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Zumerle, Sara. "Tissue-specific role of hepcidin in iron homeostasis and innate immunity." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T002.
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Le fer est un élément vital pour l’organisme, mais peut s’avérer toxique si présent en excès. L’hepcidine est le régulateur principal de l’homéostasie du fer dans l’organisme. Un défaut d’expression d’hepcidine est à l’origine de l’hémochromatose, une maladie génétique humaine caractérisée par une surcharge en fer ; inversement, une hypersécrétion d’hepcidine est la cause de différents types d’anémie. L’hepcidine est secrétée principalement par le foie, mais des découvertes récentes ont montré que de nombreux tissus de l’organisme sont capables de produire l’hormone. Au laboratoire nous avons généré un modèle de souris transgénique permettant d’invalider le gène codant pour l’hepcidine dans les tissus d’intérêt. Ce modèle permet d’étudier la contribution de différents tissus dans l’homéostasie du fer. En comparant les souris déficientes pour l’hepcidine spécifiquement dans le foie (HepcΔfoie) avec les souris présentant une délétion de l’hepcidine dans tout l’organisme (HepcΔtot), j’ai pu montrer que les souris HepcΔfoie présentent la même surcharge en fer que les souris HepcΔtot ; dans la circulation sanguine des souris HepcΔfoie, l’hepcidine n’est pas détectable, montrant ainsi que l l’hépatocyte est la source majeure d’hepcidine pour réguler les niveaux de fer dans l’organisme. En conclusion, mes résultats ont permis de montrer que l’hepcidine hépatique est le régulateur principal de l’homéostasie du fer, et que les autres tissus ne sont pas capables de compenserIron is fundamental for the organism, but can be toxic if in excess. The major regulator of iron homeostasis is hepcidin, first identified as an antimicrobial peptide. Hepcidin deficiency is associated with hereditary hemochromatosis, a human genetic disease characterized by iron overload. Conversely, abnormal hepcidin induction is the cause of some types of anemia. Hepcidin is produced and secreted mainly by the liver, but many cells and tissues express low levels of the hormone. To investigate the contribution of hepcidin-producing tissues in iron homeostasis, we generated a new mouse model in which the hepcidin gene can be conditionally inactivated: the hepcidin floxed mice. The main aim of my thesis was to evaluate the contribution of different tissues in hepcidin production and iron homeostasis regulation. I generated hepcidin liver-specific knockout mice and compared them to total knockouts: hepatic hepcidin ablation fully recapitulates the severe iron overload phenotype observed in the total knockout. Moreover, hepcidin was undetectable in the plasma of liver-specific knockouts, showing that hepatocytes are the main source of the peptide in the bloodstream. These results demonstrate that hepatic hepcidin is the major regulator of iron homeostasis and that tissues other than the liver are not able to compensate. The hepcidin floxed mice provide a useful tool for the investigation of hepcidin role in extra-hepatic tissues in physiological and pathological conditions
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Gu, Xiaomei Everett Eric T. "Physiopathology of osteoclast in bone." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1870.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirements for the degree of Master of Science in the Curriculum of Oral Biology." Discipline: Oral Biology; Department/School: Dentistry.
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GAMBASSI, SILVIA. "Novel insights into alkaptonuria physiopathology." Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1004463.
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Alkaptonuria (AKU) is an ultra-rare genetic disease resulting from a deficient activity of the enzyme homogentisate 1,2- dioxygenase (HGD), responsible for the catabolism of the aromatic amino acids Phenylalanine and Tyrosine. This condition leads to the accumulation of a toxic metabolite, HGA and of its product of oxidation BQA, whose polymerization generates melanin-like aggregates, with amyloidogenic properties, leading to the phenomenon of “Ochronosis”. The most affected structures by the deposition of these ochronotic aggregates are joints, which undergo severe arthropathy; therefore, articular cartilage is the main investigated tissue for the comprehension of AKU physiopathology.
Articular cartilage homeostasis is maintained by articular chondrocytes, which have an important role in the synthesis and release of extracellular matrix (ECM) components, essential to properly respond to mechanical compression processes the tissue is constantly subjected to. This mechanism is mediated by chondrocyte cytoskeleton, including the microtubule-based organelle primary cilium, which exerts its function through the activation of the Hedgehog (Hh) signaling pathway.
On the basis of the previous considerations, for the aims of this thesis, the set-up of in vitro AKU cellular and tissue models, was fundamental to counteract problems related to the collection of AKU samples, due to the rarity of the disease. Both experimental models were properly characterized, by highlighting the role of HGA in mediating pigment deposition and cartilage degradation processes, through histological and cytological analyses and immunofluorescence assays. Results showed that the ochronotic pigment deposits following HGA treatment lead to an oxidative stress status and to the accumulation of serum amyloid A (SAA) protein in the cartilaginous tissue. Another in vitro model was used to analyse the ability of AKU chondrocytes to respond to mechanical loading in terms of production of ECM components, by applying a 10% strain on adherent cell cultures. AKU chondrocytes resulted unable to respond properly to mechanical strain and HGA seemed to be involved in this altered responsiveness.
Afterwards, a deep investigation of the cytoskeleton characteristics of AKU chondrocytes was performed, mainly by focusing on the interaction of each cytoskeletal marker with the amyloidogenic protein serum amyloid A (SAA). An in situ proximity ligation assay confirmed the co-localization of cytoskeletal marker with SAA, thus explaining the severe alterations observed in AKU cytoskeleton.
Furthermore, another cytoskeletal component was characterized, the primary cilium, both investigating on its structural features and on its function in terms of Hedgehog (Hh) signaling activation. Primary cilia of AKU chondrocytes resulted shorter than normal chondrocytes and HGA treatment led to the same ciliary phenotype. In order to investigate the activation of the Hh pathway, the expression of the constitutive activator of the pathway (Gli-1) was evaluated both at the gene and at the protein level. This protein was found overexpressed in AKU/HGA-treated chondrocytes.
Finally, given the role of Hh activation in mediating processes of cartilage degradation in osteoarthritis-like diseases, a therapeutic approach based on the inhibition of the Hh signaling was adopted, by using treatment with lithium chloride and with small molecule antagonists of the Hh receptor Smoothened (Smo). All the testing compounds resulted efficient in inhibiting Hh signal and in restoring cilia lengths, suggesting the use of these compounds as a potential therapeutic approach for the treatment of AKU.
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De, Marco Margot. "BAG3 role in cardiomyocytes physiopathology." Doctoral thesis, Universita degli studi di Salerno, 2013. http://hdl.handle.net/10556/896.
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2010 - 2011The anti-apoptotic protein BAG3 is expressed at high levels in skeletal and cardiac muscle in vivo. Our group recently focused its interest on BAG3 role in myocardiocyte proliferation, survival and response to stressful stimuli. We found that BAG3 is upregulated during the differentiation of cardiomyoblasts. Our results prompted us to verify whether bag3 silencing could affect the differentiation state of cardiocytes and we found that bag3 silencing resulted in highly reducing the levels of myogenin. Furthermore, we analyzed BAG3 expression and localization following cell exposure to oxidative stress. In particular, we found that epinephrine in vitro increases BAG3 expression in adult human cardiomyocytes. We evaluated whether BAG3 could be involved in the Tako-tsubo cardiomyopathy (or stress cardiomyopathy) pathogenesis that is characterized by left ventricular dysfunction, with symptoms that can mimic an acute coronary syndrome. The absence of significant cardiovascular risk factors in patients affected by stress cardiomyopathy suggested that it might be associated with a possible genetic etiology. Therefore, we sequenced bag3 gene to check for polymorphisms in 29 patients and 1043 healthy donors. Three polymorphism were highly represented among patients (R71Q, C151R, P407L). We also showed for the first time that BAG3 protein is released from stressed cardiomyocytes and is found in chronic heart failure (HF) patients’ sera. Since anti-BAG3 antibodies are also present in patients’ sera, we developed an ELISA test for their specific detection. In serum samples from chronic HF patients, we found significantly higher values of anti-BAG3 antibodies respect to samples from healthy donors. The presence of anti-BAG3 antibodies in chronic HF patients’ sera and the availability of an ELISA test for their detection can contribute a novel tool for diagnostic and prognostic evaluations. [edited by author]
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Pénicaud, Sidonie. "Insights about age of language exposure and brain development : a voxel-based morphometry approach." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111591.
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Early language experience is thought to be essential to develop a high level of linguistic proficiency in adulthood. Impoverished language input during childhood has been found to lead to functional changes in the brain. In this study, we explored if delayed exposure to a first language modulates the neuroanatomical development of the brain. To do so, voxel-based morphometry (VBM) was carried out in a group of congenitally deaf individuals varying in the age of first exposure to American Sign Language (ASL). To explore a secondary question about the effect of auditory deprivation on structural brain development, a second VBM analysis compared deaf individuals to matched hearing controls. The results show that delayed exposure to sign language is associated with a decrease in grey-matter concentration in the visual cortex close to an area found to show functional reorganization related to delayed exposure to language, while auditory deprivation is associated with a decrease in white matter in the right primary auditory cortex. These findings suggest that a lack of early language experience alters the anatomical organization of the brain.
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MURESAN, XIMENA MARIA. "Role of Scavenger receptor B1 in cutaneous physiopathology." Doctoral thesis, Università degli studi di Ferrara, 2017. http://hdl.handle.net/11392/2488039.
