La néphropathie aux plantes chinoises (CHN) est une maladie rénale grave qui a été décrite pour la première fois en 1993 chez des patientes ayant suivi un régime amaigrissant à base d’extraits de plantes chinoises (Aristolochia fangchi) contenant des acides aristolochiques (AA). Cette néphropathie se caractérise par une atrophie tubulaire et une fibrose interstitielle aboutissant à l’urémie terminale et se complique fréquemment de cancers des voies urinaires. Au moment d’initier ce travail, il subsistait toujours un large débat quant au rôle étiologique réel des acides aristolochiques dans la genèse de cette maladie. En effet, les gélules à visée amaigrissante contenaient d’autres substances potentiellement néphrotoxiques. Mais surtout, il n’existait aucune preuve expérimentale que les AA pouvaient induire une fibrose rénale interstitielle.<p>Dans la première partie de ce travail, nous démontrons que l’injection par voie sous-cutanée d’AA à la dose de 10 mg/Kg/jour à des rats Wistar mâles en déplétion sodée entraîne l’apparition au 35ème jour d’une atrophie tubulaire, d’une fibrose interstitielle et d’une insuffisance rénale, reproduisant ainsi les anomalies caractéristiques de la CHN. Nous avons ensuite montré que la dexfenfluramine, substance anorexigène à action de type sérotoninergique prise concomitamment par les patientes atteintes de CHN, ne potentialise pas la toxicité rénale des AA. Enfin, la stimulation du système rénine angiotensine (SRA) par la déplétion sodée ou l’inhibition de celui-ci par un traitement pharmacologique ne modifie pas la fibrose interstitielle ni l’insuffisance rénale induite par les AA.<p>En conclusion, nous avons réussi à développer un modèle in vivo de fibrose rénale interstitielle induite par les AA. Dès lors nous avons apporté la preuve expérimentale de l’implication des AA dans le développement de la CHN. Ce modèle a permis de démontrer que les autres éléments potentiellement néphrotoxiques contenues dans la cure d’amaigrissement (dexfenfluramine, diurétique, laxatif) n’influençaient pas l’évolution de la fibrose interstitielle, ce qui confirme que la prise isolée d’AA suffit à expliquer le développement de la CHN. Cette confirmation à d’importantes implications en santé publique dans la mesure où des plantes contenant des acides aristolochiques font toujours partie des phytothérapies traditionnelles. De plus, il est apparu que, dans ce modèle, les mécanismes de la fibrose rénale interstitielle pouvaient être largement indépendants du SRA. Enfin, de par sa durée limitée et sa grande reproductibilité, ce modèle constitue un outil expérimental d’avenir pour l’étude des mécanismes physiopathologiques de la fibrose rénale interstitielle en général.<p> / Doctorat en sciences médicales / info:eu-repo/semantics/nonPublished

Es wird untersucht, ob in Schneckenextrudern verwendete Förderelemente aus Stahl durch das Oberflächenfeinwalzen der schraubförmigen Mantelfläche gleichzeitig geglättet und verfestigt werden können. Steigungsprofile, zu denen auch die Förderelemente zählen, werden bislang oft nach der Hauptformgebung wärmebehandelt und im harten Werkstoffzustand spanend feinbearbeitet. Formgebung, Wärmebehandlung und Feinbearbeitung sind voneinander getrennte Prozessschritte. In dieser Arbeit besteht das Ziel, die Verfahrenseingangsgrößen für die Kombination aus Formgebung und definierter lokaler Werkstoffverfestigung beim Walzen zu erarbeiten. Zu diesem Zweck werden sowohl am Steigungsprofil selbst als auch an einem davon abgeleiteten Rotationsprofil simulative, experimentelle sowie analytische Untersuchungen durchgeführt. Es werden geometrische, kinematische und werkstofftechnische Gesichtspunkte beleuchtet. Aufbauend auf dem Vergleich zwischen Simulationsergebnissen mit der Finite-Elemente-Methode und im Versuch ermittelten Daten werden Haupteinflussfaktoren auf die geometrischen Abweichungen sowie die Härtesteigerung in der Bauteilrandschicht ermittelt. Mit Hilfe eines neu entwickelten sensorischen Werkstückträgers wird die Drehbewegung des Werkstücks erfasst. Aus den analytischen Betrachtungen wird schließlich ein Modell zur qualitativen Beschreibung des Walzkraftverlaufs abgeleitet, das zur Vorauswahl von Verfahrenseingangsgrößen genutzt werden kann. Im Ergebnis wiederholter Messungen wird deutlich, dass