Un certain nombre d'essais cliniques contrôlés, randomisés et publiés récemment en littérature a démontré que la thrombectomie mécanique, offerte aux patients présentant un AVC ischémique aigu, est liée à une meilleure évolution clinique en comparaison au traitement standard de fibrinolyse intraveineuse. Les stents retriever ont été reconnus dans ces essais comme les dispositifs les plus efficaces pour la thrombectomie intracrânienne. Actuellement, toutes les industries produisant des dispositifs neuro-interventionnels lancent sur le marché un nombre croissant de stents retriever. Chaque nouveau dispositif proposé est censé avoir une particularité permettant de meilleures performances par rapport aux dispositifs déjà disponibles sur le marché. Néanmoins, aucune étude clinique n’a démontré, jusqu'à présent, la supériorité en termes de résultats anatomiques et cliniques d'un stent retriever donné. En outre, le mécanisme d'interaction entre les stents retriever et le thrombus n'a pas été évalué jusqu'ici de façon exhaustive. Dans la présente étude, nous avons analysé expérimentalement les performances de tous les stents retriever disponibles sur le marché français jusqu'à juin 2015. Le but de cette étude était d'identifier toutes les caractéristiques des dispositifs fonctionnels à la capture du thrombus. Chaque dispositif a été évalué par des tests mécaniques et fonctionnels : les tests mécaniques ont été effectués afin d'étudier la force radiale des dispositifs. L'objectif était d'évaluer la force radiale exercée par le stent dans deux conditions spécifiques : lors du déploiement et pendant le retrait.Les tests fonctionnels ont visé à évaluer visuellement la capacité du stent à rester en apposition sur la paroi des vaisseaux et à maintenir le thrombus à l'intérieur de ses mailles au cours du retrait. Nous avons évalué l'interaction des dispositifs avec thrombus de taille et de caractéristiques différentes que nous avons générées en utilisant du sang humain afin d'obtenir deux types de caillot : un souple « de type rouge » composé par tous les éléments du sang et un dur « de type blanc» qui a été principalement composé de plasma riche en plaquettes. Ces essais ont été effectués en utilisant un modèle vasculaire rigide reproduisant la circulation cérébrale antérieure. Deux neuro-interventionnels ayant une expérience dans les procédures de thrombectomie ont effectué les tests fonctionnels. Chaque expérience a été filmée et deux auteurs par la suite ont effectué une analyse visuelle des résultats.Les essais mécaniques ont montré un comportement différent en termes de variation de pression radiale au cours du retrait pour chaque stent. Une pression radiale constante pendant le retrait est liée à une cohésion constante sur la paroi artérielle pendant le retrait, avec un taux plus important de retrait du caillot. Tous les stents retriever glissent sur le caillot blanc de grande taille (diamètre>6 mm) ayant un très bas taux d’efficacité en termes de retrait. / A number of randomized controlled trials recently appeared in literature demonstrated that early mechanical thrombectomy offered to patients presenting with acute ischemic stroke is related to improved functional outcome in comparison to standard care intravenous fibrinolysis. Stent retrievers have been recognized in these trials as the most effective devices for intracranial thrombectomy. Currently, all industries producing neuro-interventional devices are launching into the market an increasing number of stent-based retriever tools. Each new device proposed for clinical use is supposed to have peculiar features allowing better performances in comparison to devices already available for clinical practice. Nevertheless, none clinical study has demonstrated so far the superiority, in terms of anatomical and clinical results, of a given stent retriever device. Furthermore, the mechanism of interaction between stent retrievers and thrombi has not exhaustively evaluated so far. In the present study we experimentally analyzed performances of all stent retrievers available into the French market up to Juin 2015. The aim of this study was to identify any device feature that was functional to the thrombus removal.Stent retrievers were evaluated by mechanical and functional test: mechanical tests were performed in order to investigate devices radial force, the aim was to evaluate the radial force exerted by the stent in two specific conditions: upon deployment and during the retrieval.Functional tests were aimed to visually evaluate the stent retriever’s ability in remaining in close apposition to the vessels wall and to maintain the thrombus engaged within its struts during the retrieval. We evaluated the interaction of the devices with thrombi of different features and sizes that we generated using human blood in order to obtain two types of clot: one softer “red type” that was composed by all elements of the whole blood and one stiffer “white type” that was mainly composed by platelet-rich plasma. Such tests were conducted using a rigid 3D printed vascular model reproducing the brain anterior circulation. Two neuro-interventionalists with experience in thrombectomy procedures performed functional tests, each experiment was filmed and two authors thereafter conducted visual analysis of the results.Mechanical tests showed different behavior in terms of radial pressure variation during retrieval for each stent. Constant radial pressure during retrieval was related to constant cohesion over the vessel wall during retrieval and higher rate of clot removal efficacy. All stent retrievers slide over the clot failing in clot removal when interact with white large thrombi (diameter>6 mm).

