Dissertations / Theses on the topic 'Physiological, Pathological'
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Embleton, Sally J. "Physiological and pathological human ocular perfusion characteristics." Thesis, Aston University, 2002. http://publications.aston.ac.uk/14558/.
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There were three principle aims to this thesis. Firstly, the acquisition protocols of clinical blood flow apparatus were investigated in order to optimise them for both cross-sectional and longitudinal application. Secondly, the effects of physiological factors including age and systematic circulation on ocular blood flow were investigated. Finally, the ocular perfusion characteristics of patients diagnosed with ocular diseases considered to be of a vascular origin were investigated. The principle findings of this work are:- 1) Optimisation of clinical investigations Photodiode sensitivity of the scanning laser Doppler flowmeter should be kept within a range of 70-150 DC when acquiring images of the retina and optic nerve head in order to optimise the reproducibility of capillary blood flow measures. Account of the physiological spatial variation in retinal blood flow measures can be made using standard analysis protocols of the scanning laser Doppler flowmeter combined with a local search strategy. Measurements of pulsatile ocular blood flow using the ocular blood flow analyser are reproducible, however this reproducibility can be improved when consecutive intraocular pressure pulses are used to calculate pulsatile ocular blood flow. Spectral analysis of the intraocular pressure pulse-wave is viable and identifies the first four harmonic components of the waveform. 2) Physiological variation in ocular perfusion Age results in a significant reduction in perfusion of the retinal microcirculation, which is not evident in larger vessel beds such as the choroid. Despite known asymmetry in the systemic vasculature, no evidence of interocular asymmetry in ocular perfusion is apparent. 3) Pathological variation in ocular perfusion In primary open angle glaucoma, perfusion is reduced in the retinal microcirculation of patients classified as having early to moderate visual field defects. However, ocular pulsatility defects are masked when patients and subjects are matched for systemic variables (pulse rate and mean arterial pressure); differentiation is facilitated by the application of waveform analysis to the continuos intraocular pressure curve even in the early stages of disease. Diabetic patients with adequate glycaemic control, exhibit maintenance of macular blood flow, macular topography and visual function following phacoemulsification.
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Robbie, Linda Ann. "Physiological and pathological role of inhibitors of fibrinolysis." Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU539722.
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The activity of the fibrinolytic system is dependent on the activation of plasminogen to plasmin by the activators t-PA and u-PA. These proteases are regulated by plasminogen activator inhibitor 1 (PAI-1); 2-antiplasmin (2-AP) inhibits the plasmin generated by their action. Both PAI-1 and 2-AP occur in plasma and platelets. The relative importance of the plasma and platelet inhibitors of fibrinolysis was examined using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen, fibrinogen and t-PA at concentrations close to physiological. Purified 2-AP and PAI-1 caused dose-dependent inhibition of clot lysis. The inhibition due to normal plasma, platelet-rich or platelet-poor, was neutralised only by antibodies to 2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 x 108 platelets/ml, gave rise to marked inhibition of clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of platelets to plasma, 2-AP was the dominant inhibitor. When the platelet to plasma ratio was elevated some 20-fold, platelet PAI-1 provided a significant contribution. At a platelet to plasma ratio of 50:1 the balance was shifted such that PAI-1 became the dominant inhibitor. These results indicate that the local concentration of platelet PAI-1 would have to be very high for this inhibitor to achieve a significant regulatory role relative to that of plasma 2-AP. The study was subsequently extended to examine the concentrations of these inhibitors, and other related components of the fibrinolytic system, in human thrombi formed in vivo and normal and diseased arteries.
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Luth, Eric Sloan. "Physiological and Pathological Characterization of Alpha-Synuclein Oligomers." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11513.
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α-Synuclein (αSyn) is highly abundant cytosolic protein whose conversion into insoluble fibrils is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Despite decades of research, fundamental questions regarding αSyn biology are unresolved. Soluble, prefibrillar oligomers, not their fibrillar end products, are believed to be neurotoxic in humans and in disease models, but their mechanism of action remains unknown. Evidence from our lab and others increasingly suggests that, in healthy cells, αSyn does not exist purely as an unfolded monomer, as the field has long believed, but also as aggregation-resistant, α-helical oligomers; however, their physiological role remains controversial. Thus, my aim was twofold: to characterize toxic αSyn species in the context of mitochondrial dysfunction, a central phenotypic feature of PD; and to purify helical αSyn oligomers from human brain to enable further characterization of physiological αSyn.
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Lai, Duen-mun, and 黎端敏. "The neuropsychological basis of pathological gambling." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46480456.
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Sørhaug, Sveinung. "The Pulmonary Neuroendocrine System : Physiological, pathological and tumourigenic aspects." Doctoral thesis, Norwegian University of Science and Technology, Department of Circulation and Medical Imaging, 2007. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-1760.
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Nevroendokrine (NE) celler er en benevnelse på spesialiserte celler som finnes diffust utbredt i flere organ i kroppen og som har evnen til å produsere og skille ut hormon-liknende substanser. I lungene oppfattes ansamlinger av disse cellene som sanseorgan som monitorerer oksygen-nivået, og de spiller sannsynligvis en viktig rolle for lungenes utvikling, regulering av lungesirkulasjon og luftstrøm, samt immunrespons.
Hovedmålet med avhandlingen har vært å se på ulike sider ved lungenes NE system ved fysiologiske og patologiske tilstander, med fire delarbeider som hver for seg belyser ulike aspekt ved dette.
I det første arbeidet ble den generelle NE markøren kromogranin A (CgA) målt i blodprøver fra personer som deltok i Helseundersøkelsen i Nord-Trøndelag (HUNT 1995-97). Resultatene viste at mannlige deltakere med dårlig lungefunksjon hadde høyere nivå av CgA enn deltakere med normal lungefunksjon, som et uttrykk for NE aktivering.
Det andre arbeidet omhandler et 72 ukers eksponerings-forsøk med inhalasjon av karbon monoksid (CO) hos rotter gitt i konsentrasjoner som tilsvarer blod-verdier hos stor-røykere. Bortsett fra forstørret hjerte, ble det ikke funnet andre røyke-relaterte skader på hjerte/kar-systemet eller lungene. CO hadde ingen effekt på svulstforekomst eller forandringer i antall NE celler.
I det tredje arbeidet ble ulike NE markører undersøkt med immunhistokjemiske, immunelektronmikroskopiske og biokjemiske metoder hos pasienter med ikke-småcellet lungecancer. Hovedfunnet her var et større antall svulster positive for NE markører enn tidligere beskrevet når signalforsterkende teknikker ble brukt ved immunhistokjemi. Dette kan ha betydning for forståelsen av svulstenes biologi, og kan være uttrykk for at lungenes NE celler er opphavsceller for flere slike svulster enn tidligere antatt.
Det siste delarbeidet belyser sekresjon av substanser fra lungenes NE system ved hypoksi i en isolert, ventilert og sirkulert rottelunge-modell. Ved lave oksygennivå falt konsentrasjonen av proteinet bombesin i buffer sirkulert gjennom lungekretsløpet. I tillegg ble det funnet øket antall immunmerkede celler med calcitonin gene-related peptide, noe som tyder på redusert cellulær utskillelse ved eksponering for hypoksi. Resultatene viser at hypoksi er assosiert med raske forandringer i lungenes NE system for å opprettholde en balansert ventilasjon og sirkulasjon.
Samlet gir arbeidene økt kunnskap om det nevroendokrine system ved ulike sykdoms-prosesser som luftveisobstruksjon, inhalasjon av gasser som CO, i svulstutvikling og ved fysiologiske prosesser som hypoksi.
Paper II is reprinted with kind permission of Elsevier, sciencedirect.com
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Crampton, Matthew S., and n/a. "Differential Gene Expression in Pathological and Physiological Cardiac Hypertrophy." Griffith University. School of Biomolecular and Biomedical Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070104.165826.
