Após exodontia e instalação de implantes imediatos o sítio edêntulo sofre uma substancial remodelação óssea. O objetivo do presente estudo foi avaliar a remodelação dos tecidos moles e da tábua óssea vestibular em alvéolos pósexodontia e em implantes imediatos em cães com um biotipo periodontal fino, com a associação de um material de enxerto. Oito cães tiveram a espessura da gengiva de um lado da mandíbula reduzida, os pré-molares mandibulares extraídos em cirurgia sem retalho e 4 implantes foram instalados de cada lado à 1,5 mm da tábua óssea vestibular. Os demais alvéolos foram utilizados para o estudo da dinâmica de cicatrização alveolar. Os sítios foram aleatoreamente alocados em: GT (grupo teste) = gengiva fina; GT + ME (GT com material de enxerto); GC (grupo controle) = gengiva normal; e GC + ME (GC com material de enxerto). Espessura da tábua óssea vestibular (ETOV), espessura de gengiva queratinizada (EGQ), largura alveolar (LA), altura de retração gengival (RG) e profundidade de sondagem (PS) foram avaliados clinicamente. Após 12 semanas os cães foram sacrificados e as amostras processadas para as análises de micro-tomografia computadorizada, histologia, histomorfometria, fluorescência e imunohistoquímica. Uma ETOV fina foi observada em todos os cães. Os procedimentos pré-cirúrgicos reduziram a EGQ nos grupos teste, com alterações mínimas na LA. Não houve diferenças estatísticas significantes entre os grupos para os parâmetros clínicos. Em todos os grupos o alvéolo ou o gap vestibular foram preenchidos por osso neoformado e uma leve reabsorção da tábua óssea vestibular foi observada, sem diferença estatística entre os grupos. Nos alvéolos pós-exodontia uma taxa de mineralização numericamente maior foi observada nos grupos que receberam material de enxerto em 12 semanas. A espessura do osso vestibular foi um fator fundamental na reabsorção da tábua óssea vestibular, mesmo com cirurgia sem retalho. Diminuir a gengiva para uma espessura crítica ou a adição de um biomaterial, em um biotipo fino pré-existente, não influenciou os resultados. / After tooth extraction and immediate implant placement the edentulous site undergo marked bone remodeling. The aim of the present study was to evaluate soft tissues and buccal bone remodeling in fresh extraction sockets and immediate implants in dogs with a thin periodontal biotype, with the association of a graft material. The gingiva of 8 dogs was thinned at one side of the mandible, mandibular premolars were extracted without flaps, and 4 implants were installed on each side at 1.5 mm from the buccal bone. The remaining sockets were used for the study of the alveolar healing dynamic. The sites were randomly assigned into: TG (test group) = thin gingiva; TG + GM (TG with grafting material); CG (control group) = normal gingiva; and CG + GM (CG with grafting material). Buccal bone thickness (BBT), thickness of keratinized tissue (TKT), alveolar width (AW), gingival recession height (GR) and probing depth (PD) were clinically evaluated. After 12 weeks the dogs were sacrificed and the samples were processed for microtomographic, histological, histomorphometric, fluorescence and immunohistochemistric analysis. A thin BBT was observed in all the dogs. The pre-surgical procedures reduced gingival thickness in the test groups, with minimal changes of the AW. There were no statistically significant differences among the groups for the clinical parameters. In all the groups the socket or the buccal gap was filled with newly formed bone and a slight buccal bone loss was observed, with no statistical difference among the groups. In the extraction sockets a numerically higher mineralization rate was observed for the grafted groups at 12 weeks. The thickness of the buccal bone was a fundamental factor on buccal bone plate resorption, even with a flapless approach. To reduce the gingival thickness or the addition of a biomaterial, in a thin biotype, did not influence the results.

