Dissertations / Theses on the topic 'Pathogenesis'
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Booler, Helen. "Pathogenetic mechanisms in the dystroglycanopathies pathogenesis." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669190.
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Khamas, E. J. "Pathogenesis of staphylococcosis." Thesis, University of Nottingham, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.234678.
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deLeeuw, Ronald John. "Mantle cell lymphoma pathogenesis." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/12469.
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Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with a median patient survival time of 3 years. Although the characteristic t(11;14)(q13;q32) is found in virtually all cases, experimental evidence suggests that this event alone is insufficient to result in lymphoma and secondary genomic alterations are required. Therefore, secondary genetic alterations have been proposed as essential in MCL pathogenesis. Within this thesis I describe the creation of a novel assay to determine segmental copy number alterations at a previously unprecedented resolution. This new assay necessitated the development of new analytical software to visualize and analyze the high density data sets created. The creation of this software is described in detail. With these tools in place we assayed model genomes of MCL for recurrent segmental copy number alterations. These recurrent regions were defined; however, among these were copy number variations that appeared in both cases and controls. Investigation of these natural copy number variations in this thesis revealed that the human genome has a higher plasticity than previously appreciated. In fact, thousands of loci within the genome were found to be variable in copy number that may influence sensory perception and possibly disease susceptibility. I next investigated the genomes of MCL tumor samples to determine which somatic copy number alterations are related to a poor clinical course. Among the numerous loci that showed frequent copy number alterations in MCL genomes, many were associated with poor patient outcome. Among these, the loss of 9p21 was a strong factor in determining the clinical course of patients with MCL (P=0.0004). Three additional loci (4q13, 8q24, and 13q14) were combined with 9p21 to create a survival model that was very predictive of patient outcome (P=5.87 x 10-6). Interestingly, a previously uncharacterized locus (4q13) was within this survival model. Investigating this locus further revealed that the expression of two genes (CCNG2 and CCNI) influences the overall survival of patients with MCL (P=0.0292 and 0.0201, respectively).
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Sissons, James Robert. "Pathogenesis of Alanthamoeba encephalitis." Thesis, Birkbeck (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429097.
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Cowie, Danielle. "Iron and Tuberculosis pathogenesis." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86566.
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Thesis (MSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Iron is an essential element that plays a role in the process of respiration, oxygen transport and as a principle cofactor to several enzymes. Iron homeostasis is a finely regulated process since excess levels become toxic to healthy cells via the production of reactive oxygen species. A plethora of genes that control several key points throughout this regulatory process have been identified. Research focusing on changes in expression levels and downstream functional effects of these genes has become increasingly important over the past decade. One area of particular interest has emerged since a link between iron status and host response to Mycobacterium tuberculosis infection was discovered. Although the prevalence of Tuberculosis has decreased across the globe with the exception of Africa and parts of Europe, the mortality rate remains high. Therefore, research that focuses on understanding an individual’s predetermined susceptibility to TB infection at the genetic level could provide health care practitioners with the tools required to identify and educate at-risk individuals prior to TB infection. RT-qPCR was utilised to determine expression profiles for eight iron genes (CP, CYBRD1, FTH, FTL, LTF, HFE, HMOX1, and SCL40A1) normalised to three reference genes (ACTB, GUSB, and RPL37A1). Up-regulation is demonstrated in the TB group for transcript levels recorded for CYBRD1, HFE, HMOX1, and SLC40A1. Several measured serum parameters including conjugated, unconjugated, total bilirubin, and total protein were increased in the TB group while albumin was significantly lower in this group. Correlation analysis demonstrated that a positive correlation exists between transferrin saturation and iron and a negative correlation exists between transferrin and ferritin levels. Individuals categorised with low serum iron levels demonstrated lower CP/GUSB levels and higher HMOX1/GUSB levels. Individuals categorised with low transferrin saturation levels demonstrated higher FTL/GUSB and SLC40A1/GUSB levels and lower CP/GUSB. Results from this study provide further evidence for the relationship between iron status and TB infection rates, although protein studies are required to confirm these results. The data obtained illustrate the important role that these profiles and iron parameters may play in the clinical field when identifying at-risk individuals. Further investigation that focuses on which gene profile and parameter combinations show the most distinctive utility in the clinical setting is warranted.
AFRIKAANSE OPSOMMING: Yster is ‘n noodsaaklike element wat ‘n rol speel in die proses van respirasie en die vervoer van suurstof en ook ‘n belangrike ko-faktor vir verskeie ensieme is. Yster homeostase is op ‘n fyn manier gereguleer omdat oormatige vlakke toksies kan wees vir gesonde selle wanneer reaktiewe suurstofspesies geproduseer word. ‘n Magdom gene wat verskeie sleutelpunte in hierdie proses kontroleer is voorheen identifiseer. Navorsing wat fokus op die veranderinge in geenuitdrukkingsvlakke en die funksionele gevolge daarvan het oor die afgelope dekade toenemend belangrik geword. Een gebied van spesifieke belang het na vore gekom nadat ‘n verband tussen ystervlakke en die manier waarop die immuunstelsel reageer op Mycobacterium tuberculosis infeksie, ontdek is. Alhoewel die voorkoms van Tuberkulose wêreldwyd, behalwe in Afrika en sekere dele van Europa, afgeneem het, bly die sterftesyfer hoog. Daarom kan navorsing wat daarop fokus om ‘n individu se voorafbepaalde vatbaarheid vir TB-infeksie op die genetiese vlak te verstaan dalk aan gesondheidswerkers die regte instrumente verskaf om hoë-risiko individue te identifiseer en op te voed voordat hulle TB ontwikkel. RT-qPKR is gebruik om die geenuitdrukkingsvlakke van agt ystergene, wat met drie verwysings-gene (ACTB, GUSB, en RPL37A1) genormaliseer is, te bepaal. ‘n Toename in die uitdrukkingsvlakke van CYBRD1, HFE, HMOX1, en SLC40A1 is in die TB-groep waargeneem. Die bloedvlakke van verskeie parameters insluitend gekonjugeerde, ongekonjugeerde, totale bilirubin, en totale proteïen was hoër in die TB-groep, terwyl albuminvlakke laer was in hierdie groep. Korrelasie-analise het ‘n positiewe korrelasie tussen transferrin-versadiging en yster getoon, terwyl daar ‘n negatiewe korrelasie tussen transferrin- en ferritinvlakke gevind is. Individue met lae ystervlakke het laer CP/GUSB-vlakke en hoër HMOX1/GUSB-vlakke getoon. Individue met lae transferrin-versadiging het hoër FTL/GUSB- en SLC40A1/GUSB-vlakke en laer CP/GUSB-vlakke getoon. Resultate uit hierdie studie verskaf verdere getuienis dat daar ‘n verwantskap tussen ystervlakke en TB-infeksiekoerse bestaan, alhoewel proteïenstudies nodig is om hierdie resultate te bevestig. Die data dui op die belangrike rol wat hierdie profiele en ystervlakke in die kliniese veld mag speel in die identifisering van hoë-risiko individue. Verdere ondersoek, gefokus op watter geenprofiel en parameterkombinasies die grootste nut in die kliniese omgewing bied, is geregverdig.
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Yau, Belinda. "Pathogenesis of pneumococcal meningitis." Thesis, The University of Sydney, 2014. http://hdl.handle.net/2123/12485.
