Spelling suggestions: "subject:"dicke"" "subject:"micke""
1 |
O uso do algoritmo genético na construção de mapas de perfusão cerebral e sua aplicação em pacientes com anemia falciforme / The use of genetic algorithm to calculate brain perfusion MRI maps and its application to sickle-cell disease.Silva, Nivia Aparecida da 24 April 2008 (has links)
A imagem por ressonância magnética (IRM) tem se tornado uma poderosa ferramenta clínica na avaliação da anatomia cerebral. Recentemente, várias técnicas têm tornado possível a caracterização da função cerebral através da estimativa de alguns parâmetros metabólicos. Uma dessas técnicas é a perfusão cerebral, que descreve a passagem de sangue através da rede vascular cerebral, e permite estimar, não invasivamente, algumas características das funções hemodinâmicas tais como Volume de Sangue Cerebral (CBV), Fluxo de Sangue Cerebral (CBF) e Tempo de Trânsito Médio (MTT). Neste trabalho foi desenvolvido um programa computacional, baseado na plataforma Matlab, que analisa as imagens e cria mapas de perfusão. Primeiro foi comparado o desempenho do método de ajuste de curvas convencional Levenberg-Marquardt (LM) versus o Método que utiliza o Algoritmo Genético (AG). Os resultados mostraram que os AGS são muito mais estáveis, com relação aos seus parâmetros de controle, do que o método usual LM e, portanto, fornece evidencias da eficácia do AG em relação ao método convencional. Como um segundo e principal objetivo nós aplicamos o método para construir e examinar os mapas de perfusão em pacientes com anemia falciforme (sickle cell disease -SCD), particularmente em relação a complicações neurológicas e anormalidades vistas como uma técnica de imagem complementar. Além disso, os mapas de perfusão agregam informação a respeito de aspectos funcionais do sistema vascular, que é complementar a informação anatômica. Os nossos resultados com mostraram que esses mapas são uma ferramenta importante para auxiliar na avaliação clínica dos pacientes com anemia falciforme, como também podem ser aplicados para avaliar áreas em risco tão bem quanto ajudar no tratamento clínico de tais pacientes. / Magnetic Resonance Imaging (MRI) has become a powerful clinical tool for evaluation of brain anatomy. Several recently techniques have made possible the characterization of brain function via assessment of metabolic parameters. One of these techniques is the cerebral perfusion, which describes passage of blood through the brain\'s vascular network, and al- lows estimating, non-invasively, some characteristics of hemodynamic functions such as Cerebral Blood Volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT). In this work a computational program was development, based on Matlab platform, which analyze perfusion images and create perfusion maps. First, the performance of conven- tional Levenberg-Marquardt Method (LM) versus a Genetic Algorithms (GAs) was com- pared. The results showed that the GAs are more stable than usual LM method with rela- tion to their control parameters and therefore provides evidence the effectiveness of the GAs with relation to a conventional method. As a second and principal objective we ap- plied the method to construct and examine perfusion maps of patients with sickle cell dis- ease (SCD), particularly in relation to the neurological complications and to abnormalities seen with complementary imaging techniques. Moreover, perfusion maps aggregate infor- mation about functional aspects of the vascular system, which is complementary to ana- tomical information. Our results show that these maps are an important tool to support clinical evaluation of sickle cell disease patients, as it may be applied to evaluate brain areas at risk as well as a help in the clinical treatment of such patients.