Introduction: The recurrence of the cerebral ischemic stroke after a history of TIA or ischemic stroke is 3-4% per year. One way of reducing the risk of reccurence is using antiplatelet therapy. The aim of our study was to investigate the effect of aspirin. Even though, newer antiplatelet drugs were developed, their risk/benefit profile has not been proved to be better than aspirin. Reasons for using aspirin in secondary prevention are: the longest experience, clearly proven effect in many studies and low price. On the other hand, aspirin prevents only 25% of strokes, thus there is wide space for searching for causes of failed therapy and alternative therapeutic ways. Noncompliance of aspirin use and embolic events are usually indicated as the most common causes of an ineffective therapy. The goal of our study was to find the antiplatelet therapy effectivity in patients with history of stroke treated with aspirin in daily dose of 100mg. We assured 100% compliance among these patients and as much as possible minimalized a likelihood of embolic causes of strokes. What is more, we tried to find out whether an insuffient suppression of 11-dehydrotromboxane B2 correlates with comorbidities, other used medication or laboratory parameters. Furthermore, whether by administrating an increased dose of...

Introdução: A atresia biliar (AB) é uma doença que se inicia na infância e caracteriza-se por obstrução das vias biliares extra-hepáticas, e por colangiopatia progressiva, de etiologia desconhecida. Seu tratamento consiste numa portoenterostomia, cujo sucesso é variável. Fatores como a idade na portoenterostomia e normalização de bilirrubinas séricas influenciam a sobrevida do paciente com seu próprio fígado. Nosso grupo estuda o envolvimento de uma arteriopatia na etiologia da AB. O fator de crescimento vascular endotelial (VEGF) e seus receptores VEGFR1 e VEGFR2 participam da angiogênese em situações de distúrbio vascular. Objetivo: Quantificar a expressão gênica de VEGFA e seus receptores, relacionando com variáveis moleculares, morfométricas e clínico-laboratoriais associadas com a gravidade da AB e o prognóstico pós-portoenterostomia. Métodos: Estudo de amostras de biópsias em cunha coletadas na laparotomia exploradora de pacientes com AB, na sua forma isolada IgM- para citomegalovírus (n= 32), comparando com lactentes com colestase intra-hepática (CIH, n= 09), pareados por idade. Uma amostra foi ultracongelada (análise molecular) e outra, parafinizada (análises histológica e imunoistoquímica). A expressão dos genes angiogênicos (VEGFA, VEGFR1 e VEGFR2), fibrogênico (MCP1, proteína quimiotática de monócitos) e de reação ductular (CK19, citoqueratina 19), além do gene normalizador, ribossomal 18S, foi medida por PCRq com sondas TaqMan®. As análises morfométricas, a partir de material parafinado, incluindo extensão de fibrose e reação ductular foram mensuradas através do programa Image Pro Plus 6.0. Variáveis clínico-laboratoriais foram prospectivamente coletadas no banco de dados da Unidade de Hepatologia Pediátrica do HCPA. Resultados: VEGFR2 foi menos expresso na AB em comparação com CIH (P <0,001), enquanto não houve diferença significante na expressão de VEGFR1 (P= 0,086) e apenas uma tendência de menor expressão do VEGFA (P= 0,060) no grupo AB. Quanto à expressão de VEGFA e VEGFR2, dois subgrupos de AB foram observados: um com expressão levemente superior ou igual à CIH e outro com expressão 3 vezes menor que a mediana do grupo CIH. Os subgrupos com menor expressão foram denominados loVEGFA e loVEGFR2. Na AB, a expressão do VEGFA teve correlação positiva com a de seus receptores VEGFR1 e VEGFR2 (rs=0,8; P<0,001 e rs=0,5; P=0,001). A expressão de VEGFR2 teve uma forte correlação negativa com a idade na portoenterostomia (rs=-0,6;P=0,001). As bilirrubinas