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Cardiac hypertrophy defines an adaptive process brought about in response to sustained increases in haemodynamic work. Cardiomyocytes undergo an initial compensatory phase in which enlargement and contractility alterations normalise wall stress and maintain adequate perfusion of organs. In pathological hypertrophy, this deteriorates to a decompensated state characterised by ventricular dysfunction and predisposition to heart failure. In contrast, physiological hypertrophy and associated enhanced cardiac functioning arising from chronic exercise training does not progress to heart failure. Determination of the molecular pathways underlying myocardial hypertrophy remains a challenge for cardiovascular research. The objective of the work presented in this thesis was to identify genes differentially expressed during pathological and physiological hypertrophy in order to enhance our knowledge of the mechanistic processes involved. A reverse Northern hybridisation method was applied to profile the expression of specifically selected genes in the hypertrophic models examined. Functional categories represented in the gene panel assembled included cardiac contractile and cytoskeletal markers, matrix metalloproteinases, vasoactive pathway factors, calcium handling genes, ion channels, cardiac regulatory factors, signalling pathway intermediates, apoptotic factors and histone deacetylases. In order to investigate pathological hypertrophy, a deoxycorticosterone acetate-salt (DOCA-salt) rat model was utilised. DOCA-salt treated rats used in this study demonstrated a 1.4-fold increase in heart weight to body weight ratio compared to controls. Impaired cardiac function indicative of a decompensated pathological phenotype in the DOCA-salt treated group was demonstrated by way of decreased chamber size, impaired myocardial compliance and significantly reduced cardiac output. Reverse Northern hybridisation analysis of 95 selected genes identified a number of candidates with differential expression in hearts of DOCA-salt treated rats. Increased gene expression was demonstrated for the collagenase MMP1 and stress-activated signal transduction factor Sin1. In contrast, the sarcoplasmic reticulum calcium ATPase SERCA-2 and anti-apoptotic factor BCL2l-10 genes exhibited decreased expression. To investigate changes in gene expression associated with physiological hypertrophy, use was made of an endurance run-trained rat model. The run-trained rats used in this study demonstrated a 24.1% increase in heart weight to body weight ratio and improvements in performance consistent with physiological cardiac adaptation. These performance indicators included improvements in systolic volume, cardiac output, myocardial compliance and bio-energetic function. Reverse Northern hybridisation expression analysis of 56 genes identified a number of differentially expressed mRNA transcripts in run-trained hypertrophied hearts. Four genes shown to demonstrate reduced expression in the run-trained rat model were interleukin-1 receptor associated kinase (IRAK1) and the developmentally expressed transcription factors Nkx-2.3, dHAND, and IRX-2. Based upon the reverse Northern hybridisation results, four genes were selected for Western blotting analysis of rat cardiac tissue. Of these, MMP1 and a putative isoform of Sin1 exhibited increased levels in DOCA-salt treated hypertrophic left ventricular tissue, results that correlate with the findings of increased mRNA expression for these two genes. Therefore, this study identified MMP1 and Sin1 as candidates involved in pathological but not physiological hypertrophy. This finding is in accord with other recent investigations demonstrating that pathological hypertrophy and physiological hypertrophy are associated with distinct molecular phenotypes. An aside to the major objective of identifying genes differentially regulated in left ventricular hypertrophy involved the application of the P19CL6 cell in vitro model of cardiomyogenesis to compare protein expression during hypertrophy and development. The Sin1 isoform, found to be up-regulated during DOCA-salt induced hypertrophy, was also shown to be more abundant in differentiating, than non-differentiating, P19CL6 cells. This result is consistent with the developing paradigm that implicates 'fetal' genes in the hypertrophic remodelling process.
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Hill, Nathan R. "Analysis of non-steady state physiological and pathological processes." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:c96c88a6-5dd4-43ce-989b-ac524d2654ea.
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The analysis of non steady state physiological and pathological processes concerns the abstraction, extraction, formalisation and analysis of information from physiological systems that is obscured, hidden or unable to be assessed using traditional methods. Time Series Analysis (TSA) techniques were developed and built into a software program, Easy TSA, with the aim of examining the oscillations of hormonal concentrations in respect to their temporal aspects – periodicity, phase, pulsatility. The Easy TSA program was validated using constructed data sets and used in a clinical study to examine the relationship between insulin and obesity in people without diabetes. In this study fifty-six non-diabetic subjects (28M, 28F) were examined using data from a number of protocols. Fourier Transform and Autocorrelation techniques determined that there was a critical effect of the level of BMI on the frequency, amplitude and regularity of insulin oscillations. Second, information systems formed the background to the development of an algorithm to examine glycaemic variability and a new methodology termed the Glycaemic Risk in Diabetes Equation (GRADE) was developed. The aim was to report an integrated glycaemic risk score from glucose profiles that would complement summary measures of glycaemia, such as the HbA1c. GRADE was applied retrospectively to blood glucose data sets to determine if it was clinically relevant. Subjects with type 1 and type 2 diabetes had higher GRADE scores than the non-diabetic population and the contribution of hypo- and hyperglycaemic episodes to risk was demonstrated. A prospective study was then designed with the aim to apply GRADE in a clinical context and to measure the statistical reproducibility of using GRADE. Fifty-three (Male 26, Female 27) subjects measured their blood glucose 4 times daily for twenty-one days. The results were that lower HbA1c’s correlated with an increased risk of hypoglycaemia and higher HbA1c’s correlated with an increased risk of hyperglycaemia. Some subjects had HbA1c of 7.0 but had median GRADE values ranging from 2.2 to 10.5. The GRADE score summarized diverse glycaemic profiles into a single assessment of risk. Well-controlled glucose profiles yielded GRADE scores <= 5 and higher GRADE scores represented increased clinical risk from hypo or hyperglycaemia. Third, an information system was developed to analyse data-rich multi-variable retinal images using the concept of assessment of change rather than specific lesion recognition. A fully Automated Retinal Image Differencing (ARID) computer system was developed to highlight change between retinal images over time. ARID was validated using a study and then a retrospective study sought to determine if the use of the ARID software was an aid to the retinal screener. One hundred and sixty images (80 image pairs) were obtained from Gloucestershire Diabetic Eye Screening Programme. Images pairs were graded manually and categorised according to how each type of lesion had progressed, regressed, or not changed between image A and image B. After a 30 day washout period image pairs were graded using ARID and the results compared. The comparison of manual grading to grading using ARID (Table 4.3) demonstrated an increased sensitivity and specificity. The mean sensitivity of ARID (87.9%) was increased significantly in comparison to manually grading sensitivity (84.1%) (p<0.05). The specificity of the automated analysis (87.5%) increased significantly from the specificity (56.3%) achieved by manually grading (p<0.05). The conclusion was that automatic display of an ARID differenced image where sequential photographs are available would allow rapid assessment and appropriate triage. Forth, non-linear dynamic systems analysis methods were utilised to build a system to assess the extent of chaos characteristics within the insulin-glucose feedback domain. Biological systems exist that are deterministic yet are neither predictable nor repeatable. Instead they exhibit chaos, where a small change in the initial conditions produces a wholly different outcome. The glucose regulatory system is a dynamic system that maintains glucose homeostasis through the feedback mechanism of glucose, insulin, and contributory hormones and was ideally suited to chaos analysis. To investigate this system a new algorithm was created to assess the Normalised Area of Attraction (NAA). The NAA was calculated by defining an oval using the 95% CI of glucose & Insulin (the limit cycle) on a phasic plot. Thirty non-diabetic subjects and four subjects with type 2 diabetes were analysed. The NAA indicated a smaller range for glucose and insulin excursions with the non-diabetics subjects (p<0.05). The conclusion was that the evaluation of glucose metabolism in terms of homeostatic integrity and not in term of cut-off values may enable a more realistic approach to the effective treatment and prevention of diabetes and its complications.
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Kenyon, Karla. "The physiological and pathological regulation of apoptotic cell clearance /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Immunology) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 177-196). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Aguirre, Gutiérrez Marisa Mayela. "Behavioural and physiological indices of normal and pathological sleepiness." Thesis, University of Ottawa (Canada), 1985. http://hdl.handle.net/10393/4942.
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Whittaker, Roger Graham. "The role of mitochondria in physiological and pathological cortical oscillations." Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.525023.
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Johal, N. S. "The physiological properties of the pathological and normal paediatric bladder." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1403222/.
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Congenital abnormalities of the lower urinary tract of children adversely affect bladder function, both immediately and throughout development, and can result in renal failure. Such patients with pathological bladder states often require reconstructive surgery in an attempt to restore lower urinary tract function. However, it is unknown if there are functional defects to the musculature of the bladder - the detrusor smooth muscle. The aim was to examine the functional properties of human paediatric detrusor in normal patients and those with pathological bladder conditions. Full thickness bladder specimens were taken from pathological bladder conditions such as posterior urethral valves, neuropathic bladder, and bladder exstrophy. Normal tissue was obtained from those with urachal anomalies or from those undergoing ureteric reimplantation procedures. Ethical committee approval and patient consent were obtained at the time of surgery at Great Ormond Street Hospital. The bladder contractile properties were characterised by in vitro myopathy and electrical field stimulation in all patient groups. The histological properties were also examined in these groups. Additionally, with bladder exstrophy samples the viscoelastic properties of the tissue was measured by passive stretch studies to determine their contribution to the overall mechanical properties. Finally, intracellular Ca2+ responses in single detrusor muscle cells to agonist stimulation were measured by epifluorecence microscopy. Nerve and agonist-mediated contraction amplitude was significantly less in samples from patients with pathological bladders compared to those with normal bladder. Histological evaluation revealed an increase in the connective tissue to smooth muscle ratio in pathological bladders. In bladder exstrophy the tissue was mechanically stiffer but the single cell responses were similar to the normal detrusor responses following agonist application. The data shows that detrusor from paediatric patients with pathological bladders exhibited reduced contractility, whether elicited by excitatory nerves or agonist application. Functional innervation was reduced in pathological bladders and the pattern of excitatory neurotransmitter release was altered.