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Scavenger receptor B1 (SR-B1) è una proteina transmembrana, coinvolta nel trasporto inverso di colesterolo a livello tissutale e definita anche recettore per HDL. Diversi studi hanno dimostrato che SR-B1 è implicato anche in altri processi, come regolazione dei livelli intracellulari di vitamine, riconoscimento di batteri e cellule apoptotiche e internalizzazione di vescicole. Nonostante il recettore sia localizzato principalmente a livello del fegato e dei tessuti steroidogenici, esso è significativamente espresso anche in altri tessuti compresa la cute umana, in special modo nell’epidermide. L’epidermide conferisce alla cute la funzione di barriera, attraverso la presenza dello strato corneo composto da acidi grassi, colesterolo, ceramidi, proteine e corneociti, quest’ultimi racchiusi da un involucro lipidico. La sua localizzazione e composizione fa della pelle un bersaglio per i fattori di stress ambientali. Studi in vitro condotti su cheratinociti in coltura hanno mostrato che stressors ambientali quali il fumo da sigaretta riducono l’espressione del recettore. Lo scopo del presente studio è stato quello di valutare il ruolo fisiologico di SR-B1 nella cute, attraverso l’uso di modelli cutanei 2D e 3D in cui l’espressione di SRB1 è stata geneticamente manipolata. I nostri dati dimostrano che SR-B1 è coinvolto nella proliferazione e nella migrazione cellulare. Infatti, il silenziamento di SR-B1 ha indotto una diminuzione dell’espressione di ciclina D1, così come dei livelli di MMP9 accompagnati da un difetto nella riorganizzazione del citoscheletro, influenzando perciò la capacità dei cheratinociti di riparare la ferita. Inoltre, SR-B1-KO ha un effetto sull’attivazione di NF-kB ed inoltre in modelli tridimensionali di cute ha causato cambiamenti sia a livello dello spessore che nella morfologia degli strati epidermici, insieme ad un aumento dei marcatori di differenziamento cellulare. In aggiunta, il recettore sembra avere un ruolo anche nella distribuzione epidermica dei lipidi e sul tipo di lipidi oltre ad essere implicato anche nel metabolismo lipidico nei sebociti. In fine il nostro studio ha dimostrato che i fattori di stress ambientali portano ad una riduzione di SR-B1 e questo effetto è evitato dall’uso di molecole naturali quali il resveratrolo. Riassumendo, i nostri dati suggeriscono che SR-B1 gioca un ruolo importante nella cicatrizzazione, così come nel differenziamento epidermico e nella composizione lipidica della cute, perciò la sua perdita indotta dall’esposizione ad agenti ossidanti potrebbe influenzare l’omeostasi cutanea.Scavenger receptor B1 (SR-B1) is a trans-membrane protein, known as HDLs main receptor and involved in tissue reverse cholesterol transport. Several studies have demonstrated that SR-B1 is also implicated in other processes, such as regulation of intracellular vitamins levels, recognition of bacteria and apoptotic cells and vesicles uptake. Although this receptor is mainly localized in the liver and steroidogenic tissues, it is significantly expressed also in human skin, especially in the epidermis. The epidermis provides the barrier function of skin, due to the presence of stratum corneum, composed by proteins and corneocytes, which are distributed in a lipid envelope. Its localization and composition makes the skin a target for environmetantal stressors. In vitro studies on cultured keratinocytes have shown that SR-B1 protein expression is down-regulated by environmental oxidants such as cigarette smoke. Therefore, the purpose of our study was to evaluate the physiological role of SR-B1 in the skin, with more focus on the not vascularized cutaneous epidermal layer, by using 2D and 3D skin models. We demonstrated that SR-B1 is involved in cellular proliferation and migration, since SR-B1 knockdown keratinocytes presented reduced capacity to proliferate and migrate. In fact, SR-B1 knockdown induced a decrease of Cyclin D1 expression, as well as MMP9 levels accompanied by a defect in cytoskeleton rearrangement, affecting keratinocytes ability to recover from wound scratch. Furthermore, SR-B1 appeared to affect NF-kB activation. SR-B1 knockdown in tridimensional organotypic skin equivalents induced changes in epidermis thickness and deeper layers morphology, together with increased markers of terminal differentiation. Not only, but the scavenger receptor resulted to be essential for lipids expression and epidermal distribution, and it is implicated also in sebocytes lipids metabolism. Moreover, our study demonstrated that environmental stressors down-regulate SR-B1 also in three-dimensional reconstructed epidermis and human skin and, by the use of a natural polyphenol, we showed that such down-regulation was mediated by oxidative damage. Altogether, our findings suggest that SR-B1 plays an important role in keratinocytes recovery from injuries, as well as in epidermal differentiation and lipid composition, therefore its loss induced by oxidants exposure could affect cutaneous homeostasis.
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Calara, Federico Ben. "The vascular response to oxidative and mechanical stress /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980924cala.
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Bileviciute-Ljungar, Indre. "Bilateral neurogenic mechanisms following acute unilateral inflammation /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3168-2/.
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Löfgren, Olle. "Contribution of the sensory nervous system in thermally induced inflammation : an experimental study in the rat /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-3288-3/.
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Oldner, Anders. "Splanchnic organ homeostasis in experimental endotoxin shock : with special reference to the endothelin and renin-angiotensin systems /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3574-2/.
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Ernberg, Malin. "Significance of serotonin for pain, allodynia, and hyperalgesia in the human masseter muscle /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3779-6/.
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Weinberg, Jan. "Studies on ventilatory function in chronic neuromuscular disorders /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3936-5/.
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Flyckt, Lena. "Schizophrenia as a systemic disorder : studies of peripheral and central biological functions /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4482-2/.
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Peyronnet, Julie. "Regulation of cardiorespiratory homeostasis in adult and developing rat by catecholamines : effects of hypoxia /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4549-7/.
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Valiquette, Luc François. "Association between self-reported childhood maltreatment and cortisol profiles in psychotic patients." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112314.
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Childhood maltreatment is extremely common in patients diagnosed with psychotic disorders. Moreover, it has been linked with impaired functioning of the Hypothalamic-Pituitary-Adrenal axis. Furthermore, abnormality of the HPA has been found in psychotic patients. Presence of childhood maltreatment could then explain why the HPA axis is dysfunctional in these subjects. Our objective was to clarify the role of childhood trauma in the cortisol profiles of psychotic patients. Thirty-one patients underwent assessments of childhood maltreatment. Diurnal cortisol and cortisol after a controlled psychosocial stress were also collected. Our results show that childhood trauma is associated with lower cortisol levels during the morning and during 24 hours. In men diagnosed with psychosis, childhood trauma is also associated with a higher cortisol response during psychosocial stress. This suggests an alteration of the HPA axis in psychotic patients, resulting from early trauma. Moreover, our results suggest that looking at specific types of childhood abuse may also be important.
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Zgheib, Sara. "Altérations physiologiques et récupération à long terme dans un modéle murin de séparation associée à une restriction du temps d'accés à l'alimentation : un outil pour l'étude des conséquences de l'anorexie mentale." Thesis, Littoral, 2014. http://www.theses.fr/2014DUNK0428/document.
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L'anorexie mentale (AM) est un trouble du comportement alimentaire qui se caractérise par une recherche obsessionnelle de minceur, une forte réduction de la prise alimentaire et une distorsion de l'image de soi. Elle est associée à de multiples perturbations endocriniennes et métaboliques, et à une altération de la masse et de la microarchitecture osseuses. Les facteurs et les mécanismes qui interviennent dans cette maladie sont très mal connus ce qui limite les options thérapeutiques. Il est donc nécessaire de développer un modèle animal qui reproduise les perturbations physiologiques observées en AM et permette d'étudier les facteurs associés à l'altération osseuse. Dans ce but nous avons développé un modèle murin avec une restriction du temps d'accès à l'alimentation associée à un stress induit par la séparation (separation-based anorexia, SBA). Cette phase SBA de 10 semaines est suivie d'une phase de récupération en conditions standard (REC) de 10 semaines. Chez les souris femelles C57B1/6 en fin de croissance rapide, la phase SBA induit une perte rapide et importante du poids corporel. L'analyse de la composition corporelle par DEXA révèle une diminution rapide de près de 40% de la masse grasse ainsi qu'une baisse progressive de la masse maigre et un arrêt de l'acquisition de la masse osseuse. Au niveau des tibias, la densité minérale cortical et la microarchitecture trabéculaire sont altérées. L'observation des frottis vaginaux et la mesure des ovaires révèlent une perturbation importante des fonctions reproductrices. Les tests de tolérance au glucose ont montré que les souris SBA ont une capacité très élevée à corriger la glycémie. Ces animaux sont fortement hypoleptinémiques, et l'axe GH-IGF-1 est très perturbé. L'étude de l'expression génique de différents tissus adipeux a montré une augmentation du niveau des marqueurs de lipogénèse et de lipolyse, ainsi qu'une forte induction du phénotype "adipocyte brun" dans le tissu adipeux sous-cutané. Après deux semaines de REC, les souris SBA retrouvent très rapidement leur poids corporel, leurs masses maigre et grasse. La masse minérale toujours basse à ce stade est corrigée après 10 semaines de REC, ainsi que la microarchitecture osseuse (étude préliminaire). Tous les autres paramètres étudiés sont normalisés, sauf l'hypoleptinémie qui étonnamment persiste même après 10 semaines de protocol REC et malgré la normalisation de la masse adipeuse. D'après ces résultats, on peut conclure que le modèle SBA reproduit de nombreuses perturbations physiologiques observées en AM. La phase de REC révèle que ces souris ont une importante capacité de récupération. L'hypoleptinémie persistante pourrait favoriser la récupération. L'identification des mécanismes impliqués pourrait fournir des pistes thérapeutiques afin de favoriser la reconstitution du capital osseux des patientes anorexiquesAnorexia nervosa (AN) is an eating disorder mainly developed in adolescent girls and young women. It is characterized by an obsessive search for thinness, a profound undernutrition and a distorted self-image.It is associated with multiple endocrine and metabolic disturbances, decreased bone mass and microarchitectural alteration. Some of the developed adaptations are supposed to be involved in the blockade of the pathologic state. Unfortunately, these adaptations are poorly known and most of them cannot be studied on patients. So it is necessary to develop an animal model which mimics the main consequences observed in human pathology and allows studying the recovery process. For this purpose we adapted a murine model of time restricted feeding associated with chronic stress induced by separation-based anorexia (SBA). C57B1/6 female mice are submitted to a long term SBA protocol (10 weeks) and then a long term phase of recovery (10 weeks). At the beginning of the protocol mice are 8 weeks old, so their fast growth is finishing. SBA protocol induced a rapid and significant loss of body weight. Body composition analysis by DEXA showed a 40% decrease of the fat mass, a progressive loss of lean mass and a blockade of bone mass acquisition. Mice deveoped a high glucose tolerance. The observation of vaginal smears revealed a disruption of the estrous cycle and ovarian histology showed an atrophy of the ovaries. These two alterations suggest a major alteration of reproductive functions. These animals showed a very low leptinemia, and the GH/IGF-1 axis was disrupted. The study of bone alteration by microtomography indicated an alteration of bone microarchitecture and of cortical bone mass, mimicking osteoporosis often described in AN patients. Body weight, lean and fat masses were normalized quickly during the REC protocol. Bone mineral content still low after 2 weeks of REC protocol was fully corrected after 10 weeks. The estrous cycle ovarian size and the GH/IGF-I were normalized. Surprisingly, hypoleptinemia persisted even after 10 weeks of REC and despite the normalization of the fat mass. This result has been confirmed by the low level of leptin gene expression in various adipose tissues. Finally, the SBA protocol is valuable model of AN because numerous physiological alterations described in AN are mimicked in this model. The recovery phase revealed the high capacity of mice to normalize the long term alterations. Persitent hypoleptinemia could contribute to the normalization of body composition. However, the balance between central and peripheral effects of the uncorrected hypoleptinemia remains to be determined. This persisting hypoleptinemia could be used for the revision of the therapeutic strategies aiming to correct AN-induced osteoporosis
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Grudemo, Hans. "Rhinostereometry and laser doppler flowmetry : simultaneous measurements of inflammation and steroid effects in normal and allergic human nasal mucosa /." Stockholm, 2000. http://diss.kib.ki.se/2000/20000310grud/.
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Filliol, Aveline. "Etude de l’hépatolyse induite par les cellules immunitaires dans des modèles murins d’hépatites : rôles des protéines RIPK1 et PARP1/2." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B051/document.
