Made available in DSpace on 2014-06-11T19:31:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2001Bitstream added on 2014-06-13T18:41:27Z : No. of bitstreams: 1 vailati_mcf_dr_botfm.pdf: 326485 bytes, checksum: 40ae6105076d1617c946e93f6158fd3d (MD5) / Um aspecto pouco explorado na literatura, é o caráter sistêmico das alterações vasculares induzidas pela angiotensina II (AII). Teoricamente, todos os tecidos podem ser afetados, visto que os receptores da AII já foram identificados em vários órgãos. Os trabalhos que avaliam o efeito da AII no miocárdio são concordantes no sentido de indicar lesões envolvendo vasos e tecido muscular. Não encontramos qualquer estudo que avaliasse o impacto dessas lesões na função ventricular, numa fase que precede a fibrose miocárdica. Foram utilizados 65 ratos Wistar, machos, com aproximadamente 250g de peso corpóreo, divididos em quatro grupos: controle (n=16), ratos tratados com AII (n= 17), ratos tratados com AII + carvedilol (90 mg/kg/dia; n = 15) e AII + losartan (30 mg/kg/dia; n = 17). A infusão contínua de AII foi realizada na dose de 150 hg/min, através de mini-bombas osmóticas colocadas no subcutâneo no dorso do animal. O registro das pressões arteriais caudais (PA) dos animais de cada grupo foi obtido, aproximadamente, 24h antes da implantação da minibomba e antes da realização da eutanásia. Foram realizados cortes histológicos de miocárdio, rim e fígado para coloração pela hematoxilina-eosina e observação das áreas de necrose. A intensidade das lesões foi definida por meio de escores. Uma parte dos animais foi destinada ao estudo histológico e a outra ao estudo do coração isolado. Também foi realizada a técnica de imunohistoquímica para identificação de macrófagos e a técnica vermelho-congo azul de toluidina para mastócitos e eosinófilos. A função ventricular foi avaliada no coração isolado (preparação de Langendorff). Os resultados foram comparados com os ratos do grupo controle, sem qualquer tratamento, por meio de ANOVA com nível de significância p<0,05... / The systemic aspect of vascular damage induced by angiotensin II (AII) is poorly explored in the literature. Considering the presence of AII in various organs, all these tissues might be affect by of AII. There is an agreement among the authors in relation to the effects of AII on the myocardium as involving vessels and myocytes. There is no published data regarding the impact of these lesions on ventricular function preceeding myocardial fibrosis. Sixty five male Wistar rats, (250 ± 20g) distributed in four groups were used: control (n=16), treated with AII (n=17), with AII + carvedilol (90 mg/kg/d, n=15) and AII+ losartan (30 mg/kg/d, n=17). AII was infused continuously at 150 hg/min (for 72 hs) by subcutaneous osmotic pumps. Tail cuff blood pressure was recorded 24 hours before the mini-pump implantation and before euthanasia. Histological sections of the myocardium, kidney and liver were stained by haematoxylin and eosin and observed for presence of necrosis. The injury intensity was scored. Immunohistochemistry was used for macrophages identification and congo red toluidine blue for identification of mast cells and eosinophils. The ventricular function was evaluated in the isolated heart (Langendorff preparation). The results were compared with untreated control rats, by ANOVA and the statistical significance was set at p<0,05. Blood pressure was higher in the groups AII and AII + carvedilol compared to control (165 ± 30 mmHg e 181± 35 mmHg vs 126 ± 13 mmHg, p<0,01). Losartan prevented hypertension. Histopathological analysis showed perivascular inflammation and necrosis of arteriolar wall in the myocardium, kidney, and liver. Carvedilol and losartan partially protected the organs. The intensity of tissular lesions was less than the vascular lesions, without statistical difference among the groups. There were macrophages and mast... (Complete abstract, click electronic address below)

