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1
Moore, Robert James. "Vascularization of the intervertebral disc in pathological conditions /." Title page, contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09PH/09phm8233.pdf.
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Zhu, Chunni. "The Blood-brain barrier in normal and pathological conditions." Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phz637.pdf.
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Bibliography: leaves 318-367. Examines the blood-brain barrier in normal and pathological conditions induced by intravascular and extravascular insults. Intravascular insults were induced by administration of Clostridium perfringens prototoxin; extravascular insults were induced by an impact acceleration model for closed head injury to induce traumatic brain injury. Also examines the integrity of the blood-brain barrier ultrastructurally and by its ability to exclude endogenous and exogenous tracers. Also studies the expression of 2 blood-brain barrier specific proteins, endothelial barrier antigen (EBA) and glucose transporter 1 (GLUT1)
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Khalefa, Baled Ibrahim Noufal [Verfasser]. "Opioid receptor efficacy during normal and pathological conditions / Baled Khalefa." Berlin : Freie Universität Berlin, 2014. http://d-nb.info/1046563831/34.
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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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Bull, Sarah-Jane. "Mechanisms promoting myelin formation and maintenance under normal and pathological conditions." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106240.
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Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). They develop from oligodendrocyte precursor cells and differentiate into mature myelin forming OLs. Once myelin is formed, myelinated axons are segregated into different domains around the myelin-devoid nodes of Ranvier. Maintenance of these domains is essential for efficient saltatory conduction, and several myelin proteins contribute to the maintenance of myelin structure and function. Netrin-1 and its receptor DCC were shown to be involved in the maintenance of paranodal axoglial junctions in vitro, but their role in vivo is not established. Myelin is also a major source of inhibition in the injured CNS, and several myelin proteins have been shown to inhibit axonal regeneration. In this thesis, different aspects of OL biology will be considered. First, signaling pathways involved in OL differentiation will be studied. I demonstrate a synergistic combination of growth factors that promotes late stages of OL differentiation via the PI3K/Akt/mTor pathway in vitro. In the second part, I present in vivo evidence of the involvement of DCC in paranodal and myelin maintenance, and in myelin protein composition. Furthermore, absence of DCC expression by OLs leads to the development of a balance and coordination deficit in mice. These results show that expression of DCC by OLs is required for proper maintenance and stability of myelin in vivo. Finally, I investigate the source of netrin-1 expression in the injured CNS. Our findings demonstrate that netrin-1, in addition to being a potential myelin-associated inhibitor, is also expressed by fibroblasts and some reactive astrocytes in the injured CNS. Netrin-1 expression might contribute to the inhibition of regeneration and failure of remyelination in the injured CNS. Understanding the mechanisms of myelin formation and maintenance will help to develop therapeutic strategies for the treatment of demyelinating diseases like multiple sclerosis, and to promote functional recovery following CNS injury.Les oligodendrocytes (OLs) sont les cellules myélinisantes du système nerveux central (SNC). Les OLs matures formant la myéline sont dérivés des précurseurs d'OLs, qui se différencient pendant le développement. La myélinisation engendre la formation de différents domaines axonaux autour des nœuds de Ranvier, zones non-myélinisées de l'axone. Le maintien de ces domaines est essentiel pour la conduction axonale saltatoire, et plusieurs protéines de la myéline contribuent au maintien de la structure et de la fonction de la myéline. La nétrine-1 et son récepteur DCC sont impliqués dans le maintien des jonctions paranodales in vitro, mais leur rôle in vivo n'est pas encore établi. La myéline est également une source majeure d'inhibition après une lésion du SNC. Dans cette thèse, différents aspects de la biologie des OLs seront couverts. Premièrement, les voies de signalisation impliquées dans la differentiation des OLs seront étudiées. Dans la première partie, je démontre une synergie de facteurs de croissance sur la voie de signalisation PI3K/Akt/mTor, agissant sur la différentiation morphologique des OLs in vitro. Dans la seconde partie, en utilisant des souris knockout conditionnelles, je présente des preuves de l'implication de DCC dans le maintien des paranodes, de la myéline, et de la composition protéique de la myéline. De plus, l'absence d'expression de DCC par les OLs mène au développement d'un déficit moteur de coordination et d'équilibre. Ces résultats montrent que l'expression de DCC par les OLs est requise pour le bon maintien et la stabilité de la myéline in vivo. Finalement, nous avons investigué la source de l'expression de la nétrine-1 dans les lésions du SNC. Nos résultats démontrent que la nétrine-1, en plus d'être potentiellement un inhibiteur associé à la myéline, est aussi exprimée par les fibroblastes et certains astrocytes réactifs dans les lésions de la moelle épinière. L'expression de nétrine-1 pourrait donc contribuer à l'inhibition de la regénération et l'échec de la remyélinisation après une lésion du SNC. Une meilleure compréhension des mécanismes de formation et de maintien de la myéline peut contribuer à développer des stratégies thérapeutiques pour le traitement de maladies démyélinisantes comme la sclérose en plaques, ou à promouvoir le rétablissement des fonctions après les lésions du SNC.
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Le, Gris Masha. "Mitochondrial protein expression in the developing brain and in pathological conditions." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670248.
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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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Weinrich, Kendra S. "Oral Pathological Conditions in Early Postcontact Guale, St. Catherines Island, Georgia." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587568057924649.
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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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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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Akhlaghi, Florin. "An in-shoe biaxial shear force transducer utilising piezoelectric copolymer film and the clinical assessment of in-shoe forces." Thesis, University of Kent, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259679.
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Бончев, С. Д., and О. В. Калинкевич. "Перспективи використання раньових покриттів в медицині та у наукових дослідженнях." Thesis, Видавництво СумДУ, 2009. http://essuir.sumdu.edu.ua/handle/123456789/11362.
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Göransson, Viktoria. "Hyaluronan and Renal Fluid Handling : Studies during Normal and Pathological Conditions of Renal Function." Doctoral thesis, Uppsala University, Department of Medical Cell Biology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1471.
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The kidney is the major organ responsible for the regulation of the composition and volume of the body fluids, which is essential for homeostasis. The glycosaminoglycan hyaluronan (HA), with extreme water-binding capacity, is present in the interstitium of the kidney with a heterogenous distribution. The importance of HA in renal water-handling is unknown and was the focus of the present investigation.
Acute water-loading in rats caused the amount of papillary HA to increase and during water deprivation, the amount was reduced. Gerbils, with extreme urine concentrating capacity, have less HA in the renal papilla in normal conditions and responded diametrically different to water-loading (reduction in HA). Renomedullary interstitial cells (RMICs), which are probably the main producers of HA in the renal medulla, were cultured at different media osmolalities to mimic the milieu of the medulla during variations in the water balance. The amount of HA found in the media was decreased at high osmolalities and increased at low osmolalities, thereby strengthening the in vivo results. CD44, an HA-receptor involved in the uptake and degradation of HA, was expressed on RMICs in an osmolality dependent manner. During high media osmolality, the CD44 expression increased and at lower osmolalities, the opposite occurred, probably due to the need for uptake and degradation of HA.
Renal ischemia-reperfusion injury causes a cortical accumulation of HA, up-regulation of CD44, and a depression of functional parameters. The time periods of ischemia correlated with the accumulation of HA which, in turn, was inversely correlated to GFR. Hyaluronidase injections in this setting failed to reduce HA levels and significantly improve renal function.
In conclusion, the results from the present study suggest an important role for HA and RMICs in renal water-handling and that the intrarenal distribution of HA is altered after ischemia-reperfusion injury, which correlates with renal dysfunction.
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Göransson, Viktoria. "Hyaluronan and renal fluid handling : studies during normal and pathological conditions of renal function /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5146-2/.
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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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Bouchnita, Anass. "Mathematical modelling of blood coagulation and thrombus formation under flow in normal and pathological conditions." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1300/document.
