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1
Cheung, Nga-yin Annie, and 張雅賢. "Pathobiological study of gestational trophoblastic disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31981690.
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Alexopoulou, Zoi. "The study of the deubiquitinase USP8 in Parkinson's disease pathogenesis." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:47c2941b-5232-4bd0-92fa-e59aac16af7c.
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Parkinson's disease is the second commonest neurodegenerative disease currently treated symptomatically. It is a multifactorial disease involving mechanisms ranging from protein aggregation to mitochondrial dysfunction, oxidative stress and dopamine dysregulation. The levels of α-synuclein have been causatively linked to the development and progression of Parkinson's disease. Therefore α-synuclein lowering strategies are valid approaches in Parkinson's disease. Neuropathologically, Lewy Bodies in the vulnerable substantia nigra of Parkinson's disease patients are less ubiquitinated and specifically less K-63 ubiquitinated than Lewy bodies in the cortex, suggesting differential activation or regulation of ubiquitin interactors. A targeted screen for such interactors revealed that the Deubiquitinating enzyme Usp8 is upregulated in the substantia nigra of Parkinson's disease brains and is inversely correlated with the degree of total and K-63 ubiquitination. Using genetic knockdown and overexpression techniques, Usp8 was found to colocalize and directly interact with α-synuclein. It was found to de-ubiquitinate α-synuclein and increase its half-life. Its knockdown increased the total and K-63 α-synuclein ubiquitination and decreased its levels by 35% at least partly by increasing its degradation via the lysosome. In vivo in the Drosophila melanogaster, Usp8 knockdown demonstrated protection against α-synuclein toxicity. It rescued in a specific manner the rough eye phenotype, the age-dependent locomotive defect and the loss of dopaminergic neurons caused by the expression of α-synuclein. Specific and effective pharmacological Usp8 inhibition also has the potential to lower α-synuclein levels. Collectively, the evidence produced in my thesis suggests that Usp8 could be a potential target for the future disease-modifying therapies in Parkinson's disease.
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Hofner, Maureen Catherine. "A study of foot-and-mouth disease virus pathogenesis in cattle." Thesis, University of London, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338844.
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Goldman, Jonathan Howard. "A study of immune mechanisms in the pathogenesis of idiopathic dilated cardiomyopathy." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339209.
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Higgins, Damien. "Chlamydial Disease of the Koala: A Study of Pathogenesis and Host Response." Thesis, The University of Sydney, 2004. https://hdl.handle.net/2123/25063.
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Chlamydial infection occurs commonly in koalas (Phascolarctos cinereus) and, as in humans, can cause proliferative conjunctivitis and disease of the urinary and reproductive tracts. Past studies suggest that increased expression of chlamydial disease in koalas is associated with habitats disturbed by humans, but the mechanisms and specific factors influencing susceptibility of koalas to disease have not been studied in detail. This thesis aims to further the goal of describing pathogenic mechanisms and the host-pathogen-environment interaction for chlamydial disease in koalas by developing techniques to begin exploring in koalas some of the concepts that are central to our understanding of this condition in humans. These concepts include the role of T helper 1 (Thl)/ T helper 2 (Th2) lymphocyte balance and interferon gamma, and the association of reproductive tract fibrosis and infertility with serological responses to chlamydial heat shock proteins.
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Thunberg, Therese. "Study of pathogenesis and immune response in human Puumala virus infection." Doctoral thesis, Umeå universitet, Institutionen för klinisk mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-76706.
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Hantaviruses can cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Hantaviruses are spread to humans mainly through inhalation of infectious virions, secreted from infected rodents. The human diseases are characterized by an increased capillary leakage syndrome. Hantaviruses are known to infect endothelial cells, but they are non-cytopathogenic. The mechanism behind human disease is not well understood, but an overactive immune response is implicated in the pathogenesis. The aim of my thesis has been to investigate parts of innate and adaptive immune responses in Puumala virus-infected patients. In paper I we found a sex difference in the cytokine profile during acute infection. Females had significantly higher plasma levels of IL-9, FGF-2, GM-CSF and lower levels of IL-8 and IP-10 compared to males. These differences may affect the activation and function of the immune response. In paper II we studied the phenotype and kinetics of NK cells. We observed that CD56dim NK cells were elevated during acute infection and that these, predominantly NKG2C+ NK cells, remained elevated for at least two months after symptom debut. Our novel finding of a prolonged NK cell response, implicates that NK cells may possess adaptive immunity features. In paper III we observed a vigorous cytotoxic T cell (CTL) response during acute infection, which contracted in parallel with decrease in viral load. The CTL response was not balanced by an increase in regulatory T cells. The T cells expressed inhibitory immunoregulatory receptors, known to dampen intrinsic T cell activity. In paper IV, we found that a low IgG response in patients was significantly associated with more severe disease, while the viral load did not affect the outcome. Our findings support the use of passive immunization as a treatment alternative for hantavirus-infected patients. In conclusion, my thesis contributes to an increased knowledge about the immune response in hantavirus-infected patients. The findings, combined with future studies, will hopefully lead to a better understanding of the pathogenesis and possible treatment alternatives.
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Chen, Liqiong. "The development of a novel in vitro model of human liver for the study of disease pathogenesis." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11020/.
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The development of systems for the long term in vitro culture of functional liver tissue is a major research goal. The central limitation of experimental systems to date has been the early de-differentiation of primary hepatocytes in cultures. Several factors including cell-cell interaction, cell-matrix interaction, soluble factors and 3D structures have been identified as the keys to overcome this limitation. The first aim of this project is to compare the established 3D model, co-culture of hepatocytes and hepatic stellate cells (HSCs) on PDLLA coated surfaces, to other best available systems using collagen and Matrigel. The hypothesis is that hepatocytes functionalities, established by cell-cell interaction, 3D structures and soluble factors, can be further enhanced by introduction of cell-matrix interaction. In order to test the hypothesis, rat hepatocytes were cultured in five different systems, including monoculture of hepatocytes on collagen gel, in collagen-Matrigel sandwich, co-culture of hepatocytes and HSCs on collagen gel, in collagen-Matrigel sandwich and on PDLLA coated surface. Hepatocyte specific function assays, namely albumin secretion, urea secretion, testosterone metabolism by HPLC and CYP activities by LC-MS-MS, were used to analyze cell functionalities. Homo-spheroids were only formed in monoculture on collagen gel, but hetero-spheroids were developed in all the co-culture systems. The results of function assays showed hepatocytes in collagen-Matrigel sandwich configuration had the best secretion of albumin and urea and best CYP activities during the culture period. These data demonstrated the hypothesis that hepatocyte functions of the established model can be further improved by introduction of cell-matrix interaction. In addition to establishment of rat hepatocyte culture systems, hetero-spheroids of primary human hepatocytes and primary human HSCs on PDLLA coated plates were developed successfully, due to the great improvements of isolation and culture of primary human HSCs. However, hepatocyte function assays have not been applied yet. Hepatic cell lines have several advantages that are not applicable to primary cultured human hepatocytes, namely unlimited lifespan and stable phenotype. The immortalized Fa2N-4 cell lines have recently been assessed as replacements of primary human hepatocytes in CYP induction studies. The second aim of this study was to simultaneously characterize CYP1A2, CYP2C9, CYP3A4 and CYP2B6 induction in Fa2N-4 cells through assessment of mRNA, protein and activity endpoints for a range of prototypical compounds (previously assessed in human hepatocytes) with known positive and negative induction potential. LC-MS-MS and RT-PCR were used for assessment of activity and mRNA endpoints respectively. As a result, it is considered that Fa2N-4 cells offer a substitute for primary human hepatocytes for CYP1A2 and CYP3A4 induction but not for CYP2B6 due to lack of cytosolic CAR expression.
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Jacob, Ashok J. "A study of the prevalence, pathogenesis and natural history of heart muscle disease associated with HIV infection." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/20587.
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Heart muscle disease was found in 14.2% of HIV patients and took three principal forms - dilated cardiomyopathy, borderline left ventricular dysfunction and isolated right ventricular dilation. Dilated cardiomyopathy was associated significantly with a very low CD4 count indicative of late stage HIV disease. It was invariably irreversible. In contrast, some patients with borderline left ventricular dysfunction and isolated right ventricular dilation subsequently reverted to normal. The latter was usually related to pressure or volume overload of the right ventricle rather than to a primary myopathic process. Survival curves were calculated and these showed that HIV patients with dilated cardiomyopathy met a significantly earlier death from an AIDS related condition than those from all the other groups, even after accounting for their low CD4 count. This remained true when patients with dilated cardiomyopathy were matched individually with a group of patients identical in every respect except for the presence of cardiac disease. Heart muscle disease in HIV infection is common and takes a number of forms. Dilated cardiomyopathy occurs in late stage disease, is invariably irreversible and is associated with a particularly poor prognosis. This is in contrast to borderline left ventricular dysfunction and isolated right ventricular dilation which occur at an earlier stage of HIV infection, are potentially reversible and do not carry adverse prognostic implications. Neither infection with Toxoplasma gondii and cytomegalovirus nor treatment with zidovudine appear to have a primary role in the development of heart muscle disease. Although HIV is often found within the myocardium, it does not appear to replicate within this tissue. Low serum selenium concentrations are widespread in HIV patients but do not correlate with cardiac dysfunction.
