L’hypertension artérielle pulmonaire (HTAP) est une maladie caractérisée par une obstruction des artères pulmonaires de petit calibre aboutissant, à terme, à une défaillance cardiaque droite. L’évolution de cette maladie est parfois émaillée d’épisodes de dégradation de l’état fonctionnel des patients, nécessitant une admission en unité de soins intensifs pour surveillance cardioscopique et administration de médicaments inotropes et/ou vasopresseurs. Peu d’éléments permettent à ce jour de guider les praticiens dans la prise en charge de ces patients et la physiopathologie de ces épisodes est assez peu connue.Dans un premier temps, nous avons retrouvé une mortalité de 41% en réanimation et testé certains facteurs pronostiques cliniques et biologiques simples issus de la pratique quotidienne dans une cohorte propective de patients avec une prise en charge standardisée. Nous avons identifié comme facteurs pronostiques la pression artérielle systémique, la natrémie, la créatininémie, la valeur de la C-reactive Proteine. Nous avons retrouvé une influence de ces épisodes sur l’évolution à moyen terme de ces épisodes. Dans un second temps nous avons testé la valeur pronostique des indices temporels de fonctionnement du ventricule gauche, suggérée par les études en imagerie par résonnance magnétique. Nous avons utilisé pour cela la tonométrie d’aplanation, outil original et non invasif. Nous avons retrouvé que la valeur de la durée d’éjection du ventricule gauche est associée au pronostic. Dans une troisième partie nous avons mesuré les conséquences et la valeur pronostique de l’épuration extra rénale en contexte d’ insuffisance rénale menaçante chez ces patients. Dans une étude rétrospective, nous avons observé 68 séances d’épuration extra-rénale continue ou discontinue. Ces séances se sont compliquées d’hypotension artérielle dans environ 50% des cas. La très haute mortalité en réanimation et à 3 mois, respectivement de 47% et 73%, soulève la question de la place de l’assistance circulatoire et de la transplantation urgente chez ces patients. Ces données soulignent la sévérité à court terme des épisodes aigus d’aggravation chez les patients porteurs d’HTAP. De plus amples données sont nécessaires pour améliorer la prise en charge de ces patients et organiser dans le meilleur délai la mise en place de thérapeutiques exceptionnelles comme l’assistance circulatoire et la transplantation pulmonaire ou cardio-pulmonaire. / Pulmonary arterial hypertension ( PAH) is a disease characterized by an obstruction of the small pulmonary arteries leading ultimately to right heart failure. The evolution of this disease is sometimes punctuated by episodes of deterioration of the functional status of patients requiring admission to intensive care unit for monitoring and administration of inotropic drugs and / or vasopressors. Few evidence to date are available to guide physicians in the care of these patients and the pathophysiology of these episodes is still elusive.In a first part, we found a mortality of 41% in the intensive care unit (ICU) and tested some simple clinical and biological prognostic factors from the daily practice in a prospective cohort of patients with a standardized management. We have identified systemic blood pressure, serum sodium, serum creatinine, serum C -reactive Protein as prognostic factors. We found an influence of these events on the medium-term evolution of the patients.In a second step we tested the prognostic value of time derived indices of left ventricular function, variables suggested by magnetic resonance imaging studies. In this purpose, we used aplanation tonometry, an original and non-invasive tool. We found that the value of the left ventricular ejection time was associated with in ICU prognosis.In the third part we measured the impact and prognostic value of renal replacement therapy in case of threatening kidney failure in these patients. In a retrospective study, we observed 68 sessions of renal replacement therapy, continuous hemofiltration and intermittent hemodialysis. These sessions were complicated by hypotension in 50 % of cases. The high in ICU mortality and three months mortilty, respectively 47% and 73%, raises the question of the role of extracorporeal life support and urgent transplantation in these patients.These data underscore the severity of acute worsening in patients with PAH. More data are needed to improve the management of these patients and determine the best timing of exceptional treatment such as circulatory support and pulmonary or cardiopulmonary transplantation.

Pulmonary arterial hypertension (PAH) is a group of diseases characterized by avascular obstruction leading to a progressive increase of the resistances in the pulmonary blood flow. The recent progress in the understanding of mechanisms at the origin of this disease underlines the role of extrapulmonary cells, such as circulating stem cells and bone marrow-derived progenitor cells in vascular remodeling and in PAH development. In this thesis we have shown implication of the progenitor cells and chemotactic axis in the vascular remodeling in human and experimental PAH. This work could help to develop new therapies allowing more specific and more effective treatments leading to improved survival of PAH patients. / L’hypertension artérielle pulmonaire (HTAP) est un groupe de maladies qui se caractérise par une obstruction vasculaire conduisant à une augmentation progressive des résistances à l’écoulement sanguin. Le remodelage vasculaire qui implique toutes les couches de la paroi du vaisseau est considéré comme un élément clé dans la pathogenèse de l'HTAP. Les progrès récents dans la compréhension des mécanismes à l'origine de cette maladie soulignent le rôle de cellules extrapulmonaires, telles que des cellules souches circulantes et des progéniteurs dérivés de la moelle osseuse, dans le remodelage vasculaire et dans le développement de l’HTAP. Les thérapeutiques ciblées sur la dysfonction endothéliale ne permettent pas à l'heure actuelle de guérir cette maladie, il est donc nécessaire d’identifier d'autres mécanismes physiopathologiques permettant de développer de nouvelles stratégies thérapeutiques. C’est pourquoi nous avons exploré l’implication des cellules progénitrices et des signaux chimiotactiques dans le remodelage vasculaire au cours de l’HTAP humaine et expérimentale. Nous avons mis en évidence un recrutement de cellules c-kit+ (incluant des progéniteurs et des mastocytes) ainsi que l’expansion de vasa vasorum dans les poumons des patients atteints d’HTAP. Grâce à l’utilisation du modèle expérimentale d’HTAP induit par l’hypoxie chez la souris, nous avons montré le rôle central de la chimiokine CXCL12 et de ses deux récepteurs CXCR4 et CXCR7 dans le recrutement des progéniteurs c-kit+. Le traitement combiné par les antagonistes AMD3100 et CCX771, grâce à leurs actions synergiques, inhibe le remodelage vasculaire pulmonaire, l’hypertrophie cardiaque droite, ainsi que le recrutement des progéniteurs c-kit+, induits par l’hypoxie. Par ailleurs, le blocage de c-kit par l’imatinib améliore également les paramètres d’hémodynamique et diminue le recrutement périvasculaire des cellules c-kit+, probablement en inhibant leurs expansion dans la moelle osseuse. Nous avons également mis en évidence une altération d’une population de progéniteurs mésenchymateux d’origine hématopoïétique, appelés fibrocytes, dans le sang des patients souffrant d’HTAP.Ce travail pourrait contribuer à développer des actions thérapeutiques ciblées permettant la mise en place de traitements à la fois plus spécifiques et plus efficaces susceptibles d’améliorer la survie des patients HTAP.

