L’hypertension pulmonaire (HTP) est définie par une valeur de pression artérielle pulmonaire moyenne (PAPm) supérieure à 25 mmHg au repos. Il existe des formes sévères d’HTP (HTPs) avec des valeurs de PAPm encore plus élevées associées à des symptômes plus marqués et à l’apparition de lésions anatomo pathologiques spécifiques. Le diagnostic et le développement de nouvelles thérapies sont des enjeux majeurs pour une meilleure prise encharge de ces patients À l’aide de la tomodensitométrie, nos travaux observationnels chez l’homme atteint debroncho-pneumopathie chronique obstructive (BPCO) ont montré une corrélation de l’HTP avec le remodelage bronchique et non pas avec l’emphysème. L’HTPs peut être une complication rare mais grave de la BPCO. L’évaluation in vivo des modifications du lit vasculaire pulmonaire a permis de confirmer l’existence d’un phénotype particulier chez les patients atteints de BPCO compliquée d’HTPs. De plus, la définition d’un score combiné comprenant des paramètres non invasifs tomodensitométriques devrait permettre de sélectionner plus finement les patients devant subir un cathétérisme cardiaque droit.En parallèle, dans nos travaux expérimentaux, nous avons complété la caractérisation d’un modèle d’hypertension artérielle pulmonaire chez le rat développant un phénotype sévère(HTAPs) et présentant des lésions artérielles pulmonaires caractéristiques de la maladie humaine. Ce modèle, ainsi que des modèles animaux plus classiques d’HTP, nous ont permis d’identifier un rôle du facteur de croissance des nerfs NGF dans cette pathologie, dont le ciblage pourrait ouvrir de nouvelles perspectives thérapeutiques. / Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure (mPAP) at or above 25 mmHg at rest. Severe forms of PH (sPH) are characterized by a stronger elevation of mPAP, more marked symptoms and specific pulmonary vascular lesions. Real challenges come from a better diagnosis for these patients and identification of new therapeutic targets to improve their therapeutic care. Our results show by computed tomography that PH associated to chronic obstructive pulmonary disease (COPD) is correlated to airway remodeling and not to emphysema. Severe PH is a rare and serious complication of COPD. We confirmed existence of a phenotype in COPD patients with sPH, by evaluating in vivo modifications of the pulmonary vascular bed in these patients. Moreover, we defined a combined score, which may be a non-invasive tool to select patients for right heart catheterization In parallel, we completed the characterization of a rat model of severe pulmonary arterial hypertension (sPAH) that developed a severe phenotype with pulmonary arterial specific and human-like lesions. In this model, as well as in more classical PH models, our results demonstrated an increased expression of the nerve growth factor NGF and its role in PH and sPAH pathophysiology. These results therefore suggest that NGF may be an interesting target to develop new therapeutic perspectives in this disease.

Made available in DSpace on 2016-04-29T13:18:06Z (GMT). No. of bitstreams: 1 diss completa.pdf: 1344921 bytes, checksum: 0d5eb60c4e0b5309d3eaeef2b4c9187d (MD5) Previous issue date: 2001-09-28 / Fundação de Amparo a Pesquisa do Estado de São Paulo / Chronic Mild Stress (CMS) is an experimental model for depression: Rats are submitted to a set of stressing conditions and as a result their consumption of water and water with sucrose, as well as the animals previous preference for water and water and sucrose also drops. It is argued that the stress changes the organism and, consequently, changes the reinforcing properties of water and water with sucrose. Therefore the stress would make the subjects insensible to reward. The present study investigated if what has been called sensitivity to reward could be described as a drop in the reinforcing value of a reinforcer. In other words, one of this study's goals was to evaluate if a protocol of mild stress diminished the reinforcing value of a known reinforcer, here, water with sucrose. Four male rats were submitted to a stress protocol of six weeks (as described by Willner, Towell, Sampson, Sophokleus e Muscat (1987). Two of them were also submitted to operant sessions of a FR-FR concurrent