Li Huan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 285-306). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

L’hypertension artérielle pulmonaire (HTAP) est une maladie rare caractérisée par un remodelage des artères pré-capillaires pulmonaires lié à une dysfonction des cellules endothéliales (CE) conduisant à une prolifération cellulaire vasculaire. Cette prolifération conduit à une obstruction progressive du lit artériel et à l’augmentation des résistances vasculaires. L’hypertension pulmonaire (HTP) qui en résulte provoque une hypertrophie du ventricule droit aboutissant à la défaillance cardiaque et à la mort du patient. Actuellement le seul recours possible est la transplantation pulmonaire. Les mécanismes responsables de ce remodelage vasculaire sont encore peu connus. Les premiers travaux présentés mettent en évidence in situ un nouveau mécanisme impliqué dans ce remodelage. Au cours de ce processus, appelé transition endothélio-mésenchymateuse (EndoMT), les CE se désolidarisent de l’endothélium vasculaire et envahissent l’espace sous endothélial. Ce mécanisme s’accompagne d’une perte progressive du phénotype endothélial et du gain d’un phénotype mésenchymateux invasif et proliférant. L’EndoMT est impliquée dans la formation des lésions intimale et plexiforme. L’inhibition de l’EndoMT a donné des résultats prometteurs dans des modèles in vivo et in vitro d’HTAP. Cette découverte ouvre une nouvelle voie pour le traitement de la maladie. Dans un second projet nous avons confirmé le lien suspecté entre les chimiothérapies et la maladie veino-occlusive pulmonaire (MVOP), une forme d’HTP touchant les veines et veinules pulmonaires. L’étude des cas rapportés de MVOP consécutive à une chimiothérapie indiquent une forte incidence des agents alkylants, notamment du cyclophosphamide (CP), sur le développement de la MVOP. L’exposition au CP a provoqué une HTP associée à des lésions post-capillaires chez 3 espèces animales (souris, rat et lapin) confirmant ce lien. Nous espérons que nos travaux aboutiront à une plus grande vigilance concernant cette complication rare et sévère de l’exposition aux agents alkylants. De plus, nos travaux in vivo ont permis de mettre au point le tout premier modèle expérimental de MVOP. Au cours du dernier projet présenté, nous avons démontré que le nebivolol, un β-bloquant (β1 antagoniste β2 et β3 agoniste ayant un effet vasodilatateur) de 3ème génération, permettait d’améliorer les paramètres hémodynamiques et morphologiques, ainsi que la dysfonction endothéliale, liés à l’HTAP dans les modèles in vivo et in vitro. Ces travaux suggèrent la nécessité de réévaluer les recommandations actuelles, basées sur l’étude de β-bloquants non spécifiques de 1ère génération, qui proscrivent leur utilisation dans l’HTAP. En revisitant plusieurs aspects du remodelage vasculaire, ma thèse contribue ainsi à l’innovation thérapeutique dans l’HTAP. / Pulmonary arterial hypertension (PAH) is a rare disease characterized by a severe modeling of the precapillary pulmonary arteries related to an endothelial cells (EC) dysfunction leading to vascular cell proliferation. This proliferation leads to a progressive obstruction of the distal pulmonary arterial bed and increases pulmonary vascular resistance. The resulting pulmonary hypertension (PH) leads to a progressive right ventricular hypertrophy, and subsequent right heart failure and death unless the patient receives a lung transplantation. The primary mechanisms that trigger the vascular remodeling remain poorly understood. In the first presented study, we discovered in situ a new pathological process involved in vascular remodeling in PAH. During this process called endothelial-to-mesenchymal transition (EndoMT), the EC lose their cell-junctions to leave the endothelium and invade the subendothelial space. This phenomenon involves the progressive loss of the endothelial phenotype and the gain of a pro-invasive and pro-proliferative mesenchymal phenotype. This process is implicated in the pathogenesis of intimal and plexiform lesions. The inhibition of EndoMT gave promising results in experimental in vivo and in vitro models of PAH. This finding may have therapeutic implications for PAH. During a second project presented, we confirmed the suspected potential link between chemotherapies and the pulmonary veino-occlusive disease (PVOD). PVOD is a PH with vein and venular lesions. The systematic review of cases of chemotherapy induced PVOD cases suggests that alkylating agents, and cyclophosphamide (CP) in particular, represents a risk factor for the development of PVOD. In experimental models, CP exposure induced PH in three different animal models (mouse, rat, and rabbit). We hope that our findings will allow achieving greater vigilance against this rare and severe complication after alkylating agents exposure. Moreover our in vivo results lead to the development of the 1st experimental model of PVOD. In the last part, we demonstrated that nebivolol, a 3rd generation β-blocker (β1 antagonist, β2 & β3 agonist with vasodilator effect), improved PAH in in vitro and in vivo models. The actual guidelines, based on results obtained with non-specific 1st generation β-blockers, advice against the use of β-blockers in PAH. Our results suggest that the recommendation against β-blockers might be reevaluated taking into consideration their generation and specificity. By revisiting many aspects of vascular remodeling, my thesis contributes to therapeutic innovation in PAH.

