Orientador: Gabriel Hessel / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T12:37:09Z (GMT). No. of bitstreams: 1 Freitas_RenataGermanoBorgesdeOliveiraNascimento_M.pdf: 1569637 bytes, checksum: b72c8890e15da5747d9f2995f98d2fda (MD5) Previous issue date: 2014 / Resumo: O objetivo geral do estudo foi avaliar o estado nutricional e suas relações com a atividade inflamatória e a prescrição da nutrição parenteral (NP) de pacientes internados em um hospital terciário em uso de NP. Métodos: A pesquisa foi longitudinal e desenvolvida em 3 capítulos. A coleta de dados foi realizada durante as primeiras 72 horas, no 7º e 14º dia de uso da NP entre os adultos (2 primeiros capítulos). Entre os pacientes pediátricos, foram computados os dados de 24 horas anteriores às individualizações da NP (capítulo 3). Os exames laboratoriais realizados foram: albumina, proteína C reativa (PCR), pré-albumina, colesterol total, HDL, triglicerídeos (TGL) e creatinina, glutationa peroxidase (GPx), sódio, potássio, cálcio iônico, cloreto, magnésio e fósforo inorgânico. A avaliação da gravidade foi determinada pelo cálculo do escore de Acute Physiologic and Chronic Health Evaluation (APACHE II) e Sequential Organ Failure Assessment (SOFA). Com os dados do peso e da altura, foi calculado o Índice de Massa Corporal (IMC) e com a circunferência braquial (CB) e a prega cutânea tricipital (PCT), foram calculados as medidas derivadas: circunferência muscular do braço (CMB), área muscular braquial corrigida (AMBc) e área adiposa braquial (AAB). A prescrição energética dos pacientes foi realizada de acordo com a ESPEN (2009), e ASPEN (2002) para adultos e segundo a ASPEN (2010) e a ESPGHAN (2005) para os pediátricos. Foi comparada a recomendação calórica das fórmulas Harris Benedict (HB) e ESPEN 2009. Resultados: Entres os 88 pacientes avaliados, apesar da maioria ter sido classificada como normoponderal pelo IMC (55,36%), a depleção de massa magra foi predominante segundo AMBc (93,33%) e CMB (62,5%). Os níveis da PCR estavam elevados e albumina, pré-albumina e GPx, baixos. Ao longo do estudo a pré-albumina aumentou (p=0.0261). Houve diferença entre as fórmulas (25kcal/kg/dia) e HB (p?0,0001). Entre os 53 pacientes da unidade de terapia intensiva (UTI), 20 (37,74%) foram a óbito. Foi encontrada diferença significativa do SOFA com o desfecho e uma tendência inversamente proporcional do IMC com o óbito. Foi encontrada correlação negativa e forte entre o SOFA e a pré-albumina (r = -0.64; p = 0.05). Com relação aos 12 pacientes pediátricos (49 individualizações), a maioria foi classificada com desnutrição. Observou-se que 74/254 (29,2%) dos exames bioquímicos demandaram NP individualizada por motivos indubitáveis. Conclusões: O IMC parece estar relacionado com a inflamação. Os valores baixos de pré-albumina e albumina indicam desnutrição e/ou processo inflamatório. A aplicação da fórmula (25kcal/kg/dia), já padronizada, contribuiu com a melhora do estado nutricional, evidenciado pelos valores de pré-albumina. Entre os pacientes da UTI, o SOFA foi um bom instrumento para avaliação prognóstica. A albumina foi um marcador para desnutrição. É possível que o IMC seja um parâmetro para avaliação prognóstica do paciente. Entre os pediátricos, o estado nutricional dos pacientes foi considerado crítico, na maioria dos casos. Desta forma, a individualização realizada no início da NP para a adequação energética proteica é essencial. Além disto, a NP individualizada foi indispensável em, no mínimo, 29,2% das NP, para correção das alterações dos exames bioquímicos / Abstract: This study aimed to evaluate the nutritional state and its relationships with inflammatory activity and parenteral nutrition (PN) prescription of patients using PN hospitalized in a tertiary hospital. Methods: The research was longitudinal and developed in three chapters. The data collection was performed during the first 72 hours, on the 7th and 14th days using PN in adults (two first chapters). The data from pediatric patients were computed 24 hours before PN individualizations (chapter 3). The following laboratory examinations were performed: albumin, reactive C-protein (RCP), prealbumin, total cholesterol, HDL, triglycerides (TGL) and creatinine, glutathione peroxidase (GPx), sodium, potassium, ionized