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Streptococcus pneumoniae (SP) meningitis remains a significant cause of global childhood mortality, and a potential epidemic pathogen despite improving vaccinations schemes. Neuropathology in pneumococcal meningitis (PM) is attributed to both bacterial products and the host-mediated proinflammatory response. Proinflammatory cytokine interferon-gamma (IFNγ) is associated with macrophage activation and regulating MHC Class I expression in innate immunity. IFNγ gene knockout (GKO) mice inoculated with ~5 x 103 CFU of SP/mouse were significantly protected against fatal PM, compared to C57Bl/6 WT mice, in both serotype 3 WU2 and serotype 4 TIGR4 strains. TIGR4 PM was comparatively more virulent than WU2 PM. In murine PM, IFNγ regulated induction of chemokines MCP1, CXCL9, CXCL10, the IRGM1, IRGM3 proteins and nitric oxide synthase 2 (NOS2). In WU2 PM, production of IFNγ was attributed to infiltrating Natural Killer (NK) cells, and dependent upon activation of the inflammasome complex and interleukin-18. NOS2 GKO exhibited a significantly improved survival phenotype, and reduced blood brain barrier dysfunction, compared to WT mice. Intracellular staining revealed Ly6Chi monocytes and NK cells as the source of IFNγ-dependent NOS2 in PM. Overall, this thesis addresses IFNγ production and its contribution to experimental PM pathology.
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Cartón, García Fernando. "Myosin VB in intestinal pathogenesis." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458251.
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Miosina VB es una proteína que actúa como un motor molecular usando la energía del ATP para moverse a lo largo de filamentos de actina. Participa en el trafico intracelular de endosomas de reciclaje en la parte subapical de células polarizadas y no polarizadas. Su expresión es muy abundante en el intestino donde participa en el establecimiento y mantenimiento de la polaridad de los enterocitos. Mutaciones en MYO5B causan la enfermedad de inclusión de microvellosidades, in raro trastorno congénito que afecta a las células epiteliales del intestino cursando con diarrea acuosa persistente que suele ser fatal. Esta enfermedad se caracteriza por la presencia de alteraciones morfológicas en los enterocitos, atrofia de las vellosidades y deslocalización de proteínas del polo apical y basolateral del enterocito. Su patología molecular no se conoce, principalmente por la falta de modelos animales. En el presente estudio, describimos un versátil modelo murino con inactivación constitutiva de Myo5b e inactivación condicional en las células epiteliales intestinales inducida por tamoxifeno. En ambos casos, los animales muestras un cuadro clínico muy semejantes al de los pacientes con enfermedad de inclusión de microvellosidades, presentado diarrea y deshidratación que causan la muerte del animal. A nivel histológico, el intestino muestra las mismas alteraciones en los enterocitos que las presentes en pacientes humanos, incluyendo atrofia de vellosidades y deslocalización de marcadores proteicos. Además, la inactivación de Myo5b también provocó hiperproliferación de las criptas intestinales. Por lo tanto, el modelo animal presentado constituye una herramienta muy útil para investigar las causas moleculares de la enfermedad y ensayar de manera preclínica fármacos u otras opciones terapéuticas. Por otro lado, la pérdida de polaridad y diferenciación es también una de las señas de identidad de los carcinomas metastásicos avanzados y correlaciona con un mal pronóstico de los pacientes. En concreto, para el cáncer colorrectal, investigaciones previas llevadas a cabo en nuestro laboratorio ya han demostrado que la pérdida de miosina IA promueve la progresión la enfermedad y tiene actividad supresora de tumores. Dicha proteína es abundante en el borde en cepillo de los enterocitos, y participa en el mantenimiento de la estructura polarizada. Otros estudios han señalado la relación entre la inactivación de MYO5B con un incremento en la motilidad e invasión de células de cáncer gástrico, aunque todavía no se conoce nada de su relación con en el cáncer colorrectal. Para resolver esta cuestión, hemos diseñado modelos in vitro inducibles por doxiciclina para sobre expresar y reducir la expresión de dicha proteína en líneas celulares de cáncer de colon. Además, se ha empleado la tecnología CRISPR/Cas9 para inactivar la expresión de MYO5B en la línea de cáncer de colon Caco2-BBE. Los resultados muestran cambios en la polarización y diferenciación de dichas líneas celulares, de acuerdo con observaciones previas. También se ha observado una posible relación entre MYO5B y la capacidad de movilidad e invasión de las líneas de cáncer de colon. Sin embargo, la hiperproliferación observada en el intestino de los ratones no se reproduce en las líneas de cáncer de colon empleadas tras reducir o sobre expresar MYO5B, o en modelos xenograft subcutáneos in vivo de dichas líneas. Por otro lado, usando un microarray de tejidos con 155 muestras de tumores primarios de pacientes con cáncer colorrectal en estadio Dukes C se ha comprobado que una reducción en la expresión de MYO5B se asocia con una disminución en el tiempo de recaída y en la supervivencia total de los pacientes de cáncer de colon. Además, tumores con un grado de diferenciación bajo también expresan niveles de MYO5B significativamente reducidos. Finalmente, todos estos resultados indican que MYO5B juega un papel importante en la diferenciación del intestino normal y de las líneas de cáncer de colon. De la misma manera, MYO5B también podría desempeñar un papel en la progresión del cáncer colorrectal promoviendo movilidad e invasión de las células tumorales.Myosin VB is a molecular motor protein that uses the energy of ATP to move along actin filaments. It participates in the recycling endosomes trafficking in the subapical cytoplasmic region of non-polarized and polarized cells. It is highly expressed in the small and large intestine, where its role in the establishment of polarized function in enterocytes is also well known. Inactivating mutations of MYO5B have been associated with microvillus inclusion disease (MVID), a rare congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea. It is characterized by morphological enterocyte abnormalities such as microvillus atrophy and mislocalization of apical and basolateral protein transporters. The molecular pathology of the disease is not well known mainly due to the lack of animal models. In the present study, we report a versatile murine model with targeted inactivation of Myo5b. This model allowed us to generate and characterized a constitutive Myo5b knockout mice and a tamoxifen-inducible intestinal-epithelium-specific Myo5b knockout. In both cases, the mice closely resemble the phenotype of MVID patients, developing watery diarrhea and dehydration causing the death of the animal. Histological study of the intestine showed all the characteristic enterocyte defects observed in MVID patients, including microvillus atrophy and mislocalization of protein markers. Moreover, the inactivation of MYO5B also originated hyperproliferation of the intestinal crypts. Therefore, our mice constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches. In addition, hyperproliferation as well as loss of cell polarity, differentiation, and tissue architecture are hallmarks of advanced metastatic carcinomas and strongly correlate with poor patient prognosis. Specifically, for colorectal cancer, the third most common type of cancer worldwide, we have previously demonstrated that the loss of brush border MYO1A, also involved in cell polarity, promotes cancer progression and has tumor suppressor activity. Other studies have indicated a relationship between MYO5B inactivation and gastric cancer, promoting invasion and motility, but little is known regarding its role in colorectal cancer. To address this question, we have developed novel doxycycline-inducible in vitro models of MYO5B overexpression and downregulation. Moreover, we have generated MYO5B knockout Caco2-BBE cells using CRISPR/Cas9 technology. Our results showed changes in the polarization and differentiation of colon cancer cells, in agreement with previous observations in the normal intestine. Moreover, we have observed a relationship between MYO5B and the motility and invasion capacity of colon cancer cells, indicating a possible role of MYO5B in colon cancer progression. However, the effect of MYO5B loss in cell proliferation observed in our Myo5b knockout mice could not be confirmed in our models in vitro and in vivo, employing cell line-derived xenografts. In addition, using a tissue microarray containing triplicate samples from 155 primary Dukes C colorectal tumors, reduced MYO5B expression was found to be associated with shorter disease-free and overall survival of the patients. Moreover, poorly differentiated tumors showed significantly reduced expression of MYO5B. Collectively, our results indicate that MYO5B plays an important role in the differentiation of the normal intestinal epithelium and colon cancer cells, as well as a possible role in cancer progression promoting cell motility and invasion.