Orientador: Beatriz Bojikian Matsubara / Resumo: Um aspecto pouco explorado na literatura, é o caráter sistêmico das alterações vasculares induzidas pela angiotensina II (AII). Teoricamente, todos os tecidos podem ser afetados, visto que os receptores da AII já foram identificados em vários órgãos. Os trabalhos que avaliam o efeito da AII no miocárdio são concordantes no sentido de indicar lesões envolvendo vasos e tecido muscular. Não encontramos qualquer estudo que avaliasse o impacto dessas lesões na função ventricular, numa fase que precede a fibrose miocárdica. Foram utilizados 65 ratos Wistar, machos, com aproximadamente 250g de peso corpóreo, divididos em quatro grupos: controle (n=16), ratos tratados com AII (n= 17), ratos tratados com AII + carvedilol (90 mg/kg/dia; n = 15) e AII + losartan (30 mg/kg/dia; n = 17). A infusão contínua de AII foi realizada na dose de 150 hg/min, através de mini-bombas osmóticas colocadas no subcutâneo no dorso do animal. O registro das pressões arteriais caudais (PA) dos animais de cada grupo foi obtido, aproximadamente, 24h antes da implantação da minibomba e antes da realização da eutanásia. Foram realizados cortes histológicos de miocárdio, rim e fígado para coloração pela hematoxilina-eosina e observação das áreas de necrose. A intensidade das lesões foi definida por meio de escores. Uma parte dos animais foi destinada ao estudo histológico e a outra ao estudo do coração isolado. Também foi realizada a técnica de imunohistoquímica para identificação de macrófagos e a técnica vermelho-congo azul de toluidina para mastócitos e eosinófilos. A função ventricular foi avaliada no coração isolado (preparação de Langendorff). Os resultados foram comparados com os ratos do grupo controle, sem qualquer tratamento, por meio de ANOVA com nível de significância p<0,05... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The systemic aspect of vascular damage induced by angiotensin II (AII) is poorly explored in the literature. Considering the presence of AII in various organs, all these tissues might be affect by of AII. There is an agreement among the authors in relation to the effects of AII on the myocardium as involving vessels and myocytes. There is no published data regarding the impact of these lesions on ventricular function preceeding myocardial fibrosis. Sixty five male Wistar rats, (250 ± 20g) distributed in four groups were used: control (n=16), treated with AII (n=17), with AII + carvedilol (90 mg/kg/d, n=15) and AII+ losartan (30 mg/kg/d, n=17). AII was infused continuously at 150 hg/min (for 72 hs) by subcutaneous osmotic pumps. Tail cuff blood pressure was recorded 24 hours before the mini-pump implantation and before euthanasia. Histological sections of the myocardium, kidney and liver were stained by haematoxylin and eosin and observed for presence of necrosis. The injury intensity was scored. Immunohistochemistry was used for macrophages identification and congo red toluidine blue for identification of mast cells and eosinophils. The ventricular function was evaluated in the isolated heart (Langendorff preparation). The results were compared with untreated control rats, by ANOVA and the statistical significance was set at p<0,05. Blood pressure was higher in the groups AII and AII + carvedilol compared to control (165 ± 30 mmHg e 181± 35 mmHg vs 126 ± 13 mmHg, p<0,01). Losartan prevented hypertension. Histopathological analysis showed perivascular inflammation and necrosis of arteriolar wall in the myocardium, kidney, and liver. Carvedilol and losartan partially protected the organs. The intensity of tissular lesions was less than the vascular lesions, without statistical difference among the groups. There were macrophages and mast... (Complete abstract, click electronic address below) / Doutor

Orientador: César Tadeu Spadella / Resumo: O objetivo do estudo foi avaliar a influência do diabetes sobre a camada de fotorreceptores (camada de cones e bastonetes e camada nuclear externa) da retina.Para isto, foi realizado experimento prospectivo, utilizando 20 ratos da raça Wistar, divididos em dois grupos: Grupo Controle (GC) e Grupo Diabético (GD). A indução do diabetes foi feita por injeção de aloxana, 42 mg/Kg de peso. Os animais foram observados em 3 momentos experimentais: M1-15 dias após a indução do diabetes, M2 -1 mês após M1 e M3 -12 meses após M1. Foram considerados para o estudo os animais do GD que em M1 apresentavam diabetes grave. Realizou-se acompanhamento diário de parâmetros clínicos (peso, diurese, ingestão hídrica e ingestão alimentar) e avaliação mensal de glicemia e glicose urinária. Nos momentos experimentais M2 e M3 foi realizada enucleação e preparo dos olhos para avaliação sob microscopia óptica e eletrônica de transmissão. Os resultados obtidos mostraram que os animais diabéticos tiveram importante redução de peso, aumento de ingestão hídrica, aumento de ingestão alimentar e aumento de diurese, em relação aos animais controle. Na avaliação morfológica observou-se nos animais do GC em M3, aumento de corpos densos e "cistos" glicogênicos