mit der geometrischen Gestaltung einer Walzvorform gezielt Einfluss auf Umformgrad und damit Verfestigung im Bauteil genommen werden kann. An den untersuchten hochfesten korrosionsbeständigen austenitischen Stählen ist eine Verdopplung der Halbzeughärte möglich. Die beim Spanen der Vorformen auftretenden Formabweichungen haben großen Einfluss auf die Beschaffenheit der Zielgeometrie sowie die erzielbare Härtesteigerung. Durch Kenntnis der realen Werkstückdrehbewegung während des Walzens lassen sich Rückschlüsse auf die Werkzeuggestaltung und die Walzparameter ziehen. Aufgrund der Untersuchungsergebnisse wird das Verfahren für die Anwendung an korrosionsbeständigen Bauteilen mit mittleren Verschleißschutzanforderungen empfohlen.:1 Einleitung 2 Stand der Technik 3 Zielstellung der Arbeit 4 Beschaffenheit der Werkstücke und Werkzeuge 5 Modellbildung mit Hilfe der FEM 6 Versuchsvorbereitung und Eingangsgrößen 7 Vergleich der Verfahrenskenngrößen in Simulation und Experiment 8 Analytisches Modell zur qualitativen Vorhersage der Walzkraft 9 Bauteileigenschaften nach dem Walzen 10 Zusammenfassung und Ausblick / A combined surface burnishing and mechanical hardening process for steel conveying elements in screw extruders is examined. Helical profiles, that also comprise conveying elements, are often heat treated after shaping followed by fine processing. Shaping, heat treatment and fine processing are sequential process steps. This work deals with the investigation of rolling process parameters that enable both low geometrical deviations and high work hardening of the screw material. For this purpose, helical and axisymmetric profiles are analyzed with simulative, experimental and analytical methods. The investigations highlight geometrical, kinematical and material-related aspects. The main factors with influence on screw geometry and hardness increase in the component subsurface are investigated by means of the comparison between simulative and experimental results. An intelligent workpiece carrier is applied to analyze the part rotation. Based upon analytical observations, a calculation model for the prediction of the rolling force curve over workpiece rotation is developed. This model supports predefining the process input variables. Repeated measurements indicate that the geometrical design of the machined preforms allows for individual strain and hence hardness distributions in the part subsurface. Hardness can be doubled in the investigated corrosion resistant austenitic high strength steels. Form deviations of the part and hardness increase are strongly dependent on geometrical deviations of the preform. Knowledge of part rotation during rolling enables to draw conclusions for tool design and rolling parameters. Based on the results it is suggested to apply the rolling procedure to parts in environments which require high corrosion resistance and moderate wear resistance.:1 Einleitung 2 Stand der Technik 3 Zielstellung der Arbeit 4 Beschaffenheit der Werkstücke und Werkzeuge 5 Modellbildung mit Hilfe der FEM 6 Versuchsvorbereitung und Eingangsgrößen 7 Vergleich der Verfahrenskenngrößen in Simulation und Experiment 8 Analytisches Modell zur qualitativen Vorhersage der Walzkraft 9 Bauteileigenschaften nach dem Walzen 10 Zusammenfassung und Ausblick

Les contractions rythmiques résultent de l’activité stimulatrice du nœud sinusal dans le cœur et des cellules interstitielles de Cajal (CICs) dans les intestins. Nous avons découvert un nouveau syndrome résultant d’une combinaison de la maladie du nœud sinusal (MNS) et de la pseudo-obstruction intestinale chronique (POIC). Ce syndrome, que nous avons nommé Chronic Atrial and Intestinal Dysrhythmia (CAID), résulte d’une mutation récessive du gène SGO1 (K23E). Cependant, les rôles connus de SGO1 n'expliquent pas l'apparition postnatale du syndrome ni la pathologie spécifique, suggérant que des rôles non canoniques de SGO1 conduisent aux manifestations cliniques observées. Cette hypothèse est supportée par la comparaison de CAID avec les autres cohésinopathies qui présentent principalement des phénotypes développementaux sans ou avec des défauts légers du cycle cellulaire. Ce projet visait à une découverte non biaisée des mécanismes non canoniques expliquant le syndrome CAID en utilisant le dogme de la