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Hamoudi, Rifat A. "Molecular pathogenesis of MALT lymphoma." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/238398.
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Mucosa associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH andt(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-κB pathway. Gastric MALT lymphomas harbouring such translocation do not respond to Helicobacter pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of MALT lymphoma with and without chromosome translocation, 24 cases (15 translocation-positive and 9 translocation-negative) of MALT lymphomas together with 7 follicular lymphomas and 7 mantle cell lymphomas were analysed by Affymetrix gene expression microarray platform. Unsupervised clustering showed that cases of MALT lymphoma were clustered as a single branch. However, within the MALT lymphoma group, translocation-positive cases were intermingled with translocation-negative cases. Gene set enrichment analysis (GSEA) of the NF-κB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas were characterized by an enhanced expression of NF-κB target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. The differential expression of these NF-κB target genes between MALT lymphoma with and without translocation was confirmed by quantitative RT-PCR and immunohistochemistry or Western blot. Expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-κB activation in vitro. In addition, there was cooperation between expression of BCL10, MALT1 or API2-MALT1, and stimulation of the antigen receptor or CD40 or TLR in NF-κB activation as shown by both reporter assay and IκBα degradation. Interestingly, expression of BCL10 but not API2-MALT1 and MALT1, in the presence of LPS stimulation, also triggered IκBβ degradation, suggesting activation of different NF-κB dimers between these oncogenic products. Study by co-immunoprecipitation showed that BCL10 directly interacts with MALT1. Sub-cellular localisation experiments in BJAB B-cells, showed that BCL10 localisation was affected by MALT1. When BCL10 was over-expressed, the protein was predominantly expressed in the nuclei, but when MALT1 was over-expressed, BCL10 was mainly localised in the cytoplasm. When both BCL10 and MALT1 were over-expressed, BCL10 was expressed in the cytoplasm in the early hours when the protein level was low, but in both the cytoplasm and nuclei after 9 hours when the protein level was high. Over-expression of API2-MALT1 did not shown any apparent effect on BCL10 sub-cellular localisation in vitro. Finally, comparison of MALT lymphoma expression microarray with other lymphomas showed lactoferrin to be highly expressed in MALT lymphoma. This was confirmed by qRT-PCR, showing lactoferrin to be significantly over-expressed in MALT lymphoma compared to FL and MCL. Thus lactoferrin may be a potential marker for MALT lymphoma.
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Alam, Sam Mohammad Kutubul. "Pathogenesis of Langerhans Cell Histiocytosis." Thesis, Imperial College London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487289.
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The Langerhans cell (LC) is a histiocytic cell that represents a resident immigrant population in the epidermis and functions as a professional antigen presenting cell (APC). Langerhans cell histiocytosis (LCH) is a rare disorder that can affect both adults and children and can involve various organs. Clinically the disease ranges from a solitary lytic bone lesion, which may resolve following curettage, to a disseminated leukaemia-like disease with multiple organ involvement, which can be fatal. Despite considerable advances in our understanding of the disease, the aetiology ofLCH remains obscure. The aim of this study is to identify differentially expressed genes in LCH cell as compared to normal LC to gain novel insight into potential pathologic mechanisms involved in this disease. This has been carried out by using immunoaffinity cell purification against the LC marker CDla, a technique developed in our laboratory, together with a suppressive subtractive cDNA hybridisation (SSH) technique. Because of the limited LCH RNA material, an initial study was carried out to optimise conditions for SSH using HeLa cells and YCI cells, a derivative of HeLa in which CDla is constitutively expressed. By doing these experiments, it was found that the inclusion of an additional step to the subtraction protocol, namely size fractionation and purification of subtracted cDNA, allowed efficient recovery ofcDNA clones for the differentially expressed CDla gene. Using this optimised protocol, gene expression between normal LC and LCH cells obtained from bronchial alveolar lavage from one patient with LCH have been compared. A total of 291 differentially expressed clones were identified by differential screening and sequenced. The resulting sequences were used to search DNA sequence databases and the results used to classify sequences into three groups: (i) sequences that matched known human gene sequences, (ii) sequences that were found to originate from the pathogen Mycoplasma hyorhinis (M hyorhinis) and (iii) gene sequences of unknown origin. Using RT-PCR I have evaluated the expression of these in other LCH samples and have demonstrated one of the known human genes, argininosuccinate synthetase to be differentially expressed exclusively in 18 LCH-involved tissues from 17 LCH involved patients examined to date. Further, using RT-PCR, M hyorhinis sequences were also confirmed in six out of six additional LCH samples derived from bronchial alveolar lavage and two additional LCH samples involving gum. Taken together, these findings suggest that a discrete set of genes are differentially expressed in LCH, which may be important in the pathogenesis of this disease. Further, my data suggest the possible involvement of a novel infectious agent in the disease.
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Wang, Eddy Hsi Chun. "The pathogenesis of alopecia areata." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/51360.
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The development of a hair loss disease, alopecia areata (AA), is believed to be associated with the initiation of an autoimmune response triggered by the activation of cytotoxic T-cells (CTLs) by unidentified autoantigen epitopes. The long-term sequelae of AA also have not received investigation beyond clinical observations. I hypothesized that CTLs in AA can be activated by autoantigen epitopes derived from hair follicle (HF) cells and activated CTLs may affect the viability of HF keratinocytes. Furthermore, I hypothesized the development of AA can have adverse effects on heart health and induce apoptosis of cardiomyocytes mediated in part by stress hormones. To test these hypotheses, I stimulated AA human peripheral blood mononuclear cells (PBMCs) and mouse LNCs with HF autoantigen epitope peptides. I showed that trichohyalin (TCHH) peptides induced higher frequencies of AA PBMC activation and led to keratinocyte apoptosis, while cytokeratin 16 (KRT16) peptides activate more AA mouse LNCs; both indicating the importance of keratinocyte autoantigens in AA pathogenesis. We showed that AA mice displayed significantly heavier hearts and collagen deposition in hearts compared to controls. Exposure of heart tissues to stress hormone adrenocorticotrophic hormone (ACTH) resulted in differential expression of interleukin-18 (Il18) genes and increased secretion of cardiac disease marker cardic troponin-I (cTnI). AA patients showed highest levels of cTnI compared to androgenetic alopecia (AGA) and no-hair-loss (NHL) groups. Culturing of cardiomyocytes with plasma from AA subjects with higher levels of cTnI also resulted in higher levels of apoptosis compared to cultures with plasma expressing low levels of cTnI; suggesting presence of harmful factors in the plasma. Additionally, to prove AA is a cell-mediated disease, we established a new mouse model of AA via injecting naïve C3H/HeJ mice with cultured LNCs isolated from spontaneously affected AA mice. In conclusion, AA pathogenesis is associated with higher frequencies of PBMC or LNC activation upon keratinocyte antigen epitope challenge and AA development resulted in changes in gene expression and heart morphology in mice and heart tissue remodeling markers in humans.Medicine, Faculty of
Medicine, Department of
Experimental Medicine, Division of
Graduate
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Matin, Abdul. "Pathogenesis of Balamuthia amoebic encephalitis." Thesis, Birkbeck (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500082.
