Stroke is the second most common cause of death worldwide and the commonest cause of dependency, creates a huge societal burden and is responsible for billions of pounds in health and social care costs. About 30% of strokes occur in individuals with a previous transient ischaemic attack (TIA) or minor stroke. Effective prevention would minimise the consequences. However, the diagnosis of TIA is difficult, particularly by non-experts. About 50% of patients with a suspected TIA or minor stroke have atypical TIAs or a non-vascular diagnosis (TIA/minor stroke mimics). Although there is some evidence that non-specific Transient Neurological Attacks (TNAs) have an increased risk of acute vascular events, the evidence is still both thin and controversial. The aim of my thesis has been to evaluate the burden of TIA/minor stroke mimics, TNAs and all acute cerebrovascular events among all referrals from the general population to a TIA clinic; to determine the reliability of clinical diagnosis of TIA and non-specific TNA; to improve the classification of non-specific TNAs; and to predict the risk of stroke and other major vascular events after a non-specific TNA and TNA syndromes. I have collected and analysed data from a population-based study, the Oxford Vascular Study (OXVASC). OXVASC is an ongoing prospective, population-based incidence study of all vascular diseases in all territories in Oxfordshire, UK, which started in 2002. The study population comprises approximately 92,728 individuals registered with nine GP practices and uses multiple overlapping methods of "hot" and "cold" pursuit to identify patients with acute vascular events. The research described in this thesis has several clinically relevant findings which can contribute to improving the diagnosis and treatment of patients with suspected TIAs. First, I highlighted that TIA/minor stroke mimics (mimics) were responsible for one quarter of all suspected TIAs, had similar short- and long-term risk of acute cardiac events as did TIAs, and that the majority (70%) of mimics were complex neurological conditions. Second, I showed that TIA/minor ischaemic strokes are each more common than major ischaemic strokes and that TIA/minor ischaemic stroke patients together had two-thirds of all recurrent strokes and two-thirds of all myocardial infarctions and sudden cardiac deaths. Moreover, the 10 years' cumulative risk of stroke in patients with TIA, minor stroke and major stroke was very high and the risk of death among all cerebrovascular events was greater than 50%. Third, I found that the crude incidence rate of TNAs per 1000 people in OXVASC was slightly higher than the crude incidence rate of TIAs (0.73 versus 0.67) and increased with age. In addition, I reported that among TNA syndromes, transient isolated vertigo, unilateral sensory symptoms, migraine-aura like events and transient confusion had high incidence rates, whereas transient total paralysis and transient speech arrest had low incidence rates. Fourth, I showed that about one-third of TIAs seen in the first 10 years of OXVASC did not fulfil the classical criteria (NINDS-negative TIA) and had the same short- and long-term risk of stroke as NINDS-positive TIAs. Fifth, although the 90 days stroke risk after a TNA was lower than after a NINDS-positive TIA, in the post 90 days up to 10 years period the risk of recurrent stroke was not significantly different between the two groups. Sixth, the risks of stroke were higher than expected in the background population in all TNA categories (focal-TNA, non-focal TNA and focal plus non-focal TNA) and all TNA syndromes (isolated brainstem syndrome, migraine-like syndrome, isolated sensory syndromes, isolated visual disturbance, isolated speech disturbance, transient confusion and transient unresponsiveness) except transient amnesia. Moreover, non-focal TNAs and focal plus non-focal TNAs had a six times higher risk of stroke than expected and a similar risk to NINDS-positive TIAs. Finally, transient confusion and transient unresponsiveness had a relative risk of stroke nine times higher than expected and twice the risk of NINDS-positive TIAs.