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Cette thèse est consacrée à la modélisation mathématique de la coagulation sanguine et de la formation de thrombus dans des conditions normales et pathologiques. La coagulation sanguine est un mécanisme défensif qui empêche la perte de sang suite à la rupture des tissus endothéliaux. C'est un processus complexe qui est règlementé par différents mécanismes mécaniques et biochimiques. La formation du caillot sanguin a lieu dans l'écoulement sanguin. Dans ce contexte, l'écoulement à faible taux de cisaillement stimule la croissance du caillot tandis que la circulation sanguine à fort taux de cisaillement la limite. Les désordres qui affectent le système de coagulation du sang peuvent provoquer différentes anomalies telles que la thrombose (coagulation exagérée) ou les saignements (insuffisance de coagulation). Dans la première partie de la thèse, nous présentons un modèle mathématique de coagulation sanguine. Le modèle capture la dynamique essentielle de la croissance du caillot dans le plasma et le flux sanguin quiescent. Ce modèle peut être réduit à un modèle qui consiste en une équation de génération de thrombine et qui donne approximativement les mêmes résultats. Nous avons utilisé des simulations numériques en plus de l'analyse mathématique pour montrer l'existence de différents régimes de coagulation sanguine. Nous spécifions les conditions pour ces régimes sur différents paramètres pathophysiologiques du modèle. Ensuite, nous quantifions les effets de divers mécanismes sur la croissance du caillot comme le flux sanguin et l'agrégation plaquettaire. La partie suivante de la thèse étudie certaines des anomalies du système de coagulation sanguine. Nous commençons par étudier le développement de la thrombose chez les patients présentant une carence en antihrombine ou l'une des maladies inflammatoires. Nous déterminons le seuil de l'antithrombine qui provoque la thrombose et nous quantifions l'effet des cytokines inflammatoires sur le processus de coagulation. Puis, nous étudions la compensation de la perte du sang après un saignement en utilisant un modèle multi-échelles qui décrit en particulier l'érythropoïèse et la production de l'hémoglobine. Ensuite, nous évaluons le risque de thrombose chez les patients atteints de cancer (le myélome multiple en particulier) et le VIH en combinant les résultats du modèle de coagulation sanguine avec les produits des modèles hybrides (discret-continues) multi-échelles des systèmes physiologiques correspondants. Finalement, quelques applications cliniques possibles de la modélisation de la coagulation sanguine sont présentées. En combinant le modèle de formation du caillot avec les modèles pharmacocinétiques pharmacodynamiques (PK-PD) des médicaments anticoagulants, nous quantifions l'action de ces traitements et nous prédisons leur effet sur des patients individuelsThis thesis is devoted to the mathematical modelling of blood coagulation and clot formation under flow in normal and pathological conditions. Blood coagulation is a defensive mechanism that prevents the loss of blood upon the rupture of endothelial tissues. It is a complex process that is regulated by different mechanical and biochemical mechanisms. The formation of the blood clot takes place in blood flow. In this context, low-shear flow stimulates clot growth while high-shear blood circulation limits it. The disorders that affect the blood clotting system can provoke different abnormalities such thrombosis (exaggerated clotting) or bleeding (insufficient clotting). In the first part of the thesis, we introduce a mathematical model of blood coagulation. The model captures the essential dynamics of clot growth in quiescent plasma and blood flow. The model can be reduced to a one equation model of thrombin generation that gives approximately the same results. We used both numerical simulations and mathematical investigation to show the existence of different regimes of blood coagulation. We specify the conditions of these regimes on various pathophysiological parameters of the model. Then, we quantify the effects of various mechanisms on clot growth such as blood flow and platelet aggregation. The next part of the thesis studies some of the abnormalities of the blood clotting system. We begin by investigating the development of thrombosis in patients with antihrombin deficiency and inflammatory diseases. We determine the thrombosis threshold on antithrombin and quantify the effect of inflammatory cytokines on the coagulation process. Next, we study the recovery from blood loss following bleeding using a multiscale model which focuses on erythropoiesis and hemoglobin production. Then, we evaluate the risk of thrombosis in patients with cancer (multiple myeloma in particular) and HIV by combining the blood coagulation model results with the output of hybrid multiscale models of the corresponding physiological system. Finally, possible clinical applications of the blood coagulation modelling are provided. By combining clot formation model with pharmacokinetics-pharmacodynamics (PK-PD) models of anticoagulant drugs, we quantify the action of these treatments and predict their effect on individual patients
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Rodriguez, Alejandro. "Studies of Stroma Formation and Regulation in Human Pathological Conditions and in Experimental in vivo Models." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-120688.
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Fibrosis is a sequel of chronic inflammation and is defined as an excessive deposition of collagen that ultimately leads to organ dysfunction. To date there are no effective treatments for fibrosis. The main cell type involved in collagen deposition and organization is the myofibroblast. In the first study we examined how myofibroblasts differentiate in human fibrotic conditions and in experimental animal models. Human tissues were stained with antibodies that recognize integrin receptors and in addition we also stained for α-SMA, a myofibroblast marker. We found a co-localization between these two markers in stromal cells and hypothesized that integrin α1 is important for the acquisition of the myofibroblast phenotype. To tests this hypothesis we used knockout animals for this integrin subunit. These animals showed a reduction of α-SMA positive fibroblasts, indicating that the α1 integrin subunit is required for proper myofibroblast differentiation. In the second study we used a neuroblastoma tumor model to study tumour growth when a drug targeting the synthesis of cellular NAD was administered. In treated animals an expansion of the nonvascular stroma was observed compared to controls. Normalization of the vasculature was observed in treated tumors together with a decrease in hypoxia. Moreover, this was followed by a decrease in stromal PDGF-B and VEGF expression, suggesting a deactivation of the stroma. In the third study the effects of over-expression of the two pro-fibrotic growth factors TGF-β and PDGF-B in skin was evaluated. We observed that both growth factors induced fibrosis. Over time, a decrease in blood vessel density was observed in both treatment groups. Both factors also stimulated an expansion of the connective tissue cell population originating from the microvascular pericyte, but the phenotype of these cells differed in the different treatments with regards to expression of markers. Furthermore, in tissue over-expressing PDGF-B but not TGF-β, the fibrotic process was partially reversible.
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Richards, James David. "Gait analysis under different testing conditions and their effect on non-pathological and intermittent claudication gait." Thesis, Glasgow Caledonian University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267083.
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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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Hua, Xue. "The application of tensor based morphometry in mapping human brain anatomical changes during normal and pathological conditions." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1779690341&sid=8&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Nasrallah, Kaoutsar. "Consequences of synaptic plasticity at inhibitory synapses in mouse hippocampal area CA2 under normal and pathological conditions." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCB089/document.
