Virtual reality environments (VEs) are new tools to improve functional recovery in stroke survivors. Elements essential to maximize motor learning, can be optimized in VEs. Study objectives were: (a) to determine whether training in VE with enhanced feedback about movement patterns, leads to greater gains in arm movement quality, motor performance and decreased compensation compared to training in a similarly designed Physical environment (PE); (b) to estimate whether impairments in cognitive functioning affected the changes observed after training. Twelve stroke survivors practiced 72 pointing movements in VE or PE for 10 sessions with enhanced feedback. Kinematic analysis of pointing task, evaluations of arm impairment and function were carried out pre-post training. After training, VE group had increased shoulder flexion (p<0.05), increased shoulder horizontal adduction and decreased compensation, compared to PE group. Use of feedback correlated with fewer deficits in cognitive functioning. Training in VEs may lead to greater gains in movement quality.

The Ras signaling cascade is a vital component in the processes that mediate cell survival, growth, differentiation and transformation through activation of MAP kinase (mitogen-activated protein kinase). The recent discovery of a new scaffold of the Ras signaling pathway, Kinase Suppressor of Ras (KSR), is found to be a positive effector of Ras signaling which further contributes to proliferation and transformation in the ERK/MAPK pathway. This thesis describes the roles of Ras and Kinase Suppressor of Ras 1 (KSR-1) in regulating the expression of tumor promoting genes such as urokinase plasminogen activator (uPA) in the development and progression of breast cancer in vitro and in vivo. Ras and KSR increase the proliferative capacity and migration of MDAMB-231 human breast cancer cells in vitro. In contrast, Ras and KSR decrease the invasiveness of MDA-MB-231 human breast cancer cells in vitro. Furthermore, uPA gene expression levels do not correlate with uPA protein expression levels suggesting a possible mutation induced by KSR and/or Ras. In vivo studies reveal that Ras and KSR increase tumor volume in mice, as well as more advanced osteolytic bone metastases. Collectively, these results indicate that Ras and KSR play significant roles in breast cancer development and metastasis.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 12 uppsatser.

Dissertation (Ph.D.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 115 pages. Includes vita. Includes bibliographical references.

L’arthrose est une pathologie fréquente et responsable d’une morbidité majeure. En France, cette pathologie est devenue une priorité de santé publique et jusqu’à récemment il n’existait aucune donnée épidémiologique en population générale. Mon travail a permis d’apporter les premiers chiffres de prévalence en population générale et a constitué une étape préliminaire essentielle à la réalisation d’une étude de prévalence nationale et à la constitution d’une cohorte de cas prévalents d’arthrose symptomatique des membres inférieurs. Ces travaux m’ont amené à m’intéresser à l’apport diagnostique des clichés en Schuss et ainsi mettre en évidence que ces clichés seuls sont aussi contributifs que l’association clichés en extension et clichés en Schuss classiquement réalisés pour le diagnostic de gonarthrose. L'ocytocine est une hormone exprimée dans un grand nombre de cellules dont les ostéoblastes et les adipocytes. Son rôle dans l'ostéoporose a été démontré. A ce jour aucune donnée sur son éventuel rôle dans l’arthrose n’a été publiée. J’ai donc recherché un éventuel rôle direct et/ou indirect de l'ocytocine. Pour cela, nous avons utilisé un modèle cellulaire: ’’Multipotent Adipose-Derived Stem’’ (hMADS) développé dans notre laboratoire de recherche. Nous avons, dans un premier temps, montré les capacités chondrogéniques de ces cellules ainsi que leur intérêt comme potentiel outil de tests pharmacologiques dans l’arthrose. La deuxième étape a consisté à démontrer un rôle de l’ocytocine dans la chondrogenèse. Nous avons montré que l’ocytocine a une action bénéfique sur l’expression des gènes chondrocytaire. De plus, le traitement des cellules par l'ocytocine atténue l'effet négatif de l'IL-1β sur ADAMTS-4 