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.

Made available in DSpace on 2015-05-08T14:47:51Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 436384 bytes, checksum: 70f945b2ee8c8dd86306983c06f854ef (MD5) Previous issue date: 2010-02-26 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Introduction: In the last decades it is been verified that the world population has been aging in an abrupt form, and the expectancy is that the longevity increase more and more and in a short period of time. This situation represents a great challenge for the competent organs and also for the society, highlighting the necessity of the creation of new public policies of health, aiming to offer a better quality of life to these elderly. One of the factors that can influence in the reduction of the quality of life of these people is the fall, which at the moment, due to high incidence, mortality, morbidity, and high social and economic costs, constitutes a serious problem of public health. Objectives: Knowing the social representations of the elderly attended in the health basic units about aging and risk of falls and evaluating the risk of falls in elderly. Methodology: It is an exploratory study in a quantitative-qualitative approach, done in the territory of the health family unit (HFU) Live Well , located in the neighborhood Treze de Maio, in the city of João Pessoa PB. The sample composed of one hundred and fifty elderly happened by convenience. As instruments an interview semi structured and the Fall Risk Score were used to evaluate the risk of falls. The period of data collection happened from January to April of 2009. The data collected of the interviews were analyzed from the Alceste 4.8 for the apprehension of the social representations about aging and risk of fall, afterwards interpreted according to the theoretical contribution of the social representations and for the analysis of the Fall Risk Score the SPSS 17.0. was used. Results:The analysis from the Alceste 4.8 retained 419 UCE S (64,4%), dividing the corpus in five classes. The representations of the elderly about the risk of falls and aging were permeated by dimensions much more negative that positive, like diseases, incapacities, dependence, loneliness, sadness, being represented as <<losses>> and <<incapacities>>, showing the difficulties lived by the elderly of the study facing this phase of the life. It was realized that most of the elderly (58,8%), of this study did not suffer falls, being, 63 of the elderly who fell, 71,4% said to have fallen once or twice, and the main intrinsic cause was dizziness/vertigo, while the extrinsic were sliding or wet floors. The data collected and analyzed were interpreted subsidized of the theoretical referential of the social representations. Final Considerations: The evaluation of risk of falls has a great importance in elderly in the perspective of the social representations, so that it serves of subsidies for the realization of preventive actions which aim the maximization of the quality of life of this population. / Introdução: Nas últimas décadas têm-se verificado que a população mundial vem envelhecendo de forma abrupta, e a expectativa é que a longevidade aumente cada vez mais e num curto espaço de tempo. Esta situação representa um grande desafio para os órgãos competentes e também para a sociedade, evidenciando a necessidade da criação de novas políticas públicas de saúde, com o intuito de oferecer uma melhor qualidade de vida a esses idosos. Um dos fatores que pode influenciar na diminuição da qualidade de vida dessas pessoas é a queda, que atualmente, em virtude da sua alta incidência, mortalidade, morbidade, e altos custos sociais e econômicos, constitui um grave problema de saúde pública. Objetivos: conhecer as representações sociais dos idosos atendidos nas unidades básicas de saúde sobre envelhecimento e risco de quedas e avaliar o risco de quedas em idosos. Metodologia: trata-se de um estudo exploratório em uma abordagem quanti-qualitativa, realizado no território da unidade de saúde da família (USF) Viver Bem , localizada no bairro Treze de Maio, na cidade de João Pessoa-PB. A amostra composta por cento e cinquenta idosos ocorreu por conveniência. Foram utilizados como instrumentos uma entrevista semiestruturada e o Fall Risk Score para avaliar o risco de quedas. O período de coleta de dados foi de janeiro a abril de 2009. Os dados coletados das entrevistas foram analisados a partir do Alceste 4.8 para a apreensão das representações sociais sobre envelhecimento e risco de queda, em seguida interpretado segundo o aporte teórico das representações sociais e para a análise do Fall Risk Score utilizou-se o SPSS 17.0. Resultados: A análise a partir do Alceste 4.8 reteve 419 UCE s (64,4%), dividindo o corpus em cinco classes. As representações dos idosos sobre o risco de quedas e envelhecimento foram permeadas por dimensões muito mais negativas que positivas, como doença, incapacidade, dependência, solidão, tristeza, sendo representados como «perdas» e «incapacidades», demonstrando as dificuldades vivenciadas pelos idosos do estudo frente a essa fase da vida.. Percebeu-se que a maioria dos idosos (58,8%), deste estudo não sofreu quedas, sendo que, dos 63 idosos que caíram, 71,4% relataram ter sofrido de 1 a 2 quedas, e a principal causa intrínseca foi a tontura/vertigem, enquanto que a extrínseca foi pisos escorregadios ou molhados. Os dados coletados e analisados foram interpretados subsidiados do referencial teórico das representações sociais. Considerações Finais: é de grande relevância a avaliação do risco de queda em idosos na perspectiva das representações sociais, para que sirvam de subsídios para realização de medidas preventivas que visem a maximização da qualidade de vida desta população.

