Magister Pharmaceuticae - MPharm / Cardiovascular diseases (CVDs) such as ischaemic heart diseases, heart failure and stroke remain a major cause of death globally. Various deep-rooted factors influence CVD development; these include but are not limited to elevated blood lipids, high blood pressure, obesity and diabetes. A considerable number of proteins are involved directly and indirectly in the transport, maintenance and elimination of plasma lipids, including high and low-density lipoprotein cholesterol (HDL-C and LDL-C). There are several mechanisms involved in the removal of LDL particles from systemic circulation. One such mechanism is associated with the gene that encodes proprotein convertase subtilisin/kexin type 9 (PCSK9), which has become an exciting therapeutic target for the reduction of residual risk of CVDs. Currently, statins are the mainstay treatment to reduce LDL-C, and a need exists to further develop more effective LDL-C-lowering drugs that might supplement statins. This study was aimed at contributing to the generation of knowledge regarding the effect of niacin in reducing LDL levels through PCSK9 interaction. The aims/objectives of this study were achieved by utilizing two approaches, which included animal intervention with niacin followed by genetic screening of five prioritized genes involved in cholesterol synthesis and regulation. For animal intervention, 16 vervet monkeys were divided into two groups of eight animals consisting of a control and an experimental (niacin) group. The control group was given a normal standard diet of pre-cooked maize meal throughout the study, while the experimental group received the same diet supplemented with 100 mg/kg of niacin (SR) for 12 weeks. During the niacin intervention, blood was collected at baseline, every four weeks during the treatment period and the end of the washout period. The collected blood was used for biochemical analysis (total cholesterol, triglycerides, LDL-C, and HDL-C) and downstream genetic applications. The second phase included the screening of PCSK9, LDLR, SREBP-2, CETP and APOB-100 using genotyping and gene expression. Niacin administration produced statistically significant increases in plasma HDL-C at fourtime points (T1, T2, T3 and T4), which resulted in an overall increase in plasma HDL-C. Additionally, niacin administration resulted in a slight reduction in LDL-C and total cholesterol levels. Furthermore, the genotyping analysis revealed 13 sequence variants identified in PCSK9, LDLR, SREBP-2, CETP and APOB-100 genes. Five of these variants were predicted to be disease-causing and correlated with gene expression patterns. Three identified PCSK9 variants (H177N, R148S, G635G) were categorized as LOF mutations, and this was supported by a decline in gene expression in animals harbouring these variants. The LDLR also had LOF variants that were the reason for its decreased mRNA expression. Additionally, SREBP-2 proved to be a key mediator of cholesterol pathways. Therefore, the findings of the study conclusively suggest that niacin does increase HDL-C and decrease LDL-C and total cholesterol. Moreover, an interaction between niacin administration and PCSK9 was observed which resulted in decreased gene expression.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第19322号 / 農博第2143号 / 新制||農||1036(附属図書館) / 学位論文||H28||N4950(農学部図書室) / 32324 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 植田 和光, 教授 植田 充美, 教授 阪井 康能 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

No description available.

Neste trabalho analisamos e propomos a utilização de TDM (Time Division Multiplexing) nativo canalizado/estruturado em redes PON (Passive Optical Network) com padrão GPON (Gigabit Passive Optical Network), com ênfase na estrutura de transmissão do legado das redes de telefonia. O objetivo principal é obter um aumento na eficiência de banda transmitida através da fragmentação de sinais E1 sem que seja necessário o uso de técnicas de emulação de circuito (que reduzem a eficiência de banda devido à adição de cabeçalhos). Inicialmente, é descrito o transporte TDM em redes GPON, como efetuado pelos equipamentos comerciais atuais através de duas técnicas: CES - Circuit Emulation Service e TDM nativo não estruturado. Em seguida, é introduzido o conceito de comutação digital visando sua aplicação no transporte TDM nativo estruturado em redes GPON. Nesta etapa, é proposta uma solução para este transporte, é descrito o protocolo utilizado bem como seu funcionamento. Por fim, como prova de conceito, é apresentada uma implementação em HDL (Hardware Description Language) para FPGA (Field Programmable Gate Array). / In this work we analyze and propose the use of native channeled /structured TDM (Time Division Multiplexing) in GPON (Gigabit Passive Optical Network), with emphasis on the structure for transmission of the telephone network legacy. The main target is to achieve an increase in transmitted bandwidth efficiency by fragmenting E1 signals, thus avoiding the use of circuit emulation techniques (which reduce the bandwidth efficiency due to overhead addition). Initially, it is described in TDM transport in GPON networks, as it is performed in present commercial equipment by two techniques: CES - Circuit Emulation Service and Native TDM - unstructured. Next, we introduce the concepts of digital switching aiming its application on the transport of native and structured TDM in GPON. At this stage, we propose a transport solution, describe its protocol and functionalities. Finally, for concept proof, we present an implementation in HDL (Hardware Description Language) meant to FPGA (Field Programmable Gate Array) application.

