The high incidence of gastrointestinal cancers in the general population and the presence of premalignant dysplastic precursor lesions in the gastrointestinal tract make the gastrointestinal tract an ideal environment to study cancer clonality and clonal expansion. Background: Intestinal metaplastic (IM) glands in the human stomach are clonal, contain multiple stem cells and spread by fission. This mechanism of gland fission causes field cancerisation. We hypothesised that gastric adenocarcinoma (GA) progresses through a series of genetic events arising from a founder mutation. A process analogous to niche succession may also take place in the normal oesophagus. We hypothesise that oesophageal squamous cell cancer occurs by a process of field cancerisation of the oesophagus. RHBDF2 has been identified as the gene responsible for tylosis with oesophageal carcinoma (TOC). We hypothesise that RHBDF2 germline gain of function mutations might be lost during tumour progression in TOC and this might affect iRhom2 localisation in the cell. Methods and results: A cohort of 23 patients with dysplasia and a cohort of 51 GA patients were screened for genes accounting for 75% of all somatic mutations previously reported in GA. Only 13% of dysplastic patients and 31.4% of GA patients had mutations. Three dysplastic patients and six GA patients were analysed by microdissection. Small gastric cancer foci in a cohort of hereditary diffuse gastric cancer (HDGC) patients (n=5) were also screened by laser-capture microdissection (LCM) for mutations in TP53. A cohort of 30 patients was screened for common mutations in OSCC and for RHBDF2 mutations. 36.36% of the patients presented mutations. Three patients with mutations were randomly selected and areas of oesophageal squamous cell dysplasia and OSCC were analysed by LCM. Three TOC patients were also analysed by LCM and immunohistochemistry was performed for iRhom2 and ADAM17. Conclusions: The usual mutational events established for GA development during the metaplasiadysplasia- carcinoma sequence (MCS) do not fit the results from either of our two LCM mutation studies in the human stomach. Dysplasia was shown to be clonal and GA demonstrates genetic heterogeneity through clonal evolution. Field cancerisation could not be detected in HDGC using TP53 as a clonal marker. The low incidence of OSCC patients with mutations implies that other genes may be involved in the premalignant pathway leading to OSCC. Oesophageal squamous cell dysplasia and OSCC demonstrate clonal expansion through tumour progression. RHBDF2 mutations do not occur in sporadic OSCC but germline RHBDF2 mutations can be lost during tumour progression in TOC patients with LOH in 17q. Overall, the somatic mutation theory of carcinogenesis seems to hold true for both the progression to GA and OSCC, as both carcinomas seem to evolve from a single mutated stem cell and acquire genetic heterogeneity as the tumours evolve.

Infants born prematurely are a vulnerable population with diverse nutritional needs to battle their increased risk of gastrointestinal (GI) diseases. Human milk is considered the 'gold standard' of infant nutrition. Human milk not only provides nutrition for newborn growth, but contains bioactive components which contribute to GI maturation, immune protection and neurological development. Among these bioactive components are extracellular vesicles known as exosomes. Exosomes are double-lipid membrane vesicles containing mRNA, microRNA and proteins, secreted by cells as a form of cell-to-cell communication. Human milk exosomes contain immune-related microRNA and proteins that withstand in vitro simulated human digestion, suggesting that signals are being delivered to the cells residing in the GI tract of a newborn. In premature birth, disruption of GI tract maturation predisposes the infant to increased susceptibility of GI inflammatory diseases. To prevent inflammation, immune tolerance in the GI tract of premature infants should be promoted and I hypothesized that exosomes differ between preterm and term milk, and may contribute to the anti-inflammatory effects of human milk. Human milk exosomes from mothers who gave birth to term or preterm infants were characterized based on size, surface protein markers and total protein. Preterm milk exosomes contained a more diverse protein profile. The effects of milk exosomes on intestinal epithelial cells were observed in an in vitro model using Caco-2/15 cells. Milk exosomes were able to attenuate the inflammatory response induced by heat-killed bacteria as measured by the transcription of pro-inflammatory cytokines.