High expression levels of the gene BAALC (brain and acute leukemia, cytoplasmic) are associated with poor prognosis in acute myeloid leukemia (AML) patients, but the underlying mechanisms are not yet understood. We evaluated the prognostic significance of expression levels of miR-3151, a newly discovered microRNA embedded in intron 1 of the BAALC gene, in a cohort of 179 older (≥60 years) cytogenetically normal AML (CN-AML) patients, in the context of established molecular markers and especially with regard to the possible interplay with its host gene BAALC. In multivariable analyses, high miR-3151 was associated with shorter disease-free and overall survival (OS), while higher BAALC expression strongly predicted failure of complete remission attainment and OS. Patients exhibiting both high miR-3151 and BAALC expression had worse outcome than patients expressing low levels of either one of the genes or both. Next, gene - and microRNA-expression profiles associated with miR-3151 expression were derived using microarrays, and a pathway analysis of the miR-3151 associated gene signature was performed using Ingenuity software. High miR-3151 expressers showed downregulation of genes involved in transcriptional regulation, post-translational modifications and cell-cycle control. Two genes of the ubiquitination pathway, FBXL20 and USP40, were experimentally validated as direct miR-3151 targets. In summary, we identified high expression levels of the intronic miR-3151 as a novel, independent prognosticator for poor outcome in CN-AML. Interestingly, miR-3151 impacted differently on outcome than its host gene BAALC; and the combination of both markers identified a patient subset with the poorest outcome, suggesting that the microRNA and its host gene contribute to clinical and prognostic features of CN-AML independently and through distinct mechanisms. This is the first example of the interplay of an intronic miR and its host gene in leukemia. Its discovery may have important biologic implications for future targeted treatment strategies.:Bibliografische Beschreibung 1 Referat / Abstract 2 Publikation /Publication 6 Zusammenfassung / Conclusion 16 Referenz der Publikation / Reference of the publication 27 Komplette Publikationsliste / Complete List of Publications 28 Lebenslauf / Curriculum Vitae 31 Erklärung über die eigenständige Abfassung der Arbeit 35 Danksagung / Acknowledgements 36

No description available.

published_or_final_version / abstract / Surgery / Master / Master of Surgery

Rheumatoid arthritis (RA) which affects 0.5-1% of the world population and is characterised by joint erosions and presence of the autoantibodies anti-citrullinated protein antibodies (ACPA) and rheumatoid factor. Collagen II (CII) is a joint-specific antigen and we have shown that antibodies against CII (anti-CII) are present in around 8% of RA patients. RA patients with anti-CII are characterized by acute RA onset with elevated CRP and early joint erosions at the time of RA onset. Polymorphonuclear granulocytes (PMN) and peripheral blood mononuclear cells (PBMC) are abundant in RA synovial fluids, where they can interact with anti-CII, thus forming immune complexes (IC) with CII. In my thesis I have shown that PMN upregulated the cell surface markers CD66b and CD11b and downregulated CD16 and CD32 after stimulation with anti-CII IC. These changes in CD66b and CD16 associated to joint erosions to a larger extent than did PBMC responses to anti-CII IC. PMN cocultured with PBMC and stimulated with anti-CII IC showed augmented chemokine production that was dependent on TLR4 and functionally active PMN enzymes. This mechanism can lead to accumulation of inflammatory cells in joints of RA patients who are anti-CII positive around the time of RA diagnosis, and may thus help explain the acute onset RA phenotype associated with anti-CII. In a large Swedish RA cohort, anti-CII associated with elevations in clinical and laboratory measures of disease activity at diagnosis and until 6 months, whereas ACPA associated with late inflammation. Anti-CII seropositive RA was associated with improvements in clinical measurements and was negatively associated with smoking in contrast to ACPA that was associated with worseneing of clinical symptoms and associated positively with smoking. Anti-CII levels associated to  HLADRB1*03 and  HLADRB1*01 whereas ACPA showed negative association to HLA-DRB1*03. In a Malaysian RA cohort anti-CII also associated to elevated CRP at the time of diagnosis. Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse  to the clinical, genetic and smoking associations described for ACPA. Early determinations of anti-CII in parallel to ACPA predict the inflammatory outcome in RA.

There is an abundance of reports and articles on the extent of future bioenergy usage. Decision-makers might turn to bioenergy projections in hopes of making informed decisions for policies or investments. This report aims to highlight irregularities and differences regarding calculations and results in 15 global bioenergy projection studies for the year 2050, and to find underlying connections by applying a metaanalysis with a methodological focus. Statistical distributions were made for the projected global bioenergy potentials. A growth rate study based on the projected global bioenergy potentials was made and used as a simple “reality check”. Regarding Sweden and the EU, it was investigated whether decisions has been made based on estimated bioenergy potentials. The final aim was to make recommendations for bioenergy decision-makers and policy-makers. There are many statistical distributions fitting the projections for 2050. The distribution functions showed that with a 95 % confidence level, the bioenergy projections in 2050 is 151.3 EJ. The interquartile range of all studies included in this report for primary bioenergy in the year 2050 was shown to be 120-400 EJ, with minimum value of 30 EJ and maximum of 1600 EJ. A mere third of the projection values were in the vicinity of a linear or exponential trendline based on historical values. The historical annual average growth rate for bioenergy from 1971 to 2011 was found to be 1.9 percent. A higher growth rate is required to achieve the larger quantities that are projected in most studies, the most extreme rate was 7.6 percent, which is far above the average. The EU has adopted a biomass action plan partly based on bioenergy projections by the European Energy Agency in 2006. National and international energy projection reports influence Swedish politics, albeit not directly in propositions. The difference between individual reports and articles projected bioenergy level in 2050 is significant. It is recommended to read more than one. Most forecasting models and estimates will likely perform poorly numerically, so it is recommended to look for underlying factors, connected longterm trends, or behavioral consequences.

