neurodegeneration, ataxia, diabetes, and heart failure. In an effort to understand the mechanisms of heart failure in FRDA, we investigated the role of the protein modification acetylation, which is highly abundant on mitochondrial proteins and has been implicated in regulating intermediary metabolism. Using mouse models of FRDA, we found that cardiac frataxin deficiency causes progressive hyperacetylation of mitochondrial proteins which is correlated with loss of respiratory chain subunits and an altered mitochondrial redox state. Mitochondrial protein hyperacetylation could be reversed by the mitochondria-localized deacetylase SIRT3 in vitro, suggesting a defect in endogenous SIRT3 activity. Consistently, frataxin-deficient cardiac mitochondria showed significantly decreased rates of fatty acid oxidation and complete oxidation to carbon dioxide. However, the degree of protein hyperacetylation in FRDA could not be fully explained by SIRT3 loss. Our data suggested that intermediary metabolites and perhaps acetyl-CoA, which is required for protein acetylation, are accumulating in frataxin-deficient mitochondria. Upon testing the hypothesis that mitochondrial protein acetylation is non-enzymatic, we found that the minimal chemical conditions of the mitochondrial matrix are sufficient to cause widespread non-enzymatic protein acetylation in vitro. These data suggest that mitochondrial protein hyperacetylation in FRDA cardiomyopathy mediates progressive post-translational suppression of mitochondrial oxidative pathways which is caused by a combination of SIRT3 deficiency and, likely, an accumulation of unoxidized acetyl-CoA capable of initiating non-enzymatic protein acetylation. These findings provide novel insight into the mechanisms underlying a poorly understood and fatal cardiomyopathy and highlight a fundamental biochemical mechanism that had been previously overlooked in biological systems.
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Errea, Lorenzo Oihana. "Mecanismos de degeneración axonal en neuroinflamación: papel de la disfunción mitocondrial." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/283879.
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La Esclerosis Múltiple (EM) afecta preferentemente a la conectividad cerebral lesionando los axones de forma irreversible, siendo esta lesión la principal causa de la discapacidad permanente de los pacientes. El daño axonal se produce de forma aguda debido a la cascada inflamatoria y de forma crónica (degenerativa) debido a la falta de soporte trófico de la mielina, un microambiente alterado (gliótico) y persistencia de inflamación crónica (activación microglial). Los axones son dañados en la fase aguda por el estrés oxidativo y energético y mecanismos de citotoxicidad, produciéndose un fallo del transporte axonal y un fallo de la función mitocondrial. Todos estos procesos culminan en el déficit energético, que pone en marcha mecanismos activos de transección axonal que llevan a la lesión axonal aguda. Los mecanismos de daño axonal crónico serían en parte similares a los agudos (déficit energético) extendidos en el tiempo, junto con el fallo de soporte trófico de la mielina, la modificación de la función y distribución de los canales iónicos y la consecuente alteración del microambiente.
Identificar los mecanismos y la dinámica del daño axonal agudo y crónico en la EM permitirá identificar dianas terapéuticas para las que se desarrollarían nuevas terapias neuroprotectoras que disminurían el daño axonal en la EM y por tanto las secuelas.
El objetivo del proyecto es analizar distintos aspectos de la biología mitocondrial y de su función respiratoria y energética relacionados con la degeneración axonal en un entorno neuroinflamatorio agudo. Para conseguirlo se ha utilizado un modelo de neuroinflamación in vitro consistente en cultivos organotípicos de cerebelo de ratón estimulados con lipopolisacárido bacteriano (LPS) y los cambios se han evaluado mediante técnicas de microscopía avanzada y biología molecular. A lo largo del estudio de la biología mitocondrial también se ha utilizado un estímulo causante de estrés oxidativo, el peróxido de hidrógeno (H2O2), proceso que forma parte de la neuroinflamación y afecta directamente a la función de los complejos de la cadena respiratoria mitocondrial.