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.

Made available in DSpace on 2015-09-25T12:23:46Z (GMT). No. of bitstreams: 1 Juliana.pdf: 1395632 bytes, checksum: 91003cc69a2f304a3b3284dfc027b4a8 (MD5) Previous issue date: 2011-08-15 / Chronic kidney disease (CKD) is considered a serious worldwide public health issue. Its increased incidence and prevalence stems from the increasing number of people with hypertension and diabetes, as well as the aging of the population on account of a greater life expectancy. The number of patients who are on renal replacement therapy such as hemodialysis has increased considerably. As a consequence, this has yielded great financial burden for the government, poor quality of life of the individuals involved and increased mortality, because kidney disease is a major risk factor in the sprouting of cardiovascular diseases. This piece of research is the answer to a need to understand more about this disease in order to consolidate knowledge that may support policies of care for the renal disease patients based on more rational guidelines and above all, policies that take the primary prevention as a basis to keep patients from starting hemodialysis or else to delay the need for such procedure. This study, a cross-sectional one, was carried out with hypertensive patients from the Health Center in the suburban district of Bela Vista, registered in Hiperdia, aged at least 35 and at most 98 years old through random sampling. 160 hypertensive patients took part in the survey out of a population of 340 hypertensive patients. The criteria of inclusion were: age above 35 years old and a previous history of hypertension of at least five years. The criteria of exclusion were: having no any preexisting renal disease. The objective was to study the early stages of CKD and associated factors in these individuals. In order to study the CKD, laboratory tests were made, both urine and serum types: serum creatinine, proteinuria (protein / creatinine ratio) in an isolated urine sample and the creatinine clearance was calculated as well, which corresponds to the degree of renal function, using the formula Cockcroft-Gault (CG). These tests were made in the clinical laboratory (LAC) of UEPB. In addition, data were collected from medical records, and a form for interview was prepared. Three months later the tests were repeated to define the diagnosis and classify, in stages, CKD according to the criteria of the Kidney Disease Outcomes Quality Iniciative (K/DOQI). We assessed sociodemographic, lifestyle, and clinical aspects, and adherence to antihypertensive drugs as well. After that the statistical analyses needed to assess the association of CKD with the factors studied were performed, and the chi-square test and the Fisher test were used for that purpose. All the tests took into consideration a significance level of < 0.05. A prevalence of CKD of 14.1% was observed in the present study. Patients detected to have CKD in this study were mostly of stage III CKD. There was a higher prevalence of this disease among females. There was a statistically significant association between CKD and aging with a p &#8804; of 0,001, also with the elevated systolic blood pressure (SBP) with a p &#8804; of 0.019, with increased body mass index (BMI) of old patients with a p &#8804; of 0.013, and with the use of antihypertensive drugs, class ACEI / ARB with p &#8804; of 0.005, as well as the lack of use of adrenergic inhibitors of p &#8804; 0,030. On account of the big picture we get from our analysis there is a pressing need for tracing CKD within risk groups so that the outrageously growing number of patients under replacement therapy is diminished. That can be achieved through strategic actions involving health workers and patients, who use low cost tests, so as to face the situation and which as a result cut down on government spending and which promote a better quality of life for the population as a whole and which effectively support public policies concerning renal patient care with a focus on primary prevention as a sustaining pilar. / A doença renal crônica (DRC) é considerada, no cenário mundial, um grave problema de saúde pública. O aumento da sua incidência e prevalência decorre do crescente número de hipertensos, diabéticos, bem como do envelhecimento da população pela maior expectativa de vida. O número de pacientes que estão em terapia renal substitutiva, como hemodiálise, vem aumentando consideravelmente. Isto traz como reflexo um grande gasto financeiro para o governo, piora da qualidade de vida dos indivíduos envolvidos e aumento da mortalidade, pois a doença renal é um fator de risco importante no surgimento das doenças cardiovasculares. Diante da necessidade de se entender mais acerca desta doença, para consolidar conhecimentos que sirvam de suporte para políticas de atenção ao paciente renal fundamentadas em diretrizes mais racionais, e principalmente que tratem a prevenção primária como a base para postergar ou talvez impedir o ingresso de tantos pacientes à diálise, surgiu motivação para realização desta pesquisa. Este estudo, do tipo transversal, foi realizado com hipertensos do Centro de Saúde da Bela Vista, cadastrados no Hiperdia, com idade mínima de 35 anos e máxima de 98 anos, através de uma amostragem aleatória. Participaram da pesquisa 160 hipertensos de um universo de 340 hipertensos. Os critérios de inclusão foram: idade acima de 35 anos e ser hipertenso por no mínimo 5 anos, e de exclusão: não ter doença renal preexistente. O objetivo foi estudar a DRC em estágios iniciais e fatores associados nestes indivíduos. Para o estudo da DRC foram realizados exames laboratoriais, sérico e urinário: creatinina sérica, proteinúria (relação proteína / creatinina) em amostra isolada de urina, bem como se calculou o clearance de creatinina, que corresponde ao grau de funcionamento renal, através da fórmula de Cockcroft-Gault (CG). Os referidos exames foram feitos no laboratório de análises clínicas (LAC) da UEPB. Além disso, foram levantados dados dos prontuários, bem como foi elaborado um formulário para entrevista. Após três meses os exames foram repetidos para definir o diagnóstico e classificar, em estágios, a DRC segundo os critérios do Kidney Disease Outcomes Quality Iniciative (K/DOQI). Foram avaliados aspectos sociodemográficos, hábitos de vida, clínicos, bem como adesão aos anti- hipertensivos. Após isso foram realizadas as análises estatísticas necessárias para avaliar a associação da DRC com os fatores estudados, sendo utilizados os testes de Qui-quadrado e o teste de Fisher. Em todas as análises foi considerado o nível de significância < 0,05. No presente estudo foi observada uma prevalência de DRC de 14,1%. Dos pacientes detectados como portadores de DRC nesta pesquisa foi observada uma maior prevalência do estágio III da DRC, bem como do sexo feminino. Verificou-se uma associação estatisticamente significante entre DRC e idade (p &#8804; 0,001); pressão arterial sistólica (p &#8804; 0,019); índice de massa corporal (IMC) nos hipertensos idosos (p &#8804; 0,013), e o uso de anti-hipertensivos da classe IECA/BRA (p &#8804; 0,005) e não uso de inibidores adrenérgicos (p &#8804; 0,030). Diante desse contexto, constatou-se a importância de se rastrear a doença renal crônica nos grupos de risco, para poder ser reduzido o crescimento avassalador de pacientes em terapia renal substitutiva, através de estratégias que envolvem o treinamento dos profissionais de saúde e pacientes para o enfrentamento desta situação, e que utilizam exames de baixo custo, trazendo como reflexo redução dos gastos econômicos para o governo e melhora da qualidade de vida dos indivíduos de uma forma geral, colaborando efetivamente com políticas públicas de atenção ao paciente renal focadas na prevenção primária como pilar de sustentação.

A pré-eclâmpsia (PE) é a maior causa de mortalidade e morbidade materna e perinatal. Sua etiologia permanece desconhecida, o que torna impossível a realização de prevenção primária dessa doença. O entendimento do perfil de substâncias que estão alteradas na PE é de relevância para poder atuar preventivamente. Considerando que vários hormônios envolvidos na resposta imunológica participam da fisiopatologia da PE e que, como demonstrado recentemente, a melatonina tem papel relevante na fisiopatologia da inflamação aguda, nossa hipótese seria que este hormônio poderia também atuar fisiopatologia da PE. OBJETIVOS: avaliar o perfil de citocinas e hormônios no soro de pacientes com PE para estabelecer se o eixo imune-pineal estaria ativado nesta doença. MÉTODOS: Realizamos estudo prospectivo caso-controle, no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de Outubro de 2010 a Outubro de 2013. O grupo experimental foi formado por pacientes com PE pura no momento do diagnóstico (sem medicação anti-hipertensiva inicial por 24h). Gestantes saudáveis e normotensas, pareadas por idade materna, idade gestacional e paridade, foram selecionadas como controles. Citocinas (TNF, IL-8, IL-6, IL-1beta, IL-4, IFN-y , VEGF , IL-10, IL-12p40, IL-17 e IL-2), cortisol, níveis séricos de melatonina pela manhã (08h-11h) e à noite (23h- 01h), assim como os níveis de 6-sulfatoximelatonina (6-SMT) nos diferentes períodos do dia (bl1:12h-18h, bl2:18h-24h,bl3:24h-06h,bl4:06-12h) foram avaliados por MULTIPLEX e ELISA. A diferença entre os grupos foi avaliada por Two-way ANOVA seguido de pós teste de Bonferroni. Foi considerada significativamente diferente quando a probabilidade da hipótese nula foi rejeitada (p < 0,05). A correlação entre parâmetros foi avaliada por regressão linear simples e teste de Pearson. RESULTADOS: De um total de 31 pacientes inicialmente avaliadas, 14 gestantes com PE e 12 controles foram incluídas. As características das pacientes (idade materna, paridade e idade gestacional) foram semelhantes em ambos os grupos (p > 0.05). A concentração plasmática de TNF e IL-8 foi significativamente maior em pacientes com PE do que em controles, e não foi detectada a presença de IL-6, IL-1beta, VEGF, IL-10, IL-17, IL-12p40 em ambos os grupos. A concentração de IL-4 foi similar em ambos os grupos. Níveis séricos de IFNy tenderam a ser maiores em pacientes com PE. A análise dos dados mostrou uma correlação significativamente positiva entre as concentrações plasmáticas de melatonina e TNF; melatonina e IL-8; e TNF e IL-8 no grupo PE durante período diurno. Os níveis diurnos de cortisol foram mais altos em ambos os grupos quando comparados com os noturnos; entretanto pacientes com PE apresentam níveis significativamente reduzidos de cortisol pela manhã quando comparados com o grupo controle. Níveis séricos de melatonina na pré-eclâmpsia quando comparados com controles foram maiores pela manhã, mas não à noite. O grupo controle apresentou um padrão esperado do ritmo dia/noite de melatonina, enquanto a pré-eclâmpsia não apresentou diferença significativa entre dia e noite. O ritmo circadiano de 6-SMT foi constatado em ambos os grupos, porém o valor excretado durante o dia foi maior no grupo PE que no controle. CONCLUSÃO: Nossos resultados sugerem que a PE altera negativamente o eixo hipotálamohipófise- adrenal, induzindo um aumento no TNF, que sinaliza uma resposta inflamatória aguda. Além disso, acredita-se que os altos níveis de IL-8 e TNF possam configurar um sistema de retroalimentação que contribui para o desenvolvimento do quadro e ativação do eixo-imune pineal. Portanto, este efeito pode estar associado com o aumento da melatonina diurna na PE, induzida por TNF em células imunocompetentes ativadas. Diante disso, nossos dados sugerem que o aumento tanto de melatonina como de 6-SMT nas pacientes com PE possa ser de origem extra-pineal / Preeclampsia (PE) is a major cause of maternal and perinatal mortality and morbidity. Since its etiology remains unknown, it is impossible to have a primary prevention of the disease. The understanding of the substance profiles that are altered in PE is important to prevent the disease. Considering that many hormones involved in immune response are involved in the physiopathology of PE and that melatonin has a relevant role in the acute inflammatory process, our hypothesis is that this hormone would also be involved in the physiopathology of PE. OBJECTIVES: To analyze the serum profile of cytokines and hormones in pregnant women with PE in order to evaluate if the immune-pineal axis is activated in this disease. METHODS: A prospective case-control study was conducted at the Clinical Hospital USP between October 2010 and October 2013. Only patients with