|
2 |
O uso do algoritmo genético na construção de mapas de perfusão cerebral e sua aplicação em pacientes com anemia falciforme / The use of genetic algorithm to calculate brain perfusion MRI maps and its application to sickle-cell disease.Nivia Aparecida da Silva 24 April 2008 (has links)
A imagem por ressonância magnética (IRM) tem se tornado uma poderosa ferramenta clínica na avaliação da anatomia cerebral. Recentemente, várias técnicas têm tornado possível a caracterização da função cerebral através da estimativa de alguns parâmetros metabólicos. Uma dessas técnicas é a perfusão cerebral, que descreve a passagem de sangue através da rede vascular cerebral, e permite estimar, não invasivamente, algumas características das funções hemodinâmicas tais como Volume de Sangue Cerebral (CBV), Fluxo de Sangue Cerebral (CBF) e Tempo de Trânsito Médio (MTT). Neste trabalho foi desenvolvido um programa computacional, baseado na plataforma Matlab, que analisa as imagens e cria mapas de perfusão. Primeiro foi comparado o desempenho do método de ajuste de curvas convencional Levenberg-Marquardt (LM) versus o Método que utiliza o Algoritmo Genético (AG). Os resultados mostraram que os AGS são muito mais estáveis, com relação aos seus parâmetros de controle, do que o método usual LM e, portanto, fornece evidencias da eficácia do AG em relação ao método convencional. Como um segundo e principal objetivo nós aplicamos o método para construir e examinar os mapas de perfusão em pacientes com anemia falciforme (sickle cell disease -SCD), particularmente em relação a complicações neurológicas e anormalidades vistas como uma técnica de imagem complementar. Além disso, os mapas de perfusão agregam informação a respeito de aspectos funcionais do sistema vascular, que é complementar a informação anatômica. Os nossos resultados com mostraram que esses mapas são uma ferramenta importante para auxiliar na avaliação clínica dos pacientes com anemia falciforme, como também podem ser aplicados para avaliar áreas em risco tão bem quanto ajudar no tratamento clínico de tais pacientes. / Magnetic Resonance Imaging (MRI) has become a powerful clinical tool for evaluation of brain anatomy. Several recently techniques have made possible the characterization of brain function via assessment of metabolic parameters. One of these techniques is the cerebral perfusion, which describes passage of blood through the brain\'s vascular network, and al- lows estimating, non-invasively, some characteristics of hemodynamic functions such as Cerebral Blood Volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT). In this work a computational program was development, based on Matlab platform, which analyze perfusion images and create perfusion maps. First, the performance of conven- tional Levenberg-Marquardt Method (LM) versus a Genetic Algorithms (GAs) was com- pared. The results showed that the GAs are more stable than usual LM method with rela- tion to their control parameters and therefore provides evidence the effectiveness of the GAs with relation to a conventional method. As a second and principal objective we ap- plied the method to construct and examine perfusion maps of patients with sickle cell dis- ease (SCD), particularly in relation to the neurological complications and to abnormalities seen with complementary imaging techniques. Moreover, perfusion maps aggregate infor- mation about functional aspects of the vascular system, which is complementary to ana- tomical information. Our results show that these maps are an important tool to support clinical evaluation of sickle cell disease patients, as it may be applied to evaluate brain areas at risk as well as a help in the clinical treatment of such patients.
|
3 |
Optimierte Sickengestaltung im Konstruktionsprozess dünnwandiger Bauteile / Optimized bead creation within the construction process of thin-walled partsKrauß, Alexander 04 September 2017 (has links) (PDF)
Dünnwandige Strukturen erreichen bei richtiger Gestaltung ein sehr gutes Masse-Steifigkeitsverhältnis und besitzen damit großes Potential für effektiven Strukturleichtbau. In ebenen und schwach gekrümmten Bereichen weisen diese jedoch eine geringe Biegesteifigkeit auf, welche häufig nicht den gestellten Anforderungen entspricht. Zur Formversteifung werden hier Sicken eingesetzt. Diese rinnenartigen oder flächigen Vertiefungen werden mithilfe einer Blechumformung, wie Tiefziehen, in das jeweilige Bauteil eingebracht.
Damit ein Sickenfeld die maximale Versteifungswirkung erreicht, muss es beanspruchungsgerecht ausgelegt werden. In der Praxis werden Sicken häufig erfahrungsbasiert oder mit den Erkenntnissen aus Sickenkatalogen in ein Bauteil eingebracht. Allerdings bleibt hier die Frage nach einer beanspruchungsgerechten Auslegung der Sickenparameter, wie Position und Ausrichtung, offen. Bei komplexeren Bauteilen generiert die FE-Netz basierte Formoptimierung hingegen ein deutlich besseres Ergebnis. Allerdings muss dieses für ein fertigungsgerechtes Sickenbild manuell im CAD rekonstruiert werden. Dieser Prozess ist im CAD-System zeitaufwändig und fehleranfällig.