Los resultados del estudio nos llevan a proponer el siguiente modelo de la respuesta mitocondrial en un entorno neuroinflamatorio agudo: mientras que a nivel tisular las mitocondrias responden aumentando su capacidad respiratoria y la producción de ATP, a nivel axonal las mitocondrias responden morfológicamente a la inflamación aumentando su tamaño y la complejidad de sus crestas mitocondriales, pero su transporte se ve completamente alterado. La paralización de las mitocondrias se produce en una etapa temprana y aguda de la inflamación, antes de que los daños axonales sean irreversibles. Por tanto, nuestro modelo indica que el mecanismo más crítico en la disfunción mitocondrial en la neuroinflamación aguda es la alteración del transporte axonal de mitocondrias (especialmente el retrógrado). Por tanto, nuestro estudio sugiere la preservación del transporte mitocondrial como una diana terapéutica de neuroprotección en lesiones agudas de EM.The main cause of permanent disability in Multiple Sclerosis (MS) patients is axonal degeneration. In acute phases of the disease axonal damage is a consequence of the inflammatory cascade and oxidative stress that cause direct damage to mitochondria, inhibiting OXPHOS complexes. In more chronic phases axonal degeneration is due to loss of myelin trophic support, gliosis, redistribution of axonal sodium channels and extended energetic deficiency. Mitochondrial dysfunction is a common player in both stages. Therefore, the elucidation of axonal degeneration mechanisms is important for the identification of new therapeutic targets and the development of neuroprotective therapies that decrease axonal damage in MS. The objective of the project is to analyze different aspects of mitochondrial biology and their respiratory and energetic functions related with axonal degeneration in an acute neuroinflammatory environment. Organotypic slice cultures of mouse cerebellum were stimulated with LPS to activate microglia and simulate neuroinflammation, and mitochondrial changes were evaluated with advanced techniques of molecular biology and microscopy. The results suggest that tissular mitochondria are responding to acute neuroinflammation increasing their respiratory capacity and their production of ATP, and axonal mitochondria react morphologically increasing their size and their cristae complexity. However, axonal mitochondrial transport is completely impaired, in an early stage of acute inflammation before axonal damage is irreversible. Therefore, we propose that the critical mechanism of mitochondrial dysfunction in acute neuroinflammation is the impairment of axonal mitochondrial transport. As a result, the preservation of axonal mitochondrial transport represents a therapeutic target for neuroprotection in acute MS lesions.
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Consciência, José Alberto de Castro Guimarães. "Estabilização dinâmica em patologia degenerativa da coluna lombar: estado da arte e contributo pessoal." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2007. http://hdl.handle.net/10362/5204.
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Resumo
Este trabalho encontra-se dividido em três capítulos distintos. No primeiro, é caracterizada a doença degenerativa lombar, demorando-se o autor na descrição pormenorizada das alterações anatómicas,
biomecânicas, e bioquímicas inerentes à sua ocorrência. Segue-se a descrição da evolução das diferentes formas de terapêutica, enumerando as que de forma clássica mais frequentemente são utilizadas (cirúrgicas e não cirúrgicas).
No segundo capítulo, são referidos os mais recentes avanços tecnológicos nesta área, mencionando, nas suas vertentes biomecânicas,
clínicas e terapêuticas, as particularidades das estabilizações dinâmicas interespinhosas e pediculares, bem como da artroplastia de disco. Após esta longa introdução, inicia-se o terceiro capítulo no qual se apresenta um estudo prospectivo da avaliação clínica, funcional, imagiológica e da variação da densidade mineral óssea vertebral em 20
doentes com patologia degenerativa, tratados com sistemas de estabilização dinâmica semi-rígida interespinhosa, e seguidos durante dois anos. Do estudo realizado conclui-se que os sistemas referidos são eficazes clínica e funcionalmente no tratamento de doentes com doença degenerativa lombar. Mais ainda, estes instrumentais proporcionam um aumento da altura do disco confirmado na incidência radiográfica de perfil no nível instrumentado.