calcium, chloride, magnesium, inorganic phosphorus. The evaluation of severity was determined by the calculation of the score of Acute Physiologic and Chronic Health Evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA). The body mass index (BMI) was calculated using weight and height, and using brachial circumference (BC) and triceps skinfold thickeness (TST), the following derived measurements were calculated: mid arm muscle circumference (MAMC), corrected arm muscle area (CAMA) and arm fat area (AFA). The energy requirement of patients was performed according to the ESPEN (2009) and ASPEN (2002) for adults, and the ASPEN (2010) and ESPGHAN (2005) for pediatric patients. The calorie recommendation of the formulas Harris Benedict (HB) and ESPEN 2009 were compared. Results: Among the 88 evaluated patients, although most of them has been classified as normoponderal by the BMI (55.36%), malnutrition was prevalent according to AMBc (93.33%) and CMB (62.5%). While the PCR levels were elevated, albumin, prealbumin and GPx levels were low. During the study, prealbumin increased (p=0.0261). There was difference between the formulas (25kcal/kg/day) and HB (p?0.0001). Amont the 53 patients in the intensive therapy unit (ITU), 20 (37.74%) died. It was found a significant difference of SOFA with outcome, and a inversely proportional trend of BMI with death. There was a negative and strong correlation between SOFA and prealbumin (r = -0.64; p = 0.05). Most of the 12 pediatric patients (49 individualizations) were classified as having malnutrition. It was observed that 74/254 (29.2%) of biochemical examinations demanded individualized PN due to indubitable reasons. Conclusions: BMI seems to be related to inflammation. The low values of prealbumin and albumin indicate malnutrition and/or inflammatory process. The application of the already standardized formula (25kcal/kg/day) contributed to an improvement in the nutritional state, evidenced by prealbumin values. SOFA was a good instrument for prognostic evaluation in patients in the ITU. Albumin was a marker of malnutrition. It is possible that the BMI is a parameter for prognostic evaluation of patients. The nutritional state of most pediatric patients was considered critical. Thus, the individualization performed in the beginning of the PN for energy protein adequacy is essential. In addition, the individualized PN was indispensable in at least 29.2% of PN, for correction of alterations of biochemical examinations / Mestrado / Saude da Criança e do Adolescente / Mestra em Ciências

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No / Inflammatory changes, characterized by an increase in pro-inflammatory cytokine production and up-regulation of the corresponding signaling pathways, have been described in the brains of aged rats and rats treated with the potent immune modulatory molecule lipopolysaccharide (LPS). These changes have been coupled with a deficit in long-term potentiation (LTP) in hippocampus. The evidence suggests that anti-inflammatory agents, which attenuate the LPS-induced and age-associated increase in hippocampal interleukin-1ß (IL-1ß) concentration, lead to restoration of LTP. Here we report that atorvastatin, a member of the family of agents that act as inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, exerts powerful anti-inflammatory effects in brain and that these effects are mediated by IL-4 and independent of its cholesterol-lowering actions. Treatment of rats with atorvastatin increased IL-4 concentration in hippocampal tissue prepared from LPS-treated and aged rats and abrogated the age-related and LPS-induced increases in pro-inflammatory cytokines, interferon-¿ (IFN¿) and IL-1ß, and the accompanying deficit in LTP. The effect of atorvastatin on the LPS-induced increases in IFN¿ and IL-1ß was absent in tissue prepared from IL-4¿/¿ mice. The increase in IL-1ß in LPS-treated and aged rats is associated with increased microglial activation, assessed by analysis of major histocompatibility complex II expression, and the evidence suggests that IFN¿ may trigger this activation. We propose that the primary effect of atorvastatin is to increase IL-4, which antagonizes the effects of IFN¿, the associated increase in microglial activation, and the subsequent cascade of events.