Introdução: Estudos têm demonstrado a associação de doença arterial coronária (DAC) grave com triglicérides (TG) pós prandial. No entanto, a relação entre a aterosclerose leve a moderada e TG pós prandial não está bem estabelecida. No presente estudo avaliamos a relação entre TG pós prandial e DAC detectada por angiografia coronária por tomografia computadorizada (TC cor). Material e Métodos: Foram incluídos 130 pacientes (85 com DAC detectado pelo TC cor coronária e 45 sem DAC), submetidos a um teste de tolerância oral de gordura. Estudamos a lipemia pós prandial medindo TG de T0h para T6H com intervalos de duas horas, e analisamos a mudança TG ao longo do tempo através de um modelo linear misto multivariável longitudinal, utilizando como desfecho primário o log normal do TG. Resultados: Os pacientes com DAC eram mais velhos (56,5 ± 6,8 vs. 50,4 ± 7,1 anos, p < 0,001), predominantemente do sexo masculino (68,2% vs. 37,8%, p < 0,001) e com HDL-colesterol (HDL-C) menor (49 ± 14 vs. 54 ± 12 mg / dl, p = 0,015). A maioria dos indivíduos com DAC tinha aterosclerose leve com doença não obstrutiva (63,5%). Pacientes com DAC tiveram uma depuração mais lenta TG pós prandial de 4h a 6h (p < 0,05) em comparação com pacientes sem DAC. Estes resultados permanecerem significativos mesmo após ajuste para o TG de jejum, idade, sexo, índice de massa corporal e glicemia de jejum. No entanto, essas diferenças não foram significativas após o ajuste para o HDL-C de jejum. Conclusão: Os pacientes com DAC leve e moderada detectados pelo TC cor demonstraram alteração do metabolismo de TG pós prandial, com remoção mais lenta de TG, especialmente entre 4h e 6h quando comparados a indivíduos sem DAC. Esta diferença foi explicada em parte pelo menor HDL-C de jejum no grupo com DAC. Assim, embora TG pós prandial possa contribuir para o desenvolvimento de DAC, esta associação é parcialmente relacionada com a menor concentração de HDL-C em indivíduos com DAC / Background: Studies have demonstrated the association of severe coronary artery disease (CAD) with postprandial triglycerides (TG). Nevertheless the relationship between less severe atherosclerosis and postprandial triglycerides is less established. Objective: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). Material and Methods: We enrolled 130 patients, (85 with CAD detected by coronary CTA and 45 without); who underwent an oral fat tolerance test. We studied the postprandial lipemia measuring TG from T0h to T6h with 2 hour intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome.Results: Patients with CAD were older (56.5 ± 6.8 vs. 50.4 ± 7.1 years, p < 0.001), predominantly male (68.2% vs. 37.8%, p < 0.001) and had lower HDL-cholesterol (HDL-C) (49 ± 14 vs. 54 ± 12 mg/dL, p=0.015). The majority of individuals with CAD had mild atherosclerosis with non-obstructive disease (63.6%). Patients with CAD had a slower clearance of postprandial TG change from 4h to 6h (p < 0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG, age, gender, body mass index and glucose. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. Conclusion: Patients with mild and moderate CAD detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to the low HDL-C in individuals with CAD

