Las apolipoproteínas más abundantes de HDL son la apoA-I y la apoA-II. La concentración plasmática de apoA-I está inversamente relacionada con el riesgo de enfermedad coronaria y su papel en las HDL es bien conocido. La apoA-I tiene un papel estructural muy importante en HDL, interacciona con receptores de HDL provocando el eflujo de colesterol de membranas celulares y es cofactor de la LCAT. En cambio, el papel que juega la apoA-II en el metabolismo lipoproteico y en el desarrollo de la arteriosclerosis es menos conocido. La línea de ratones transgénicos con más expresión de apoA-II humana (línea 11.1) alimentada con dieta aterogénica desarrolla hiperlipemia combinada, deficiencia de HDL y aumento notable de susceptibilidad a la arteriosclerosis. Los ratones transgénicos de apoA-II humana de la línea 11.1 presentaron un gran aumento del área de tinción para epítopos derivados de oxidación en estas lesiones respecto de los controles. En el estudio de las propiedades antioxidantes de las HDL de los ratones 11.1, éstas presentaron una menor capacidad de protección frente a la oxidación de lipoproteínas con apoB, que las HDL de ratones controles y que los transgénicos 25.3 (baja expresión de apoA-II). Las HDL de los ratones transgénicos 11.1 presentaron una composición alterada con gran cantidad de apoA-II humana, y disminución de apoA-I, PON1 y PAF-AH, que probablemente explican la menor protección frente a la oxidación que proveen estas HDL. Estos cambios en las partículas de HDL no son debidos a cambios en la transcripción de los genes de apoA-I, PON1, PAF-AH, LCAT. Sin embargo, en ensayos in vitro se comprobó que la apoA-II humana es capaz de desplazar la PON1 de la partícula de HDL. La alteración en la capacidad antioxidante de las HDL de transgénicos 11.1 explica, al menos en parte, la susceptibilidad a la arteriosclerosis aumentada en estos animales en dieta aterogénica. En el estudio de la capacidad de estas HDL de realizar transporte reverso de colesterol, los resultados mostraron que, a pesar de la deficiencia parcial de HDL que presentan, los ratones transgénicos 11.1 no mostraron una alteración importante en el ritmo de transporte reverso de colesterol específico de macrófagos, respecto de los ratones controles. Así pues, la susceptibilidad a la arteriosclerosis en ratones transgénicos 11.1 alimentados con dieta aterogénica, no parece ser atribuible a una disminución del transporte reverso de colesterol específico de macrófagos. / ApoA-I and apoA-II are the most abundant apolipoprotein in HDL. ApoA-I plasma concentration is inversely related to coronary artery disease risk and its role in HDL is well known. ApoA-I has a very important structural role in HDL, it binds to HDL receptors triggering cholesterol efflux from cell membranes and is LCAT cofactor. However, the role of apoA-II in lipoprotein metabolism and atherosclerosis development is less known.The high expressor human apoA-II transgenic mice (line 11.1) challenged with atherogenic diet develops combined hiperlipidemia, HDL deficiency and high atherosclerosis susceptibility. Line 11.1 mice showed a dramatic increase in staining area for oxidation-derived epitopes in aortic lesions, compared to control mice. HDL from 11.1 line presented impaired ability to protect apoB lipoprotein against oxidation when compared to control and 25.3 mouse line (low human apoA-II expressor). HDL from 11.1 mice showed an altered composition with high quantities of human apoA-II, low apoA-I, PON1 and PAF-AH, that likely accounts for the impaired protection against oxidation found in these mice. However, these changes are not due to changes in transcription of apoA-I, PON1, PAF-AH or LCAT genes. On the other hand, human apoA-II is able to displace PON1 from the HDL particle, as shown by in vitro assays. Impairment of antioxidant ability of HDL from 11.1 transgenic mice could explain, at least in part, the enhanced atherosclerosis susceptibility found in these animals in atherogenic diet.In the study of the ability of HDL from 11.1 transgenic mice to carry out reverse cholesterol transport, the results showed that, despite their HDL deficiency, 11.1 transgenic mice did not presented an altered flux in macrophage-specific reverse cholesterol transport. Therefore, the enhanced atherosclerosis susceptibility of 11.1 transgenic mice does not seem attributable to an impaired macrophage-specific reverse cholesterol transport.