biologie moléculaire (ADN→ARNm→protéine) comme ligne directrice. Pour ce faire, nous avons effectué des criblages multi-omiques sur des fibroblastes de peau de patients CAID et de contrôles sains. Les résultats des criblages ont été validés par électrophysiologie, étude des voies de signalisation pertinentes, immunohistochimie, pyroséquençage des rétrotransposons LINE-1 et quantification des marques d’histones. Nos études multi-omiques ont confirmé des changements dans la régulation du cycle cellulaire, mais aussi dans la conduction cardiaque et la fonction des muscles lisses. Plus spécifiquement, plusieurs canaux potassiques étaient sous-régulés. L’électrophysiologie a confirmé une diminution du courant potassique rectifiant entrant (IK1). L'immunohistochimie des coupes intestinales de patients CAID a confirmé l’augmentation de l’expression de SGO1 et BUB1, un régulateur de la voie de signalisation TGF-β. De plus, la voie canonique de TGF-β est augmentée et est découplée de la voie non canonique. Au niveau épigénétique, une signature unique d’hyperméthylation et de fermeture de la chromatine a été observée. Ce qui est soutenu par l’augmentation de la méthylation de H3K9me3 et de H3K27me3. En conclusion, le syndrome CAID est associé à plusieurs changements ayant possiblement un effet cumulatif plutôt que d’une seule voie de signalisation dérégulée. Nos résultats désignent la perturbation du courant IK1, la dérégulation de la signalisation TGF-β, l’hyperméthylation de l’ADN et la compaction de la chromatine comme éléments conducteurs potentiels des manifestations cliniques observées. La voie TGF-β et les changements épigénétiques peuvent être ciblées par des médicaments existants, constituant ainsi des cibles thérapeutiques prometteuses pour le traitement du syndrome CAID. / Rhythmic contractions are driven by the pacemaker activity of the cardiac sinus node and the intestinal interstitial cells of Cajal (ICC). We have discovered a new syndrome resulting from a combination of sick sinus syndrome (SSS) and chronic intestinal pseudo-obstruction (CIPO). This syndrome, which we have named Chronic Atrial and Intestinal Dysrhythmia (CAID), results from a recessive mutation in the SGO1 gene (K23E). However, the known roles of SGO1 do not explain the postnatal onset of the syndrome nor the specific pathology, suggesting that non-canonical roles of SGO1 lead to the clinical manifestations observed. This hypothesis is supported by the comparison of CAID with other cohesinopathies which mainly exhibit developmental phenotypes without or with mild cell cycle defects. This project aimed towards an unbiased discovery of noncanonical mechanisms explaining CAID using the molecular biology dogma (DNA→mRNA→protein) as a guideline. We performed multi-omic screens on skin fibroblasts from CAID patients and healthy controls. Screening results were validated by electrophysiology, study of relevant signaling pathways, immunohistochemistry, LINE-1 retrotransposon pyrosequencing, and histone marks quantification. Our multiomics analyses confirmed changes in cell cycle regulation, but also in cardiac conduction and smooth muscle function. More specifically, several potassium channels were downregulated. Electrophysiology studies confirmed a decrease in the inward rectifier potassium current (IK1). Immunohistochemistry in CAID patient’s intestinal sections confirmed overexpression of SGO1 and BUB1, a regulator of TGF-β signaling pathway. Additionally, the canonical TGF-β signaling was increased and decoupled from noncanonical signaling. At the epigenetic level, CAID patient fibroblasts have a unique signature of hypermethylation and chromatin closure. This is supported by the increased methylation of H3K9me3 and H3K27me3. In conclusion, CAID syndrome is associated with several changes that, may have a cumulative effect rather than a single deregulated signaling pathway. Our results reveal the disturbance of the IK1 current, the deregulation of TGF-β signaling, DNA hypermethylation and chromatin accessibility changes as potential conductors of intestinal and cardiac manifestations of CAID syndrome. In particular, the TGF-β pathway and epigenetic changes, may be targeted by existing drugs, thus constituting promising therapeutic targets for the treatment of CAID syndrome.