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L'hippocampe est une région du cerveau importante pour la formation de mémoire. Des études récentes ont montré que la zone CA2 de l'hippocampe, longtemps ignorée, joue un rôle clef dans certaines formes de mémoire et notamment dans la mémoire sociale. De plus, des études post-mortem ont révélé des altérations spécifiques à la région CA2 chez les patients schizophrènes. Cependant, l’implication des neurones de CA2 dans les circuits de l'hippocampe reste peu connu, tant dans des conditions physiologiques que pathologiques. En combinant pharmacologie, génétique et électrophysiologie sur tranches d’hippocampe de souris, nous avons étudié comment les neurones pyramidaux (NP) CA2 sont recrutés dans les circuits hippocampiques après des changements d’inhibition et comment le recrutement des NP CA2 pourrait moduler l’information sortant de l'hippocampe. D’autre part, nous avons examiné les altérations fonctionnelles de la zone CA2 dans le modèle murin Df(16)A+/- de la microdélétion 22q11.2, le facteur génétique de risque de schizophrénie le plus élevé. Dans la région CA2 de l’hippocampe, les synapses inhibitrices contrôle les afférences des collatérales de Schaeffer (CS) et expriment une dépression à long-terme (DLTi) unique qui dépendant des récepteurs delta-opioïdes (RDO). Contrairement aux synapses CS-CA1, les synapses excitatrices CS-CA2 n’expriment pas de potentialisation à long-terme après application des protocoles d'induction. Cependant, nous avons constaté que différents types d'activités induisent une augmentation durable de l’amplitude des potentiels post-synaptiques (PPS) évoqués aussi bien par une stimulation des CS que des afférences distales des NP CA2, et ceci via une modulation de la balance excitation/inhibition. Nous avons démontré que ces augmentations du rapport excitation/inhibition sont les conséquences directes de la DLTi RDO-dépendante. De plus, la DLTi permet le recrutement des NP CA2 par les NP CA3 alors qu’une inhibition intacte empêche complètement leur activation en réponse aux stimulations des CS. Par ailleurs, le recrutement des pyramides de CA2 par les CS après disinhibition activité-dépendante ajoute une composante polysynaptique (SC-CA2-CA1) au PPS monosynaptique (SC-CA1) dans les NP CA1 et augmente leur activité. De plus, l’inactivation des interneurones exprimant la parvalbumine à l’aide d’outils pharmacogénétiques, a montré que ces cellules inhibitrices contrôlent fortement l'amplitude du PPS et l’activité des NP CA2 en réponse à la stimulation des CS et qu’elles sont nécessaires à l'augmentation RDO-dépendante du rapport excitation/inhibition entre CA3 et CA2. Enfin, l'étude de la zone CA2 chez les souris Df(16)A+/- a révélé plusieurs modifications dépendantes de l'âge dont une réduction de l'inhibition, une altération de la plasticité du rapport excitation/inhibition entre CA3 et CA2 et une hyperpolarisation NP CA2. Ces modifications cellulaires peuvent expliquer les déficiences de mémoire sociale que nous observons chez les souris Df(16)A+/- adultes. L’ensemble de nos études a permis de mettre en évidence le rôle des neurones CA2 dans les circuits de l'hippocampe. Enfin pour conclure, nous postulons que le recrutement des neurones CA2 dans les réseaux neuronaux sous-tend des aspects particuliers de la fonction de l'hippocampeThe hippocampus is a region of critical importance for memory formation. Recent studies have shown that the long-overlooked hippocampal region CA2 plays a role in certain forms of memory, including social recognition. Furthermore, post-mortem studies of schizophrenic patients have revealed specific changes in area CA2. As yet, the role of CA2 neurons in the hippocampal circuitry remains poorly understood under both normal physiological and pathological conditions. By combining pharmacology, mouse genetics and electrophysiology, we investigated how CA2 pyramidal neurons (PNs) could be recruited in hippocampal circuits in mice hippocampal slices following an activity-dependent change in the strength of their inhibitory inputs. We further investigated how subsequent recruitment of CA2 PNs could modulate hippocampal output. Moreover, we examined the functional alterations of area CA2 in the Df(16)A+/- mouse model of the 22q11.2 microdeletion, a spontaneous chromosomal deletion that is the highest known genetic risk factor for developing schizophrenia. In area CA2, inhibitory synapses exert a powerful control of Schaffer collateral (SC) inputs and undergo a unique long-term depression (iLTD) mediated by delta-opioid receptor (DOR) activation. Unlike SC-CA1 synapses, SC-CA2 excitatory synapses fail to express long-term potentiation after classical induction protocols. However, we found that different patterns of activity persistently increase both the SC and the distal input net excitatory drive onto CA2 PNs via a modulation of the balance between excitation and inhibition. We demonstrated that increases in the excitatory/inhibitory ratio are direct consequences of the DOR-mediated iLTD. Interestingly, we found that the inhibition in area CA2 completely preventing CA3 PNs to activate CA2 PNs, and following iLTD, SC stimulation allows CA2 PNs to fire action potentials. Moreover, the recruitment of CA2 PNs by SC intra-hippocampal inputs after their activity-dependent disinhibition adds a delayed SC-CA2-CA1 response to the SC-CA1 monosynaptic post-synaptic potential (PSP) in CA1 and increases CA1 PN activity. Furthermore, pharmaco-genetic silencing of parvalbumin-expressing interneurons revealed that these inhibitory cells control the PSP amplitude and the firing of CA2 PNs in response to SC stimulation and are necessary for the DOR-mediated increase in excitatory/inhibitory balance between CA3 and CA2. Finally, we found several age-dependent alterations in area CA2 in Df(16)A+/- mouse model of the 22q11.2 microdeletion. These included a reduction in inhibition, an impaired activity-dependent modulation of the excitatory drive between CA3 and CA2 and a more hyperpolarized CA2 PN resting potential. These cellular disruptions may provide a potential mechanism for the social memory impairment that we observe in Df(16)A+/- adult mice. Altogether, our studies highlight the role of CA2 neurons in hippocampal circuitry. To conclude, we postulate that the recruitment of CA2 neurons in neuronal networks underlies key aspects of hippocampal function
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Hellström, Martin. "Hyaluronan and the receptor CD 44 in the heart and vessels : a study in normal and pathological conditions." Doctoral thesis, Umeå universitet, Medicin, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1128.
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Tissues are not solely composed of cells. The extracellular matrix is important for the cell well-being and cell-cell communication. The glycosaminoglycan hyaluronan (HYA) is a widely distributed extracellular matrix (ECM) component. The molecule has prominent physicochemical properties, foremost viscoelastic and osmotic, but participates in many biological processes such as cell migration, proliferation, tissue turnover, wound healing and angiogenesis. HYA is synthesised by either of three different hyaluronan-synthesising enzymes, HAS1-3, and its main ligand is the transmembrane receptor CD44. In the heart and vessels the matrix components are of great importance for endurance and elasticity which are prerequisites for a normal function. The aims of the study were to describe the distribution of HYA and its receptor CD44 in normal cardiovascular tissue and to investigate the ECM composition in myocardial hypertrophy. Normal conditions were studied in a rat model. These studies showed that the tunica adventitia in almost all vessels stained strongly for HYA. The expression in the tunica intima and media on the venous side, differed between the vessels and was almost absent on the arterial side. In the adult animals only minute amounts of CD44 were detected. The expression of both HYA and CD44 was increased in newborn rats. In the heart HYA was unevenly distributed in the interstitium. Strong HYA-staining was seen in the valves and in the adventitia of intramyocardial vessels. Almost no CD44-staining was observed. Notably, there was no obvious difference between newborn and adult animals. In an experimental rat model of pressure-induced cardiac hypertrophy the mRNA-levels of HAS1, HAS2, CD44, basic Fibroblast Growth Factor (FGF-2) and Fibroblast Growth Factor Receptor-1 (FGFR-1) were elevated on day 1 after aortic banding. HAS2, CD44 and FGFR-1 were at basal levels on day 42. The HYA-concentration was significally elevated on day 1. HYA was detected in the interstitium by histochemistry and CD44 was detected mainly in and around the intramyocardial vessels. The HYA-staining was increased in myectomi specimens from patients with HCM compared to controls. HYA was detected in the interstitium, in fibrous septas and in the adventitia of intramyocardial vessels. No CD44 was detected in HCM or in control specimens. Our results indicate that HYA and CD44 play an active role in the maturing vessel tree and that the ECM content of HYA is increased in experimental myocardial hypertrophy and human hypertrophic cardiomyopathy.
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Jimenez-Mejia, Jorge Hernan. "The loading and function of the mitral valve under normal, pathological and repair conditions : an in vitro study /." Diss., Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-11102006-003456/.
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Thesis (Ph. D.)--Biomedical Engineering, Georgia Institute of Technology, 2007.Ajit Yoganathan, Committee Chair ; Thomas Vassiliades, Committee Member ; Joseph Gorman, Committee Member ; Marc Levenston, Committee Member ; John N. Oshinski, Committee Member.
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Hellström, Martin. "Hyaluronan and the receptor CD 44 in the heart and vessels : a study in normal and pathological conditions /." Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1128.
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Bodea, Liviu-Gabriel [Verfasser]. "Implication of the TREM2/DAP12 Complex in Miroglial-mediated Tissue Homeostasis under Healthy and Pathological Conditions / Liviu-Gabriel Bodea." Bonn : Universitäts- und Landesbibliothek Bonn, 2014. http://d-nb.info/1077289456/34.
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Chroni, Elisabeth. "F chronodispersion and F tacheodispersion : a study of conduction properties of motor nerve fibres in normal and pathological conditions." Thesis, King's College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320463.
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Maggioni, Martina Anna [Verfasser]. "The deconditioned and the trained heart: responses to physical exercise in pathological and physiological extreme conditions / Martina Anna Maggioni." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2021. http://d-nb.info/1238595898/34.
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Chelysheva, Irina [Verfasser], and Andrew [Akademischer Betreuer] Torda. "Analysing deep-seq data to reveal the hidden translational features in normal and pathological conditions / Irina Chelysheva ; Betreuer: Andrew Torda." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2020. http://d-nb.info/1212180933/34.
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Reynell, C. "Identification and functional characterization of CNS pericytes and the role they play in neurovascular coupling in physiological and pathological conditions." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1413174/.