A hipertensão arterial sistêmica (HAS) apresenta alterações vasculares significativas como o remodelamento vascular e o aumento da atividade das metaloproteinases de matriz (MMPs), principalmente a MMP-2, responsáveis pela proteólise da matriz extracelular. No remodelamento vascular, ocorre uma mudança no fenótipo das células musculares lisas vasculares (CMLV) de contrátil para sintético, com redução de proteínas da maquinaria contrátil como a calponina-1. Essa alteração fenotípica confere às CMLV a capacidade de migração e proliferação, contribuindo ao remodelamento arterial durante a HAS. A calponina-1 foi degradada pela MMP-2 em aorta de ratos endotoxêmicos e este efeito contribuiu para a menor contração vascular da sepse. Sua redução foi associada ao aumento de atividade de MMP-2 e proliferação de CMLV em aortas de ratos hipertensos. A hipótese do presente trabalho é de que a MMP-2 contribui para as alterações morfofuncionais induzidas pela hipertensão em artérias de condutância e de resistência pela regulação de calponina-1. Para testar tal hipótese, ratos Wistar foram submetidos ao modelo de hipertensão dois rins-um clipe (2R-1C) ou apenas laparatomia e tratados por via oral com doxiciclina (inibidor da atividade de MMPs na dose de 30 mg/kg/dia) ou água durante sete dias. A pressão arterial sistólica (PAS) foi aferida diariamente por pletismografia de cauda. Aorta e artérias mesentéricas foram removidas para a execução de zimografia in situ e em gel, imunofluorescência para calponina-1, imunohistoquímica para Ki-67 e análise morfológica. Artérias mesentéricas e aortas também foram utilizadas para curva concentração-efeito com fenilefrina. Observou-se que a PAS aumentou em ratos 2R-1C e o tratamento com doxiciclina não a reduziu. A análise morfológica da aorta mostrou que a razão média por lúmen e a área de secção transversal aumentaram nos animais hipertensos em relação aos grupos Sham. Não houve alteração nestes parâmetros nas artérias mesentéricas. Houve aumento de proliferação das CMLV em aortas de ratos 2R-1C e a doxiciclina reverteu essa alteração. Nas artérias mesentéricas não foi observada alteração na proliferação celular. A atividade gelatinolítica de MMP-2 e sua expressão estão aumentadas nos dois leitos arteriais de ratos 2R-1C e o tratamento com doxiciclina as reduziu. A expressão de calponina-1 está reduzida nas aortas e aumentada nas artérias de resistência de animais 2R-1C e o tratamento reverteu estes efeitos. A contração à fenilefrina das aortas e artérias mesentéricas está aumentada nos animais 2R-1C e o tratamento a reduziu. Os resultados indicam que a MMP-2 tem ações diferentes na regulação de calponina-1 nos dois leitos arteriais. Nas artérias de condutância, a redução de calponina-1 pela MMP-2 pode ser o gatilho para a mudança de fenótipo das células musculares lisas vasculares, o que conduz ao remodelamento hipertrófico. Nas artérias de resistência, a MMP-2 pode contribuir para a função contrátil do leito arterial aumentando os níveis de calponina-1. / Hypertension is a global public health problem that lead to significant vascular changes. Among them, the chronic remodeling and increased activity of matrix metalloproteinase (MMP)-2, which is responsible for extracellular matrix proteolysis, are the main mediators of the vascular maladaptation. During vascular remodeling, there is a change in the phenotype of vascular smooth muscle cells (VSMC) of contractile to synthetic form, with a reduction of contractile proteins such as calponin-1. This phenotype switch provides to the VSMC the ability of migration and proliferation, thus contributing to hypertension-induced arterial remodeling. Calponin-1 was degraded by MMP-2 in rat endotoxemic aortas and this effect contributed to the vascular hypocontractility. In addition, its reduction was associated with increased activity of MMP-2 and proliferation of VSMC in aortas of rats submitted to renovascular hypertension. Therefore, the hypothesis of this study is that MMP-2 contributes to hypertension-induced morphological and functional changes in conductance and resistance arteries by regulating calponin-1. To test such hypothesis, male Wistar rats were submitted to the two kidney- one clipe (2K-1C) hypertension model and were treated with doxycycline (inhibitor of MMPs activity at 30 mg/kg/day) or water for one week. Systolic blood pressure (SBP) was daily checked by tail-cuff plethysmography. Aortas and mesenteric arteries were removed to perform in situ and gel zymography, immunofluorescence for calponin-1, immunohistochemistry for Ki-67 and morphological analysis. Mesenteric arteries and aortas were also used for concentration-effect curve for phenylephrine. It was observed that SBP has increased in 2K-1C rats and doxycycline did not reduce it. Morphological analysis of the aorta showed that both media per lumen ratio and arterial cross sectional area increased in hypertensive animals compared to Sham. There was no changes in this two parameters in mesenteric arteries. Furthermore, there was an increase of VSMC proliferation in rat aortas and doxycycline was able to revert this alteration. In the mesenteric arteries, no changes were observed in VSMC proliferation. Gelatinolytic activity of MMP-2 and its expression were increased in both arterial beds of 2K-1C rats and treatment with doxycycline reduced it. Calponin-1 expression was reduced in aortas and increased in resistance arteries from 2K-1C animals and the treatment was able to improve both scenarios. The contractile function of aortas and mesenteric arteries was increased in 2K-1C rats and treatment has reduced it. So, what follows is that MMP-2 has different actions in the regulation of calponin-1 in both arterial beds. In conductance arteries, reduction of calponin-1 by MMP-2 may trigger the VSMC phenotype switch, which leads to the hypertrophic remodeling. In resistance arteries, MMP-2 contributes to the hypercontractility of the arterial bed by increasing calponin-1. This effect may be particularly related to extracellular actions of MMP-2.