Le syndrome de Sézary (SS) est un variant leucémique et érythrodermique de lymphomes T cutanés épidermotropes. Son diagnostic repose à la fois sur des critères cliniques, la présence de lymphocytes T à noyau atypique cérébriforme sur un frottis sanguin et la mise en évidence dans la peau, les ganglions et le sang d’un clone lymphocytaire T CD4+. Notre laboratoire a identifié KIR3DL2 comme premier marqueur membranaire spécifique des cellules tumorales de Sézary. KIR3DL2 peut ainsi être utilisé pour le diagnostic et le suivi des patients atteints du SS. Toutefois, aucune étude n’a démontré de lien entre sa structure de récepteur inhibiteur et sa fonction dans les lymphocytes tumoraux de Sézary, et plus particulièrement son implication possible dans les mécanismes régulant la prolifération et/ou la résistance à l’apoptose des cellules tumorales.Au cours de ce travail deux axes ont été développés :- Un premier axe visant à mieux comprendre la fonction de KIR3DL2 et les mécanismes de signalisation intracellulaire initiés lors de son engagement par l’anticorps AZ158 dans les lymphocytes T tumoraux de Sézary. Nos résultats mettent en évidence un rôle de corécepteur inhibiteur pour KIR3DL2 dans les cellules tumorales de Sézary. En effet, l’engagement de KIR3DL2 inhibe la prolifération et l’AICD induites par la stimulation CD3, cette inhibition étant corrélée à une modulation négative des signaux médiés par le TCR. Ainsi, KIR3DL2 ne se comporte pas comme une unité de signalisation indépendante dans les cellules tumorales de Sézary, contrairement à ce qui est observé dans les cellules NK.- Un second axe portant sur l’évaluation d’une nouvelle fonction de KIR3DL2 comme récepteur pour les ODN CpG. Ainsi, nous rapportons pour la première fois un effet direct de l’ODN CpG sur les cellules tumorales T CD4+ de Sézary. En effet, nous avons observé un effet apoptotique de l’ODN CpG-C caspases-dépendant sur les lignées et les cellules tumorales circulantes. De plus, le traitement des cellules tumorales de patients Sézary avec l’ODN CpG-C conduit à une inhibition de l’activation constitutive du facteur de transcription STAT3.La réalisation de cette étude a permis de mieux comprendre la fonction et les mécanismes initiés à partir de KIR3DL2 dans les cellules tumorales T CD4+ de Sézary. De plus, ce travail ouvre de nouvelles perspectives thérapeutiques basées sur le ciblage direct et spécifique des cellules tumorales de Sézary pouvant être associé à une stimulation des acteurs immuns grâce à l’action des ODN CpG. / Sézary syndrome (SS) is an aggressive leukemic and erythrodermic variant of cutaneous T-cell lymphoma. It is characterized by the presence of a clonal CD4+ T lymphocyte population in the skin, lymph nodes and peripheral blood. Our laboratory has previously identified the NK cell receptor KIR3DL2 as a valuable diagnostic and prognostic marker for the detection of the tumoral T cell burden of Sézary syndrome patients. However, the function of this receptor on the malignant T lymphocyte population remained unexplored. The specific expression of KIR3DL2 by SS patients malignant cells prompted us to investigate its possible influence on mechanisms regulating the tumoral cells outgrowth and apoptosis process.To this aim, two axes were developed. The first axis aimed to highlight the function of KIR3DL2 on the malignant T lymphocyte population