schedule of reinforcement, with responses followed either by water or water with sucrose prior and after the stress protocol. Results showed that all four subjects diminished their overall liquid consumption while the stress protocol was in effect. Results also showed the two subjects preferred water with sucrose on the FRFR condition (with higher rates of responses on the lever associated with water with sucrose), and that these subjects recovered their overall consumption and their preference for water with sucrose faster than the two subjects not submitted to the operant condition / Chronic Mild Stress (CMS) é um modelo animal experimental proposto como um modelo de depressão, ao qual ratos são submetidos. Após passarem por um conjunto de "situações de estresse suave", o consumo de água e de água com sacarose desses animais decresce. Considera-se que a submissão ao conjunto de estressores modifica o organismo e, consequentemente, a propriedade recompensadora da água e da água com sacarose. Supõe-se, então, que o sujeito toma-se "Insensível" à recompensa. O presente estudo pretendeu replicar os resultados de Willner, Towell, Sampson, Sopholeus e Muscat (1987) e também verificar se o que é denominado "Insensibilidade à recompensa" poderia ser descrito como diminuição do valor reforçador do estímulo, uma vez que este estímulo, nos estudos de CMS, não é produzido sistematicamente por uma ação/resposta dos sujeitos sistematicamente medida. Ou seja, a submissão ao "regime de estresse" afetaria o valor reforçador do estímulo? Ratos machos foram sujeitos. Dois sujeitos foram submetidos a um conjunto de condições de estresse suave, por 6 semanas, conforme descritos por Willner e cols. (1987), como por exemplo, privação de água e comida, barulho intermitente, iluminação contínua, agrupamento de dois sujeitos na mesma gaiola, luz estroboscópica, cheiro, apresentação de uma garrafa vazia após privação de água, acesso restrito a comida, inclinação da gaiola, presença de um objeto estranho na gaiola e chão da gaiola sujo. Verificou-se uma diminuição no consumo total de líquido e na preferência por água com sacarose destes sujeitos durante e após este procedimento. Outros dois sujeitos foram submetidos a sessões operantes sob um esquema concorrente FR15-FRI5 com água e água com sacarose como estímulos reforçadores antes e após a submissão ao mesmo conjunto de estressores. Também com estes sujeitos observou-se diminuição no consumo de líquido e na preferência por água com sacarose em testes semanais de consumo de líquido, durante as semanas de exposição ao estresse, o que indicaria um aparente efeito do regime de estresse sobre o valor reforçador dos estímulos. Observou-se também, com estes sujeitos, que a submissão à condição operante após o período de estresse parece ter alterado o efeito produzido pelo CMS, aumentando o consumo de líquido e a preferência pela água com sacarose nos testes realizados nas semanas seguintes à exposição ao regime de estresse

Le retard de croissance intra-utérin (RCIU) est une complication fréquente de la grossesse qui se traduit à la naissance par un poids et/ou une taille inférieurs au dixième percentile par rapport à l’âge gestationnel. Il représente un problème majeur de santé publique avec une augmentation de la morbi-mortalité néonatale et un risque accru de développer des maladies cardiovasculaires et un diabète à l’âge adulte. Le RCIU humain est une pathologie complexe et multifactorielle avec une physiopathologie incomplètement élucidée dans près de 30 à 40% des cas. L’objectif de ce travail a été de progresser sur la physiopathologie du RCIU humain et de proposer des gènes candidats impliqués. J’ai analysé les perturbations d’expression génique dans des placentas issus de grossesses avec et sans RCIU, participé à la caractérisation d’un modèle animal de rate gestante soumise à un régime hypoprotidique, mis au point et validé un modèle cellulaire de cellules JEG-3 transformées par surexpression du gène PDX1 et/ou déplétées en acides aminés constituant un modèle important des effets du RCIU. J’ai étudié le rôle et l’implication de plusieurs gènes candidats : IMP3, les Cullines et PDX1. J’ai enfin participé à l’identification de nouveaux gènes soumis à empreinte dans le placenta. Ce