L’hypertension artérielle pulmonaire (HTAP) correspond à un groupe de maladies qui se caractérise par une obstruction vasculaire suite à une vasoconstriction excessive, une prolifération cellulaire et la création de thromboses in situ, conduisant à une augmentation progressive des résistances vasculaires pulmonaires puis au décès. De nombreuses avancées dans la prise en charge de l’HTAP ont été réalisées ces dernières années avec la mise à disposition de médicaments principalement vasodilatateurs. Cependant, aucun de ces médicaments n’est curatif de la maladie témoignant de la nécessité à obtenir de nouvelles thérapeutiques. Des molécules axant leur effet sur la lutte contre la prolifération cellulaire liée à l’activation des récepteurs à tyrosine-kinases (RTK) ou le stress oxydant (SO) paraissent aujourd’hui comme de potentielles innovations thérapeutiques dans l’HTAP. Cependant, à l’heure actuelle, les données sur le SO dans l’HTAP sont trop peu détaillées pour cibler correctement cette voie physiopathologique. De même, les inhibiteurs de tyrosine-kinases ont montré un bénéfice dans la prise en charge de l’HTAP mais associé à des effets indésirables graves tels qu’une toxicité cardiaque. Dans ce travail, nous avons approfondi le mécanisme d’action du SO dans la physiopathologie de l’HTAP et complété l’identification des RTK dans le remodelage vasculaire pulmonaire afin de permettre la mise au point de thérapeutiques efficaces avec un rapport bénéfice risque favorable pour le patient. / Pulmonary arterial hypertension (PAH) corresponds to a group of diseases characterized by a vascular obstruction due to vasoconstriction, cellular proliferation and in situ thrombosis, leading to a progressive increase in pulmonary vascular resistances. New knowledge in the PAH management were performed in the last few years, specifically for vasodilators. However, none of those treatments cure the disease and new drugs are still needed. Molecules targeting cellular proliferation induced by tyrosine kinases receptors (TKR) activation or oxidative stress (OS) seem to be potential therapeutic innovations. However, knowledge on OS in PAH is not enough accomplished in PAH to target accurately this pathophysiologic pathway. Similarly, tyrosine kinase inhibitors have shown efficacy in PAH management but associated with severe adverse events as cardiac toxicity. In this study, mechanism of action of OS in pathophysiology of PAH was detailed and identification of TKR involved in vascular remodeling was completed in order to find efficient therapeutics with a favorable risk benefit ratio for PAH patient.