Ziel dieser Arbeit ist es, die FEM gestützte Sickenauslegung effektiver zu gestalten. Eine Teilaufgabe ist die Verbesserung der Ergebnisinterpretation von formoptimierten FE-Netzen. Weiterhin werden neue Methoden gezeigt, welche ohne Interpretation verzerrter FE-Netze eine CAD-integrierte Sickenauslegung ermöglichen. / Thin-walled structures are used within various products, due to their optimal relation between mass and stiffness. Nevertheless those structures have a low bending stiffness in areas with less curvature. To bypass this disadvantage channels or flattened areas, so called beads, are embossed. To maximize the stiffening effect the position and orientation of the bead is essential. One of the latest methods for bead creation is based on the experience of the designer supported with construction catalogues. They offer predefined bead patterns, tested on simple plate structures and various load cases. The adoption of the predefined bead pattern on complex real live parts is often impossible. A second method uses FEM based optimization algorithms. They are more effective but the actual workflow of interpreting the distorted FEM meshes in CAD and resulting adoption on manufacturing constrains lead to non-optimal results, too.
The aim of this thesis is to represent new methods for bead creation with a high CAD integration level. As a result, three new methods are developed. At first, the workflow for the interpretation of bead patterns created by a FEM based optimization algorithm was simplified using tailor made CAD features for the reverse engineering process. The designer is now able to recreate tangency steady CAD geometry with the provided deformed FE mesh. The second method focuses on channel shaped beads. Herefore, the stress distribution is calculated within the FE-shell first and then analyzed. With this information the direction of a bead profile can be estimated in every FE-node and displayed to the user as vector field. In the second step guidelines similar to streamlines are created using the vector field. These guidelines are the basic elements for channels shaped beads represented as CAD features. This approach enables the designer to create load step depending bead patterns without distorted FE-Meshes in CAD. The last scheme represents a semi-analytical approach to create the guidelines without Finite Elements Analyses for simple plate like structures. The vector field is calculated with the stresses using Kirchoff-Love's theory of plates. The investigation shows that the resulting guidelines can be approximated with superellipse. All methods are tested with parts of the automotive industry and academic examples.
|
4 |
Optimierte Sickengestaltung im Konstruktionsprozess dünnwandiger Bauteile / Optimized bead creation within the construction process of thin-walled partsKrauß, Alexander 13 September 2017 (has links) (PDF)
Dünnwandige Strukturen erreichen bei richtiger Gestaltung ein sehr gutes Masse-Steifigkeitsverhältnis und besitzen damit großes Potential für effektiven Strukturleichtbau. In ebenen und schwach gekrümmten Bereichen weisen diese jedoch eine geringe Biegesteifigkeit auf, welche häufig nicht den gestellten Anforderungen entspricht. Zur Formversteifung werden hier Sicken eingesetzt. Diese rinnenartigen oder flächigen Vertiefungen werden mithilfe einer Blechumformung, wie Tiefziehen, in das jeweilige Bauteil eingebracht.
Damit ein Sickenfeld die maximale Versteifungswirkung erreicht, muss es beanspruchungsgerecht ausgelegt werden. In der Praxis werden Sicken häufig erfahrungsbasiert oder mit den Erkenntnissen aus Sickenkatalogen in ein Bauteil eingebracht. Allerdings bleibt hier die Frage nach einer beanspruchungsgerechten Auslegung der Sickenparameter, wie Position und Ausrichtung, offen. Bei komplexeren Bauteilen generiert die FE-Netz basierte Formoptimierung hingegen ein deutlich besseres Ergebnis. Allerdings muss dieses für ein fertigungsgerechtes Sickenbild manuell im CAD rekonstruiert werden. Dieser Prozess ist im CAD-System zeitaufwändig und fehleranfällig.