Universidade Federal do Cearà / O presente trabalho relata o estudo quÃmico dos constituintes volÃteis das folhas e frutos de Myrcia sp., coletados no municÃpio de Amontada-CE em marÃo de 2005 e a obtenÃÃo de fraÃÃes e substÃncias provenientes do decocto das folhas frescas e do extrato etanÃlico das folhas secas de Cissus verticillata, bem como o estudo concomitante do seu potencial farmacolÃgico como hipoglicemiante atravÃs de testes realizados com a fraÃÃo solÃvel em metanol, fraÃÃo rica em tiramina e com a tiramina, obtidos de C. verticillata. Os Ãleos essenciais de Myrcea sp. foram analisados por cromatografia gÃs-lÃquido acoplada à espectrometria de massa (CGL/EM) e, quantitativamente, atravÃs do uso de CGL acoplada a detector do tipo FID. A anÃlise do Ãleo essencial das folhas de Myrcia sp. (GAOFOLHAS), permitiu a identificaÃÃo de treze componentes: d-elemeno, b-elemeno, trans-cariofileno, a-humuleno, b-chamigreno, germacreno D, b-selineno, a-guaieno, a-selineno, a-Z-bisaboleno, d-cadineno, epi-a-murolol e a-cadinol. O Ãleo essencial dos frutos de Myrcia sp. (GAOFRUTOS) permitiu a identificaÃÃo de onze componentes: d-elemeno, b-elemeno, trans-cariofileno, a-guaieno, a-humuleno, germacreno D, b-selineno, a-selineno, germacreno A, d-cadineno e germacreno B. O estudo fitoquÃmico do decocto de C. verticillata resultou na fraÃÃo rica em tiramina (CVFDSM-F19-24) que apÃs fracionamento cromatogrÃfico permitiu o isolamento da substÃncia tiramina, inÃdita no gÃnero Cissus. Os testes realizados com esta fraÃÃo e com a tiramina, em ratos com diabetes aloxan-induzida, mostraram reduÃÃo na glicemia, colesterol total, triglicÃrides e nÃveis de VLDL e aumento nos nÃveis de HDL. O fracionamento cromatogrÃfico da fraÃÃo hexÃnica, proveniente do extrato etanÃlico das folhas secas de C. verticillata, permitiu o isolamento dos esterÃides, b-sitosterol e b-sitosterol-glicosilado. A caracterizaÃÃo estrutural das substÃncias isoladas de C. verticillata foi realizada atravÃs do uso de tÃcnicas espectroscÃpicas, tais como, infravermelho e RMN de 1H e 13C, incluindo tÃcnicas uni e bidimensionais (HMBC e HMQC), bem como a comparaÃÃo com dados descritos na literatura. / The present work reports on the volatile constituents from leaves and fruits of Myrcia sp. collected in Amontada County-Cearà State, in march/2006. It also reports on the phytochemical analysis of the decoction solution from fresh leaves, and the ethanol extract of dried leaves of Cissus verticillata in a concomitant study of its pharmacological potential as hipoglycemiant. GLC/MS and GLC/FID analysis of the essential oil from leaves (GAOFOLHAS) allowed the identification of 13 components: d-elemene, b-elemene, trans-caryophyllene, a-humulene, b-chamigrene, germacrene D, b-selinene, a-guaiene, a-selinene, a-Z-bisabolene, d-cadinene, epi-a-murolol and a-cadinol, while the essential oil from fruits (GAOFRUTOS) allowed the identification of 11 components: d-elemene, b-elemene, trans-cariophylene, a-guaiene, a-humulene, germacrene D, b-selinene, a-selinene, germacrene A, d-cadinene and germacrene B. The silica-gel chromatography analysis of the decoction solution of fresh leaves of C. verticillata allowed the separation of a fraction rich in tyramine, and from it, pure tyramine. Pharmacological tests on rats with aloxan-induced glycemia with both the tyramine rich fraction and pure tyramine allowed reduction on the glycemia levels, as well as for total cholesterol, triglycerids and VLDL, but HDL increasing. Silica-gel chromatography analyses of the ethanol extract from dried leaves of C. verticillata allowed the isolation of b-sitosterol and its glucoside derivative. Structure determination of all substances of C. verticillata was accomplished by means of spectroscopic techniques such as IR, 1H and 13C NMR, including uni and bi-dimensional pulse sequences (HMBC and HMQC) ad comparison with data from the literature.