En perspective de la prolongation de la durée de vie en service des REPs, il est de plus en plus important d’obtenir une évaluation fiable de l’évolution de la microstructure des aciers constituant la cuve des REPs et de leurs propriétés correspondantes. Un mécanisme de fragilisation non-durcissante, dû à la ségrégation intergranulaire du P qui affaiblirait la cohésion des joints de grains, pourrait contribuer à la fragilisation et doit donc être étudié. Les présents travaux ont pour objectifs d’étudier la ségrégation intergranulaire du P dans un acier de cuve de réacteur afin (i) de connaître l’influence du type de joint de grain sur la ségrégation du P, (ii) de clarifier l’influence des conditions de vieillissement (vieillissement thermique et irradiation ionique) sur la ségrégation du P et (iii) de faire une comparaison avec les modèles disponibles et proposés ici.Pour cela, une méthodologie corrélative -Diffraction des Électrons Rétrodiffusés (EBSD), Diffraction de Kikuchi en Transmission (TKD) et Sonde Atomique Tomographique (APT) -a été adoptée pour étudier la ségrégation intergranulaire. Les informations cristallographiques (5 paramètres) et la composition chimique ont été collectées et systématiquement corrélées. Les aciers ont une microstructure complexe de ferrite aciculaire et de carbures intergranulaires. La ségrégation des solutés aux joints des grains (joints des grains faiblement désorientés (LAGB), joints des grains fortement désorientés généraux (HAGB) et Σ3HAGBs) et aux interfaces (interfaces carbure-ferrite M2.0-3.2C et interfaces cémentite-ferrite) a été quantifiée. Il existe une ségrégation évidente d'un élément ou de plusieurs espèces chimiques (C, P, Mn, Mo, Cr, Si et Ni) pour tous ces types de défauts plans. Tenant compte de la nature des éléments ségrégants et de la cristallographie du joint de grain, les ségrégations interstitielles et substitutionnelles ont été quantifiées et discutées. Sur la base d’un grand nombre de données, il apparaît que les niveaux moyens des segrégations en P sont plus élevés dans les HAGBs généraux ou les LAGBs que les autres types d'interfaces quel que soit le vieillissement envisagé. Par ailleurs, les résultats expérimentaux ont été comparés avec les résultats prévus par des modèles analytiques pour des systèmes binaires, ternaires et multi-composants. Bien qu'ayant un niveau de ségrégation du P prédit plus élevé, le modèle ternaire Fe-P-C se rapproche le plus des résultats expérimentaux. / With expectations for extending the service lifespans of PWRs, it is of great importance to get a reliable evaluation of the microstructural evolution and the corresponding property changes of RPV steels. A non-hardening mechanism, due to intergranular P segregation that impairs the grain boundary (GB) cohesion, may contribute to the embrittlement and thus needs to be studied. The present work aims to investigate the intergranular P segregation behavior in a RPV steel in order to (i) determine the influence of GB type on P segregation behavior, (ii) clarify the influence of ageing conditions (thermal ageing and ion irradiation) on P segregation behavior and (iii) make a comparison with the existing analytical models. To reach these objectives, a correlative - Electron Backscatter Diffraction (EBSD), Transmission Kikuchi Diffraction (TKD) and Atom Probe Tomography (APT) - methodology was adopted to study the GB segregation behavior. The crystallographic information (5 parameters) and chemical composition were collected simultaneously. The steels have a complex microstructure of acicular ferrite and intergranular carbides. The solute segregation at GBs (Low Angle Grain Boundaries (LAGBs), general High Angle Grain Boundaries (HAGBs) and Σ3 HAGBs) and interfaces (M2.0-3.2C carbide-ferrite interfaces and cementite-ferrite interfaces) were quantified. There is an obvious segregation of one element or several chemical species (C, P, Mn, Mo, Cr, Si and Ni) at all boundary types. Taking into account the nature of segregants and the five-parameter GB crystallography, both interstitial and substitutional segregation behaviors were discussed. Based on a large dataset, it appears that the average P segregation levels are higher in general HAGBs or LAGBs than in other boundary types. Besides, the experimental results were compared to the predicted ones from analytical models for binary, ternary and multicomponent systems. Though with a higher predicted P segregation level, the Fe-P-C ternary model seems to better fit the experimental results in all ageing conditions.