qui est responsable de la dégradation de l'aggrécane. L’ensemble de ces résultats indique que l'ocytocine représente un modulateur positif de la formation des chondrocytes et prometteur comme traitement potentiel pour l'arthrose. / Osteoarthritis is the most frequent cause of rheumatic complaints in Rheumatology. Osteoarthritis is responsible of major morbidity. Increase of life span is accompanied by an increase of aging diseases such as osteoporosis and osteoarthritis. In France, the disease became a public health priority, and until recently, there was no osteoarthritis epidemiologic data in the general population concerning lower limbs. My clinical studies enabled me to bring the first prevalence study in the general population. It was an essential preliminary step for a national prevalence study, and the constitution of a prevalent symptomatic cases cohort of lower limbs osteoarthritis. These observations let me to analyze the diagnostic contribution of Schuss X rays and to show that Schuss X-rays alone do not provide less information’s for the diagnosis of knee osteoarthritis, than the usual association standard extension X rays -Schuss X rays. Oxytocin is a hormone expressed by a large number of cells including osteoblasts and adipocytes. Recently, its role in osteoporosis has been shown. So far, no data about its potential role in osteoarthritis are available. I thus searched for a possible direct and / or indirect role of oxytocin on chondrogenesis. For that, I used a cellular model developed in our research laboratory: the “Multipotent Adipose-Derived Stem’’ (hMADS) cells. A first step, I show that hMADS cells are endowed with a chondrogenic capacity, and they represent a powerful tool for therapeutic test in osteoarthritis. The second step was to analyze the role of oxytocin in chondrogenesis. We shown that oxytocin has a benefic effect especially on the aggrecan (increase), probably via a negative effect on ADAMTS4, and also several other major chondrogenesis genes such as COMP and Sox9. Taken together, these results indicate that oxytocin represents a positive modulator of chondrocyte formation and holds promise as a potential therapy for osteoarthritis.

La mort des hépatocytes est un des éléments initiateurs de la progression des maladies hépatiques par l’induction de processus inflammatoires et de régénération. Ces événements, bénéfiques à court terme pour le rétablissement de l’homéostasie hépatique sont parfois dérégulés et peuvent conduire au développement de la fibrose, de la cirrhose, voire d’un carcinome hépatocellulaire. Ainsi, les voies conduisant à la mort des hépatocytes et leur blocage comme une potentielle approche thérapeutique sont aujourd’hui étudiées. Les cellules de l’immunité innée et acquise sont responsables de l’induction ou de l’amplification de cette hépatolyse, principalement via l’expression et la libération de ligands de mort appartenant à la superfamille du TNF-α, dont TNF-α, FasL et TRAIL. Des travaux suggèrent le rôle des protéines RIPK1 et PARP1/2 dans l’induction de l’hépatolyse dans l’hépatite induite par la Concanavaline A (ConA) chez la souris. Par l’utilisation de modèles chimiques et génétiques, nous avons étudié l’implication de ces protéines dans le processus de mort des hépatocytes.Tout d’abord, nous nous sommes intéressés au double rôle de la protéine RIPK1 dans le contrôle de la vie et la mort de l’hépatocyte. En bloquant son activité kinase nous avons confirmé son rôle dans l’induction de l’hépatolyse dans l’hépatite induite par la ConA. Cependant, en utilisant des souris conditionnellement déficientes pour RIPK1 dans les cellules parenchymateuses hépatiques (LPC) (Ripk1LPC-KO) nous avons révélé sa fonction nécessaire à la survie des hépatocytes et au maintien de l’homéostasie hépatique au cours de l’hépatite. Ces travaux démontrent que l’absence de RIPK1 sensibilise les hépatocytes à l’apoptose induite par le TNF-α en déstabilisant la protéine TRAF2. Ainsi RIPK1 joue un rôle clef dans la protection des hépatocytes au cours des hépatites induites par la ConA, le lipopolysaccharide (LPS), les motifs CpG ou induite par une co-administration d’IFN--γ et de TRAIL recombinantes. De plus, nous avons mis en évidence que RIPK1 protège partiellement de l’hépatolyse et de l’hépatite