and to elucidate the intracellular signaling mechanisms initiated by engagement of the receptor with the monoclonal antibody AZ158. Our results show that KIR3DL2 can exert an inhibitory co-receptor function in malignant Sézary cells. Indeed, triggering of KIR3DL2 inhibits the CD3-mediated proliferation and cell death of the CD4+ KIR3DL2+ cells, this inhibition being correlated to a down-modulation of the TCR-mediated signals. Thus, KIR3DL2 does not behave as an independent signaling unit in Sézary cells, unlike NK cells.The second axis aimed to evaluate a new function of KIR3DL2 as CpG ODN receptor. We show for the first time a direct effect of CpG ODN on tumoral CD4+ T Sézary cells. Thus, we observed a caspase-dependent apoptotic effect of CpG ODN-C on Sézary cell lines and circulating malignant T cells. This process of cellular death is correlated to a dephosphorylation of the transcription factor STAT3, which is found constitutively phosphorylated and activated in Sézary cells.This study has provided new insights into the function and the intracellular signaling pathways initiated by KIR3DL2 in malignant Sézary T cells. Furthermore, this work opens new therapeutic perspectives based on the direct and specific targeting of tumor cells that could be associated to immune cell stimulation through the use of ODN CpG.

Neste trabalho foram pesquisados os efeitos in vitro da metaloproteinase jararagina, em modelo de células de tumores de mama humana MCF7, T47D e murina (Tumor de Ehrlich), além de células normais, avaliando-se a viabilidade celular, morfologia, modificações nas fases do ciclo celular e tipo de morte celular; como os efeitos no modelo murino nas formas ascítica e sólido-ortotópica de Ehrlich. Os resultados obtidos mostraram que a jararagina diminui significativamente a viabilidade e adesão de maneira dose dependente, formação de agregados e estruturas tipo esferoides com formação túbulo-acinar. Os parâmetros antitumorais in vivo, não mostraram diminuição no volume tumoral ascítico, entretanto, no modelo ortotópico, a jararagina induz resposta inflamatória e remodelação da matriz extracelular e resulta em alterações na distribuição e organização do colágeno. Conclui-se que a jararagina induz citotoxicidade nas linhagens de células tumorais de mama e normais, e foi capaz de induzir infiltrado inflamatório durante o crescimento e disseminação das células tumorais. / The present study investigated the in vitro effects of metalloproteinase jararhagin in human breast tumor cells model MCF7 and T47D, murine tumor cells (Ehrlich\'s tumor), and normal cells, assessing cell viability, morphological alterations, changes in the cell cycle phases and death cell, as the effects on ascitic and solid orthotopic murin Ehrlich tumor. The results showed that jararhagin significantly decreases adhesion and cell viability in a dose dependent, with cells aggregates and spheroids with tubulo-acinar formation. The in vivo parameters showed no decrease in ascites tumor volume, however, the orthotopic model, jararhagin induces the inflammatory response and extracellular matrix remodeling with changes in the collagen distribution and organization. It is concluded that jararhagin induces cytotoxicity in breast tumor and normal cell lines, and was able to induce inflammatory infiltrate during the growth and dissemination of tumor cells.