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La mort des hépatocytes est un des éléments initiateurs de la progression des maladies hépatiques par l’induction de processus inflammatoires et de régénération. Ces événements, bénéfiques à court terme pour le rétablissement de l’homéostasie hépatique sont parfois dérégulés et peuvent conduire au développement de la fibrose, de la cirrhose, voire d’un carcinome hépatocellulaire. Ainsi, les voies conduisant à la mort des hépatocytes et leur blocage comme une potentielle approche thérapeutique sont aujourd’hui étudiées. Les cellules de l’immunité innée et acquise sont responsables de l’induction ou de l’amplification de cette hépatolyse, principalement via l’expression et la libération de ligands de mort appartenant à la superfamille du TNF-α, dont TNF-α, FasL et TRAIL. Des travaux suggèrent le rôle des protéines RIPK1 et PARP1/2 dans l’induction de l’hépatolyse dans l’hépatite induite par la Concanavaline A (ConA) chez la souris. Par l’utilisation de modèles chimiques et génétiques, nous avons étudié l’implication de ces protéines dans le processus de mort des hépatocytes.Tout d’abord, nous nous sommes intéressés au double rôle de la protéine RIPK1 dans le contrôle de la vie et la mort de l’hépatocyte. En bloquant son activité kinase nous avons confirmé son rôle dans l’induction de l’hépatolyse dans l’hépatite induite par la ConA. Cependant, en utilisant des souris conditionnellement déficientes pour RIPK1 dans les cellules parenchymateuses hépatiques (LPC) (Ripk1LPC-KO) nous avons révélé sa fonction nécessaire à la survie des hépatocytes et au maintien de l’homéostasie hépatique au cours de l’hépatite. Ces travaux démontrent que l’absence de RIPK1 sensibilise les hépatocytes à l’apoptose induite par le TNF-α en déstabilisant la protéine TRAF2. Ainsi RIPK1 joue un rôle clef dans la protection des hépatocytes au cours des hépatites induites par la ConA, le lipopolysaccharide (LPS), les motifs CpG ou induite par une co-administration d’IFN--γ et de TRAIL recombinantes. De plus, nous avons mis en évidence que RIPK1 protège partiellement de l’hépatolyse et de l’hépatite induite par l’activation de Fas. Enfin, nous avons montré que l’absence de la protéine PARP2 conduisait à une diminution du nombre de NKT invariants systémiques, dont hépatiques, conduisant à une inhibition de la mort des hépatocytes induite par l’administration de ConA. Ces travaux ont permis de préciser le rôle de RIPK1 et de PARP2 dans les hépatites aiguës. La capacité de RIPK1 à contrôler la mort et la survie de la cellule suggère son implication au cours des hépatites chroniques et ouvre la porte à son investigation dans les maladies hépatiques humainesHepatocyte death is a starting point of liver disease progression by promoting inflammatory and regenerative processes. These events are beneficial at the beginning of the pathology for the restoration of hepatic homeostasis. However when they are unregulated, they lead to the development of fibrosis, cirrhosis or hepatocellular carcinoma. Thus, it is important to study the signaling pathways leading to the hepatocyte death as their inhibition is a potential therapeutic approach to reduce liver diseases progression. Innate and acquired immune cells play key roles in the induction or amplification of hepatolysis, mainly mediated by expression and release of death ligands belonging to the TNF-superfamily including TNF-α, FasL and TRAIL. Some studies had already suggested the role of RIPK1 and PARP1/2 proteins in the induction of hepatocyte death during hepatitis induced by Concanavalin A (ConA) in mice. Through chemical and genetic approaches, we studied the role of these proteins in the hepatocyte death process during hepatitis. First, we were interested in the dual role of RIPK1 protein that controls the cell fate by promotingsurvival or death. By blocking its kinase activity, we confirme its role in the induction of liver injury induced by ConA. However, using specific conditional mice deficient in RIPK1 only in liver parenchymal cells (LPC) (Ripk1LPC-KO), we reveale its necessary function in the protection of hepatocyte during hepatitis. These works demonstrate that deletion of RIPK1 sensitizes hepatocytes to TNF-α-induced apoptosis by TRAF2 destabilization. Thus RIPK1 plays a key role in the protection of hepatocytes during hepatitis induced by ConA, lipopolysaccharide (LPS), DNA-CpG, or recombinant IFN-γ and TRAIL co-administration. In addition, we demonstrate that RIPK1 partially protects from hepatitis and hepatocyte death induced by the activation of Fas. Finally, we showe that PARP2 deficiency leads to a systemic decrease of the number of the invariant NKT-subpopulation of lymphocytes, including in the liver, which prevente hepatocyte death during ConA hepatitis. To conclude, this work helps to clarify the roles of RIPK1 and PARP2 during acute hepatitis. The ability of RIPK1 to control hepatocyte death and survival suggests its involvement during chronic hepatitis and opens the door to its investigation into human liver diseases
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Belarbi, Essia. "Etude de la physiopathologie des infections à alphavirus arthritogènes par une approche d’imagerie in vivo." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS073.
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Les alphavirus arthritogènes de la rivière Ross (RRV) et du chikungunya (CHIKV) sont des arbovirus à l’origine de maladies inflammatoires musculosquelettiques chez l'homme. Ils sont largement distribués dans le monde et provoquent périodiquement des épidémies explosives. Les principaux signes cliniques lors d’une infection par un alphavirus arthritogène sont les myalgies, polyarthrites et arthralgies intenses pouvant persister plusieurs mois après l'infection. Les mécanismes de développement de l’infection et des manifestations persistantes sont peu connus. Pour étudier la pathogenèse de l'infection par RRV, nous avons généré un virus recombinant exprimant une nouvelle luciférase brillante et brillante. Nous avons montré que les monocytes humains, malgré une faible susceptibilité à l'infection in vitro par RRV, étaient capables de maintenir une réplication virale jusqu'à 45 jours post infection indiquant leur rôle potentiel dans les formes chroniques. Grâce un modèle expérimental de l’infection par RRV, nous avons suivi les phases aiguë et chronique de la maladie in vivo. Nous avons montré que les cinétiques de réplication du virus recombinant étaient proches de celles du virus parental. Nous avons également observé un tropisme musculaire et articulaire et une corrélation entre le signal bioluminescent et la charge virale confirmant ainsi la relevance de ce modèle. En étudiant la dissémination virale, nous avons montré que le Bindarit, une molécule anti-inflammatoire diminuant le développement de la maladie dans le modèle murin, induit une plus grande réplication dans le tissu cardiaque. Enfin, nous avons pu observer une réplication virale dans les tissus musculaires durant la phase chronique de la maladie et avons montré le rôle de la dose inoculée dans le développement de la persistance virale. Suite à un traitement immunosuppresseur, nous avons observé une légère augmentation du signal bioluminescent indiquant un contrôle de la réplication virale persistante par la réponse immunitaire adaptative. Ce nouveau modèle d’imagerie in vivo permet un suivi en temps réel de la dissémination virale permettant des études de pathogenèse et l'évaluation de stratégies thérapeutiquesRoss River virus (RRV) and chikungunya virus (CHIKV) are mosquito-transmitted viruses that cause musculoskeletal inflammatory diseases in humans. They are widely distributed and periodically cause explosive epidemics. After infection with RRV, patients experience fever, maculopapular rash, myalgia and intense pain in the peripheral joints. Approximately 30% of patients develop a chronic form of the disease with myalgia and poly-arthralgia persisting for months to years after infection. The mechanisms underlying these persistent symptoms remain unclear. To study the dynamics and pathogenesis of RRV infection in vitro and in living animals, we generated a recombinant virus expressing a novel small and bright luciferase. First we showed that human monocytes, despite a low susceptibility to RRV infection, were able to maintain viral replication in vitro up to 45 days post infection. Then, using a murine model of RRV infection, we monitored the acute and chronic phases of the disease. We observed near native replication kinetics and a muscular/articular tropism after infection with our recombinant virus. Moreover, the bioluminescent signal correlated with the viral load further confirming the relevance of this new imaging model. After monitoring of the viral dissemination in live mice, we showed that Bindarit, an anti-inflammatory molecule known to prevent the development of the alphaviral disease in a mouse model, induces a higher replication in the cardiac tissue; thereby indicating that caution must be used before treatment of patients. We were also able to observe viral replication in the muscles during the chronic stage of the disease when using a low inoculation dose. Finally, following an immunosuppressive treatment, we observed a slight increase in the bioluminescent signal indicating a control of remnant viral replication by the adaptive immune response. This new model provides a non-invasive real-time assessment of viral replication and dissemination allowing pathogenesis studies and therapeutic strategies evaluation
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Ragnarsson, Gudmundur. "Abdominal symptoms and anorectal function in outpatients with the irritable bowel syndrome (IBS) /." Linköping : Univ, 2000. http://www.bibl.liu.se/liupubl/disp/disp2000/med651s.pdf.
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Hehenberger, Karin M. "In vitro studies of the diabetic condition using cultured fibroblasts with focus on wound healing /." Stockholm, 1997. http://diss.kib.ki.se/1997/19971219hehe.
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Wikström, Jonsson Eva. "Functional characterisation of receptors for cysteinyl leukotrienes in smooth muscle /." Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2897-5.
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Lundberg, Steffan. "Assessment of tubal infertility : with radionuclide-labelled particles and falloposcopy /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980918lund.
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López, Annika. "The pelvic floor and genital prolapse : a clinical, physiological and radiological study /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4083-5/.
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Ylitalo, Riitta. "Clinical studies of contact granuloma and posterior laryngitis with special regard to esophagopharyngeal reflux /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4420-2/.
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Radell, Peter J. "Studies of diaphragm fatigue and dysfunction /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4751-1/.
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López, Serrano Clara. "Role of lysophosphatidic acid receptors in spinal cord injury physiopathology." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458682.
Full textAbstract:
La médula espinal, la cual constituye una parte vital para el sistema nervioso central (SNC), puede resultar dañada a pesar de estar muy bien protegida por la columna vertebral, dando lugar a importantes consecuencias. La lesión medular provoca una alteración de las redes neuronales que están involucradas en diversas funciones fisiológicas. De hecho, dado que los axones del SNC de mamíferos adultos no pueden regenerarse tras una lesión, y que las células dañadas no pueden ser reparadas, esta patología viene acompañada de una pérdida funcional irreversible para los pacientes afectados.
La fisiopatología de la lesión medular se compone de dos fases degenerativas. La fase primaria es consecuencia directa del trauma en la médula, la cual provoca muerte celular, daño axonal y pérdida de mielina. Esta primera fase es sucedida por una secundaria, en la cual se produce un proceso inflamatorio, crucial para el desarrollo de la enfermedad. Aunque la regeneración de los axones dañados y el reemplazo de las neuronas perdidas tras la lesión son objetivos importantes, minimizar el daño secundario a axones, neuronas, mielina y células gliales que sigue al trauma inicial es posiblemente más interesante desde un punto de vista terapéutico. En concreto, la respuesta inflamatoria de esta fase secundaria juega un papel muy importante en la lesión, siendo, por tanto, una buena diana para la búsqueda de una terapia efectiva.