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Brant, Stephen. "Distribution of renal S100 proteins in physiological and pathological models." Thesis, University of East London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342101.
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Levonyak, Nicholas S. "The role of neuropilin 2 in physiological and pathological angiogenesis." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12145.
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Thesis (M.A.)--Boston UniversityNeuropilin 2 (NRP2) is a transmembrane receptor protein that was first discovered on neurons and then endothelial cells. On endothelial cells, it serves as co-receptor with the vascular endothelial growth factor receptor (VEGFR) to bind VEGF and induce a pro-(lymph)angiogenic intracellular signal. In addition to VEGF, NRP2 is also a receptor for semaphorin 3F (SEMA3F), which upon binding to NRP2 and Plexin A1 induces a strong anti-angiogenic signal. It is our hypothesis that SEMA3F could be a potentially effective treatment for metastatic cancers. A greater understanding of the regulation and expression of its receptor, NRP2, is needed. While NRP2 has been most robustly studied for its role in the vasculature, recent studies have shown that it is expressed on other cell types as well such as dendritic cells, T-cells, and visceral smooth muscle cells. In this study, we used western blot and immunohistochemistry to explore various different organs and cell types in an attempt to locate other novel locations of NRP2 expression. In particular, we found several new tissues that express NRP2 including the uterus and adipose tissue. Interestingly, NRP2 is expressed much more strongly in brown adipose tissue than white adipose tissue. In addition, we found that expression of NRP2 in adult organs is weaker than during development but is apparent, particularly on lung vascular EC and the intestinal lymphatic lacteal. In addition, we used several in vivo angiogenesis assays in order to help understand how NRP2 is regulated in the mature vasculature. We found that in the cutaneous wound healing assay, Nrp2 knockout mice healed at the same rate as their wild-type and heterozygous littermates. However, when delayed type hypersensitivity reactions were induced in these mice, the Nrp2 knockouts demonstrated persistent swelling over a longer period of time in comparison to littermates. We also examined how the loss of NRP2 affected pathological angiogenesis by orthotopically injecting a murine syngeneic pancreatic adenocarcinoma cell line (Panc0H7) into the Nrp2 knockout mice. These mice displayed smaller tumors, less grossly apparent metastases, and less ascites. Taken together, these data suggest that NRP2 is important in physiological and pathological angiogenesis. Anti-NRP2 or SEMA3F strategies may represent promising anti-metastatic therapies.
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Nimmo, Judith E. "Plasma 5-S-cysteinyldopa in physiological and pathological pigmentary states." Thesis, University of Edinburgh, 1985. http://hdl.handle.net/1842/19193.
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Takehashi, Masanori. "Physiological and pathological roles of septin 3 in human brain." Kyoto University, 2004. http://hdl.handle.net/2433/145272.
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Keller, Matthias [Verfasser]. "Formation of Intracardiac Electrograms under Physiological and Pathological Conditions / Matthias Keller." Karlsruhe : KIT Scientific Publishing, 2014. http://www.ksp.kit.edu.
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Pujols, Pujol Jordi. "Connection between protein disorder, folding and aggregation: Physiological and Pathological implications." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/671603.
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Les Proteïnes o Regions Intrínsecament Desordenades (IDPs, IDRs) son una classe de polipèptids que són incapaços d’adoptar una estructura tridimensional definida en el seu estat natiu. La seva funció depèn de la flexibilitat estructural i de la fluctuació entre un conjunt de conformacions diferents. Aquest fet els permet interaccionar amb una gran varietat de macromolècules i regular la transmissió de senyals cel·lulars. Els canvis en els factors ambientals, les modificacions post-traduccionals i la interacció amb altres proteïnes influeixen en el seu estat estructural, induint-ne el plegament condicional i, per tant, modificant-ne la seva funció. En aquesta tesi enfoquem la transició desordre-ordre des de dues perspectives diferenciades. D’una banda, el seu paper en les funcions fisiològiques i, per l’altra, la seva implicació en el desenvolupament de malalties. En primer lloc, estudiem com l’estat redox afecta en la transició estructural de dues proteïnes riques en disulfur que localitzen a l’espai intermembranós del mitocondri. Tot i compartir la mateixa conformació nativa, demostrem que ambdues proteïnes segueixen vies de plegament independents. Tant la seqüència primària d’aminoàcids com l’estat conformacional inicial defineixen la via de plegament. Per una banda, COX17 es troba desordenada en l’estat reduït i el tancament de la regió pròxima al loop estructural dirigeix el plegament. Per l’altra, l’estat reduït de TRIAP1 es comparable a un molten globule. Aquesta conformació empaquetada limita la reacció de plegament, però es indispensable per a que TRIAP1 pugui realitzar la seva funció cel·lular. En segon lloc, estudiem la correlació seqüencial entre regions d’interacció i la tendència a formar agregats amiloides, en el context de les regions desordenades. Demostrem que Hsf1, una proteïna reguladora de la proteostasis, conté un domini críptic d’agregació prion-like en la seva regió desordenada del C-terminal. Efectivament, aquest domini agrega i forma fibres amiloides. Finalment, ens centrem en l’agregació de la proteïna α-synuclein, responsable de la malaltia del Parkinson. El desordre estructural d’aquesta proteïna impedeix l’ús d’estratègies racionals que permetin dissenyar molècules que inhibeixin la seva agregació. En aquest context, implementem un cribratge massiu com a metodologia per identificar noves molècules que puguin ser efectives. Mitjançant aquesta tècnica, hem identificat tres candidats amb activitat inhibidora: Syunclean-D, ZPD-2, and ZPDm. En aquesta tesi, mostrem les seves propietats anti-amiloides i neuroprotectores, al mateix temps que discutim el seu potencial farmacològic.Las proteínas o Regiones Intrínsecamente Desordenadas (IDPs, IDRs) son una clase de polipéptidos incapaces de adoptar una estructura tridimensional definida en su estado nativo. Su función depende de la flexibilidad estructural y de la fluctuación entre un conjunto de diferentes conformaciones. Esto les permite interaccionar con una gran variedad de macromoléculas y regular la transmisión de señales celulares. Variaciones en los factores ambientales, las modificaciones post-traduccionales y la interacción con otras proteínas influyen en su estado estructural de éstas, lo que induce su plegamiento condicional y modifica su función. En esta tesis enfocamos la transición desorden-orden desde dos perspectivas deferentes. Por un lado, su papel en las funciones fisiológicas y, por el otro, su implicación en el desarrollo de enfermedades. En primer lugar, estudiamos como el estado redox afecta en la transición estructural de dos proteínas ricas en disulfuros, que localizan en el espacio intermembranalde la mitocondria. Aunque comparten a misma conformación nativa, demostramos que las dos proteínas siguen vías de plegamiento independientes. Tanto su secuencia primaria de amino ácidos como su estado conformacional inicial definen su plegamiento. Por un lado, COX17 se encuentra desordenada en su estado reducido y el cierre de la región proximal al loop estructural dirige su plegamiento. Por el otro, el estado reducido de TRIAP1 es comparable a un molten globule. Esta conformación empaquetada limita su reacción de plegamiento, pero es indispensable para que TRIAP1 pueda realizar su función celular. En segundo lugar, estudiamos la correlación secuencial entre regiones de interacción y su tendencia a formar agregados amiloides, en el contexto de las regiones desordenadas. Demostramos que Hsf1, una proteína reguladora de la proteostasis, contiene un dominio críptico de agregación prion-like en la región desordenada del C-terminal. Confirmamos que este dominio agrega y forma fibras amiloides. Finalmente, nos centramos en la agregación de la proteína α-synucleina, responsable de la enfermedad del Parkinson. El desorden estructural de dicha proteína impide el uso de estrategias racionales que permitan diseñar moléculas inhibidoras de su agregación. En este contexto, implementamos un cribaje masivo como metodología para identificar nuevas moléculas. Mediante esta técnica, hemos identificado tres candidatos con esta actividad inhibidora: Syunclean-D, ZPD-2, and ZPDm. En esta tesis, mostramos sus propiedades anti-amiloides y neuroprotectoras, al mismo tiempo que discutimos su potencial farmacológico.