Introdução: Nas últimas décadas, a reestenose tem sido o \"calcanhar de Aquiles\" da intervenção coronária percutânea (ICP), limitando seus resultados no médio e longo prazo. Estudos preliminares demonstraram que após a injúria inicial com catéter balão e/ou com stents coronarianos, há desnudação endotelial, dissecção, deposição plaquetária e atração de leucócitos como resposta imediata, podendo levar à reestenose no seguimento mais tardio. A injúria local na parede arterial após implante de stent pode promover a expressão genética e liberação de mediadores inflamatórios, interleucinas, proteínas de fase aguda e fatores de coagulação, deposição de plaquetas e formação de trombos. Estes processos podem estar diretamente relacionados ao prognóstico da doença cardiovascular, porém são escassos os estudos que caracterizem a resposta inflamatória aguda pós-implante de stent coronariano e à ocorrência de eventos adversos. Objetivos: Neste estudo, pretendeu-se avaliar os efeitos de dose de ataque de Rosuvastatina (40mg) sobre a resposta inflamatória aguda após implante de stent coronariano, bem como correlacionar as variações das concentrações de citocinas e a respectiva expressão gênica. Métodos: Pacientes portadores de doença coronária estável sem uso de estatina (há mais de 7 dias), submetidos à intervenção coronária percutânea eletiva em artéria coronária nativa foram randomizados para receberem dose única de ataque de rosuvastatina (40 mg via oral, 3 horas prévias ao procedimento; Grupo Tratado (GT); n=63) versus Grupo Controle (GC) (Ausência da administração de rosuvastatina); n=61. Foram obtidas amostras do sangue periférico antes da administração via oral da medicação (A), 3 horas após medicação (B) e 3 horas após implante do stent coronariano (C). Avaliou-se hemograma completo, dosagem de proteína C reativa (PCR), óxido nítrico (NO) e análise da expressão dos genes e das proteínas, por meio de RT-qPCR e multiplex luminex, dos mediadores IL-1 ?, IL-6, IL-8, PAI-1, MCP- 1, TNF-? e TGF-?. Os pacientes foram acompanhados clinicamente por doze meses após o procedimento. Resultados: Os grupos não apresentaram diferenças significantes em relação às características clínicas, angiográficas e técnicas, com exceção da ICP para lesões em bifurcação, mais comum no GC (19,7% versus 6,2%; p=0,032). Para a expressão gênica, observou-se redução para IL-6 (p<0,001), da IL-1 ? (p=0,016) e PAI-1 (p=0,002) no Grupo Tratado. Para as interleucinas analisadas, observou-se uma diminuição progressiva nas concentrações de IL-6 0,209 pg/ml (IC 0,156;0,28 p<0,001), IL-1? 0,491 pg/ml (IC 0,349;0,692; p<0,001) e PAI-1 0,986 pg/ml com pinteração<0,001) no Grupo Tratado. Houve redução da concentração de PCR no tempo C no GT (p=0,04). Para o NO, ocorreu elevação dos valores do tempo A para C no Grupo Tratado (p=0,004). Na fase intra-hospitalar, ocorreu mais infarto periprocedimento entre os pacientes do Grupo Controle (23% vs 4,7%; p=0,004). No acompanhamento clínico de 12 meses ocorreram mais eventos combinados no Grupo Controle GC (9,8% vs 1,6%; p=0,058). Conclusão: Os resultados deste estudo demonstraram que a rosuvastatina em sua dose de ataque máxima preconizada (40mg), reduz os níveis séricos de marcadores inflamatórios agudos (IL-1 ?, IL-6, PAI-1 e PCR), com incremento dos valores de NO após ICP. / Restenosis remains as the \"Achilles\' heal\" of interventional cardiology, limiting the mid to long term efficacy of percutaneouos coronary interventions (PCI). Preliminary studies have shown that after initial injury with balloon catheter and/or metallic stents, there is endothelial denudation, dissection, platelet deposition and leukocyte attraction as an immediate response, which might limit the late benefits of PCI. Local injury to the arterial wall after stent implantation may promote the gene expression and release of inflammatory mediators, interleukins, acute phase proteins and coagulation factors, platelet deposition and thrombus formation, which are directly related to the prognosis of cardiovascular disease. Despite their importance, there are few studies that characterize the acute inflammatory response after coronary stent implantation and correlate it to the occurrence of adverse events.Objectives: We sougth to evaluate the effects of the loading dose of Rosuvastatin (40mg) on the acute inflammatory response after PCI with mettalic stents, as