La broncho-pneumopathie chronique obstructive (BPCO) est une maladie respiratoire inflammatoire chronique caractérisée par une limitation progressive et irréversible des débits aériens causée par l’inhalation à long terme de particules nocives telles que le tabac. La BPCO présente un remodelage majeur et hétérogène des voies aériennes comportant une grande variabilité inter-individuelle. La réponse inflammatoire et immunitaire au cours de la BPCO est caractérisée par une infiltration du tissu respiratoire par les polynucléaires neutrophiles (PN), les macrophages et par les cellules T. La dégradation des fibres élastiques du poumon en peptides solubles d’élastine (PE) par le biais de la sécrétion de protéases par les cellules de l’immunité innée est une caractéristique constante de la BPCO. Ces PE participent à la physiopathologie de la BPCO comme cela a été démontré dans différents modèles murins de la maladie emphysémateuse. L’orientation de la réponse des cellules T helper (Th) et des cellules T cytotoxiques (Tc) au cours de la BPCO n’est pas élucidée et reste controversée. L’objectif principal de ce travail de thèse a été de définir l’orientation de la réponse Th et Tc ainsi que le rôle des PE dans le remodelage associé à la BPCO. Pour cela, nous avons étudié la signature cytokinique Th-1/Tc-1 (IFN-), Th-2/Tc-2 (IL-4), Th-17/Tc-17 (IL-17) spécifique du remodelage bronchique associé à la BPCO au niveau cellulaire, mais également transcriptionnel et fonctionnel. L’association entre les résultats expérimentaux obtenus et le phénotype des patients inclus a été analysé de manière à déterminer le rôle de ces mécanismes dans l’expression clinique de cette pathologie respiratoire chronique. Les résultats obtenus ont mis en évidence une diminution de l’expression de l’IL-4 (Th2) chez les patients BPCO par rapport aux sujets contrôles ainsi qu’une potentialisation de l’expression de cette cytokine en présence des PE. / Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory pathology characterized by a progressive and irreversible limitation of airflow caused by the long-term inhalation of harmful particles such as tobacco. COPD presents a major and heterogeneous remodeling of the airways with important inter-individual variability. The inflammatory and immune response during COPD is characterized by infiltration of pulmonary tissue by neutrophils (PN), macrophages, and T cells. The degradation of lung elastic fibers into soluble elastin peptides (EP) is caused by the secretion of proteases by innate immunity cells and it is a consistent feature of COPD. These EP participate in the pathophysiology of COPD as demonstrated in different murine models of the emphysematous disease. The T helper (Th) and the T cytotoxic (Tc) orientation during COPD is unclear andremains controversial. The main objective of this work was to define the Th and Tc responses as well as the role ofEP in airways remodeling associated to COPD. For this purpose, we studied the cytokine signature Th-1/Tc-1 (IFN- ), Th-2/Tc-2 (IL-4), Th-17/Tc-17 (IL-17) specific of the airway remodeling associated to COPD both at the cellular, transcriptional and functional level. Association between the experimental results obtained and the phenotype of the patients included in the study was analyzed in order to determine the role of these mechanisms in the clinical expression of this chronic respiratory pathology. The results obtained showed a decrease in the expression of IL-4 (Th2) in COPD patients compared to control subjects as well as a potentiation of this cytokine expression in the presence of EP.

Thesis. 1977. M.Arch.--Massachusetts Institute of Technology. Dept. of Architecture. / MICROFICHE COPY VAILABLE IN ARCHIVES AND ROTCH. / Bibliography : leaves 33-34. / M.Arch.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1982. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Includes bibliographical references. / The proliferation of over 500 fitness programs for the employees of American corporations marks a turning point for the way American corporations regard employee and corporate health. Typically, sports facilities were the province of recreation or education facility planners. A category of sports activities has been isolated, however, for its cardiovascular characteristics and is the basic component of a fitness program The physiological characteristic which are of concern are those activities which contribute to the "training effect" of the heart or the ability of the heart to pump blood and oxygen to the body. The benefits of this conditioning are manifold. Longitudinal medical studies indicate that there are positive relationships across a large population for aerobic exercises or exercises which demand oxygen and decreased risk of heart attack in later life. While the correlation between exercise and good health seems merely the confirmation of good sense, it is a recent occurrence that this relationship has been quantified by corporations and utilized to increase "corporate health," through the construction of fitness facilities for employees. The intention behind this thesis is to explore the existing information about fitness centers and design a facility as the reuse of an historic building in Brooklyn, New York. / by Diane Theodora Georgopulos. / M.Arch.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Architecture, 1986. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Includes bibliographical references (leaves 209-213). / The focus of this design investigation is the warehouse fabric of the Fort Point Channel and its potentials as a model for further development This extensive configuration of warehouses and access roads is the product of an integrated process of planning. design and building. As such, it forms a useful model for creating a cohesive urban fabric. The warehouses reflect the rules of a concise architectural language. Thus, while each building was designed separately for different clients over the span of fifty years. all work together to form an urban environment which is intense. coherent and humane. Functionally, this fabric has undergone continuous change. Some of the warehouses now accommodate small printing houses and workshops; professional offices. shops, museums, studios and loft apartments. Thus. this tightly ordered 'family' of buildings has proven to be inherently inhabitable. The model represented by the warehouse fabric embodies my own goals and strategies for redeveloping and expanding the Fort Point Channel District as a living and working neighbourhood. My thesis proposes strategies for infrastructure and building typologies which will support high density, lowrise development as an extension to the existing fabric. The new development should be flexible, yet · harmonious: specific enough to suggest a distinct, overall character but open-ended enough to allow innovation in individual buildings and changing uses over time. The method tested through this investigation is therefore a process of layering. Rather than develop highly particularized solutions for each property, strategies are applied to the site as a whole. Once such overall strategies are agreed upon, specific solutions can be developed incrementally, but 'thematically', adjusting to changing circumstances as the need arises but contributing to a coherent whole. / by John Randall Dale. / M.S.