Redução da ingestão alimentar, inapetência e disfagia são sintomas que comprometem o estado nutricional de pacientes oncológicos. Apesar destes sintomas serem relevantes para a magnitude do problema do câncer que acomete o trato gastrointestinal (TGI), eles têm sido avaliados isoladamente ou em combinação com outros fatores para compor parte de questionários de qualidade de vida, ferramentas de risco e estado nutricional. Dessa forma, verificou-se a necessidade de criar e validar uma ferramenta específica que analise esses aspectos conjuntamente como parâmetro de “capacidade” alimentar em pacientes com câncer do TGI e servir como parâmetro auxiliar no diagnóstico do estado nutricional. Este é um estudo piloto, transversal, prospectivo, no qual 41 pacientes de ambos os sexos (20 do sexo feminino e 21 do sexo masculino), maiores de 18 anos de idade, com média de idade de 59 anos, com neoplasias malignas do TGI superior (esôfago, estômago, pâncreas, vesícula biliar e fígado) e inferior (cólon, reto), atendidos no Serviço de Cirurgia do Hospital de Clínicas de Porto Alegre (HCPA), foram avaliados utilizando-se um novo escore para capacidade alimentar, o Score of “Eat-ability” (SEA) comparando-se à ASG-PPP, antropometria e métodos laboratoriais.Entre os pacientes avaliados, 11 (26,8%) tinham capacidade alimentar plena (SEA=0);3(7,3%) moderada (SEA=1) e 27 (65,9%) crítica (SEA ≥2). Houve diferença significativa entre capacidade alimentar, quando comparados TGI superior e inferior(p=0,05). Os pontos de corte do SEA (1 e ≥2) determinados pela curva ROC em relação à ASG-PPP (B e C), demonstrou sensibilidade de 80% (IC95%:0,48-0,95) e especificidade de 80% (IC95%:0,63-0,91); com área abaixo da curva(AUC) ROCde 0,79 (IC95%:0,64-0,95; p=0,006). Pacientes com SEA ≥2 apresentaram maior percentual de perda ponderal aos 3 (p=0,001) e 6 meses (p<0,001), quando comparados aos pacientes com escore SEA 0 e 1. A incidência de óbitos foi superior tanto no grupo de pacientes gravemente desnutridos (84,2%), quando analisados pela ASG-PPP, quanto no grupo com capacidade alimentar crítica no SEA (76,9%);(ambos p=0,01). A avaliação conjunta da ingestão alimentar, disfagia e apetite parece permitir classificar indivíduos com capacidade alimentar comprometida, que significativamente repercute no estado nutricional e no risco de óbito de pacientes com tumores do TGI. / Decreased food intake, inappetence and dysphagia are symptoms that compromise the nutritional status of cancer patients. Although these symptoms are relevant to the magnitude of the cancer problem that affects the gastrointestinal tract (GIT), they have been assessed separately or in combination with other factors to form part of quality of life questionnaires, risk assessment tools and nutritional status. Therefore, it was verified the need to create and validate a specific instrument that can identify "food capacity" in patients with cancer of the GITand to help as an ancillary parameter in the assessment of the nutritional status. This is a cross-sectional prospective study in which 41 patients of both sexes (20 females and 21 males), over 18 years, with a mean age of 59 years, with malignant neoplasms of the upper (esophagus, stomach, pancreas, gallbladder and liver) and lower GIT (colon, rectum), attended at the Department of Surgery, Hospital de Clínicas of Porto Alegre, University Attached (HCPA), were evaluated using a new proposed approach – The Score of “Eat-ability” (SEA) as compared to PG-SGA, anthropometry and laboratory profile. Of the patients evaluated, 11(26.8%) had full food capacity (SEA = 0); 3 (7.3%) moderate (SEA 1) and 27 (65.9%) poor (SEA ≥2). Significant difference was found between food capacity, when comparing upper and lower GIT (p = 0.05). By ROC curves SEA 1 and ≥2 in relation to ASG-PPP (B and C) showed an 80% (95%CI: 0.48-0.95) sensibility as well as an 80% specificity (95%CI: 0.63-0.91); with area under curve (AUC) of 0.79 (95%CI: 0.64-0.95; p=0.006). Patients with SEA ≥2 had a significantly weight loss within 3 (p=0.001) and 6 months (p<0.001) when compared to patients with SEA 0 and 1. Mortality was higher among severely unnourished (84.2%) patients by PG-SGA or critical food capacity by SEA (76.9%);(both p=0.01). The combined evaluation of food intake, dysphagia and appetite allows a reliable classification of individuals with compromised food capacity significantly affecting nutritional status and consequently in the risk of death of patients with TGI tumors.