pure PE at the moment of diagnosis (without anti-hypertensive medication for the initial 24h after diagnosis) were included. Normotensive healthy pregnant women that were matched by maternal age, gestational age and parity were included as controls. Cytokines (IL-6, IL-1b, IL-8, TNF and IFNy), cortisol and serum melatonin levels in the morning (08h-11h) and at night (23h-01h), as well as 6-sulfatoximelatonin (6-SMT) levels in different periods of the day (bl1:12h- 18h, bl2:18h-24h, bl3:24h-06h, bl4:06-12h) were measured by MULTIPLEX and ELISA. Differences between groups were analyzed using two-way ANOVA followed by Bonferronis\'s test. Statistical difference was considered when the null hypothesis was rejected (p < 0.05). Correlations between parameters were analyzed using linear regression and Pearson test. RESULTS: From a total of 31 patients initially evaluated, 14 patients with PE and 12 controls were included. Demographics such as maternal age, parity, gestational age at the dosages, body-mass index were similar in both groups (p > 0.05). TNF and IL-8 levels were higher in the preeclampsia group than controls, while IL-6, IL-1beta, VEGF, IL-10, IL-17 and IL-12p40 were not detected in both groups. IL-4 levels were similar in both groups. There was a tendency of higher levels of IFNy, in patients with PE when compared to controls. Our analysis revealed a positive correlation between melatonin and TNF, melatonin and IL-8, TNF and IL-8 in PE group. Daytime cortisol levels were higher in both groups when compared to nighttime; however, patients with preeclampsia had reduced morning levels of cortisol when compared to the control group. Melatonin serum level was higher at daytime, but not at nighttime, in patients with PE when compared to controls. Controls had the expected day/nighttime rhythm of the melatonin levels, while patients with PE did not have it. In contrast, 6-SMT rhythm was observed in both groups, but with higher daytime levels in patients with PE when compared to controls. CONCLUSION: Our results suggest that PE alters negatively the hypothalamic-pituitary-adrenal axis, but induces an increase in TNF, which signalizes an acute inflammatory response. Furthermore, it is believed that high levels of IL-8 and TNF can configure a feedback system that contributes to the development of the disease and immune pineal axis activation. Therefore, this effect may be associated with increased daytime melatonin levels in PE, induced by TNF in immunocompetent cells. Thus, our data suggest that the increased melatonin and 6-SMT in patients with PE may be originated from an extra-pineal axis

Introdução: Diferentes ambientes intrauterinos podem influenciar na variação de peso corporal materno pré-gestacional até seis meses após o parto. A variação de peso é um importante traço materno na direção do ganho de peso gestacional, uma vez que um ganho de peso insuficiente é relacionado ao parto prematuro, ao baixo peso ao nascer ou a um recém-nascido pequeno para a sua idade gestacional, enquanto o seu excesso está associado com o desenvolvimento de diabetes gestacional, parto prematuro, parto cesáreo, recém-nascidos grandes para a sua idade gestacional, retenção de peso materno e, consequentemente, sobrepeso e obesidade. Objetivo: Avaliar a variação do peso materno pré-gestacional até o sexto mês após o parto em puérperas de diferentes ambientes intrauterinos, verificando a associação de fatores sociodemográficos, obstétricos, nutricionais e comportamentais com este desfecho. Métodos: Trata-se de um estudo observacional longitudinal, utilizando uma amostra de conveniência de pares de mães e filhos divididos em quatro grupos: gestantes diabéticas (DM), hipertensas (HAS), tabagistas (TAB) e um grupo controle (CTL). A amostra foi recrutada em três hospitais públicos de Porto Alegre, capital do Rio Grande do Sul, no período de 2011 a 2016. Entrevistas domiciliares e no Centro de Pesquisa Clínica do Hospital de Clínicas de Porto Alegre foram realizadas para a coleta de dados. Foram coletadas informações de peso corporal materno, índice de massa corporal (IMC) pré-gestacional, ingestão alimentar, orientação nutricional durante a gestação e práticas de lactação como variáveis nutricionais-antropométricas; escolaridade materna, etnia, idade, renda familiar e estado civil, como variáveis sociodemográficas; planejamento da gestação, tipo de parto, número de consultas pré-natais e paridade como variáveis obstétricas e percepção de estresse, sintomas depressivos, e nível de atividade física durante a gestação, como variáveis comportamentais. As variáveis nutricionais-antropométricas, sociodemográficas e obstétricas foram coletadas por questionários estruturados. As variáveis comportamentais foram coletadas por meio de instrumentos validados (Escala de Estresse Percebido – 14, Escala de Depressão Pós-Parto de Edimburgo e Questionário Internacional de Atividade Física – versão curta). Regressões lineares múltiplas e modelos de estimativas generalizadas (GLMs) foram conduzidas para a identificação dos fatores associados à variação de peso materno 6 meses após o parto. Todas as análises foram realizadas no programa SPSS, versão 18.0, e o nível de significância adotado para todas as análises foi fixado em 5%, exceto para as comparações aos pares por GLMs, sendo estes em 10%. Resultados: A amostra foi composta de 124 puérperas distribuídas entre diferentes ambientes intrauterinos e um grupo controle. Para todas as GLMs, as medidas de peso materno foram ajustadas para algumas variáveis (estatura materna, paridade, escolaridade materna e tipo de parto), e foram fixadas 3 medições de tempo (peso pré-gestacional, peso antes do parto e 15 dias após o parto) para todas as análises. Os grupos DM e TAB apresentaram maior peso antes do parto, quando comparados com as demais medições. O grupo CTL apresentou maiores pesos 15 dias e 1 mês após o parto, enquanto o grupo HAS apresentou maior peso antes e 15 dias após o parto, em relação às outras avaliações. Um modelo hierárquico associou proximamente o diagnóstico materno de hipertensão arterial e o IMC pré-gestacional de sobrepeso com o ganho de peso materno aferido até o sexto mês após o parto (a diferença entre o peso materno ao sexto mês e o peso pré-gestacional). Já os IMCs pré-gestacionais