Introdução: Estudos têm demonstrado a associação de doença arterial coronária (DAC) grave com triglicérides (TG) pós prandial. No entanto, a relação entre a aterosclerose leve a moderada e TG pós prandial não está bem estabelecida. No presente estudo avaliamos a relação entre TG pós prandial e DAC detectada por angiografia coronária por tomografia computadorizada (TC cor). Material e Métodos: Foram incluídos 130 pacientes (85 com DAC detectado pelo TC cor coronária e 45 sem DAC), submetidos a um teste de tolerância oral de gordura. Estudamos a lipemia pós prandial medindo TG de T0h para T6H com intervalos de duas horas, e analisamos a mudança TG ao longo do tempo através de um modelo linear misto multivariável longitudinal, utilizando como desfecho primário o log normal do TG. Resultados: Os pacientes com DAC eram mais velhos (56,5 ± 6,8 vs. 50,4 ± 7,1 anos, p < 0,001), predominantemente do sexo masculino (68,2% vs. 37,8%, p < 0,001) e com HDL-colesterol (HDL-C) menor (49 ± 14 vs. 54 ± 12 mg / dl, p = 0,015). A maioria dos indivíduos com DAC tinha aterosclerose leve com doença não obstrutiva (63,5%). Pacientes com DAC tiveram uma depuração mais lenta TG pós prandial de 4h a 6h (p < 0,05) em comparação com pacientes sem DAC. Estes resultados permanecerem significativos mesmo após ajuste para o TG de jejum, idade, sexo, índice de massa corporal e glicemia de jejum. No entanto, essas diferenças não foram significativas após o ajuste para o HDL-C de jejum. Conclusão: Os pacientes com DAC leve e moderada detectados pelo TC cor demonstraram alteração do metabolismo de TG pós prandial, com remoção mais lenta de TG, especialmente entre 4h e 6h quando comparados a indivíduos sem DAC. Esta diferença foi explicada em parte pelo menor HDL-C de jejum no grupo com DAC. Assim, embora TG pós prandial possa contribuir para o desenvolvimento de DAC, esta associação é parcialmente relacionada com a menor concentração de HDL-C em indivíduos com DAC / Background: Studies have demonstrated the association of severe coronary artery disease (CAD) with postprandial triglycerides (TG). Nevertheless the relationship between less severe atherosclerosis and postprandial triglycerides is less established. Objective: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). Material and Methods: We enrolled 130 patients, (85 with CAD detected by coronary CTA and 45 without); who underwent an oral fat tolerance test. We studied the postprandial lipemia measuring TG from T0h to T6h with 2 hour intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome.Results: Patients with CAD were older (56.5 ± 6.8 vs. 50.4 ± 7.1 years, p < 0.001), predominantly male (68.2% vs. 37.8%, p < 0.001) and had lower HDL-cholesterol (HDL-C) (49 ± 14 vs. 54 ± 12 mg/dL, p=0.015). The majority of individuals with CAD had mild atherosclerosis with non-obstructive disease (63.6%). Patients with CAD had a slower clearance of postprandial TG change from 4h to 6h (p < 0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG, age, gender, body mass index and glucose. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. Conclusion: Patients with mild and moderate CAD detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to the low HDL-C in individuals with CAD

Neste trabalho analisamos e propomos a utilização de TDM (Time Division Multiplexing) nativo canalizado/estruturado em redes PON (Passive Optical Network) com padrão GPON (Gigabit Passive Optical Network), com ênfase na estrutura de transmissão do legado das redes de telefonia. O objetivo principal é obter um aumento na eficiência de banda transmitida através da fragmentação de sinais E1 sem que seja necessário o uso de técnicas de emulação de circuito (que reduzem a eficiência de banda devido à adição de cabeçalhos). Inicialmente, é descrito o transporte TDM em redes GPON, como efetuado pelos equipamentos comerciais atuais através de duas técnicas: CES - Circuit Emulation Service e TDM nativo não estruturado. Em seguida, é introduzido o conceito de comutação digital visando sua aplicação no transporte TDM nativo estruturado em redes GPON. Nesta etapa, é proposta uma solução para este transporte, é descrito o protocolo utilizado bem como seu funcionamento. Por fim, como prova de conceito, é apresentada uma implementação em HDL (Hardware Description Language) para FPGA (Field Programmable Gate Array). / In this work we analyze and propose the use of native channeled /structured TDM (Time Division Multiplexing) in GPON (Gigabit Passive Optical Network), with emphasis on the structure for transmission of the telephone network legacy. The main target is to achieve an increase in transmitted bandwidth efficiency by fragmenting E1 signals, thus avoiding the use of circuit emulation techniques (which reduce the bandwidth efficiency due to overhead addition). Initially, it is described in TDM transport in GPON networks, as it is performed in present commercial equipment by two techniques: CES - Circuit Emulation Service and Native TDM - unstructured. Next, we introduce the concepts of digital switching aiming its application on the transport of native and structured TDM in GPON. At this stage, we propose a transport solution, describe its protocol and functionalities. Finally, for concept proof, we present an implementation in HDL (Hardware Description Language) meant to FPGA (Field Programmable Gate Array) application.