Ziel dieser Arbeit ist es, die FEM gestützte Sickenauslegung effektiver zu gestalten. Eine Teilaufgabe ist die Verbesserung der Ergebnisinterpretation von formoptimierten FE-Netzen. Weiterhin werden neue Methoden gezeigt, welche ohne Interpretation verzerrter FE-Netze eine CAD-integrierte Sickenauslegung ermöglichen. / Thin-walled structures are used within various products, due to their optimal relation between mass and stiffness. Nevertheless those structures have a low bending stiffness in areas with less curvature. To bypass this disadvantage channels or flattened areas, so called beads, are embossed. To maximize the stiffening effect the position and orientation of the bead is essential. One of the latest methods for bead creation is based on the experience of the designer supported with construction catalogues. They offer predefined bead patterns, tested on simple plate structures and various load cases. The adoption of the predefined bead pattern on complex real live parts is often impossible. A second method uses FEM based optimization algorithms. They are more effective but the actual workflow of interpreting the distorted FEM meshes in CAD and resulting adoption on manufacturing constrains lead to non-optimal results, too.
The aim of this thesis is to represent new methods for bead creation with a high CAD integration level. As a result, three new methods are developed. At first, the workflow for the interpretation of bead patterns created by a FEM based optimization algorithm was simplified using tailor made CAD features for the reverse engineering process. The designer is now able to recreate tangency steady CAD geometry with the provided deformed FE mesh. The second method focuses on channel shaped beads. Herefore, the stress distribution is calculated within the FE-shell first and then analyzed. With this information the direction of a bead profile can be estimated in every FE-node and displayed to the user as vector field. In the second step guidelines similar to streamlines are created using the vector field. These guidelines are the basic elements for channels shaped beads represented as CAD features. This approach enables the designer to create load step depending bead patterns without distorted FE-Meshes in CAD. The last scheme represents a semi-analytical approach to create the guidelines without Finite Elements Analyses for simple plate like structures. The vector field is calculated with the stresses using Kirchoff-Love\'s theory of plates. The investigation shows that the resulting guidelines can be approximated with superellipse. All methods are tested with parts of the automotive industry and academic examples.
|
5 |
Optimierte Sickengestaltung im Konstruktionsprozess dünnwandiger BauteileKrauß, Alexander 21 December 2016 (has links)
Dünnwandige Strukturen erreichen bei richtiger Gestaltung ein sehr gutes Masse-Steifigkeitsverhältnis und besitzen damit großes Potential für effektiven Strukturleichtbau. In ebenen und schwach gekrümmten Bereichen weisen diese jedoch eine geringe Biegesteifigkeit auf, welche häufig nicht den gestellten Anforderungen entspricht. Zur Formversteifung werden hier Sicken eingesetzt. Diese rinnenartigen oder flächigen Vertiefungen werden mithilfe einer Blechumformung, wie Tiefziehen, in das jeweilige Bauteil eingebracht.
Damit ein Sickenfeld die maximale Versteifungswirkung erreicht, muss es beanspruchungsgerecht ausgelegt werden. In der Praxis werden Sicken häufig erfahrungsbasiert oder mit den Erkenntnissen aus Sickenkatalogen in ein Bauteil eingebracht. Allerdings bleibt hier die Frage nach einer beanspruchungsgerechten Auslegung der Sickenparameter, wie Position und Ausrichtung, offen. Bei komplexeren Bauteilen generiert die FE-Netz basierte Formoptimierung hingegen ein deutlich besseres Ergebnis. Allerdings muss dieses für ein fertigungsgerechtes Sickenbild manuell im CAD rekonstruiert werden. Dieser Prozess ist im CAD-System zeitaufwändig und fehleranfällig.