na camada de cones e bastonetes e dispersão da cromatina na camada nuclear externa. Os ratos diabéticos apresentaram as mesmas alterações observadas no GC em M3, em maior intensidade. Observou-se ainda, que os animais do GD em M3 tiveram mais alterações que os do GD em M2. Concluiu-se que o diabetes provoca lesões progressivas nos fotorreceptores retinianos. / Abstract: The objective of the study was to evaluate the influence of diabetes on the photoreceptors layer (layer of cones and rods and external nuclear layer) of retina. For this, prospective experiment was accomplished, using 20 Wistar rats, divided in two groups: Control Group (CG) and Diabetic Group (DG). The diabetes induction was made by aloxana injection, 42 mg/Kg of weight. The animals had been observed at 3 experimental moments: M1-15 days after the diabetes induction, M2 -1 month M1 and M3 -12 months after M1. They were considered for the study the animals of the DG that presented serious diabetes in M1. Clinical parameters had daily been followed (weight, diuresis, water ingestion and alimentary ingestion) and monthly evaluation of glycemia and urinary glucose. At the experimental moments M2 and M3 it was realized enucleation and preparation of the eyes for optic microscopy and electronic transmission microscopy evaluation. The gotten results had shown that the diabetic animals had had important weight reduction, water ingestion increase, alimentary ingestion increase and diuresis increase, compared to the animals of the CG. In the morphologic evaluation it has been observed in the animals of CG- M3: dense bodies and glycogenic "cists" increase in the cones and rods layer and chromatin dispersion in the external nuclear layer. The diabetic rats had presented the same alterations observed in the CG-M3, in larger intensity. It was still observed, that the animals of DG-M3 had more alterations than the ones on DG-M2. It was ended that diabetes provokes progressive injuries in the retinal photoreceptors. / Mestre

A toxoplasmose é causada pelo protozoário coccídio Toxoplasma gondii e consiste em um dos processos parasitários mais comuns entre os animais endotérmicos. A presença desse protozoário em cetáceos pode estar associada à exposição dos animais aos oocistos de T. gondii eliminados pelas fezes de felídeos e/ou contato com solo contaminado com o parasita, que tenham comprometido a água do mar a partir de drenagens fluviais e fluentes ou ainda pelo escoamento de água de navios. O objetivo desse trabalho foi investigar a ocorrência de T. gondii em cetáceos encalhados, ou provenientes de captura acidental, ou que vieram a óbito durante o processo de reabilitação ou cativeiro, ao longo da costa brasileira, valendo-se para tanto de avaliações histopatológicas e de técnicas imuno-histoquímicas (IHQ). Os principais órgãos examinados foram fígado, pulmão, linfonodos, baço e cérebro. Esse estudo avaliou tecidos de 186 exemplares de 21 espécies diferentes de cetáceos da costa brasileira entre 1988 e 2014, cujas amostras foram encaminhadas e encontram-se depositadas no Banco de Tecidos de Mamíferos Marinhos, do Laboratório de Patologia Comparada dos Animais Selvagens (LAPCOM) do Departamento de Patologia, FMVZ-USP. Dos mamíferos marinhos analisados, a ocorrência de T. gondii foi confirmada em 1,1% (2/186), justificada pela presença de pelo menos um cisto em pulmão e/ou fígado. Os animais positivos pertenciam a duas espécies diferentes, provenientes do sudeste do Brasil; um golfinho nariz-de-garrafa (Tursiops truncatus) encalhado vivo no Rio de Janeiro - RJ, e uma orca (Orcinus orca) proveniente de cativeiro. As principais observações histopatológicas encontradas foram hepatite necrotizante, broncopneumonia fibrinosa supurativa com presença de cistos compatíveis com T. gondii, pneumonia broncointersticial fibrinosa com carneificação, glomérulonefrite membranosa e linfadenite necrótica. Devido à severidade das lesões suspeita-se que esse protozoário teve um importante papel no encalhe/óbito desses dois indivíduos. Esse estudo acrescentou duas novas espécies de cetáceos àquelas já reportadas como suscetíveis à infecção pelo protozoário, mas nunca antes descritos no Brasil. Os resultados ratificaram a ocorrência da infecção por T. gondii em cetáceos da costa brasileira e a sua importância em mamíferos marinhos em cativeiro e de vida livre / Toxoplasmosis is caused by the coccidian Toxoplasma gondii - phylum Apicomplexa, which is one of the most common parasites affecting endothermic animals. The