La infecció pel VIH ha esdevingut una malaltia crònica gràcies a la introducció del tractament antiretroviral. Tot i la disminució de la mortalitat, la incidència de complicacions metabòliques relacionades amb el tractament i la infecció adquireixen cada cop més rellevància clínica. La infecció pel VIH promou un estat pro-oxidatiu que afavoreix la mateixa replicació viral i l'aparició d'alteracions metabòliques com l'aterosclerosi o la lipodistròfia. L'aterosclerosi és reconeguda com una malaltia inflamatoria crònica. La paraoxonasa-1 (PON1) és un enzim associat a les lipoproteïnes d'alta densitat (HDL) que li confereix gran capacitat antioxidant. Tot i que el seu sustrat fisiològic encara no es coneix, s'ha estudiat el seu rol protector en diverses malaties cròniques. Per aquesta raó creiem interessant investigar la possible funció d'aquest enzim antioxidant en la evolució immunològica i virològica de la infecció pel VIH i així també en l'aparició de complicacions metabòliques com l'aterosclerosi. / HIV infection has become a chronic disease since introduction of antiretroviral treatments. Despite the decline in mortality, the incidence of metabolic complications related to treatment and the infection itself are becoming more relevant. HIV infection promotes a pro-oxidative status that favors viral replication and the emergence of the metabolic disorders such as atherosclerosis and lipodystrophy. Atherosclerosis is recognized as a chronic inflammatory disease. The paraoxonase-1 (PON1) is an enzyme bound to high-density lipoprotein (HDL), which confers high antioxidant properties. Although its physiological sustrat is not yet known, it has been studied its protective role in several chronic diseases with an increase in oxidative stress and atherosclerosis. For this reason we believe is of interest to investigate the possible role of this antioxidant enzyme in the immunological and the virological evolution of HIV infection and in the apparition of metabolic complications such as atherosclerosis.

Fluorometric density gradient ultracentrifugation is used to measure the lipoprotein density profile for cardiovascular disease risk assessment. The work presented establishes the effectiveness of using a single-spin separation as both an analytical tool and a preparative tool, while yielding valuable density information. This research expands on the analytical power of density gradient ultracentrifugation (DGU) by combining novel ethylenediaminetetraacetic acid (EDTA) gradient solutions, a fluorescent probe for analysis, and modern statistical methods for classification of heart disease risk. Sub-classes of lipoproteins are analyzed based on their density from the fluorescent lipoprotein density profile. The application of linear discriminant analysis (LDA) and sliced average variance estimation (SAVE) to the fluorometric DGU data yields a powerful classification tool. This method is capable of determining differences between control and cardiovascular disease patients that do not exhibit the traditional risk factors. The combination of these methods has great potential to serve as analytical tools for researchers in understanding the mechanisms of disease development and as a diagnostic tool for clinicians.