Una de las moléculas involucradas en el proceso inflamatorio es el ácido lisofosfatídico (del inglés, LPA), el cual es un lípido bioactivo extracelular que juega un papel importante en diversas funciones fisiológicas. El LPA señaliza a través de seis receptores acoplados a proteína G (LPA1-6), los cuales se clasifican en dos familias: la familia del gen de diferenciación endotelial (del inglés, Edg), que comprende los receptores LPA1-3, y la familia de receptores que no pertenecen a la familia Edg, es decir, Non-Edg (LPA4-6). El LPA se sintetiza a partir de dos vías principales: (i) mediante la acción de la enzima autotaxina (ATX), la cual es la responsable de la síntesis de LPA en plasma, y (ii) mediante la acción de fosfolipasas de tipo de A2 (PLA2), las cuales se encargan de la síntesis en tejido.
El LPA juega un papel importante en la fase secundaria de la lesión medular, ya que sus niveles se ven aumentados en el parénquima medular tras el trauma, dando lugar a desmielinización y pérdida de la función locomotora. De hecho, la ausencia de los receptores LPA1 y LPA2 tras la lesión medular mejora la recuperación funcional de los animales y la preservación mielínica en la médula. En esta tesis, revelamos que la activación de los receptores LPA1 y LPA2 microgliales provoca la muerte de los oligodendrocitos. Además, mostramos que los efectos citotóxicos que se desencadenan tras la estimulación de dichos receptores son mediados por la secreción de purinas y la subsecuente activación del receptor P2X7 en oligodendrocitos. Por otro lado, también demostramos que, al contrario de los receptores LPA1 y LPA2, los receptores LPA4 y LPA5 no contribuyen a la fisiopatología de la lesión medular.
En el presente trabajo, también mostramos que la inhibición farmacológica de la ATX no tiene ningún efecto en la recuperación funcional ni el daño secundario tras la lesión medular, lo cual sugiere que la fuente principal de LPA en esta patología no es la síntesis en plasma. Además, demostramos que el bloqueo combinado de LPA1 y LPA2 no tiene efectos aditivos en la lesión medular.
En general, los resultados de esta tesis sugieren que la inhibición farmacológica del LPA1 y, preferiblemente el LPA2, abren una nueva ventana terapéutica para el tratamiento de la lesión medularThe spinal cord is an extremely vital part of the central nervous system (CNS) and, although it is well protected by the spinal column, it can be damaged, resulting in serious consequences. Spinal cord injury (SCI) leads to a disruption of the neuronal networks that are involved in many physiological functions. Since CNS axons of adult mammals do not regenerate following the lesion, and dead neurons and glial cells are not successfully replaced, this results in an irreversible functional loss in patients suffering from SCI. The pathophysiology of SCI involves two degenerative stages, known as primary and secondary injury. The first one results from the direct mechanical trauma to the spinal cord, directly causing cell death, damage to axons, and loss of myelin. This is followed by a secondary wave of tissue degeneration that can extend for several weeks, in which inflammation plays a crucial role. Although regeneration of damaged axons and replacement of lost neurons and glial cells are important goals for the restoration of the injured spinal cord, minimizing secondary damage to axons, neuronal cell bodies, myelin and glial cells that follows the initial trauma is likely to be more easily amenable to treatment. Since inflammation is a major contribution to secondary damage in SCI, targeting the detrimental actions of this physiological response could result in the development of novel approaches for the treatment of this pathology. Lysophosphatidic acid (LPA) is an extracellular bioactive lipid with many physiological functions. It signals through six known G-protein coupled receptors (LPA1-6), which are classified into two families: Endothelial differentiation family gene (Edg) LPA receptors (LPA1-3) and Non-Edg family gene LPA receptors (LPA4-6). LPA synthesis is carried out by two different pathways: (i) by the action of the enzyme named autotaxin (ATX), which is the main responsible in synthesis of this lipid in plasma, and (ii) by action of the phospholipase A2 (PLA2) family enzymes, which are the main route of LPA synthesis in tissues. LPA is a key trigger of secondary damage after SCI, since its increased levels in the spinal cord parenchyma following injury leads to demyelination. Indeed, the lack of LPA1 and LPA2 signalling after SCI enhances functional recovery and myelin sparing. In this thesis, we show that activation of microglial LPA1 and LPA2 leads to oligodendrocyte cell death. We reveal that the cytotoxic actions underlying by microglial cells stimulated with LPA are mediated by the release of purines and the subsequent activation of P2X7 in oligodendrocytes. We also show that, unlike LPA1 and LPA2, LPA4 and LPA5 receptors do not contribute to SCI physiopathology. In the present thesis, we also show that pharmacological inhibition of ATX does not have any effect in functional outcomes and secondary tissue damage after SCI, suggesting that this enzyme is unlikely to be involved in the production of LPA in the spinal cord parenchyma after injury. We also demonstrate that combinatory targeting of LPA1 and LPA2 does not results in additive effects in SCI. Overall, the results shown here suggest that pharmacological inhibition of LPA1, and preferably LPA2, may open a new therapeutic avenue for the treatment of SCI.
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Valli, Emanuele <1983>. "The role of MYCN-mediated transcriptional repression in neuronal physiopathology." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4809/1/Valli_Emanuele_tesi.pdf.
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MYC is a transcription factor that can activate transcription of several targets by direct binding to their promoters at specific DNA sequences (E-box).
Recent findings have also shown that it can exert its biological role by repressing transcription of other set of genes. C-MYC can mediate repression on its target genes through interaction with factors bound to promoter regions but not through direct recognition of typical E-Boxes.
In this thesis, we investigated whether MYCN can also repress gene transcription and how this is mechanistically achieved.
Moreover, expression of TRKA, P75NTR and ABCC3 is attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and transcriptional repression of these three genes.
We found that MYCN is physically associated with gene promoters in vivo in proximity of the transcriptional start sites and this association requires interactions with SP1 and/or MIZ-1.
Furthermore, we show that this interaction could interfere with SP1 and MIZ-1 activation functions by recruiting co-repressors such as DNMT3a or HDACs.
Studies in vitro suggest that MYCN interacts through distinct domains with SP1, MIZ-1 and HDAC1 supporting the idea that MYCN may form different complexes by interacting with different proteins.
Re-expression of endogenous TRKA and P75NTR with exposure to the TSA sensitizes neuroblastoma to NGF-mediated apoptosis, whereas ectopic expression of ABCC3 decreases cell motility without interfering with growth.
Finally, using shRNA whole genome library, we dissected the P75NTR repression trying to identify novel factors inside and/or outside MYCN complex for future therapeutic approaches.
Overall, our results support a model in which MYCN can repress gene transcription by direct interaction with SP1 and/or MIZ-1, and provide further lines of evidence on the importance of transcriptional repression induced by Myc in tumor biology.
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Valli, Emanuele <1983>. "The role of MYCN-mediated transcriptional repression in neuronal physiopathology." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4809/.
Full textAbstract:
MYC is a transcription factor that can activate transcription of several targets by direct binding to their promoters at specific DNA sequences (E-box).
Recent findings have also shown that it can exert its biological role by repressing transcription of other set of genes. C-MYC can mediate repression on its target genes through interaction with factors bound to promoter regions but not through direct recognition of typical E-Boxes.
In this thesis, we investigated whether MYCN can also repress gene transcription and how this is mechanistically achieved.
Moreover, expression of TRKA, P75NTR and ABCC3 is attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and transcriptional repression of these three genes.
We found that MYCN is physically associated with gene promoters in vivo in proximity of the transcriptional start sites and this association requires interactions with SP1 and/or MIZ-1.
Furthermore, we show that this interaction could interfere with SP1 and MIZ-1 activation functions by recruiting co-repressors such as DNMT3a or HDACs.
Studies in vitro suggest that MYCN interacts through distinct domains with SP1, MIZ-1 and HDAC1 supporting the idea that MYCN may form different complexes by interacting with different proteins.
Re-expression of endogenous TRKA and P75NTR with exposure to the TSA sensitizes neuroblastoma to NGF-mediated apoptosis, whereas ectopic expression of ABCC3 decreases cell motility without interfering with growth.
Finally, using shRNA whole genome library, we dissected the P75NTR repression trying to identify novel factors inside and/or outside MYCN complex for future therapeutic approaches.
Overall, our results support a model in which MYCN can repress gene transcription by direct interaction with SP1 and/or MIZ-1, and provide further lines of evidence on the importance of transcriptional repression induced by Myc in tumor biology.
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Jensen-Urstad, Kerstin. "Heart rate variability and vascular function in healthy subjects and in patients with insulin-dependent (Type 1) diabetes mellitus /." Stockholm, 1997. http://diss.kib.ki.se/1997/19970822jens.
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Calota, Andra. "Reliability of spasticity measurement based on tonic stretch reflex threshold." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111947.
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Studies suggest that deficits in central regulation of stretch reflex thresholds (SRT) underlie both spasticity and other disorders of motor control. We investigated intra- and inter-evaluator reliability to quantify spasticity based on tonic SRT (TSRT) and the relationship between TSRT and Modified Ashworth Scale (MAS, clinical assessment of resistance to stretch). Spasticity was evaluated in 20 subjects with chronic stroke-related spasticity in two different days, by three evaluators. Twenty different velocity-dependent dynamic SRT (angle where biceps brachii EMG signal increased for a given velocity of stretch) were recorded. TSRT (excitability of motoneurons at 0°/sec) was then computed. Spasticity was also estimated with MAS. Reliability was moderately good for subjects with moderately high spasticity (intra--evaluator: 0.46 to 0.68, inter--evaluator: 0.53 to 0.68). There was no correlation between TSRT and MAS since they measure different phenomena. TSRT is a promising new measure of spasticity. Further improvements for its quantification are suggested.
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Roux, Christian. "Arthrose des membres inférieurs : aspects épidémiologiques, cliniques et fondamentaux." Thesis, Nice, 2014. http://www.theses.fr/2014NICE4001/document.