travail de thèse a confirmé le rôle essentiel de l’apoptose et des régulations épigénétiques, plus particulièrement les modifications de profil de méthylation de l’ADN, dans le RCIU. L’analyse transcriptomique des placentas humains de grossesse avec RCIU a confirmé le rôle essentiel de 3 gènes : la leptine, IGFBP1 et RBP4. Enfin l’utilisation de notre modèle cellulaire a permis de confirmer l’implication de PDX1 dans le RCIU, PDX1 contrebalance les effets transcriptomiques de la déplétion en acides aminés sur les cellules JEG en culture. En extrapolant ces résultats à la pathologie humaine, on peut émettre l’hypothèse que l’induction placentaire de PDX1 en situation de RCIU permettrait de contrebalancer ou de limiter les effets délétères du RCIU pour la survie du fœtus. La leptine, IGFBP, RBP4 et PDX1 sont de bons candidats à la fois pour l’origine du RCIU et également pour la prédiction de l’évolution possible vers un syndrome métabolique chez les adultes anciens RCIU. Des études complémentaires sur le rôle et l’implication de ces 4 gènes dans la physiopathologie du RCIU ainsi que dans la programmation fœtale des pathologies cardiovasculaires, de l’obésité et de l’intolérance glucidique à l’âge adulte restent nécessaires. / Intra-uterine growth restriction (IUGR) is a frequent complication of pregnancy that leads to a baby with a birth weight and/or size below the 10th percentile for a given gestational age. IUGR represents a major public health problem associated with neonatal increased morbidity and mortality and an increased risk to develop cardiovascular pathologies and diabetes in adulthood. Human IUGR is a complex and multi-factorial pathology with an incompletely characterised physiopathology in up to 30 to 40% of cases. The goal of this work was to improve the knowledge on the physiopathology of IUGR and to propose implicated candidate genes.I analysed modulations of gene expression in placentas from pregnancies with and without IUGR, participated to the characterisation of an IUGR animal model of female rat fed with a hypoprotidic diet during gestation, set up and validated a cellular model of JEG-3 cells transformed by over-expression of the PDX1 gene and/or depletion of amino acids to provide a handy model of IUGR effects. I studied the role and implication of candidate genes: IMP3, the Cullin family and PDX1. Finally I participated to the identification of new imprinted genes in the human placenta. This thesis work confirmed the essential role of apoptosis and epigenetic regulations, in particular modifications of DNA methylation profiles, in IUGR. Transcriptomic analysis of human placentas from IUGR and control pregnancies confirmed the crucial role of 3 genes: leptin, IGFBP1 and RBP4. Finally, the use of our cellular model strengthened the role of PDX1 in IUGR, where it counterbalances the transcriptomic effects of amino acid depletion in cultured JEG-3 cells. By extrapolating these results to the human pathology, we can suggest the hypothesis that the placental induction of PDX1 in IUGR could counterbalance or limit the deleterious effects of IUGR on the foetus’ survival. Leptin, IGFBP1, RBP4 and PDX1 are good candidates to explain the origin of IUGR as well as to predict the potential evolution towards a metabolic syndrome in adults that suffered from IUGR. Complementary studies on the role and function of these 4 genes in IUGR physiopathology and also in foetal programming of cardiovascular pathologies, obesity and glucidic intolerance in adulthood remain necessary.

L’insuffisance placentaire par défaut de vascularisation est une pathologie fréquente de la grossesse, de diagnostic difficile, avec des complications potentiellement graves (retard de croissance intra utérin, prééclampsie). L’objectif de ce travail de Thèse a été de développer l’IRM fonctionnelle multiparamétrique pour l’exploration du placenta à 4.7 T chez la rate gestante. Matériel et méthode : L’IRM de diffusion (SE- EPI DWI) avec analyse IVIM et l’IRM dynamique avec injection de gadolinium (DCE) et haute résolution temporelle (< 1s) ont été développées puis étudiées sur un modèle murin contrôlé d’hypoperfusion placentaire par ligature du pédicule vasculaire utérin gauche au 17ème jour de gestation. Les paramètres obtenus sur