Current state: Using tools to identify and analyse risks is presently very important in nursing to minimise the risk of harm to patients that can be prevented. The FMEA (Failure Mode and Effect Analysis) is a very efficient tool to address the failure issue. It is an important preventive method determining possible failures and proposing preventive measures to minimise the risk of errors. The RCA (Root Cause Analysis) is another important tool to handle failures. Objectives of the work: The objective of the research was to determine processes with the highest risks in nursing and to find out the most common risks associated with the nurse profession. Another objective is to describe the undesirable events reporting methods and to find out the utilisation of all risk analysis methods by nurses. And the final objective was to describe the intervention fall prevention programmes.Methodology: A qualitative research method was used to prepare the empirical part of the thesis. Data were collected using in-depth interviews. Qualitative data were coded using the pencil and paper technique; data were then categorised and respective subcategories were determined and shown in the SmartArt application. Research participants: Interviews were conducted with the head nurse, quality manager, senior nursing officer and departmental sister from the department of internal medicine, department of neurology and aftercare department. The first research was conducted in Nemocnice Jindřichův Hradec, a.s., the second in Nemocnice Tábor, a.s. and the final one in Nemocnice Písek, a.s. Results: It was found out from the results of the qualitative research that the most risky processes included medication in form of pills when, for example, generics drugs are given incorrectly or drugs of wrong strength are administered. The second risk process is the preparation of drugs from concentrated solutions of kalium, heparin or insulin. Administering intravenous drugs and infusion solutions is the third risky process. Too many activities of a nurse at one time is often the cause. Non-cooperation, poor communication of the patient and his/her family also lead to risky situations.Another serious group of risky processes includes patient transfer, moving the patient from a stretcher to a bed or going to the toilet. Further, it was found out that the most common risks are nosocomial infections, falls and decubital ulcers. Too much workload of nurses and new staff undergoing training are also mentioned as a risk. They include in particular medical assistants. Prescribing drugs through a computer system where the doctor relies on the nurse that she will alert when wrong drugs are prescribed although it is not her obligation to do so is also considered a common risk. Closing the infectious department in a hospital is the next risk. Patients who have a suspicion for certain diseases are then examined in a department. Nurses working there are afraid of getting infected from the ill person. And quite often, a disease is really found in the patients. Respondents gave different answers to the procedure of reporting undesirable events. The answers were different from one hospital to another. Nevertheless, all the reporting go to the hospital management that evaluates it. Nurses in the inquired hospitals do not use any risk analysis method. Not even nurses in management positions do not work with the methods and do not know the FMEA method. A direct analysis is addressed by the quality manager who most often uses the RCA analysis. Its results are discussed at meetings of nurses in the department, meetings of senior nursing officers or meetings of chief physicians. As for preventive programmes reducing the risk of falls it was found out that in all hospitals the screening of the risk of falls is standardly performed in all patients upon admission, except hospitalisations shorter than 3 days.