Title: Finances in Tennis: Analysis and Prognosis of Prize Money Objectives: Analysis of prize money trend in tennis and its prognosis until the year 2030, comparison of prize money in tennis with earnings in selected sports. Methods used: Prognostic methods in Microsoft Excel - linear, exponential and power trendlines, R-squared value. Results: Prize money comparison of tennis tournaments at different categories, summary of prize money prognosis in tennis until the year 2030. Key words: Finances, prize money, sport, tennis, prognosis.

L’endocardite infectieuse est une maladie grave dont sont victimes chaque année près de 2000 personnes en France et 17000 aux Etats-Unis. Malgré les progrès thérapeutiques, le taux de décès reste encore élevé avec des chiffres d’environ 20% pour la seule période hospitalière. Ces échecs sont en partie la conséquence d’un diagnostic souvent trop tardif et d’une évaluation pronostique insuffisante. En effet, il semble que la stratégie pour réduire la mortalité repose sur l’utilisation de nouveaux outils pour un diagnostic et une stratification du risque plus rapides, une diminution du délai d’instauration du traitement antibiotique, un transfert des patients à haut risque vers des centres médico-chirurgicaux spécialisés, des indications chirurgicales plus larges et un suivi prolongé.Depuis plusieurs années nous avons développé un programme de recherche basé sur une étroite collaboration entre les chercheurs de l’UMR 6236-CNRS et les médecins et chirurgiens des services de cardiologie et de chirurgie cardiaque. Cette thèse rapporte les résultats de cette recherche translationnelle sur la prise en charge des endocardites, synthèse de l’expérience clinique et fondamentale acquise par notre équipe. Nous avons démontré que la standardisation des processus de diagnostic et de décisions chirurgicales au sein d’une équipe multidisciplinaire permet de réduire la mortalité. Afin d’améliorer encore cette prise en charge, des innovations telles que l’utilisation de nouveaux marqueurs biologiques représente une approche importante. A partir d’une analyse du profil transcriptionnel propre à l’endocardite, nous avons pu identifier plusieurs gènes fortement impliqués dans la physiopathologie de la maladie. Ainsi, ces travaux montrent que la métalloproteinase-9 de la matrice extracellulaire, la S100A11 et l’aquaporine-9 constitueraient de nouveaux biomarqueurs pour le diagnostic et la prédiction des complications des endocardites. / Infective endocarditis is a serious disease affecting around 2000 patients in France and 17000 in the United-States. Despite therapeutic progress, in-hospital mortality remains high, around 20%. This is mainly the consequence of a too late diagnosis and insufficiencies in the risk stratification. In fact, novel perspectives on the management of endocarditis are emerging and offer a hope for decreasing the rate of residual deaths by accelerating the process of diagnosis and risk stratification, a reduction of delays of instauration of antimicrobial therapy, the rapid transfer of high-risk patients to specialised medio-surgical centres, the development of new surgical modalities, and close long-term follow-up.Since many years, we have developed, in our institution, a research program based on a close collaboration between the researchers of the UMR 6236-CNRS and the physicians and the surgeons of the Cardiology and Cardiac Surgery Departments. This thesis reports the results of this translational research on the management of endocarditis. We have demonstrated that the standardization of the diagnostic process and of the surgical indications reduces infective endocarditis-related mortality in infective endocarditis. To improve the management, innovations such as the use of new biomarkers represent a critical new approach for this disease. From a transcriptional based approach, we have identified several new genes strongly involved in the pathophysiology of infective endocarditis. Thus, our works shows that the matrix metalloproteinase-9, S100A11 and aquaporin-9 would be potential new biomarkers for the diagnosis and the prediction of complications during infective endocarditis.