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Brain blood flow increases, evoked by neuronal activity, power neural computation and are the basis of BOLD functional imaging. However, it is controversial whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes. The experimental work within this thesis examines capillary pericytes, and the role they play in neurovascular coupling in physiological and pathological conditions. I show that pericytes can be identified using several protein markers and that, using the same technique, pericytes can be distinguished from other perivascular cell types. I demonstrate that pericytes respond to the neurotransmitters noradrenaline and glutamate. Noradrenaline depolarizes pericytes and constricts capillaries, and this constriction reflects pericyte contraction while glutamate, mimicking neuronal activity, hyperpolarizes pericytes and dilates capillaries, and this dilation reflects pericyte relaxation. Glutamate-evoked dilation is mediated by prostaglandin E₂ or a related compound acting at EP4 receptors, but requires nitric oxide release to suppress synthesis of the vasoconstrictor 20-HETE. In pathology, I show that pericytes die when exposed to ischaemia. This may lead to pericytes irreversibly constricting capillaries and to damage of the blood-brain barrier. Pericyte death increases on reperfusion after ischaemia, and is reduced by block of glutamate receptors or Ca2+ removal, but not by scavenging reactive oxygen species. These data establish pericytes as active regulators of capillary tone and thus as potential regulators of brain blood flow. My data also suggest prevention of pericyte death as a strategy to reduce the long-lasting blood flow decrease which contributes to neuronal death after stroke. This thesis also contains a discussion of how energy supply to the brain alters with age, and how this may affect the BOLD signal.
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Lo, Van Amanda. "Study of the effects of docosahexaenoic acid (DHA) and a structured phospholipid containing DHA on physiological and pathological conditions of neurogenesis in vitro." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSEI005/document.
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L'acide docosahexaénoïque (DHA, 22:6n-3) est un acide gras polyinsaturé (AGPI) oméga-3. Il est particulièrement abondant dans le cerveau et la rétine et est nécessaire pour le bon développement et fonctionnement du cerveau. Tandis qu'une déficience en DHA a été montrée être liée à l'émergence de maladies cérébrales (i.e. maladie d'Alzheimer ou maladie de Parkinson), des études ont également montré qu'un apport alimentaire en AGPI oméga-3 pouvait empêcher ou atténuer les perturbations neurologiques liées au vieillissement ou aux maladies neurodégénératives. Il est alors primordial de transporter efficacement le DHA au cerveau. Le laboratoire français a synthétisé auparavant une forme stabilisée de la lysophosphatidylcholine-DHA, qui est le vecteur principal d'apport de DHA au cerveau, de structure 1-acétyl,2-docosahexaénoyl-glycérophosphocholine, brevetée et nommée AceDoPC®. L'injection d'AceDoPC ou de DHA après un accident vasculaire cérébral ischémique provoqué expérimentalement a montré que ces deux molécules étaient neuroprotectrices. Ces effets sont supposés être dus en partie à la conversion du DHA en métabolites oxygénés. Notre étude vise à examiner les effets du DHA et de ses métabolites dérivés, estérifiés ou non dans des phospholipides structurés sur un modèle de neurogenèse in vitro en conditions physiologiques ou pathologiques. Le premier objectif de ce travail a été de synthétiser le phospholipide structuré contenant du DHA, l’AceDoPC®, la protectine DX (métabolite oxygéné du DHA), et un nouveau phospholipide structuré contenant la protectine: 1-acétyl,2-protectine DX-glycérophosphocholine (AceDoxyPC). Le second objectif était d’étudier les effets du DHA, de l'AceDoPC et de la PDX sur la neurogenèse en utilisant un modèle in vitro de neurogenèse, constitué de cultures de cellules souches progénitrices neurales (NSPCs) dérivées de cerveaux de souris adultes, dans des conditions physiologiques ou pathologiques (ischémiques ici). Enfin, le troisième objectif de cette thèse a été d'identifier les mécanismes impliqués dans la réponse des cellules aux conditions ischémiques. La synthèse du phospholipide structuré AceDoxyPC a été réalisée avec succès par une double lipoxygénation enzymatique de l'AceDoPC, et l'identification du produit a été possible grâce à l'utilisation de techniques avancées de chromatographie liquide couplée à la spectrométrie de masse (LC/ESI/MS). De futures études sur ce transporteur de molécule neuroprotectrice potentielle doivent être réalisées prochainement. Les cellules incubées en présence d’AceDoPC présentent une augmentation de neurogenèse comparativement à celles cultivées avec addition de DHA non estérifié ou du véhicule contrôle, notamment sous conditions pathologiques. Les études préliminaires des mécanismes potentiellement impliqués dans la neuroprotection indiquent que les effets neuroprotecteurs et régénératifs de l'AceDoPC pourraient être en partie dus à des effets anti-oxidantsDocosahexaenoic acid (DHA, 22:6n-3) is an essential omega-3 polyunsaturated fatty acid (PUFA). It is specifically enriched in the brain and the retina and it is required for visual acuity, proper brain development and cerebral functions. While DHA deficiency in the brain was shown to be linked to the emergence of cerebral diseases (i.e. Alzheimer’s disease or Parkinson’s disease), studies showed that a dietary intake of omega-3 PUFA could prevent or attenuate neurologic disturbances linked with ageing or neurodegenerative diseases. In this context, it is primary to deliver DHA efficiently to the brain. Targeting the brain with DHA might offer great promise in developing new therapeutics for neurodegenerative diseases. The French host laboratory previously synthesized a stabilized form of lysophosphatidylcholine-DHA, which is main vector of DHA transportation to the brain, of structure 1-acetyl,2-docoshexaenoyl-glycerophosphocholine, patented and named AceDoPC®. Injection of AceDoPC or DHA after experimental ischemic stroke showed that both molecules also had neuroprotective effects. These potential neuroprotective effects are expected to be due, in part, to DHA conversion into oxygenated metabolites. This study aims to investigate the beneficial effects of DHA and its derived metabolites either unesterified or esterified within structured phospholipids on a model of neurogenesis in vitro under physiological or pathological conditions. The first objective of this work was then to synthesize the DHA-containing structured phospholipid AceDoPC®, DHA oxygenated derivative protectin DX (PDX) and a novel structured phospholipid of protectin: 1-acetyl,2-protectinDX-glycerophosphocholine (AceDoxyPC). The second objective was to investigate the effects of DHA, AceDoPC and PDX on neurogenesis using an in vitro model of neurogenesis, namely cultures of neural stem progenitor cells (NSPCs) derived from the adult mouse brain under physiological or pathological conditions (ischemic conditions). Following this, the third objective of this work was to identify the mechanisms involved in such response to stress induced under pathological conditions. Synthesis of the novel structured phospholipid AceDoxyPC was successfully performed by double enzymatic lipoxygenation of AceDoPC and identification of the product was possible using advanced techniques of liquid chromatography (LC)/electrospray ionization (/ESI)/mass spectrometry (/MS). Future studies on this potential neuroprotective molecule transporter are to be investigated in the near future. Neurogenesis study of cell cultures with AceDoPC showed enhanced neurogenesis compared to addition of unesterified DHA or vehicle control, especially under pathological conditions. Preliminary studies of the potential mechanisms involved in neuroprotection hinted that AceDoPC neuroprotective and regenerative effects might be due in part to its anti-oxidative effects
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Collier, Justin B., Ryan M. Whitaker, Scott T. Eblen, and Rick G. Schnellmann. "Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions." AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016. http://hdl.handle.net/10150/622726.
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Previous studies have shown that extracellular signal-regulated kinase 1/2 (ERK1/2) directly inhibits mitochondrial function during cellular injury. We evaluated the role of ERK1/2 on the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene, a master regulator of mitochondrial function. The potent and specific MEK1/2 inhibitor trametinib rapidly blocked ERK1/2 phosphorylation, decreased cytosolic and nuclear FOXO3a/1 phosphorylation, and increased PGC-1 alpha gene expression and its downstream mitochondrial biogenesis (MB) targets under physiological conditions in the kidney cortex and in primary renal cell cultures. The epidermal growth factor receptor (EGFR) inhibitor erlotinib blocked ERK1/2 phosphorylation and increased PGC-1 alpha gene expression similar to treatment with trametinib, linking EGFR activation and FOXO3a/1 inactivation to the down-regulation of PGC-1 alpha and MB through ERK1/2. Pretreatment with trametinib blocked early ERK1/2 phosphorylation following ischemia/reperfusion kidney injury and attenuated the downregulation of PGC-1 alpha and downstream target genes. These results demonstrate that ERK1/2 rapidly regulates mitochondrial function through a novel pathway, EGFR/ERK1/2/FOXO3a/1/PGC-1 alpha, under physiological and pathological conditions. As such, ERK1/2 down-regulates mitochondrial function directly by phosphorylation of upstream regulators of PGC-1 alpha and subsequently decreasing MB.