les placentas hypoperfusés de la corne gauche ligaturée étaient comparés à ceux des placentas normaux de la corne droite. L’effet de l’hyperoxygénation maternelle était étudié en diffusion. Résultats : Ont été étudiés 73 placentas, dont 23 pathologiques (n= 10 rates) en diffusion et 53 placentas, dont 11 pathologiques (n=12 rates) en DCE. Les paramètres significativement diminués du côté hypoperfusé étaient le coefficient apparent de diffusion (ADC), la fraction de perfusion (f) en diffusion et le flux sanguin maternel (F) en DCE. Sous hyperoxygénation maternelle, l’ADC et le coefficient de diffusion (D) augmentaient et f diminuait. Les paramètres obtenus en diffusion et en DCE n’étaient pas nettement corrélés entre eux. Conclusion : Un outil d’IRM fonctionnelle placentaire multiparamétrique a été développé à 4.7 T chez la rate gestante. La DWI comme la DCE apparaissent complémentaires pour le diagnostic d’hypoperfusion placentaire. / Placental insufficiency caused by deficient vascularization is common during pregnancy, difficult to diagnose and can lead to severe materno-fetal complications (intrauterine growth restriction, preeclampsia). The aim of this work was to develop multi-parametric functional magnetic resonance imaging (MRI) to assess the placenta at 4.7 T on a murine model. Materials and methods : Diffusion-weighted imaging (SE-EPI-DWI) with the intravoxel incoherent motion (IVIM) analysis and dynamic contrast enhanced MRI (DCE) with a high-time resolution (<1 s) were developed and evaluated on a controlled rat model of reduced placental perfusion, achieved by ligation of the left uterine vascular pedicle on the 17th embryonic day. Parameters from the placentas in the left ligated horn were compared to those from the normal placentas in the non ligated horn. The effect of maternal hyperoxygenation on placental microvascularization was studied with DWI.Results: For DWI, 73 placentas were examined, 23 from the ligated side (n=10 rats). For DCE, 53 placentas were analysed, 11 from the ligated side (n=12 rats). In the uterine horn with reduced perfusion, the apparent diffusion coefficient (ADC), the perfusion fraction (f) obtained with DWI and the placental blood flow (F) obtained with DCE were significantly decreased. Under maternal hyperoxygenation, ADC and the diffusion coefficient (D) increased whereas f decreased. DWI and DCE parameters were not significantly correlated with each other. Conclusion: Multi-parametric MRI has been developed for murine placental analysis at 4.7T. DWI and DCE are complementary tools for the diagnosis of reduced placental perfusion.

A artroscopia e a artrocentese são procedimentos considerados minimamente invasivos utilizados para o tratamento das disfunções temporomandibulares (DTM) e são métodos considerados intermediários entre a terapia conservadora e a cirurgia aberta da articulação temporomandibular (ATM). Apresentam como vantagem, em relação a cirurgia aberta, a pequena morbidade e o breve tempo de recuperação necessária aos pacientes. Desde o início do desenvolvimento da artroscopia esteve presente a preocupação com a possibilidade de danos a estruturas internas da ATM, com essa finalidade vários estudos em animais foram desenvolvidos evidenciando que realmente podem ocorrer lesões iatrogênicas as estruturas internas desencadeando processo degenerativo na articulação. A avaliação do mesmo potencial de lesão para artrocentese não existe, assim o objetivo deste trabalho foi avaliar o trauma operatório da artrocentese comparativamente a artroscopia aos tecidos da ATM em suínos. Realizou-se experimento em vinte ATM de dez cabeças de suínos sendo seis artroscopias; seis artrocenteses e oito ATM utilizadas como controle. Após a realização dos procedimentos as ATM foram cuidadosamente dissecadas, examinadas e fotografadas com registro de alterações traumáticas ao disco articular e as fibrocartilagens da fossa articular e da cabeça da mandíbula. As imagens das estruturas foram analisadas por outro examinador que não tinha conhecimento prévio de qual procedimento havia sido realizado em cada ATM classificando as lesões de acordo com o número e localidade em: ausente (sem alteração visível); leve (descolamento de fibrocartilagem da fossa ou cabeça da mandíbula isoladas