maternos de desnutrição e de obesidade se associaram com a diminuição de peso corporal seis meses após o parto. Conclusões: Em uma população de diferentes ambientes intrauterinos verificou-se que o IMC de sobrepeso prégestacional e o diagnóstico de hipertensão arterial materna se relacionam com o aumento de peso corporal materno seis meses após o parto. / Introduction: Different intrauterine environments may influence maternal prepregnancy weight variation up to six months after delivery. Gestational weight gain has important maternal-infant repercussions, affecting outcomes of pregnancy and delivery. Insufficient weight gain is related to preterm birth, low birth weight and to newborns small for their gestational age, while its excess is associated with the development of gestational diabetes, preterm delivery, cesarean delivery, newborns large for their gestational age, maternal postpartum weight retention and, consequently, overweight and maternal obesity. Aim: To evaluate the prepregnancy weight gain up to the sixth month after delivery in mothers from different intrauterine environments, verifying its association with sociodemographic, obstetric, nutritional and behavioral factors. Methods: This was a longitudinal observational study, using a convenience sample of mothers and children divided according to four groups of pregnant women: diabetic (DM), hypertensive (HM), smokers (SM), and control (CM) women. The sample was recruited from three public hospitals in Porto Alegre, capital of Rio Grande do Sul, from 2011 to 2016, and the interviews were home conducted or at the Clinical Research Center of the Clinical Hospital of Porto Alegre. Data collection included information on maternal body weight, prepregnancy body mass index (BMI), food intake, nutritional orientation during gestation and lactation practices as nutritionalanthropometric variables; maternal educational level, ethnicity, age, family income and marital status as sociodemographic variables; gestation planning, type of delivery, number of antenatal care visits and parity as obstetric variables; and perceived stress, depressive symptoms, and physical activity level during gestation as behavioral variables. The sociodemographic, nutritional, anthropometric and obstetric variables were collected by structured questionnaires, and the behavioral ones by validated instruments (Perceived Stress Scale – 14, Edinburgh Postpartum Depression Scale, and the International Physical Activity Questionnaire – short version). Multiple linear regressions and Generalized estimates models (GLMs) were conducted to identify factors associated with maternal weight variation up to six months after delivery. The significance level adopted for all analyzes was set at 5%, except for the pairwise comparisons by GLMs, which were set at 10%. All analyzes were performed in the SPSS, version 18.0. Results: The samples consisted of 124 mothers distributed among the four different intrauterine environments. For all GLMs analyzes, maternal weight measures were adjusted for some variables (maternal height, parity, educational level and the type of delivery) and 3 measurements were fixed (prepregnancy, preceding delivery, and 15 days weight after delivery). The DM and SM groups presented greater weight preceding delivery when compared with all other measurements. The CM group displayed higher weights 15 days and 1 month after delivery, while the HM group presented higher weight 15 days after delivery, in relation to other evaluations. A hierarchical model associated maternal diagnosis of hypertension and prepregnancy BMI of overweight with maternal weight gain measured up to the sixth month after delivery (the difference between maternal weight at 6 months and prepregnancy weight). Maternal prepregnancy BMIs of malnutrition and obesity were associated with a decrease in body weight gain six months after childbirth. Conclusions: In a population of different intrauterine environments, it was verified that the prepregnancy overweight BMI and the diagnosis of maternal hypertension were related to maternal body weight gain six months after delivery.

Mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of heritable pulmonary arterial hypertension (PAH). However, given the reduced penetrance of BMPR2 mutations in affected families, a major outstanding question is the identity of additional factors or pathways that are responsible for the manifestation of clinical disease. Furthermore, limited human tissue is available for study and usually only from patients with end-stage disease, making it difficult to understand how PAH is established and progresses. Alternative human models of PAH are therefore required. This thesis describes the characterisation of the first human iPSC-derived smooth muscle cell (iPSC-SMC) model of PAH and elucidates the role of BMPR2 deficiency in establishing PAH-associated phenotypes in iPSC-derived SMCs. To achieve this, I used CRISPR-Cas9 gene editing to generate wild-type and BMPR2+/- iPSC lines with isogenic backgrounds which were subsequently differentiated into lineage-specific iPSC-SMCs that displayed a gene expression profile and responses to BMP signalling akin to those present in distal pulmonary artery smooth muscle cells (PASMCs). Using these cells, I found that the introduction of a single BMPR2 mutation in iPSC-SMCs was sufficient to recapitulate the pro-proliferative and anti-apoptotic phenotype of patient-derived BMPR2+/- PASMCs. However, acquisition of the mitochondrial hyperpolarisation phenotype was enhanced by inflammatory signalling and required an interaction between BMPR2 mutations and environmental stimuli provided by exposure to serum over time. Furthermore, I showed that BMPR2+/- iPSC-SMCs had an altered differentiation state and were less contractile compared to wild-type iPSC-SMCs, phenotypes which have not been observed previously in PAH-derived PASMCs. Finally, RNA sequencing analysis identified genes that were differentially expressed between wild-type and BMPR2+/- iPSC-SMCs and may hence provide further insights into PAH pathobiology. The iPSC-SMC model described in this study will be useful for identifying additional factors involved in disease penetrance and for validating therapeutic approaches that target BMPR2.