As alterações do equilíbrio postural representam um dos principais sintomas relatados pelos pacientes com Esclerose Múltipla (EM), surgem logo no início da doença em pacientes minimamente comprometidos e são consideravelmente incapacitantes . Esses déficits são muitas vezes pouco valorizados pelas avaliações clínicas neurológicas convencionais. Os objetivos desse estudo foram descrever as alterações de equilíbrio em pacientes com diagnóstico de EM e diferenciar as alterações clínicas entre pacientes com e sem queixa de desequilíbrio. Foram avaliados 98 pacientes, classificados através da Escala Expandida do Estado de Incapacidade (EDSS) entre 0 e 4,5. Os pacientes foram divididos em 2 grupos de acordo com a presença da queixa de desequilíbrio (Grupo sem queixa - GS; Grupo com queixa - GQ). O protocolo de avaliação constou de escalas observacionais do equilíbrio (Escala de equilíbrio de BERG: EEB e Índice de marcha dinâmica: DGI), avaliação da percepção de vertical visual subjetiva (VVS), Escala de Severidade da Fadiga (FSS) e através do Inventário Beck de Depressão (BDI). Os grupos GS e GQ foram compostos por 49 pacientes cada um. Não houve diferença estatística na idade dos indivíduos entre os grupos, porém encontramos diferença significativa entre o tempo de diagnóstico da EM entre ambos. Foram encontradas diferenças significativas entre GS e GQ para os valores de EDSS, no entanto ambos os grupos permaneceram dentro da classificação de incapacidade leve da escala. Esse dado reforça a ideia de que o EDSS é insensível para detectar déficits funcionais sutis. Também foram encontradas diferenças significativas nos testes clínicos de equilíbrio, refletindo que o GQ apresenta pior equilíbrio estático e dinâmico, EEB e DGI, respectivamente. O GQ apresentou pior percepção da vertical gravitacional, VVS, com valor estatisticamente significativo, além de um pior relato nas avaliações de fadiga (FSS), e depressão (BDI). Adicionalmente, observamos correlações negativas significantes entre os valores de EDSS os testes de equilíbrio (EEB e DGI), e correlações positivas significantes entre o EDSS e a avaliação da VVS e FSS. Não observamos correlação entre o EDSS e BDI. A relação entre o teste da VVS e os testes observacionais do equilíbrio também se mostrou estatisticamente significante. Os resultados do nosso estudo evidenciaram que vários aspectos devem ser considerados para caracterizarmos adequadamente as alterações de equilíbrio em indivíduos com EM. Os testes clínicos do equilíbrio postural e a avaliação da fadiga devem ser adicionados à avaliação funcional de pacientes com EM, permitindo dessa forma, que os déficits funcionais mais sutis sejam detectados. Nenhum teste clínico isolado é capaz de avaliar com precisão tais alterações. Sendo assim, concluímos que os testes propostos contemplam a avaliação da complexa rede de informações responsáveis pela manutenção do controle postural e contribuem para a melhor caracterização das alterações do equilíbrio postural na EM, facilitando a elaboração de protocolos individuais de reabilitação física e o seguimento do curso clínico da doença. / Abnormal balance in patients with Multiple Sclerosis (MS) represents one of the major symptoms reported and emerging since the onset of the disease in MS patients with subtle impairments. These deficits are usually underestimated by common neurological clinical evaluation. In this study, our objective was to report balance alteration in MS patients and distinguish clinical alterations between MS patients with and without balance disorders complaints. Ninety eight MS patients were evaluated, with Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Patients were divided into two groups according to their complaint about balance disorders (Without complaint - GS; with complaint - GQ). Patients were evaluated by qualitative balance assessments (Berg Balance Scale - BERG and Dynamic Gait Index - DGI), perception of subjective visual vertical test (SVV), fatigue severity scale (FSS) and Beck depression inventory (BDI). Both groups were constituted by forty-nine patients. GQ patients had higher EDSS score than GS patients, however, both were classified with mild impairments by the scale. These data reinforce the concept that EDSS is not sensitive to detect subtle impairments. GQ had worse performance in balance clinical tests (BERG and DGI) than GS patients. They had also worse perception of verticality and high levels of fatigue and depression than patients without balance disorders complaints. In addition, significant correlations were found between EDSS and BERG, DGI, SVV test and FSS. EDSS and BDI were not significantly correlated. These results showed that several clinical features must be considered to characterize balance disorders in MS. Balance clinical assessments and fatigue evaluation must be added to functional classification, allowing subtle impairments to be detected. Better characterization of balance disorders in MS improves the development of individual rehabilitation programs and allows the clinical course of disease follow-up