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L’arthrose est une pathologie fréquente et responsable d’une morbidité majeure. En France, cette pathologie est devenue une priorité de santé publique et jusqu’à récemment il n’existait aucune donnée épidémiologique en population générale. Mon travail a permis d’apporter les premiers chiffres de prévalence en population générale et a constitué une étape préliminaire essentielle à la réalisation d’une étude de prévalence nationale et à la constitution d’une cohorte de cas prévalents d’arthrose symptomatique des membres inférieurs. Ces travaux m’ont amené à m’intéresser à l’apport diagnostique des clichés en Schuss et ainsi mettre en évidence que ces clichés seuls sont aussi contributifs que l’association clichés en extension et clichés en Schuss classiquement réalisés pour le diagnostic de gonarthrose. L'ocytocine est une hormone exprimée dans un grand nombre de cellules dont les ostéoblastes et les adipocytes. Son rôle dans l'ostéoporose a été démontré. A ce jour aucune donnée sur son éventuel rôle dans l’arthrose n’a été publiée. J’ai donc recherché un éventuel rôle direct et/ou indirect de l'ocytocine. Pour cela, nous avons utilisé un modèle cellulaire: ’’Multipotent Adipose-Derived Stem’’ (hMADS) développé dans notre laboratoire de recherche. Nous avons, dans un premier temps, montré les capacités chondrogéniques de ces cellules ainsi que leur intérêt comme potentiel outil de tests pharmacologiques dans l’arthrose. La deuxième étape a consisté à démontrer un rôle de l’ocytocine dans la chondrogenèse. Nous avons montré que l’ocytocine a une action bénéfique sur l’expression des gènes chondrocytaire. De plus, le traitement des cellules par l'ocytocine atténue l'effet négatif de l'IL-1β sur ADAMTS-4 qui est responsable de la dégradation de l'aggrécane. L’ensemble de ces résultats indique que l'ocytocine représente un modulateur positif de la formation des chondrocytes et prometteur comme traitement potentiel pour l'arthroseOsteoarthritis is the most frequent cause of rheumatic complaints in Rheumatology. Osteoarthritis is responsible of major morbidity. Increase of life span is accompanied by an increase of aging diseases such as osteoporosis and osteoarthritis. In France, the disease became a public health priority, and until recently, there was no osteoarthritis epidemiologic data in the general population concerning lower limbs. My clinical studies enabled me to bring the first prevalence study in the general population. It was an essential preliminary step for a national prevalence study, and the constitution of a prevalent symptomatic cases cohort of lower limbs osteoarthritis. These observations let me to analyze the diagnostic contribution of Schuss X rays and to show that Schuss X-rays alone do not provide less information’s for the diagnosis of knee osteoarthritis, than the usual association standard extension X rays -Schuss X rays. Oxytocin is a hormone expressed by a large number of cells including osteoblasts and adipocytes. Recently, its role in osteoporosis has been shown. So far, no data about its potential role in osteoarthritis are available. I thus searched for a possible direct and / or indirect role of oxytocin on chondrogenesis. For that, I used a cellular model developed in our research laboratory: the “Multipotent Adipose-Derived Stem’’ (hMADS) cells. A first step, I show that hMADS cells are endowed with a chondrogenic capacity, and they represent a powerful tool for therapeutic test in osteoarthritis. The second step was to analyze the role of oxytocin in chondrogenesis. We shown that oxytocin has a benefic effect especially on the aggrecan (increase), probably via a negative effect on ADAMTS4, and also several other major chondrogenesis genes such as COMP and Sox9. Taken together, these results indicate that oxytocin represents a positive modulator of chondrocyte formation and holds promise as a potential therapy for osteoarthritis
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Bouasse, Malik. "Mise en place d’un modèle cellulaire permettant l’exploration fonctionnelle du canal ionique NALCN : caractérisation du courant de fuite induit par le canal humain NALCN et de différents mutants rencontrés dans un contexte pathologique." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT026.
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L'activité électrique des neurones dépend de la l’expression et de l'activité des canaux ioniques, dont le canal de fuite de sodique récemment décrit, appelé NALCN. Dans les neurones, NALCN est un canal activé par un récepteur couplé aux protéines G qui conduit un courant de fuite de sodium résistant à la TTX et résistant à Cs + et contribue à la mise en place du potentiel de la membrane du repos. Chez l'homme, des mutations récessives et dominantes de NALCN ont récemment été décrites dans des troubles neurologiques complexes tels que la Dystrophie Neuroaxonale Infantile (syndrome INAD) et l'Arthrogryposis Distal de Type 2A (syndrome CLIFHADD). Ces troubles partagent des symptômes communs tels que l'ataxie, les crises épileptiques, l'hypotonie, le retard cognitif et le retard de développement. Les conséquences fonctionnelles de ces mutations NALCN ne sont toutefois pas connues principalement en raison de l'absence d'un modèle cellulaire reproductible pour réaliser une analyse électrophysiologique du courant NALCN. Dans la présente étude, nous décrivons les propriétés des canaux NALCN recombinants dans la lignée cellulaire neuronale, NG108-15. Ces cellules, qui expriment les sous-unités auxiliaires UNC79 et UNC80 de NALCN, ont été transfectées avec des constructions encodant NALCN (type sauvage ou mutants) et sa sous-unité NLF-1. Après la transfection du NALCN de type sauvage, les enregistrements par la technique de patch-clamp ont révélé la présence d'un courant de fuite entrant dans des cellules différenciées. A noter que la transfection des mutants CLIFHADD a entraîné l'expression d'un courant de fuite de sodium significativement plus élevé, comparé aux cellules exprimant des canaux NALCN de type sauvage. Au contraire, aucun courant de ce genre n'a été observé dans les cellules exprimant le mutant INAD. Ces résultats confirment fortement l'hypothèse selon laquelle les mutations dominantes CLIFHADD est un gain de fonction, alors que l'INAD est une mutation de perte de fonction. En conclusion, nos données démontrent que la lignée cellulaire NG108-15 est un modèle cellulaire fiable pour étudier l'activité électrophysiologique des canaux NALCN de type sauvage et mutantElectrical activity of neurons is critically dependent on the presence and activity of ion channels, including the recently described “sodium-leak channel” named NALCN. In neurons, NALCN is a G protein-coupled receptor-activated channel that conducts a TTX-resistant and Cs+-resistant sodium-leak current and contributes to setting-up the resting’s membrane potential. In humans, both recessive and dominant mutations of NALCN were recently described in complex neurological disorders such as Infantile Neuroaxonal Dystrophy (INAD) and Type 2A Distal Arthrogryposis (CLIFHADD). These disorders share common symptoms such as ataxia, epileptic seizures, hypotonia, cognitive delay and developmental retardation. The functional consequences of these NALCN mutations are however not known mainly because of the lack of a reliable cellular model to achieve electrophysiological analysis of the NALCN current. In the present study, we describe the properties of recombinant NALCN channels in the neuronal cell line, NG108-15. These cells, which express the NALCN’s ancillary subunits Unc79 and Unc80, were transfected with constructs encoding NALCN (wild-type or mutants) and its NLF-1 subunit. Following transfection of the wild-type NALCN, patch-clamp recordings revealed the presence of an inward background current in differentiated cells. Importantly, transfection of the CLIFHADD mutants resulted in the expression of a significantly larger sodium-leak current, compared to cells expressing wild-type NALCN channels. On the contrary, no such current was observed in cells expressing the INAD mutant. These results strongly support the hypothesis that CLIFHADD are gain-of-function, while INAD are loss-of-function mutations. Altogether, our data demonstrate that the NG108-15 cell line is a reliable cellular model to study electrophysiological activity of wild-type and mutant NALCN channels
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Anaf, Vincent. "Contribution to the physiopathology, symptomatology and treatment of deep infiltrating endometriosis." Doctoral thesis, Universite Libre de Bruxelles, 2004. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211116.
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L’endométriose est définie comme la présence de tissu endométrial et de stroma en dehors de la cavité utérine. Ses localisations les plus fréquentes sont le péritoine pelvien et les ovaires. L’endométriose infiltrante est classiquement décrite comme la présence de tissu endométriotique plus de cinq millimètres sous le péritoine pelvien ou la séreuse d’un organe. Histologiquement il s’agit d’une lésion endométriotique mais qui contrairement aux lésions ovariennes ou péritonéales contient significativement plus de muscle lisse et de fibrose et est davantage associée à la douleur. Les lésions infiltrantes peuvent être responsables de dysménorrhée, dyspareunie profonde et douleurs pelviennes chroniques sévères ayant un charactère hyperalgique tel qu’on peut le retrouver dans les douleurs neuropathiques. Ces douleurs nécessitent souvent la prise de quantités importantes d’antalgiques et ont des répercussions importantes sur la vie professionnelle, quotidienne et sexuelle des femmes atteintes. L’endométriose infiltrante présente un rapport histologique étroit avec les structures nerveuses du rétropéritoine ou les nerfs des organes atteints. Dans sa localisation rectovaginale il existe une relation histologique étroite entre les lésions d’endométriose et les nerfs ainsi qu’une correlation entre l’intensité de la douleur et le nombre de structures nerveuses envahies par l’endometriose ou engaînées dans la fibrose. Ces lésions infiltrantes expriment le «nerve growth factor» (NGF), une neurotrophine qui joue un rôle clé dans la genèse de l’hyperalgie et de la douleur. Les structures nerveuses du rétropéritoine pelvien expriment quant à elles le récepteur spécifique pour la neurotrophine NGF. Le système «NGF-récepteur spécifique» peut être responsable d’un chimiotactisme tissulaire entre les tissus sécrétant du NGF et les nerfs qui expriment le récepteur pour le NGF. Le système «NGF- récepteur spécifique» au sein de la relation endométriose-nerfs pourrait rendre compte du caractère hyperalgique des lésions endométriotiques infiltrantes ainsi, qu’expliquer pourquoi les lésions nodulaires n’apparaissent que dans les sites anatomiques richement innervés (ligaments utérosacrés, lame rectovaginale, paroi du rectum ou du côlon…) et pas ailleurs. Le traitement de première intention est chirurgical. Il convient d’être suffisamment agressif sur les lésions tout en engendrant le moins de séquelles postopératoires possibles sachant que nombre de ces femmes sont stériles. En cas d’atteinte digestive basse, les modalités de l’intervention sont dictées par l’extension et le degré d’infiltration de la paroi digestive. Dans le but de réaliser dans la majorité des cas une chirurgie minimalement invasive (laparoscopique) avec des cicatrices de petites tailles, nous avons développé une stratégie de traitement basée sur le degré d’infiltration de la paroi digestive. Dans ce cadre nous avons développé une technique laparo-assistée de résection colique segmentaire et de résection antérieure du rectum.Doctorat en sciences médicales
info:eu-repo/semantics/nonPublished
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Tokuno, Shinichi. "Adaptation to ischemia with special emphasis on nitric oxide /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-023-7/.
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Hedenberg-Magnusson, Britt. "Masseter muscle pain and its relation to pain mediators in fibromyalgia and local myalgia /." Stockholm : [Karolinska institutets bibl.], 2001. http://diss.kib.ki.se/2001/91-7349-038-5/.
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Martin, Claes. "Pain and sensory function in HIV-infection : with and without antiretroviral therapy /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4238-2/.
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Chen, Jen-Kai 1971. "Neural substrates of persistent post-concussive symptoms : functional and structural neuroimaging studies with concussed male athletes." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111893.
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Mild head injury or concussion accounts for as many as 90% of all traumatic brain injuries and can sometime result in long-lasting and disabling post-concussion symptoms (PCS), even in the absence of detectable structural damage to the brain by morphological imaging. To date, the nature of persistent PCS following mild head injury remains poorly understood as objective and scientifically valid diagnostic tools are practically absent. This, in turn, likely accounts for missed diagnoses, prevents accurate assessment of the severity of the injury and creates difficulties for achieving proper patient management.This dissertation describes 4 functional magnetic resonance imaging (fMRI) studies designed to establish whether there is a pathological basis to persistent PCS following cerebral concussion in male athletes. Study 1 was intended to evaluate the feasibility of using fMRI to detect changes in brain activation following concussion. The results showed that concussed athletes displayed reduced prefrontal activities compared to a healthy control group when performing a working memory task. In Study 2, we examined the relationship between self-reported PCS and the pattern of brain activity measured by fMRI. The severity of self-reported PCS was found to be associated with blood oxygen level dependent (BOLD) activation patterns in the region of interest: the higher the PCS score the lower the BOLD signal. In Study 3, we used serial fMRI approach to investigate brain activation pattern in the course of injury recovery. The results showed that symptom resolution was accompanied by a return to normal BOLD response patterns. Study 4 was designed to investigate the nature of depression, a common PCS, following concussion. Concussed athletes with depression showed less activation in the dorsolateral prefrontal cortex, and attenuated deactivation in the medial prefrontal region, consistent with functional neuroimaging findings in major depression. Again, depression severity correlated with the strength of the fMRI signal in the region of interests.