Intrinsically Disordered Proteins (IDPs) and Regions (IDRs) are a class of polypeptides that lack defined three-dimensional structures. Instead, they populate a dynamic ensemble of flexible conformers that endorse them with unique properties to interact with multiple partners and mediate in signal transduction. Environmental factors, post-translational modifications, and binding partners impact the IDPs’ conformational space, promoting structural transitions that regulate their functions. This thesis has addressed the disorder-to-order transition phenomenon from two perspectives: its physiological function and its implication in disease. First, we studied the redox-driven conformational transition of two small disulfide-rich mitochondrial proteins. We demonstrate that both polypeptides follow different folding pathways despite sharing a common fold. The reaction is determined by the primary sequence of amino acids and the reduced and unfolded species’ conformational state. Reduced COX17 is mostly disordered, and its folding is directed by the local packing of a loop region. In contrast, TRIAP1 reduced state resembles a molten globule. This early loosely packed conformer biases and slows down the folding pathway, but its population is unavoidable, because it arises from functional constraints in the folded state. Second, we addressed the sequential overlap between amyloidogenic and interaction regions in the context of disordered proteins, to demonstrate that the extended C-terminus of the proteostasis guardian protein, Hsf1, contains a cryptic prion-like domain with the potential to assemble into amyloid fibrils. Finally, we focused our attention on the aggregation of α-synuclein, the main culprit of the onset and progression of Parkinson’s Disease. This protein’s disordered nature precludes the use of rational strategies to design effective drugs that block its transition to ordered and deleterious amyloids. Therefore we implemented a blind high-throughput screening methodology to identify novel small molecules that might succeed in that purpose. This effort rendered three promising candidates: Syunclean-D, ZPD-2, and ZPDm. Their anti-amyloidogenic and neuroprotective properties were characterized, and their pharmacologic potential was discussed.”
Universitat Autònoma de Barcelona. Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina
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Buarque, de Lima Neto Fernando. "Modelling neural processing using Venn-networks in physiological and pathological scenarios." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404797.
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Kelly, James Francis. "A clinical study of physiological and pathological tremor in the elderly." Thesis, Queen's University Belfast, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356865.
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Orsi, Antonia. "Physiological regulation and pathological inhibition of tissue respiration by nitric oxide." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394170.
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Huang, Charlie Chia Wei. "Regulation of Cat-1 gene transcription during physiological and pathological conditions." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270242874.
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Govender, Shogan. "Oral physiological pigmentation in a Western Cape sample." University of the Western Cape, 2018. http://hdl.handle.net/11394/6514.
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Magister Chirurgiae Dentium - MChDOral physiological pigmentation presents with great variability with respect to sites, forms, patterns and contrasts in colour. Knowledge of the existence of pigmented lesions and their significance remained unclear for both the general public and oral clinicians alike. The possibility of malignant transformation of some pigmented lesions makes them important to monitor and biopsy. The prevalence of physiological pigmentation is unknown for the defined population group in this study. The results will be beneficial as part of a larger multicentre study with South Africa (Feller et al, 2015). Methodology: A cross sectional analytical study of patients that attended the University of the Western Cape Oral Health centres for routine treatment was conducted. After obtaining informed consent, patients were screened and asked a series of questions using a standardized questionnaire. From these completed questionnaires a prevalence relating to oral physiological pigmentation was determined. Oral physiological pigmentation did not have a male or female predominance in this study population group, but was associated with increased age. Oral pigmentation seemed to be well represented after 18 years of age. Patients were not usually aware of the pigmented gingiva unless being made aware off it.
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Pritchard, Ronald Douglas. "Magnetic resonance spectroscopy studies of the myocardium under physiological and pathological conditions." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362882.
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Situ, Chen. "Development of region-specific antisera to GLP-1 : physiological and pathological studies." Thesis, Queen's University Belfast, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388192.
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Muzyamba, Morris Chivwaba. "Physiological and pathological modulation of K⺠transport in red blood cells." Thesis, University of Liverpool, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343617.
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Morotti, Stefano <1984>. "Computational Modeling of Cardiac Excitation-Contraction Coupling in Physiological and Pathological Conditions." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5427/.
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The cardiomyocyte is a complex biological system where many mechanisms interact non-linearly to regulate the coupling between electrical excitation and mechanical contraction. For this reason, the development of mathematical models is fundamental in the field of cardiac electrophysiology, where the use of computational tools has become complementary to the classical experimentation. My doctoral research has been focusing on the development of such models for investigating the regulation of ventricular excitation-contraction coupling at the single cell level. In particular, the following researches are presented in this thesis:
1) Study of the unexpected deleterious effect of a Na channel blocker on a long QT syndrome type 3 patient. Experimental results were used to tune a Na current model that recapitulates the effect of the mutation and the treatment, in order to investigate how these influence the human action potential. Our research suggested that the analysis of the clinical phenotype is not sufficient for recommending drugs to patients carrying mutations with undefined electrophysiological properties.
2) Development of a model of L-type Ca channel inactivation in rabbit myocytes to faithfully reproduce the relative roles of voltage- and Ca-dependent inactivation. The model was applied to the analysis of Ca current inactivation kinetics during normal and abnormal repolarization, and predicts arrhythmogenic activity when inhibiting Ca-dependent inactivation, which is the predominant mechanism in physiological conditions.
3) Analysis of the arrhythmogenic consequences of the crosstalk between β-adrenergic and Ca-calmodulin dependent protein kinase signaling pathways. The descriptions of the two regulatory mechanisms, both enhanced in heart failure, were integrated into a novel murine action potential model to investigate how they concur to the development of cardiac arrhythmias.
These studies show how mathematical modeling is suitable to provide new insights into the mechanisms underlying cardiac excitation-contraction coupling and arrhythmogenesis.Il cardiomiocita è un sistema biologico complesso in cui molti meccanismi interagiscono non linearmente nel processo che accoppia l'eccitazione elettrica alla contrazione meccanica. Lo sviluppo di modelli matematici è quindi fondamentale nel settore dell'elettrofisiologia cardiaca, dove l'uso di strumenti computazionali è diventato complementare alla classica sperimentazione. La mia attività di ricerca si è concentrata sullo sviluppo di tali modelli allo scopo di investigare la regolazione dell'accoppiamento eccitazione-contrazione nella cellula ventricolare. In particolare, questa tesi presenta le seguenti attività: 1) Studio delle inaspettate deleterie conseguenze della somministrazione di un bloccante del canale sodio ad un paziente affetto da sindrome del QT lungo di tipo 3. I risultati sperimentali sono stati usati per riprodurre con un modello di corrente sodio gli effetti di mutazione e trattamento farmacologico, al fine di studiare come questi influenzino il potenziale d'azione umano. La nostra ricerca ha suggerito che l'analisi del fenotipo clinico non è sufficiente per somministrare un farmaco a pazienti che presentano mutazioni con indefinite proprietà elettrofisiologiche. 2) Sviluppo di un modello di inattivazione del canale calcio di tipo L nel cardiomiocita di coniglio allo scopo di riprodurre fedelmente i contributi di inattivazione voltaggio e calcio-dipendente. Il modello, applicato all'analisi delle cinetiche di tale corrente durante normale ed anormale ripolarizzazione, ha predetto lo sviluppo di attività aritmica in caso di inibizione del meccanismo calcio-dipendente, il cui effetto è predominante in condizioni fisiologiche. 3) Analisi delle conseguenze aritmogene dell'interazione tra le vie di segnalazione di stimolazione beta-adrenergica e proteina chinasi calcio-calmodulina dipendente. Le descrizioni dei due sistemi regolatori, entrambi aumentati in condizioni di insufficienza cardiaca, sono state integrate in un nuovo modello di potenziale d'azione murino, al fine di studiare come questi concorrono nell'insorgenza di aritmie. Questi studi mostrano come la modellistica matematica permetta di investigare i meccanismi che regolano l'accoppiamento eccitazione-contrazione e l'aritmogenesi.
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Sculthorpe, Nicholas. "Left ventricular long axis dynamics in pathological and physiological left ventricular hypertrophy." Thesis, University of South Wales, 2002. https://pure.southwales.ac.uk/en/studentthesis/left-ventricular-long-axis-dynamics-in-pathological-and-physiological-left-ventricular-hypertrophy(eeeb9f18-b0d5-433b-b261-2907df223717).html.