RESUME Contexte La maladie rénale chronique (MRC) constitue un problème mondial majeur de Santé publique. Son ampleur réelle en Afrique demeure inconnue. Malgré, les progrès réalisés dans lidentification et la prévention de la MRC et le traitement de la phase terminale de la maladie, ces domaines restent un grand défi en Afrique Sub-saharienne à cause du manque cruel des ressources nécessaires. Objectif Ce travail a pour objectif de cerner lépidémiologie de la MRC à Kinshasa en vue délaborer des stratégies de dépistage précoce et de prévention adaptées. Le but ultime est de contribuer à la réduction de la morbidité et la mortalité rénales mais aussi cardiovasculaires. Méthodes : Le présent travail est une revue synthétique de 4 études menées à Kinshasa : Une étude documentaire des 412 cas réalisée aux Cliniques Universitaires de Kinshasa (CUK), durant la période allant de Janvier 2001 à Décembre 2004 pour identifier le profil épidémiologique et clinique des patients atteints de la MRC. Les résultats de cette étude ont motivé le besoin dévaluer lampleur de la maladie dans la population et dans les structures de santé existantes. Il en a résulté trois études. Une étude épidémiologique de type transversal effectuée à partir de 503 ménages sélectionnés de manière aléatoire selon un plan de sondage à plusieurs degrés dans 10 des 35 Zones de santé composant Kinshasa, capitale de la République Démocratique du Congo (RDC). Une seconde étude, aussi de type transversal, réalisée à partir de 527 patients à risque de MRC, fréquentant neuf Centres de santé (CS) de niveau primaire et quatre hôpitaux de référence de la ville de Kinshasa. Une campagne de dépistage de la protéinurie et des facteurs de risque de la MRC chez 3.018 sujets. Résultats : Lanalyse des données enregistrées en milieu hospitalier a montré : Une augmentation annuelle progressive et inquiétante des proportions (60,6%, 65,9%, 67,4% et 70,5%) de la MRC admises aux CUK quasi exclusivement au stade terminal de la maladie nécessitant une prise en charge rapide par la dialyse péritonéale. Malheureusement, 11% seulement pouvaient accéder à ce traitement onéreux. La majorité des malades à prédominance masculine (sexe ratio 2,2/1) décèdent prématurément à un âge moyen (45,8±14,5 ans), à un moment de leur vie où ils sont encore économiquement très productifs. Les causes probables de la MRC chez ces patients sont la glomérulonéphrite chronique (37%), lhypertension artérielle (27%) et le diabète sucré (26%). Les études transversales dans la population générale et les institutions de santé traditionnelles de la ville de Kinshasa ont mis en évidence les caractéristiques épidémiologiques suivantes: La prévalence globale (tous les stades confondus) de la MRC est de 12% dans la population générale, mais 3% seulement sont conscients de leur état de rein. Celle de linsuffisance rénale chronique (IRC) estimée par le débit de filtration glomérulaire (DFGe) < 60 ml/min/1,73 m² est de 8%. Cette MRC touche particulièrement les adultes (52±15 ans). Les facteurs de risque potentiels de la MRC, liés à des maladies non transmissibles (MNT) sont en progression comparativement aux études antérieures. Ces facteurs sont lhypertension (28%), le diabète sucré (12%) et lobésité (15%). Dans les Centres de santé de Kinshasa, la prévalence globale de la MRC méconnue parmi les sujets à risque est le triple de celle rapportée dans la population générale de la même ville. Parmi cette population malade, les proportions de la MRC atteignent 44% chez les hypertendus, 39% chez les diabétiques ; 16% chez les obèses et 12% chez les sujets infectés par le Virus de limmunodéficience humaine (VIH). 82% des diabétiques avaient une glycémie à jeun non contrôlée (> 126 mg/dl) et 78% dhypertendus navaient pas une pression artérielle sous la cible la moins stricte, cest à dire contrôlée à moins de 140/90 mmHg. Les déterminants identifiés de lIRC ont été lhypertension (OR ajusté 3,3), le diabète sucré (OR 2) et la protéinurie (OR 2,9). Les principaux déterminants de DFGe < 60 ml/min/1,73 m² chez les diabétiques étaient lâge et la durée du diabète sucré. Les résultats de la campagne de dépistage de la protéinurie et des facteurs de risque de la MRC ont révélé ce qui suit : La prévalence de la protéinurie a été de 17%. Les autres facteurs de risque de la MRC identifiés chez les sujets en bonne santé apparente ont été: lhypertension (37%), le diabète sucré (9%), lobésité (11%) et le syndrome métabolique (5%). Pour identifier un cas de protéinurie, il est nécessaire de dépister 4 diabétiques, 5 hypertendus, 4 sujets avec syndrome métabolique, 5 sujets âgés de plus de 50 ans et 9 personnes ne présentant aucune des conditions susmentionnées. Les déterminants majeurs de la protéinurie étaient lâge > 50 ans (OR ajusté 1,4), le diabète sucré (OR 1,3), le surpoids (OR 1,2) et le niveau socio-économique bas (OR 1,4). Conclusion : Ces études établissent pour la toute première fois dans une population africaine la forte prévalence de la MRC et ses facteurs de risque notamment lhypertension, le diabète sucré, lobésité, lâge > 50 ans et linfection à VIH. La maladie affecte ladulte encore jeune comparée aux Etats-Unis où elle prédomine à la vieillesse. Nos études ont montré aussi à la fois la forte prévalence de la protéinurie chez les sujets sans facteurs de risque traditionnels précités, le déficit du dépistage précoce de la MRC et de prise en charge des facteurs de risque dans le système de santé traditionnel favorisant la référence tardive et/ou les décès prématurés, ainsi que les limites malheureuses par manque de moyens de la prise en charge de la maladie au stade tardif. Ces études plaident pour la nécessité dun