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Brown, Graham Alfred. "A study of bovine herpesvirus 1 pathogenesis using laboratory models." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304239.
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Sun, Jun. "Study of neuronal networks and mechanisms implicated in locomotor reactivity and Parkinson's disease pathogenesis in the Drosophila model." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS434.
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La maladie de Parkinson (MP) est un trouble moteur neurodégénératif progressif, caractérisé par la perte des neurones dopaminergiques (DA) de la substance noire et la présence d'inclusions cytoplasmiques composées principalement de synucléine α (syn α), appelées corps de Lewy. Les objectifs de mon travail de thèse étaient de caractériser un modèle de la MP développé chez la drosophile afin de comprendre comment l'accumulation de syn α dans les neurones DA peut perturber progressivement la locomotion et de rechercher de nouvelles protéines neuroprotectrices. Nous avons d'abord identifié des réseaux cérébraux impliqués dans la modulation de la réactivité locomotrice chez la drosophile, qui incluent des sous-ensembles de neurones DA associés aux corps pédonculés. Nous avons ensuite obtenu des évidences que l'expression de la syn α dans les neurones DA perturbe la dynamique mitochondriale à la fois dans ces neurones eux-mêmes et, par un processus non-autonome cellulaire, dans les neurones-cibles cholinergiques des corps pédonculés. Enfin, nous montrons que la protéine Argonaute Piwi est induite par le stress oxydatif et a un effet neuroprotecteur dans un modèle de MP sporadique chez la drosophile. Dans l’ensemble, ces travaux mettent en lumière des mécanismes pathologiques et neuroprotecteurs qui pourraient constituer de nouvelles cibles pour le traitement thérapeutique de la MP<br>Parkinson's disease (PD) is a progressive neurodegenerative motor disorder, characterized by the loss of dopaminergic neurons from the substantia nigra and the presence of cytoplasmic inclusions composed mainly of α-synuclein (α-syn), called Lewy bodies. The objectives of my thesis work were to characterize a PD model developed in Drosophila in order to understand how the accumulation of α-syn in DA neurons can progressively disturb locomotion and to search for new neuroprotective proteins. We first identified brain networks involved in modulating locomotor reactivity in Drosophila, which include subsets of DA neurons associated with the mushroom bodies. We then obtained evidence that the expression of α-syn in DA neurons disrupts mitochondrial dynamics both in these neurons themselves and, through a non-cell-autonomous process, in their cholinergic target neurons of the mushroom bodies. Finally, we show that the Argonaute Piwi protein is induced by oxidative stress and has a neuroprotective effect in a sporadic PD model in Drosophila. Our evidence suggests that Piwi could delay neuronal aging and PD progression by reducing deleterious transcription of transposable elements. Overall, these studies highlight pathological and neuroprotective mechanisms that may constitute novel targets for the therapeutic treatment of PD
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Ferrari, Eleonora. "Characterization of mouse models to study the pathogenesis of celiac disease and the role played by the dysregulation of the intestinal microbiota." Doctoral thesis, Università del Piemonte Orientale, 2021. http://hdl.handle.net/11579/127592.
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Celiac disease (CD) is a permanent intolerance to dietary protein, gluten, from wheat rye and barley. It occurs in about 1% worldwide population, in genetically predisposed individuals bearing human leukocyte antigen DQ2/DQ8. Although gut epithelial cell stress and the innate immune activation are responsible for the breaking oral tolerance to gliadin, the gluten component, the exact mechanisms through which gliadin can stimulate CD onset are still unclear. Here I show how is important to identify in vivo preclinical models of CD to study its pathogenesis, at molecular level. The increasing prevalence of positive serological marker of CD in Cystic Fibrosis (CF) affected patients let to the hypothesis of a link between the two disorders. Results from my studies indicate that CFTR is potentially involved in the pathogenesis of CD, with gliadin peptides inhibiting CFTR activity and expression. Today, the only treatment for CD is a long-term gluten-free diet. Several evidences show that an altered composition of the intestinal microbiota could play a key role in the pathogenesis of CD, through the modulation of intestinal permeability and the regulation of the immune system. Indeed, although further studies are still required to unveil the molecular mechanisms, results reported in the present work clearly indicate that rebalancing the gut microbiota composition by probiotics administration might represent a new strategy to treat CD affected patients.
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Wheeler, Ennis Edmund. "A study of the role of 5-hydroxytryptamine (5-HT, seratonin) in the aetiology and pathogenesis of coeliac disease." Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278095.
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Cardoso, da Silva Danielle [Verfasser]. "Gene expression analysis approaches to study barrier dysfunction in celiac disease and pathogenesis of colitis-associated cancer / Danielle Cardoso da Silva." Berlin : Freie Universität Berlin, 2021. http://nbn-resolving.de/urn:nbn:de:kobv:188-refubium-31985-3.
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Patel, Milan K. "A Study of Host Factors that Affect Herpes Simplex Virus 1 Pathogenesis: The Role of Cold Sore Susceptibility Gene 1 (CSSG1) in HSV1 Replication." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/944.
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Numerous factors that affect herpes simplex virus 1 (HSV1)-mediated pathogenesis have been identified. Such factors directly impact the replication of HSV1 as well as modulate host immune responses following HSV1 infection. In this work, I characterize how HSV1 replication is impacted by expression of the protein encoded by C21orf91, or “Cold Sore Susceptibility Gene” (CSSG1), that has been linked to HSV1 reactivation in humans.
I investigated expression of CSSG1 mRNA expression in various tissues and found that CSSG1 mRNA was present in several tissues of importance in HSV1 disease, including brain, trigeminal ganglia (TG), cornea and spleen. Western blot analysis demonstrated that CSSG1 protein is expressed in human cells. Subcellular fractionation analysis reveals that CSSG1 is predominantly found in the cell nucleus, where it colocalizes with chromatin and with Tip60, a chromatin-binding histone modifying protein that has been shown to be essential for the replication of herpesviruses. I also discovered that CSSG1 is present in the cytosol of cells where it forms large cytosolic aggregates in presence of TRAF6, a downstream adapter that plays an important role in innate immune receptor signaling.
To determine if CSSG1 directly impacts viral replication, I generated CSSG1 knockdown human cell lines. I found that HSV1 replication was reduced in CSSG1 knockdown cells compared to control cells, whereas replication of the unrelated virus, vesicular stomatitis virus (VSV), was not affected by knockdown of CSSG1. I demonstrate that CSSG1 was necessary for efficient expression of HSV1 viral proteins during infection. Western blot analysis and measurement of expression of HSV1 proteins expressed at various stages of viral replication illustrates that CSSG1 was required for HSV1 replication at very early stage of infection. I also noted that CSSG1 expression impacted the DNA damage response in HSV1 infected cells. Levels of H2AX phosphorylation, a marker of the DNA damage response, were increased in HSV1-infected CSSG1 knockdown cells compared to control cells. DNA damage responses are thought to promote HSV1 reactivation from latency and HSV1 gene expression, indicating a potential mechanism for role of CSSG1 in HSV1 replication through modulating the DNA damage response.
Overall, my work demonstrates that CSSG1 affects HSV1 replication and provides insight on how CSSG1 polymorphisms in humans could affect HSV1 reactivation and replication to promote cold sores. These discoveries may also lead to a better understanding of pathogenesis of other herpesviruses in humans.
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Njelekela, Marina Magdalane Alois. "The Pathogenesis of Lifestyle Related Diseases in Developing Countries : Results From CARDIAC Study in Tanzania." Kyoto University, 2003. http://hdl.handle.net/2433/148928.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(人間・環境学)<br>甲第10291号<br>人博第178号<br>14||142(吉田南総合図書館)<br>新制||人||44(附属図書館)<br>UT51-2003-H712<br>京都大学大学院人間・環境学研究科人間・環境学専攻<br>(主査)教授 津田 謹輔, 教授 谷口 貞善, 教授 森谷 敏夫<br>学位規則第4条第1項該当
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Gonzalez, Jorge Del Pozo. "A study of the aetiology and control of rainbow trout gastroenteritis." Thesis, University of Stirling, 2009. http://hdl.handle.net/1893/1081.