Taken together, these results demonstrate the value of functional MRI in the evaluation of cerebral concussion, and provide evidence of an underlying pathology in persistent PCS following concussion.
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Roux, Christian. "Arthrose des membres inférieurs : aspects épidémiologiques, cliniques et fondamentaux." Electronic Thesis or Diss., Nice, 2014. http://theses.unice.fr/2014NICE4001.
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L’arthrose est une pathologie fréquente et responsable d’une morbidité majeure. En France, cette pathologie est devenue une priorité de santé publique et jusqu’à récemment il n’existait aucune donnée épidémiologique en population générale. Mon travail a permis d’apporter les premiers chiffres de prévalence en population générale et a constitué une étape préliminaire essentielle à la réalisation d’une étude de prévalence nationale et à la constitution d’une cohorte de cas prévalents d’arthrose symptomatique des membres inférieurs. Ces travaux m’ont amené à m’intéresser à l’apport diagnostique des clichés en Schuss et ainsi mettre en évidence que ces clichés seuls sont aussi contributifs que l’association clichés en extension et clichés en Schuss classiquement réalisés pour le diagnostic de gonarthrose. L'ocytocine est une hormone exprimée dans un grand nombre de cellules dont les ostéoblastes et les adipocytes. Son rôle dans l'ostéoporose a été démontré. A ce jour aucune donnée sur son éventuel rôle dans l’arthrose n’a été publiée. J’ai donc recherché un éventuel rôle direct et/ou indirect de l'ocytocine. Pour cela, nous avons utilisé un modèle cellulaire: ’’Multipotent Adipose-Derived Stem’’ (hMADS) développé dans notre laboratoire de recherche. Nous avons, dans un premier temps, montré les capacités chondrogéniques de ces cellules ainsi que leur intérêt comme potentiel outil de tests pharmacologiques dans l’arthrose. La deuxième étape a consisté à démontrer un rôle de l’ocytocine dans la chondrogenèse. Nous avons montré que l’ocytocine a une action bénéfique sur l’expression des gènes chondrocytaire. De plus, le traitement des cellules par l'ocytocine atténue l'effet négatif de l'IL-1β sur ADAMTS-4 qui est responsable de la dégradation de l'aggrécane. L’ensemble de ces résultats indique que l'ocytocine représente un modulateur positif de la formation des chondrocytes et prometteur comme traitement potentiel pour l'arthroseOsteoarthritis is the most frequent cause of rheumatic complaints in Rheumatology. Osteoarthritis is responsible of major morbidity. Increase of life span is accompanied by an increase of aging diseases such as osteoporosis and osteoarthritis. In France, the disease became a public health priority, and until recently, there was no osteoarthritis epidemiologic data in the general population concerning lower limbs. My clinical studies enabled me to bring the first prevalence study in the general population. It was an essential preliminary step for a national prevalence study, and the constitution of a prevalent symptomatic cases cohort of lower limbs osteoarthritis. These observations let me to analyze the diagnostic contribution of Schuss X rays and to show that Schuss X-rays alone do not provide less information’s for the diagnosis of knee osteoarthritis, than the usual association standard extension X rays -Schuss X rays. Oxytocin is a hormone expressed by a large number of cells including osteoblasts and adipocytes. Recently, its role in osteoporosis has been shown. So far, no data about its potential role in osteoarthritis are available. I thus searched for a possible direct and / or indirect role of oxytocin on chondrogenesis. For that, I used a cellular model developed in our research laboratory: the “Multipotent Adipose-Derived Stem’’ (hMADS) cells. A first step, I show that hMADS cells are endowed with a chondrogenic capacity, and they represent a powerful tool for therapeutic test in osteoarthritis. The second step was to analyze the role of oxytocin in chondrogenesis. We shown that oxytocin has a benefic effect especially on the aggrecan (increase), probably via a negative effect on ADAMTS4, and also several other major chondrogenesis genes such as COMP and Sox9. Taken together, these results indicate that oxytocin represents a positive modulator of chondrocyte formation and holds promise as a potential therapy for osteoarthritis
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Mengoni, Ilaria <1986>. "Microglial involvement in brain physiopathology: in vitro studies using rat primary cultures." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6466/1/mengoni_ilaria_tesi.pdf.
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Microglial involvement in neurological disorders is well-established, being microglial activation not only associated with neurotoxic consequences, but also with neuroprotective effects.
The studies presented here, based on microglia rat primary cell cultures and mainly on microglial conditioned medium (MCM), show insights into the mechanism of Superoxide dismutase 1 (SOD1) and Apolipoprotein E (ApoE) secretion by microglia as well as their neuroprotective effect towards primary cerebellar granule neurons (CGNs) exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA).
SOD1 and ApoE are released respectively through non-classical lysosomal or the classical ER/Golgi-mediated secretion pathway. Microglial conditioned medium, in which SOD1 and ApoE accumulated, protected CGNs from degeneration and these effects were replicated when exogenous SOD1 or ApoE was added to a non-conditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. ApoE release is negatively affected by microglia activation, both with lipopolysaccharide (LPS) and Benzoylbenzoyl-ATP (Bz-ATP) but is stimulated by neuronal-conditioned medium as well as in microglia-neurons co-culture conditions. This neuronal-stimulated microglial ApoE release is differently regulated by activation states (i.e. LPS vs ATP) and by 6-hydroxydopamine-induced neurodegeneration. In co-culture conditions, microglial ApoE release is essential for neuroprotection, since microglial ApoE silencing through siRNA abrogated protection of cerebellar granule neurons against 6-OHDA toxicity. Therefore, these molecules could represent a target for manipulation aimed at promoting neuroprotection in brain diseases.
Considering a pathological context, and the microglial ability to adopt a neuroprotective or neurotoxic profile, we characterize the microglial M1/M2 phenotype in transgenic rats (McGill-R-Thy1-APP) which reproduce extensively the Alzheimer’s-like amyloid pathology. Here, for the first time, cortical, hippocampal and cerebellar microglia of wild type and transgenic adult rats were compared, at both early and advanced stages of the pathology. In view of possible therapeutic translations, these findings are relevant to test microglial neuroprotection, in animal models of neurodegenerative diseases.
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Mengoni, Ilaria <1986>. "Microglial involvement in brain physiopathology: in vitro studies using rat primary cultures." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6466/.
Full textAbstract:
Microglial involvement in neurological disorders is well-established, being microglial activation not only associated with neurotoxic consequences, but also with neuroprotective effects.
The studies presented here, based on microglia rat primary cell cultures and mainly on microglial conditioned medium (MCM), show insights into the mechanism of Superoxide dismutase 1 (SOD1) and Apolipoprotein E (ApoE) secretion by microglia as well as their neuroprotective effect towards primary cerebellar granule neurons (CGNs) exposed to the dopaminergic toxin 6-hydroxydopamine (6-OHDA).
SOD1 and ApoE are released respectively through non-classical lysosomal or the classical ER/Golgi-mediated secretion pathway. Microglial conditioned medium, in which SOD1 and ApoE accumulated, protected CGNs from degeneration and these effects were replicated when exogenous SOD1 or ApoE was added to a non-conditioned medium. SOD1 neuroprotective action was mediated by increased cell calcium from an external source. ApoE release is negatively affected by microglia activation, both with lipopolysaccharide (LPS) and Benzoylbenzoyl-ATP (Bz-ATP) but is stimulated by neuronal-conditioned medium as well as in microglia-neurons co-culture conditions. This neuronal-stimulated microglial ApoE release is differently regulated by activation states (i.e. LPS vs ATP) and by 6-hydroxydopamine-induced neurodegeneration. In co-culture conditions, microglial ApoE release is essential for neuroprotection, since microglial ApoE silencing through siRNA abrogated protection of cerebellar granule neurons against 6-OHDA toxicity. Therefore, these molecules could represent a target for manipulation aimed at promoting neuroprotection in brain diseases.
Considering a pathological context, and the microglial ability to adopt a neuroprotective or neurotoxic profile, we characterize the microglial M1/M2 phenotype in transgenic rats (McGill-R-Thy1-APP) which reproduce extensively the Alzheimer’s-like amyloid pathology. Here, for the first time, cortical, hippocampal and cerebellar microglia of wild type and transgenic adult rats were compared, at both early and advanced stages of the pathology. In view of possible therapeutic translations, these findings are relevant to test microglial neuroprotection, in animal models of neurodegenerative diseases.
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GALASSO, LETIZIA. "ACTIGRAPHIC ASSESSMENT OF SLEEP-ACTIVITY CYCLE IN PHYSIOPATHOLOGY: EXPERIMENTAL AND METHODOLOGICAL STUDIES." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/607722.
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The principal objective of my research during my PhD has been the investigation of the rest-activity circadian rhythms in physiopathology, dealing with both experimental and methodological issues. On the experimental side, the focus of my research program was centered on the investigation of the rest-activity circadian rhythms in patients with binge eating disorders. On the methodological side, my activity was aimed at exploring the relationships between the actigraphy-based assessment of circadian rhythmicity and the questionnaire-based assessment of circadian typology.
The thesis is organized in 11 Chapters. Chapter 1 provides a short introduction to chronobiology and to the components of a circadian rhythm. Chapter 2 describes the two most common methods used to evaluate the circadian rhythmicity, namely actigraphy and self-administered questionnaires. These two approaches have remarkable strengths and weaknesses. Actigraphy is a non-invasive method (usually based on a small, wearable actigraphic unit) that allows one to monitor the activity levels during the 24 hours, to detect the rest-activity circadian rhythm, to evaluate the activity levels during the nocturnal sleep and to assess the quality and quantity of sleep by specific sleep parameters. One alternative approach to assessment of the circadian typology of a subject is based on self-administered questionnaires. Questionnaires are obviously less objective than actigraphy-based assessments, but have the advantage of being simple and cost-effective. Chapter 3 provides a general overview of all the research projects I have taken part in throughout my PhD course. This chapter has been written with the reader in mind and aims to succinctly describe the structure and function of the subsequent chapters, 4 through 11. In Chapters 4 to 7, I will focus on the experimental core of my research activity during my PhD course, which is the chronobiological investigation of obese patients suffering from binge eating disorder. First, I will provide an overview of the features characterizing this disorder. Then, I will describe three experimental studies that were carried out in these patients with the purpose of i): quantifying their rest-activity circadian rhythm (RARs); ii) describing their sleep behaviour; iii) evaluating the effectiveness of a physical activity program as an auxiliary therapeutic approach to the traditional treatment for BED.
In Chapters 8 to 10, I will illustrate the methodological core of my research activity during my PhD which aims to develop predictive formulas - based on linear regression - enabling investigators to use the questionnaire-based assessment of circadian typology (Morningness-Eveningness Questionnaire, MEQ) as a surrogate of the actigraphy-based assessment of circadian rhythmicity. A methodological project of this kind was successful is showing that both MEQ and its reduced version rMEQ are appropriate for the prediction of the actigraphy-based acrophase and this may prove useful when actigraphy-based measurements are not applicable, in so far as they result either too complex or time-consuming.