e únicas), moderado (perfurações do disco e mais de um descolamento de fibrocartilagem da fossa ou cabeça da mandíbula) e severo (lacerações do disco e lesões múltiplas em mais de uma estrutura). Os dados também foram classificados em ausente e presente para uma comparação direta. Foi realizada análise estatística dos dados. No grupo controle ocorreram danos em duas das oito ATM durante a dissecção, que apresentaram características distintas das lesões constatadas após os procedimentos, nas outras seis nenhuma alteração traumática pode ser evidenciada. No grupo submetido a artrocentese os danos foram ausentes, leves e moderados em 16.7% respectivamente e severos em 50% da amostra. No grupo submetido a artroscopia ocorreram danos moderados em 66.7%, severos em 16.7%, ausentes em 16.7% e não ocorreram danos leves. Em ambos os grupos foram evidenciadas a presença de lesões em 83.3% das amostras. Apesar de não haver diferença estatisticamente significativa entre os danos verificados, em uma análise direta, a severidade das lesões constatadas após artrocentese foi maior. Conclui-se que a artrocentese e a artroscopia não são isentas de morbidade aos tecidos articulares e independentemente de serem procedimentos considerados minimamente invasivos não se pode desprezar o potencial de danos as superfícies articulares. / Arthroscopy and arthrocentesis are considered minimally invasive procedures for the treatment of temporomandibular disorders (TMD) and are situated between conservative therapies and open surgery of the temporomandibular joint (TMJ). When compared to open surgery they present the advantages of having a brief post operatory recovery time for the patient and little morbidity. Since the beginning of the development of arthroscopy the possibility of damage to the inner structures of the TMJ was a concern, as a result a series of studies in animals were made and it became clear that iatrogenic damage can really happen and trigger degenerative alterations in the joint. Considering that there are no studies that investigate the potential of causing structural damage to the TMJ during arthrocentesis the objective of this study was to evaluate the operative trauma of arthroscopy and arthrocentesis to the tissues of the TMJ using swine heads. Twenty TMJ of ten swine heads were used for six arthroscopies; six arthrocentesis and eight that were used as a control group. After the procedures the TMJ were carefully dissected, examined and photographed. Traumatic alterations to the articular disk and to the fossa and head of the mandible fibrocartilage were recorded. The images of the structures were analyzed by other examiner that did not had previous knowledge of witch procedure each TMJ was subjected to. The lesions that were identified were classified according to the location and number as: absent (no visible alteration); light (one isolated scuffing of the fibrocartilage of the fossa or the head of the mandible); moderate (disk perforation or multiple scuffing of the fibrocartilage of the fossa or head of the mandible) and severe (disk laceration or multiple lesions in more than one structure). The obtained data was also classified as absent or present for a direct comparison. Statistical analyses of the obtained data were made. In the control group damage to two of the eight TMJ was perceived during dissection, the characteristics of those lesions were clearly different from those observed after the procedures, in the other six none traumatic damage could be noticed. In the arthrocentesis group the damages were absent, light and moderate in 16.7% respectively and were severe in 50% of the sample. In the arthroscopy group damage was moderate in 66.7%, severe in 16.7%, absent in 16.7 and no light damage occurred. In both groups damage was present in 83.3% of the sample. Even though the difference between the groups was not statistically significant, making a direct analysis of the data, the severity of the lesions found in the arthrocentesis group was higher. It was concluded that arthrocentesis and arthroscopy are not absent of morbidity to the TMJ tissues and regarded of being minimally invasive procedures the potential of damage to the structures of the TMJ should not be minimized.

No description available.