presence of T. gondii in cetaceans may be associated with feline feces and/or soil contaminated with the parasite, which may reach water bodies through run-off. This study investigated the occurrence of T. gondii in cetaceans along the Brazilian coast. Tissue samples of 186 individuals stranded along the Brazilian coast between 1988 and 2014, belonging to 21 species of cetaceans and currently part of the Marine Mammal Tissue Bank of the Laboratory of Comparative Pathology, Pathology Department, School of Veterinary Medicine and Animal Sciences, University of São Paulo. Immunohistochemistry (IHC) for T. gondii was performed using formalin-fixed, paraffin embedded tissue sections of liver, lung, lymph nodes, spleen and brain. Infected tissues of a Guiana dolphin (Sotalia guianensis) were used as positive controls. A total of 1.1 % (2/186) of the animals evaluated were positive, which was justified by the presence of least one cyst in one of the evaluated organs/tissues. These specimens belong to two different species of cetaceans: Killer whale (Orcinus orca) and bottlenose dolphin (Tursiops truncatus), both from southeastern Brazil. One individual stranded alive in Rio de Janeiro (T. truncatus); and one was kept in captivity (O. orca) in São Paulo state. The most noteworthy lesions observed through microscopy included necrotizing hepatitis, fibrinous suppurative bronchopneumonia with cysts compatible with T. gondii, bronchointersticial fibrinous pneumonia, membranous glomerulonephritis and necrotizing lymphadenitis. Due to the severity of lesions protozoan was suspected to have an important role in the stranding/death of the two wild individuals. This study added two new species of cetaceans to those already reported as susceptible to infection by T. gondii, never before described in Brazil. These results confirm the occurrence of T. gondii infection in cetaceans from the Brazilian coast and the importance of this parasite to marine mammals kept in captivity and free ranging dolphins

<p>U okviru doktorske disertacije prikazani su rezultati ispitivanja razliĉitih tehnolo&scaron;kih postupaka u cilju prevencije nastanka o&scaron;tećenja tabanskih jastuĉića brojlerskih pilića. Istraţivanja su sprovedena u 4 ogleda i to u jednom u kome su vr&scaron;ena ispitivanja fiziĉko &ndash; hemijskih i higroskopnih osobina materijala koji se mogu koristiti kao prostirka, kao i tri biolo&scaron;ka ogleda koji su imali za cilj da ispitaju uticaj razliĉitih faktora na o&scaron;tećenja tabanskih jatuĉića kod brojlerskih pilića. Cilj biolo&scaron;kih ogleda je bio da odgovore na pitanje da li se razliĉitim tretmanima prostirke, primenom razliĉitih preparata i ishranom moţe uticati na prevenciju nastanka tabanskih lezija kod brojlerskih pilića. Pored toga, cilj ovih ogleda je bio da se utvrdi kako primenjene tehnologije utiĉu na proizvodne rezultate brojlera. Od fiziĉkih karakteristika materijala koji se mogu koristiti kao prostirka u tovu brojlera ispitivane su sposobnost vezivanja i otpu&scaron;tanja vode, a od hemijskih sadrţaj suve materije, sadrţaj sirovih vlakana kao i pojedine frakcije (NDF, ADF, hemiceluoza, celuloza i lignin). Biolo&scaron;ki ogledi su sprovedeni u objektima eksprimentalne farme (mikro ogled) i u proizvodnim uslovima (makro ogled). U biolo&scaron;kim ogledima kao prostirka je kori&scaron;ćena p&scaron;eniĉna slama, a tretmani kojima je poku&scaron;ano pobolj&scaron;anje njenih karakteristika su bili seckanje, kao i dodatak mikrobiolo&scaron;ko-enzimskog preparata (Micropan Complex&reg;) i lignina. Uticaj ishrane na o&scaron;tećenja tabanskih jastuĉića ispitivan je u biolo&scaron;kom ogledu, ishranom brojlerskih pilića sme&scaron;ama sa smanjenom energijom i dodavanjem enzima koji pobolj&scaron;ava varenje hrane. Kao rezultat uticaja pomenutih tretmana ispitivani su kvalitet prostirke (vlaga, pH i emisija amonijaka), proizvodnih parametri u tovu brojlera (telesna masa, uto&scaron;ak hrane, konverzija, mortalitet i proizvodni indeks), pona&scaron;anje brojlera, kao i nastanak i stepen o&scaron;tećenja tabanskih jastuĉića.