Suburothelial myofibroblasts (sMF) are located underneath the urothelium in close proximity to afferent nerves and show spontaneous calcium activity in vivo and in vitro. They express purinergic receptors and calcium transients can be evoked by ATP. Therefore they are supposed to be involved in afferent signaling of the bladder fullness. Myofibroblast cultures, established from cystectomies, were challenged by exogenous ATP in presence or absence of purinergic antagonist. Fura-2 calcium imaging was used to monitor ATP (10-16 to 10-4 mol/l) induced alterations of calcium activity. Purinergic receptors (P2X1, P2X2, P2X3) were analysed by confocal immunofluorescence. We found spontaneous calcium activity in 55.18% ± 1.65 (mean ± SEM) of the sMF (N=48 experiments). ATP significantly increased calcium activity even at 10-16 mol/l. The calcium transients were partially attenuated by subtype selective antagonist (TNP-ATP, 1μM; A-317491, 1μM), and were mimicked by the P2X1, P2X3 selective agonist α,β-methylene ATP. The expression of purinergic receptor subtypes in sMF was confirmed by immunofluorescence. Our experiments demonstrate for the first time that ATP can modulate spontaneous activity and induce intracellular Ca2+ response in cultured sMF at very low concentrations, most likely involving ionotropic P2X receptors. These findings support the notion that sMF are able to register bladder fullness very sensitively, which predestines them for the modulation of the afferent bladder signaling in normal and pathological conditions.:1. Introduction............................................................................ 1 1.1. Anatomy and histology of the human urinary bladder..................... 1 1.1.1. Anatomy of the human urinary bladder..................................... 1 1.1.2. Structure of the human urinary bladder wall............................... 2 1.2. Normal bladder function and bladder dysfunction.......................... 3 1.2.1 Normal bladder function......................................................... 3 1.2.2 Sensory aspect.................................................................... 4 1.2.3 Overactivity or hypersensitivity of bladder.................................. 5 1.3 The role of functional cell types and interaction in urinary bladder... 6 1.3.1 The role of urothelium.......................................................... 7 1.3.2Theroleofsuburotheliamyofibroblast...................................... 7 1.3.3Theroleofdetrusorsmoothmusclecells.................................. 9 1.3.4 Possible interactions in urinary bladder cell types........................ 10 1.4 ATP function and Purinergic signalling in bladder........................... 11 1.5 Spontaneous activity of bladder................................................... 13 2. Objective.................................................................................. 15 3. Material and methods............................................................... 16 3.1. Ethics Statement........................................................................ 16 3.2. Cell preparation.......................................................................... 16 3.3. Solutions and chemicals............................................................. 19 3.4. Intracellular calcium measurements............................................. 20 2.4.1. Preparing cells for Calcium Imaging.......................................... 20 2.4.2. Preparing workspace of calcium imaging................................... 20 2.4.3. Calcium imaging recording...................................................... 22 3.5 Data analysis with automated Fluorescence analysis..................... 22 3.6 Confocal Immunofluorescence.................................................... 25 3.7 Statistics................................................................................. 26 4. Results.................................................................................. 27 4.1 Spontaneous calcium activity of sMF........................................... 27 4.2 ATP effects on calcium response in sMF...................................... 27 4.3 Analysis of purinergic receptors involved.................................... 30 3.3.1 Agonist stimulation.............................................................. 30 3.3.2 Signal inhibition by specific antagonists................................... 31 4.4 Confocal immunofluorescence of purinergic receptors.................. 32 5. Discussion............................................................................. 34 5.1 Myofibroblast identification....................................................... 34 5.2 Spontaneous activity in the bladder............................................ 36 5.3 ATP modulated calcium activity in sMF....................................... 37 5.4 purinergic signalling in sMF........................................................ 39 6. Summary................................................................................ 42 7. References.............................................................................. 45 Declaration............................................................................. 50 Acknowledgements................................................................. 51