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Linden, Paul Jan Quirien van der. "On the pathogenesis of endometriosis." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=8348.
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Fulcher, Robert Aubrey Kawula Thomas Hardin. "Effectors of Haemophilus ducreyi pathogenesis." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,969.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Dec. 18, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology." Discipline: Microbiology and Immunology; Department/School: Medicine.
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Simard, Marie-Chantal. "Nef pathogenesis in transgenic mice." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103182.
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In order to study the functions of SIV Nef in vivo, in a small animal model, transgenic (Tg) mice expressing the SIVmac239 nef gene, under the control of the human CD4 gene promoter (CD4C) were generated. The transgene was found to be expressed in the same cells targeted by the virus, in vivo. These CD4C/SHIV-nef SIV Tg mice develop a severe AIDS-like disease, including premature death, failure to thrive/weight loss, wasting, thymic atrophy, exhibit an especially low number of peripheral CD8+ T cells as well as low number of peripheral CD4+ T cells, diarrhea, splenomegaly, kidney (interstitial nephritis, segmental glomerulosclerosis), lung (lymphocytic interstitial pneumonitis) and heart disease. In addition, these Tg mice fail to mount a class-switched antibody response after immunization with ovalbumin, produce anti-DNA autoantibodies and some of them develop P. Carinii lung infection. These CD4C/SHIV-nefSIV Tg mice develop an AIDS-like disease very similar to that of CD4C/HIV Tg mice, except that the kidney and cardiac diseases were more severe, and that a thymic developmental defect was observed. Heart enlargement was very severe in CD4C/SIV Tg mice during early breeding on the C3H background. Histopathological lesions in the heart of these mice were also multifocal and were similar to those found in CD4C/HIV Tg mice. Data from echocardiography analysis are not yet available for these Tg mice. The low number of peripheral CD8+ and CD4 + T cells likely reflects a thymic defect and may be similar to the DiGeorge-like "thymic defect" immunophenotype described in a subgroup of HIV-1 infected children. Ontogeny studies show that the Tg mice were born with a smaller thymus and that this phenotype is not progressive in nature. As young as embryonic day 17, the thymic absolute cell numbers are lower in the Tg mice when compared to their non-Tg controls and there is a defect in thymocyte maturation in the transition between DN3 and DN4, with a failure to generate normal numbers of DP cells. Fetal liver transplantation studies have ruled out a significant impairment of the thymic epithelium and have suggested that this defect is likely a direct consequence of abnormal T cell progenitors in the thymus.Therefore, it appears that SIV Nef alone expressed in mice, in appropriate cell types and at sufficient levels, can elicit many of the phenotypes of simian and human AIDS. These Tg mice should be instrumental in studying the pathogenesis of SIV Nef-induced phenotypes.
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Elliot-Smith, Elena. "GM1 gangliosidosis : therapy and pathogenesis." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425028.
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Cordes, Frank Stephan. "Biophysical studies of bacterial pathogenesis." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404113.
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Mehasseb, Mohamed Khairy. "The pathogenesis of uterine adenomyosis." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9048.
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The exact aetiology and pathogenesis of uterine adenomyosis are not clear. Increased endometrial invasiveness has been proposed in the literature, but without conclusive evidence. This thesis was undertaken to examine the pathogenesis of adenomyosis and the differences between affected and unaffected uteri, testing two possibilities with adenomyosis: (i) that the myometrium is permissive to invasion by a normal basal endometrium, or (ii) that the basal endometrium has a higher invasive potential and penetrates a normal myometrium. To examine the early phases of development of adenomyosis, a mouse model was used, where adenomyosis was induced by dosing female pups with tamoxifen. The same experiment was used on C57/BL6J strain to examine strain differences in response to tamoxifen and predisposition to adenomyosis. Adenomyosis in the human uterus was characterised, examining the immunohistochemical, light and electron microscopy structure, and RNA microarrays of affected and unaffected uteri. The invasive properties of the stroma and its interaction with the underlying myometrium were further studied in a co-culture model. Adenomyosis was successfully induced in the CD1 mice, with abnormal development and disruption of the inner circular myometrium. However, the C57/BL6J did not develop adenomyosis inspite of the presence of inner myometrial abnormalities comparable to the CD1 mice. Affected human uteri showed distinct myometrial features such as reduced myometrial cellular density and enlarged nuclei with hypertrophy and hyperplasia seen on light microscopy. Electron microscopy revealed ultrastructural features (e.g. reduced caveolae and increased myelin bodies, intermediate filaments and dense bands) in adenomyotic uteri. A large number of dysregulated genes were detected between affected and unaffected uteri, with Wnt5a being a key downregulated gene. Steroid reception expression was equally altered in cases of adenomyosis (e.g. reduced progesterone receptors and increased estrogen receptor beta). Increased vimentin immunostaining was equally observed in the inner myometrium of diseased uteri. An increased adenomyotic stromal invasiveness and increased myometrial permissiveness was observed in the co-culture model. The thesis demonstrates that the endometrial – myometrial interface behaves differently in uteri with adenomyosis, concluding that adenomyosis is a uterine disease characterized by both increased endometrial invasiveness and myometrial defects that play a facilitative role for this invasion. Both the myometrium and endometrial stroma of diseased uteri show a unique phenotype, gene expression and protein expression profiles.
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Craff, Melody Nikki. "The pathogenesis of fructose toxicity." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620036.
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Pettersson, Lisa. "TRANSMISSION AND PATHOGENESIS OF HANTAVIRUS." Doctoral thesis, Umeå universitet, Institutionen för klinisk mikrobiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-99687.