<br />Ocena o&scaron;tećenja tabanskih jastuĉića je vr&scaron;ena makroskopski (primenom skale od 0-3, a u skladu sa zahvaćenom povr&scaron;inom) i mikroskopski, histolo&scaron;kom analizom koţe tabanskih jastuĉića. Rezultati ispitivanja fiziĉko-hemijskih karakteristika razliĉitih materijala pokazuju da p&scaron;eniĉna slama upija velike koliĉine vode, a usled niskog sadrţaja NDF slabo optu&scaron;ta vodu te shodno tome predstavlja lo&scaron; izbor za prostirku u pogledu nastanka o&scaron;tećenja tabanskih jastuĉića. MeĊutim, rezultati su pokazali da seckanje slame, kao tehnolo&scaron;ki postupak, moţe uticati na nastanak i stepen o&scaron;tećenja tabanskih jastiĉića, ali da dovodi i do povećanja telesnih masa brojlera kao i promena u pona&scaron;anju pilića. Dodatak mikrobiolo&scaron;ko-enzimskog preparata dovodi do smanjenja pojave i stepena o&scaron;tećenja tabanskih jastuĉića brojlera gajenih i na seckanoj i na nesckanoj slami. Rezultati takoĊe pokazuju da se, u proizvodnim uslovima, primenom lignina u<br />prostirci od neseckane slame moţe smanjiti o&scaron;tećenje tabanskih jastuĉića. Upotreba sme&scaron;a koje sadrţe smanjene koliĉine energije uz primenu enzima dovodi do prevencije u pogledu nastanka tabanskih lezija, bez znaĉajnog uticaja na proizvodne rezultate. Histolo&scaron;ka analiza tabanskih jastuĉića je pokazala da sistem ocenjivanja koji se zasniva na zahvaćenoj povr&scaron;ini tabanskih jastuĉića u saglasnosti sa stepenom i ozbiljno&scaron;ću o&scaron;tećenja koţe tabanskih jastuĉića i da moţe predstavljati standardi model za ocenjivanje na liniji klanja. Na osnovu rezultata ove disertacije se moţe zakljuĉiti da primenjeni tehnolo&scaron;ki postupci mogu znaĉajno uticati na prevenciju o&scaron;tećenja tabanskih jastuĉića, bez negativnog uticaja na proizvodne rezultate u tovu brojlera.</p> / <p>Within this dissertation, the results of various technological processes are shown in order to prevent the occurrence of damage to the foot pads of broiler chickens. The study was conducted in four trials, one in which we investigated the physical - chemical and hygroscopic properties of materials that can be used as litter, as well as three biological trials which were aimed to examine the influence of various factors on the damage to the foot pads in broiler chickens. The objective of the biological experiments was to answer the question whether the various treatments of litters, usage of different preparations and nutrition can prevent occurrence of foot lesions in broiler chickens. In addition, the aim of this experiment was to determine how the applied technology affects performance of broiler chickens. Among physical properties of materials that can be used as litter in fatting broilers, absorption and release of water were investigate, and among chemical properties there were content of dry matter, crude fiber content as well as individual fractions (NDF, ADF, hemicelluloses, cellulose and lignin). Biological experiments were conducted in the facilities of experimental farm (micro experiment) and in production conditions (macro experiment). In biological experiments wheat straw was used as litter and treatments which attempted to improve its characteristics were chopping and addition of microbial-enzyme preparation (Micropan Complex&reg;) and lignin. Feeding influence on damage to the foot pad was tested in a biological experiment, by feeding broilers with reduced energy diet and by adding enzymes that improve digestion. As a result of the impact of the above mentioned treatments there were tested the litter quality (moisture, pH and ammonia emissions), production parameters in fattening broilers (body weight, feed consumption, conversion, mortality and production index), the behavior of broilers, as well as the onset and degree of damage to the foot pads.<br />Assessment of the damage to the foot pads was done macroscopically (on a scale from 0-3, and according to the affected area) and microscopically, by histological analysis of skin of foot pads. Test results of physic-chemical characteristics of different materials indicate that wheat straw absorbs large amounts of water, due to the low content of NDF it releases water slowly and consequently represents a bad choice for a litter in terms of damage to the foot pads. However, the results showed that chopping straw as a technological procedure may influence the onset and degree of damage to the foot pads, but it also leads to an increase in body weight of broilers as well as changes in their behavior. Addition of microbial-enzyme preparation leads to a decrease in the occurrence and level of damage to the foot pads in broilers grown on both chopped and unchopped straw. The results have also shown that, under production conditions, using lignin in<br />the unchopped straw litter it can reduce the damage to the foot pads. The use of mixtures containing a reduced amount of energy with the use of the enzyme leads to prevention in terms of occurrence of foot lesions, without significant impact on performance. Histological analysis of foot pads have showed that the grading system that is based on the affected area of foot pads in accordance with the extent and severity of damage of the skin of foot pads and that it can represent a model for the assessment of standards on the slaughter line. Based on the results of this dissertation it can be concluded that the applied technological procedures can significantly influence the prevention ofdamage to the foot pads, with no negative impact on production results in fattening broilers.</p>