induite par l’activation de Fas. Enfin, nous avons montré que l’absence de la protéine PARP2 conduisait à une diminution du nombre de NKT invariants systémiques, dont hépatiques, conduisant à une inhibition de la mort des hépatocytes induite par l’administration de ConA. Ces travaux ont permis de préciser le rôle de RIPK1 et de PARP2 dans les hépatites aiguës. La capacité de RIPK1 à contrôler la mort et la survie de la cellule suggère son implication au cours des hépatites chroniques et ouvre la porte à son investigation dans les maladies hépatiques humaines. / Hepatocyte death is a starting point of liver disease progression by promoting inflammatory and regenerative processes. These events are beneficial at the beginning of the pathology for the restoration of hepatic homeostasis. However when they are unregulated, they lead to the development of fibrosis, cirrhosis or hepatocellular carcinoma. Thus, it is important to study the signaling pathways leading to the hepatocyte death as their inhibition is a potential therapeutic approach to reduce liver diseases progression. Innate and acquired immune cells play key roles in the induction or amplification of hepatolysis, mainly mediated by expression and release of death ligands belonging to the TNF-superfamily including TNF-α, FasL and TRAIL. Some studies had already suggested the role of RIPK1 and PARP1/2 proteins in the induction of hepatocyte death during hepatitis induced by Concanavalin A (ConA) in mice. Through chemical and genetic approaches, we studied the role of these proteins in the hepatocyte death process during hepatitis. First, we were interested in the dual role of RIPK1 protein that controls the cell fate by promotingsurvival or death. By blocking its kinase activity, we confirme its role in the induction of liver injury induced by ConA. However, using specific conditional mice deficient in RIPK1 only in liver parenchymal cells (LPC) (Ripk1LPC-KO), we reveale its necessary function in the protection of hepatocyte during hepatitis. These works demonstrate that deletion of RIPK1 sensitizes hepatocytes to TNF-α-induced apoptosis by TRAF2 destabilization. Thus RIPK1 plays a key role in the protection of hepatocytes during hepatitis induced by ConA, lipopolysaccharide (LPS), DNA-CpG, or recombinant IFN-γ and TRAIL co-administration. In addition, we demonstrate that RIPK1 partially protects from hepatitis and hepatocyte death induced by the activation of Fas. Finally, we showe that PARP2 deficiency leads to a systemic decrease of the number of the invariant NKT-subpopulation of lymphocytes, including in the liver, which prevente hepatocyte death during ConA hepatitis. To conclude, this work helps to clarify the roles of RIPK1 and PARP2 during acute hepatitis. The ability of RIPK1 to control hepatocyte death and survival suggests its involvement during chronic hepatitis and opens the door to its investigation into human liver diseases.

L'anorexie mentale (AM) est un trouble du comportement alimentaire qui se caractérise par une recherche obsessionnelle de minceur, une forte réduction de la prise alimentaire et une distorsion de l'image de soi. Elle est associée à de multiples perturbations endocriniennes et métaboliques, et à une altération de la masse et de la microarchitecture osseuses. Les facteurs et les mécanismes qui interviennent dans cette maladie sont très mal connus ce qui limite les options thérapeutiques. Il est donc nécessaire de développer un modèle animal qui reproduise les perturbations physiologiques observées en AM et permette d'étudier les facteurs associés à l'altération osseuse. Dans ce but nous avons développé un modèle murin avec une restriction du temps d'accès à l'alimentation associée à un stress induit par la séparation (separation-based anorexia, SBA). Cette phase SBA de 10 semaines est suivie d'une phase de récupération en conditions standard (REC) de 10 semaines. Chez les souris femelles C57B1/6 en fin de croissance rapide, la phase SBA induit une perte rapide et importante du poids corporel. L'analyse de la composition corporelle par DEXA révèle une diminution rapide de près de 40% de la masse grasse ainsi qu'une baisse progressive de la masse maigre et un arrêt de l'acquisition de la masse osseuse. Au niveau des tibias, la densité minérale