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Disease has been identified as a major problem in the aquaculture industry for the welfare of the fish stocked as well as for its economic impact. The number of diseases affecting cultured fish has increased significantly during recent years with the emergence of several conditions that have added to the overall impact of disease on the industry. Frequently, a lack of scientific knowledge about these diseases is compounded by an absence of effective treatment and control strategies. This has been the case with rainbow trout gastroenteritis (RTGE), an emerging disease of rainbow trout (Oncorhynchus mykiss Walbaum). This study investigated several aspects related to its aetiology and control. A retrospective survey of UK rainbow trout farmers was undertaken to ascertain the extent and severity of RTGE in the UK as well as to identify RTGE risk factors at the site level. Participants in this study accounted for over 85% of UK rainbow trout production in 2004. It was found that the total number of RTGE-affected sites had risen from 2 in the year 2000 to 7 in 2005. The disease was only reported from sites producing more than 200 tonnes of trout/year for the table market. Analysis of risk factors associated with RTGE at the site level showed that this syndrome was associated with large tonnage and rapid production of rainbow trout for the table market. The data collected during this study enabled the identification of those sites that were most likely to present with RTGE the following year and this information was used to study the epidemiology of RTGE at the unit level. A prospective longitudinal study was undertaken in 12 RTGE-affected UK sites. It described in detail the impact, presentation, current control strategies and spread pattern of RTGE within affected UK sites. The risk factors associated with RTGE presence and severity were also investigated. Data were collected for each productive unit (i.e. cage, pond, raceway or tank) on the mortalities, fish origin, site management and environmental factors. RTGE was identified using a case definition based on gross pathological lesions. Analysis of these data revealed that RTGE behaved in an infectious manner. This conclusion was supported by the presence of a pattern typical of a propagating epidemic within affected units. Also, the risk of an unaffected unit becoming RTGE positive was increased if it had received fish from or was contiguous to a RTGE-affected unit. The presentation also suggested an incubation period of 20-25 days. Risk factor analysis identified management and environmental risk factors for RTGE, including high feed input and stressful events, which could be used to generate a list of control strategies. A study of the histopathological and ultrastructural presentation of RTGE was conducted. The location of segmented filamentous bacteria (SFB) and pathological changes found in affected fish were examined. Pyloric caeca were the digestive organ where SFB were found more frequently and in higher numbers, suggesting that this was the best location to detect SFB in RTGE-affected trout. Scanning and transmission electron microscopy revealed a previously undescribed interaction of SFB with the mucosa of distal intestine and pyloric caeca and this included the presence of attachment sites and SFB engulfment by enterocytes, as previously described in other host species. The SFB were not always adjacent to the pathological changes observed in the digestive tract of RTGE-affected trout. Such changes included cytoskeletal damage and osmotic imbalance of enterocytes, with frequent detachment. These observations suggested that if SFB are indeed the cause of RTGE their pathogenesis must involve the production of extracellular products. Analysis of the gross presentation and blood biochemistry in RTGE-affected fish was used to examine the patho-physiologic mechanisms of RTGE. To enable identification of positive RTGE cases for this study, a case definition was created from the information available on RTGE gross presentation in the literature. This case definition was assessed in a sample including 152 fish cases and 152 fish controls from 11 RTGE-affected UK sites, matched by unit of origin. The analysis of these fish using bacteriology, packed cell volume (PCV) and histopathology revealed that RTGE occurred simultaneously with other parasitic and bacterial diseases in a percentage of fish identified with this case definition. With the information gained after analysing the gross presentation, RTGE-affected fish without concurrent disease were selected for the study of the pathogenesis, which included blood biochemical analyses. These analyses revealed a severe osmotic imbalance, and a reduced albumin/globulin ratio suggesting selective loss of albumin, typical for a protein losing enteropathy. The role of the SFB “Candidatus arthromitus” in the aetiology of RTGE was assessed using a newly developed “C. arthromitus”-specific polymerase chain reaction assay (PCR) in conjunction with histological detection. This technique was applied to eight different groups of trout, including an RTGE-affected group and seven negative control groups. This analysis was conducted on DNA extracted from paraffin wax-embedded tissues as well as fresh intestinal contents. The results revealed the presence of “C. arthromitus” DNA in apparently healthy fish from sites where RTGE had never been reported. Additionally, SFB were observed histologically in two trout from an RTGE-free hatchery. These findings do not permit the exclusion of “C. arthromitus” as the aetiological agent for RTGE, although they suggest that the presence of these organisms in the digestive system of healthy trout is not sufficient to cause clinical disease, and therefore other factors are necessary. In conclusion, this study has used a multidisciplinary approach to the study of RTGE which has generated scientific information related to the epidemiology, pathogenesis and aetiology of this syndrome. The results of this project have suggested priority areas where further work is required, including experimental transmission of RTGE, field assessment of the control strategies proposed and further investigation into the aetiology of RTGE.
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Cysique, Lucette Adeline Juliette St Vincent's Hospital UNSW. "Aids dementia complex in the era of highly active antiretroviral therapy: a neuropsychological study." Awarded by:University of New South Wales. St. Vincent's Hospital, 2005. http://handle.unsw.edu.au/1959.4/22074.
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The aim of the thesis was to undertake an evaluation of the neuropsychological functioning of non-demented and demented patients with advanced HIV-infection who have been treated with Highly Active Antiretroviral Therapy (HAART) for several years. One hundred and one non-demented HIV-infected individuals and 23 patients with mild or moderate AIDS Dementia Complex (ADC), from the outpatient clinics and Neurology department at St. Vincent's Hospital, Sydney, Australia were randomly selected to participate in a prospective study of the neurological and neuropsychological complications of HIV disease. All had advanced HIV-infection and all had been on HAART for five years on average. Thirty-one seronegative controls were recruited as controls. All participants completed a standard neuropsychological examination assessing nine cognitive domains. Non-demented advanced HIV-infected individuals participated in three follow-up visits. In addition, we report the results of a multi-centre cohort of 78 patients with mild to moderate ADC on HAART (Abacavir ADC trial). The main findings of our research were that the prevalence of neuropsychological impairment in advanced HIV-infected individuals remains equivalent to the era that preceded the introduction of HAART. Moreover, while complex attention / psychomotor speed remained a marker of HIV-related neuropsychological impairment in the HAART era, impairment in learning, memory and aspects of complex attention may be new indicators of HIV-associated neurocognitive impairment. While progression of neuropsychological impairment is associated with past HIV-related history of brain involvement, we demonstrated that deterioration does not occur in a linear fashion and that over a 27 month period neuropsychological performance stabilizes in the majority. Stabilization of performance may be related to relapses in the course of HIV-associated neurocognitive impairment and HAART optimization especially with antiretrovirals that have good brain tissue penetrance. Our research showed that plasma viral load and current CD4 cell count were generally not associated with the neuropsychological performance, but rather that nadir CD4 cell count was associated with neuropsychological performance suggesting a relation between past immune deterioration and current cognitive status. Cerebrospinal markers of immune and virological activity were found to be partly dissociated from current neurological in contrast to what was observed in the pre-HAART era. Future studies will need to evaluate new factors for underlying HIV-associated neurocognitive impairment as well as factors for underlying partial recovery.
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Cheung, Kwok-ho Alvin, and 張國豪. "Genetic and pharmacological approaches to study the role of the polyolpathway enzymes in diabetic and ischemic retinopathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39558617.
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Fossati, S. "Acute cardiovascular effects of exposure to airborne particulate matter : a study of possible pathogenetic mechanisms." Doctoral thesis, Università degli Studi di Milano, 2009. http://hdl.handle.net/2434/64549.
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Introduction
Increased levels of particulate matter air pollution (PM) have been associated with increased cardiovascular morbidity and mortality, especially in elderly adults and in people suffering from cardiovascular or lung diseases. The mechanisms behind these effects are still unknown, although some hypothesis have been postulated that include a modification of autonomic regulation of heart rhythm and the induction of arrhythmic events. Which fraction of PM is the most harmful is still controversial, and few studies investigated the role of personal exposure to different fractions, and in particular ultrafine particles.
*Aim
The aim of this thesis is to assess: i) the association between the individual exposure to PM and the modification of HRV (an index of autonomic regulation of heart rhythm) and QTec (an index of a pro-arrhythmic status), both in healthy subjects and in subjects suffering from chronic ischemic heart disease or chronic lung disease; ii) the potential role of inflammation and baseline health status in these associations; iii) the role of different PM fractions in these associations.
*Materials and methods
27 healthy individuals (“Healthy” group), 34 individuals with chronic ischemic heart disease (Heart group), 18 with chronic asthma or COPD (Lung group) underwent a 24-hour exposure/clinical evaluation protocol during their habitual activities, both in the warm season (Summer) and in the cold season (Winter). Individual exposure to UFPs, fine and coarse particles number concentration, gravimetric PM2.5 and PM10 was assessed for each subject, along with a 24-hour ambulatory ECG, for the assessment of heart rate variability and QT period. Mixed effects models were used to evaluate the associations between exposure to particles and clinical parameters, during 24-hour, day- and night-time.
*Results
The mean±SD age of the study population was 64±10 years and 65% were male. 24-hour individual exposure levels to UFPs, PM2.5 and PM10 (median (25th-75th) or mean±SD) were 19.643 (14.520-30.328) #/cm3, 41,53±22,52 µg/m3 and 51,97±24,31 µg/m3 respectively. Higher individual exposure was observed during day-time, except for particles in the accumulation mode (FP0,3-1). A -5,69% (95% C.I. -10,76 to -0,62) and -8,61% (-17,57 to 0,35) decrease in night-time SDNN (night-SDNN) in the total sample and in the Heart group respectively, was observed for an interquartile range (IQR) increase in FP0,3-1 during the night period (night-FP0,3-1). The same, even stronger, association was observed between day-FP0,3-1 and night-SDNN, and was confirmed in all groups. In subjects with higher levels of hsCRP, an increase in all night-time vagal indices (PNN50>HF>rMSSD) was observed in the totality of subjects for an IQR increase in day-FP2.5-10, and confirmed in healthy subjects only. In all subjects with lower levels of hsCRP, a +12,21% (95% C.I. 2,67 to 22,64) and +7,09 (0,12 to 14,55) increase in night-HF for an IQR increase in night-FP0,3-1 and in night-FP2,5-10 respectively was found, coupled to a decrease in the LF/HF ratio. These findings were confirmed in healthy subjects only. These associations were even stronger between day-FP and night-HRV in the total sample, and confirmed in the “Healthy” and the Heart groups.