Les cytokines sont d’importants médiateurs dans la physiopathologie des lymphomes hodgkiniens (LH). A partir d’une cohorte de 464 patients, nous avons évalué l’impact pronostique de onze SNPs parmi les gènes de cytokines : IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629) ; IL6 (rs1800795) ; IL1B (rs16944) ; ILRN (rs419598) ; INFG (rs2430561) ; IL12 (rs3212227) ; CCL17 (rs223828). Le génotypage du SNP de l’IL12 montre une distribution différente de celle attendue dans la population générale selon le test de Hardy-Weinberg. Ce résultat suggère que les variations génétiques de l’IL12 pourraient être impliquées dans la susceptibilité au LH. Les patients porteurs du génotype IL10-1082AA présentent un taux de rémission complète au traitement initial supérieur aux patients présentant un autre génotype (95% vs. 88% P = .02). Pour les patients de stade avancé III-IV, le taux de survie globale à 6 ans est statistiquement différent entre les génotypes IL10-592AA/CC/AC et IL10-819TT/CC/CT (100%, 94%, 78%, P = .03). Ce résultat est retrouvé pour les patients porteurs de LH n’exprimant pas l’EBV. Pour les LH EBV négatif, le taux de survie sans progression à 6 ans est différent en fonction du génotype du TNFA-308AA/GG/AG (100%, 84%, 68%, P = .03). Il n’a été pas retrouvé de corrélation entre les génotypes et les dosages plasmatiques de l’IL-10, TNFA, IL-1RA, IL-6. Cette étude montre que le ‘‘fond génétique immun’’ est important à prendre en considération pour définir le pronostic des patients. Le rôle des SNPs de l’IL10 et du TNFA dans les LH EBV négatif devra être confirmé ainsi que l’influence des variations génétiques de l’IL12 dans la susceptibilité au LH. / Cytokines are important immune mediators implicated in Hodgkin lymphoma (HL) pathogenesis but little is known on the role of immune gene variations. We assessed prospectively the prognostic role of cytokine gene single nucleotide polymorphisms (SNPs) in HL patients (pts) : IL10 (rs1800890, 448 pts; rs1800896, 459 pts ; rs1800871, 446 pts ; rs1800872, 447 pts), TNFA (rs1800629, 464 pts) ; IL6 (rs1800795, 201 pts) ; IL1B (rs16944, 198 pts) ; ILRN (rs419598, 199 pts) ; INFG (rs2430561, 200 pts) ; IL12 (rs3212227, 259 pts) ; CCL17 (rs223828, 198 pts). IL12 genotype distribution appears significantly different from what observed in general population according to Hardy-Weinberg test which was already observed in another published study. IL10-1082AA genotype was associated with better complete response than other IL10 genotypes (95% vs. 88% P = .02). For patients with stage III-IV HL, the 6-year overall survival was statistically different between IL10-592AA/CC/AC and IL10-819TT/CC/CT genotypes (100%, 94%, 78%, P = .03). This prognostic effect was observed in EBV-negative but not in EBV-positive HL. In EBV-negative HL, TNFA-308AA/GG/AG genotypes had a different 6-year progression-free survival (100%, 84%, 68%, P = .03). No correlation was observed between genotypes and IL-10, TNFA, IL-1RA, IL-6 cytokine levels. This exploratory study suggests an effect of IL10 and TNFA SNPs in predicting HL outcome but other studies are needed to decipher the role of the host immunogenetic background, in particular the relation with EBV. Regarding the IL12 genotyping results, whether IL12 polymorphism is implicated in HL susceptibility needs also to be clarify.