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Valero, Freitag Susana [Verfasser], and Nikolaus [Akademischer Betreuer] Plesnila. "Local and remote effects of pathological conditions on pyramidal neurites : a longitudinal study using in vivo two-photon microscopy / Susana Valero Freitag ; Betreuer: Nikolaus Plesnila." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1220631930/34.
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Mulugeta, Ezra. "Muscarinic M₁ and M₄ receptor subtypes in normal and pathological conditions in the central nervous system : studies on human and animal tissues using subtype selective ligands /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-643-X/.
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Gertig, Ulla [Verfasser], Wolfgang [Akademischer Betreuer] [Gutachter] Brück, Hannelore [Gutachter] Ehrenreich, Fred [Gutachter] Wouters, Jutta [Gutachter] Gärtner, Hauke [Gutachter] Werner, and Ralf [Gutachter] Heinrich. "Constitutive heterogeneity and response diversity of microglia in pathological conditions / Ulla Gertig ; Gutachter: Wolfgang Brück, Hannelore Ehrenreich, Fred Wouters, Jutta Gärtner, Hauke Werner, Ralf Heinrich ; Betreuer: Wolfgang Brück." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1122348789/34.
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Austin, Kimberley W. "Biological Mechanisms and Symptom Outcomes of Uncertainty and Psychological Stress in Parkinson’s Disease." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4716.
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The purpose of this work was to examine biological mechanisms and symptom outcomes of illness uncertainty and psychological stress in Parkinson’s disease (PD). Parkinson’s disease is a chronic, progressive neurodegenerative disorder characterized by complex symptoms that fluctuate in onset, severity, level of disability, and responsiveness to treatment. In addition to characteristic motor symptoms of tremor, rigidity, bradykinesia, and postural instability, a considerable number of individuals with PD also experience debilitating pain, fatigue, and medication-induced motor complications of dyskinesia, dystonia, and on-off phenomena. The unpredictable nature of PD symptoms and motor complications coupled with the inability to halt or slow disease progression may result in uncertainty and psychological stress. Evidence is lacking regarding biological mechanisms and symptom outcomes of uncertainty and psychological stress in PD. As such, 80 men and women diagnosed with PD after the age of 49 were recruited to participate in this study. Data specific to characteristics that may contribute to uncertainty and psychobehavioral measures of uncertainty, appraisal, psychological stress, and symptom outcomes of motor symptoms, pain, and fatigue were collected. Biological measures of neuropeptide Y (NPY) and cytokines were obtained. The results revealed that participants perceived a moderate level of illness uncertainty. Uncertainty correlated significantly with motor symptoms, pain severity, and pain interference and predicted more severe pain severity and pain interference. Psychological stress correlated significantly with motor symptoms, pain severity, pain interference, and fatigue and predicted more severe symptoms across all outcomes. NPY was positively correlated with threat appraisals and psychological stress. Cytokines were below the level of detection in this sample, and not used beyond descriptive analyses. In summary, this study found uncertainty and psychological stress contributed to more severe symptom outcomes in PD. This knowledge may be used to guide future studies aimed at further elucidating biobehavioral symptom and health outcomes of uncertainty and psychological stress in PD. It will also facilitate the development of interventions specifically targeted to uncertainty and psychological stress for the ultimate purpose of improving symptom management, health outcomes, and disease progression in PD.
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Simon, Remil B. S., Darshan M. D. Shah, Peter B. S. Blosser, Demetrio M. D. Macariola, and Jeffrey M. D. Carlsen. "Treatment of CMV Vitritis in a Preterm Newborn." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/165.
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Title: Treatment of CMV Vitritis in a Preterm Newborn
Author’s Section: Remil Simon1, Darshan Shah1, Peter Blosser1, Demetrio Macariola1, Jeffrey Carlsen2
1.Department of Pediatrics, Quillen College of Medicine, East Tennessee State University, Johnson City, TN
2.Johnson City Eye Clinic, Johnson City, TN
Body: Cytomegalovirus (CMV) infection in the neonate is an infrequent occurrence in the developing world, and observing the symptoms of ocular CMV infection such as vitritis is rare. Treating CMV infection promptly is necessary to prevent mortality and potential neurological deficits including blindness and hearing loss. We encountered a preterm infant presenting with CMV sepsis immediately after birth. Our question was: will the current standard of treatment for CMV sepsis prevent CMV ocular infection? With our method of treatment, we followed the current standard of treatment for CMV infection by administering intravenous Gancyclovir for 6 weeks and oral Valgancyclovir for 6 months. Despite using the standard treatment to prevent neurological sequelae, the patient developed CMV vitritis and retinitis bilaterally. Although the treatment did not prevent CMV ocular infection, the severity of CMV retinitis and vitritis improved with treatment, and full resolution of vitritis was noted by day of life 61.
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Nath, Bharath D. "Hypoxia Inducible Factors in Alcoholic Liver Disease: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/525.
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Chronic intake of alcohol can result in a range of pathology in the liver. Whilst the earliest changes observed with chronic ethanol, including the accumulation of lipid, or steatosis, are readily reversible upon cessation of alcohol consumption, longer exposure to ethanol may achieve more complex disease states including steatohepatitis, fibrosis, and cirrhosis that can cause irreversible damage and progress to fulminant hepatic failure. A key concept in the pathogenesis of alcoholic liver disease is that chronic ethanol primes the liver to increased injury through an interplay between hepatocytes and non-parenchymal cells, chiefly immune cells, of the liver. These relationships between hepatocytes and non-parenchymal cell types in alcoholic liver disease are reviewed in Chapter 1A.
The Hypoxia Inducible Factors are a set of transcription factors that classically have been described as affecting a homeostatic response to conditions of low oxygen tension. Alcoholic liver disease is marked by increased hepatic metabolic demands, and some evidence exists for increased hepatic tissue hypoxia and upregulation of hypoxia-inducible factor mRNA with chronic alcohol. However, the biological significance of these findings is unknown. In Chapter 1B, we review the literature on recent investigations on the role of hypoxia inducible factors in a broad array of liver diseases, seeking to find common themes of biological function.
In subsequent chapters, we investigate the hypothesis that a member of the hypoxia inducible- factor family, HIF1α, has a role in the pathogenesis of alcoholic liver disease. In Chapter 2, we establish a mouse model of alcoholic liver disease and report data confirming HIF1α activation with chronic ethanol. We demonstrate that HIF1α protein, mRNA, and DNA binding activity is upregulated in ethanol-fed mice versus pair-fed mice, and that some upregulation of HIF2α protein is observable as well. In Chapter 3, we utilize a mouse model of hepatocyte-specific HIF1α activation and demonstrate that such mice have exacerbated liver injury, including greater triglyceride accumulation than control mice. Using cre-lox technology, we introduce a degradation resistant mutant of HIF1α in hepatocytes, and after four weeks of ethanol feeding, we demonstrate that mice with the HIF1α transgene have increased liver-weight to body weight ratio and higher hepatic triglyceride levels. Additionally, several HIF1α target genes are upregulated. In Chapter 4, we examine the relationship between HIF1α activation and hepatic lipid accumulation using a recently published in vitro system, in which lipid accumulation was observed after treating Huh7 cells with the chemokine Monocyte Chemoattractant Protein-1 (MCP-1). We report that MCP-1 treatment induces HIF1α nuclear protein accumulation, that HIF1α overexpression in Huh7 cells induces lipid accumulation, and finally, that HIF1α siRNA prevents MCP-1 induced lipid accumulation. In Chapter 5, we use mouse models to investigate the hypothesis that suppression of HIF1α in hepatocytes or cells of the myeloid lineage may have differing effects on the pathogenesis of alcoholic liver disease. We find that ethanol-fed mice expressing a hepatocyte-specific HIF1α deletion mutant exhibit less elevation in liver-weight body ratio and diminished hepatic triglycerides versus wild-type mice; furthermore, we find that challenging these mice with lipopolysaccharide (LPS) results in less liver enzyme elevation and inflammatory cytokine secretion than in wild-type mice. In Chapter 6, we offer a final summary of our findings and some directions for future work.
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Sultan, Sadaf [Verfasser], Giuliano [Akademischer Betreuer] Ramadori, Nils [Akademischer Betreuer] Brose, Michael [Akademischer Betreuer] Hoppert, and Uwe [Akademischer Betreuer] Groß. "Serum Lipocalin-2 (LCN-2) as a major acute phase protein under different pathological conditions in vivo and in vitro studies / Sadaf Sultan. Gutachter: Nils Brose ; Michael Hoppert ; Uwe Groß. Betreuer: Giuliano Ramadori." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/1042670137/34.