O tromboembolismo pulmonar causado por obstrução de ramos arteriais pulmonares por trombos originados de outras partes do corpo apresenta elevada incidência. Em 5% dos casos ocorre a cronificação do processo e manutenção ou agravamento da hipertensão pulmonar Duas hipóteses explicam a cronificação nos casos de embolia pulmonar: 1. manutenção do fator oclusivo como fundamental para o desenvolvimento da resposta vascular pulmonar caracterizada por hipertrofia da camada média; 2. hipertensão pulmonar secundária a uma arteriopatia inicial, nos pacientes que evoluíram de maneira desfavorável. Este estudo tem por objetivo avaliar sob critérios histopatológicos qualitativos e quantitativos o comportamento do leito arterial pulmonar distal (pré e intra-acinar), comparativamente em pulmões de pacientes sem tromboembolismo prévio e de pacientes portadores de tromboembolismo agudo e crônico. Para tanto, estudou-se a resposta vascular através de estudo histológico de 31 casos de embolia (aguda e crônica), comparando-os com 24 pacientes do grupo controle (Infarto agudo do miocárdio) (análise de autópsias). As lâminas de tecido pulmonar foram preparadas e coradas em hematoxilina-eosina e Miller. A análise realizada foi dividida em qualitativa (vasoconstrição e proliferação intimal concêntrica) e quantitativa (hipertrofia da camada média). Foram observadas alterações histopatológicas do leito arterial pulmonar distal nos pacientes portadores de quadro tromboembólico agudo e crônico, em relação aos pacientes sem tromboembolismo prévio. Estas alterações, entre os grupos agudo e crônico, foram: diferentes quanto aos critérios qualitativos, caracterizadas por maior vasoconstrição nos quadros tromboembólicos agudos e maior proliferação intimal concêntrica nos crônicos; semelhantes quanto aos critérios quantitativos, caracterizadas por hipertrofia da camada média. A isquemia decorrente da obstrução parece exercer um importante papel nestas alterações, o que, entretanto, necessita de comprovação futura / The pulmonary embolism, caused by pulmonary artery branches obstruction from thrombus originated on other parts of the body, has a high incidence. However, just 5% of the cases develop the cronification and pulmonary hypertension. Two hypotheses can explain the cronification of tromboembolic pulmonary events: 1. maintenance of occlusive factor with pulmonary vascular response characterized by medial hypertrophy; 2. pulmonary hypertensive response as an initial arteriopathy in patients with bad evolution. This study aims to evaluate histologic aspects of pulmonary arterial bed (quantitative and qualitative), and to compare the results from embolic cases with non embolic cases. The study evaluated 55 patients (31 with pulmonary embolic disease and 24 in the control group myocardium infarction). From the selected cases, the blades with pulmonary tissue were colored by two techniques (haematoxilin-eosin and Miller). The analysis encompassed qualitative (vasoconstriction and intimal proliferation) and quantitative (mensuration of medial thickness) observations. It has been observed histologic changes between the two groups with pulmonary embolic disease (chronic or acute), and the control group. The changes between the embolic groups were: 1. higher vasoconstriction in the acute group, 2. more intimal proliferation in the chronic group, 3. no difference in the quantitative response (medial thickness). The ischemic response to obstruction can perform an important role in these changes, but further studies are necessary. There was a similar response in chronic and acute cases

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 101-113).