*Discussion and conclusion
The observed results suggest a major role of fine particles leading to acute and delayed alteration in autonomic control of heart rhythm in healthy subjects and subjects with chronic ischemic heart disease, probably not related to the inflammatory status. On the other hand, coarse particles possibly need higher concentrations to exert their effects on autonomic control of heart rhythm, and these effects could be linked to inflammatory mechanisms in healthy subjects. Ultrafine particles appear to be less involved in the observed associations suggesting for these particles mechanisms other than those investigated in this study.
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Lindell, Gert. "Smoking and peptic ulcer disease a clinical and experimental study with special reference to possible pathogenetic mechanisms induced by smoking /." Lund : Dept. of Surgery, Lund University, 1992. http://books.google.com/books?id=YT9sAAAAMAAJ.
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Bueno, Carmen Ruiz de Valbuena. "Fabry disease: pathogenesis and hispathology." Doctoral thesis, Faculdade de Medicina da Universidade do Porto, 2011. http://hdl.handle.net/10216/63774.
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Aula, Nina. "Molecular pathogenesis of Salla disease." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/aula/.
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Bueno, Carmen Ruiz de Valbuena. "Fabry disease: pathogenesis and hispathology." Tese, Faculdade de Medicina da Universidade do Porto, 2011. http://hdl.handle.net/10216/63774.
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Clark, Kim Michelle. "Mitochondrial DNA disease : pathogenesis and treatment." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262993.
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Turner, C. "The molecular pathogenesis of Huntington's disease." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/19056/.
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Huntington’s Disease (HD) is caused by an expansion in the CAG repeats of the huntingtin gene. This thesis describes an Ecdysone cell model which expressed inducible wild type (WT) and mutant (MT) N-terminal huntingtin (htt) in HEK 293 cells and constitutive EYFP full length (FL) htt in SH-SY5Y cells. WT and MT EYFP FL htt was diffusely localised to the cytoplasm whereas endogenous FL htt and N-terminal htt localised to the nucleus and cytoplasm suggesting that htt has a role both in the nucleus and cytoplasm and EYFP inhibited nuclear translocation. Nterminal htt partially colocalised with vesicular and mitochondrial markers suggesting that N-terminal htt may be involved in vesicle trafficking and mitochondrial function. The decrease in mitochondrial complex IV activity in MT FL htt cells supported previous reports that a complex IV defect is an early event in the pathogenesis of HD. Normal mitochondrial respiratory chain activities in cells expressing N-terminal htt contrasted with some cells models demonstrating a complex II/III defect when highly expanded CAG repeats were expressed. This suggested that a detectable complex II/III defect is not an early feature in the pathogenesis of HD. Muscle biopsies from HD patients revealed a relationship between clinical progression, CAGs and a decrease in complex II/III:CS ratio, consistent with the defect in HD brains and cell models and suggested that muscle may be a useful tissue to study the disease. Decreased aconitase activity with MT FL htt expression and increased sensitivity to paraquat with MT N-terminal htt expression demonstrated that MT htt was associated with increased oxidative stress or compromised antioxidant defences. There was evidence of proteasomal dysfunction in the MT FL htt clones and inhibition of the proteosome by lactacystin caused the formation of perinuclear "aggresome-like" inclusions in both WT and MT FL htt clones. These inclusions contained FL htt which suggested that the proteasome was necessary for processing of FL WT and MT htt. Under normal conditions there was no evidence of cleavage of WT or MT FL htt, however following treatment with lactacystin, an additional 11 kDa N-terminal htt fragment was present in most MT FL htt clones representing a novel mutation-specific cleavage product which may play an important role in the toxicity of MT htt. This thesis has demonstrated several defects in cellular function in the absence of gross cell death and htt inclusion formation. These findings expand on previous hypotheses in the pathogenesis of HD involving abnormal MT htt cleavage, oxidative stress, mitochondrial dysfunction and proteasomal inhibition.
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Näpänkangas, J. (Juha). "Pathogenesis of calcific aortic valve disease." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223520.
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Abstract Calcific aortic valve disease (CAVD) represents a disease spectrum, ranging from mild aortic valve sclerosis to severe obstructive aortic stenosis (AS), associated with a high risk of myocardial infarction and cardiovascular death. It is a common disease in the Western countries, and with their aging populations, its prevalence is likely to increase. Today, CAVD is recognized as an actively regulated disease. Mechanical stress and endothelial injury are the initiating factors, followed by lipid accumulation and oxidation, leading to inflammation, fibrosis and calcification. Ultimately, the progressive calcification hinders the normal valvular function and obstructs the flow of blood through the valve. The only effective treatment for symptomatic AS is aortic valve replacement. The trials with pharmacological treatments, mainly with anti-atherosclerotic drugs, have not been successful in slowing the progression of the disease. This study was aimed to identify differentially expressed transcripts, and molecular markers taking part in the pathophysiology behind CAVD. In particular, factors related to the renin-angiotensin system, and the apelin – APJ pathway, were investigated during the development of CAVD. In addition, the expressions of granzymes and perforin, as well as podoplanin, were studied in different stages of CAVD. It was demonstrated that these molecules are expressed in aortic valves and dysregulated in AS. These results can help to clarify the mechanisms driving CAVD, thus being potential targets for pharmacological therapy. Furthermore, the studied molecules may reflect the stage and possible subgroups of CAVD<br>Tiivistelmä Aorttaläpän ahtauma edustaa tautijatkumoa, joka alkaa lievästä aorttaläpän paksuuntumisesta eli aorttaskleroosista ja jatkuu vaikeaan aorttaläpän kalkkeutuneeseen ahtaumaan eli aorttastenoosiin, johon liittyy korkea sydäninfarktin ja sydän- ja verisuonitatutiperäisen kuoleman riski. Aorttaläpän ahtauma on yleinen tauti länsimaissa, ja väestön ikääntyessä sen esiintyvyys on luultavimmin lisääntymässä. Nykyään aorttaläpän ahtauman tiedetään olevan aktiivisesti säädelty tauti. Mekaaninen rasitus ja endoteelivaurio käynnistävät tautiprosessin, läppäkudokseen kertyy lipidejä ja ne hapettuvat, mikä johtaa tulehdukseen, sidekudoksen lisääntymiseen ja kalkkeutumiseen. Lopulta etenevä kalkkeutuminen heikentää läpän normaalia toimintaa ja estää veren normaalia virtausta sydämestä aorttaan. Ainoa tehokas hoito oireiseen aorttastenoosiin on aorttaläpän korvausleikkaus. Lääkehoitoina on kokeiltu erityisesti ateroskleroosin hoitoon käytettäviä lääkkeitä, mutta niillä ei ole onnistuttu estämään taudin etenemistä. Tässä väitöskirjatyössä tutkittiin molekyylejä ja biokemiallisia reittejä, jotka liittyvät reniini-angiotensiinijärjestelmään ja apeliini-APJ-reittiin. Lisäksi tutkittiin grantsyymien ja perforiinin sekä podoplaniinin ilmentymistä aorttaläpän ahtauman eri kehitysvaiheissa. Tulosten perusteella näitä tekijöitä ilmennetään aorttaläpässä ja niiden määrä on muuttunut kalkkeutuneessa läpässä. Tulokset auttavat osaltaan ymmärtämään aorttaläpän ahtaumaan ja kalkkeutumiseen johtavia mekanismeja, joita voidaan hyödyntää uusia lääkehoidon kohteita suunniteltaessa. Tutkitut molekulaariset tekijät voivat kuvastaa aortan ahtaumataudin vaiheita ja mahdollisia alaryhmiä
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Critchley, Alison. "Congenital disorders of glycosylation and disease pathogenesis." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424758.
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Johal, Shawinder Singh. "The pathogenesis of Clostridium difficile induced disease." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403400.
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Cramer, Paige E. "Nuclear Receptor Activation and Alzheimer's Disease Pathogenesis." Case Western Reserve University School of Graduate Studies / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1332962440.
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Suleman, Verjee Liaquat. "Myofibroblasts and the pathogenesis of Dupuytren's disease." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6119.