Transcranial direct current stimulation (tDCS), together with speech therapy, is known to relieve the symptoms of aphasia. Knowledge about amount of current to apply and stimulation location is needed to ensure the best result possible. Segmented tissues are used in a finite element method (FEM) simulation and by creating a mesh, information to guide the stimulation is gained. Thus, correct segmentation is crucial. Manual segmentation is known to produce the most accurate result, although it is not useful in the clinical setting since it currently takes weeks to manually segment one image volume. Automatic segmentation is faster, although both acute stroke lesions and nectrotic stroke lesions are known to cause problems. Three automatic segmentation routines are evaluated using default settings and two sets of tissue probability maps (TPMs). Two sets of stroke patients are used; one set with acute stroke lesions (which can only be seen as a change in image intensity) and one set with necrotic stroke lesions (which are cleared out and filled with cerebrospinal fluid (CSF)). The original segmentation routine in SPM8 does not produce correct segmentation result having problems with lesion and paralesional areas. Mohamed Seghier’s ALI, an automatic segmentation routine developed to handle lesions as an own tissue class, does not produce satisfactory result. The new segmentation routine in SPM8 produces the best results, especially if Chris Rorden’s (professor at The Georgia Institute of Technology) improved TPMs are used. Unfortunately, the layer of CSF is not continuous. The segmentation result can still be used in a FEM simulation, although the result from the simulatation will not be ideal. Neither of the automatic segmentation routines evaluated produce an acceptable result (see Figure 5.7) for stroke patients. Necrotic stroke lesions does not affect the segmentation result as much as the acute dito, especially if there is only a small amount of scar tissue present at the lesion site. The new segmentation routine in SPM8 has the brightest future, although changes need to be made to ensure anatomically correct segmentation results. Post-processing algorithms, relying on morphological prior constraints, can improve the segmentation result further.

No description available.

<p>Studying the early stages of cancer can provide important insight into the molecular basis of the disease. In many human cancers, such as prostate, pancreatic, and colon cancer, a pre-neoplastic, or intermediate, stage of the disease has been identified. The pre-neoplastic stage is presumed to be a transition during which normal cells undergo malignant transformation. However, the link between the pre-neoplastic cells and end-stage disease has never been formally established. To investigate the fate of such cells, the patched (ptc) mutant mouse, a model for the brain tumor medulloblastoma was used. Pre-neoplastic cells (PNCs) are found in most ptc mutants during early adulthood, but only 15% of these animals develop tumors. Although PNCs are found in mice that develop tumors, the ability of PNCs to give rise to tumors has never been demonstrated directly, and the fate of cells that do not form tumors remains unknown. Genetic fate mapping and orthotopic transplantation provided definitive evidence that PNCs give rise to tumors and showed that the predominant fate of PNCs that do not form tumors is differentiation. Moreover, N-myc, a gene commonly amplified in medulloblastoma, can dramatically alter the fate of PNCs, preventing differentiation and driving progression to tumors. Importantly, N-myc allows PNCs to grow independently of hedgehog signaling, making the resulting tumors resistant to hedgehog antagonists. These studies provide the first direct evidence that PNCs can give rise to tumors, and demonstrate that identification of genetic changes that promote tumor progression is critical for designing effective therapies for cancer.</p> / Dissertation