Ziel dieser Arbeit ist es, die FEM gestützte Sickenauslegung effektiver zu gestalten. Eine Teilaufgabe ist die Verbesserung der Ergebnisinterpretation von formoptimierten FE-Netzen. Weiterhin werden neue Methoden gezeigt, welche ohne Interpretation verzerrter FE-Netze eine CAD-integrierte Sickenauslegung ermöglichen. / Thin-walled structures are used within various products, due to their optimal relation between mass and stiffness. Nevertheless those structures have a low bending stiffness in areas with less curvature. To bypass this disadvantage channels or flattened areas, so called beads, are embossed. To maximize the stiffening effect the position and orientation of the bead is essential. One of the latest methods for bead creation is based on the experience of the designer supported with construction catalogues. They offer predefined bead patterns, tested on simple plate structures and various load cases. The adoption of the predefined bead pattern on complex real live parts is often impossible. A second method uses FEM based optimization algorithms. They are more effective but the actual workflow of interpreting the distorted FEM meshes in CAD and resulting adoption on manufacturing constrains lead to non-optimal results, too.
The aim of this thesis is to represent new methods for bead creation with a high CAD integration level. As a result, three new methods are developed. At first, the workflow for the interpretation of bead patterns created by a FEM based optimization algorithm was simplified using tailor made CAD features for the reverse engineering process. The designer is now able to recreate tangency steady CAD geometry with the provided deformed FE mesh. The second method focuses on channel shaped beads. Herefore, the stress distribution is calculated within the FE-shell first and then analyzed. With this information the direction of a bead profile can be estimated in every FE-node and displayed to the user as vector field. In the second step guidelines similar to streamlines are created using the vector field. These guidelines are the basic elements for channels shaped beads represented as CAD features. This approach enables the designer to create load step depending bead patterns without distorted FE-Meshes in CAD. The last scheme represents a semi-analytical approach to create the guidelines without Finite Elements Analyses for simple plate like structures. The vector field is calculated with the stresses using Kirchoff-Love's theory of plates. The investigation shows that the resulting guidelines can be approximated with superellipse. All methods are tested with parts of the automotive industry and academic examples.
|
6 |
Optimierte Sickengestaltung im Konstruktionsprozess dünnwandiger BauteileKrauß, Alexander 13 September 2017 (has links)
Dünnwandige Strukturen erreichen bei richtiger Gestaltung ein sehr gutes Masse-Steifigkeitsverhältnis und besitzen damit großes Potential für effektiven Strukturleichtbau. In ebenen und schwach gekrümmten Bereichen weisen diese jedoch eine geringe Biegesteifigkeit auf, welche häufig nicht den gestellten Anforderungen entspricht. Zur Formversteifung werden hier Sicken eingesetzt. Diese rinnenartigen oder flächigen Vertiefungen werden mithilfe einer Blechumformung, wie Tiefziehen, in das jeweilige Bauteil eingebracht.
Damit ein Sickenfeld die maximale Versteifungswirkung erreicht, muss es beanspruchungsgerecht ausgelegt werden. In der Praxis werden Sicken häufig erfahrungsbasiert oder mit den Erkenntnissen aus Sickenkatalogen in ein Bauteil eingebracht. Allerdings bleibt hier die Frage nach einer beanspruchungsgerechten Auslegung der Sickenparameter, wie Position und Ausrichtung, offen. Bei komplexeren Bauteilen generiert die FE-Netz basierte Formoptimierung hingegen ein deutlich besseres Ergebnis. Allerdings muss dieses für ein fertigungsgerechtes Sickenbild manuell im CAD rekonstruiert werden. Dieser Prozess ist im CAD-System zeitaufwändig und fehleranfällig.
Ziel dieser Arbeit ist es, die FEM gestützte Sickenauslegung effektiver zu gestalten. Eine Teilaufgabe ist die Verbesserung der Ergebnisinterpretation von formoptimierten FE-Netzen. Weiterhin werden neue Methoden gezeigt, welche ohne Interpretation verzerrter FE-Netze eine CAD-integrierte Sickenauslegung ermöglichen. / Thin-walled structures are used within various products, due to their optimal relation between mass and stiffness. Nevertheless those structures have a low bending stiffness in areas with less curvature. To bypass this disadvantage channels or flattened areas, so called beads, are embossed. To maximize the stiffening effect the position and orientation of the bead is essential. One of the latest methods for bead creation is based on the experience of the designer supported with construction catalogues. They offer predefined bead patterns, tested on simple plate structures and various load cases. The adoption of the predefined bead pattern on complex real live parts is often impossible. A second method uses FEM based optimization algorithms. They are more effective but the actual workflow of interpreting the distorted FEM meshes in CAD and resulting adoption on manufacturing constrains lead to non-optimal results, too.