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Michigan, 1992.

Thesis--University of Copenhagen. / Resumé in Danish. Bibliography: p. [171]-184.

Thesis (M.S.)--University of Michigan, 1992.

Thesis--University of Copenhagen. / Resumé in Danish. Bibliography: p. [171]-184.

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No. of bitstreams: 1 pezarini_io_me_mar.pdf: 1107147 bytes, checksum: 0311407025ded97a7e4daafb560d7a92 (MD5) Previous issue date: 2017-04-24 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Objetivos: descrever o desempenho ortográfico de crianças quanto ao registro de fonemas oclusivos do PB; verificar se a ausência do acento fonológico influencia a ocorrência de possíveis erros na ortografia desses fonemas; classificar o padrão de distribuição desses possíveis erros; classificar a distribuição dos possíveis erros em traços de ponto ou vozeamento; e verificar qual a direção dos traços envolvidos nesses possíveis erros. Métodos: foram analisados 21.049 registros ortográficos de fonemas oclusivos extraídos de 1.064 produções textuais de 76 crianças da 1ª série do Ensino Fundamental em duas escolas públicas do interior paulista. Relativos ao primeiro objetivo: os dados foram divididos em acertos e erros; relativos ao segundo objetivo, os erros foram classificados conforme ocorressem em sílabas acentuadas – tônicas e monossílabos tônicos – e não-acentuadas – pretônicas, postônicas e monossílabos átonos; relativos ao terceiro objetivo, os erros foram classificados, em um primeiro momento, em substituições e omissões, as substituições, por sua vez, foram subclassificados em ortográficas não fonológicas, ortográficas fonológicas e híbridas. As ortográficas fonológicas foram subdivididas, ainda, conforme envolvessem fonemas dentro e fora da classe das oclusivas; relativos ao quarto objetivo, as substituições fonológicas dentro da classe foram classificadas conforme envolvessem traços de ponto ou de vozeamento; e, finalmente, relativo ao quinto objetivo, os traços foram analisados de acordo com a direção da substituição envolvendo tanto ponto quanto vozeamento. Resultados: observou-se, quanto ao primeiro objetivo, maior número de acertos (20.318) quando comparado ao número de erros (729), resultado que sugere significativa estabilidade das crianças (já no primeiro ano de alfabetização) no registro de grafemas que correspondem a fonemas oclusivos; quanto ao segundo objetivo, maior concentração dos erros no interior das sílabas não-acentuadas (440) quando comparado àqueles em sílabas acentuadas (289), que se dá pelo fato de as sílabas não-acentuadas apresentarem características acústicas menos favoráveis à percepção auditiva do escrevente; quanto ao terceiro objetivo, observou-se distribuição dos erros em substituições (523) e omissões (206); nas substituições foram observados erros ortográficos fonológicos (298), híbridos (132) e ortográficos não-fonológicos (93). Extraídas as omissões, que se explicam por variação linguística do tipo *correno, para “correndo”, grande parte das substituições justifica-se pelo fenômeno da transparência ortográfica; ainda quanto ao terceiro objetivo, em relação à distribuição dos erros ortográficos fonológicos, maior ocorrência deles envolvendo fonemas da própria classe das oclusivas (258) quando comparado aos fonemas fora dessa classe (40), que se justifica pelo fato de as crianças já se mostrarem capazes de perceber características fonético-fonológicos que tornam possível a distinção entre fonemas de diferentes classes; quanto ao quarto objetivo, observou-se maior número de erros fonológicos DC que envolveram vozeamento (222) quando comparado aos erros envolvendo ponto (47), resultado que sugere que a aquisição das oclusivas na escrita infantil segue, de certa forma, a trajetória de sua aquisição na fala; por fim, quanto ao quinto objetivo, observou-se, em relação aos erros de ponto, que a maioria envolvia o traço coronal, resultado que vai contramão da literatura, uma vez que se esperava maior instabilidade no traço dorsal; por fim, ainda quanto ao quinto objetivo, em relação aos erros de vozeamento, apesar da diferença numérica, não houve diferença estatística entre as direções das substituições. Conclusão: A análise do desempenho ortográfico global permite entender, quanto à especificidade dos