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Dupuytren’s disease is defined in Green’s Operative Hand Surgery as a condition of the hand characterised by the development of new tissue in the form of nodules and cords. Hand function can be significantly impaired and whilst the mainstay of treatment is surgery, recurrence has been reported in approximately 40-50% of patients. Myofibroblasts are central to the pathogenesis of Dupuytren’s disease although what regulates the myofibroblast phenotype during Dupuytren’s disease remains unclear. This thesis set out to test the hypothesis that the myofibroblast phenotype in Dupuytren’s disease is regulated by dermal fibroblasts and inflammatory mediators, specifically advanced glycation end products (AGEs) and TNF-α. I aimed to (1) systematically characterise the distribution of myofibroblasts (α-smooth muscle actin positive cells (α-SMA)) throughout excised Dupuytren’s tissue in relation to clinical disease activity (fixed flexion deformity and recurrence); (2) establish an in vitro contraction model to examine Dupuytren’s myofibroblasts and (3) use this model to examine how myofibroblast phenotype may be regulated by dermal fibroblasts and inflammatory mediators. I examined 103 Dupuytren’s cords and correlated the histological findings with the patient’s clinical flexion contracture and disease severity. Histological nodules, defined as a focal condensation of α-SMA positive cells, were seen in two-thirds of excised digital cord samples. These nodules were found in the vicinity of the proximal interphalangeal joints of the fingers. Nodules were more frequently observed in digits with less severe contractures and more active disease, whereas non-nodular cords were significantly associated with advanced digital contracture, reflecting end stage disease. Based on our current understanding of how myofibroblasts thrive on tension and contract against resistance, a mechanism for digital contraction has been proposed: nodules containing highly contractile myofibroblasts are present in active Dupuytren’s disease where digital flexion and extension of the interphalangeal joints is still possible and these nodules involute in end-stage disease, where severe contractures limit digital movement. In order to further study Dupuytren’s myofibroblasts, I also compared cell contraction in stress-released collagen gels with that in restrained gels using a culture force monitor (CFM). With the latter I was able to reliably measure cell-generated forces within restrained collagen gels. By using genetically matched sets of cells from patients, I also correlated cell contractility with α-SMA expression. Unlike control skin cells that initially contract and then plateau, Dupuytren’s myofibroblasts show continually increasing contractile force. Furthermore, increased contractility of Dupuytren’s myofibroblasts was reflected by higher α-SMA protein content and alignment of the α-SMA to stress fibres. Interestingly mRNA levels of α-SMA were similar in all matched cells, reflecting post-translational regulation of protein levels in myofibroblasts. Based on the observation that recurrence is significantly reduced following dermofasciectomy, I also tested whether dermal fibroblasts down-regulate the contractile Dupuytren’s myofibroblast. I co-cultured Dupuytren’s myofibroblasts and dermal fibroblasts and found that contractility of Dupuytren’s cells is not influenced by dermal cells. Therefore, reduced recurrence rate following dermofasciectomy may be due to other factors, such as more complete excision of affected tissue combined with reduced tension following application of full thickness skin grafts. Finally, recent studies have suggested that inflammatory mediators and AGE-RAGE interaction play a role in the development of the myofibroblast phenotype. I therefore used the CFM to examine the effect of AGEs and TNF-α on myofibroblast contractility. No difference in contractility of dermal fibroblasts was observed with AGEs, although a two-fold increase was seen with TNF-α. Overall, I have characterised the distribution of myofibroblasts in Dupuytren’s tissue and these data have led to interesting insights into disease pathogenesis. I have also established a reliable in vitro model for assessing Dupuytren’s myofibroblast phenotype and used this to demonstrate that whilst dermal fibroblasts do not downregulate myofibroblast activity, pro-inflammatory mediators may play a key role in modulating myofibroblast phenotype in this disease.
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Ventham, Nicholas Toby. "Epigenetic biomarker discovery in inflammatory bowel disease : unearthing clues for disease pathogenesis?" Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/23608.
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Epigenetic alterations including DNA methylation and microRNAs may provide important insights into gene-environment interaction in complex immune diseases such as inflammatory bowel disease (IBD). An integrative genome-wide approach was used to analyse whole blood genetic, DNA methylation and gene expression data in 240 newly diagnosed IBD patients and 190 controls. Using the Illumina 450k array, differences in whole blood DNA methylation were observed in IBD cases versus controls including 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs). The top DMP (RPS6KA2, discovery Holm adjusted p=1.22×10-16, replication p=1×10-9) and DMRs (VMP1, ITGB2, TXK) were replicated in an independent cohort using pyrosequencing. Paired genetic and epigenetic data allowed the identification of methylation quantitative trait loci (meQTL); two of the five DMRs (VMP1, ITGB2) demonstrated significant association with genetic polymorphisms. Methylation in the VMP1/microRNA-21 region was significantly associated with two single nucleotide polymorphisms (cg18942579 -rs10853015 [meQTL FDR adjusted p=9.4 × 10-5], cg16936953 - rs8078424 [meQTL FDR adjusted p=8.8 × 10-5]), both of which are in linkage disequilibrium with a known IBD susceptibility variant (rs1292053). Separated leukocyte methylation data highlight the cell type of origin of epigenetic signals seen in whole blood. IBD-associated hypermethylation within the TXK gene transcription start-site negatively correlated with gene expression in whole blood and CD8+ T-cells, but not other cell types, highlighting that cell-specificity and gene location-specificity of DNA methylation change is critical when associating methylation and gene expression. These data offer significant translational potential as diagnostic biomarkers. Least absolute shrinkage and selection operator (lasso) modelling identified 30 methylation probes can be used to accurately discriminate IBD cases from controls (Area under receiver operating characteristic curve = 0.898, sensitivity = 90.6%, specificity = 84.7%). MicroRNAs (miRNA) are small non-coding nucleic acids that have the capacity to modulate gene expression. MiRNAs have been increasingly implicated in many of the important IBD pathogenic pathways including autophagy, intestinal epithelial barrier integrity and the Th17 pathway. In common with all epigenetic mechanisms, miRNA expression is dynamic and cell-specific. Small RNA sequencing (RNA-seq) was performed on RNA extracted from CD14+, CD4+ and CD8+ cells isolated from 8 newly diagnosed cases of ileal or ileocolonic CD and 8 age and sex matched controls. There was a median of 2.4 million reads per sample (range 132,800-12.8 million reads per sample). One microRNA was differentially expressed in CD compared with controls (hsa-miR-503-5p log fold change = 0.7, FDR adjusted p = 9.1 × 10-5) in CD4+ lymphocytes, however this finding did not remain significant when alternative normalisation methods were used. The small number of cases used in microRNA analyses raises the possibility of both type I and II error, and limits the ability to draw firm conclusion from this series of experiments. Site-specific differences in DNA methylation in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression. This is the most detailed characterisation of the epigenome carried out in IBD to date. The findings strongly validate this approach in complex disease, are replicable, and provide clear translational opportunities.
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Zheng, Lin. "Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease." Doctoral thesis, Linköpings universitet, Geriatrik, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-73412.
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Alzheimer’s disease (AD), the major cause of senile dementia, is associated with progressive formation of neurofibrillary tangles and extraneuronal plaques composed of amyloid beta peptide (Aβ). Aβ has been also found within Alzheimer neurons in association with the lysosomal system, an acidic vacuolar compartment possessing numerous hydrolytic enzymes. Lysosomes have been shown to be involved in both the formation of Aβ and its toxicity to neurons. Another line of evidence implicates oxidative stress as an important factor in the development of AD. It is reported that oxidative damage is one of the earliest changes in AD and plays an important role in the development of the disease. Although both the lysosomal system and reactive oxygen species are involved in AD, the mechanisms of this involvement are not well understood. To gain insight into the relationship between oxidative stress and the lysosomal system in AD pathogenesis, we focused our study on: 1) The effect of oxidative stress on intracellular distribution of Aβ; 2) the role of endogenous Aβ in oxidant-induced apoptosis; 3) the role of autophagy and APP processing in oxidant induced damage; and, 4) the intraneuronal localization of Aβ and its relationship to the lysosomal system. In our study, hyperoxia (40% versus 8% ambient oxygen) was used as a model of mild oxidative stress in vitro, while transfected cells producing different amounts of Aβ were used to assess toxicity due to endogenous Aβ. It was found that: 1) oxidative stress induces autophagic uptake of Aβ, resulting in its partial accumulation within lysosomes; 2) oxidative stress can induce neuronal death through macroautophagy of Aβ and consequent lysosomal membrane permeabilization; 3) increased cellular Aβ production is associated with enhanced oxidative stress and enhanced macroautophagy, resulting in increased intralysosomal Aβ accumulation and consequent apoptosis; and, 4) in normal conditions, intracellular Aβ shows primarily cytosolic distribution, not related to lysosomes and other acidic vacuoles, endoplasmic reticulum, Golgi complexes, synaptic vesicles or mitochondria. Only a minor portion of Aβ shows partial colocalization with cellular organelles. Inhibition of secretion significantly increased Aβ colocalization with endoplasmic reticulum, Golgi complexes, synaptic vesicles and lysosomes, as well as the amount of mitochondrial and cytosolic Aβ. Oxidative stress induces intralysosomal autophagy-generated Aβ accumulation, consequently causing lysosomal membrane permeabilization and apoptosis. Our findings provide a possible explanation of the interactive role of oxidative stress and lysosomal system in AD pathogenesis, and may be helpful for a future therapeutic strategy against AD.