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Hantaviruses are the causative agents of hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Transmission to humans usually occurs by inhalation of aerosolized virus-contaminated rodent excreta. To date, human-to-human transmission has only been described for the Andes hantavirus. The mode of transmission of Andes hantavirus is not yet known, but transmission through saliva has been suggested. In Sweden, we have one hantavirus that is pathogenic to humans, Puumala virus (PUUV), which is endemic in Central and Northern Europe. It induces a relatively mild form of HFRS, also called nephropathia epidemica (NE). The rodent reservoir is the bank vole (Myodes glareolus). The mechanism behind the pathogenesis of hantavirus is complex and probably involves both virus-mediated and host-mediated mechanisms. The aim of this project was to investigate the transmission mechanisms and pathogenesis of hantavirus disease in humans. In our first study, we described the largest outbreak of PUUV so far in Sweden. We investigated factors that might be important for causing the outbreak, and suggested that a peak in the bank vole population together with concurrent extreme weather conditions most probably contributed to the outbreak. Our next studies concentrated on human-to-human transmission of hantaviruses. We found PUUV RNA in saliva from PUUV-infected patients, suggesting that there is PUUV in the saliva of infected humans, although no person-to person transmission appears to occur with PUUV. In the studies that followed, we showed that human saliva and human salivary components could inhibit hantavirus replication. We also found PUUV-specific IgA in the saliva of PUUV-infected patients, which might prevent person-to-person transmission of the virus. In the final study, we focused on the pathogenesis of NE. One hundred five patients were included in a prospective study. They were divided into a group with mild disease and a group with moderate or severe disease. We found that the immune response had a dual role in disease development. It was partly responsible for development of severe disease, with significantly higher amounts of neutrophils in severely ill patients, but it was also protective against severe disease, because patients with mild disease had higher levels of PUUV-specific IgG. In conclusion, a peak in the bank vole population in combination with extreme weather will increase the risk of human infection, PUUV RNA is present in saliva, PUUV-specific IgA and salivary components inhibit person-to-person transmission of PUUV, and the immune response is important for the pathogenesis of PUUV and the severity of the disease.Hantavirus är en grupp av virus som finns hos gnagare som bär på viruset utan att själva bli märkbart sjuka. Varje hantavirus har anpassat sig till sin egen art av gnagare som de infekterar (kallas virusets reservoar). Hantaviruset kan överföras till människor från gnagare och kallas då för en zoonos eftersom detsprids från djur till människa. I människa orsakar hantavirus blödarfeber med njurpåverkan i Eurasien och blödarfeber med med hjärt och lungpåverkan i Nord- och Sydamerika. I Sverige har vi bara ett hantavirus som är sjukdomsframkallande hos människor, Puumala-viruset som även finns i delar av övriga Europa. Det framkallar en relativt mild form av blödarfeber, som kallas sorkfeber eller Nephropathia epidemica. Puumala-virusets reservoar är skogssorken (Myodes glareolus). Människor smittas oftast av hantavirus när de andas in infekterat damm som innehåller utsöndringar (avföring, urin eller saliv) från gnagare som har torkat in och sedan blivit luftburet. Vad man vet hittills så finns det bara ett hantavirus som smittar från person till person, för övriga hantavirus är människan en ”dead end”. Det virus som kan smitta från person till person heter Andes hantavirus och finns i Sydamerika. Andes hantavirus har en mus som reservoar från vilken människor kan smittas, sedan har smittan i vissa fall förts vidare från människa till människa, som tur är har dessa utbrott gått att stoppa. Fastän utbrotten har varit små har många personer dött, eftersom dödligheten är så hög, ungefär 30-40% av de diagnostiserade fallen dör. Hur Andes hantavirus överförs från människa till människa är inte känt men överföring genom saliv har föreslagits. Hur viruset ger upphov till sjukdom hos människa är inte klarlagt. Studier talar för att mekanismen bakom sjukdomsutvecklingen (den så kallade patogenesen) hos hantavirusorsakade blödarfebrar är komplex. Sannolikt beror patogenesen både på egenskaper hos viruset och värden d.v.s. människan som är smittad av viruset. Vårt mål med detta projekt var att undersöka vad som hindrar överföring av Puumala hantavirus från människa till människa och att undersöka hur virusinfektionen påverkar sjukdomsutvecklingen hos människan. I vår första studie beskrev vi det största utbrottet av sorkfeber hittills i Sverige och vi undersökte faktorer som kan ha orsakat utbrottet. Vi föreslog att en topp i skogssorkpopulationen samtidigt med extremt varmt väder troligen bidrog till utbrottet. Utbrottet skedde i december och det extremt varma vädret medförde att snön smälte bort. Sorkarna bor vanligtvis under snön på vintern, vi tror att frånvaro av snötäcke fick sorkarna att söka sig till byggnader för att söka skydd och där kom i kontakt med människor. Våra efterföljande studier fokuserade på överföring av hantavirus från människa till människa. Vi hittade Puumala-virusets arvsmassa (RNA) i saliv från sorkfeberpatienter, vilket tyder på att det finns Puumala-virus i saliven hos infekterade människor, även om ingen överföring från person till person verkar inträffa. I efterföljande studier visade vi att mänsklig saliv och mänskliga salivkomponenter minskar hantavirus smittsamhet. Vi fann också Puumala-virusspecifika IgA-antikroppar i saliven från sorkfeberpatienter, vilket kan förhindra överföring från person till person. I den sista studien fokuserade vi på patogenesen hos människor efter hantavirusinfektion. 105 patienter ingick i en prospektiv studie och delades in i en grupp med mild sjukdom och en grupp med måttlig/svår sjukdom. Vi hittade en dubbel roll hos immunsvaret för sjukdomsutvecklingen. Immunsvaret var delvis ansvarig för utveckling av svår sjukdom med betydligt högre mängd neutrofiler hos svårt sjuka patienter, men det var också skyddande mot allvarlig sjukdom, eftersom patienter med en mild sjukdom hade högre nivåer av Puumalavirusspecifika IgG-antikroppar. Detta talar för att behandling med IgG-antikroppar specifikt riktade mot hantavirus skulle kunna vara effektiv hos hantavirusinfekterade patienter. Sammanfattningsvis; en topp i skogssorkspopulationen i kombination med extremt väder ökar risken för infektion hos människor; Puumala-virus arvsmassa (RNA) finns i saliv; Puumala-virusspecifika IgA-antikroppar och salivkomponenter hämmar överföring av Puumalavirus från person till person; immunsvaret är viktigt för Puumala-virus patogenes och sjukdomens svårighetsgrad.
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Johnson, Patricia A. "The pathogenesis of autoimmune vasculitis." Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295394.
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Hadden, Robert David Martin. "Pathogenesis of Guillain-Barr syndrome." Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394003.
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Hackett, A. P. "Investigating pathogenesis of reflux aspiration." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3007474/.
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Calvo, Sarah E. "Mitochondrial parts, pathways, and pathogenesis." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/54449.
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Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.Cataloged from PDF version of thesis.
Includes bibliographical references.
In title on title page, the word "Mitochondrial" is spelled "Mitochondial."
Mitochondria are cellular compartments that perform essential roles in energy metabolism, ion homeostasis, and apoptosis. Mitochondrial dysfunction causes disease in 1 in 5,000 live births and also has been associated with aging, neurodegeneration, cancer, and diabetes. To systematically explore the function of mitochondria in health and in disease, it is necessary to identify all of the proteins resident in this organelle and to understand how they integrate into pathways. However, traditional molecular and biochemistry methods have identified only half of the estimated 1200 mitochondrial proteins, including the 13 encoded by the tiny mitochondrial genome. Now, newly available genomic technologies make it possible to identify the remainder and explore their roles in cellular pathways and disease. Toward this goal, we performed mass spectrometry, GFP tagging, and machine learning on multiple genomic datasets to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues. We linked poorly characterized proteins in this inventory to known mitochondrial pathways by virtue of shared evolutionary history. We additionally used our matched mRNA and protein measurements to demonstrate a widespread role of upstream open reading frames (uORFs) in blunting translation of mitochondrial and other cellular proteins. Next we used the mitochondrial protein inventory to identify genes underlying inherited diseases of mitochondrial dysfunction. In collaboration with clinicians, we identified causal mutations in five genes underlying diseases including hepatocerebral mtDNA depletion syndrome, autosomal dominant mitochondrial myopathy, and several forms of inherited complex I deficiency. These discoveries have enabled the development of diagnostic tests now widely available. More broadly, the mitochondrial compendium provides a foundation for systematically exploring the organelle's contribution to both basic cellular biology and human disease.
by Sarah E. Calvo.