Les objectifs de ce travail étaient l’évaluation de stades précoces et tardifs de l’arthrose grâce à une étude histologique et biologique de l’arthrose sur un modèle de rupture de ligament croisé crânial chez le lapin (RLCC) et l’évaluation de l’effet de l’âge sur l’évolution de la maladie. L’étude biologique a été réalisée par le dosage sérique d’un marqueur de la dégradation du collagène de type II, le CTX-II, jusqu’à 20 semaines post-chirurgie. Chez les animaux adultes, les concentrations du CTX-II étaient influencées par la chirurgie et par le développement de la pathologie. Chez les jeunes animaux, les niveaux de CTX-II étaient plus élevés en début d’étude et diminuaient au cours du temps. Chez ce groupe d'animaux, les taux de CTX-II n’étaient pas modifiés par l’intervention chirurgicale. L’étude histologique a été réalisée avec une analyse histomorphologique du cartilage et des analyses histomorphométriques du cartilage et de l’os sous-chondral. L’évaluation histologique a permis d’observer des changements liés à l’arthrose chez tous les animaux opérés. Les altérations au niveau du cartilage étaient plus sévères chez les animaux adultes que chez les jeunes, ces derniers présentant une meilleure capacité de compensation à l’instabilité articulaire. Il a été démontré que l’analyse de la plaque osseuse sous-chondrale a permis de distinguer les animaux opérés des animaux non-opérés dans les 2 groupes d’âge, mais les surfaces articulaires affectées n’étaient pas toujours les mêmes. En conclusion, ce travail suggère l’intérêt du CTX-II dans l’évaluation de l’arthrose, mais aussi la pertinence d’effectuer plusieurs temps d’analyse pour mieux connaître l’évolution de la maladie. Les analyses histologiques ont permis de mettre en évidence des changements au niveau du cartilage et de l’os sous-chondral. Les différences observées entre les lapins adultes et les jeunes remettent en question l'utilisation d’animaux trop jeunes dans les études portant sur l’arthrose / The goals of this work were the evaluation of early and late stages of osteoarthritis through a histological and biological study of osteoarthritis using a rabbit model of the anterior cruciate ligament transaction (ACLT) and the evaluation of the effect of age on the evolution of the disease. Biological study was performed with longitudinal analysis of serum level of CTX-II, a marker a type II collagen degradation. In adult animals, serum concentration of CTX-II was influenced by the ACLT surgery and varied with time. In the young rabbits, the serum levels of CTX-II were more elevated at the beginning of study and decrease after. In this animal group, the rates of CTX-II were not influenced by surgical operation. Histological study was accomplished with both histomorphological analysis of the cartilage and with histomorphometric study of both cartilage and sub-chondral bone. Histological evaluation showed osteoarthritis changes in all operated animals. Changes of the cartilage appeared more severe in the adult group compared to the young rabbits, suggesting that these last have a better compensation capacity during articular instability. Bony changes allowed to differentiate operated animals from the unoperated, but the affected articular surfaces were not always the same. In conclusion, this study suggest the interest of the CTX-II biomarker in the evaluation of osteoarthritis, but also the pertinence to perform several time points of analysis to know better the disease evolution. The histological analysis allowed to put in an obvious place changes at the levels of the cartilage and of the sub-chondral bone. Difference noticed between the adult animals and the young rabbits offers a new look for the use of too young animals in osteoarthritis studies

La caractéristique neuropathologique majeure de la maladie de Parkinson (MP) est la perte progressive des neurones dopaminergiques (DA) de la substance noire (SN). Nous avons examiné si un dysfonctionnement aigu des EAATs pourrait contribuer au cercle vicieux entretenant la progression des pertes DA. Les effets du PDC, un inhibiteur substrat des EAATs, ont été analysés chez le rat. L'analyse cinétique (4-120 jours) des effets d'une seule injection intranigrale de PDC montre une perte progressive spécifique des neurones DA, avec une évolution unilatérale vers bilatérale et caudo-rostrale. Le processus dégénératif associe déplétion en glutathion et augmentation de l'activité de la γ-glutamyltranspeptidase, stress oxydatif, processus excitotoxiques, autophagie et réactivités gliales. L'antioxydant N-acétylcystéine et les antagonistes des récepteurs NMDA ifenprodil et mémantine exercent un effet neuroprotecteur. Des effets compensatoires transitoires au niveau de marqueurs de la fonction DA dans la SN et le striatum accompagnent la perte cellulaire et des dystrophies axonales. Des troubles moteurs apparaissent de façon tardive lorsque la perte neuronale ipsilatérale avoisine les 50%. Ces résultats montrent un lien fonctionnel entre dysfonctionnement des EAATs et plusieurs mécanismes pathogéniques ainsi que des caractéristiques neuropathologiques majeures de la MP, et fournissent le premier modèle progressif de la maladie induit de façon aiguë. / Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra (SN) dopaminergic neurons. Central players in PD pathogenesis, including mitochondrial dysfunction and oxidative stress, might affect the function of excitatory amino acid transporters (EAATs). Here, we investigated whether acute EAATs dysfunction might in turn contribute to the vicious cycles sustaining the progression of dopamine neuron degeneration. PDC application on nigral slices triggered sustained glutamate-mediated excitation selectively in dopamine neurons. In vivo time-course study (4-120 days) revealed that a single intranigral PDC injection triggers progressive degeneration of exclusively dopamine neurons with unilateral to bilateral and caudorostral evolution. This degenerative process associates GSH depletion and specific increase in γ-glutamyltranspeptidase activity, oxidative stress, excitotoxicity, autophagy and glial reaction. The anti-oxidant N-acetylcysteine and the NMDA receptor antagonists ifenprodil and memantine provided significant neuroprotection Transient compensatory changes in dopamine function markers in SN and striatum accompanied cell loss and axonal dystrophy. Motor abnormalities (hypolocomotion and forelimb akinesia) showed late onset, when ipsilateral neuronal loss exceeded 50%. These findings outline a functional link between EAATs dysfunction and several PD pathogenic mechanisms and pathological hallmarks, and provide the first acutely-triggered rodent model of progressive parkinsonism.