cortical et la microarchitecture trabéculaire sont altérées. L'observation des frottis vaginaux et la mesure des ovaires révèlent une perturbation importante des fonctions reproductrices. Les tests de tolérance au glucose ont montré que les souris SBA ont une capacité très élevée à corriger la glycémie. Ces animaux sont fortement hypoleptinémiques, et l'axe GH-IGF-1 est très perturbé. L'étude de l'expression génique de différents tissus adipeux a montré une augmentation du niveau des marqueurs de lipogénèse et de lipolyse, ainsi qu'une forte induction du phénotype "adipocyte brun" dans le tissu adipeux sous-cutané. Après deux semaines de REC, les souris SBA retrouvent très rapidement leur poids corporel, leurs masses maigre et grasse. La masse minérale toujours basse à ce stade est corrigée après 10 semaines de REC, ainsi que la microarchitecture osseuse (étude préliminaire). Tous les autres paramètres étudiés sont normalisés, sauf l'hypoleptinémie qui étonnamment persiste même après 10 semaines de protocol REC et malgré la normalisation de la masse adipeuse. D'après ces résultats, on peut conclure que le modèle SBA reproduit de nombreuses perturbations physiologiques observées en AM. La phase de REC révèle que ces souris ont une importante capacité de récupération. L'hypoleptinémie persistante pourrait favoriser la récupération. L'identification des mécanismes impliqués pourrait fournir des pistes thérapeutiques afin de favoriser la reconstitution du capital osseux des patientes anorexiques. / Anorexia nervosa (AN) is an eating disorder mainly developed in adolescent girls and young women. It is characterized by an obsessive search for thinness, a profound undernutrition and a distorted self-image.It is associated with multiple endocrine and metabolic disturbances, decreased bone mass and microarchitectural alteration. Some of the developed adaptations are supposed to be involved in the blockade of the pathologic state. Unfortunately, these adaptations are poorly known and most of them cannot be studied on patients. So it is necessary to develop an animal model which mimics the main consequences observed in human pathology and allows studying the recovery process. For this purpose we adapted a murine model of time restricted feeding associated with chronic stress induced by separation-based anorexia (SBA). C57B1/6 female mice are submitted to a long term SBA protocol (10 weeks) and then a long term phase of recovery (10 weeks). At the beginning of the protocol mice are 8 weeks old, so their fast growth is finishing. SBA protocol induced a rapid and significant loss of body weight. Body composition analysis by DEXA showed a 40% decrease of the fat mass, a progressive loss of lean mass and a blockade of bone mass acquisition. Mice deveoped a high glucose tolerance. The observation of vaginal smears revealed a disruption of the estrous cycle and ovarian histology showed an atrophy of the ovaries. These two alterations suggest a major alteration of reproductive functions. These animals showed a very low leptinemia, and the GH/IGF-1 axis was disrupted. The study of bone alteration by microtomography indicated an alteration of bone microarchitecture and of cortical bone mass, mimicking osteoporosis often described in AN patients. Body weight, lean and fat masses were normalized quickly during the REC protocol. Bone mineral content still low after 2 weeks of REC protocol was fully corrected after 10 weeks. The estrous cycle ovarian size and the GH/IGF-I were normalized. Surprisingly, hypoleptinemia persisted even after 10 weeks of REC and despite the normalization of the fat mass. This result has been confirmed by the low level of leptin gene expression in various adipose tissues. Finally, the SBA protocol is valuable model of AN because numerous physiological alterations described in AN are mimicked in this model. The recovery phase revealed the high capacity of mice to normalize the long term alterations. Persitent hypoleptinemia could contribute to the normalization of body composition. However, the balance between central and peripheral effects of the uncorrected hypoleptinemia remains to be determined. This persisting hypoleptinemia could be used for the revision of the therapeutic strategies aiming to correct AN-induced osteoporosis.