séricas total e direta foram negativamente correlacionadas com VEGFA (rs=-0,5;P=0,007 e rs=-0,4;P=0,033) e VEGFR2 (rs=-0,5;P=0;004 e rs=-0,6;P=0,001). No subgrupo loVEGFR2 a expressão de CK19 estava diminuída, e a de MCP1 não se associou à expressão gênica das moléculas angiogênicas. Conclusões: Na AB há um subgrupo com diminuição na expressão de VEGFA e VEGFR2. A expressão de ambas as moléculas correlacionou-se ao comportamento das variáveis associadas a gravidade da doença e obstrução do fluxo biliar na portoenterostomia, incluindo bilirrubinas séricas e idade. O subgrupo de baixa expressão do VEGFR2 apresentou diminuição da massa de colangiócitos, segundo a expressão do CK 19, mas foi independente da expressão do marcador de fibrose, MCP1. / Background: Biliary atresia (BA) is a disease that begins in infancy and is characterized by complete obstruction of extrahepatic biliary ducts and a progressive cholangiopathy of undefined etiology. Treatment of BA consists of a portoenterostomy, whose success is variable. Factors such as age at portoenterostomy and post-operative normalization of serum bilirubin influence the native liver survival. Our group studies the role of an arteriopathy, and thus of hypoxia, in the etiology of BA. Expression of vascular endothelial growth factor (VEGF) A and its receptors, VEGFR1 and VEGFR2, induce angiogenesis in response to hypoxia. Aim: To assess gene expression of VEGFA and its receptors in BA, correlating with molecular, morphometric and clinical-laboratory variables associated with the disease severity and the post-portoenterostomy prognosis of BA. Methods: Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n=32) and intrahepatic cholestasis (IHC, n=9) were evaluated. A sample was ultrafrozen (for molecular analysis) and the other was paraffin-embedded (for histological and morphometric analyzes). The expression of genes involved in angiogenic (VEGFA, VEGFR1 and VEGFR2), biliary fibrosis (MCP1 - monocyte chemotaxis protein 1) and cholangiocyte phenotype (CK19 – cytokeratin 19), was measured by TaqMan® probes with qPCR, using ribosomal 18S as the normalizing gene. Extents of fibrosis and ductular reaction were morphometrically assessed using the Image Pro Plus 6.0. Clinical-laboratory variables were collected from the database of the Pediatric Hepatology Unit of Hospital de Clínicas de Porto Alegre. Results: VEGFR2 was less expressed in BA compared with IHC (P <0.001), whereas there was no significant difference in the expression of VEGFR1 (P=0.086) and only a trend of a lower expression of VEGFA (P=0.060) in the BA group. Regarding VEGFA and VEGFR2, two subgroups of BA were defined: low expression, with values 3 times lower than the median of the IHC group, and high expression. In BA, VEGFA expression was positively correlated with that of VEGFR1 and VEGFR2 (rs=0.8, P<0.001; rs=0.58, P=0.001). The expression of VEGFR2 had a strong negative correlation with age at portoenterostomy (rs=-0.6, P=0.001). Total and direct reacting bilirubins were both negatively correlated with VEGFA expression (rs=-0.5, P=0.007; rs=-0.4,P=0.033) and VEGFR2 (rs=-0.5,P=0.004; rs=-0.6,P=0.001). In the low VEGFR2 expression (loVEGFR2) subset, gene expression of CK19, marker of cholangiocyte phenotype, was decreased. MCP1, marker of fibrosis, was not associated with he expression of the angiogenic factors. Conclusion: In BA there is a subset of patients with decreased expression of VEGFA and VEGFR2. The expression of these molecules is correlated with variables associated to disease severity and bile flow obstruction at portoenterostomy, including age and serum bilirubin levels. The loVEGFR2 expression is associated with a decreased cholangiocyte mass as evaluated by CK19 expression, and is independent of the expression of the fibrosis marker MCP1.