The aim of this thesis is to represent new methods for bead creation with a high CAD integration level. As a result, three new methods are developed. At first, the workflow for the interpretation of bead patterns created by a FEM based optimization algorithm was simplified using tailor made CAD features for the reverse engineering process. The designer is now able to recreate tangency steady CAD geometry with the provided deformed FE mesh. The second method focuses on channel shaped beads. Herefore, the stress distribution is calculated within the FE-shell first and then analyzed. With this information the direction of a bead profile can be estimated in every FE-node and displayed to the user as vector field. In the second step guidelines similar to streamlines are created using the vector field. These guidelines are the basic elements for channels shaped beads represented as CAD features. This approach enables the designer to create load step depending bead patterns without distorted FE-Meshes in CAD. The last scheme represents a semi-analytical approach to create the guidelines without Finite Elements Analyses for simple plate like structures. The vector field is calculated with the stresses using Kirchoff-Love\'s theory of plates. The investigation shows that the resulting guidelines can be approximated with superellipse. All methods are tested with parts of the automotive industry and academic examples.
|
7 |
Implication du stress oxydant dans la physiopathologie de la drépanocytose : crises vaso-occlusives, taux d'anticorps anti-bande 3 et oxydation du globule rouge / Implication of oxidative stress in the pathophysiology of sickle cell disease : vaso-occlusive crisis, antiband 3 antibodies levels and red blood cell oxidationHierso, Régine 08 July 2015 (has links)
A partir du défaut premier de la drépanocytose, la polymérisation de l’hémoglobine S (HbS), se développe toute une série de processus anormaux qui contribuent au développement d’une réponse inflammatoire et d’un stress oxydant dus à une hypoxie-reperfusion traumatisante et à l’auto-oxydation de l’HbS. L’exacerbation du stress oxydatif semble participer de manière active aux mécanismes physiopathologiques de la maladie et jouer un rôle dans la survenue des crises vaso-occlusives (CVO). Les travaux menés dans le cadre de cette thèse avaient pour objectif de mieux documenter les effets délétères du stress oxydant sur le globule rouge et son impact dans le développement des CVO. Nous avons, en premier lieu, évalué in vitro l’impact du stress oxydant sur la rhéologie sanguine des patients drépanocytaires SS et SC à l’aide d’un agent à fort potentiel oxydant, le t-butyl hydroperoxide (TBHP). Nous avons montré que les globules rouges des patients drépanocytaires (GR SS) produisent en présence du TBHP davantage de radicaux libres que les GR provenant de sujets contrôles (GR AA) et que ces GR SS présentent un système de défense anti-oxydant diminué. L’induction d’un stress oxydant accentue les altérations rhéologiques déjà présentes chez les patients drépanocytaires (i.e, déformabilité diminuée, diminution de l’indice d’agrégation, augmentation du seuil de désagrégation) tandis qu’il induit chez les sujets contrôles un profil hémorhéologique altéré proche de celui déjà préexistant chez les patients drépanocytaires. Ces résultats suggèrent que le stress oxydant, en participant aux anomalies hémorhéologiques associées à la drépanocytose, pourrait être l’un des facteurs favorisant la survenue des complications drépanocytaires. Nous nous sommes de plus attachés à documenter directement l’impact du stress oxydant dans le développement des CVO en analysant des prélèvements sanguins provenant de patients drépanocytaires SS en crise et à l’état de base. Il s’agissait : 1) de tester l’hypothèse selon laquelle la protéine bande 3, protéine de la membrane du GR, est une cible majeure des espèces réactives de l’oxygène qui provoquent au niveau de cette protéine l’apparition d’épitopes de senescence reconnus par des auto anticorps anti-bande 3 ; 2) d’évaluer l’évolution de marqueurs moléculaires et cellulaires pro- et anti-oxydants ; 3) d’étudier l’évolution des paramètres hémorhéologiques ; 4) d’explorer l’activité du système nerveux autonome, considéré comme un marqueur potentiel de sévérité. Nous avons mis en évidence au cours des CVO : 1) une exacerbation du