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Sub-endocardial fibres line the inner surface of both ventricles and are responsible for longitudinal oscillations of the mitral annulus, such oscillations may be measured using tissue Doppler echocardiography (IDE). During systole the annulus descends and during early diastole (ETDE) and atrial systole (ATDE) itascends. This thesis examined whether changes in the velocity of the annulus ineach of these phases of oscillation, measured using tissue Dopplerechocardiography (TDE), could determine the nature of increases in left ventricular size (pathological or physiological). Study one examined differences at rest in longitudinal velocities between individuals with hypertrophic cardiomyopathy (HCM), hypertension (HT), weightlifters, runners and controls, (n = 15 all groups) and all groups were aged between 20 - 36 years. The results demonstrated that both pathological groups had systolic and ETDE velocities significantly lower than groups with physiological hypertrophy (weightlifters or runners) or controls p < 0.05. AIDE however was not significantly different between groups. Additionally runners also demonstrated a significantly higher ETDE than either weightlifters or controls (p < 0.05). Binomial logistic regression identified longitudinal systolic velocity < 9 cm s" 1 and ETDE velocity < 11 cm s" 1 as the best combination of variables to predict pathological increases in heart size. Study two examined older subjects in order to determine whether the criteria set out in study one were applicable to senior athletes. The subject groups were the same as in study one however all subjects were aged between 36-55. In this case systolic annular velocity was significantly lower in groups with pathological LVH but ETDE < 9 cm s" 1 was a better differentiator. Binomial logistic regression identified ETDE < 9 cm s" 1 and a mitral E / A ratio < 1 as the best combination of variables to predict pathological LVH. Study three examined the age related changes in long axis function using the pooled data from studies one and two. This demonstrated that in the pathological LVH groups only ETDE / ATDE ratio was significantly correlated with age (r = - 0.5 p < 0.05) suggesting that there appears to be no summation of the effects of pathology and age on mitral annular velocities. The control groups demonstrated a significant age related reduction in all long axis variables (systolic velocity r = - 0.7 p < 0.05; ETDE r = - 0.6 p < 0.01; ATDE r = 0.5 p < 0.05; ETD E / ATDE r = - 0.5 p< 0.01). Weightlifters however did not demonstrate an age related decline in either systolic or diastolic annular velocities. Runners had no age related decline in systolic annular velocities, and whilst they had an age dependent fall in ETDE ( r = - 0.62 p < 0.05) the older runners ETDE were still significantly faster (p < 0.05) than that seen in control subjects. Study four investigated relationship between mitral annular velocity and VOiruK in runners, weightlifters and controls. These results demonstrated peak exercise E TDE strongly correlated to VO^PEAK (r = 0.8 p < 0.01). ConclusionsTaken together these data suggest that longitudinal velocities of the mitral annulus may be useful in determining the nature of increases in heart size, in addition the increased performance of endurance - trained athletes is due in part to functional changes of the long axis.
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Thouverey, Cyril. "Origin, characterization and roles of matrix vesicles in physiological and pathological mineralization." Lyon 1, 2008. http://tel.archives-ouvertes.fr/docs/00/30/42/14/PDF/THESIS_CyrilTHOUVEREY.pdf.
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Les vésicules matricielles (VM) sont impliquées dans l'initiation des minéralisations physiologique ou pathologique. Le pyrophosphate (PPi) est une source de phosphate (Pi) pour maintenir la formation d'hydroxyapatite (HA) mais aussi un inhibiteur de la croissance de ces minéraux. Nous avons montré que la formation d’HA était optimale lorsque le rapport molaire Pi/PPi était supérieur à 140, tandis que du calcium pyrophosphate dihydraté, marqueur de l’arthrose, était exclusivement formé lorsque ce rapport était inférieur à 6. Des analyses protéomiques et en compositions lipidiques sur les VM et les microvillosités des cellules Saos-2 ont révélé que les VM étaient formées dans le réticulum endoplasmique et qu'elles possèdent des lipides et protéines caractéristiques de radeaux lipidiques. Finalement, nous avons montré que les VM sont libérées à partir des microvillosités grâce aux actions coordonnées de protéines dépolymérisant l'actine et de protéines contractiles. Les protéines impliquées dans la biogenèse des VM peuvent être des nouvelles cibles thérapeutiques pour prévenir des calcifications pathologiquesMatrix vesicles (MVs) are involved in the initiation of mineralization in tissues undergoing physiological and pathological calcification. Pyrophosphate (PPi) has a dual effect on mineralization: a source of phosphate (Pi) to sustain hydroxyapatite (HA) formation and an inhibitor of HA growth. We found that formation of HA was optimal when the Pi/PPi molar ratio was above 140, while calcium pyrophosphate dihydrate, identified in osteoarthritis was exclusively produced by MVs when the ratio was below 6. Proteomic analysis and lipid compositions on both MVs and microvilli from osteoblast-like Saos-2 cells, revealed that MVs have an endoplasmic reticular origin and characteristic lipids and proteins as in lipid rafts. Finally, we demonstrated that MV release from microvilli is caused by the concomitant actions of actin-depolymerizing and contractile motor proteins. Proteins involved in MV biogenesis could be new therapeutic targets to prevent pathological calcification
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Sénéchal, Yann. "SiRNA-mediated knockdown of amyloid precursor protein expression : Physiological and pathological implications." Université Louis Pasteur (Strasbourg) (1971-2008), 2006. http://www.theses.fr/2006STR13204.
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La maladie d’Alzheimer (MA) est caractérisée au niveau histopathologique par la présence de plaques amyloides dans le cerveau. Ces plaques sont formées par l’accumulation de peptides amyloides (A) issus du clivage de la Protéine Précurseur Amyloide (APP). Les fonctions physiologiques précises de cette protéine ubiquitaire restent à ce jour peu connues. Le but de cette thèse a consisté à étudier les rôles physiologiques et pathologiques joués par APP in vivo, en utilisant une approche d’interférence de l’ARN. La première phase de ce travail a consisté à identifier des petits ARN interférents efficaces dirigés contre la forme murine (mAPP-siRNA) et la forme humaine (hAPP-siRNA) de APP. Les effets comportementaux de l’injection dans le cerveau de ces siRNAs ont ensuite été observés dans des souris sauvages et transgéniques. Tout d’abord, l’administration de mAPP-siRNAs dans le cerveau de souris sauvages a provoqué une diminution de 30% de l’expression de APP dans l’hippocampe, et a induit des déficits dans un test d’alternance spontanée, ce qui suggère une implication de APP dans la mémoire de travail spatiale. En revanche, des souris APP knockout n’ont pas présenté de déficits dans ce même test, ce qui suggère la mise en place probable de phénomènes compensatoires. Enfin, l’application de la technologie siRNA au modèle murin APP23 de la MA a révélé la réversibilité de l’hyperactivité locomotrice, suggèrant une implication directe de la surexpression de APP/A dans l’hyperactivité locomotrice de ces souris. Il est probable que des applications thérapeutiques des siRNAs seront développées dans les prochaines années, y compris pour certaines maladies neurodégénérativesAlzheimer’s Disease (AD) is characterized at the histopathological level by the presence of amyloid plaques in the brain. Amyloid plaques are formed by the accumulation of Abeta peptides (A), which are derived from the proteolytic processing of Amyloid Precursor Protein (APP). The precise physiological functions of this ubiquitous protein remain elusive. The aim of the present thesis was to study the physiological and pathological roles of APP in vivo by using a RNA interference approach. In the first in vitro phase of the thesis, effective small interfering RNAs were identified for mouse APP (mAPP-siRNAs) and human APP (hAPP-siRNAs). Then, the behavioral effects of the infusion of these active APP-siRNAs in the brain were examined in wild type and transgenic mice. In a first study, the infusion of mAPP-siRNAs in the brain of wild type mice resulted in a 30% knockdown of APP expression in the hippocampus accompanied by spontaneous alternation deficits at the behavioral level. This finding suggests that APP could play a role in spatial working memory. In contrast, APP KO mice were not impaired in spontaneous alternation behavior, suggesting the probable occurrence of compensatory mechanisms. Finally, the siRNA-technology was applied to the APP23 AD mouse model and revealed the reversibility of the locomotor hyperactivity phenotype. This last result suggests a direct implication of APP/A overexpression in the locomotor hyperactivity phenotype displayed by these mice. Therapeutic applications of siRNAs will likely be developed in the next years, maybe even for the treatment of certain neurodegenerative disorders
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Sharma, Shruti. "Assessing the physiological and pathological functions of tissue Transglutaminase using FRET analysis." Thesis, Aston University, 2016. http://publications.aston.ac.uk/29332/.
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Tissue Transglutaminase (TG2) is a cross-linking enzyme that links proteins by the formation of covalent bonds and confers resistance to proteolytic degradation. TG2 acts as a cell adhesion protein by binding to matrix fibronectin, cell surface heparan sulphates and integrins. TG2 has been implicated in a variety of diseases such as neurodegenerative disease, fibrosis and cancer. However, little is known about the mechanisms involved in its secretion, intracellular or extracellular activation or how these are regulated. The activity of TG2 is tightly controlled by GTP binding and calcium is required for its activation. TG2 assumes two strikingly different conformations, a catalytically inactive compact one in the presence of GTP and an active extended one in the presence of Ca2+. This conformation change affects the functions of TG2 including its transamidating activity, its affinities and juxtaposition of binding sites for fibronectin, heparan sulphates and integrins. To study this, a FRET (Förster Resonance energy Transfer) sensor was constructed using the fluorescent proteins CFP and YFP fused to the N and C terminus of TG2, respectively. The FRET sensor has demonstrated different fluorescent characteristics depending on the conformation of TG2 and was used to monitor the conformational change that is induced by calcium or GTP binding.