As porfirias, síndromes associadas a deficiências de atividade enzimática da biossíntese do grupo heme, presente em quase todas células do organismo, com maior atividade no fígado e medula óssea, agrupam-se em formas hereditárias ou primárias e secundárias ou químicas. No caso das primárias ocorre déficit da expressão de enzimas ou inibição da atividade de outras. A variação dos metabólitos acumulados é o que tange o polimorfismo clínico. Dentre as secundárias, destacam-se o saturnismo (intoxicação por chumbo) e a tirosinemia subaguda ou crônica (onde o acúmulo de succinilacetona, intermediário da degradação de tirosina, inibe a ALA desidratase, enzima biossintética do grupo heme). Nestas últimas e na porfiria aguda intermitente (PAI), de herança autossômica dominante do cromossomo 11q, além de outros intermediários menores, ocorre o acúmulo do ácido 5-aminolevulínico (ALA) no sangue e outros tecidos. O ALA é uma α-aminocetona passível de rápida enolização em pH fisiológico. Foi demonstrado que o enol formado sofre oxidação subsequente catalisada por complexos de ferro em pH fisiológico com formação de espécies reativas de oxigênio e ALA enoil radical. Este comportamento causa dano oxidativo em mitocôndria, lipossomos, DNA e proteínas. A formação do ânion superóxido (O2•-) no meio promove liberação de ferro do retículo endoplasmático e de ferritina e in vivo aumenta significantemente a concentração de ferro não-hemínico em fígado de rato. Vários estudos se seguiram para demonstrar que ALA acumulado nos distúrbios porfirínicos sofreria oxidação a partir do enol, tendo como produto final o ácido 4,5-dioxovalérico (DOVA), e este comportamento seria o responsável pelas alterações neurobioquímicas encontradas: aumento da captação de cálcio em sinaptosomas, elevação de ferro total cortical e estriatal seguido por elevação secundária de ferritina, aumento da atividade CuZnSOD (cobre-zinco superóxido dismutase), bem como proteínas oxidadas e produtos de lipoperóxidos nos homogenatos totais de córtex de rato. In vitro, estes efeitos foram todos inibidos por agentes antioxidantes, químicos ou enzimáticos. As evidências neuroquímicas clássicas para as manifestações neuropsiquiátricas supostamente promovidas pelo ALA apoiavam-se na similaridade estrutural ALA/GABA, proposta por Brennan e Cantrill em 1979. Nosso estudo modelo, utilizando membranas sinápticas, evidenciou através de ensaios de radioligação com 3H-muscimol na presença de 10 mM de ALA ou após tratamento crônico com 40 mg/kg em ratos, alteração do Kd (constante de dissociação do complexo receptor-ligante), mas sem mudança no \"pool\" total de receptores. Outro aspecto não esclarecido era se o DOVA afetaria o sistema GABAérgico, não pelo mecanismo oxidativo, mas através de um antagonismo farmacológico (similaridade estrutural com o GABA) ou através de sua reatividade ao formar adutos cíclicos com proteínas similar ao que acontece nos AGEs (\"Advanced Glication End Products\"). Nesta dissertação estudamos o mecanismo de captação de cálcio por sinaptosomas influenciada por ALA e DOVA. São discutidos os resultados dos ensaios de radioligação com 3H-muscimol na verificação do efeito de DOVA nos sítios GABAérgicos também em sinaptosomas corticais de ratos. Os estudos usando cultura de células transformadas de linhagem neuronal WERI (derivadas de retinoblastoma humano com mutação no gene rb) foram conduzidos para avaliar a citotoxicidade ao ALA e DOVA, bem como extender a análise da via GABAérgica, envolvida na fisiopatologia dos efeitos citados. Nossos resultados demonstram o efeito de ALA, metabolito intermediário acumulado nas porfirias, em particular na PAI e saturnismo, como espécie pro-oxidante nociva ao sistema sinaptosomal. Seu efeito é mediado pela quebra na homeostade do cálcio desencadeando colapso energético mitocondrial, cujo efeito tem reversão parcial com o uso de antioxidantes e bloqueadores de canal de cálcio. Já o DOVA tem demonstrado seu efeito principalmente comprometendo a vitalidade celular não relacionada à homeostase do cálcio, mas com envolvimento do sistema GABAérgico de receptores ligados ao canal de cloreto. Tal efeito parece estar relacionado com a alteração do \"pool\" total de receptores celulares e sua citolocalização. / Abstract not available.