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Abu-Aliat, Abdullah Saeed Mohammed Sabrah. "Fungi and bacteria in pathogenesis of nail disease." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406193.
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Shadbolt, Tammy. "The pathogenesis of Tasmanian Devil facial tumour disease." Thesis, Royal Veterinary College (University of London), 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766334.
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Beavan, M. S. "Glucocerebrosidase mutations and the pathogenesis of Parkinson disease." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1470802/.
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To date, a mutation of the glucocerebrosidase gene (GBA) is the strongest genetic risk factor associated to Parkinson’s disease (PD). This leads to my prospective cohort study of a GBA mutation positive cohort for early features of PD. This study indicates that as a group, GBA mutation positive individuals show deterioration in clinical markers consistent with the prodrome of PD. I have generated cell culture models from individuals within the clinical cohort studied, in order to delineate the molecular mechanism of mutant GBA to the pathogenesis of PD. My results on skin fibroblast cultures reproduce the glucocerebrosidase enzyme (GCase) enhancement seen from previous studies following treatment with pharmacological chaperone (PC) molecules. These data further provide support for a link between GBA mutations and changes in the autophagic/lysosomal system, which could predispose to neurodegeneration. Due to the limitation of fibroblasts as a model for interrogating the complete pathway in PD, I studied human adipose neural crest stem cell (NCSC) derived dopaminergic (DA) neurons. This model recapitulated the defects identified in the fibroblast model including: reductions in GCase activity and protein level, and lysosomal abnormalities including impairments of autophagy. In addition, reduced GCase was associated with increased α-synuclein (SNCA). PC treatment restored GCase function, upregulated macroautophagy and lead to a reduction in SNCA levels. PC therapy could represent a novel therapeutic approach for PD.
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Boutin, Samuel R. 1952. "Molecular pathogenesis of Helicobacter hepaticus induced liver disease." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/35696.
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Thesis (Ph. D. in Molecular and Systems Bacterial Pathogenesis)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.<br>This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.<br>Includes bibliographical references.<br>Helicobacter hepaticus infection of A/JCr mice is a model of liver cancer resulting from chronic active inflammation. We monitored hepatic global gene expression profiles and correlated them to histological liver lesions in H. hepaticus infected and control male A/JCr mice at 3 months, 6 months, and 1 year of age. We used an Affymetrix-based oligonucleotide microarray platform on the premise that a specific genetic expression signature at isolated time points would be indicative of disease status. Model based expression index comparisons generated by dChip yielded consistent profiles of differential gene expression for H. hepaticus infected male mice with progressive liver disease versus uninfected control mice within each age group. Linear discriminant analysis and principal component analysis allowed segregation of mice based on combined age and lesion status, or age alone. Up-regulated genes present throughout the 12 month study involved inflammation, tissue repair, and host immune function. Upregulation of putative tumor and proliferation markers correlated with advancing hepatocellular dysplasia. Transcriptionally down-regulated genes in mice with liver lesions included those related to peroxisome proliferator, cholesterol, and steroid metabolism pathways. Transcriptional profiling of hepatic genes documented gene expression signatures in the livers of H. hepaticus infected male A/JCr mice with chronic progressive hepatitis and preneoplastic liver lesions, complemented the histopathological diagnosis, and suggested molecular targets for the monitoring and intervention of disease progression prior to the onset of hepatocellular neoplasia. Our laboratory, in collaboration with Professors Suerbaum and Schauer, recently identified a<br>(cont.) 70kb genomic island in Helicobacter hepaticus strain ATCC 51488 as a putative pathogenicity island (HhPAI) (Suerbaum et al, PNAS, 2003). This region within H. hepaticus contains genes HH0233-HH0302, a differential GC content, several long tandem repeats but no flanking repeats, and three components of a type IV secretion system (T4SS). A/JCr mice were experimentally infected with three naturally occurring strains of H. hepaticus including the type strain H. hepaticus ATCC 51488 strain (Hh 3B1) isolated from A/JCr mice, MIT 96-1809 (Hh NET) isolated from mice shipped from the Netherlands, and MIT-96-284 (HhG) isolated from mice acquired from Germany.4 HhNET (missing most of the HhPAI) infected male A/JCR mice exhibited a significantly lower prevalence (p<.05) of hepatic lesions at 6 months post infection than Hh 3B1 with an intact HhPAI. Hh G also has a large segment of the genomic island deleted, but not as many genes are deleted as compared to Hh NET. Hh G also demonstrated a lower prevalence of hepatic lesions. This variable pathological effect was evident in male mice only. The severity of chronic active inflammation in the liver of the H. hepaticus infected A/JCr mice depended on H. hepaticus liver colonization levels. The in vivo results support the presence of the HhPAI as a legitimate virulence determinant and predictor of severity of liver lesions in H. hepaticus infected A/JCr male mice. To further determine the differences in virulence of the H. hepaticus strains Hh 3B1, Hh NET, Hh G and an isogenic mutant H. ...<br>by Samuel R. Boutin.<br>Ph.D.in Molecular and Systems Bacterial Pathogenesis
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Hart, P. E. "Human mitochondrial disease : from pathogenesis to therapeutic intervention." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444782/.
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The spectrum of diseases caused by mitochondrial dysfunction is very broad and encompasses the archetypal mtDNA mutation diseases, mutations of nuclear genesencoding mitochondrial proteins (including those of the oxidative phosphorylation system), and a variety predominantly neurodegenerative diseases in which the primary cause of mitochondrial dysfunction remains undefined. The last two decades have seen an explosion in our understanding of the archetypal i mitochondrial disorders. Attention has now focused on the nuclear encoded mitochondrial disorders. Furthermore, nuclear factors may be of significance in the pathogenesis of the archetypal disorders associated with mitochondrial DNA mutations. These conditions are typified by their clinical diversity and poor phenotype-genotype correlation. One of several potential explanations for this is that nuclear genes determine the fate of mtDNA mutations, or that secondary mtDNA mutations have a modulating effect upon the expression of the primary mutation. In this thesis I have sought to address several aspects of the biochemical and clinical features of mitochondrial diseases. In chapter 3 cell cybrids have been used to study the role of the nuclear genome on the biochemical expression of mtDNA mutations in an attempt to understand potential influences on phenotypic expression. An extension of this was the use of xenomitochondrial cybrids to analyse nuclear-mitochondrial interactions and the function of the respiratory chain. At the biochemical/clinical interface, skeletal muscle from patients with focal dystonia has been used as a model to investigate the role that mitochondrial dysfunction might play in this movement disorder. Finally, the clinical role of therapy for mitochondrial disorders has been investigated in the context of Friedreich's ataxia (FRDA). Existing rating scales have been assessed and new ones developed to lay a firm foundation for evaluating disease-modifying therapies. These have been piloted in a long term intervention trial for FRDA.
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Mutsaers, Chantal. "Mechanisms of disease pathogenesis in Spinal Muscular Atrophy." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9774.
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Low levels of survival motor neuron (SMN) protein cause the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA), through mechanisms that are poorly defined. SMN protein is ubiquitously expressed, however the major pathological hallmarks of SMA are focused on the neuromuscular system, including a loss of lower motor neurons in the ventral horn of the spinal cord and atrophy of skeletal muscle. At present there is no cure for SMA. Most research to date has focused on examining how low levels of SMN lead to pathological changes in motor neurons, therefore the contribution of other tissues, for example muscle, remains unclear. In this thesis I have used proteomic techniques to identify intrinsic molecular changes in muscle of SMA mice that contribute to neuromuscular pathology in SMA. I demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomics data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. In addition robust up-regulation of VDAC2 and down-regulation of parvalbumin was confirmed in two mouse models of SMA as well as in patient muscle biopsies. Thus intrinsic pathology of skeletal muscle is an important event in SMA. I then used proteomics to identify individual proteins in skeletal muscle of SMA that report directly on disease status. Two proteins, GRP75 and calreticulin, showed increased expression levels over time in different muscles as well as in skin samples, a more accessible tissue for biopsies in patients. Preliminary results suggest that GRP75 and calreticulin can be detected and measured in SMA patient muscle biopsies. These results show that proteomics provides a powerful platform for biomarker identification in SMA, revealing GRP75 and calreticulin as peripherally accessible potential protein biomarkers capable of reporting on disease progression in muscle as well as in skin samples. Finally I identified a role for ubiquitin-dependent pathways in regulating neuromuscular pathology in SMA. Levels of ubiquitin-like modifier activating enzyme 1 (UBA1) were reduced in spinal cord and skeletal muscle tissue of SMA mice. Dysregulation of UBA1 and subsequently the ubiquitination pathways led to the accumulation of β-catenin. I show here that pharmacological inhibition of β-catenin robustly ameliorates neuromuscular pathology in animal models of SMA. Interestingly, downstream disruption of β-catenin was restricted to the neuromuscular system in SMA mice. Pharmacological inhibition of β-catenin failed to prevent systemic pathology in organs. Thus disruption of ubiquitin homeostasis, with downstream consequences for β-catenin signalling, contributes to the pathogenesis of SMA, thereby highlighting novel therapeutic targets for this disease.