Constatámos ainda que a densidade mineral óssea vertebral dos doentes intervencionados, avaliada com sistema DXA, não demonstra diferenças com significância estatística ao longo do tempo, omparativamente à determinada em idêntica população mas sem qualquer patologia lombar. Acresce que se obteve uma correlação entre a
funcionalidade física e a BMD radial, com significância estatística crescente
nas duas medições realizadas.
Abstract
This study is divided in three different chapters. In the first one the author describes the anatomical, biomechanical and biochemical changes that go along with degenerative lumbar spine disease. The therapeutically possibilities are mentioned, mainly with the classic fusion and decompression as well as the non surgical options.
Then, in the second chapter, the author describes, from the biomechanical, clinical and therapeutically point of view, the new techniques of dynamic stabilization, interspinous and pedicular systems, as well as disc replacement.
After this introduction, in the third chapter a prospective clinical, functional, imagiologic and vertebral bone mineral density variation study is presented. Twenty patients with degenerative lumbar spine disease are selected, and operated with a semi rigid interspinous system device, and followed for a two year period.
The author concludes that the interspinous semi rigid systems were clinically and functionally effective in lumbar degenerative patients. It was also founded that the disc height at the implant segment level increased after surgery.
Bone density was assessed with a DXA system device. As far as vertebral bone density is concerned, the author found no differences what so ever inside the group during the study, or to an identical control group without any lumbar pathology.
The correlation study between the BMD and physical function showed that there was only significant statistically data in radial BMD measurement, and this happened with growing correlation from year 2006 to 2007.
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Garcia, Diaz Anna Isabel. "Visuospatial and visuoperceptual impairment and its structural correlates as measures of cognitive decline in Parkinson’s disease." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/663847.
Full textAbstract:
Parkinson’s disease is a common neurodegenerative disorder that manifests with a wide range of non-motor symptoms. Among them, cognitive impairment is present in a high proportion of patients, having a great impact on quality of life and prospective outcome. Initiatives have aimed to describe the features of cognitive impairment in Parkinson’s disease and, although findings are not conclusive, the visuospatial and visuoperceptual neuropsychological domain can be impaired early in the disease course, and these deficits sustain a relationship with disease severity and progression. Moreover, posterior cortically-based deficits are prognostic markers of the emergence of dementia in Parkinson’s disease. Hence, their early identification is an important undertaking in clinical settings.
In our studies, we have investigated visuospatial and visuoperceptual impairment in Parkinson’s disease patients, as well as its evolution over time. We assessed 121 Parkinson’s disease patients and 41 healthy matched control subjects, applying well-validated and widely used neuropsychological tests, and followed the sample for an approximate period of four years. We identified the neuroanatomical substrates of these deficits using surface-based cortical thickness measures and tract-based spatial statistics for white matter microstructure integrity parameters.
Parkinson’s disease patients exhibit a posterior temporo-parieto-occipital pattern of cortical thinning that is related to the impairment of visual cognition processes; however, these correlates do not appear to follow the classical dissociation described in the current literature of the healthy visual system pathways. In Parkinson’s disease patients with mild cognitive impairment, this degeneration is more pronounced and widespread, and follows a posterior-anterior pattern of cortical thinning. Moreover, after a four-year follow-up, Parkinson’s disease patients with mild cognitive impairment exhibit a differential pattern from cognitively normal patients, that involves temporo-parieto-occipital regions, and is related to changes over time in visuospatial and visuoperceptual measures. Conversely, white matter microstructure appears altered in the posterior corpus callosum in Parkinson’s disease, whereas visuospatial, visuoperceptual and visuoconstructive measures exhibit widespread long- and short-range correlates with white matter degeneration.