Chapter 11, the final chapter, is concerned with providing concise summaries of the other studies I have been involved in during my PhD course. Seven experimental studies are described in relation to: i) the influence of chronotype on circadian rhythm (RARs), on sleep, on physical activity and on cardiac autonomic function; ii) the effects of aerobic physical activity on sleep and on markers of insulin resistance in breast cancer women; iii) the effects of short and prolonged exposure to cave environments on human physiology.
The thesis also comprises an appendix containing the list of all the scientific papers that I co-authored in the course of my PhD thesis. The list reports both the published and the submitted articles.
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Nesbitt, Catherine. "Variations in maternal lickinggrooming influences both dam and offspring's hypothalamic-pituitary-adrenal hormone profile." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111562.
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Pup directed maternal licking and grooming (LG) increases with corticosterone (CORT) supplimentation (Rees et al 2004). Increases in LG lead to an attenuation of the adult offspring's HPA response to stress (Liu et aI1997). Similarly, Neonatal increases in glucocorticoids lead, in adulthood, to the same attenuation of the HPA stress response (Catalani et aI1993). We hypothesize that dams exhibiting increased LG will have increased circulating CORT, and this increase will be reflected in their offspring. This thesis characterizes the HPA hormone profile adrenocorticotropic hormone (ACTH), CORT & Corticosterone Binding Globulin (CBG) in High LG (H) and Low LG (L) litters, 5 days postpartum (P4). Furthermore pup plasma CORT levels are determined at (P) 3,4,6,10 & 14. Finally P10 Hand L LG ACTH, CORT & CBG will be assessed after stress. RESULTS: H compared to L LG dams have significantly increased plasma CORT (p=0.03). At P4, H LG offspring have significantly increased plasma CORT (p=0.03) and significantly decreased plasma ACTH (p=0.04) as compared to L LG offspring. Plasma CBG levels are significantly lower in H compared to L LG offspring (p=0.01) at the same age. Across the Stress Hyporesponsive Period (SHRP) H LG offspring had significantly increased plasma CORT (p= 0.00) compared to L LG offspring at P3. Challenged with a stressor at P10, H LG offspring have an exaggerated plasma CORT response (p=0.00). This data suggests increases in plasma CORT in the dams leads to increased CORT in the high offspring, contributing perhaps to a more mature stress response at P10.Key word abbreviation: (1) CORT - CORTicosterone, (2) ACTH - AdrenoCorticoTropin releasing Hormone, (3) CBG - Corticosteroid Binding Globulin, (4) SHRP - Stress Hypo-Responsive Period, (5) P - Post-natal day, (6) HPA - Hypothalamic-Pituitary-Adrenal, (7) LG - Licking/Grooming, (8) ADX/OVX - ADrenalectomized/OVarectomized.
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Gamboa, Teresa Paula Rocha Soeiro Tavares. "Repercussões crónicas nas vias aéreas da hiperóxia neonatal : modelo experimental." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2007. http://hdl.handle.net/10362/5516.
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RESUMO: O objectivo deste trabalho foi avaliar se a exposição crónica neonatal à hiperóxia mo-derada induz alterações funcionais e estruturais persistentes nas vias aéreas. Desenvolveu-se um modelo animal, no rato, a partir do qual se retiraram implicações para a compreensão das repercussões crónicas da hiperóxia neonatal sobre as vias aéreas de displasia broncopulmonar (DBP), em duas fases distintas: imediatamente após a exposi-ção neonatal a 50%O2 (grupo 50%O2) e após três semanas de recuperação em ar ambiente (grupo 50%O2+Ar).Compararam-se os resultados da resposta do músculo liso de traqueia (MLT) à esti-mulação in vitro com metacolina e salbutamol e avaliaram-se as alterações quantitativas da área de MLT, bem como as alterações qualitativas da estrutura da traqueia. Demonstrou-se que a exposição a 50% de oxigénio não tinha repercussões imediatas sobre a resposta in vitro do MLT à estimulação colinérgica, mas que induzia um aumento do relaxamento em resposta ao salbutamol. A contractilidade do MLT em resposta à estimula-ção com metacolina no grupo 50%O2+Ar foi significativamente superior à do grupo de con-trolo da mesma idade e também superior à observada no grupo 50%O2, enquanto que a resposta ao salbutamol se voltou a aproximar dos valores de controlo após a recuperação em normóxia. Não se observaram diferenças estatisticamente significativas na área de MLT entre os grupos experimental e de controlo, o que se deve provavelmente ao número reduzido de amostras avaliadas e à variabilidade deste parâmetro no grupo de controlo; contudo, verifi-cou-se um aumento médio de 15% imediatamente após a exposição à hiperóxia que persis-tiu após o período de recuperação.As alterações qualitativas sobre a arquitectura da traqueia, avaliadas por microscopia óptica, revelaram no grupo 50%O2 aumentos da espessura da matriz extracelular e da den-sidade de mastócitos desgranulados na submucosa e adventícia vizinhas do MLT, sem outras alterações relativamente ao grupo de controlo com 15 dias. As alterações da matriz extrace-lular foram reversíveis após a recuperação em ar ambiente. A densidade de mastócitos per-maneceu superior à do grupo de controlo de 36 dias de idade, apresentando-se em maior contiguidade com o MLT relativamente ao grupo 50%O2. Em síntese, demonstrou-se que a hiperóxia neonatal crónica em níveis moderados in-duz alterações da resposta contráctil do MLT e da estrutura da traqueia que podem ter ex-pressão funcional após a exposição ter cessado. Assim, o contributo original do presente trabalho foi o desenvolvimento de um modelo animal que permite avaliar os mecanismos pelos quais a hiperóxia é capaz de induzir, isoladamente, alterações crónicas da contracti-lidade, do relaxamento do ML e da estrutura das vias aéreas que podem ser responsáveis pela HRB persistente em doentes sujeitos a oxigenioterapia neonatal.-------------ABSTRACT: The aim of this work was to evaluate whether chronic neonatal exposure to hyperoxia in-duces persistent structural and functional airway changes. An animal model was developed, using neonatal rats, in order to understand the chronic effects of neonatal hyperoxia on the airways, in bronchopulmonary dysplasia, in two distinct phases: immediately after neonatal exposure to 50%O2 (50%O2 group) and after three weeks of recovery at ambient air (50%O2+Ar group).The results from the tracheal smooth muscle (TSM) response to in vitro stimulation with metacholine and salbutamol were compared and quantitative changes in TSM area, as well as qualitative changes in tracheal structure were evaluated. It was demonstrated that while exposure to 50% oxygen had no immediate effects on in vitro TSM response to cholinergic stimulation, it induced an increase in relaxation as a result of salbutamol administration. TSM contractility as a result of methacholine administration in the 50%O2 + Ar group was significantly higher than that of the same-age control group, and also higher than the one observed in the 50%O2 group, whereas the response to salbutamol admini-stration was once again closer to the control values after recovery in normoxia. There were no statistically significant differences in the TSM area between the experi-mental and control groups, which is most likely due to the reduced number of samples evalu-ated and to the variability of this parameter in the control group. However, there was an aver-age increase of 15% immediately after exposure to hyperoxia, which persisted after the recov-ery period. Qualitative changes in tracheal architecture, evaluated by optic microscopy, revealed that the 50%O2 group suffered an increase in the thickness of the extracellular matrix and degranu-lated mast cell density in the submucosa and adventitia adjacent to the TSM, without further changes when compared with the control group at 15 days of age. The changes in extracellular matrix were reversible after recovery in ambient air. Mast cell density remained higher than that of the control group at 36 days of age, and more contiguous to TSM than the 50%O2 group. In conclusion, it has been demonstrated that moderate levels of chronic neonatal hyperoxia in-duce changes in TSM contractile response and tracheal structure, which may be functionally ex-pressed after discontinuation of exposure. Therefore, the original contribution of the present work was the development of an animal model which allows the evaluation of the mechanisms through which hyperoxia alone can induce chronic changes in contractility and relaxation of SM and also in airway structure that can be responsible for the persistent airway hyperrespon-siveness found in patients who were submited to neonatal oxygen therapy.
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Oskarsson, Per. "Studies on glucagon secretion in patients with type 1 diabetes : clinical and experimental studies /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3835-0/.
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Boström, Carina. "Shoulder and upper extremity impairments, activity limitation and physiotherapeutic exercise in women with rheumatoid arthritis : a biopsychosocial approach /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4192-0/.
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Schmotzer, Hans. "Knee joint contact stresses : the influence of deformity and muscle activity." Doctoral thesis, University of Cape Town, 1991. http://hdl.handle.net/11427/26674.
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Studies have shown that the alignment of the knee in the coronal plane has a significant effect on the joint contact stress. However, gait analysis demonstrated that factors other than alignment contributed significantly to the outcome of corrective surgery. It was therefore hypothesized that muscle contraction can alter the stress distribution within the knee joint and that overloading can occur in the absence of a deformity. Six normal knees were harvested from different donors. The exact orientation of all muscle groups was recorded and their tendinous insertions carefully preserved. Custom built pressure transducers (6 per compartment, 0.5 mm thick, 10 mm diameter) were inserted through 2 small, posterior, capsular incisions and placed on the tibial surface and the menisci. The knees were mounted in a loading system which allowed free self-alignment of the joint under load. All muscles were replaced by wire cables instrumented with force transducer, tensioner and grip. Several alignment models (5, 10 degree varus, neutral, 5 degree valgus and 15 degree of flexion) as well as the effect of contraction of all major muscles crossing the knee joint were tested. An even pressure distribution was seen in neutral alignment. In a varus deformity the peak pressure shifted medially and laterally in valgus. Unloading of the opposite compartment was seen for deformities as small as 5 degrees. A flexion deformity produced a postero-lateral shift of the peak pressure area. Muscle contraction increased the pressure significantly in a region next to the muscle. Generally, unloading - though less significant - was seen in a region diagonally across the joint. These results suggest that muscular hyperactivity may considerable increase the contact stresses. However, muscle weakness or lack of muscular contraction may indirectly play a significant role in affecting the contact pressure distribution. If the muscle force is insufficient to counterbalance the external moment condylar lift-off occurs. This increases the angulation between femur and tibia thereby overloading the compartment where contact takes place; One can therefore conclude that abnormal gait patterns or neuromuscular control mechanisms may result in unphysiologically high contact stresses which may cause the development of unicompartmental osteoarthritis and subsequently, a deformity.
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Fraser, R. K. "The hip in the midlumbar myelomeningocele patient." Master's thesis, University of Cape Town, 1992. http://hdl.handle.net/11427/26257.
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Cambuli, Francesca Maria. "Study of Musashi1-Expressing cells and of Musashi1 function in mouse intestinal physiopathology." Thesis, Lyon, École normale supérieure, 2012. http://www.theses.fr/2012ENSL0794.