Background. The published reports of the effectiveness of simvastatin in treatment of hypercholesterolemia were mostly conducted in western populations, and only few studies in Asian or domestic populations have ever been reported. By regulations from Bureau of National Health Insurance, the effective dosage of lipid lowering agents should be started from lower dose, such as 20 mg of simvastatin per day. Whether this dosage of simvastatin is effective for treatment of patients with hypercholesterolemia and the efficacy and safety of such dosage are the objects of this study. Materials and Methods. After the approval of IRB in a medical center located at north Taiwan, a randomized 12-week study was conducted to evaluate the efficacy and safety of 20mg/day simvastatin treatment on hypercholesterolemia. By randomization 65 patients, followed up at cardiovascular outpatient department under the diagnosis of primary hypercholesterolemia, were enrolled into a 4-week washout period, and finally 49 intent-to-treat patients entered a 12-week treatment with 20mg simvastatin per day, given through oral routine in the evening. Demographic and laboratory data were obtained before and after treatment. The primary efficacy measure was the changes from baseline in lipid parameters. Tolerability was assessed in terms of the overall incidence of adverse experiences and the most commonly reported adverse experiences. Results. The per-protocol analyses included 39 hypercholesterolemic patients whom completed 12 weeks of therapy. Total cholesterol and LDL cholesterol at the end of the study period showed significant reductions by 22.5¢H (p<0.001) and 29.8¢H(p<0.001), respectively. Triglyceride also showed a significant reduction by 31.8% (p=0.006), whereas total alkaline phosphatase and calcium showed a weak and insignificant change over the study period. The female group had significantly greater reduction in triglyceride than that in the male group, and the non-smoking group also had significantly greater reduction in triglyceride than that in smoking group after 12-week treatment. There were 17 studied cases (34.7%) had minor transient but clinical insignificant increases in serum aspartate aminotransferase and alanine aminotransferase, and 7 cases (14.3%) experienced symptom of painful muscle, of whom 3 cases (6.1%) dropped out this study. Conclusion. Our results, although obtained from a small scale of hypercholesterolemic patients, suggest a probable positive efficacy and good tolerability with only few minor side effects of simvastatin on blood lipids.

No description available.

Résumé : Les maladies cardio-vasculaires (MCV) constituent l'une des principales causes de mortalité et de morbidité dans le monde. De nombreuses études épidémiologiques montrent que les niveaux des lipoprotéines de haute densité (HDL) sont inversement corrélés au risque des MCV. Les propriétés antiathérogènes des HDL sont attribuées, en partie, à l'action de l'enzyme Paraoxonase 1 (PON1) qui leur est associée exclusivement. Le rôle de la PON1 dans l’activité antioxydante des HDL a été largement étudié, alors que le mécanisme par lequel la PON1 exerce ses effets anti-inflammatoires reste à établir. La prévalence accrue des MCV avec l'augmentation de l'âge incite à rechercher certains facteurs qui pourraient expliquer cette tendance. Peu de travaux se sont intéressés à l'impact d'une réduction de la fonctionnalité de HDL dans le développement de l'athérosclérose et encore moins en présence d'un facteur de risque pour les MCV, tel que l'âge. À ce jour, plusieurs travaux ont mis en évidence une diminution de l'activité antioxydante de HDL et de la PON1 chez la personne âgée. Cependant, il n'existe pas de données sur l'effet de la réduction de l'activité de la PON1 sur l'activité anti-inflammatoire des HDL. Nos objectifs sont d'élucider le rôle de la PON1 dans les activités anti-inflammatoires des HDL et de déterminer l'effet de sa modulation sur l'activité athéroprotectrice des HDL chez les personnes âgées. Nos résultats montrent que la PON1 diminue significativement le niveau d'expression des molécules d'adhésion intercellulaire-1 (lCAM-1) au niveau des cellules endothéliales inhibant ainsi l'induction de l'inflammation en présence de phospholipides oxydés. Cette activité anti-inflammatoire de la PON1 est due à la fois à sa capacité de réduire l'oxydation des lipides (effet antioxydant) mais aussi à son activité phospholipase like, hydrolysant ainsi les lipides oxydés. Toutefois, cet effet anti-inflammatoire dépend de son association aux HDL. Nos résultats démontrent ainsi que l'effet anti-inflammatoire des HDL est dû en grande partie à la PON1. Cette