Introdução: A atresia biliar (AB) é uma doença que se inicia na infância e caracteriza-se por obstrução das vias biliares extra-hepáticas, e por colangiopatia progressiva, de etiologia desconhecida. Seu tratamento consiste numa portoenterostomia, cujo sucesso é variável. Fatores como a idade na portoenterostomia e normalização de bilirrubinas séricas influenciam a sobrevida do paciente com seu próprio fígado. Nosso grupo estuda o envolvimento de uma arteriopatia na etiologia da AB. O fator de crescimento vascular endotelial (VEGF) e seus receptores VEGFR1 e VEGFR2 participam da angiogênese em situações de distúrbio vascular. Objetivo: Quantificar a expressão gênica de VEGFA e seus receptores, relacionando com variáveis moleculares, morfométricas e clínico-laboratoriais associadas com a gravidade da AB e o prognóstico pós-portoenterostomia. Métodos: Estudo de amostras de biópsias em cunha coletadas na laparotomia exploradora de pacientes com AB, na sua forma isolada IgM- para citomegalovírus (n= 32), comparando com lactentes com colestase intra-hepática (CIH, n= 09), pareados por idade. Uma amostra foi ultracongelada (análise molecular) e outra, parafinizada (análises histológica e imunoistoquímica). A expressão dos genes angiogênicos (VEGFA, VEGFR1 e VEGFR2), fibrogênico (MCP1, proteína quimiotática de monócitos) e de reação ductular (CK19, citoqueratina 19), além do gene normalizador, ribossomal 18S, foi medida por PCRq com sondas TaqMan®. As análises morfométricas, a partir de material parafinado, incluindo extensão de fibrose e reação ductular foram mensuradas através do programa Image Pro Plus 6.0. Variáveis clínico-laboratoriais foram prospectivamente coletadas no banco de dados da Unidade de Hepatologia Pediátrica do HCPA. Resultados: VEGFR2 foi menos expresso na AB em comparação com CIH (P <0,001), enquanto não houve diferença significante na expressão de VEGFR1 (P= 0,086) e apenas uma tendência de menor expressão do VEGFA (P= 0,060) no grupo AB. Quanto à expressão de VEGFA e VEGFR2, dois subgrupos de AB foram observados: um com expressão levemente superior ou igual à CIH e outro com expressão 3 vezes menor que a mediana do grupo CIH. Os subgrupos com menor expressão foram denominados loVEGFA e loVEGFR2. Na AB, a expressão do VEGFA teve correlação positiva com a de seus receptores VEGFR1 e VEGFR2 (rs=0,8; P<0,001 e rs=0,5; P=0,001). A expressão de VEGFR2 teve uma forte correlação negativa com a idade na portoenterostomia (rs=-0,6;P=0,001). As bilirrubinas séricas total e direta foram negativamente correlacionadas com VEGFA (rs=-0,5;P=0,007 e rs=-0,4;P=0,033) e VEGFR2 (rs=-0,5;P=0;004 e rs=-0,6;P=0,001). No subgrupo loVEGFR2 a expressão de CK19 estava diminuída, e a de MCP1 não se associou à expressão gênica das moléculas angiogênicas. Conclusões: Na AB há um subgrupo com diminuição na expressão de VEGFA e VEGFR2. A expressão de ambas as moléculas correlacionou-se ao comportamento das variáveis associadas a gravidade da doença e obstrução do fluxo biliar na portoenterostomia, incluindo bilirrubinas séricas e idade. O subgrupo de baixa expressão do VEGFR2 apresentou diminuição da massa de colangiócitos, segundo