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L’épithélium intestinal est une monocouche de cellules qui tapisse la lumière intestinale, constitué d’un compartiment différencié, les villosités dans l’intestin grêle et les plateaux épithéliaux dans le colon, et d’un compartiment prolifératif, les cryptes de Lieberkühn. Ce tissue se renouvelle de façon rapide et continue tout au long de la vie de l’individu, grâce à la présence de cellules souches adultes dans le fond des cryptes. Ces cellules s’autorenouvellent et donnent naissance à des progéniteurs prolifératifs (capables d’engendrer les différents cytotypes épithéliaux) qui se différencient tout en migrant vers le compartiment différencié. Mon travail de these a porté sur l’étude d’une marqueur putatif de ces cellules souches épithéliales intestinales: Musashi1 (Msi1).Dans ce contexte, mon premier axe d’étude s’est focalisé sur l’isolement et la caractérisation des cellules souches épithéliales intestinales chez la souris. Pour cela, nous avons généré des souris transgéniques exprimant la protéine fluorescente GFP sous le contrôle du promoteur de Msi1. Les cellules souches intestinales de ces souris coexpriment donc Msi1 et la GFP. Ce modèle a été validé et nous à permis de isoler les cellules GFP/Msi1 positives dans l’intestin. A l'aide de différentes approches cellulaires et moléculaires, nous avons confirmé leur nature de cellules souches et nous avons apporté des nouvelles données sur la composition de la zone proliférative de l’épithélium intestinal murin.Le second axe de mes travaux de thèse a porté sur l’étude de la fonction de Msi1 dans l'homéostasie de l’épithélium intestinal chez la souris, par son sur-expression tous au long de l’épithélium. Nous avons montré que la sur-expression de cette protéine, qui est un régulateur des voies Wnt et Notch, perturbe l’architecture intestinale, a propriétés pro-prolifératives et un potentiel tumorigèniqueThe intestinal epithelium is a monolayer of cells surrounding the intestinal lumen. It consists of a differentiated compartment, the villi in the small intestine and a flat surface in the colon, and a proliferative compartment, the crypts of Lieberkühn. This tissue self-renews rapidly and continuously throughout life, due to the presence of adult stem cells in the bottom of the crypts. These cells are capable of self-renewing and give rise to proliferating progenitors (capable of generating all the different epithelial cytotypes) that differentiate and migrate toward the differentiated compartment. My thesis focused on the study of the intestinal epithelial stem cells marker Musashi1 (Msi1).In this context, the first part of my thesis work focused on the isolation and characterization of the intestinal epithelial stem cells that express Msi1 in the mouse. For this, we generated transgenic mice expressing the fluorescent protein GFP under the control of the promoter of Msi1. The intestinal stem cells of these mice co-express Msi1 and GFP. This model has been validated and allowed us to isolate GFP+/Msi-expressing cells in the intestine. By using different cellular and molecular approches, we confirmed their nature of stem cells and provided new data on the composition of the proliferative zone in the murine intestinal epithelium.The second part of my thesis has focused on the study of the function of Msi1 in the intestinal epithelium homeostasis in the mouse, by its over- and ectopic expression all along the epithelium. We have shown that the over-expression of this protein, which is a regulator of the Wnt and Notch pathways, perturbs the intestinal architecture, has pro-proliferative properties and tumorigenic potential
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Huang, Yen-Lin. "Analyse des altérations oncogéniques associées aux lymphomes NK/T de type nasal." Thesis, Paris Est, 2009. http://www.theses.fr/2009PEST0052.
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Dans les pays occidentaux, les lymphomes T périphériques et NK représentent environ 10% des lymphomes non-Hodgkiniens. Le lymphome NK/T de type nasal est l'une des entités de présentation extra-ganglionnaire les plus fréquentes, en Asie, et en Amérique Centrale et du Sud. Il survient classiquement dans la sphère nasopharyngée avec une prédilection pour les adultes jeunes. Morphologiquement, la tumeur est souvent angiocentrique avec une invasion de la paroi des vaisseaux par les cellules tumorales d'aspect variable. Ces lymphomes ont le plus souvent une origine NK avec un phénotype CD3+ (cytoplasmique), CD5-, CD56+, CD4-/CD8-, expression des molécules cytotoxiques et absence de réarrangement des gènes des récepteurs T. Le virus d'Epstein-Barr est présent dans la quasi-totalité des cellules tumorales dans sa forme clonage épisomale, avec une latence de type II, suggérant son rôle dans l'oncogenèse. A côté des mutations fréquentes des gènes FAS et TP53 (p53) et des méthylations de TP73 et CDKN2A (p16), des délétions du bras long du chromosome 6q sont fréquemment observées. Très récemment, des méthylations et des mutations des gènes suppresseurs de tumeur PRDM1, ATG5, et AIM1 localisés en 6q21 ont été retrouvées dans les lignées de lymphome NK/T de type nasal. Nous avons réalisé une analyse combinée du profil d'expression génique et du profil génomique par hybridation comparative sur puces, d'échantillons tumoraux de lymphome NK/T de type nasal (n=9) et de lignées, comparés à celle de lymphocytes NK normaux et de lymphomes T périphériques, sans autre spécificité (PTCL, NOS). Nous avons identifié la signature moléculaire particulière du lymphome NK/T de type nasal caractérisée par un haut niveau des trascrits de marqueurs de cellules NK et de molécules cytotoxiques, notamment de granzyme H dans les lymphomes NK/T de type nasal comparé aux PTCL, NOS. Par immunohistochimie, nous avons validé l'expression "spécifique" de granzyme H par les cellules tumorales du lymphome NK/T de type nasal, qui pourrait constituer un nouveau marqueur de ces lymphomes. Comparé aux cellules NK normales, le lymphome NK/T de type nasal a une signature plus proche des cellules NK activées que des NK au repos et sur-expriment des gènes associés à la biologie vasculaire, des gènes induits par l'EBV, et PDGFRA. Nous avons confirmé l'expression protéique de PDGFRAa et de sa forme phosphorylée, et montré in vitro la sensibilité de la lignée tumorale MEC04 à l'imatinib mesytale. La dérégulation des voies de signalisation AKT, JAK-STAT et NF-kB, suggérée par les analyses bioinformatiques, a été corroborée par la mise en évidence d'une expression nucléaire des formes phosphorylées d'AKT, de STAT3 et de RelA dans les lymphomes NK/T de type nasal. De plus, plusieurs gènes dérégulés dans ces voies moléculaires sont localisés dans des régions altérées de manière récurrente par des gains ou des pertes (AKT3 (1q44), IL6R (1q21.3), CCL2 (17q12), TNFRSF21 (6p12.3)). En plus de l'activation constitutive de STAT3 confirmée par l'expression nucléaire de phospho-STAT3, l'inhibition de croissance et l'augmentation de la mort cellulaire des cellules de la lignée MEC04 résultant de l'inhibition de STAT3 conforte le rôle de STAT3 dan la lymphomagenèse du lymphome NK/T nasal. L'analyse intégrée a également mis en évidence la dérégulation du gène suppresseur de tumeur HACE1 en 6q21, confirmée par RT-PCR quantitative. Bien que les mécanismes exacts conduisant à l'activation de plusieurs voies moléculaires, de même qu'à la dérégultaion de HACE1 ne soient pas déterminés, nos résultats identifient plusieurs voies oncogéniques impliquées dans le lymphome NK/T de type nasal ainsi que de nouveaux biomarqueurs diagnostiques - comme granzyme H - et des cicles thérapeutiques d'intérêt. L'étude en cours du profil d'expression des microARNs pourrait apporter un éclairage sur les mécanismes impliqués dans certaines voies identifiéesIn Western countries, mature natural killer (NK)- and T-cell lymphomas account for 15% to 20% of aggressive lymphomas and around 10 % of all non-Hodgkin lymphomas. This number is higher in Asia, with 25% in Japan and 39% in Taiwan. Among those T- and NK-cell lymphomas with primary extranodal presentation, extranodal NK/T-cell lymphoma of nasal type (nasal NKTCL) is one of the most common entities in Asian, Central and South American populations. It classically arises in the nasal region showing a predilection for young adults with male predominance. This tumor morphologically exhibits an angiocentric and angio destructive growth pattern, admixed with polymorphous non-neoplastic infiltrates. Most tumor cells have a cytoplasmic CD3+, CD5-, CD56+, CD4-/CD8- phenotype with expression of cytotoxic granule-associated proteins and without rearrangement of T-cell receptors genes. Killer immunoglobulin-like receptors have been reproted to be expressed in a subset of this lymphoma and its expression might be associated with prognosis. Epstein-Barr virus is present in virtually all neoplastic cells in its clonal episomal form with type II latency program, implying a role in oncogenesis. Although the results were variable between different studies, methylations of TP73 (p73) and CDKN2A (p16) and mutations of FAS and TP53 (p53) were frequently found in nasal NKTCL. Genomic alterations have also been reported in nasal NKTCL with frequent deletion in chromosome 6q. A very recent study also identified both methylations and mutations of three putative tumor suppressor genes PRDM, ATG5, and AIM1 mapping to del6q21 in nasal NKTCL cell times. We performed integrative gene expression profiling and array-based comparative genomic hybridization analyses of nasal NKTCL tumors as well as tumour-derived cell lines, compared to that of normal NK cells and peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS). We identified the distinctive molecular signature of nasal NKTCL with high transcript levels for NK-cell markers ans cytotoxic molecules, especially granzyme H in nasal NKTCL compared to PTCL, NOS. By immunohistochemistry, we validated expression of grnzyme H which appears a novel sensitive biomarker of nasal NKTCL. Compared to normal NK cells, nasal NKTCL tumors were closer to activated than resting cells and overexpressed several genes related to vascular biology, EBV-induced genes and PDGFRA. Notably, we confirmed the expression of PDGFRa and its phosphorylated form at the protein level, and in vitro the MEC04, nasal NKTCL-cell line, was sensitive to imatinib mesylate. Deregulation of the AKT, JAK-STAT and NF-kB pathways suggested by bioinformatical analysis, was corroborated by nuclear expression of phosphorylated AKT, STAT3 and RelA in nasal NKTCL, and several deregulated genes in these pathways mapped to regions of recurrent copy number aberrations (AKT3 (1q44), IL6R (1q21.3), CCL2 (17q12), TNFRSF21 (6p12.3)). In addition to constitutive activation of STAT3 as confirmed by the demonstration of phosphorylated STAT3 in the nuclei of neoplastic nasal NKTCL cells, growth inhibition and cell death of nasal NKTCL cells induced by STAT3 inhibition implied the role of STAT3 in the nasal NK/T-cell lymphomagenesis. Integrative analysis and qRT-PCR analysis also evidenced deregulation of another tumor suppressor HACE1 in the frequently deleed 6q21 region. Although the exact mechanism of activation of several pathways as well as that of HACE1 deregulation remains to be determined, our studies highlight emerging oncogenic pathways in nasal NKTCL and identify novel diagnostic and therapeutic targets. The ongoing investigation of microRNA expression profiling might shed light in a better understanding of the pathogenesis of nasal NKTCL and especially of the activation of oncogenic pathways. Connectivity map analysis may also help to depict other targeted therapies useful to improve the prognosis of this agressive lymphoma