stress oxydant ; 2) une diminution du taux d’anticorps anti-bande 3 et une augmentation de la concentration plasmatique de microparticules érythrocytaires, suggérant que ces deux processus sont liés au phénomène de clusterisation de la protéine bande 3 déclenché par le stress oxydant ; 3) une exacerbation des anomalies hémorhéologiques se traduisant par une réduction de la déformabilité érythrocytaire, une augmentation de l’agrégation érythrocytaire et du seuil de désagrégation ; 4) une altération du système nerveux autonome marqué par un retrait de l’activité parasympathique, ce déséquilibre étant accentué au cours des CVO. Les travaux de cette thèse se traduisent par à une meilleure compréhension de la physiopathologie extrêmement complexe de la drépanocytose en précisant l’impact du stress oxydant dans le déclenchement des CVO, première cause d’hospitalisation des sujets drépanocytaires. Les données obtenues, qui mettent en évidence des marqueurs pertinents de ce stress oxydant au cours de la CVO du sujet drépanocytaire, pourront favoriser la mise en œuvre de nouvelles pistes thérapeutiques anti-oxydantes et une amélioration in fine de la prise en charge des patients. / Besides the primary defect of sickle cell disease, hemoglobin S (HbS) polymerization, other abnormal processes may contribute to the development of an inflammatory response and to an oxidative stress caused by traumatic hypoxia-reperfusion and autoxidation of HbS. The exacerbation of oxidative stress seems to participate actively in the pathophysiology of the disease and play a role in vaso-occlusive crisis (VOC). The aim of this thesis was to document the deleterious effects of oxidative stress on the red blood cell and its impact in the development of VOC. First, we have evaluated the impact of tert-butyl hydroperoxide-induced oxidative stress on blood rheology of SS and SC sickle cell patients. We have shown that sickle red blood cells (SS RBC) produce more free radicals in the presence of tert-butyl hydroperoxide (TBHP) than control subject red blood cells (AA RBC). Furthermore, SS RBC have a decreased anti-oxidant defense system. Induction of oxidative stress increases the rheological alterations already present in sickle cell patients (ie, decreased deformability, reduced aggregation, increased disaggregation threshold). In control subjects, oxidative stress induces an altered hemorheological profile close to that already present in sickle cell patients. These results suggest that oxidative stress by modulating the hemorheological abnormalities associated with sickle cell disease, could be one of the factors promoting the occurrence of sickle cell complications. Then, we have studied the impact of oxidative stress in the development of VOC, analyzing blood samples from SS patients in crisis and at steady state. 1) We have tested the hypothesis that the protein band 3 of RBC, is a major target of reactive oxygen species, which cause the appearance of senescence epitopes of this protein recognized by auto anti-band 3 antibodies; 2) We have evaluated pro- and anti-oxidants molecular and cellular markers; 3) We have studied the evolution of hemorheological parameters; 4) We have explored the activity of the autonomic nervous system, seen as a potential marker of severity. Our results show during VOC: 1) an exacerbation of the oxidative stress; 2) a decrease in anti-band 3 antibodies levels and an increase in the plasma concentration of erythrocyte microparticles, suggesting that these two processes are linked to the clustering phenomenon of band 3 protein triggered by oxidative stress; 3) an exacerbation of hemorheological abnormalities resulting in a reduction of SS RBC deformability, increased aggregation and disaggregation threshold; 4) an impairment of the autonomic nervous system marked by a withdrawal of parasympathetic activity and this imbalance is accentuated during VOC. This work allows a better understanding of the complex pathophysiology of sickle cell disease, highlighting the impact of oxidative stress in the development of VOC, the leading cause of hospitalization of sickle cell subjects. The data obtained, which reveal relevant markers of oxidative stress during VOC, could promote the implementation of new antioxidant therapeutic approaches and help improving sickle cell patients care.
|
Page generated in 0.0419 seconds