<p>Subcutaneous administration has become a common approach for drug delivery of biotherapeutics, such as monoclonal antibodies, which is achieved mainly by absorption through the lymphatic system. This dissertation focuses on the computational modeling of the fluid flow and solute transport in the skin tissue and the quantitative investigation of lymphatic uptake. First, the various mechanisms governing drug transport and lymphatic uptake of biotherapeutics through subcutaneous injection are investigated quantitatively through high-fidelity numerical simulations, including lymphatic drainage, blood perfusion, binding, and metabolism. The tissue is modeled as a homogeneous porous medium using both a single-layered domain and a multi-layered domain, which includes the epidermis, dermis, hypodermis (subcutaneous tissue), and muscle layers. A systematic parameter study is conducted to understand the roles of different properties of the tissue in terms of permeability, porosity, and vascular permeability. The role of binding and metabolism on drug absorption is studied by varying the binding parameters for different macromolecules after coupling the transport equation with a pharmacokinetic equation. The interstitial pressure plays an essential role in regulating the absorption of unbound drug proteins during the injection, while the binding and metabolism of drug molecules reduce the total free drugs. </p> <p>  </p> <p>The lymphatic vessel network is essential to achieve the functions of the lymphatic system. Thus, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. The explicit heterogeneous vessel network is embedded into the continuum model to investigate the role of explicit heterogeneous vessel network in drug transport and absorption. The solute transport across the vessel wall is investigated under various transport conditions. The diffusion of the drug solutes through the explicit vessel wall affects the drug absorption after the injection, while the convection under large interstitial pressure dominates the drug absorption during the injection. The effect of diffusion cannot be captured by the previously developed continuum model. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. The injection volume significantly affects lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence. At last, the binding and metabolism of drug molecules are studied to bridge the simulation to the experimentally measured drug clearance. </p> <p><br></p> <p>Convective transport of drug solutes in biological tissues is regulated by the interstitial fluid pressure, which plays a crucial role in drug absorption into the lymphatic system through the subcutaneous (SC) injection.  An approximate continuum poroelasticity model is developed to simulate the pressure evolution in the soft porous tissue during an SC injection. This poroelastic model mimics the deformation of the tissue by introducing the time variation of the interstitial fluid pressure. The advantage of this method lies in its computational time efficiency and simplicity, and it can accurately model the relaxation of pressure. The interstitial fluid pressure obtained using the proposed model is validated against both the analytical and the numerical solution of the poroelastic tissue model. The decreasing elasticity elongates the relaxation time of pressure, and the sensitivity of pressure relaxation to elasticity decreases with the hydraulic permeability, while the increasing porosity and permeability due to deformation alleviate the high pressure. </p> <p><br></p> <p>At last, an improved Kedem-Katchalsky model is developed to study solute transport across the lymphatic vessel network, including convection and diffusion in the multi-layered poroelastic tissue with a hybrid discrete-continuum vessel network embedded inside. The effect of different drug solutes with different Stokes radii and different structures of the lymphatic vessel network, such as fractal trees and Voronoi structure, on the lymphatic uptake is investigated. The drug solute with a small size has a larger partition coefficient and diffusivity across the openings of the lymphatic vessel wall, which favors drug absorption. The Voronoi structure is found to be more efficient in lymphatic uptake. </p> <p><br></p> <p>The systematic and quantitative investigation of subcutaneous absorption based on high-fidelity numerical simulations can provide guidance on the optimization of drug delivery systems and is valuable for the translation of bioavailability from the pre-clinical species to humans. We provide a novel approach to studying the diffusion and convection of drug molecules into the lymphatic system by developing the hybrid discrete-continuum vessel network. The study of the solute transport across the discrete lymphatic vessel walls further improves our understanding of lymphatic uptake. The novel and time-efficient computational model for solute transport across the lymphatic vasculature connects the microscopic properties of the lymphatic vessel membrane to macroscopic drug absorption. The comprehensive hybrid vessel network model developed here can be further used to improve our understanding of the diseases caused by the disturbed lymphatic system, such as lymphedema, and provide insights into the treatment of diseases caused by the malfunction of lymphatics.</p>

No description available.