Ph.D.
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Everest, Paul Howard. "The pathogenesis of Campylobacter diarrhoea." Thesis, University of Leicester, 1992. http://hdl.handle.net/2381/34407.
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Campylobacter jejuni/coli are the most common cause of acute diarrhoeal disease in man. The disease is worldwide, affects all age groups, and is mostly sporadic although common source outbreaks are frequently reported. The organism characteristically causes infection of the small intestine with extension into the colon and rectum, the disease being an acute enterocolitis. Illness may be inflammatory, with mucosal oedema and polymorphonuclear infiltration and blood in the faeces, or non-inflammatory with watery diarrhoea. The pathogenesis of the disease is unknown. Bacterial invasion of intestinal mucosa has been proposed as a mechanism of mucosal inflammation causing tissue damage. Investigation of the enterocyte-like Caco-2 and other epithelial cell lines for the ability of clinically characterised strains to adhere and invade showed that strains from colitic illness exhibited a greater tendency to invade than strains from non-inflammatory illness. Colitis and some non-inflammatory strains were also shown to transcytose from the apical to the basolateral cell membrane. Phosphorylation of mammalian cell proteins (such as ion channels) is important in diarrhoeal illness, mediated by bacterial cells and their secreted toxins. C. jejuni bacterial cells and a secreted toxin in culture supernatants caused phosphorylation of Caco-2 cell proteins, effects that mimic protein kinase C phosphorylation of myosin light chain. Culture supernatants increased intracellular calcium, an effect known to mediate fluid secretion. These effects are independent of the cholera-like toxin that is found in small amounts in culture supernatants. Colitis strains tested in rabbit ileal loops induced similar histological effects to those seen in man, caused fluid secretion, and white cell infiltrate consisting of polymorphonuclear leucocytes and macrophages. Villi were shortened and tissue was oedematous with submucosal bleeding. Tissue damage may prevent effective absorption of fluid and contribute to diarrhoea but biochemical analysis suggests a true secretory component to the diarrhoea. By contrast a non-inflammatory strain showed no histological changes in loops and elicited no fluid secretion. Large amounts of the host derived secretagogue prostaglandin E2 were induced in infected ileal loops and correlated with the tissue white cell infiltrate (along with leukotriene B4). In the absence of a cholera-like toxin produced by the bacteria PGE2 seems to be responsible for the increase in infected tissue cyclic AMP. PGE2 acts by binding to a cellular receptor and activating cell adenylate cyclase resulting in a rise in cAMP. Thus a host inflammatory mediator may contribute to fluid secretion in C. jejuni enterocolitis.
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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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Marques, Sara Andréia de Barros Costa. "Protothecosis: agent characterization and pathogenesis." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2010. http://hdl.handle.net/10216/53701.
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Beard, Philippa M. "Epidemiology and pathogenesis of paratuberculosis." Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/29893.
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Investigations into three aspects of the epidemiology and pathogenesis of paratuberculosis were undertaken - infection of wildlife with Mycobacterium avium subsp paratuberculosis (M. a. paratuberculosis), the early host immune response mounted against organism, and the influence of host genotype on susceptibility to the disease. The pathology of natural rabbit paratuberculosis was investigated and described, with rabbits exhibiting either mild or severe lesions. The changes noted in the severely affected rabbits included the presence of giant cells containing over 50 nuclei and many acid fast bacteria. M. a. paratuberculosis was cultured from the faeces and urine of the naturally infected rabbits, revealing two possible routes of interspecies transmission of the organism. To investigate the impact of natural rabbit paratuberculosis on the disease in ruminant livestock, young calves were inoculated orally with a strain of M. a. paratuberculosis isolated from a naturally infected rabbit. After an incubation period of six months, the organism was recovered from the intestinal tissues of seven out of eight inoculated calves, with three of these calves also exhibiting pathological changes consistent with chronic paratuberculosis, suggesting that M.a.paratuberculosis from rabbits is capable of causing paratuberculosis in cattle. In a parallel experiment, two groups of rabbits were inoculated with either a bovine or leporine derived strain of M. a. paratuberculosis, but no evidence of infection was noted after a six month incubation period, suggesting that further, as yet unidentified factors, are involved in the pathogenesis of paratuberculosis in rabbits. A large survey in rural Scotland revealed M.a. paratuberculosis infection of 10 species of wildlife - fox, stoat, weasel, crow, rook, jackdaw, rat, wood mouse, hare, and badger. The investigations into wildlife reservoirs of M.a. paratuberculosis, the influence of host genes on susceptibility to the disease, and the role of gd T cells in the initial response to M.a. paratuberculosis infection provide new information on the epidemiology and pathogenesis of this disease, and may have a role to play in creating more effective control measures against paratuberculosis.
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Greenfield, Bethany Patricia Jane. "Metarhizium pathogenesis of mosquito larvae." Thesis, Swansea University, 2014. https://cronfa.swan.ac.uk/Record/cronfa42819.
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Islam, M. R. "Pathogenesis of avian reovirus infection." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.383443.
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McKay, Siobhan. "The molecular pathogenesis of cholangiocarcinoma." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11098.
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Introduction: Cholangiocarcinoma (CC) is a malignancy of the biliary tract. It has a dismal prognosis and complete surgical resection offers the only chance of cure. The aim of this study was to identify prognostic DNA/microRNA signatures, and to identify key targets and pathways in CC to improve treatment. Methods: We performed a retrospective study to assess the role of surgery and adjuvant therapy on the survival outcomes of patients with CC based on the experience of two institutions. We investigated the molecular pathogenesis of CC assessing DNA copy number alterations and differential miRNA expression. We used array comparative genomic hybridization (CGH) (1Mb BAC array-CGH, and 180K Oligonucleotide array-CGH) on 71 UK and 24 Thai cases CC. We performed microRNA-arrays (Agilent Human miRNA slides V3) on 34 CC and 10 normal cholangiocyte samples. Results: Survival analysis showed a statistically significant difference in survival between those resected and those receiving medical management only. Thai CC cases exhibited a lower proportion of CNA compared to UK cases. A common UK alteration was seen at 17q12, the region encoding ErbB-2. The copy number gain at 17q12 was validated using CISH and IHC for ErbB-2 expression, revealing heterogeneous expression. Copy number gain of chromosome 8q24.21-24.3 was significantly related to survival. Median survival was 14.4 months vs 28.3 months with and without the gain (p = 0.016). Thirty-eight miRNAs showed significantly different expression, including several microRNAs implicated in other malignancies, with predicted gene targets including the p53 signaling pathway and the TGF-beta signaling pathway. We identified a 4-microRNA signature that correlated with overall survival. With a median survival of 15.7 months vs 35.6 months: p = 0.00016. Conclusion: This study illustrates the genetic variability of CC, highlights several potential therapeutic targets, and identified a DNA and miRNA signature that correlated with prognosis.
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Wiskur, Brandt Justin. "Pathogenesis of Klebsiella pneumoniae endophthalmitis." Oklahoma City : [s.n.], 2008.
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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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Beatson, Scott. "Pseudomonas aeruginosa genomics and pathogenesis /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16848.pdf.
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Yang, Ian Anthony. "Genetic variation in COPD pathogenesis /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16860.pdf.