Orientador: Elizabeth Moreira dos Santos Schmidt / Resumo: Este trabalho encontra-se dividido em três capítulos. O capítulo 1 versa sobre uma revisão de literatura que teve como objetivo a realização de um levantamento retrospectivo sobre os endoparasitas em bovinos no Brasil, que também incluiu dados mundiais. No capítulo 2, objetivou-se investigar os nematódeos gastrintestinais (GI) e pulmonares que parasitam bovinos jovens. Para isso, foram utilizados 140 bezerros mestiços, de dois a 12 meses de idade, clinicamente saudáveis, de duas propriedades leiteiras nos municípios de Botucatu e Manduri, estado de São Paulo. Durante um ano, trimestralmente, amostras de fezes foram coletadas diretamente da ampola retal para a realização da contagem de OPG pela técnica de McMaster modificada e pesquisa de L1 de Dictyocaulus viviparus pela modificação da técnica de Baermann. Além disso, coproculturas foram realizadas em pool de amostras para a observação das larvas infectantes. Na propriedade de Manduri, houve um aumento significativo da contagem de OPG no inverno. Na propriedade de Botucatu, os animais com até três meses de idade apresentaram maiores contagens de OPG quando comparados aos animais mais velhos. Em geral, foram observados ovos de estrongilídeos, Strongyloides spp., Moniezia spp., Trichuris spp. e oocistos de Eimeria spp. Nas coproculturas, em ordem de prevalência, foram recuperadas larvas infectantes de Cooperia spp., Haemonchus spp., Oesophagostomum spp. e Trichostrongylus spp. As L1 de D. viviparus foram recuperadas somente na ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This work was divided into three chapters. The chapter 1 aimed to perform a review article based on a retrospective survey of epidemiological studies examining endoparasites that affect bovine in different regions of Brazil, which also included international data. The chapter 2 aimed to determine the gastrointestinal (GI) and pulmonary parasites that affect calves. For this, we used 140 clinically healthy crossbred calves, two to 12 months old, which belonged to two private farms in the municipalities of Botucatu and Manduri, São Paulo state. The animals were monitored for 12 months. Feces were collected directly from the rectum every three months. Fecal egg counts were determined using the modified McMaster technique with a sensitivity of 50 eggs per gram of feces (EPG). Coproculture was performed on pooled samples to identify Strongylida infective larvae. First-stage larvae of Dictyocaulus viviparus were identified by a modified Baermann method. The calves from Manduri farm showed a significant increase in the fecal egg counts in the winter when to compare to other seasons. The Botucatu farm calves differed significantly in the age groups in that younger calves (2 – 3 months old) showed a higher EPG than older calves (8 – 12 months old). Generally, we found Strongyle type-eggs, Strongyloides spp., Moniezia spp., and Trichuris spp. eggs and Eimeria spp. oocysts. The most prevalent genera in all coprocultures were: Cooperia spp., Haemonchus spp., Oesophagostomum spp., and Tri... (Complete abstract click electronic access below) / Mestre

O uso de agentes de contraste em técnicas de diagnóstico por imagem é uma prática médi-ca rotineira. Certos compostos, presentes em agentes de contraste, possuem propriedades paramagnéticas que podem afetar os sinais da tomografia por ressonância magnética, \"Mag-netic Resonance Imaging\"(MRI). Em estudos aplicados ao trato gastrintestinal (GI), os meios de contraste são amplamente utilizados por via endovenosa, mas também podem ser admi-nistrados oralmente. Porém, a adoção do uso oral é limitada, principalmente, porque os agentes convencionais são caros e causam, geralmente, efeitos colaterais. Desta forma, a-presentamos a caracterização e os resultados preliminares da implementação da polpa do fruto da Euterpe olerácea para um possível uso clínico como agente de contraste oral em MRI do trato GI. A polpa da Euterpe olerácea, conhecida como Açaí, de origem amazônica, apre-senta um aumento de sinal de MRI ponderado em T1 equivalente ao do Gd-DTPA e, tam-bém, um decréscimo de sinal em imagens ponderadas em T2. Investigamos propriedades intrínsecas que possam estar correlacionadas com o aumento de sinal em T1 e à opacidade em T2. O espectro de absorção atômica revelou a presença de íons Fe, Mn e Cu no Açaí, o que contribui para o valor susceptométrico encontrado de -4,83 . 