Our results give support to the hypothesized relationship between impairment in visuospatial and visuoperceptual functions and the degeneration of predominantly posterior cortices over time, establish-ing the structural basis of cognitive decline in Parkinson’s disease. These findings could have translational implications and contribute to the validation of the use of these tests in clinical as well as research settings. Further research involving multimodal approaches of structural and functional neuroimaging techniques in longitudinal settings could shed light on the characterization of the neuroanatomical substrate of cognitive decline in Parkinson’s disease.La malaltia de Parkinson és un trastorn neurodegeneratiu d’elevada incidència que es manifesta amb una gran varietat de símptomes no-motors. Entre els sintomes no-motors, el deteriorament cognitiu és present en una elevada proporció del pacients i produeix un gran impacte en la seva qualitat de vida i el seu pronòstic. La caracterització del deteriorament cognitiu en la malaltia de Parkinson és un important repte de recerca i, tot i que existeix una elevada disparitat entre les troballes actuals, els dèficits visoespacials i visoperceptius es poden considerar com un domini específic que pot mostrar alteracions de forma primerenca i mostrar una relació amb la gravetat de la malaltia i la seva progressió. Els dèficits originats en el còrtex posterior es consideren un marcador pronòstic de l’aparició de demència a la malaltia de Parkinson, fet que posa de relleu la importància de la seva identificació primerenca en el maneig clínic. En els nostres estudis, hem identificat i catacteritzat el deteriorament visoespacial i visoperceptiu a la malaltia de Parkinson, així com la seva evolució en el temps. Hem recollit dades de 121 pacients i 41 controls sans aparellats segons variables sociodemogràfiques, tot aplicant tests validats i àmpliament utilitzats en l’àmbit clínic. Hem seguit la seva evolució per un període aproximat de quatre anys. Per tal de identificar els substrats neuroanatòmics d’aquests dèficits, hem utilitzat mesures de gruix cortical basades en l’estimació de superfícies, i mesures adreçades a l’avaluació de la integritat de la microestructura de la substància blanca. Els malalts de Parkinson presenten un patró de deteriorament cortical localitzat en regions posteriors temporo-parieto-occipitals, que està relacionat amb els dèficits observats en les funcions visoespacials i visoperceptives. Tot i així, aquests correlats no segueixen la dissociació descrita a la literatura clàssica sobre les vies del sistema visual en subjectes normals. En pacients amb deteriorament cognitiu lleu, els patrons d’atrofia cerebral són mes pronunciats i generalitzats, tot seguint un patró posterior-anterior de pèrdua del gruix cortical. El seguiment realitzat ens ha permès identificar un patró diferencial de degeneració en els pacients amb deteriorament cognitiu lleu, localitzat principalment en la regió temporo-parieto-occipital i que està relacionat amb la pèrdua de funcions visoespacials i visoperceptives. De forma coherent, l’alteració de la microestructura de la substància blanca es localitza a la part posterior del cos callós. Ara bé, la pèrdua de funcions visoespacials, visoperceptives i visoconstructives es relaciona amb la pèrdua de la integritat de regions cerebrals més extenses, que impliquen fascicles intra- i interhemisfèrics. Els resultats evidencien la relació entre el deteriorament de les funcions visoespacials i visoperceptives i la degeneració neuroanatòmica predominantment del còrtex posterior. Aquestes troballes contribueixen a establir la base estructural del deteriorament cognitiu en la malaltia de Parkinson i poden tenir implicacions translacionals, ja que contribueixen a la validació de l’ús d’un conjunt de tests en el maneig clínic i en termes de recerca. En el futur, la combinació d’estudis multimodals estructurals i funcionals de caire longitudinal poden contribuir en la caracterització del substrat neuroanatòmic i neurofuncional del deteriorament cognitiu a la malaltia de Parkinson i determinar-ne el valor pronóstic d’evolució a demència.
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Garnier, Mickaël. "Modèles descriptifs de relations spatiales pour l'aide au diagnostic d'images biomédicales." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05S015/document.