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Colaço, Alexandria Nicole. "Niemann-Pick Type C disease : pathogenesis and therapy." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:d75bf036-acc9-4c6f-89ad-7708d2996937.
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Niemann-Pick disease Type C is a rare, lysosomal storage disorder caused by defects in either NPC1 (95% of cases) or NPC2, and characterized by progressive neurodegeneration that ultimately results in premature death. The function of the NPC1 protein still remains poorly understood and how the NPC1 or NPC2 proteins interact, or the functions of the pathways they regulate still remains unknown. We have found unexpected links between NPC and other human diseases - particularly Tangier disease, suggesting that the NPC cellular pathway is more broadly involved in human disease than previously suggested. To gain further insight into the function of NPC1 and proteins it interacts with we used the yeast orthologue, Ncr1p. I recreated the ?ncr1 mutant and characterized the mutant using an array of systematic screens to identify different processes and pathways that may play a role in NPC pathogenesis. The screen implicated mitochondrial dysfunction, defects in metal ion homeostasis and lipid trafficking, cytoskeleton dysfunction and nutrient sensing deficiencies. These screens were validated in the Npc1-/- mouse model, where the effects of modulating kinases also emerged as a potential therapeutic option. In addition to kinases, we examined the therapeutic potential of the FDA-approved hypertension drug, losartan. Losartan ameliorated the acidic store Ca2+ defect, which characterizes NPC, and all downstream pathologies as well as in combination with miglustat reduced levels of neuroinflammation in the mouse model. Furthermore, the cyclodextrin analogue Crysmeb was also examined as a novel therapy for NPC, and was found to have significant survival benefits as compared to HPβCD, the cyclodextrin compound currently in clinical trials. Taken together, in this thesis I have identified novel aspects of NPC pathogenesis, as well as mechanistic links between NPC and Tangier disease - which has led to miglustat treatment options for two patients at Addenbrooke's Hostpital, Cambridge. Additionally, taking advantage of the convergent disease mechanisms I have examined treatments (losartan/Crysmeb) that take advantage of the similarities and differences between these two disorders paving the way for potential clinical studies in the future.
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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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Xia, Qiong. "Inflammatory Mediators in the Pathogenesis of Vascular Disease." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16742.
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This thesis explores the role of inflammation in vascular disease in human subjects. Three disparate models of vascular disease have been explored: atherosclerotic vascular disease, which examined the common carotid artery, was compared to two forms of hereditary thoracic aortic aneurysm, one of purely hereditary origin, Marfan syndrome (MFS), and the other of a combined hereditary and haemodynamic stress aetiology, bicuspid aortic valve (BAV)-associated thoracic aortic aneurysm. Inflammation was found to be an important contributor to the pathogenesis in all cases. To examine inflammation in these three diseases, we chose to determine the expression levels of a range of inflammatory markers. In the case of atherosclerosis, where there is an extensive literature on the involvement of inflammation, we chose to analyse four novel cytokines that have been recently examined in the context of a range of inflammatory diseases, but which had not been analysed in atherosclerosis. On the other hand, due to the almost complete paucity of literature on the role of inflammation in heritable thoracic aortic aneurysm, we chose to examine both basic and novel inflammatory cytokines, in addition to markers of specific inflammatory cell types. The study that examined atherosclerotic plaque revealed for the first time that the novel, pro-inflammatory cytokines, IL-31, IL-32 and IL-34, are substantially upregulated in clinically symptomatic plaques when compared to asymptomatic plaques, suggesting that these inflammatory mediators contribute to the severity of the disease. Moreover, we found that these mediators also correlated with both clinical symptoms and a clinical intervention, namely the used of lipid-lowering statins. On the other hand, the anti- inflammatory cytokine IL-33 was significantly upregulated in asymptomatic patients with stable atherosclerotic plaque, suggesting an active role of IL-33 in maintaining a stable plaque phenotype. Overall, these data imply that such mediators might be used as prediction markers to monitoring the severity of plaque formation and may also be potential therapeutic targets for preventing plaque progression. In the studies that examined the contribution of inflammation to the formation of thoracic aneurysms in the two hereditary forms of thoracic aortopathy, we examined a set of basic inflammatory markers (IL-10, IL-17, MPO and CD3) and several novel inflammatory markers (IL-36, and γ, IL-37 and IL-38). We found that inflammation is present within the aortic wall in both of these diseases, and that the level of inflammation in BAV-associated thoracic aortopathy is higher than in MFS. These data are consistent with the aetiology of these two diseases, namely, that MFS is a “purely” inherited disease, while BAV-associated aneurysm also has a substantial contribution from haemodynamic stress.
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Culver, Emma L. "Natural history and pathogenesis of IgG4-related disease." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:31650f77-91ca-4fb9-8dbe-88bad1948145.
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IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition characterised by elevated serum IgG4 and an abundance of IgG4 plasma cells in involved organs. The natural history of disease and pathogenic mechanisms are poorly understood, and are explored in this thesis. The diagnosis of IgG4-RD is a challenge. Evidence to support a serum IgG4 level of 2.8g/l in differentiating IgG4-RD from non-IgG4-RD conditions, a serum IgG1:IgG4 ratio of 0.24 in differentiating IgG4-sclerosing cholangitis from primary sclerosing cholangitis with elevated serum IgG4, and the role of serum IgE in those with a history of allergy and atopy is provided. Furthermore, observational data highlighting new environmental risk factors and disease associations are revealed. Despite being considered a benign corticosteroid-responsive condition, evidence for disease relapse, organ dysfunction and failure, malignancy and mortality in a prospective cohort is shown. Patterns of disease presentation and levels of serum IgG4 and IgE at diagnosis are used to identify those who relapse and develop multi-organ disease. A single antigen initiating disease has yet to be found. Polyclonal IgG4 responses to multiple environmental antigens in IgG4-RD are reported, and evidence against Helicobacter pylori plasminogen binding peptide as a microbial antigen is shown. Novel HLA class II associations, linked to disease susceptibility in a UK cohort provide support for immune-mediated pathogenesis. Gene expression analysis implicates cytokines in driving IgG4 switch and proliferation, chemokines in trafficking and homing of lymphocytes to end organs, complement proteins in the classical and lectin pathways, and members of the TGF-beta pathway as putative immune drivers of disease. Differences in the phenotype of IgG1 and IgG4 B cells in health and IgG4-RD are reported, including responses to complement activation and immune complexes. Finally, elevated IgE levels, the presence of IgE-positive mast cells in involved tissues, and up-regulation of the Fc-Epsilon receptor on the surface of IgG4 cells, support the role of an IgE-mediated response.
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Sun, Xiulian. "Molecular mechanism of Alzheimer's disease pathogenesis in Down syndrome." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31167.
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Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia. Neuritic plaques and neurofibrillary tangles are the two hallmarks of AD neuropathology. The molecular mechanism underlying AD pathogenesis remains unknown. It is believed that deposition of amyloid β (Aβ) protein in the brain plays a pivotal role in AD pathogenesis. Aβ, the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) by sequential cleavages by β- and γ-secretase. Nearly all individuals with Down Syndrome (DS) show characteristic AD pathological changes after their 30s. The molecular mechanism by which AD pathogenesis develops in DS patients is poorly defined. BACE1 is the major β-secretase in vivo. BACE2 is the homolog of BACE1 and located on chromosome 21. In this study, we cloned and functionally characterized BACE2 gene promoter. Our studies show that the BACE2 gene promoter has a higher activity in non-neuronal cells while BACE1 promoter has a higher activity in neuronal cells. Although both can be activated by SP1, the transcription of BACE1 and BACE2 are distinctly regulated. Even though they are homologous in amino acid sequence, BACE1 and BACE2 cleave APP at distinct sites, leading to their opposing functions in AP production. N-terminal sequencing of BACE2 cleavage product shows that the cleavage site of BACE2 in APP is located between the 19th and 20th amino acid of Aβ. Thus, BACE2 is identified as a novel θ-secretase. Overexpression of BACE2 drastically decreases AP production in cells, whereas overexpression of BACE1 greatly increases Aβ production. We and others have shown that Aβ is elevated in brains of DS patients. Our study further shows that β-secretase activity is abnormally increased. Further study reveals that BACE1 protein levels are markedly increased in DS fetal brain tissues. Time-lapse live imaging, cell fractionation, and pulse-chase experiments show that BACE1 accumulates abnormally in the Golgi of DS cells. These data demonstrate that abnormal BACE1 accumulation leads to elevated β-secretase activity and subsequent Aβ deposition in DS patients. Our results provide a novel molecular mechanism by which AD develops in DS and suggest that inhibiting BACE1 or potentiating BACE2 would benefit AD patients.<br>Medicine, Faculty of<br>Graduate
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Iancu, Simona Ioana. "Epithelial mechanisms in the microbial pathogenesis of periodontal disease." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/epithelial-mechanisms-in-the-microbial-pathogenesis-of-periodontal-disease(90dedf1b-d1dd-455b-92ff-47c8af10b995).html.