Muito se tem pesquisado sobre os efeitos adversos dos antidepressivos tricíclicos (p.e. imipramina) sobre o sistema respiratório, embora pouco ou quase nada se encontre com relação a tal aspecto na literatura médica sobre a fluoxetina (Prozac®)– um inibidor seletivo da recaptação de serotonina, até porque esta droga começou a ser utilizada somente há cerca de quinze anos. Ambas substâncias (fluoxetina e imipramina, ou seus congêneres) agem basicamente sobre quadros depressivos, fóbicos e obsessivo-compulsivos, obesidade, anorexia, e outras indicações de várias naturezas, indo desde a ansiedade até a sindrome do pânico. Nota-se entretanto, que na maioria dos pacientes com tais quadros (sob tratamento com a fluoxetina ou não), são muito frequentes as queixas de natureza respiratória, como tosse, falta de ar, “angústia" no peito etc. Alguns efeitos adversos da fluoxetina e seus derivados são descritos na literatura, embora raros. Entre eles, destaca-se o comprometimento do aparelho respiratório na forma de doença pulmonar intersticial, pneumonia de hipersensibilidade e fosfolipidose. Apresentamos a seguir um projeto de trabalho experimental em cobaias com intuito de verificar a ação da fluoxetina sobre o aparelho respiratório, com relação à mecânica pulmonar, influência sobre o óxido nítrico exalado e resposta histopatológica pulmonar frente a possíveis injúrias, comparados a animais controles sem efeito da droga. Nosso modelo descreve um protocolo em que os animais foram submetidos ao cloridrato de fluoxetina por via oral durante 30 dias consecutivos, sendo ainda submetidos a uma reação de estresse tipo pânico– a natação forçada. / Although high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants like fluoxetine has not received much attention. Imipramine and fluoxetine have their action in depression, obesity, panic and anxiety among other indications. However, accumulation of selective serotonin-reuptake inhibitors- like fluoxetine, in the human lungs has been reported. Besides, it is very frequent to most patients (under fluoxetine treatment or not) present respiratory symptoms and/or signs, just like dyspnea, cough, chest anguish and so on. There also have been some adverse effects of fluoxetine described in the literature, although being few and isolated ones, related to hypersensitivity pneumonitis, phospholipidosis and interstitial lung disease. The purpose of this project is to investigate the fluoxetine action in respiratory tract, more specifically over the pulmonary interstitium, using an experimental model in guinea-pigs. Our project comprehends an experimental model with the animals under treatment of fluoxetine so that we could evaluate the substance effects on the respiratory system, concerning the mechanics and the lung histopathological aspects, compared to the control animals. We created then a protocol where the animals were treated with fluoxetine for 30 consecutive days and submmited to the forced swimmig test, a kind of panic-like reaction.