a expressão do CK 19, mas foi independente da expressão do marcador de fibrose, MCP1. / Background: Biliary atresia (BA) is a disease that begins in infancy and is characterized by complete obstruction of extrahepatic biliary ducts and a progressive cholangiopathy of undefined etiology. Treatment of BA consists of a portoenterostomy, whose success is variable. Factors such as age at portoenterostomy and post-operative normalization of serum bilirubin influence the native liver survival. Our group studies the role of an arteriopathy, and thus of hypoxia, in the etiology of BA. Expression of vascular endothelial growth factor (VEGF) A and its receptors, VEGFR1 and VEGFR2, induce angiogenesis in response to hypoxia. Aim: To assess gene expression of VEGFA and its receptors in BA, correlating with molecular, morphometric and clinical-laboratory variables associated with the disease severity and the post-portoenterostomy prognosis of BA. Methods: Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n=32) and intrahepatic cholestasis (IHC, n=9) were evaluated. A sample was ultrafrozen (for molecular analysis) and the other was paraffin-embedded (for histological and morphometric analyzes). The expression of genes involved in angiogenic (VEGFA, VEGFR1 and VEGFR2), biliary fibrosis (MCP1 - monocyte chemotaxis protein 1) and cholangiocyte phenotype (CK19 – cytokeratin 19), was measured by TaqMan® probes with qPCR, using ribosomal 18S as the normalizing gene. Extents of fibrosis and ductular reaction were morphometrically assessed using the Image Pro Plus 6.0. Clinical-laboratory variables were collected from the database of the Pediatric Hepatology Unit of Hospital de Clínicas de Porto Alegre. Results: VEGFR2 was less expressed in BA compared with IHC (P <0.001), whereas there was no significant difference in the expression of VEGFR1 (P=0.086) and only a trend of a lower expression of VEGFA (P=0.060) in the BA group. Regarding VEGFA and VEGFR2, two subgroups of BA were defined: low expression, with values 3 times lower than the median of the IHC group, and high expression. In BA, VEGFA expression was positively correlated with that of VEGFR1 and VEGFR2 (rs=0.8, P<0.001; rs=0.58, P=0.001). The expression of VEGFR2 had a strong negative correlation with age at portoenterostomy (rs=-0.6, P=0.001). Total and direct reacting bilirubins were both negatively correlated with VEGFA expression (rs=-0.5, P=0.007; rs=-0.4,P=0.033) and VEGFR2 (rs=-0.5,P=0.004; rs=-0.6,P=0.001). In the low VEGFR2 expression (loVEGFR2) subset, gene expression of CK19, marker of cholangiocyte phenotype, was decreased. MCP1, marker of fibrosis, was not associated with he expression of the angiogenic factors. Conclusion: In BA there is a subset of patients with decreased expression of VEGFA and VEGFR2. The expression of these molecules is correlated with variables associated to disease severity and bile flow obstruction at portoenterostomy, including age and serum bilirubin levels. The loVEGFR2 expression is associated with a decreased cholangiocyte mass as evaluated by CK19 expression, and is independent of the expression of the fibrosis marker MCP1.