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Sultan, Sadaf Verfasser], Giuliano [Akademischer Betreuer] Ramadori, Nils [Akademischer Betreuer] Brose, Michael [Akademischer Betreuer] Hoppert, and Uwe [Akademischer Betreuer] [Groß. "Serum Lipocalin-2 (LCN-2) as a major acute phase protein under different pathological conditions in vivo and in vitro studies / Sadaf Sultan. Gutachter: Nils Brose ; Michael Hoppert ; Uwe Groß. Betreuer: Giuliano Ramadori." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://nbn-resolving.de/urn:nbn:de:gbv:7-webdoc-3400-1.
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Briggs, Virginia G. "Injection Treatment for Lower Back Pain in Older Adults with Lumbar Spinal Stenosis: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/439.
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Background:Lower back pain is one of the most common health-related complaints in the adult population. Thirty percent of Americans 65 years and older reported symptoms of lower back pain in 2004. With an aging population, the proportion of people over the age of 65 is expected to reach 20% by the year 2030. Because of this increase in older adults, lumbar spinal stenosis (LSS) associated with arthritic changes will also likely increase. In older adults, lower back pain is most often caused by degenerative lumbar spinal stenosis. Stenosis is the narrowing ofthe spinal canal, causing pressure on the nerve roots and is frequently treated surgically. Lumbar spinal stenosis is one of the most common reasons for back surgery in patients 65 years and older 2. However, risks associated with surgery increase with age 3-5 and older patients may choose non-surgical treatment for their lower back pain, including injection treatment.
Injection treatment, usually consisting of anti-inflammatory medications and analgesics, has improved since the mid-1990's when fluoroscopic guidance was developed. Information about injection treatment for lower back pain is limited, especially in the older population. An extensive review of published literature regarding injection treatment revealed a paucity of information about older adults diagnosed with lumbar spinal stenosis. In this study, three aims were designed to gain more information about the effectiveness of injection treatment in older patients with lumbar spinal stenosis. In the first (retrospective) study, information about receipt of second injections and time between injections was collected to examine injection usage. In the second and third (prospective) studies, information about pain relief and functional return following injection treatment was collected to examine the effectiveness of injection treatment in patients age 60 and older diagnosed with lumbar spinal stenosis. To our knowledge, such results have not been repolted for this population in the literature.
Objective:Injection treatment is a commonly used non-surgical procedure to alleviate lower back pain in older adults. However, older patients do not have enough information about how long pain relief will last after treatment or the amount of pain relief and functional return they will experience. These studies focused on three topics: 1) usage of injection treatment; 2) effectiveness of injection treatment on pain relief; 3) effectiveness of injection treatment on functional return. In addition, the variations of the effectiveness were examined by selected patient attributes.
Methods:In a retrospective study, medical records of patients aged 60 years or older from a high volume dedicated spine center at the University of Massachusetts Memorial Hospital were retrospectively reviewed. This study included those diagnosed with degenerative LSS, who had not received an injection for lower back pain within six months, and whom were treated between June I, 2006 and May 31, 2007.
In two prospective studies, patients scheduled for lumbar injection treatment between January 1 and June 30, 2008 were selected from the University of Massachusetts Memorial Hospital Spine Center. Selection criteria included patients age 60 and over, diagnosed with degenerative lumbar spinal stenosis and no previous lumbar injection within 6 months or lumbar surgery within 2 years. The Pain sub-score of the SF-36 questionnaire was used to measure pain at baseline and at one and three months post injection. The Physical Component Score (PCS) of the SF-36 questionnaire and the Oswestry Disability Index (ODI) were used to measure function at baseline and at one and three months post injection. Variations in longitudinal changes in scores by patient characteristics were analyzed in both unadjusted (univariate) analyses using one-way analysis of variance (ANOVA), and adjusted (multiple regression) analyses using linear mixed effects models.
Results: In the retrospective cohort, the mean age of the cohort was 68, 64% were female, 59% were married, with a mean Body Mass index of 32 kg/m2. Of 92 eligible patients, 57% returned for a second injection within six months of the first. The mean number of months between injections was 4.8 for all patients, ranging from 1 to 22 months. When patient characteristics were examined, the only variable that showed a statistically significant difference was age. Patients aged 70 years and older were found to be 67% less likely to return for a second injection when compared to patients age 60-69 (OR=0.33 (0.12 - 0.94)p In the prospective cohort, information was collected on 62 patients. Mean Pain scores improved significantly from baseline to one month (14.1 points), and from baseline to three months (8.3 points). Post injection changes in Pain scores varied by Body Mass Index (BMI) and baseline emotional health. Based on a linear mixed effects model analysis, higher baseline emotional health, as measured by the SF-36 Mental Component Score (MCS>50), was associated with greater reduction in pain over three months when compared to lower emotional health (MCS Conclusion: Patients over age 70 do not return for repeat injection as frequently as patients age 60-69. In addition, each year a patient ages over age 60, they are 10% less likely to return for a repeat injection. Lower back pain in older adults with LSS is clinically significantly alleviated after injection treatment. In addition, injection treatment for LSS is associated with return of lost function needed for daily living activities in older adults. Pain relief and functional return varies by patient personal and clinical characteristics. Higher emotional health was associated with more pain relief and more functional return experienced over three months following injection treatment. Additional information is needed about why older patients do not return for second injections at the same rate as younger patients and how emotional health affects response to injection treatment in older adults.
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Tran, Khanh-Van T. "Origin of White and Brown Adipose Cells From Vascular Endothelium: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/591.
Full textAbstract:
Obesity is associated with insulin resistance, dyslipidemia, and cardiovascular disease. The current obesity epidemic is the result of surplus energy consumption. Excess energy is stored in expanding adipose tissue. Adipose tissue growth entails the enlargement of existing adipocytes, the formation of new fat cells from preexisting progenitors, and the coordinated development of supporting vasculature. Identifying adipocyte progenitors and the mechanism of adipose tissue expansion is crucial for the development of new strategies to combat obesity and its complications.
Though important progress has been made towards understanding the developmental origin of adipocytes, the identities of adipocyte progenitors are still not completely known. The main objective of this study is to determine whether endothelial cells of the adipose tissue can give rise to new adipocytes. Our results indicate that murine endothelial cells of adipose tissue are pluripotent and can potentially give rise to preadipocytes. Lineage tracing experiments using the VE-Cadherin-Cre transgenic mouse reveal localization of reporter genes in endothelial cells, preadipocytes and white and brown adipocytes. Moreover, capillary sprouts from human adipose tissue, which have predominantly endothelial cell characteristics, are found to express Zfp423, a preadipocyte determination factor. In response to PPARγ activation, endothelial characteristics of sprouting cells are progressively lost, and cells form structurally and biochemically defined adipocytes. Taken together, our data support an endothelial origin of a population of adipocytes. The ability of the vascular endothelium to give rise to adipocytes may explain how angiogenesis and adipogenesis can be temporally and spatially coordinated.
Analysis of BAT and WAT revealed that adipose depots have distinct compositions of adipocyte progenitors. Of the CD45-CD29+Sca1+CD24+ progenitor population, only 17% and 52% express VE-Cadherin in WAT and BAT, respectively. Our data show that the number of these specific progenitors in BAT and WAT are highly variable and suggest that a considerable number of adipocytes progenitors may have a non-endothelial cell origin. Differences in composition and types of adipocyte progenitors may explain the differences in the adipocytes phenotypes that we observe in discrete depots.
In brief, we find that the vascular endothelium gives rise to a population of brown and white fat cells, and that the number of endothelial-derived adipocyte progenitors residing in BAT and WAT is highly variable. These results expand our current understanding of adipose tissue growth, and, we hope, will accelerate the development of treatments for obesity-related complications.
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McManus, David D. "Incidence, prognosis, and factors associated with cardiac arrest in patients hospitalized with acute coronary syndromes (the GRACE Registry): A master's thesis." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/593.
Full textAbstract:
Objectives: Contemporary data are lacking with respect to the incidence rates of, factors associated with, and impact of cardiac arrest from ventricular fibrillation or tachycardia (VF-CA) on hospital survival in patients admitted with an acute coronary syndrome (ACS). The objectives of this multinational study were to characterize trends in the magnitude of in-hospital VF-CA complicating an ACS and describe its impact over time on hospital prognosis.