Thesis. 1978. M.Arch.--Massachusetts Institute of Technology. Dept. of Architecture. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH. / Bibliography: leaves 103-105. / M.Arch.

Thesis (M. Arch.)--Massachusetts Institute of Technology, Dept. of Architecture, 1982. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ROTCH / Includes bibliographical references. / Recent technological changes in railroads, mergers, major shifts in urban land use patterns, and declining rail passenger travel has resulted in a surplus of urban rail lands. These lands represent a significant resource for land poor cities. An unparalleled opportunity exists for major new intervention without the usual adverse effects of land assemblage and so called "urban renewal". This work is an urban design study for a 22 acre rail site and 15 acres of adjacent waterfront land in Tacoma, Washington. The site, including Union Station and its yards, is on the edge of Tacoma's central business district. Union Station represents the largest assembled parcel of developable land in the downtown area. An attempt is made to illustrate a possible site use scenario which reflects the divergent and often conflicting goals of various differing interests. / by Jeffrey David Rhoads. / M.Arch.

ALK1 est un récepteur de la famille du TGF-β, principalement exprimé dans les cellules endothéliales. Le ligand physiologique et circulant d'ALK1, BMP9, a été découvert par notre laboratoire en 2007, ce qui a ouvert des possibilités d'étude de la fonction d'ALK1. La première partie de ma thèse a été consacrée à l'analyse fonctionnelle de mutants d'ALK1, retrouvés sur des patients atteints de la maladie de Rendu-Osler de type 2, en réponse à BMP9. Cette étude a permis de : 1) proposer l'haploinsuffisance fonctionnelle comme modèle de la maladie ; 2) développer un test diagnostique pour discriminer les mutations pathogènes des polymorphismes rares, basé sur leur réponse à BMP9 ; 3) d'avoir une meilleure connaissance des acides aminés d'ALK1 importants dans la réponse à BMP9. Un second travail a consisté en la production de la forme mature de BMP9 et du domaine extracellulaire d'ALK1 en vue de l'étude de la structure cristallographique du complexe. L'expression des protéines et leur purification sont en phase d'optimisation. Enfin, un troisième projet consistait en l'analyse du rôle de BMP9 dans l'angiogenèse in vivo. La neutralisation de BMP9 par deux stratégies distinctes induit une augmentation de la densité vasculaire dans la rétine de la souris. Le mécanisme est en cours d'investigation. / ALK1 is a TGF-β family receptor, mainly expressed on endothelial cells. The physiologic and circulating ligand of ALK1, BMP9, was discovered by our laboratory in 2007, which opened opportunities for studying the function of ALK1. The first part of my thesis was on the functional analysis of ALK1 mutants from HHT-2 patients in response to BMP9. This study allowed us to: 1) propose functional haploinsufficiency as a model for HHT-2; 2) develop a diagnostic tool to discriminate pathogenic mutations from rare polymorphisms, based on their BMP9 response; 3) increase our knowledge of important amino acids in ALK1 for the BMP9 response. A second work was on the production of the mature form of BMP9 and of the extracellular domain of ALK1 in order to study the crystallographic structure of the complex. The expression of these proteins and their purification are in optimization phase. Lastly, a third project was on the analysis of the role of BMP9 in angiogenesis in vivo. Neutralization of BMP9 using two strategies induces an increase of the vascular density of the retina in mouse. Mechanism of action is under investigation.