activité des HDL diminue significativement au cours du vieillissement. Nos résultats montrent aussi que 12 semaines de consommation d'huile d'olive extra vierge (EVOO) augmentent significativement l'activité anti-inflammatoire des HDL. Cet effet est dû à une augmentation de l'activité de PON1 et d'une réduction du niveau de stress oxydant. Cet effet bénéfique de l'EVOO est plus significatif chez les personnes âgées que chez les personnes jeunes. Conclusions: Nos résultats apportent la démonstration de l'implication de la PON1 dans la régulation des activités antiathérogènes des HDL et proposent des mécanismes de l'implication de la PON1 dans la régulation de cette activité anti-inflammatoire des HDL. Aussi, nos résultats montrent l'importance de la diète de type méditerranéen dans la régulation des fonctions antiathérogènes des HDL, et plus particulièrement, en présence d'un facteur de risque pour les MCV, tel que le vieillissement. // Abstract : Cardiovascular diseases are one of the main causes of mortality and morbidity throughout the world. Several epidemiologic studies show that there is an inverse correlation between the levels of high density lipoproteins (HDL) and cardiovascular risk. The antiatherogenic properties of HDL are due, in part, to paraoxonase 1 (PON1) enzyme, which is associated exclusively to HDL. The role of PON1 in the antioxidant activity of HDL has been widely studied. However, the mechanism by which PON1 exerts its antiinflammatory effect remains to be determined. Increased prevalence of cardiovascular diseases and the increasing life span encourages investigations for certain predisposing factors that could explain this tendency. Few studies have focused on the impact of a reduction of HDL activity within the development of atherosclerosis during the aging process. Nowadays, several studies had demonstrated a reduction in the antioxidant activities of HDL and PON1 in the elderly population. However, there is no data of the effect of aging on the anti-inflamm atory activities of PON 1 and HDL. The main objectives of the present study were to explain the role of the PON1 in the anti-inflammatory properties of the HDL and to determine the effect of the modulation of PON1 activity on the atherprotective effect of HDL in the elderly population. Our results show that PON1 decreased significantly ICAM-1 expression within the endothelial cells, which inhibits the induction of inflammation in the presence of oxidized phospholipids. The anti-inflammatory activity of PON1 is due to its capacity to reduce lipid oxidation (antioxidant effect) and to its phospholipase-like activity, which consists of hydrolyzing oxidized lipids. Our results also show that 12 weeks of extra virgin oil (EVOO) increase significantly the anti-inflammatory activity of HDL. This effect is due principally to an improvement of the activity of PON1 and reduction of oxidative stress status. This beneficial effect of EVOO was more significant in the elderly than in young subjects. Conclusions: Our results demonstrate the role of the PON1 in the regulation of the antiatherogenic activities of HDL and suggest a mechanism for the implication of PON1 in the regulation of the anti-inflammatory activity of HDL. In addition, our results show the importance of the Mediterranean diet in the regulation of antiatherogenic function HDL, and particularly, in the presence of a risk factor for cardiovascular disease such as aging.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Thesis (M.D.)--University of Utrecht, 1984. / Foreword and summary in Dutch. Includes bibliographical references (p. 161-188).

Submitted by Hiolanda Rêgo (hiolandar@gmail.com) on 2013-05-06T18:44:44Z No. of bitstreams: 1 Dissertação_Nut_ Ana Paula de Seixas.pdf: 1200212 bytes, checksum: 99650b638aa3bb5d21f38fb9fe69dc78 (MD5) / Approved for entry into archive by Flávia Ferreira(flaviaccf@yahoo.com.br) on 2013-05-07T19:35:51Z (GMT) No. of bitstreams: 1 Dissertação_Nut_ Ana Paula de Seixas.pdf: 1200212 bytes, checksum: 99650b638aa3bb5d21f38fb9fe69dc78 (MD5) / Made available in DSpace on 2013-05-07T19:35:51Z (GMT). No. of bitstreams: 1 Dissertação_Nut_ Ana Paula de Seixas.pdf: 1200212 bytes, checksum: 99650b638aa3bb5d21f38fb9fe69dc78 (MD5) / Objetivo: As dislipidemias integram o grupo das Doenças Crônicas Não Transmissíveis e se constituem também em fatores de risco para algumas destas doenças. Esses eventos vêm acometendo cada vez mais precocemente crianças e adolescentes. As dislipidemias podem ser identificadas por indicadores bioquímicos, entre eles o colesterol não-HDL. Assim, objetivouse com este estudo estimar a prevalência de colesterol não-HDL elevado