renforcement de la capacité du personnel soignant dans le domaine de détection précoce et de prise en charge des MNT dont la MRC. Elles montrent également quun dépistage annuel de masse de la population de la protéinurie et des facteurs de risque de la MRC est faisable et pourra, nous lespérons, constituer la base dune élaboration dune politique nationale de prévention. Mots-clé : diabète sucré, équation (Cockcroft & Gault, MDRD), hypertension artérielle, maladie rénale chronique, prévalence, protéinurie. SUMMARY Background Chronic kidney disease (CKD) is a worldwide public health problem. Little is known about its burden in Africa. Despite the advances in identification and prevention of CKD and management of end stage renal disease (ESRD), sub-Saharan Africa has been left far behind regarding these advances. This is because of the scarcity of necessary resources. Objective This work was designed to ascertain the epidemiologic knowledge of CKD in Kinshasa in order to define suitable baseline preventive strategies. It would aims ultimately, to reduce the morbidity and mortality from renal disease and related cardiovascular events. Methods: This current work summarises results of 4 studies undertaken in Kinshasa: A retrospective cross sectional study of 412 cases which was done in the Academic hospital of Kinshasa (AHK), from January 2001 to December 2004 to identify the epidemiologic and clinical profile of patients with CKD. The results of this study motivated us to investigate the extent of the burden of CKD in the population and the existing structures of healthcare. Thus, three further studies were carried out; In an epidemiologic cross sectional study, 503 adult residents in 10 of the 35 health zones of Kinshasa, the capital of the DRC were studied in a randomly selected sample; In a second study of higher risk subjects, 527 people in primary and secondary health care areas in the city of Kinshasa were studied from a random sample of at-risk out-patients with hypertension, diabetes, obesity, or who were infected by HIV; Finally, a mass screening for proteinuria and CKD risk factors was conducted in Kinshasa which involved 3,018 subjects. Results: The analysis of the data recorded in health care had showed: An overwhelmingly annual increasing proportion of CKD (60.6%, 65.9%, 67.4% and 70.5%) in AHK, unfortunately for the majority at stage 5, in other words at ESRD. Tragically enough, only 11% of them could be treated by peritoneal dialysis depending on their financial resources. The majority of the patients are young males (sex ratio 2.2/1) undergoing premature death (45.8±14.5). The probable causes of CKD in these subjects were chronic glomerulonephritis (37%), hypertension (27%) and diabetes mellitus (26%). The cross-sectional studies in the general population and the traditional structures of health care (HC) of the city of Kinshasa highlighted the following: The overall prevalence of CKD is 12% in the general population, but only 3% of those with CKD were aware of their condition. The prevalence of chronic renal failure (CRF) (eGFR < 60 ml/min/1.73 m ²) is 8%; CKD affects particularly young adults (52±15 years); Risk factors for CKD considered in this study, including hypertension (28%), diabetes (12%) and obesity (15%), are increasing compared to the former studies. In HC, the overall prevalence of undiagnosed CKD among at-the risk subjects is three times higher the prevalence of CKD in the general population of the same city. In those with the at-risk conditions, the % of CKD was: 44% in the hypertensive, 39% in the diabetics; 16% in the obese and 12% in those who were infected by the human immunodeficiency virus (HIV). 82% of those with history of diabetes had fasting serum glucose levels (> 126 mg/dl), and 78% of those with a history of hypertension did not have blood pressure controlled to less than 140/90 mmHg. The strongest determinants of CRF or CKD 3+ were: hypertension (adjusted OR 3.3), diabetes (OR 2) and proteinuria (OR 2.9). The principal determinants of eGFR < 60 ml/min/1.73 m² in the diabetic patients were age and the duration of diabetes. The results of the campaign of early detection for proteinuria and CKD risk factors revealed that: The prevalence of proteinuria was 17%. The other CKD risk factors identified were: hypertension (37%), diabetes (9%), obesity (11%) and metabolic syndrome (5%). To identify 1 case of proteinuria, one would need to screen 4 persons with diabetes, 5 persons with hypertension, 4 subjects having metabolic syndrome, 5 subjects aged ≥ 50 years and 9 people without any of the conditions mentioned above. The strongest determinants of proteinuria were age > 50 years (adjusted OR 1.4), diabetes (OR 1.3) and overweight (OR 1.2) and low socioeconomic status (OR 1.4). Conclusion: This work documents for the first time in Africa the high prevalence of CKD and its risk factors mainly hypertension, diabetes, obesity and HIV infection. CKD affects younger people in DRC, in contrast to the United States, where CKD is more prevalent in older. Our work also shows the high prevalence of proteinuria among subjects with neither diabetes nor hypertension, the deficit of the early detection and management of CKD risk factors in the traditional health care system leading to late referral or premature deaths, and the limits of renal replacement treatment. They also show that an annual mass screening of the population for proteinuria and CKD risk factors is feasible and will, it is hoped, provide the basis for building a nationwide prevention strategy. Key words: chronic kidney disease, diabetes mellitus, equation (Cockcroft &Gault, MDRD), arterial hypertension, prevalence, proteinuria.