As alterações do equilíbrio postural representam um dos principais sintomas relatados pelos pacientes com Esclerose Múltipla (EM), surgem logo no início da doença em pacientes minimamente comprometidos e são consideravelmente incapacitantes . Esses déficits são muitas vezes pouco valorizados pelas avaliações clínicas neurológicas convencionais. Os objetivos desse estudo foram descrever as alterações de equilíbrio em pacientes com diagnóstico de EM e diferenciar as alterações clínicas entre pacientes com e sem queixa de desequilíbrio. Foram avaliados 98 pacientes, classificados através da Escala Expandida do Estado de Incapacidade (EDSS) entre 0 e 4,5. Os pacientes foram divididos em 2 grupos de acordo com a presença da queixa de desequilíbrio (Grupo sem queixa - GS; Grupo com queixa - GQ). O protocolo de avaliação constou de escalas observacionais do equilíbrio (Escala de equilíbrio de BERG: EEB e Índice de marcha dinâmica: DGI), avaliação da percepção de vertical visual subjetiva (VVS), Escala de Severidade da Fadiga (FSS) e através do Inventário Beck de Depressão (BDI). Os grupos GS e GQ foram compostos por 49 pacientes cada um. Não houve diferença estatística na idade dos indivíduos entre os grupos, porém encontramos diferença significativa entre o tempo de diagnóstico da EM entre ambos. Foram encontradas diferenças significativas entre GS e GQ para os valores de EDSS, no entanto ambos os grupos permaneceram dentro da classificação de incapacidade leve da escala. Esse dado reforça a ideia de que o EDSS é insensível para detectar déficits funcionais sutis. Também foram encontradas diferenças significativas nos testes clínicos de equilíbrio, refletindo que o GQ apresenta pior equilíbrio estático e dinâmico, EEB e DGI, respectivamente. O GQ apresentou pior percepção da vertical gravitacional, VVS, com valor estatisticamente significativo, além de um pior relato nas avaliações de fadiga (FSS), e depressão (BDI). Adicionalmente, observamos correlações negativas significantes entre os valores de EDSS os testes de equilíbrio (EEB e DGI), e correlações positivas significantes entre o EDSS e a avaliação da VVS e FSS. Não observamos correlação entre o EDSS e BDI. A relação entre o teste da VVS e os testes observacionais do equilíbrio também se mostrou estatisticamente significante. Os resultados do nosso estudo evidenciaram que vários aspectos devem ser considerados para caracterizarmos adequadamente as alterações de equilíbrio em indivíduos com EM. Os testes clínicos do equilíbrio postural e a avaliação da fadiga devem ser adicionados à avaliação funcional de pacientes com EM, permitindo dessa forma, que os déficits funcionais mais sutis sejam detectados. Nenhum teste clínico isolado é capaz de avaliar com precisão tais alterações. Sendo assim, concluímos que os testes propostos contemplam a avaliação da complexa rede de informações responsáveis pela manutenção do controle postural e contribuem para a melhor caracterização das alterações do equilíbrio postural na EM, facilitando a elaboração de protocolos individuais de reabilitação física e o seguimento do curso clínico da doença. / Abnormal balance in patients with Multiple Sclerosis (MS) represents one of the major symptoms reported and emerging since the onset of the disease in MS patients with subtle impairments. These deficits are usually underestimated by common neurological clinical evaluation. In this study, our objective was to report balance alteration in MS patients and distinguish clinical alterations between MS patients with and without balance disorders complaints. Ninety eight MS patients were evaluated, with Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Patients were divided into two groups according to their complaint about balance disorders (Without complaint - GS; with complaint - GQ). Patients were evaluated by qualitative balance assessments (Berg Balance Scale - BERG and Dynamic Gait Index - DGI), perception of subjective visual vertical test (SVV), fatigue severity scale (FSS) and Beck depression inventory (BDI). Both groups were constituted by forty-nine patients. GQ patients had higher EDSS score than GS patients, however, both were classified with mild impairments by the scale. These data reinforce the concept that EDSS is not sensitive to detect subtle impairments. GQ had worse performance in balance clinical tests (BERG and DGI) than GS patients. They had also worse perception of verticality and high levels of fatigue and depression than patients without balance disorders complaints. In addition, significant correlations were found between EDSS and BERG, DGI, SVV test and FSS. EDSS and BDI were not significantly correlated. These results showed that several clinical features must be considered to characterize balance disorders in MS. Balance clinical assessments and fatigue evaluation must be added to functional classification, allowing subtle impairments to be detected. Better characterization of balance disorders in MS improves the development of individual rehabilitation programs and allows the clinical course of disease follow-up