e seus fatores associados em escolares de Salvador. Métodos: Estudo transversal envolvendo amostra representativa de adolescentes de escolas estaduais de Salvador, Bahia, Brasil. A regressão de Poisson foi utilizada na análise estatística adotando-se o colesterol não-HDL elevado como a variável dependente. As variáveis independentes foram representadas por fatores demográficos, antropométricos, econômicos, do estágio maturacional e do consumo alimentar. Resultados: A prevalência do colesterol não-HDL elevado foi de 32,3% e foi mais acentuada nos adolescentes que tinham excesso de peso (RP: 1,50; IC95%: 1,23-1,83), glicemia elevada (RP: 1,37; IC95%: 1,10-1,72) e TG elevados (RP: 2,04; IC:95%: 1,69-2,46), quando comparada com a prevalência daqueles que tinham estes parâmetros adequados. O consumo baixo ou moderado de alimentos protetores também imprimiu risco (RP: 1,30; IC95%: 1,07-1,59) para a ocorrência de níveis de colesterol não-HDL elevado. Conclusões: Foi observada alta ocorrência de colesterol não-HDL elevado entre os adolescentes do estudo. Parâmetros bioquímicos (glicemia e nível de TG) e antropométricos (Índice de Massa Corporal) alterados assim como consumo baixo ou moderado de alimentos protetores para dislipidemia aumentam a prevalência de colesterol não-HDL elevado. Dessa forma, faz-se necessário a promoção de medidas para a redução da ocorrência de colesterol não-HDL elevado na adolescência. / Salvador

The need for a more general hardware description language aimed specifically at processors, and vague notions and visions of how that language would be realized, lead to this thesis. The aim was to use the visions and initial ideas to evolve and formalize a language and begin implementing the tools to use it. The language, called NoGAP Common Language, is designed to give the programmer freedom to implement almost any processor design without being encumbered by many of the tedious tasks normally present in the creation process. While evolving the language it was chosen to borrow syntaxes from C++ and verilog to make the code and concepts easy to understand. The main advantages of NoGAP Common Language compared to RTL languages are; -the ability to define the data paths of instructions separate from each other and have them merged automatically along with assigned timings to form the pipeline. -having control paths automatically routed by activating named clauses of code coupled to control signals. -being able to specify a decoder, where the instructions and control structures are defined, that control signals are routed to. The implemented compiler was created with C++, Bison, and Flex and utilizes an AST structure, a symbol table, and a connection graph. The AST is traversed by several functions to generate the connection graph where the instructions of the processor can be merged into a pipeline. The compiler is in the early stages of development and much is left to do and solve. It has become clear though that the concepts of NoGAP Common Language can be implemented and are not just visions. / Behovet av ett mer generellt hårdvarubeskrivande språk specialiseret för processorer och visioner om ett sådant gav upphov till detta examensarbete. Målet var att utveckla visionerna, formalisera dem till ett fungerande språk och börja implementera dess verktyg. Språket, som kallas NoGAP Common Language, är designat för att ge programmeraren friheten att implementera nästan vilken processordesign som helst utan att bli nedtyngd av många av de enformiga uppgifter som annars måste utföras. Under utvecklingsprocessen valdes det att låna många syntax från C++ och verilog för att göra språket lätt att förstå och känna igen för många. De största fördelarna med att utveckla i NoGAP Common Language jämfört med vanliga RTL språk som verilog är; -att kunna specificera datavägar för instruktioner separat från varandra och få dem automatiskt förenade med hjälp av tidsangivelser till en pipeline. -att få kontrollvägar automatiskt dragna genom att aktivera namngivna klausuler med kod kopplade till kontrollsignaler. -att kunna specifiera en avkodare som kontrollvägarna kan kopplas till där kodning för instruktioner kan anges. Kompilatorn som implementerats med C++, Bison och Flex använder sig av en AST struktur, en symboltabell och en signalvägsgraf. AST strukturen traverseras av flera funktioner som bygger upp signalvägsgrafen där processorns instruktioner förenas till en pipeline. Utvecklingen av kompilatorn är ännu bara i de första stadierna och mycket är kvar att göra och lösa. Det har dock blivit klart att det är möjligt att implementera koncepten i NoGAP Common Language och att de inte bara är lösa visioner.