La décompensation cardiaque se manifeste par une symptomatologie de dyspnée et de fatigue, et par une diminution de l’aptitude aérobie. La décompensation cardiaque peut être globale ou gauche (DCG), ou droite comme dans le cas de l’hypertension artérielle pulmonaire (HTAP). Les mesures fonctionnelles de repos (fonction ventriculaire gauche ou pression artérielle pulmonaire moyenne) sont peu corrélées à l’aptitude aérobie, qui est cependant un élément important de la mise au point et du suivi clinique des patients atteints de DCG ou d’HTAP. L’aptitude aérobie est évaluée par une ergospirométrie. Réalisée sur cycloergomètre ou sur tapis roulant elle mesure l’évolution des variables ventilatoires (ventilation, consommation en oxygène et production de CO2), la fréquence cardiaque et la tension artérielle lors d’un effort à intensité croissante jusqu’à l’effort maximal. Elle apporte une analyse fine du comportement à l’exercice des patients, de la cause de la limitation à l’effort et permet la détermination précise de la consommation d’oxygène maximale (VO2max). Plus simple que l’ergospirométrie, le test de marche de 6 minutes (TDM6) mesure la distance maximale parcourue en marchant 6 minutes. Il évalue la réponse intégrée des systèmes cardiovasculaire, respiratoire et musculaire à l’effort, mais, contrairement à l’ergospirométrie, il ne permet pas d’identifier les facteurs déterminants l’aptitude aérobie. Le TDM6 est corrélé de façon significative, mais non étroite, à la VO2 max et à la classe fonctionnelle telle qu’évaluée par l’échelle à 4 points de la New York Heart Association. Les travaux réunis dans le présent travail ont eu pour but de contribuer à l’étude de la pathophysiologie de l’aptitude aérobie et à la compréhension des tests utilisés pour l’évaluer dans l’HTAP et de la DCG. Dans une première étude, nous avons comparé le profil ergospirométrique et le périmètre de marche de 6 minutes chez les patients DCG ou HTAP. Les résultats montrent que la VO2 max et le TDM sont diminués dans les mêmes proportions chez des patients à handicap fonctionnel (NYHA) comparable, avec toutefois une propension plus marquée à l’hyperventilation dans l’HTAP. Dans une seconde étude, nous avons mesuré la réponse métabolique au TDM6 au moyen d’un ergospiromètre portable chez des patients HTAP. Les résultats montrent que le TDM6 est réalisé à une VO2 correspondant à la VO2max mesurée à l’ergospirométrie sur cycloergomètre, avec cependant une ventilation, un quotient respiratoire et une fréquence cardiaque inférieures. Durant le TDM6, les patients stabilisent leur effort à un quotient respiratoire légèrement inférieur à 1. Ces résultats s’expliquent soit par la cinétique de la VO2 durant l’ergospirométrie à protocole standardisé comportant un incrément de charge trop rapide par minute, soit par une différence des masses musculaires mises en œuvre durant la marche ou l’effort sur bicyclette. Ces résultats suggèrent que le TDM6 pourrait être un test plus adéquat que l’ergospirométrie pour évaluer l’aptitude aérobie dans l’HTAP. Dans un troisième travail, plus modeste, nous avons réalisé la réplique du précédent, dans la DCG. Nous y avons observé les mêmes résultats. Dans un dernier travail nous avons évalué la valeur pronostique de l’ergospirométrie et du TDM6 dans l’HTAP. Nous avons analysé les ergospirométries et TDM6 de 65 patients atteints d’HTAP et discerné un sous groupe de patients atteints d’HTAP idiopathique ou associée à la prise d’anorexigène. Le TDM6 et le produit « distance x poids » étaient pronostiques de mortalité dans le groupe entier de patients et dans le sous groupe de patients atteints d’HTAP idiopathique ou associée à la prise d’anorexigène. La pente VE/VCO2 n’était facteur pronostique de mortalité que dans le groupe de patients atteints d’HTAP idiopathique ou associée à la prise d’anorexigène. La VO2pic n’était prédictive de mortalité dans aucun des groupes de patients. En conclusion, nos travaux ont montré que la DCG et l’HTAP menaient à une diminution similaire de la capacité à l’exercice. Ils ont également contribué à montrer l’intérêt du TDM6 (avec mesures ergospirométriques) dans l’évaluation de cette amputation de l’aptitude à l’effort. Le TDM6 paraît plus adéquat pour la mesure de l’aptitude purement aérobie (quotient respiratoire < 1). Ceci permet probablement de comprendre la supériorité du TDM6 par rapport à l’ergospirométrie en tant que facteur pronostique et en sensibilité aux effets d’interventions thérapeutiques.

EINLEITUNG: Die „Hypertension and Diabetes Risk Screening and Awareness (HYDRA-)-Studie“ beschrieb und quantifizierte erstmals umfassend und bundesweit in einer Reihe von Publikationen1- 10 (siehe auch www.hydra-studie.de) die hausärztliche Versorgungssituation von Patienten mit arterieller Hypertonie und Diabetes mellitus. Mit Hilfe dieser Studie konnten neue Erkenntnisse zur Häufigkeit und Schwere, zu häufigen Begleit- oder Folgeerkrankungen, sowie zur Therapie dieser beiden Erkrankungen gewonnen werden. Insgesamt wurden im September 2001 in einer bundesrepräsentativen Stichprobe von 1.912 zufällig ausgewählten primärärztlichen Praxen (auf der Grundlage des IMS-Registers, Instituts für Medizinische Statistik, Frankfurt) eine Stichtagsbefragung von 45125 nicht-selektierter, konsekutiver Patienten ab dem 16. Lebensjahr durchgeführt (60,0 Prozent Frauen; Altersgruppen: 12,7 Prozent 16 bis 29 Jahre, 21,9 Prozent 30 bis 44 Jahre, 23,2 Prozent: 45 bis 59 Jahre, 42,2 Prozent: = 60 Jahre) und ihre Erkrankungen und Interventionen dokumentiert. Im folgenden Beitrag sollen die Ergebnisse für Sachsen gesondert berichtet und den bundesdeutschen Ergebnissen gegenübergestellt werden. In Sachsen nahmen an der HYDRA-Studie n=126 Ärzte teil, die an zwei aufeinander folgenden Studientagen insgesamt 2.407 Patienten dokumentierten. Die Datenerhebung erfolgte im Rahmen eines klinischepidemiologischen Stufendesigns: (i) Zunächst wurden die teilnehmenden Ärzte in einer Voruntersuchung hinsichtlich ihrer Ausbildungsund Praxismerkmale, ihren Erfahrungen und Problemen mit Hypertonikern und Diabetikern sowie ihren Einstellungen zu diesen Patientengruppen befragt. (ii) Am Erhebungstag wurden alle Patienten, die die teilnehmenden Praxen aufsuchten, ausführlich zu ihren Beschwerden, Krankheiten sowie zu ihrem Gesundheitsverhalten befragt (Patientenfragebogen). (iii) Die Ärzte dokumentierten dann für jeden Patienten die von ihnen vergebenen klinischen Diagnosen sowie die Therapie (Arztbogen); zudem wurden ausgewählte Messwerte am Studientag erfasst (Blutdruck, Mikroalbuminurie mit Micral-Teststreifen) und weitere Laborwerte aus der Akte entnommen. Für die ärztlichen Diagnosen wurden keine Vorgaben (zum Beispiel Nennung von Grenzwerten) gemacht. Die Methodik der Studie und wesentliche Ergebnisse wurden in einer Reihe von Originalarbeiten detailliert beschrieben.5