INTRODUÇÃO: As doenças cardiovasculares estão entre as principais causas de óbito no Brasil e no mundo. Dentre as doenças cardiovasculares, a insuficiência cardíaca (IC) participa de maneira importante para morbi-mortalidade por ser via final de todas as entidades que acometem o coração. A internação hospitalar constitui momento crucial no tratamento e sobrevida dos pacientes com IC. Neste momento, em que o estado da doença atinge seu período mais crítico, é de grande importância o conhecimento dos pacientes com maior risco, que necessitam de cuidados mais intensos. No entanto, a apuração dos custos hospitalares é tarefa difícil, principalmente nas situações de alta complexidade, onde a utilização de recursos nos diversos setores do hospital, materiais e medicamentos, é muito heterogênea. Assim, a busca de variáveis clínicas capazes de ajudar a identificar os pacientes com maior risco, morbidade hospitalar (e conseqüente maior tempo de internação), e o custo destas internações foram o escopo deste estudo. OBJETIVO: primariamente, identificar variáveis clínicas capazes de predizer prognóstico de sobrevida e custos de internação numa população de pacientes internados por IC. Secundariamente, determinar custo mediano destas internações, correlacionando os as variáveis clínicas, de etiologia da cardiopatia de base, e com o perfil hemodinâmico na admissão hospitalar. Visamos ainda projetar os dados da Instituição no modelo de regressão por árvore de decisão proposto pelo estudo ADHERE. MÉTODOS: Realizamos um estudo retrospectivo na qual foram analisados dados consecutivos referentes a internações de pacientes que chegaram ao Pronto Socorro do InCor e permaneceram no Hospital por mais de 24 horas, sendo internados nos anos de 2006 e 2007. Foram avaliados dados clínicos na chegada ao pronto atendimento e evolutivos durante a internação. Foi realizada avaliação de custo da doença durante internação hospitalar através de modelo misto de análises de custos diretos contabilizados por absorção total e rateio dos setores de apoio. Análises estatísticas incluíram modelos de: regressão de proporcional de Cox para variáveis de morbidade-permanência hospitalar, regressão logística para variáveis de mortalidade hospitalar, e regressão através de árvores de decisão para definição de variáveis prioritárias. RESULTADOS: Foram avaliadas 577 internações de pacientes diferentes, sendo 60% do sexo masculino, e idade mediana de 69 anos (57-77). As principais variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico C, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As principais variáveis clínicas preditoras de mortalidade foram: fração de ejeção, pressão arterial sistólica, clearence estimado de creatinina, ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Todas estas variáveis compuseram os modelos de regressão. O custo mediano das internações foi de R$ 4.450 (1.353 - 13.432), sendo o fator independente na análise multivariada, o tempo de internação hospitalar, que teve mediana de 5 dias (2-13). A mortalidade hospitalar geral foi de 132 pacientes (23%). CONCLUSÃO: As variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As variáveis clínicas preditoras de mortalidade foram a fração de ejeção, a pressão arterial sistólica, o clearence estimado de creatinina, a ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Estas variáveis foram diferentes daquelas apontadas por outros estudos. A etiologia chagásica se correlacionou à maior incidência de choque cardiogênico, caracterizando assim maiores taxas de mortalidade, tempo de permanência, e custos frente às outras etiologias. A presença de choque cardiogênico na entrada se correlacionou a altas taxas de mortalidade, internações mais prolongadas, e maiores de custos de internação. O modelo descrito pelo estudo ADHERE pôde ser aplicado em nossa população, porém, propusemos outro modelo de árvore de decisão composto pelas variáveis: presença de choque cardiogênico uréia sérica, e pressão arterial sistólica, que apresentou maior acurácia em relação ao desfecho mortalidade hospitalar. O custo das internações variou muito de acordo com a evolução clínica dos pacientes, e conseqüentemente, seu tempo de internação hospitalar. No caso de pacientes atendidos pelo SUS, menos de um terço das internações tiveram custos inferiores ao valor médio das AIHs pagas por internações de pacientes com IC. / BACKGROUND: Heart diseases are the main mortality cause in Brazil and the rest of the world. Among those diseases, heart failure (HF) is utmost importance because it is the final pathway for overall heart diseases. Acute decompensate HF is a crucial situation while treating this disease because of its severity. At this critical time, stratification of risk is imperative in order to determine care. Hospital costs determination, however, is difficult in high complexity situations that use resources in a heterogeneity manner. The look for the clinical variables that could identify patients at higher risk for morbidity (and length of stay), mortality, and costs were the main aims of this study. OBJECTIVES: primarily to identify clinical variable able to predict survive and costs in a population of patients admitted by HF. Secondarily, determine median costs for the admissions, correlating these values to clinical variables, etiologies of HF, and hemodynamic profile at entrance. We aimed also to run our data in the tree regression model previously proposed by the ADHERE registry. METHODS: we reviewed consecutively 577 admissions records of different patients admitted by acute decompensated heart failure that stayed for more than 24 hours at the hospital during 2006 and 2007. Clinical data at the admissions and in-hospital follow-up data were analyzed. Costs analysis was performed through a mix model of microcosting (for direct resources) and average costing (for indirect resources). Statistical analysis included regression models as follows: Cox proportional for length of stay variables, logistic for hospital mortality, and classification and regression tree for defining priority variables. RESULTS: among the 577 patients, 60% were men; median age was 69 years (57- 77). The main predictor variables for length of stay were as follows: C hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. All these variables composed the regression models. Median admission cost was R$ 4.450 (1.353 13.432). Length of stay was an independent factor for predicting costs, with median of 5 days (2-13). Inhospital mortality rate was 23% (132 patients). CONCLUSION: The main predictor variables for length of stay were as follows: hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. These variables differ from other studies that evaluated similar outcomes. Chagas heart disease etiology was correlated to higher rates of cardiogenic shock, mortality rates, length of stay, and costs. The model used in the ADHERE registry could be used in our population; however, we proposed another variables integrating the regression and classification tree (systolic blood pressure, blood urea nitrogen, and hemodynamic profile C). This model presented greater accuracy for hospital mortality in our population. The cost of admissions ranged according to clinical evolution of the patients, and as consequence of length of stay. Less than a third of the admissions reimbursed by the government had their costs below the mean estimated value for reimbursement