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Cubie, Heather A. "Human papillomavirus : pathogenesis and immunity." Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/27846.
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The involvement of human papilloma virus (HPV) in the aetiology and progression of cervical intraepithelial neoplasia (CIN) is still unresolved. This study was designed to assess the immunological responses to HPV types in patients presenting with varying degrees of CIN and in control groups, using in vitro measures of cellular and humoral responses. Lymphocyte proliferation assays (LPA) were performed using peripheral blood mononuclear cells (PBM) and various papillomavirus (PV) antigens. Twenty -five per cent (23/92) of patients with CIN responded to antigens derived from purified BPV, HPV -1 or HPV -2 with or without detergent disruption. The responses correlated with a past history of skin warts rather than cervical abnormalities, and the percentage of responders was similar to that in laboratory personnel (30 %) and lower than that in a group with recalcitrant common warts (50 %). Antigens specific to HPV -16 and HPV -18, in the form of bacterially expressed fusion proteins derived by the transcription and translation of the E6 and E4 open reading frames (ORF), occasionally produced specific positive responses, provided contaminating E.coli B galactosidase sequences had been removed during purification. Responses were low and suggested that the numbers of memory T cells specific to PV antigens were low and at the lower limit of detection of LPA. An indirect ELISA was developed to detect circulating IgG to PV antigens in colposcopy patients. Fifty per cent of patients had antibodies to disrupted HPV -1, HPV -2 or both, suggesting that a predominantly type- specific response was being detected. No correlation of immune responses with a degree of dysplasia or the presence of koilocytes in cervical biopsies was noted, but a high incidence of forgotten or inapparent past infection with cutaneous HPV types was found. In situ hybridisation (ISH) methods using non -radioactively labelled, cloned probes and synthetic oligonucleotide probes were developed for use on paraffin sections. Synthetic probes allowed a quicker, less destructive hybridisation protocol, with the sensitivity of detection being (y) improved by an anti -biotin -immunogold conjugated immunoglobulins -silver enhancement (IGSS) detection system. Double staining of PV antigen and nucleic acid on the same section was achieved. Synthetic oligonucleotides offer an exciting new tool for diagnostic virology, worthy of exploitation in many systems. Implantation of human foreskin infected with HPV -11 was shown to provide an animal model, albeit technically difficult, in which HPV could be produced, but a more practical technique of productive HPV infection in vitro is still required if the biology and pathogenesis of HPV infections is to be clarified further.
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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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Marques, Sara Andréia de Barros Costa. "Protothecosis: agent characterization and pathogenesis." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2010. http://hdl.handle.net/10216/53701.
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RECCHIA, DEBORAH. "Steroid Myopathy: Understanding the pathogenesis." Doctoral thesis, Università degli studi di Pavia, 2019. http://hdl.handle.net/11571/1301291.
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Muscle plasticity is a key element in human health and disease. Exercise is an important element that leads to many positive adaptations, which improve survival and quality of life. Conversely, muscle atrophy is a condition found in many chronic diseases. Atrophy is the oucome of an imbalance between the processes that lead to protein synthesis (MPS) and the processes that lead to muscle protein breakdown (MPB) resulting in net muscle mass loss.
Chronic administration of glucocorticoids causes steroid myopathy characterized by muscle weakness, fatigue and atrophy. The primary pathogenetic phenomenon causing such condition is still unknown. The present study aims to identify the molecular phenomena involved in triggering the myopathic process.
To achieve such goal, the adapations of intracellular signalling pathways which have been previously shown to be potentially involved in steroid myopathy were studied. A single dose of desametasone (DEX) was administered intravenously to healthy subjects. Muscle biopsies were taken from vastus lateralis muscle 1h, 4h and 8h after DEX injection. Western blot and real time PCR were used to assess the adaptations of markers related to the ubiquitine-protesome degradation pathway (UPS),
protein synthesis, autophagy, muscle metabolism, redox status and mitochondrial remodelling.
Results suggest that DEX induced increased gene expression of Atrogin1, mitochondrial dysfunction and impairment of oxidative metabolism. The latter phenomenon would cause redox imbalance. Redox imbalance could further stimulate muscle MPB. This vicious loop results in an increased activation of the
autophagy pathway. The activation of the autophagy process together with the activation of the pathway of protein degradation would finally lead to muscle atrophy.
The ability by two-week intake of a mixture of branched chain amino to counteract the effects of DEX on intracellular pathways have been also tested. Preliminary data are reported.Muscle plasticity is a key element in human health and disease. Exercise is an important element that leads to many positive adaptations, which improve survival and quality of life. Conversely, muscle atrophy is a condition found in many chronic diseases. Atrophy is the oucome of an imbalance between the processes that lead to protein synthesis (MPS) and the processes that lead to muscle protein breakdown (MPB) resulting in net muscle mass loss. Chronic administration of glucocorticoids causes steroid myopathy characterized by muscle weakness, fatigue and atrophy. The primary pathogenetic phenomenon causing such condition is still unknown. The present study aims to identify the molecular phenomena involved in triggering the myopathic process. To achieve such goal, the adapations of intracellular signalling pathways which have been previously shown to be potentially involved in steroid myopathy were studied. A single dose of desametasone (DEX) was administered intravenously to healthy subjects. Muscle biopsies were taken from vastus lateralis muscle 1h, 4h and 8h after DEX injection. Western blot and real time PCR were used to assess the adaptations of markers related to the ubiquitine-protesome degradation pathway (UPS), protein synthesis, autophagy, muscle metabolism, redox status and mitochondrial remodelling. Results suggest that DEX induced increased gene expression of Atrogin1, mitochondrial dysfunction and impairment of oxidative metabolism. The latter phenomenon would cause redox imbalance. Redox imbalance could further stimulate muscle MPB. This vicious loop results in an increased activation of the autophagy pathway. The activation of the autophagy process together with the activation of the pathway of protein degradation would finally lead to muscle atrophy. The ability by two-week intake of a mixture of branched chain amino to counteract the effects of DEX on intracellular pathways have been also tested. Preliminary data are reported.
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Gillespie, Stephen Henry. "Infection: pathogenesis, diagnosis, treatment and epidemiology." Thesis, Queen's University Belfast, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485197.
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New drugs for tuberculosis are a major need for international public health. The results of clinical trials focussed on evaluation of fluoroquinolones for pulmonary tuberculosis are presented. From this work have emerged new methods to evaluate clinical trials data that have influenced methodology internationally. Isolates obtained in these studies have been the subject of molecular epidemiological typing methods. This led to the discovery ofpotential false matches in typing data bases. Later studies led to the demonstratiQP of the evolutionary pathways that individual strains take as lineages of M tuberculosis are transmitted in human communities. Studies demonstrating for the first time the fit~ess deficit associated with acquisition of resistance are presented and expanded to include the adaptation that occurs following the transmission of drug resistant strains between patients. Diagnostic methods have been studied, including not only studies of sensitivity and specificity but of the impact ofthese tests on management decisions. Lower respiratory tract infections are critically important 'and work is presented about the epidemiological spectrum. diagnosis of infection and antibiotic resistance. Diagnosis based on C-polysaccharide antigen led to studies on the biology of this organism and attempts to purify the enzymes involved in its synthesis led to the purification of pneumococcal enolase and important pathogenicity determinant. More recent work ·on the diagnosis of capsular serotype by molecular means is presented. Further experiments in evolution of drug resistance resulted in the demonstration of the unique evolutionary pathway to fluoroquinolones for the pneumococcus. The practical application ofmodem diagnosis is presented in studies ofadults and children in the UK and Africa. Further work to improve the diagnosis of bacteriological and parasitological infections including the results of clinical trials of treatment are presented that has allowed and extension of our knowledge ofthe clinical spectrum and epidemiology of these important infections.