Abstract Coronary heart disease (CHD), a manifestation of atherosclerosis, is the leading single cause of death in Finland. CHD is affected by numerous genetic and environmental factors, their combined effects and interactions between them. Low HDL-cholesterol (HDL-C) is an independent risk factor for atherosclerosis and the most common dyslipidemia associated with early onset CHD, but the mechanisms regulating HDL-C levels and protecting from atherosclerosis are still not completely understood. Adiponectin is a hormone that is secreted by adipose tissue and has several anti-atherosclerotic effects. There is multiple evidence suggesting that adiponectin could protect against CHD via positive effects on HDL metabolism. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has a potentially conflicting role in atherosclerosis; it may have protecting or predisposing effects. The objective of this thesis was to study the genetic background of HDL-C regulation and atherosclerosis. Three studies were executed using extended families with CHD or case-control setting, with samples collected from Northern Finland. In the first study, seven chromosomal regions showing suggestive evidence of linkage were identified for HDL-C regulation, using genome-wide linkage approach. In the second study, we found a strong correlation between HDL-C and adiponectin, but failed to show evidence of a shared genetic background. However, a genetic correlation between adiponectin and low-density lipoprotein-cholesterol was revealed. We also studied the genetic regulation of adiponectin, and for the first time its most active form, high-molecular weight adiponectin, and found suggestive evidence of linkage to three chromosomal regions. In the third study, it was discovered that the studied VEGF gene polymorphisms did not have a major effect on atherosclerosis quantified as carotid intima-media thickness or the risk of acute myocardial infarction (AMI). This thesis presents potential regions for the genetic regulation of HDL-C and adiponectin and gives new information about their relationship and the effect of VEGF polymorphisms in atherosclerosis. The strong correlation between adiponectin and HDL-C was further strengthened, but we failed to show a shared genetic background between them. / Tiivistelmä Sepelvaltimotauti, eräs valtimonkovettumataudin ilmentymä, on yleisin yksittäinen kuolinsyy maassamme. Taudin syntyyn vaikuttavat lukuisat geneettiset ja ympäristötekijät sekä niiden väliset yhteis- ja vuorovaikutukset. Pieni HDL-kolesterolipitoisuus on valtimonkovettumataudin itsenäinen riskitekijä ja yleisin kolesterolipoikkeavuus, joka liittyy varhain ilmenevään sepelvaltimotautiin. HDL-kolesterolin vaihtelun syitä ja tämän "hyvän kolesterolin" sepelvaltimotaudilta suojaavia vaikutusmekanismeja ei kuitenkaan pystytä täysin selittämään. Adiponektiini on rasvakudoksen tuottama hormoni, jonka sepelvaltimotaudilta suojaavan ominaisuuden on ehdotettu johtuvan siitä, että se vaikuttaisi HDL-kolesterolin aineenvaihduntaan. VEGF (vascular endothelial growth factor) on verisuonten sisäseinämissä vaikuttava kasvutekijä, jolla saattaa olla joko sepelvaltimotaudilta suojaavia tai sille altistavia vaikutuksia. Väitöskirjatyön tavoitteena oli tutkia HDL-kolesterolin ja valtimonkovettumataudin geneettistä taustaa. Kolmessa osatyössä tutkittiin suuria pohjoissuomalaisia sepelvaltimotautisukuja; lisäksi käytettiin väestö- ja potilasaineistoja. Ensimmäisessä tutkimuksessa löydettiin koko genomin kytkentäkartoitusmenetelmällä seitsemän kromosomialuetta, jotka saattavat vaikuttaa HDL-kolesterolin säätelyyn. Toisessa tutkimuksessa selvitettiin adiponektiinin, ja ensimmäistä kertaa myös sen aktiivisimman muodon, HMW-adiponektiinin geneettistä taustaa. Kytkentäanalyysissä saatiin viitteitä kolmesta adiponektiineja mahdollisesti säätelevästä kromosomialueesta. Havaittiin myös, että HDL-kolesterolin ja adiponektiinin pitoisuudet korreloivat vahvasti keskenään, mutta yhteistä geneettistä säätelytekijää ei pystytty osoittamaan. LDL-kolesterolin ja adiponektiinin välillä kuitenkin havaittiin geneettinen korrelaatio. Kolmannessa tutkimuksessa todettiin, ettei tutkituilla VEGF-geenin nukleotidimuutoksilla todennäköisesti ole merkittävää syy-yhteyttä valtimonkovettumatautiin kaulavaltimoiden sisäseinämän paksuudella tai sydäninfarktiriskillä mitattuna. Tämä tutkimus tuo uutta tietoa HDL-kolesterolin ja adiponektiinin geneettisestä säätelystä ja niiden suhteesta sekä VEGF-geenin nukleotidimuutosten osuudesta valtimonkovettumataudissa. Tutkimus vahvistaa edelleen HDL-kolesterolin ja adiponektiinin yhteyden, muttei pysty osoittamaan niille yhteistä geneettistä tekijää.