Diversos autores têm apontado o diabetes como fator de risco independente para a doença isquêmica do coração (DIC). Diferenças metodológicas têm, entretanto, prejudicado a comparabilidade de alguns estudos. O objetivo desta investigação foi testar a associação do diabetes mellitus com a DIC, procedendo-se a ajustamentos para as possíveis variáveis de confusão e/ou modificadoras de efeito. Avaliou-se também a existência de um gradiente dose resposta para as variáveis duração do diabetes, duração da hipertensão arterial, duração da hipercolesterolemia, duração do hábito de fumar, no cigarros consumidos/dia e duração da menopausa. O estudo foi planejado sob a forma de um desenho tipo caso-controle, tendo-se utilizado a estratégia de compor cinco bancos de dados, onde os casos foram comparados com cinco diferentes conjuntos de controles. Manteve-se nas análises de cada banco de dados o mesmo elenco de possíveis variáveis de confusão e/ou modificadoras de efeito. A população do estudo foi constituída por indivíduos de ambos o sexos, na faixa etária de 30 a 69 anos completos, sendo todos residentes no município de São Paulo. O estudo teve início em março de 1993 e estendeu-se até fevereiro de 1994. A amostra total foi composta por 833 indivíduos. A técnica estatística utilizada para análise dos dados foi a regressão logística multivariada. Os resultados do estudo permitiram identificar o diabetes mellitus como um fator de risco independente para a doença isquêmica do coração (\"odds ratio\" ajustado=2,6; I.C.95 por cento : 1,18- -5,80). O achado consistente de um possível efeito de proteção na categoria intermediária de duração do diabetes (>5$<10 anos) conduziu à hipótese de que o controle metabólico da doença, no período, poderia estar exercendo tal influência sobre o risco de DIC. Foi também possível identificar um efeito independente para as variáveis hipertensão arterial, hipercolesterolemia, hábito de fumar e antecedentes familiares de cardiopatia. Verificou-se, de forma consistente, a presença de um gradiente linear para duração da hipertensão arterial e número de cigarros consumidos/dia. As interações consideradas de interesse, combinando-se história positiva de diabetes com as categorias de exposição das outras variáveis não apresentaram significância estatística. São discutidas algumas razões de ordem metodológica que exerceriam influência sobre a magnitude das medidas de efeito em diferentes combinações de controles. / Several authors have reported diabetes as an independent risk factor to ischaemic heart disease (IHD). However, the use of different methodologies have been an obstacle in comparing these studies. The objective of this investigation was to test the association between diabetes and IHD, after adjusting for known confounders and/or modifiers of effect. There was interest in evaluating the existence of a linear gradient for known duration of diabetes, arterial hypertension, hypercholesterolemia, menopause, smoking and daily number of cigarretes consumed. The study was designed as a case-control and the cases were compared with five different kinds of controls. The same group of variables were maintained in the analysis. The population was composed by male and female, aged 30-69 years living in the city of São Paulo. The period of the study was one year (march/93 until february/94). The sample included 833 individuais. Logistic regression was the statistical method to analysis of the data. The results showed that diabetes is an independent risk factor to lliD (adjusted odds ratio=2.6; C.I.95 per cent : 1.18-5.80). There was a consistent protection effect on the \">5 <1O\" years stratum of known duration of diabetes and it was proposed that metabolic control of diabetes during this period had some influence to the IHD risk. Hypertension, hypercholesterolemia, smoking and familial antecedents of cardiovascular diseases were considered major risk factors to IHD. It was detected a linear gradient for known duration of hypertension and daily number of cigarettes consumed. The interaction between diabetes and exposure levels of other variables did not present statistical significance. Some methodological issues are presented to explain different magnitudes of effect according to the different kinds o f controls.

Ischemic stroke is characterized by a disruption of blood supply to a part of the brain tissue, which leads to a focal ischemic infarct. The expression and activity of MMP-9 is increased in ischemic stroke and is considered to be one of the main factors responsible for damages to the cerebral vasculature, resulting in compromised blood-brain barrier (BBB) integrity. However, the regulatory mechanisms of MMP-9 expression and activity are not well established in ischemic stroke. Since hypoxia/ischemia and reperfusion generates reactive oxygen species (ROS), I hypothesize that ROS is one of factors involved in up-regulation of MMP-9 expression in brain cells and ROS-mediated effect may occur via MAPK signaling pathway. My study has provided the evidence that ROS is responsible for an increase in MMP-9 expression in astrocytes mediated via MAPK-AP1 signaling pathway. Preliminary studies with an in vitro model of the BBB suggest that inhibition of MMP-9 is a critical component of reducing ROS-induced BBB permeability.