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Vongerichten, A. N. "Imaging physiological and pathological activity in the brain using electric impedance tomography." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1461127/.
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Electric Impedance Tomography (EIT) is a promising medical imaging technique that reconstructs the internal conductivity of an object from boundary measurements. EIT is currently being used to monitor the lung during ventilation clinically. Amongst other suggested uses for imaging it can also be used to image neuronal function. There are different ways on how EIT can image neuronal function and two of these are tested in this thesis. The overall aim of our work was to advance imaging of physiological and pathological neuronal activity using EIT and assess its potential for future clinical use. In Chapter 1, a general introduction into brain imaging techniques and EIT is given. In Chapter 2, the effect of different anaesthetics on the neuronal signal was assessed to prepare for EIT recordings under anaesthesia. In Chapter 3, we assessed the validity of two biophysical models regarding the behaviour of the impedance in response to alterations in the carrier frequency experimentally. This allowed an assessment of the ideal carrier frequency to image physiological neuronal activity. In Chapter 4, the source of the fast neural signal in EIT is discussed further. In Chapter 5, the possibility of imaging physiological neuronal activity throughout the brain is tested and its limitations are discussed. In Chapter 6, the impedance response to epileptiform activity is characterized and the potential use of EIT in imaging epileptic foci in epilepsy patients is discussed. In Chapter 7, imaging of epileptic foci in subcortical structures is tested using two different ways of imaging with EIT.
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Crisóstomo, Maria Rosa Rebordão Cordeiro Simões. "Mare endometrium : physiological and pathological involvement of hormones and neutrophil extracellular traps." Doctoral thesis, Universidade de Lisboa, Faculdade de Medicina Veterinária, 2018. http://hdl.handle.net/10400.5/15134.
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Tese de Doutoramento em Ciências Veterinárias, Especialidade de Ciências Biológicas e Biomédicas.Two reproductive topics in mares were addressed in this thesis. The aims of the studies were to evaluate: (i) the effect of chronic oxytocin administration to mid-luteal phase mares on luteal maintenance and its cellular and molecular mechanisms at endometrial level; (ii) the capacity of equine neutrophils to produce neutrophil extracellular traps (NETs) in vitro when stimulated with bacteria obtained from mares with endometritis, and to determine if NETs release also occurred in vivo in mares with endometritis; (iii) the in vitro effects of some NETs components on mare endometrial fibrogenic capacity and to determine if they could depend on endometrial inflammatory lesions or estrous cycle phases; and (iv) the involvement of PGF2α and PGE2 pathways in collagen deposition on mare endometrium, challenged with NETs proteases. In the first study, luteal maintenance occurred in 67% of oxytocin treated mares, which may be related to oxytocin and progesterone (PGR) receptors spatial expression in endometrium. Reduction of endometrial estrogen receptor 2 (ESR2) may be responsible for the maintenance of PGR in luminal and glandular epithelium and may attenuate ESR1 endometrial transcriptional activity. Equine neutrophils were able to release NETs in the presence of bacteria that cause mare endometritis, and might be a complementary mechanism to fight endometritis. By in vitro studies with NETs proteases, increased collagen type I (COL1) production characteristic of fibrosis was observed, although endometrial response to each NETs protease depended on estrous cycle and/or endometrial category. Also, NETs proteases were linked to fibrogenesis, by increased synthesis of PGF2a and/or PGF2a receptor transcripts and impaired PGE2 or PGE2 receptor 2 transcripts associated to increased COL1. These effects were influenced by endometrium type and estrous cycle phases. Injury induced-changes on PG mediators by NETs components may instigate PGF2α or PGE2 vias, as additional pathways in mare endometrial fibrogenesis.
RESUMO - Endométrio da égua: envolvimento fisiológico e patológico de hormonas e de redes extracelulares de neutrófilos - Nesta tese foram abordados dois temas reprodutivos em éguas. Os objectivos destes estudos consistiram na avaliação: (i) da administração crónica de ocitocina na manutenção do corpo lúteo em éguas na fase lútea média, e os mecanismos celulares e moleculares no endométrio; (ii) da capacidade dos neutrófilos equinos para produzirem redes extracelulares de neutrófilos (NETs) in vitro e in vivo quando estimulados com bactérias de éguas com endometrite; (iii) dos efeitos in vitro de componentes das NETs na fibrogénese do endométrio equino e sua associação com lesões inflamatórias no endométrio ou com o ciclo éstrico; e (iv) do envolvimento das vias da PGF2α e PGE2 na deposição de colagénio no endométrio da égua, incubado com proteases das NETs. No primeiro estudo, o prolongamento da função lútea em 67% das éguas tratadas com ocitocina, parece estar relacionado com alteração da expressão espacial dos receptores de ocitocina e progesterona (PGR) no endométrio. A diminuição do receptor 2 dos estrogénios (ESR2) pode ser responsável pela manutenção do PGR no epitélio luminal e glandular do endométrio e atenuar a transcrição do ESR1. Os neutrófilos equinos libertaram NETs na presença de bactérias causadoras de endometrite podendo ser um mecanismo complementar no combate à endometrite. As proteases das NETs in vitro aumentaram a produção de colagénio do tipo I (COL1), característico de fibrose, no endométrio, embora a resposta a cada protease dependesse do ciclo éstrico e/ou da categoria do endométrio. O aumento do COL1 associado ao incremento de PGF2α e/ou da transcrição do seu receptor e à diminuição da PGE2 e/ou do seu receptor 2, parecem implicar as prostaglandinas e as proteases das NETs na fibrogénese no endométrio equino. Alterações nos mediadores das prostaglandinas, induzidas pelos componentes das NETs, podem instigar as vias da PGF2a ou da PGE2, como mecanismos adicionais de fibrose do endométrio da égua.
N/A
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Hindmarch, Charles Colin Thomas. "The Impact of Physiological and Pathological Modulation on the Central Nervous System Transcriptome." Thesis, University of Bristol, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499851.
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Chan, Benjamin Yick-Yeung. "Physiological, pharmacological and pathological regulation of osteoclast activity in vitro and in vivo." Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.443923.
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Kruppa, Daniel [Verfasser], and Leena [Akademischer Betreuer] Bruckner-Tuderman. "Role of astacin-like proteinases in physiological and pathological wound healing and scarring." Freiburg : Universität, 2020. http://d-nb.info/1228270198/34.
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Murphy, John. "Physiological and pathological intracellular calcium release in human and murine pancreatic acinar cells." Thesis, University of Liverpool, 2011. http://livrepository.liverpool.ac.uk/4693/.
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Sustained, toxic elevations of pancreatic acinar cell cytosolic free calcium ion concentration ([Ca2+]C), such as those observed with supramaximal secretagogue stimulation (CCK) are implicated in acute pancreatitis. However, Cholecystokinin (CCK) has been thought to act only indirectly on human pancreatic acinar cells via vagal nerve stimulation, rather than by direct CCK receptor activation as observed in rodent pancreatic acinar cells. However, in the series of experiments presented here using human pancreatic acinar cells, CCK at physiological concentrations (1-20 pM) elicited rapid, robust, oscillatory rises of the cytosolic Ca2+ ion concentration ([Ca2+]C), showing apical to basal progression in acinar cells, in the presence of atropine and tetrodotoxin. The [Ca2+]C rises were followed by increases in mitochondrial ATP production and secretion, concluding that CCK acts directly on acinar cells in the human pancreas. The earliest pathological mechanisms, such as sustained, toxic elevations of the acinar cytosolic free calcium ion concentration ([Ca2+]C), incriminated in experimental pancreatitis have been previously demonstrated by non-oxidative metabolites of ethanol (FAEE’s), as well as bile salts, at supramaximal concentrations. However, in the clinical situation such hyperstimulation is unlikely to occur. To simulate a more clinically relevant stimulus, pancreatic acinar cells were stimulated with lower doses of FAEE’s and/or bile salts in combination with physiological doses of secretagogues - a process which may precipitate pancreatitis clinically. Illustrated here, the toxic transformation of secretagogue induced physiological Ca2+ signalling occurs with the perfusion of low doses of TLCS and POAEE resulting in cell injury. The intracellular second messengers implicated are IP3, cADPR and NAADP with the IP3 receptor channel pivotal with both toxins. However, as previously demonstrated with supramaximal concentrations of POAEE, if supplementary ATP is added to the intracellular milieu, cellular injury is avoided with continued extrusion of large quantities of Ca2+ from the cytosol indicating functional Ca2+ ATPase pumps. This is not observed in cells which do not receive supplementary ATP. The toxic sustained Ca2+ elevation is also be prevented by the removal of external Ca2+ or blockade of IP3 receptor using caffeine and cell injury is again avoided. Therefore, it may be concluded, that it is the large, sustained toxic [Ca2+]c load which impairs mitochondrial function and ATP production leading to Ca2+ATPase pump failure and ultimately cell death. Lowering sustained intracellular [Ca2+]c by blockade of IP3 receptor channels may reduce cell injury in clinical acute pancreatitis.