10-6. Essa medida fomen-ta a hipótese de que as mudanças de contraste nas imagens são devido à presença de mate-rial paramagnético, revelando um contraste clinicamente satisfatório nas porções superiores do trato GI. Estudos preliminares indicaram que a homogeneidade e a intensidade do sinal da polpa do Açaí (Euterpe olerácea), no estômago, e duodeno, são próximos daquele encon-trado em agentes convencionais. Além disso, ele não apresentou efeito colateral algum. Devido ao aumento de contraste associado ao Açaí, podemos observar a parede gástrica de forma singular. Ainda, este agente contribuiu para o diagnóstico das vias pancreática e biliar em exames de colangiopancreatografia por ressonância magnética, Magnetic Resonance Colan-giopancreatography (MRCP), com seqüências ponderadas em T2, por reduzir o sinal das alças intestinais. / The use of contrast agents is a common practice in medical imaging protocols. Paramagnetic properties of certain compounds present in contrast agents can affect Magnetic Resonance Imaging (MRI) signals. For abdominal applications, they are usually injected, but may also be administered orally. However, their use as a routine technique is limited, mainly due to the lack of appropriate oral contrast agent. Standard agents are expensive and cause, generally, some kind of side effect. We herein present the preliminary characterization and results for implementation of Euterpe olerácea (popularly named Açaí) as a possible clinical oral contrast agent for MRI of the gastrointestinal (GI) tract. The pulp of Açaí, a fruit from the Amazon area, presented an increase in T1-weighted MRI signal, equivalent to that of Gd-DTPA, and a signal decrease in T2-weighted images. We looked for intrinsic properties that could be responsible for the T1 signal enhancement and T2 opacification. Atomic Absorption spectra revealed the presence of Fe, Mn and Cu ions in Açai. The presence of such ions contribute to the susceptometric value found of -4.83 x 10-6 . This finding assents with the hypothesis that image contrast changes were due to the presence of paramagnetic material. The first measurements in vivo demonstrate a clear increase of contrast due to signal intensity and homogeneity in stomach and bowel walls with the pulp of Açaí, which look like the effects related to standard agents. Consistently, the increase in T1-weighted and the opacification in a T2-weighted acquisition was evident, revealing a biphasic contrast on gastric tissues. Besides, the pulp does not present any side effect. It still has contributed to the diagnostic of pancreatobiliary system at Magnetic Resonance Cholangiopancreatography (MRCP), by reducing overlap of the surround tissues and those structures.

In this thesis, we develop and apply top-down, quantitative approaches to gain novel insights into various complex biological systems. Beginning at the multicellular level, we study human gut microbiome dynamics from an ecological perspective. We develop computational frameworks to enable a global understanding of the spatiotemporal variability of gut bacterial abundances. We demonstrate the utility of our frameworks to elucidate the ecological processes governing abundance changes of gut microbiota. We then shift our focus to the intracellular level by investigating the metabolic limitations of cancer cell growth. We use coarse-grained mathematical modeling to identify a major growth limitation of cancer cells associated with electron acceptor deficiency, which we then experimentally validate. Collectively, these set of approaches help to decipher the organizing principles of complex biological systems at both the individual and multicellular levels.