The disruption of the blood-brain barrier (BBB) occurs after ischemic and hemorrhagic stroke and contributes to secondary brain damage. Matrix metalloproteinase-9 (MMP9) has been identified to be the main mediator of post-stroke BBB disruption. It is unknown whether deposition of heme/iron in the brain following stroke would affect MMP9 expression. In this study, I have demonstrated that heme/iron up-regulated MMP9 expression in rat astrocytes and that this upregulation was most likely due to reactive oxygen species (ROS) generated by heme/iron deposition on cells. ROS can activate AP-1 and NFκB signaling pathways which were responsible for increased MMP9 expression. Inhibiting AP-1 and NFκB decreased MMP9 expression. Heme/iron deposition also activated Nrf-2 and increased the expression of neuroprotective heme oxygenase-1. My study suggests that heme and iron deposition generates ROS and increases MMP9 expression through AP-1 and NFκB signaling pathways and that targeting these pathways or clearance of heme and iron may modulate MMP9 expression for reduced damage.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13401号 / 論医博第2225号 / 新制||医||1051(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 渡邊 直樹, 教授 江藤 浩之 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction: The recurrence of the cerebral ischemic stroke after a history of TIA or ischemic stroke is 3-4% per year. One way of reducing the risk of reccurence is using antiplatelet therapy. The aim of our study was to investigate the effect of aspirin. Even though, newer antiplatelet drugs were developed, their risk/benefit profile has not been proved to be better than aspirin. Reasons for using aspirin in secondary prevention are: the longest experience, clearly proven effect in many studies and low price. On the other hand, aspirin prevents only 25% of strokes, thus there is wide space for searching for causes of failed therapy and alternative therapeutic ways. Noncompliance of aspirin use and embolic events are usually indicated as the most common causes of an ineffective therapy. The goal of our study was to find the antiplatelet therapy effectivity in patients with history of stroke treated with aspirin in daily dose of 100mg. We assured 100% compliance among these patients and as much as possible minimalized a likelihood of embolic causes of strokes. What is more, we tried to find out whether an insuffient suppression of 11-dehydrotromboxane B2 correlates with comorbidities, other used medication or laboratory parameters. Furthermore, whether by administrating an increased dose of...

A loss of sarcolemmal dystrophin was observed by immuno-fluorescence studies in rabbit hearts subjected to in situ myocardial ischemia and by immuno-blotting of the Triton soluble membrane fraction of isolated rabbit cardiomyocytes subjected to in vitro ischemia. This ischemic loss of dystrophin was a specific event in that no ischemic loss of sarcolemmal α-sarcoglycan, γ-sarcoglycan, αDG, or βDG was observed. The maintenance of sarcolemmal βDG (43 Kd) during ischemia was interesting in that dystrophin binds to the C-terminus of βDG. However, during late in vitro ischemia, a 30 Kd band was observed that was immuno-reactive for βDG. Additionally, this 30 Kd-βDG band was observed in rabbit myocardium subjected to autolysis. Finally, the 30 Kd-βDG was observed in the purified sarcolemmal fraction of rabbit cardiomyocytes subjected to a prolonged period of in vitro ischemia, confirming the sarcolemmal localization of this band. The potential patho-physiologic significance of this band was indicated by the appearance of this band at 120-180 min of in vitro ischemia, directly correlating with the onset of irreversible injury, as manifested by osmotic fragility. Additionally the appearance of this band was significantly reduced by the endogenous cardioprotective mechanism, in vitro ischemic preconditioning, which delays the onset of osmotic fragility. In addition to dystrophin, βDG binds caveolin-3 and Grb-2 at its C-terminus. The presence of Grb-2 and caveolin-3 in the membrane fractions of oxygenated and ischemic cardiomyocytes was determined by Western blotting. An increase in the level of membrane Grb-2 and caveolin-3 was observed following ischemic preconditioning as compared to control cells. The formation of this 30 Kd-βDG degradation product is potentially related to the transition from the reversible to the irreversible phase of myocardial ischemic cell injury and a decrease in 30 Kd-βDG might mediate the cardioprotection provided by ischemic preconditioning.