<p>The aim of this thesis was to test the capability of Artificial Neural Networks (ANN) to estimate respiratory mechanics during mechanical ventilation (MV). ANNs are universal function approximators and can extract information from complex signals. </p><p>We evaluated, in an animal model of acute lung injury, whether ANN can assess respiratory system resistance (R_RS) and compliance (C_RS) using the tracings of pressure at airways opening (P_AW), inspiratory flow (V’) and tidal volume, during an end-inspiratory hold maneuver (EIHM). We concluded that ANN can estimate C_RS and R_RS during an EIHM. We also concluded that the use of tracings obtained by non-biological models in the learning process has the potential of substituting biological recordings.</p><p>We investigated whether ANN can extract C_RS using tracings of P_AW and V’, without any intervention of an inspiratory hold maneuver during continuous MV. We concluded that C_RS can be estimated by ANN during volume control MV, without the need to stop inspiratory flow.</p><p>We tested whether ANN, fed by inspiratory P_AWand V’, are able to measure static total positive end-expiratory pressure (PEEP_tot,stat) during ongoing MV. In an animal model we generated dynamic pulmonary hyperinflation by shortening expiratory time. Different levels of external PEEP (PEEP_APP) were applied. Results showed that ANN can estimate PEEP_tot,stat reliably, without any influence from the level of PEEP_APP.</p><p>We finally compared the robustness of ANN and multi-linear fitting (MLF) methods in extracting C_RS when facing signals corrupted by perturbations. We observed that during the application of random noise, ANN and MLF maintain a stable performance, although in these conditions MLF may show better results. ANN have more stable performance and yield a more robust estimation of C_RS than MLF in conditions of transient sensor disconnection.</p><p>We consider ANN to be an interesting technique for the assessment of respiratory mechanics.</p>

The aim of this thesis was to test the capability of Artificial Neural Networks (ANN) to estimate respiratory mechanics during mechanical ventilation (MV). ANNs are universal function approximators and can extract information from complex signals. We evaluated, in an animal model of acute lung injury, whether ANN can assess respiratory system resistance (RRS) and compliance (CRS) using the tracings of pressure at airways opening (PAW), inspiratory flow (V’) and tidal volume, during an end-inspiratory hold maneuver (EIHM). We concluded that ANN can estimate CRS and RRS during an EIHM. We also concluded that the use of tracings obtained by non-biological models in the learning process has the potential of substituting biological recordings. We investigated whether ANN can extract CRS using tracings of PAW and V’, without any intervention of an inspiratory hold maneuver during continuous MV. We concluded that CRS can be estimated by ANN during volume control MV, without the need to stop inspiratory flow. We tested whether ANN, fed by inspiratory PAW and V’, are able to measure static total positive end-expiratory pressure (PEEPtot,stat) during ongoing MV. In an animal model we generated dynamic pulmonary hyperinflation by shortening expiratory time. Different levels of external PEEP (PEEPAPP) were applied. Results showed that ANN can estimate PEEPtot,stat reliably, without any influence from the level of PEEPAPP. We finally compared the robustness of ANN and multi-linear fitting (MLF) methods in extracting CRS when facing signals corrupted by perturbations. We observed that during the application of random noise, ANN and MLF maintain a stable performance, although in these conditions MLF may show better results. ANN have more stable performance and yield a more robust estimation of CRS than MLF in conditions of transient sensor disconnection. We consider ANN to be an interesting technique for the assessment of respiratory mechanics.