Full textAbstract:
La pathologie numérique s’est développée ces dernières années grâce à l’avancée récente des algorithmes d’analyse d’images et de la puissance de calcul. Notamment, elle se base de plus en plus sur les images histologiques. Ce format de données a la particularité de révéler les objets biologiques recherchés par les experts en utilisant des marqueurs spécifiques tout en conservant la plus intacte possible l’architecture du tissu. De nombreuses méthodes d’aide au diagnostic à partir de ces images se sont récemment développées afin de guider les pathologistes avec des mesures quantitatives dans l’établissement d’un diagnostic. Les travaux présentés dans cette thèse visent à adresser les défis liés à l’analyse d’images histologiques, et à développer un modèle d’aide au diagnostic se basant principalement sur les relations spatiales, une information que les méthodes existantes n’exploitent que rarement. Une technique d’analyse de la texture à plusieurs échelles est tout d’abord proposée afin de détecter la présence de tissu malades dans les images. Un descripteur d’objets, baptisé Force Histogram Decomposition (FHD), est ensuite introduit dans le but d’extraire les formes et l’organisation spatiale des régions définissant un objet. Finalement, les images histologiques sont décrites par les FHD mesurées à partir de leurs différents types de tissus et des objets biologiques marqués qu’ils contiennent. Les expérimentations intermédiaires ont montré que les FHD parviennent à correctement reconnaitre des objets sur fonds uniformes y compris dans les cas où les relations spatiales ne contiennent à priori pas d’informations pertinentes. De même, la méthode d’analyse de la texture s’avère satisfaisante dans deux types d’applications médicales différents, les images histologiques et celles de fond d’œil, et ses performances sont mises en évidence au travers d’une comparaison avec les méthodes similaires classiquement utilisées pour l’aide au diagnostic. Enfin, la méthode dans son ensemble a été appliquée à l’aide au diagnostic pour établir la sévérité d’un cancer via deux ensembles d’images histologiques, un de foies métastasés de souris dans le contexte du projet ANR SPIRIT, et l’autre de seins humains dans le cadre du challenge CPR 2014 : Nuclear Atypia. L’analyse des relations spatiales et des formes à deux échelles parvient à correctement reconnaitre les grades du cancer métastasé dans 87, 0 % des cas et fourni des indications quant au degré d’atypie nucléaire. Ce qui prouve de fait l’efficacité de la méthode et l’intérêt d’encoder l’organisation spatiale dans ce type d’images particulierDuring the last decade, digital pathology has been improved thanks to the advance of image analysis algorithms and calculus power. Particularly, it is more and more based on histology images. This modality of images presents the advantage of showing only the biological objects targeted by the pathologists using specific stains while preserving as unharmed as possible the tissue structure. Numerous computer-aided diagnosis methods using these images have been developed this past few years in order to assist the medical experts with quantitative measurements. The studies presented in this thesis aim at adressing the challenges related to histology image analysis, as well as at developing an assisted diagnosis model mainly based on spatial relations, an information that currently used methods rarely use. A multiscale texture analysis is first proposed and applied to detect the presence of diseased tissue. A descriptor named Force Histogram Decomposition (FHD) is then introduced in order to extract the shapes and spatial organisation of regions within an object. Finally, histology images are described by the FHD measured on their different types of tissue and also on the stained biological objects inside every types of tissue. Preliminary studies showed that the FHD are able to accurately recognise objects on uniform backgrounds, including when spatial relations are supposed to hold no relevant information. Besides, the texture analysis method proved to be satisfactory in two different medical applications, namely histology images and fundus photographies. The performance of these methods are highlighted by a comparison with the usual approaches in their respectives fields. Finally, the complete method has been applied to assess the severity of cancers on two sets of histology images. The first one is given as part of the ANR project SPIRIT and presents metastatic mice livers. The other one comes from the challenge ICPR 2014 : Nuclear Atypia and contains human breast tissues. The analysis of spatial relations and shapes at two different scales achieves a correct recognition of metastatic cancer grades of 87.0 % and gives insight about the nuclear atypia grade. This proves the efficiency of the method as well as the relevance of measuring the spatial organisation in this particular type of images
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Kamishina, Hiroaki. "Degenerative joint disease of the hip in cats imaging, pathologic, and in vitro studies /." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0001203.
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Fourgeux, Cynthia. "Cholestérol-24S-hydroxylase (CYP46A1) et homéostasie du cholestérol dans la rétine en conditions physiologiques et pathologiques." Phd thesis, Université de Bourgogne, 2012. http://tel.archives-ouvertes.fr/tel-00905888.