Orientador: Aparecida Machado de Moraes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T11:25:06Z (GMT). No. of bitstreams: 1 Cordeiro_RaquelCristinaTancsik_D.pdf: 1883576 bytes, checksum: c00bc86b625d6d904784f53f3f6041e6 (MD5) Previous issue date: 2009 / Resumo: A estria atrófica cutânea ou striae distensae (SD) é uma afecção muito comum, sendo causa freqüente de procura por consultas dermatológicas. Ainda que não representem qualquer risco à saúde física, produzem impacto emocional e induzem busca por tratamentos trabalhosos, caros e dolorosos e, com freqüência, inadequados. Além disso, o surgimento de striae distensae pode refletir alteração do tecido conjuntivo e indicar condições patológicas locais e sistêmicas. Alguns autores descrevem as estrias cutâneas como uma condição de estiramento ou distensão da pele, com perda ou ruptura das fibras elásticas na região acometida. Entretanto, vários autores observam que as estrias não surgem com frequência sobre a pele acima de tumores abdominais, ascites, hemorragias extensas ou grandes hérnias. Atualmente admite-se que sua etiopatogenia é multifatorial, englobando aspectos mecânicos, bioquímicos e genéticos. No entanto, considerando-se a multiplicidade de fatores envolvidos, a literatura é divergente e inconclusiva. Portanto, através do estudo de fatores clínicos associados às SD e dos receptores hormonais (estrógeno, andrógeno e glicocorticóide), pretendeu-se entender melhor a participação dos hormônios na fisiopatogênese das estrias. Para o estudo clínico foram selecionados pacientes com queixa de estrias cutâneas e a comparação foi feita com grupo controle de número semelhante, atendido aleatoriamente por outras queixas no Ambulatório Geral de Dermatologia do HC, FCM/UNICAMP. O estudo da expressão dos receptores hormonais foi realizado por Western blot em oito amostras de pele de estrias recentes, com menos de um ano de evolução, comparando com a avaliação de pele sem lesão de região palpebral de oito pacientes que se submenteram a blefaroplastia. Observou-se que fatores como adolescência, gestação e obesidade estão significativamente relacionados ao surgimento das SD. Constatou-se ainda que a idade materna jovem e o ganho ponderal durante a gestação são importantes fatores associados ao desenvolvimento das lesões. Além disso, a localização das lesões correlaciona-se ao fator causador das estrias. Em relação ao estudo dos receptores hormonais, observou-se que na SD recentes há duas vezes mais expressão de receptores de estrógeno e 1,7 vezes mais expressão receptores de andrógeno e glicocorticóide. Alguns autores interpretam SD como cicatrizes. Após influência hormonal, haveria uma reação inflamatória inicial que determinaria a destruição de fibras elásticas e colágenas. O processo seria seguido de regeneração das fibras, um fenômeno de remodelação dinâmica,ou seja, um balanço entre síntese de colágeno e sua quebra, o qual reestrutura o tecido para acomodar as forças que agem sobre ele, resultando na formação das SD. O balanço entre a expressão de receptores de estrógeno, andrógeno e glicocorticóide poderia induzir as modificações específicas da matriz extracelular, o que levaria a esse fenômeno de remodelação. Em concordância com outros estudos, observamos que as estrias surgem em situação de grande modificação sistêmica, como adolescência e gestação. Através das observações morfológicas e moleculares, nota-se que as SD estão correlacionadas com intensas alterações do tecido conectivo. Os resultados mostram-se relevantes e representam mais um passo na compreensão do mecanismo fisiopatológico da estrias cutâneas e abrem espaço para novas linhas de pesquisa, relacionadas às SD e a outras alterações do tecido conectivo. / Abstract: Stretch marks or striae distensae (SD) are a very common condition which often results in persons searching dermatological treatment. While not presenting any risk to one's physical health, the emotional impact often induces those so affected to demand medical treatments, which are often laborious, expensive and painful, and frequently ineffective. Beyond this, the appearance of SD may indicate other alterations in conjunctive tissues, including both local and systemic pathologies. Some authors described cutaneous strias as a condition of stretching or distension of the skin which results in the loss or rupture of elastic fibers in the affected areas. However, many authors have also observed that SD do not occur frequently associated with abdominal tumors, ascites, extensive hemorrhages or large hernias. Current medical opinion is that its etiopathogenesis is multifactored, englobing mechanical, biochemical and genetic aspects. Nevertheless, in view of the multiplicity of the factors involved, the literature is divergent and inconclusive. This study was proposed to look for better understanding of the role played by hormones in the physiopathology of SD studying clinical factors associated with SD and hormone receptors (estrogen, androgen and glycocorticoid). Patients