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Zheng, Thomas Wen-Juan. "Neurophysiological and pharmacological study of carbamazepine on physiological and pathological GABAergic-dependent thalamocortical oscillations." Strasbourg, 2010. http://www.theses.fr/2010STRA6131.
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La CBZ est un anticonvulsivant largement prescrit, utilisé dans le traitement des épilepsies focales et de troubles psychiatriques. Cependant, il est connu que son large spectre d'action sur différentes cibles moléculaires contribue à des effets secondaires communs et sévères. La CBZ interagit directement avec les récepteurs GABAA, qui jouent un rôle critique dans l’électrogenèse d’oscillations TC/CT physiologiques et pathologiques. Mon travail de thèse offre des arguments solides pour dire que la CBZ module les propriétés de décharge et d’oscillations des neurones thalamiques, au moins dans le système somatosensoriel, au travers d’une augmentation des activités dépendantes de récepteurs GABAA. Ce mécanisme semble être le plus vraisemblable dans l’aggravation des absences. Le travail présenté dans cette thèse offre aussi d’importantes clés pour comprendre les mécanismes sous-tendant l'initiation et la propagation des DPO liées aux absences. Ces résultats mettent en évidence la présence d'activités de type précurseur dans S2 et IC durant l’électrogenèse des DPO. Il est donc tentant de mettre en avant l'hypothèse selon laquelle les aires corticales S2 et IC forment un circuit critique à partir duquel une excitation se propage dans des aires corticales interconnectées : S1, des aires corticales motrice et plus frontales. La propagation de cette excitation caudo-rostral pourrait être un élément neuronal clé dans l'initiation des crises d'absences. La CBZ est efficace chez les GAERS pour supprimer les DPO relatives aux absences uniquement lors d'une injection proche ou au niveau du site d'initiation présumé de cet embrasement excitateur caudo-rostralCBZ is a widely prescribed anticonvulsant used for the treatment of focal epilepsy and psychiatric disorders. However it is also known for its broad spectrum of action on several molecular targets contributing to common and severe side effects. CBZ directly interacts with GABAA receptors, which play a critical role in the generation of physiological and pathological TC/CT oscillations. My thesis work provides strong evidence that CBZ affects the firing and oscillation properties of thalamic neurons, at least in the somatosensory system, through enhancement of GABAA receptor-mediated activities, the likely mechanisms that underlie the aggravation of absence seizures. The work presented in this thesis also provides several important leads to mechanisms underlying the initiation and propagation of absence-related SWDs. The present findings demonstrate the presence of precursor cellular and network rhythmic activities in S2 and IC during the generation of absence-related SWDs. Therefore it is tempting to put forward the assumption that S2 and IC cortical areas contain a critical circuit from which excitation spreads to interconnected S1, motor and more frontal cortical areas. This spreading caudo-rostral excitation might be a key neuronal mechanism in the initiation of absence seizures. To all appearances CBZ is effective in suppressing absence-related SWDs
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Dawson, Leigh Helen Jane. "Physiological, behavioural and pathological effects of sea lice, Lepeophtheirus salmonis (Krøyer, 1837), on Salmonids." Thesis, University of Aberdeen, 1997. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU483280.
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This thesis examined the physiological, behavioural and pathological effects of sea lice, Lepeophtheirus salmonis (Krøyer, 1837), on wild sea trout, Salmo trutta L., and experimentally infected sea trout and Atlantic salmon, Salmo salar L. to determine how, and to what extent, sea lice cause mortality of their infected hosts. A feeding hierarchy was established in groups of sea lice infected and uninfected Atlantic salmon as a physiological stressor. Results indicated that chalimus did not stimulate physiological changes leading to marine mortality and the intensity of the sea lice infection on a fish was independent of that individual's food consumption. However, preadult stages caused appetite suppression, severe skin lesions and changes in the blood biochemistry of the fish with subsequent recovery to the levels of uninfected fish as the parasite moulted through to the adult stages of the lifecycle. The effects of sea lice on sea trout at either 2 or 6 weeks after sea water transfer were assessed. Both infection intensity and developmental rate were not significantly different between the groups, but a trend of fewer lice on the fish infected 6 weeks after sea water transfer was recorded. Fewer of the fish infected 2 weeks after sea water transfer had resumed feeding by the end of the experiment, leading to a loss of body condition, and suffered more severe damage to the skin and detrimental changes in the physiological integrity as a consequence of feeding preadult lice. The mortal impact of sea lice infection was significantly enhanced in the fish infected 2 weeks after sea water transfer. The findings from this thesis have shown that preadult sea lice can cause mortality of wild and experimentally infected sea trout and Atlantic salmon, particularly if infected at the time of sea water transfer, but under certain conditions sea lice infected hosts can recover from the detrimental effects of both chalimus and mobile stages.
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Belanger, Scott E. "Functional and pathological responses of selected aquatic organisms to chrysotile asbestos." Diss., This resource online, 1985. http://scholar.lib.vt.edu/theses/available/etd-05222007-091305/.
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Dwyer, Laura. "Functional role of non-selective cation channels on colonic excitability in physiological and pathological conditions." abstract and full text PDF (UNR users only), 2009. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3387805.
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Stock, Kristin [Verfasser]. "New insights into TRPV1 function in the brain under physiological and pathological conditions / Kristin Stock." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1031587144/34.
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Rasmussen, Tyler Paul. "Mitochondrial calcium uniporter is a nodal regulator of physiological and pathological stress responses in myocardium." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3169.
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A long held hypothesis in mitochondrial biology holds that increases in mitochondrial Ca2+ levels stimulate the activity of matrix dehydrogenases that catalyze production of NADH and eventually donate electrons to electron transport in order to increase ATP formation. At the same time, mitochondrial Ca2+ overload is a deleterious event leading to opening of the mitochondrial permeability transition pore, increasing reactive oxygen species and initiating pathways that contribute to cell death. These fundamental hypotheses are best studied in the heart because of the critical energy supply-demand relationship in myocardium, but were untestable in vivo until the discovery of the mitochondrial Ca2+ uniporter (MCU). The molecular identity of the MCU pore forming subunit was recently discovered, which allowed me to study a transgenic mouse with myocardial delimited expression of a dominant negative MCU.
My lab developed mice with myocardial-delimited transgenic expression of a dominant negative MCU to test these fundamental hypotheses and to determine how MCU controls physiological and pathological stress responses in vivo, ex vivo, and in situ. My studies provide new, unanticipated information that contributes to our understanding the relationship between mitochondrial Ca2+, oxygen utilization, cardiac pacemaking and pathologic stress responses in heart. Here, I show that mice with myocardial-targeted MCU inhibition have hearts with surprisingly high oxygen consumption rates due to elevated cytoplasmic Ca2+ in response to physiological stress. Loss of MCU effectively preserved inner mitochondrial membrane potential and prevented an oxidative burst thought to drive myocardial injury and death, but nevertheless failed to protect myocardium from ischemia-reperfusion injury. Increases in oxygen consumption, elevation in cytoplasmic Ca2+ and transcriptional reprogramming mitigate the protective actions of MCU inhibition in vivo. Mice with myocardial selective MCU inhibition have a reduced response to isoproterenol-induced heart rate increase but have normal baseline heart rates. My studies provide novel insight into how MCU contributes to myocardial Ca2+ homeostasis, metabolism, and transcription leading to surprising actions on physiological and pathophysiological responses in heart.
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Qi, Xiuling. "The effects of vascular and endocardial endothelia on rat myocardial performance in physiological and pathological situations." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0010/NQ38828.pdf.
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Heger, Klaus-Dieter. "Assessing the physiological and pathological functions of mast cells by the use of novel mouse models." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-172404.
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Brunner, Clément. "Functional ultrasound imaging (fUSi) to assess brain function in physiological and pathological conditions : application to stroke." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB123/document.