Full textAbstract:
Le cholestérol est le principal stérol présent dans la rétine. Dans sa forme libre, le cholestérol est distribué dans toutes les couches cellulaires de la rétine, alors que le cholestérol estérifié s'accumule essentiellement à la base de l'épithélium pigmentaire rétinien. La capacité intrinsèque de la rétine à synthétiser le cholestérol paraît limitée, ce qui implique nécessairement que des voies extra-rétiniennes participent activement à suppléer la rétine en cholestérol. Les cellules gliales de Müller contribueraient à l'apport de cholestérol aux neurones de la rétine, en particulier pour la formation des synapses. Les conséquences délétères d'une accumulation ou à l'inverse d'un déficit en cholestérol dans les neurones sur leur survie souligne l'importance de maintenir l'équilibre entre l'apport et la néosynthèse du cholestérol d'une part et son élimination d'autre part. Pour cela, la rétine neurale a en particulier la capacité de convertir, pour l'éliminer, le cholestérol en 24S-hydroxycholestérol. En effet, le transport du 24S-hydroxycholestérol au travers des membranes est facilité par la présence d'un groupe hydroxyle supplémentaire, lui conférant une polarité plus importante par rapport au cholestérol. L'enzyme qui catalyse cette réaction est la cholestérol-24S-hydroxylase (CYP46A1). Des liens ont été établis entre CYP46A1, 24S-hydroxycholestérol et processus neurodégénératifs dans le cerveau, suggérant un rôle potentiel dans certaines pathologies comme la maladie d'Alzheimer. CYP46A1 est exprimée dans la rétine neurale, et plus particulièrement dans les cellules ganglionnaires de la rétine. Le rôle de CYP46A1 dans la rétine reste pour l'instant inconnu. Cependant, par analogie avec le cerveau, nous pouvons supposer une fonction dans le contrôle de l'homéostasie du cholestérol dans les neurones et envisager une association avec des pathologies dégénératives de la rétine comme la Dégénérescence Maculaire Liée à l'Âge (DMLA) ou le glaucome. Dans ce contexte, l'objectif de nos travaux a consisté à évaluer le rôle de la cholestérol-24S-hydroxylase dans la rétine en conditions physiologiques et pathologiques. Par une approche clinique, nous avons trouvé qu'un polymorphisme génétique dans CYP46A1 était un facteur de risque de glaucome (Risque relatif=1,26, intervalle de confiance à 95%=1,006-1,574, p<0,05) (Fourgeux et al. 2009, Invest Ophthalmol Vis Sci 50:5712-7). Par contre, ce polymorphisme génétique n'a pas été retrouvé, en tant que tel, comme facteur de risque chez des patients DMLA, mais pourrait l'être chez les patients non porteurs d'allèles à risque dans les gènes CFH et LOC388715 (Fourgeux et al. 2012, Invest Ophthalmol Vis Sci 53:7026-33). Deux approches expérimentales nous ont permis de suggérer qu'il existe un lien entre le stress des cellules de la rétine et le 24S-hydroxycholestérol. En effet, dans une étude in vivo faite chez le rat, après avoir reproduit une caractéristique principale du glaucome par l'augmentation de la pression intraoculaire, nous avons suggéré le rôle crucial de la glie dans le maintien de l'expression de CYP46A1 au cours de la neurodégénérescence de la rétine (Fourgeux et al. 2012, Acta Ophthalmol, Sep 23 ; doi: 10.1111/j.1755-3768.2012.02490.x.). Enfin, l'inhibition pharmacologique de l'activité CYP46A1 dans la rétine par le voriconazole injecté in vivo chez le rat nous a permis de mettre en évidence que la diminution du contenu en 24S-hydroxycholestérol de la rétine était associée à une dysfonction des cellules ganglionnaires, évaluée par électrorétinographie. En parallèle, nous avons observé une activation gliale, dont l'amplitude était amplifiée par l'inhibition de l'activation microgliale induite par la minocycline [...]