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Tucker, Tracy. "Pathogenesis of neurofibromatosis 1 associated neurofibromas." Thesis, University of British Columbia, 2006. http://hdl.handle.net/2429/31176.
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Neurofibromatosis 1 (NF1) is an autosomal dominant disease. Neurofibromas, benign tumours that develop from peripheral nerves, are a hallmark feature of NF1. Malignant peripheral nerve sheath tumours (MPNSTs) are one of the leading causes of death in people with NF1. Clinical evidence suggests that most MPNSTs develop from pre-existing plexiform neurofibromas. Most studies treat all NF1-associated neurofibromas as a single entity, ignoring important differences between pathological details, clinical presentation and natural history. I analysed clinical information on 476 probands with NF1 from the Henri Mondor database and found that individuals with subcutaneous neurofibromas were 3 times more likely to have internal plexiform neurofibromas and that individuals with internal plexiform neurofibromas were 20 times more likely to have MPNSTs than individuals without such tumours. These findings suggest that pathogenic differences in some neurofibromas may lead to different risks of progressing to malignancy. I collected formalin-fixed paraffin-embedded samples from NF1 patients and classified them histologically as nodular or diffuse neurofibromas. By using histochemistry, I found that mast cells were absent in MPNSTs and significantly more abundant in diffuse neurofibromas than in nodular neurofibromas. Mast cells were located at the periphery of nodular neurofibromas but were evenly distributed throughout diffuse neurofibromas. Double immunofluorescent staining of S100 (a marker of Schwann cells, the presumed tumour progenitor cell type) and neurofibromin (the protein product of NF1 gene) (Nf) showed that diffuse neurofibromas had significantly more S100+/Nf+ cells and fewer S100-/Nf- cells than nodular neurofibromas. Using laser microdissection of immunofluorescently stained slides, I found that some neurofibromas show evidence of clonal (presumably neoplastic) proliferation of S100+/Nf- cells while other neurofibromas appear to be neurofibromin haploinsufficient and polyclonal, and thus may be hyperplastic rather than neoplastic lesions. The results presented in this thesis support the hypothesis that neurofibromas in people with NF1 are pathogenically heterogeneous and that some kinds of neurofibromas are associated with the development of MPNSTs. These findings have important implications for the surveillance and treatment of people with NF1.Medicine, Faculty of
Medical Genetics, Department of
Graduate
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Osmond, Ronald Ian William. "Barley family five pathogenesis-related proteins." Title page, abstract and contents only, 2000. http://web4.library.adelaide.edu.au/theses/09APSP/09apspo83.pdf.
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Bibliography: leaves 119-143. The work described in this thesis was designed to investigate one component of the plant's defence against pathogen attack, namely the production of PR-5 proteins... Several roles have been proposed for PR-5 proteins including adaption of plant cells to osmotic stress, antifreeze activity, polysaccharide hydrolase activity, fungal plasma membrane pore forming activity, and a-amylase/trypsin inhibition. The experiments that are described in the thesis were aimed at defining the function of barley PR-5 proteins.(abstract)
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Hindersson, Maria. "Coxsackie B virus pathogenesis in mice /." Stockholm : Karolinska institutet, 2006. http://diss.kib.ki.se/2006/20060608hind/.
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Björkholm, Britta. "Helicobacter pylori : cellular interactions and pathogenesis /." Stockholm : [Karolinska institutets bibl.], 2001. http://diss.kib.ki.se/2001/91-7349-084-9/.
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Dahl, Helena. "Epidemiology and pathogenesis of HHV-6 /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-100-4/.
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Klingström, Jonas. "Hantaviruses : animal models, immunology and pathogenesis /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-071-0/.
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Jong, Ype Peter de. "Pathogenesis of immune-mediated murine colitis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2002. http://dare.uva.nl/document/64772.
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Bonhoeffer, Sebastian. "Models of viral evolution and pathogenesis." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294217.
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Fahim, Ahmed. "The pathogenesis of idiopathic pulmonary fibrosis." Thesis, University of Hull, 2011. http://hydra.hull.ac.uk/resources/hull:5296.
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Idiopathic pulmonary fibrosis (IPF) is a restrictive pulmonary disorder of unknown aetiology with a relentless disease course and a median survival of 3 years after the diagnosis. It is the most common idiopathic interstitial lung disease (ILD) with a basal and peripheral predominance associated with temporal and geographical heterogeneity. As the pathogenesis of this disease is poorly understood, the aim of this work was to investigate the pathobiology of IPF in a prospective manner. There is evidence of a strong association of gastro-esophageal reflux and vascular disease with IPF. Moreover, a proportion of patients have evidence of immunological antibodies without any evidence of connective tissue or autoimmune disease. The data presented in this thesis suggest that platelet-monocyte complexes may be involved in the pathogenesis of IPF at molecular level as suggested by the flow cytometric data utilizing monoclonal antibodies to platelets (CD42a) and monocytes (CD14). Moreover, expression of CD40L, P-selectin and PSGL-1 on platelets and subpopulation of leukocytes suggested that platelet expression of these molecules is not significantly different in IPF as compared to ILD other than IPF or non-ILD controls. Furthermore, platelet mediated injury hypothesis is supported by significant elevation of platelet endothelial cell adhesion molecule in plasma of IPF patients. Reflux of gastric secretions into the tracheo-bronchial tree is another attractive hypothesis in light of remarkably high prevalence of gastro-esophageal reflux disease (GERD) in IPF. The data suggest that patients with IPF have significantly higher gastro and extra-esophageal reflux symptoms when assessed by Hull airway reflux questionnaire (HARQ). However, there was a lack of objective evidence of extra-esophageal reflux measured by exhaled breath pepsin concentration or significantly higher prevalence of Helicobacter Pylori. Furthermore, there was evidence of immune mediated injury in IPF by indirect immunofluorescence study of alveolar epithelial (A549) cells as significant membranous enhancement of A549 cells by anti-IgG antibodies was demonstrated in IPF patients’ sera. However, Human umbilical vein endothelial cells (HUVEC) did not show any differential staining pattern with either anti-IgG or IgM. Hence, there is a suggestion of alveolar epithelial disruption mediated by immune mechanisms with a predominant involvement of IgG antibodies. Furthermore, epithelial derangement may extend into the respiratory epithelium with release of carcinoembryonic antigen (CEA) in peripheral circulation as evidenced by a significant correlation of raised CEA level and lung function impairment in IPF. These findings provide clinical and molecular evidence of novel mechanisms of pathogenesis of IPF with increased platelet-monocyte aggregation. Moreover, immune mediated alveolar epithelial dysfunction involving IgG antibodies may provide further insight into the understanding of the pathogenesis and natural history of this fibrotic disease.
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Scully, Marie Ann. "The pathogenesis of thrombotic Thrombocytopenic Purpura." Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498417.
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容振威 and Chun-wai Yung. "A molecular study of NPC pathogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1994. http://hub.hku.hk/bib/B31212748.
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