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Depuis le milieu du XXème siècle, les techniques d’imagerie fonctionnelles ont un rôle grandissant dans notre compréhension sur les fonctions du cerveau en conditions physiologique et pathologique. Bien que l’IRMf fasse partie des techniques les plus communément utilisées pour l’imagerie du cerveau complet lors d’études préclinique et clinique, cette modalité souffre de sa résolution spatiotemporelle et sa sensibilité pour enregistrer finement les fonctions et activités cérébrales. Récemment l’imagerie fonctionnelle par ultrason (ifUS) a subi des développements permettant d’être complémentaires à l’IRMf ainsi qu’aux autres techniques d’imagerie cérébrales classiquement employées. Contrairement aux ultrasons focalisés conventionnels, l’imagerie hémodynamique proposé par l’ifUS repose sur une illumination ultrasonore plane permettant la détection des globules rouges en mouvement et la mesure de leur vitesse dans les micro-vaisseaux cérébraux. De ce fait, l’ifUS est indirectement lié à l’activité cérébrale d’où l’importance d’une meilleure compréhension des mécanismes du couplage neuro-vasculaire liant l’activité neuronale et les variations cérébrales d’apport en sang. De plus, cette technique a le potentiel pour fournir des informations précises sur les processus de certaines pathologies à la fois sur des modèles précliniques et chez l’homme. Dans un premier temps, j’exposerais mes travaux sur les récents développements techniques permettant l’ifUS in vivo (i) en condition chronique, (ii) sur l’animal éveillé, libre de mouvement et effectuant une tache comportementale et (iii) des vaisseaux capillaires chez le rongeur et l’homme. Dans un second temps, je démontrerais que l’ifUS in vivo peut fournir des informations nouvelles sur des pathologies telles que l’accident vasculaire cérébraleSince the middle of the 20th century, functional imaging technologies are making an increasing impact on our understanding on brain functions in both physiological and pathological conditions. Even if fMRI is nowadays one of the most used tool for whole brain imaging in pre-clinical and clinical studies, it lacks sufficient spatiotemporal resolution and sensitivity to assess fine brain function and activity. Functional ultrasound imaging (fUSi) has been recently developed and presents a potential to complement fMRI and other existing brain imaging modalities. Contrary to conventional ultrasound using focus beams, fUSi relies on hemodynamic imaging based on ultrasound plane-wave illumination to detect red blood cells movement and velocity in brain micro-vessels. Consequently, the fUSi signal is indirectly related to brain activity and it is therefore important to better understand the mechanisms of the neurovascular coupling linking neural activity and cerebral blood changes. Here again, fUSi may provide relevant information about disease processes in preclinical models but also in humans. First, I will present recent technical developments allowing in vivo fUSi (i) in chronic condition, (ii) in freely moving and behaving rats and (iii) in rodents and human brain capillaries. Second, I will demonstrate how fUSi could provide new insights in brain pathologies such as stroke
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Monelli, Erika. "Deciphering the role of endothelial cells in the regulation of physiological and pathological white adipose tissue remodelling." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/572073.
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In response to nutritional variation, white adipose tissue (WAT) undergoes a physiological remodelling that involves qualitative and quantitative changes in resident cells and is coordinated with angiogenesis. In a condition of chronic over nutrition WAT expansion is associated to insufficient vascularisation which in turn leads to local hypoxia, inflammation and adipocytes death (hallmark of obesity). Currently, enhanced WAT angiogenesis is believed to be a promising intervention to ameliorate obesity associated metabolic dysfunctions. However, we still lack understanding of the cell intrinsic function of endothelial cells in WAT remodelling. Here we take advantage of our mouse model of PTEN (a dual lipid/protein phosphatase that counterbalance the
activity of PI3K) deletion in ECs to promote vessel growth, in a cell autonomous manner. To this end, we crossed Ptenflox/flox mice with PdgfbiCreERT2 transgenic mice that express a tamoxifen-inducible Cre recombinase in ECs; 4-hydroxytamoxifen was administered in vivo at postnatal day 1 (P1) and P2 to activate Cre expression.
Increased ECs proliferation, induced by PTEN loss, promotes vascular hyperplasia exclusively in WAT and leads to a progressive loss of WAT mass. PTEN null ECs undergo a metabolic switch towards an oxidative metabolism; in vivo inhibition of - oxidation is sufficient to revert both vascular hyperplasia and loss of WAT mass. Enhanced adipose vascularisation prevents from high fat diet induced WAT hypertrophy, limits body weight gain and improves glucose tolerance. Taken together our results suggest that, under obesogenic stimuli, more functional ECs prevent unhealthy WAT expansion and consequently the onset of obesity related comorbidity.
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Kong, Wing-cheung Billy, and 江詠璋. "Age-related physiological and pathological changes in the regulation of endothelium-dependent relaxations in mice and rats." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46917305.
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Charlesworth, Martyn. "The role of the secondary messenger NAADP in physiological and pathological calcium signalling in pancreatic acinar cells." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/105294/.
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Acute Pancreatitis (AP) is inflammatory disease characterised by the pathological activation of the digestive enzymes and extensive necrosis of the pancreases and surrounding tissue, which currently has no effective treatment. Pathological agents like the bile acid taurolithocholic acid-3-sulfate (TLC-S) have been shown to induce necrosis of pancreatic acinar cells by causing intracellular calcium (Ca2+) to reach cytotoxic concentrations. TLC-S acts on elements of the secondary Ca2+ messenger pathways normally used in physiological signalling to achieve these Ca2+ increases. Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most novel of these secondary Ca2+ messengers to be identified and several recent advancements have been made regarding its activity. This study has used these advancements to better characterise NAADP-induced Ca2+ release in PAC, and its role in both physiological and pathological Ca2+ signalling. NAADP-induced Ca2+ release was found to involve the activity of both Two-pore channel (TPC) and Ryanodine receptor (RyR) Ca2+ channels; with a varying involvement of the 2 TPC and 3 RyR isoforms. The NAADP antagonist Ned-19 completely inhibited Ca2+ responses to a physiological concentration of the secretagogue cholecystokinin (CCK) and had a protective effect against a pathological concentration of CCK. The size of the Ca2+ response to TLC-S was significantly inhibited in the presence of Ned-19, and the antagonist significantly reduced the amount of necrosis induced. Another related bile acid, cholate, was found to have a similar necrotic effect to PAC as a result of pathological increases in cytosolic Ca2+. While neither Ned-19 or GSK-7975A (an inhibitor of store-operated Ca2+ entry) alone had a significant effect on cholate-induced necrosis, a combination of the two did have a protective effect. These findings suggest that Ned-19 may provide a potential therapeutic solution to AP, though it may need to be used in combination with inhibitors of other Ca2+ signalling to be effective.
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Thompson, Cole S. "Poa trivialis: physiological and pathological components of summer decline, and cultural, selective, and non-selective control methods." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/17143.
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Doctor of PhilosophyDepartment of Horticulture, Forestry, and Recreation Resources
Jack Fry and Megan Kennelly
Rough bluegrass (RBG, Poa trivialis L.) is a difficult-to-control weed that commonly infests cool-season turfgrass swards after movement of vegetative propagules or contamination from seed lots. Rough bluegrass is less tolerant of heat stress than desirable cool-season species such as tall fescue (TF, Festuca arundinacea Schreb. Syn [italicize]Schedonorus [italicize]arundinaceus Schreb.), and often declines during mid-summer due to biotic or abiotic stresses. The objectives of these 2011-2013 controlled environment and field experiments were to: 1) observe growth and physiological differences between ‘Laser’ and ‘Pulsar’ RBG and TF; 2) differentiate between physiological and pathological contributors to RBG decline; 3) determine the effects of TF seeding rate and mowing height on TF/RBG establishment when RBG is a seed contaminant; 4) evaluate herbicide combinations for selective RBG control; and 5) evaluate seasonal timing of glyphosate for nonselective RBG control. Tall fescue was less affected by elevated temperature than RBG. At 35°C, Laser and Pulsar experienced similar reductions in quality, gross photosynthesis (Pg), shoot and root biomass, and root length density compared to when grown at 23°C, but maximum electrolyte leakage was greater for Pulsar (63%) than for Laser (49%). Cell membrane thermostability could contribute to the better heat tolerance of Laser RBG. Evaluation of RBG foliage and roots did not reveal a fungal pathogen associated with RBG decline. Still, repeated applications of azoxystrobin (610 g a.i. ha⁻¹) or pyraclostrobin (556 g a.i. ha⁻¹) increased RBG quality, cover, and Pg during summer compared to untreated RBG, possibly due to poorly understood non-target physiological effects of the fungicides. Mowing TF at 7.6 or 11.4 cm reduced RBG incidence up to 57% compared to mowing at 3.8 cm. Tall fescue seeding rate had no effect on RBG incidence. Several herbicides and herbicide combinations resulted in some RBG injury in the field, but bispyribac-sodium was the only treatment that provided RBG control (16 to 92%) in Manhattan, KS; Hutchinson, KS; and Mead, NE. Spring-applied glyphosate resulted in the lowest RBG coverage (1 to 31%) among field studies in Manhattan and Mead, followed by late-summer applications (6 to 58%), and mid-summer applications (9 to 86%).
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Schramme, Michael Camille Marie-Therese A. J. "The role of insulin-like growth factor-I in the physiological and pathological responses of equine articular cartilage." Thesis, Royal Veterinary College (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368108.
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