complaining of SD were selected for inclusion in this clinical study, and comparisons were made with a control group of a similar number of persons who had been treated for other medical conditions at the General Ambulatory Dermatology Care Facility at HC, FCM/UNICAMP. The expression of hormone receptors was undertaken of the Western Blot testing of recent skin striations, in comparison with lesion-free skin taken from the eyelids of patients who had undergone blepharoplasty. The study revealed that factors such as adolescence, pregnancy and obesity are significantly related to the appearance of SD. It was further established that age (the younger the gravid, the greater the possibility of SD) and significant weight gain during pregnancy are important factors associated with the development of SD lesions. In addition, there was a positive correlation with the location of the lesions. In relation to the study of hormone receptors, it was observed that recently-formed SD have two times more expression of estrogen receptors, and 1,7 times more expression of androgen and glycocorticoid receptors. Some authors classify SD as scars. Under hormonal influence, there is an initial inflammatory reaction which results in the destruction of elastic fibers and collagens. This is followed by the regeneration of the destroyed fibers, a phenomenon of dynamic remodeling, a balance between the synthesis and destruction of collagens, which restructures the tissue in order to accommodate the forces acting upon it, resulting in the formation of SD. The balance between the expression of estrogen, androgen and glycocorticoid may elicit the specific modifications of the extracellular matrix which leads to the phenomenon of remodalation. In agreement with other studies, we observed that the strias arise under conditions of significant system modification, such as adolescence and pregnancy. The observation of morphological and molecular changes showed that there is a correlation between SD and with intense alterations in connective tissue. The results of this study are relevant and represent an important step in the understanding of physiopathological mechanisms in stretch marks, opening new horizons for new directions in research of SD and other alterations in connective tissues as well. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Os sintomas negativos têm sido apontados como grande causa de sobrecarga nos pacientes esquizofrênicos, apesar dos recentes avanços no tratamento. Este estudo teve por objetivo investigar a correlação entre os sintoma s negativos e a qualidade de vida, em pacientes esquizofrênicos refratários e super-refratários. Cento e dois pacientes que preenchiam os critérios DSM-IV para esquizofrenia foram observados durante seis meses. Os pacientes foram divididos de acordo com critérios pré-estabelecidos, em três grupos: não refratários (N=22), refratários (N= 47) e super-refratários (N= 31), A psicopatologia foi avaliada por meio da Escala para Avaliação da Síndrome Positiva e Negativa (PANSS), Entrevista para Síndrome Deficitária (SDS) e Escala de Calgary para Depressão na Esquizofrenia. A qualidade de vida foi medida pela Escala de Qualidade de Vida (QV) . Os super-refratários tiveram os menores escores de QV, quando comparados ao grupo não refratário (p < 0,05). Não houve diferenças significativas nos escores médios de QV entre os refratários e superrefratários. Pacientes não refratários apresentaram menos sintomas negativos e melhores escores de QV. Os sintomas negativos tiveram uma correlação negativa com a qualidade de vida. Pacientes super-refratários, com mais sintomas negativos, tenderam a ter os menores escores de qualidade de vida / Negative symptoms have been reported as a major cause of burden in schizophrenic patients and often do not respond to drug treatment, in spite of recent advances in antipsychotic therapy. The present study aims to investigate the correlation of negative symptoms with quality of life in refractory schizophrenic patients. One hundred two outpatients meeting DSM-IV criteria for schizophrenia, were observed during 6 months. Subjects were divided into 3 groups: non-refractory (N=22), refractory (N= 47) and superrefractory (N= 31), according to pre-established criteria. Psychopatology was assessed with the Positive and Negative Syndrome Scale (PANSS), Schedule for Deficit Syndrome (SDS) and the Calgary Depression Scale for Schizophrenia. Quality of life was measured with the Quality of Life Scale (QoL). The super-refractory group had significantly lower QoL scores compared with the non-refractory group (P< 0,05). Mean QoL scores of superrefractory and refractory patients did not show a significant difference between them. Nonrefractory patients had fewer negative symptoms and better QoL scores. Negative symptoms negatively correlate with quality of life in schizophrenic patients. Superrefractory schizophrenic patients have the highest level of negative symptoms, and therefore the lowest QoL scores