well as to correlate the variations in cytokine levels and their respective gene expression. Methods: Patients with stable coronary disease without statin (>=7 days) undergoing elective PCI to de novo lesions in the native coronary arterywere randomized to receive a loading dose of 40 mg of rosuvastatin [N = 63] versus a control group (CG) (absence of loading dose); [N = 61]. Blood samples were obtained prior to oral administration of the statin (A), 3 hours after medication (B) and 3 hours after PCI (C). The following laboratory tests were conducted: complete blood count, C-reactive protein (CRP), nitric oxide (NO) and analysis of gene and protein expression by means of RT-qPCR and multiplex luminex, IL-1 mediators, IL-6, IL-8, PAI-1, MCP-1, TNF-? and TGF-?. Clinical follow up was achieved up to 12 months after the procedure. Results: The groups did not significantly differ regarding clinical, angiographic and procedure characteristics, except for the higher amount of bifurcation lesions in the CG (19.7% versus 6.2%, p = 0.032). Among patients pre treated wit the statin, there was a reduction in gene expression for IL-6 (p <0.001), IL-1? (p = 0.016) and PAI-1 (p = 0.002). For the IL analyses, a progressive decrease in the concentrations of IL-6 0.209 pg / ml (IC 0.156; 0.28 p <0.001), IL-1? 0.491 pg / ml (IC 0.349; 0.692, p <0.001) and PAI-1 0.986 pg / ml with paving <0.001) were observed among patients treated with the statin. Furthermore, a progressive reduction in the concentration of CRP was observed in the three timepoints among patients of the rosuvastatin cohort (p = 0.04). An increase in NO concentration was observed from timepoint A to C in the statin group (p = 0.004). During the in hospital period, more periprocedural MI occurred among patients in the control group (23% vs 4.7%, p = 0.004). Also, 12-month MACE rate was higher in the control group (9.8% vs 1.6%, p = 0.058). Conclusion: Pre loading with high dose of rosuvastatin resulted in a marked reduction in the expression of the main inflammatory markers (IL-1 ?, IL-6, PAI-1 and CRP) associated with restenosis after PCI with stents. Additionally, an increase in the NO blood concentration and expression was noticed among these patients.

In normal adult physiology, intestinal smooth muscle cells (ISMC) are characterized as contractile and non-proliferative. Inflammation induces permanent changes to the intestine including hypertrophy of the smooth muscle layer largely due to smooth muscle cell (SMC) proliferation. While the consequences of this hyperplasia are largely unknown, increased muscularis mass may present permanent challenges to organ motility. Similar SMC hyperplasia is observed in other inflammatory pathologies including atherosclerosis and pulmonary arterial hypertension (PAH) where SMC de-differentiate into a ‘synthetic’ phenotype and the mitogens responsible for hyperplasia have been well studied. However, there are limited investigations of SMC mitogens in intestinal inflammation. The identification of these factors may be of critical importance in the case of intestinal strictures, whereby recurring inflammation can lead to bowel obstruction requiring surgical intervention. A novel, primary rat ISMC model was developed to identify the factors responsible for ISMC proliferation in vitro. Primary ISMC cultures are likely more representative of SMC in vivo than the commonly used late-passage cultures. As such, this primary ISMC model is valuable in the evaluation of mitogens involved in the onset of proliferation. This primary ISMC model was used to conduct a comprehensive evaluation of potential mitogens including basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor-BB (PDGF-BB. This work identified IGF-1 and PDGF-BB as ISMC mitogens. However, multiple lines of evidence indicated that PDGF-BB was a more potent mitogen and the involvement of PDGF-BB was subsequently examined in vivo using the trinitrobenzenesulfonic acid (TNBS) model of rat intestinal inflammation. While control ISMC lacked expression of the PDGF-BB receptor (PDGF-Rβ), robust expression was observed within only 6 hr following the induction of TNBS inflammation. By Day 2, when ISMC proliferation in vivo is maximal, freshly isolated ISMC showed on-going PDGF-Rβ activation that was further increased by exogenous PDGF-BB. Taken together, the conclusions from this work in vitro identify PDGF-BB as a potent ISMC mitogen in vivo. Further, this work establishes PDGF-BB and its receptor as potential targets in the medical treatment of intestinal stricture formation. / Thesis (Ph.D, Biology) -- Queen's University, 2012-09-24 19:26:57.201