Muito se tem pesquisado sobre os efeitos adversos dos antidepressivos tricíclicos (p.e. imipramina) sobre o sistema respiratório, embora pouco ou quase nada se encontre com relação a tal aspecto na literatura médica sobre a fluoxetina (Prozac®)– um inibidor seletivo da recaptação de serotonina, até porque esta droga começou a ser utilizada somente há cerca de quinze anos. Ambas substâncias (fluoxetina e imipramina, ou seus congêneres) agem basicamente sobre quadros depressivos, fóbicos e obsessivo-compulsivos, obesidade, anorexia, e outras indicações de várias naturezas, indo desde a ansiedade até a sindrome do pânico. Nota-se entretanto, que na maioria dos pacientes com tais quadros (sob tratamento com a fluoxetina ou não), são muito frequentes as queixas de natureza respiratória, como tosse, falta de ar, “angústia" no peito etc. Alguns efeitos adversos da fluoxetina e seus derivados são descritos na literatura, embora raros. Entre eles, destaca-se o comprometimento do aparelho respiratório na forma de doença pulmonar intersticial, pneumonia de hipersensibilidade e fosfolipidose. Apresentamos a seguir um projeto de trabalho experimental em cobaias com intuito de verificar a ação da fluoxetina sobre o aparelho respiratório, com relação à mecânica pulmonar, influência sobre o óxido nítrico exalado e resposta histopatológica pulmonar frente a possíveis injúrias, comparados a animais controles sem efeito da droga. Nosso modelo descreve um protocolo em que os animais foram submetidos ao cloridrato de fluoxetina por via oral durante 30 dias consecutivos, sendo ainda submetidos a uma reação de estresse tipo pânico– a natação forçada. / Although high-affinity imipramine binding sites have been reported in both rat and human lung, the role of the lungs in the pharmacokinetics of antidepressants like fluoxetine has not received much attention. Imipramine and fluoxetine have their action in depression, obesity, panic and anxiety among other indications. However, accumulation of selective serotonin-reuptake inhibitors- like fluoxetine, in the human lungs has been reported. Besides, it is very frequent to most patients (under fluoxetine treatment or not) present respiratory symptoms and/or signs, just like dyspnea, cough, chest anguish and so on. There also have been some adverse effects of fluoxetine described in the literature, although being few and isolated ones, related to hypersensitivity pneumonitis, phospholipidosis and interstitial lung disease. The purpose of this project is to investigate the fluoxetine action in respiratory tract, more specifically over the pulmonary interstitium, using an experimental model in guinea-pigs. Our project comprehends an experimental model with the animals under treatment of fluoxetine so that we could evaluate the substance effects on the respiratory system, concerning the mechanics and the lung histopathological aspects, compared to the control animals. We created then a protocol where the animals were treated with fluoxetine for 30 consecutive days and submmited to the forced swimmig test, a kind of panic-like reaction.

Do metal particles (including particles of pure metals, alloys, metal oxides and compounds) pose a hazard or risk to human health? In the light of this question, this thesis summarizes results from research conducted on metal particles, and describes the elaboration and implementation of an in vitro test methodology to study metal release from particles through corrosion and dissolution processes in synthetic biological media relevant for human exposure through inhalation/ingestion and dermal contact. Bioaccessible metals are defined as the pool of released metals from particles that potentially could be made available for absorption by humans or other organisms. Studies of bioaccessible metals from different metal particles within this thesis have shown that the metal release process is influenced by material properties, particle specific properties, size distribution, surface area and morphology, as well as the chemistry of synthetic biological test media simulating various human exposure scenarios. The presence of metal particles in proximity to humans and the fact that metals can be released from particles to a varying extent is the hazard referred to in the title. The bioavailable metal fraction of the released metals (the fraction available for uptake/absorption by humans through different exposure routes) is usually significantly smaller than the bioaccessible pool of released metals, and is largely related to the chemical form and state of oxidation of the released metals. Chemical speciation measurements of released chromium for instance revealed chromium to be complexed to its non-available form in simulated lung fluids. Such measurements provide an indirect measure of the potential risk for adverse health effects, when performed at relevant experimental conditions. A more direct way to assess risks is to conduct toxicological in-vitro testing of metal particles, for instance on lung cell cultures relevant for human inhalation. Induced toxicity of metal particles on lung cells includes both the effect of the particles themselves and of the released metal fraction (including bioaccessible and bioavailable metals), the latter shown to be less predominant. The toxic response was clearly influenced by various experimental conditions such as sonication treatment of particles and the presence of serum proteins. Thorough characterization of metal particles assessing parameters including chemical surface composition, degree of agglomeration in solution, size distribution, surface area and morphology was performed and discussed in relation to generated results of bioaccessibility, bioavailability and induced toxicity. One important conclusion was that neither the surface composition nor the bulk composition can be used to assess the extent of metals released from chromium-based alloy particles. These findings emphasize that information on physical-chemical properties and surface characteristics of particles is essential for an in-depth understanding of metal release processes and for further use and interpretation of bioaccessibility data to assess hazard and reduce any risks induced by human exposure to metal particles. / QC 20100803