erros, que, além de características fonético-fonológicas relacionadas à classe das oclusivas, a escrita inicial sofre influência de outros fatores, como a transparência/opacidade da escrita desses fonemas e a variação linguística. / Objectives: describe the orthographic performance of children regarding the recording of Brazilian Portuguese occlusive phonemes; verify if the absence of the phonological accent influences the occurrence of possible errors in the orthography of these phonemes; classify the distribution pattern of these possible errors; classify the distribution of possible errors in traits of point or voicing; and check the direction of the traits involved in these possible errors. Methods: 21,049 orthographic records of occlusive phonemes extracted from 1,064 textual productions of 76 children from the first grade of Elementary School were analyzed in two public schools in the interior of São Paulo State. Regarding the first objective: the data were divided into hits and errors; for the second objective, the errors were classified as accentuated syllables - tonics and tonic monosyllables - and unstressed – pre tonic, post tonic and unstressed monosyllables; for the third objective, the errors were initially classified in substitutions and omissions; the substitutions were sub-classified in non-phonological orthographic, phonological orthographic and hybrid. The phonological orthographic was further subdivided as they involved phonemes within and outside the class of occlusives; concerning the fourth objective, phonological substitutions within the class were classified as involving traits of point or voicing; and finally, regarding the fifth objective, the traits were analyzed according to the direction of the substitution involving both point and voicing. Results: a higher number of correct answers (20,318) was observed when compared to the number of errors (729), which suggests a significant stability of children (earlier in the first year of literacy) in the registry of graphemes corresponding to occlusive phonemes; as for the second objective, there was a greater concentration of errors within the unaccented syllables (440) when compared to those in accented syllables (289), which is due to the fact that unaccented syllables present acoustic characteristics less favorable to the auditory perception of the scribe; for the third objective, we observed a distribution of errors in substitutions (523) and omissions (206); in the substitutions, orthographic phonological (298), hybrids (132) and non-phonological orthographic (93) errors were observed. Extracting the omissions which are explained by linguistic variation like “correno” for "correndo" , most of the substitutions are justified by the phenomenon of orthographic transparency; still on the third objective, regarding the distribution of phonological orthographic errors, there was a higher occurrence involving the occlusive phonemes (258) when compared to phonemes outside this class (40), which is justified by the fact that the children already show up able to perceive phonetic-phonological characteristics that make possible the distinction between phonemes of different classes; as to the fourth objective, a greater number of phonological errors within the class involving voicing (222) was observed when compared to errors involving point (47), a result that suggests that the acquisition of occlusives in children's writing follows, to a certain extent, the trajectory of their acquisition in speech; finally, regarding the fifth objective, in relation to the point errors, it was observed that the majority involved the coronal trait, a result that goes against the literature, since greater instability was expected in the dorsal trait; still regarding the fifth objective, in relation to voicing errors, there was no statistical difference between the directions of the substitutions despite the numerical difference. Conclusion: The analysis of the global orthographic performance, regarding the specificity of the errors, allows us to understand that in addition to phonetic-phonological characteristics related to the class of occlusives, the initial writing is influenced by other factors, such as the transparency/opacity of the writing of these phonemes and the linguistic variation. / FAPESP: 2015/03208-7