El canvi en l’estil de vida que s’ha produït en les societats desenvolupades els darrers anys ha tingut com a contrapartida l’aparició de conductes sedentàries i modificacions en la dieta. Com a conseqüència d’aquests factors s’han produït diverses alteracions metabòliques que han causat un augment de la prevalença de l’obesitat. Aquesta obesitat té una sèrie d’efectes adversos sobre la fisiologia cardiovascular i és considerada un important factor de risc pel desenvolupament de la insuficiència cardíaca. De fet, el consum de dietes amb un elevat contingut en greixos (HFD) s’ha relacionat amb una sèrie d’alteracions cardíaques directes com són la inflamació, la hipertròfia i la disfunció contràctil. Durant el procés inflamatori que es produeix en les esmentades malalties cardiovasculars, les cèl•lules cardíaques humanes secreten citocines i quimiocines proinflamatòries com el TNF-α, MCP-1, i IL-6, molècules que es troben sota el control transcripcional del factor de transcripció ubic i induïble anomenat NF-κB. Aquestes citocines exerceixen diversos efectes pleiotròpics autocrins en les cèl•lules cardíaques, tot produint un efecte de retroalimentació positiva del procés inflamatori que contribueix al desenvolupament d’aquestes malalties. En condicions normals, el cor de mamífers adults obté energia en forma d’ATP principalment a partir de la β-oxidació d’àcids grassos en el mitocondri, encara que aquest orgànul és capaç de catabolitzar altres substrats com la glucosa o el lactat per tal d’assegurar una font constant d’energia. Ara bé, en determinades circumstàncies, com és el cas de la hipertròfia i la insuficiència cardíaques, aquesta flexibilitat de substrat es veu compromesa i la β-oxidació d’àcids grassos es redueix degut a que la font principal d’energia passa a ser la glucosa. Aquests canvis metabòlics comporten una desregulació del control transcripcional de gens relacionats amb el transport, captació i catabolisme dels àcids grassos i la glucosa. En el miocardi, els factors de transcripció implicats en el control d’aquests gens inclouen ERRα i PPARβ/δ. Ambdós factors de transcripció, participen en l’activació de la PDK4, enzim clau en la modulació homeostàtica de la glucosa. Aquesta cinasa regula l’activitat de la PDC, enzim que catalitza la reacció de descarboxilació del piruvat a acetil-CoA, tot limitant l’ús de carbohidrats com a font d’energia en mitocondris i afavorint així la β-oxidació d’àcids grassos. En l’activació de la transcripció de PDK4 també hi participa PGC-1α, que interacciona amb ERRα i PPARβ/δ, tot incrementant-ne la seva activitat transcripcional. Estudis recents però, semblen indicar que no només aquests dos factors de transcripció participen en la regulació de PDK4. És el cas d’E2F1, un factor de transcripció clau en la regulació de la transició de la fase G1 a la fase S del cicle cel•lular i del qual la regió promotora del gen que codifica per PDK4 en presenta dos llocs d’unió. Estudis recents suggereixen que PPARβ/δ, que és la forma predominant en les cèl•lules cardíaques, pot atenuar les vies de senyalització inflamatòries i, per tant, interferir en la remodelació cardíaca. Aquesta funció és en gran mesura deguda a la capacitat dels PPAR, un cop han estat activats per agonistes, de formar complexos amb altres factors de transcripció activats, com ara NF-κB i STAT resultant així en la inhibició de l’activitat transcripcional d’aquests últims. Així l’ús d’agonistes PPARβ/δ podria ser un camí força interessant de cara a trobar potencials fàrmacs per tal de pal•liar les afeccions cardíaques derivades d’alteracions metabòliques i amb un rerefons inflamatori. En conjunt en aquest treball es presenten una sèrie de resultats destinats a conèixer de forma més detallada els mecanismes moleculars que relacionen les alteracions metabòliques i els processos inflamatoris en cor, per tal de poder buscar potencials dianes farmacològiques amb l’objectiu de prevenir i tractar aquests estats patològics. / The change in lifestyle that has occurred in developed societies in recent years has been accompanied by the rise of sedentary behavior and changes in diet that