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Periodontitis, a major cause of tooth loss, is a bacterially induced inflammatory disease that has been associated with certain bacterial species. The aim of this thesis was to identify the epithelial mechanisms activated by commensal and periodontal pathogens to determine which signalling pathways, transcription factors, and pro-inflammatory cytokine responses are associated with periodontitis. The H400 gingival epithelial cell line was infected with the health-associated Actinomyces naeslundii and periodontopathogens Fusobacterium nucleatum and Porphyromonas gingivalis. Differential pathway activation was observed between the three species. A. naeslundii induced phosphorylation of JNK and NF-κB, similarly to F. nucleatum which activated all MAPK pathways (including p38 and ERK1/2) and NF-κB. P. gingivalis induced minimal levels of p-JNK. Differential transcription factor activation was observed in response to the three bacteria. A. naeslundii and F. nucleatum induced activation of c-Fos and c-Jun, while P. gingivalis transiently activated binding of ATF-2. Notably, F. nucleatum was the most potent activator. Both A. naeslundii and F. nucleatum induced a pro-inflammatory response, together stimulating release of IL-1α, IL-1β, IL-6, GM-CSF and G-CSF. P. gingivalis was the least stimulatory bacterium, an observation supported by a lack of cytokine production, IL-8 down-regulation and a reduction in lactate dehydrogenase release (measure of damage). To determine the functional role of these signalling pathways in inducing effector responses, the MAPK and NF-κB pathways were inhibited. Results indicate that the p38 MAPK pathway is the main regulator of inflammatory responses in A. naeslundii and F. nucleatum infections while in P. gingivalis infections, the JNK pathway appears to be the major regulator of oral epithelial responses. Furthermore, the possible involvement of P. gingivalis virulence factors in the bacterium’s ability to prevent epithelial cell activation was investigated. It was observed that the Lys-gingipain (Kgp) of P. gingivalis plays a role in supressing activation of the MAPK and NF-κB pathways and the c-Fos transcription factors in oral epithelial cells. Overall, the data in this thesis suggests that epithelial cells recognise and respond differently to commensal bacteria compared to periodontal pathogens and that P. gingivalis Kgp may be a key virulence factor involved in immune subversion.
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Angel, Carole Ann. "The aetiology, pathogenesis and cellular origin of Hodgkin's disease." Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/29546.
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Hodgkin's disease (HD) is a lymphoproliferative disorder characterised by the presence of the Reed-Sternberg cell and its variants (HRS cells) in a polymorphic cellular background. Cure can now be achieved in more than 85% but the aetiology, pathogenesis and cellular origin have remained unclear despite extensive research. This thesis describes the results of histological, immunhistological and molecular biological studies of Hodgkin's disease. Previous immunohistological studies had suggested that one of the subtypes, nodular lymphocyte predominant HD, was a separate disease entity and was of B-cell origin. The results of this study instead suggest that all subtypes of the disease are derived from B-cells and that the different histological subtypes of the disease reflect differing host responses to the single pathogenetic process. Monoclonal B-cell proliferation was not identified by the molecular studies performed. It is likely that this reflects the relative insensitivity of the techniques used, since subsequent studies now indicate that most cases of NLPHD and a proportion of cases of classical HD are B-lymphoproliferative disorders. Finally, an aetiological role for EBV in a proportion of cases is suggested. When the results of these studies are analysed in the light of subsequent similar studies, a coherent hypothesis for the aetiology, pathogenesis and cellular origin of HD can be proposed. It is suggested that HD is a B-lymphoproliferative disorder arising when genetically predisposed individuals encounter particular environmental stimuli, one of which is EBV. This predisposition is currently poorly characterised but relates to defects in cellular immunity. Future studies should aim to characterise the underlying immune deficit, elucidate factors influencing progression, investigate aetiological agents in EBV-negative disease and assess the relevance of such findings to the prevention and management of Hodgkin's disease.
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Khan, Usman. "Studies on the pathogenesis of cerebral small vessel disease." Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539378.
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Chinnery, Patrick Francis. "The pathogenesis, investigation and management of mitochondrial DNA disease." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324935.
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Flanagan, Paul Kevin. "Bacteria-macrophage interactions in the pathogenesis of Crohn's disease." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3008673/.
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Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly E. coli that replicate inside macrophage phagolysosomes. In this thesis several hypotheses were tested: (i) that CD macrophages might be defective at killing and or responding to Gram-negative bacteria, particularly E. coli; (ii) that killing of phagocytosed bacteria within macrophages might be enhanced by drugs such as hydroxychloroquine (HCQ) (previously shown to raise intravacuolar pH), and vitamin D (previously shown to enhance macrophage function). I assessed CD peripheral blood monocyte-derived macrophages (MDM) for their abilities to kill E. coli, with and without HCQ and vitamin D, and to generate neutrophil chemoattractants. MDM from patients with CD were similar to those from healthy controls (HC) in allowing replication of phagocytosed CD-derived E. coli: HM605 [CD N=10, mean fold replication in 3h: 1.08, (95% confidence interval (CI) 0.39-1.78); HC N=9, 1.50, (95%CI 1.02-1.97); P=0.15] and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD 2.55, 95%CI 2.31-2.80; HC 2.65, 95%CI 2.46-2.85, P=0.42). The only possible exception was reduced bacterial killing in macrophages from the relatively rare patients homozygous for ATG16L1 polymorphisms, reported previously and confirmed in the single example in this series. HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intra-macrophage E .coli replication 3h post-infection, HCQ: 73.9% inhibition (P < 0.001) at 1μg/mL, accompanied by raised intra-phagosomal pH, and 1,25OH2-Vitamin D3: 80.7% inhibition (P < 0.05) at 80nM. HCQ had synergistic effects with doxycycline and ciprofloxacin on killing of phagocytosed E. coli. Thus: CD and HC macrophages generally perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics.
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Wasylenko, Theresa Anne. "Understanding Huntington's Disease pathogenesis using next generation sequencing analyses." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/103260.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February 2016.<br>Cataloged from PDF version of thesis. "February 2015."<br>Includes bibliographical references (pages 215-240).<br>Huntington's disease is one of nine expanded (CAG) repeat disorders. The expansion in Huntington's disease lies in the first exon of the huntingtin (HTT) gene and is pathogenic when (CAG)>/= 40 . Individuals with Huntington's disease develop motor, cognitive, and psychiatric symptoms in adulthood. These symptoms progress for approximately 15 years at which time they become fatal. The clinical manifestation of HD largely results from the extreme degeneration of neurons in the striatum and cortex. The HTT gene encodes the huntingtin (HTT) protein. Over the years, researchers have developed a rich understanding of the consequences of loss of wildtype HTT function, gain of toxic mutant HTT function, and mutant HTT RNA toxicity. However, the mechanisms through which pathology develops are still largely ambiguous. Given the widespread involvement of HTT in cellular processes, next generation DNA sequencing technologies offer a rich opportunity to explore genome-wide effects of the HD mutation and may help answer mechanistic questions. The application of many next generation DNA sequencing methods is a new luxury for researchers. DNA sequencing methods have undergone a rapid technical evolution which has accelerated the financial feasibility of applying DNA sequencing involved methods on a routine basis. In this thesis, two high throughput analysis techniques, RNA-Seq and ChIP-Seq, were applied to Huntington's disease models to better understand disease mechanisms, and a third high throughput analysis technique, Ribo-Seq, was optimized for future HD studies. RNA-Seq on Huntington's disease model mice and their wildtype littermates demonstrated extensive and progressive dysregulation of the transcriptome in HD striatum and cortex, with most of the affected genes having a lower steady state expression in mutant tissues. ChIP-Seq with an antibody against trimethylated- Histone3-Lysine4 (H3K4Me3) demonstrated both a general reduction of H3K4me3 levels and a unique histone profile at the promoters of HD downregulated genes. Analysis of RNA-Seq results for splicing changes showed that mutant HTT itself is mis-spliced. This mis-splicing product is translated into a small, pathogenic HTT fragment which may have considerable implications for HD therapeutic design. In addition to CNS degeneration, severe muscle dysfunction is an early clinical observation in HD and many CAG repeat expansion disorders. Proper muscle form and function is dependent on an extensive alternative splicing program. Thus RNASeq data on muscle tissue from mouse models of several CAG expansion disorders was examined for genome-wide splicing alterations. Widespread mis-splicing was detected in the muscle of both Spinocerebellar ataxia 7 and Huntington's disease mouse models and minor splicing dysregulation was detected in Spinal-bulbar muscular atrophy. Lastly, methods were developed to examine translational control and mRNA localization in the brain of Huntington's disease mice. Concurrent Ribo-Seq and RNA-Seq in diseased and wildtype animals would answer if there was altered translational control. The Ribo-Seq protocol designed in cell culture was optimized for use on brain tissue and is ready for application in HD mouse models. Analysis of the localization of mRNA transcripts to neuronal projections can be studied by combining fractionation experiments with RNA-Seq. A method to prepare high quality RNA from isolated neuronal projections was developed and is now applicable to RNA-Seq studies.<br>by Theresa Anne Wasylenko.<br>Ph. D.
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Sweet, D. G. "Studies on the pathogenesis of neonatal chronic lung disease." Thesis, Queen's University Belfast, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395367.
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