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Heusel-Gillig, Lisa, and Courtney D. Hall. "Effectiveness of Physical Therapy Intervention in Patients with Degenerative Cerebellar Ataxia." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etsu-works/571.
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Garnier, Mickaël. "Modèles descriptifs de relations spatiales pour l'aide au diagnostic d'images biomédicales." Electronic Thesis or Diss., Paris 5, 2014. http://www.theses.fr/2014PA05S015.
Full textAbstract:
La pathologie numérique s’est développée ces dernières années grâce à l’avancée récente des algorithmes d’analyse d’images et de la puissance de calcul. Notamment, elle se base de plus en plus sur les images histologiques. Ce format de données a la particularité de révéler les objets biologiques recherchés par les experts en utilisant des marqueurs spécifiques tout en conservant la plus intacte possible l’architecture du tissu. De nombreuses méthodes d’aide au diagnostic à partir de ces images se sont récemment développées afin de guider les pathologistes avec des mesures quantitatives dans l’établissement d’un diagnostic. Les travaux présentés dans cette thèse visent à adresser les défis liés à l’analyse d’images histologiques, et à développer un modèle d’aide au diagnostic se basant principalement sur les relations spatiales, une information que les méthodes existantes n’exploitent que rarement. Une technique d’analyse de la texture à plusieurs échelles est tout d’abord proposée afin de détecter la présence de tissu malades dans les images. Un descripteur d’objets, baptisé Force Histogram Decomposition (FHD), est ensuite introduit dans le but d’extraire les formes et l’organisation spatiale des régions définissant un objet. Finalement, les images histologiques sont décrites par les FHD mesurées à partir de leurs différents types de tissus et des objets biologiques marqués qu’ils contiennent. Les expérimentations intermédiaires ont montré que les FHD parviennent à correctement reconnaitre des objets sur fonds uniformes y compris dans les cas où les relations spatiales ne contiennent à priori pas d’informations pertinentes. De même, la méthode d’analyse de la texture s’avère satisfaisante dans deux types d’applications médicales différents, les images histologiques et celles de fond d’œil, et ses performances sont mises en évidence au travers d’une comparaison avec les méthodes similaires classiquement utilisées pour l’aide au diagnostic. Enfin, la méthode dans son ensemble a été appliquée à l’aide au diagnostic pour établir la sévérité d’un cancer via deux ensembles d’images histologiques, un de foies métastasés de souris dans le contexte du projet ANR SPIRIT, et l’autre de seins humains dans le cadre du challenge CPR 2014 : Nuclear Atypia. L’analyse des relations spatiales et des formes à deux échelles parvient à correctement reconnaitre les grades du cancer métastasé dans 87, 0 % des cas et fourni des indications quant au degré d’atypie nucléaire. Ce qui prouve de fait l’efficacité de la méthode et l’intérêt d’encoder l’organisation spatiale dans ce type d’images particulierDuring the last decade, digital pathology has been improved thanks to the advance of image analysis algorithms and calculus power. Particularly, it is more and more based on histology images. This modality of images presents the advantage of showing only the biological objects targeted by the pathologists using specific stains while preserving as unharmed as possible the tissue structure. Numerous computer-aided diagnosis methods using these images have been developed this past few years in order to assist the medical experts with quantitative measurements. The studies presented in this thesis aim at adressing the challenges related to histology image analysis, as well as at developing an assisted diagnosis model mainly based on spatial relations, an information that currently used methods rarely use. A multiscale texture analysis is first proposed and applied to detect the presence of diseased tissue. A descriptor named Force Histogram Decomposition (FHD) is then introduced in order to extract the shapes and spatial organisation of regions within an object. Finally, histology images are described by the FHD measured on their different types of tissue and also on the stained biological objects inside every types of tissue. Preliminary studies showed that the FHD are able to accurately recognise objects on uniform backgrounds, including when spatial relations are supposed to hold no relevant information. Besides, the texture analysis method proved to be satisfactory in two different medical applications, namely histology images and fundus photographies. The performance of these methods are highlighted by a comparison with the usual approaches in their respectives fields. Finally, the complete method has been applied to assess the severity of cancers on two sets of histology images. The first one is given as part of the ANR project SPIRIT and presents metastatic mice livers. The other one comes from the challenge ICPR 2014 : Nuclear Atypia and contains human breast tissues. The analysis of spatial relations and shapes at two different scales achieves a correct recognition of metastatic cancer grades of 87.0 % and gives insight about the nuclear atypia grade. This proves the efficiency of the method as well as the relevance of measuring the spatial organisation in this particular type of images
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Flouzat, Lachaniette Charles-Henri. "Régénération tissulaire en pathologie rachidienne et orthopédique." Thesis, Paris Est, 2015. http://www.theses.fr/2015PESC0032.