Methods: The study population consisted of 59,161 patients enrolled in the Global Registry of Acute Coronary Events Study between 2000 and 2007. Overall, 3,618 patients (6.2%) developed VF-CA during their hospitalization for an ACS. Incidence rates of VF-CA declined over time, albeit in an inconsistent manner. Patients who experienced VF-CA were on average older and had a greater burden of cardiovascular disease, yet were less likely to receive evidence-based cardiac therapies than patients in whom VF-CA did not occur. Hospital death rates were 55.3% and 1.5% in patients with and without VF-CA, respectively. There was a greater than 50% decline in the hospital death rates associated with VF-CA during the years under study. Patients with a VF-CA occurring after 48 hours were at especially high risk for dying during hospitalization (82.8%).
Conclusions: Despite reductions in the magnitude of, and short-term mortality from, VF-CA between 2000 and 2007, VF-CA continues to exert a significant adverse effect on survival among patients hospitalized with an ACS. Opportunities exist to improve the identification and treatment of ACS patients at risk for VF-CA to reduce the incidence of, and mortality from, this serious arrhythmic disturbance.
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Benoit, Vivian M. "Host Cell Attachment by Lyme Disease and Relapsing Fever Spirochetes: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/512.
Full textAbstract:
Host cell attachment by pathogenic bacteria can play very different roles in the course of infection. The pathogenic spirochetes Borrelia hermsii and Borrelia burgdorferi sensu lato which cause relapsing fever and Lyme disease, respectively, are transmitted by the bite of infected ticks. After transmission, these spirochetes can cause systemic infection. Relapsing fever spirochetes remain largely in the bloodstream causing febrile episodes, while Lyme disease will often colonize a variety of tissues, such as the heart, joint and nervous system, resulting in a chronic multisystemic disorder. Borrelia species have the ability to bind to various cell types, a process which plays a crucial role in pathogenesis and may influence spirochetal clearance from the bloodstream. Colonization of multiple tissues and cell types is likely promoted by the ability to bind to components found in target tissues, and many B. burgdorferi adhesins have been shown to promote attachment to a wide variety of cells and extracellular matrix components. Different Lyme disease strains have been shown to preferentially colonize certain tissues, although the basis of this tissue tropism is not well understood. In this study we found that among different Lyme disease strains, allelic variation of the adhesin DbpA contributes to variation in its in vitro binding activities raising the possibility that this variation contributes to tissue tropism in vivo. In studying B. hermsii infection, we found evidence by both histological and fluorescence in situ hybridization (FISH) analysis of tissues that indicated that red blood cells were removed by tissue resident macrophages in infected mice. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream. Our findings indicate that host cell attachment play a key role in the establishment of Lyme disease infection, and in contrast contributes to the clearance of relapsing fever infection.
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Awad, Hamza H. "Use of Multinational Registries to Assess and Compare Outcomes of Patients with an Acute Coronary Syndrome: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/546.
Full textAbstract:
Background Acute coronary syndromes (ACS) are a major cause of mortality and morbidity in the developed world. By 2020, ACS will be the leading cause of morbidity and mortality worldwide, largely due to substantial increases in ACS burden in developing countries. The developing world has been under-represented in international ACS registries. The Arabian Gulf area is a part of the developing world where little is known about the epidemiology of ACS. The first aim of the dissertation is to compare ACS patient characteristics, current practice patterns, and in-hospital outcomes in the Arabian Gulf area to a large multinational sample. Patients with an ACS suffer numerous clinical complications that worsen their prognosis. Cardiogenic shock (CS) is the most serious complication of ACS and the leading cause of in-hospital death. Despite advances in therapies; CS hospital mortality rates continue to exceed 50%. The second aim of the dissertation is to describe the characteristics of patients presenting with ACS complicated by cardiogenic shock, their management, and outcomes in a large multinational sample.
In recent years, ACS has been increasingly affecting younger patients. While marked age-related differences have been observed in the risk of developing as well as the prognosis of ACS, few studies however examined time trends in the epidemiology of ACS in young adult patients. The third aim of the dissertation is to examine trends in frequency rates, patient characteristics, treatment practices, and outcomes in young adults hospitalized with an ACS.
Methods Data from two large multinational registries of patients hospitalized with an ACS were used for this investigation. Nearly 65,000 patients were enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, while 6,700 patients participated in the Gulf Registry of Acute Coronary Events (Gulf RACE) in 2007.
Results Aim1: Patients in Gulf RACE were significantly younger and were more likely to be male, diabetic, and smoke Compared to GRACE. Patients in Gulf RACE were less likely to receive evidence based therapies. Short-term mortality rates were comparable between the two patient cohorts. Aim2: Compared to patients with no CS, patients with CS were more likely to be older, female, have a history of diabetes, and heart failure. Patients with CS were less likely to receive effective cardiac catheterization and adjunctive cardiac medications. In-hospital case-fatality rate of patients with CS were 59.4%. While in-hospital mortality declines over the study period, incidence rates only showed minor declines. Aim2: Baseline characteristics of patients < 55 years of age did not significantly change, while the use of evidence based therapies increased significantly during the years under study. Rates of short-term adverse outcomes and mortality significantly declined over time.
Conclusions We observed marked regional differences in the risk profile, clinical management, and outcomes of patients with an ACS internationally compared to the Arab Middle East. Despite the encouraging trends in the use of evidence based therapies which have likely contributed to the improving trends in the prognosis of ACS, rates of development of ACS, as well as mortality due to ACS complications, remain high.
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Helfand, Benjamin K. I. "Measurement in Health: Advancing Assessment of Delirium." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1122.
Full textAbstract:
Rationale: Delirium is a serious, morbid condition affecting 2.6 million older Americans annually. A major problem plaguing delirium research is difficulty in identification, given a plethora of existing tools. The lack of consensus on key features and approaches has stymied progress in delirium research. The goal of this project was to use advanced measurement methods to improve delirium’s identification.
Aims and Findings:
(1) Determine the 4 most commonly used and well-validated instruments for delirium identification. Through a rigorous systematic review, I identified the Confusion Assessment Method (CAM), Delirium Observation Screening Scale (DOSS), Delirium Rating Scale-Revised-98 (DRS-R-98), and Memorial Delirium Assessment Scale (MDAS).
(2) Harmonize the 4 instruments to generate a delirium item bank (DEL-IB), a dataset containing items and estimates of their population level parameters. In a secondary analysis of 3 datasets, I equated instruments on a common metric and created crosswalks.
(3) Explore applications of the harmonized item bank through several approaches. First, identifying different cut-points that will optimize: (a) balanced high accuracy (Youden’s J-Statistic), (b) screening (sensitivity), and (c) confirmation of diagnosis (specificity) in identification of delirium. Second, comparing performance characteristics of example forms developed from the DEL-IB.
Impact: The knowledge gained includes harmonization of 4 instruments for identification of delirium, with crosswalks on a common metric. This will pave the way for combining studies, such as meta-analyses of new treatments, essential for developing guidelines and advancing clinical care. Additionally, the DEL-IB will facilitate creating big datasets, such as for omics studies to advance pathophysiologic understanding of delirium.
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Heilman, Susan Ann. "Cooperative Oncogenesis and Polyploidization in Human Cancers: A Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/327.
Full textAbstract:
A common phenotype observed in most cancers is chromosomal instability. This includes both structural and numerical chromosomal aberrations, which can promote carcinogenesis. The fusion gene CBFB/MYH11 is created by the structural chromosomal inversion(16)(p13.1q22), resulting in the fusion protein CBFβ-SMMHC, which blocks differentiation in hematopoietic progenitor cells. This mutation alone, however, is not sufficient for transformation, and at least one additional cooperating mutation is necessary.
The role of wildtype Cbfb in modulating the oncogenic function of the fusion protein Cbfβ-SMMHC in mice was examined. Transgenic mice expressing the fusion protein, but lacking a wild-type copy of Cbfb, were created to model the effects of these combined mutations. It was found that wild-type Cbfb is necessary for maintaining normal hematopoietic differentiation. Consequently, complete loss of wild-type Cbfb accelerates leukemogenesis in Cbfb/MYH11 mice compared to mice expressing both the fusion and wild-type proteins. While there is no evidence in human patient samples that loss of wild-type Cbfb expression cooperates with the fusion protein to cause transformation, it is apparent from these experiments that wild-type Cbfβ does play a role in maintaining genomic integrity in the presence of Cbfβ-SMMHC. Experiments have also shown that loss of Cbfb leads to accumulation of hematopoietic progenitor cells, which may acquire additional cooperating mutations.