Betel quid¡]BQ¡^chewing is recognized as a major risk factor for oral precancerous lesions¡]OPLs¡^in Taiwan. The compositions of Betel quid could cause DNA damage. X-ray repair cross complementing Group 1¡]XRCC1¡^plays a crucial role in the process of DNA repair. Polymorphisms in XRCC1 gene may affect DNA repairing ability and modulate the susceptibility of OPLs. The aim of this study was to investigate the association of XRCC1 genetic variants with the risk of BQ-related oral precancerous lesions, including oral leukoplakia¡]OL¡^ and oral submucous fibrosis ( OSF ). A total of 449 males¡]169 OL cases, 82 OSF cases, and 208 healthy controls¡^who habitually chewed BQ were recruited. The genotypes were determined by PCR-RFLP and TaqMan real-time assays. The C allele and T/C+C/C genotypes at XRCC1 -77 were associated with the reduced risk of OL ( AOR=0.54, 95%CI:0.34-0.85 and AOR=0.47, 95%CI:0.28-0.78, respectively ). The 399Gln allele and 399 Arg/Gln+Gln/Gln genotypes were associated with the increased risk of OL¡]AOR=1.94; 95%CI: 1.41-2.67 and AOR=2.64; 95%CI: 1.73-4.03, respectively¡^and OSF ( AOR=1.67; 95%CI: 1.11-2.49 and AOR=2.30; 95%CI: 1.35-3.91, respectively ). The haplotypes or diplotypes contain fewer risk alleles¡]-77T or 399Gln¡^ were with lower risk of OL¡]both Ptrend<0.001¡^and OSF (Ptrend=0.056 and Ptrend=0.040, respectively). In conclusion, our results suggest that polymorphisms of XRCC1 at -77 and 399 may be associated with the risk of OPLs.

Kawasaki disease (KD) is the most common cause of paediatric acquired heart disease which may be attributed to the combined effects of infection, immunological response, and genetic susceptibility. Acute coronary artery lesions (CALs) develop in 20-48 % KD children. In addition, chronic CALs develop in approximately 20-30% of untreated KD children. Although KD children treated with IVIG, 2-6% still develop chronic CALs. According to recent epidemiological studies, Asian populations have a much higher incidence of KD. Taiwan has the third highest annual incidence in the world (69 per 100,000 children < 5 years of age between 2003 and 2006). Several studies have shown that KD patients spontaneously produce high levels of IL- 10. Plasma or serum IL-10 levels of KD children in acute phase were nearly 8-33 fold and 4-5 fold higher than those of healthy controls and those of the acute febrile children, respectively. The elevated IL-10 levels during the acute phase of KD not only decreased during subacute and convalescent phase, but also decreased immediately after IVIG administration, coincidently rapid improvement of inflammatory symptoms. The above studies show a correlation of high IL-10 levels with inflammatory features of KD, but do not answer the question of whether high levels of IL-10 may be simply a byproduct of acute KD, or whether it may play a role in the pathogenesis of KD. Therefore, a family-based linkage study of 134 case-parents trios, a case-control study of 247 KD children and 129 normal controls, and a matched case-control study of 76 KD cases with acute coronary artery lesions (CALs) and 76 KD controls without acute CALs were carried out to evaluate the association of genetic single nucleotide polymorphisms (SNP) in IL-10 promoter (-1082, -819, and -592) with the risk of KD and acute CALs. Based on the Transmission Disequilibrium test (TDT) results, significant undertransmission of haplotype ATA and overtransmission of haplotype (ACC+GCC) were found for KD (p = 0.023 and 0.011, respectively), even after 1,000 times permutation (p = 0.026 and 0.010, respectively). In addition, the TC and CC genotype of IL-10-819T>C were significantly associated with the decreased risk of acute CALs (AOR, 0.93; 95% CI, 0.47-1.81 and AOR, 0.07; 95% CI, 0.01-0.62, respectively), as compared to TT genotype. The carries of AC and CC genotype in IL-10-592A>C were with significantly decreased risk of acute CALs (AOR, 0.90; 95%CI, 0.46-1.75 and AOR, 0.17; 95%CI, 0.03-0.87, respectively), as compared to those with AA genotype. Furthermore, as compared with ATA/ATA diplotype, GCC+ACC/GCC+ACC diplotype of IL10 was associated with the decreased risk of acute CALs (AOR, 0.18; 95% CI, 0.04-0.72). In conclusion, the haplotype and diplotype of IL10-1082/-819/-592 were significant differences in the transmission in KD families and that the IL10-819 and -592 SNPs played important role for the sequelae of acute CALs.