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La dégénérescence discale lombaire (DDL) est caractérisée par un vieillissement prématuré du disque intervertébral (DIV) et une déshydratation progressive du nucleus pulposus (NP) entrainant in fine des lombalgies. L'objectif général de ce travail est d'établir des données précliniques afin de régénérer le DIV en cas de DDL modérée. Dans un premier chapitre, nous avons déterminé une association de facteur de croissance et un mode de culture visant à obtenir une prédifférentiation nucléopulpogénique de cellules stromales mésenchymateuses (CSMs) humaines issues de la moelle osseuse. Nos résultats montrent que la culture tridimensionnelle des CSMs en billes d'alginate en présence de TGF-β3, GDF-5 et BMP-7 les oriente vers un phénotype cartilagineux. Dans un deuxième chapitre, nous avons élaboré un modèle porcin de DDL induite par cryolésion et nous l'avons comparé aux techniques de référence. L'évaluation de l'importance de la DDL a été effectuée par scanner, IRM et histologiquement. Un score histologique de DDL porcine a été décrit et validé. La cryolésion a permis d'obtenir une DDL plus importante que les autres techniques. Dans un troisième chapitre, nous avons injecté les CSMs préorientées dans les DIV lésés. L'analyse IRM a montré une amélioration de l'intensité du signal et de la surface du NP après injection des cellules. L'analyse immunohistologique a montré une survie des CSMs dans les DIV porcins à 2 mois. Dans un quatrième chapitre, nous avons comparé les taux de fusion et de complication pour la RhBMP-2 et la greffe spongieuse autologue dans les arthrodèses lombaires par voie antérieure dans une même cohorte de patients. La RhBMP-2 était associée à un taux de fusion inférieur et un taux de complications radiologiques supérieur à l'autogreffe spongieuseDegenerative disc disease (DDD) is characterized by premature aging of the intervertebral disc (IVD) and gradual dehydration of the nucleus pulposus (NP), ultimately causing back pain. The general objective of this work is to establish preclinical data to regenerate the IVD in moderate DDD. In the first chapter, we have identified a growth factor association and a culture method to achieve nucleopulpogenic prédifférentiation of mesenchymal stromal cells (MSCs) derived from human bone marrow. Our results show that the three-dimensional culture of MSCs in alginate beads in the presence of TGF-β3, GDF-5 and BMP-7 directs them to a cartilaginous phenotype. In the second chapter, we developed a porcine model of DDD, induced by cryoinjury, and compared it to reference techniques. Assessing the importance of DDD was performed by CT, MRI and histologically. A histological score of porcine DDD has been described and validated. Cryoinjury yielded a higher DDD that other techniques. In a third chapter, we injected preoriented MSCs in cryo-injured IVDs. MRI analysis showed an improvement in the signal intensity and the surface of the NP after the injection. The immunohistological analysis showed a survival of the MSCs in the porcine IVD 2 months after injection. In a fourth chapter, we compared the rate of fusion and complication for rhBMP-2 and autologous cancellous graft in the anterior lumbar interbody fusion, in the same cohort of patients. RhBMP-2 was associated with a lower fusion rate and a higher rate of radiological complications than the cancellous autograft
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Bonnel, Christophe. "Modélisation ostéo-articulaire du pied et apport de l'infographie." Montpellier 1, 1998. http://www.theses.fr/1998MON11152.
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