have caused an increasing obesity prevalence. Obesity has a huge number of adverse effects on cardiovascular physiology and is considered an important risk factor for heart failure developement. In fact, high fat diets have been linked with direct cardiac abnormalities such as inflammation, hypertrophy and contractile dysfunction. During the inflammatory process that occurs in these diseases, human cardiac cells secrete proinflammatory cytokines and chemokines such as TNF-α, MCP-1, and IL-6, molecules that are under the control of the ubiquitous and inducible transcription factor NF-κB. In certain circumstances, such in hypertrophy and heart failure, the substrate flexibility in heart is compromised and the fatty acids β-oxidation is reduced because the main source of energy becomes the glucose. These metabolic changes lead to a deregulation on the transcriptional control of genes associated with transport, uptake and catabolism of fatty acids and glucose. In the myocardium, among the transcription factors involved in the control of these genes we found ERRα and PPARβ/δ. Both transcription factors, are involved in PDK4 activation, an important enzyme in the homeostatic modulation of glucose. This kinase regulates PDC activity, an enzyme that catalyzes the decarboxylation from pyruvate to acetyl-CoA, limiting the use of carbohydrates as energy source in mitochondria and thus favoring the fatty acid β-oxidation. In the PDK4 transcription activation also participates PGC-1α, which interacts with ERRα and PPARβ/δ, increasing its transcriptional activity. However recent studies, suggest that not only these two transcription factors are involved in PDK4 regulation. Other transcription factors as E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Overall, the results shown in this work are aimed to learn in more detail the molecular mechanisms linking the metabolic disorders and inflammatory processes in heart, in order to find potential drug targets to prevent and treat these pathological states.

abstract: This research investigated using impedance as a minimally invasive oral cancer-screening tool by modeling healthy and diseased tissue. This research developed an ultra-structurally based tissue model for oral mucosa that is versatile enough to be easily modified to mimic the passive electrical impedance responses of multiple benign and cancerous tissue types. This new model provides answers to biologically meaningful questions related to the impedance response of healthy and diseased tissues. This model breaks away from the old empirical top down "black box" Thèvinin equivalent model. The new tissue model developed here was created from a bottom up perspective resulting in a model that is analogous to having a "Transparent Box" where each network element relating to a specific structural component is known. This new model was developed starting with sub cellular ultra-structural components such as membranes, proteins and electrolytes. These components formed the basic network elements and topology of the organelles. The organelle networks combine to form the cell networks. The cell networks combine to make networks of cell layers and the cell layers were combined into tissue networks. This produced the complete "Transparent Box" model for normal tissue. This normal tissue model was modified for disease based on the ultra-structural pathology of each disease. The diseased tissues evaluated include cancers type one through type three; necrotic-inflammation, hyperkeratosis and the compound condition of hyperkeratosis over cancer type two. The impedance responses for each of the disease were compared side by side with the response of normal healthy tissue. Comparative evidence from the models showed the structural changes in cancer produce a unique identifiable impedance "finger print." The evaluation of the "Transparent Box" model for normal tissues and diseased tissues show clear support for using comparative impedance measurements as a clinical tool for oral cancer screening. / Dissertation/Thesis / normal oral mucosal tissue model / cancer type 1 oral mucosal tissue model / cancer type 2 oral mucosal tissue model / cancer type 3 oral mucosal tissue model / hyperkeratosis oral mucosal tissue model / hyperkeratosis over cancer type 2 oral mucosal tissue / necrotic inflammation oral tissue model / Ph.D. Electrical Engineering 2012