Not unlike CBFB/MYH11, the human papillomavirus (HPV) E6 and E7 proteins are not sufficient for cellular transformation. Instead, high risk HPV E7 causes numerical chromosomal aberrations, which can lead to accumulation of additional cooperating mutations. Expression of HPV-16 E7 and subsequent downregulation of the retinoblastoma protein (Rb) has been shown to induce polyploidy in human keratinocytes. Polyploidy predisposes cells to aneuploidy and can eventually lead to transformation in HPV positive cells.
There are several possible mechanisms through which E7 may lead to polyploidization, including abrogation of the spindle assembly checkpoint, cleavage failure, abrogation of the postmitotic checkpoint, and re-replication. Rb-defective mouse and human cells were found to undergo normal mitosis and complete cytokinesis. Furthermore, DNA re-replication was not found to be a major mechanism to polyploidization in HPV-E7 cells upon microtubule disruption. Interestingly, upon prolonged mitotic arrest, cells were found to adapt to the spindle assembly checkpoint and halt in a G1-like state with 4C DNA content. This post-mitotic checkpoint is abrogated by E7-induced Rb-downregulation leading to S-phase induction and polyploidy.
This dissertation explores two examples of the multi-step pathway in human cancers. While certain genes or genetic mutations are often characteristic of specific cancers, those mutations are often not sufficient for transformation. The genetic or chromosomal abnormalities that they produce often stimulate the additional mutations necessary for oncogenesis. The studies with Cbfb/MYH11 and HPV E7 further exemplify the significance of numerical and structural chromosomal aberrations in multi-step carcinogenesis.
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Moore, Nathan F. "Slow-Cycling Cancer Cells: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/620.
Full textAbstract:
Tumor recurrence after chemotherapy is a major cause of patient morbidity and mortality. Recurrences are thought to be due to small subsets of stem-like cancer cells that are able to survive chemotherapy and drive tumor re-growth. A more complete understanding of stem-like cancer cell regulation is required to develop therapies to better target and eliminate these cells.
Slow-cycling stem cells are integral components of adult epithelial tissues and may give rise to cancer stem cell populations that share similar characteristics. These slow-cycling adult stem cells are inherently resistant to traditional forms of chemotherapy and transference of this characteristic may help to explain therapy resistance in cancer stem cell populations. Using a novel application for the proliferation marker CFSE, we have identified populations of slow-cycling cancer cells with tumor initiating capabilities. As predicted, slow-cycling cancer cells exhibit a multi-fold increase in chemotherapy resistance and retain the ability to re-enter the cell cycle. Furthermore, we observed consistent over-expression of the CDK5 activator, p35, in slow-cycling cancer cells. Manipulation of p35 expression in cancer cells affects cell cycle distribution and survival when these cells are treated with traditional forms of chemotherapy. Additionally, we demonstrate that alterations in p35 expression affect BCL2 levels, suggesting a mechanism for the survival phenotype.
Combined, our data suggest a model whereby slow-cycling stem-like cancer cells utilize the p35/CDK5 complex to slow cell cycling speed and promote resistance to chemotherapy. Future p35 targeting, in combination with traditional forms of chemotherapy, may help eliminate these cells and reduce tumor recurrence rates, increasing long-term patient survival.
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Clayton, Nicholas J. "Bromodomain and Extraterminal Domain (BET) Inhibitor RVX-208 Ameliorates Periodontal Bone Loss." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5380.
Full textAbstract:
Periodontal disease affects 47% of Americans over 30 and is a growing global concern. Current treatments for periodontal disease focus on the mechanical elimination of periodontal biofilms. Very few treatments are available that target the rampant, unregulated host immune response that is ultimately responsible for tissue degradation. BET proteins have been shown to play critical roles in inflammatory gene regulation and are therefore potentially ideal therapeutic targets for treating periodontal disease. RVX-208 is a selective BET-inhibitor with a high affinity for Bromodomain 2 (BD2) as compared to BD1 in BET proteins. Our previous studies have shown that RVX-208 inhibits inflammatory cytokine production and suppresses osteoclast differentiation. Cell culture assays have provided proof of concept for RVX-208 and its feasibility as a treatment for periodontal disease. As such, our long term goal is to develop RVX-208 as a front-line treatment for periodontitis. The objectives of this study were to determine the ability of RVX-208 to reduce bone loss in a ligature-induced periodontitis model, and to further investigate the mechanisms through which RVX-208 mediates its anti-inflammatory and osteoclastogenesis-suppressive effects. The specific aims of this study were: 1) To further validate the in vivo effects of RVX-208 on a ligature-induced periodontitis model in rats, and 2) To determine the molecular mechanisms of RVX-208 on preventing alveolar bone loss in periodontal disease. To investigate, a ligature-induced periodontitis model was created in rodents. Those rodents were treated with increasing dosages of RVX-208 (0-2.5 mM) by subgingival injection every other day. After 2 weeks, the maxillae were harvested and analyzed via a micro-CT protocol that had been created and validated through statistical analyses. To study the ability of RVX-208 to suppress osteoclastogenesis, RAW264.7 cells were induced into osteoclasts by RANKL and then treated with RVX-208. To ensure RVX-208 was not species specific, THP-1 cells were challenged with either E. coli-LPS or P. gingivalis bacteria and then treated with RVX-208. Linear and volumetric micro-CT analysis showed that RVX-208 could significantly ameliorate bone loss in a ligature-induced periodontitis model. RVX-208 was shown to prevent osteoclast differentiation by suppressing the expression of genes closely associated with osteoclast differentiation and maturation. RVX-208 was found to not be species specific, as it was able to mediate its effects on a human cell line, and had consistent anti-inflammatory effects regardless of whole pathogen or LPS-induced inflammatory response. Therefore, RVX-208 is a promising therapeutic for treatment of periodontal diseases.
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Evans, Sean M. "Orientia tsutsugamushi secretes two ankyrin repeat-containing effectors via a type 1 secretion system to inhibit host NF-κB function." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4813.
Full textAbstract:
Scrub typhus is a potentially fatal infection that threatens one billion persons in the Asia-Pacific region and is caused by the obligate intracellular bacterium, Orientia tsutsugamushi. How this organism facilitates its intracellular survival and pathogenesis is poorly understood. Intracellular bacterial pathogens utilize the Type 1 (T1SS) or Type 4 secretion system (T4SS) to translocate ankyrin repeat-containing proteins (Anks) into the host cell to modulate host cell processes. The O. tsutsugamushi genome encodes one of the largest known bacterial Ank libraries as well as Type 1 and Type 4 secretion systems (T1SS and T4SS), which are expressed during infection. In silico analyses of the Anks’ C-termini revealed that they possess characteristics of T1SS secretion signals. Escherichia coli expressing a functional T1SS was able to secrete chimeric hemolysin proteins bearing the C-termini of 19 of 20 O. tsutsugamushi Anks. In addition to infecting endothelial cells, O. tsutsugamushi infects professional phagocytes. To better understand why these innate immune cells are unable to eliminate O. tsutsugamushi, we addressed the activity of host NF-κB proinflammatory transcription factor. Screening of O. tsutsugamushi infected cells at an MOI of 1 revealed inhibition of NF-κB nuclear accumulation as early as 8 hours in HeLa and bone-marrow derived macrophage cells. When stimulating infected cells with TNF-α, IκBα degradation still occurs, however NF-κB dependent gene transcription remains downregulated. Immunofluorescence microscopic analysis of TNF-α treated cells ectopically expressing all O. tsutsugamushi Anks revealed that two nuclear trafficking Anks, Ank1 and Ank6, result in a significant decrease in NF-κB nuclear accumulation. Additionally, these Anks also significantly inhibited NF-κB dependent gene transcription. Co-immunoprecipitation experiments revealed that both Anks interact with importin-β1, exportin-1, and the p65 NF-κB subunit. Treating cells with importazole significantly reduces the nuclear accumulation of Ank1 and Ank6. Finally, treating infected cells or cells ectopically expressing Ank1 or Ank6 with leptomycin B resulted in restoration of NF-κB nuclear accumulation. With these data, we propose that O. tsutsugamushi secretes Ank1 and Ank6 to initially interact with importin-β1, which permits their nuclear entry where they then interact with NF-κB and subsequently exportin-1 to prevent NF-κB nuclear accumulation.