Ho Toi Sze Joyce. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 65-74). / Abstracts in English and Chinese. / Acknowledgement --- p.ii / Contents --- p.iii / Abstract --- p.viii / List of Abbreviations --- p.xvii / List of Tables --- p.xix / List of Figures --- p.xx / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- The role of Non-steroidal anti-inflammatory drugs (NSAIDs) --- p.1 / Chapter 1.2 --- NSAID-induced gastrointestinal (GI) toxicity --- p.1 / Chapter 1.2.1 --- Pathogenesis of NSAID-induced GI toxicity --- p.2 / Chapter 1.2.2 --- GI symptoms --- p.4 / Chapter 1.2.3 --- GI ulcers --- p.4 / Chapter 1.2.4 --- GI complications --- p.5 / Chapter 1.2.5 --- Risk factor for GI complications --- p.6 / Chapter 1.2.6 --- Ulcerogenicity of different NSAIDs in upper GI events --- p.6 / Chapter 1.3 --- Prevention of NSAID-induced GI toxicity --- p.7 / Chapter 1.3.1 --- H2-receptor antagonists --- p.8 / Chapter 1.3.2 --- Misoprostol --- p.8 / Chapter 1.3.3 --- Proton Pump Inhibitor (PPI) --- p.9 / Chapter 1.3.4 --- Selective COX-2 Inhibitors --- p.10 / Chapter 1.3.4.1 --- GI safety of selective COX-2 inhibitors --- p.11 / Chapter 1.3.4.1.1 --- Gastrointestinal outcomes research of rofecoxib --- p.13 / Chapter 1.3.4.1.2 --- Celecoxib Long term Arthritis Safety Study --- p.14 / Chapter 1.3.4.2 --- Cardiovascular toxicity of NSAIDs --- p.15 / Chapter 1.3.4.2.1 --- Cardiovascular toxicity of non-selective NSAIDs --- p.15 / Chapter 1.3.4.2.2 --- Cardiovascular toxicity of selective COX-2 inhibitors --- p.16 / Chapter 1.4 --- Guidelines on the management of osteoarthritis (OA) and rheumatoid arthritis (RA) --- p.21 / Chapter 1.4.1 --- American College of Rheumatology (ACR) Subcommittee --- p.22 / Chapter 1.4.2 --- National Institute for Clinical Excellence (NICE) --- p.23 / Chapter 1.4.3 --- Hong Kong Hospital Authority (HA) --- p.23 / Chapter 1.5 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong and cost analysis of selective COX-2 inhibitor with non-selective NSAID plus gastroprotective agent --- p.24 / Chapter 1.6 --- Objectives --- p.25 / Chapter Chapter 2 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong --- p.26 / Chapter 2.1 --- Methods --- p.28 / Chapter 2.1.1 --- Study site --- p.28 / Chapter 2.1.2 --- Cohort participants --- p.28 / Chapter 2.1.3 --- Resource data collection --- p.29 / Chapter 2.1.4 --- Cost data --- p.30 / Chapter 2.1.5 --- Statistical Methods --- p.31 / Chapter 2.1.6 --- Study perspective --- p.31 / Chapter 2.2 --- Results --- p.31 / Chapter 2.2.1 --- Demographic data --- p.31 / Chapter 2.2.2 --- Total direct medical cost of upper GI complaints in UCH --- p.33 / Chapter 2.3 --- Discussion --- p.35 / Chapter 2.3.1 --- Total direct medical cost of upper GI events --- p.35 / Chapter 2.3.2 --- Cost of upper GI events associated with NSAID usage --- p.38 / Chapter 2.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.38 / Chapter 2.3.4 --- Limitation --- p.39 / Chapter 2.3.5 --- Future study --- p.41 / Chapter 2.4 --- Conclusion --- p.41 / Chapter Chapter 3 --- Cost analysis of selective COX-2 inhibitor versus non-selective NSAID with gastroprotective agent --- p.43 / Chapter 3.1 --- Methods --- p.46 / Chapter 3.1.1 --- Local randomized clinical trial --- p.46 / Chapter 3.1.1.1 --- Study population --- p.46 / Chapter 3.1.1.2 --- Cost data --- p.47 / Chapter 3.1.1.3 --- Statistical Methods --- p.48 / Chapter 3.1.1.4 --- Sensitivity analysis --- p.49 / Chapter 3.1.2 --- Large randomized clinical trial --- p.49 / Chapter 3.1.2.1 --- Study population --- p.49 / Chapter 3.1.2.2 --- Cost data --- p.50 / Chapter 3.2 --- Results --- p.50 / Chapter 3.2.1 --- Local randomized clinical trial --- p.51 / Chapter 3.2.1.1 --- Demographic data --- p.51 / Chapter 3.2.1.2 --- Cost analysis --- p.52 / Chapter 3.2.1.3 --- Sensitivity analysis --- p.53 / Chapter 3.2.2 --- Large randomized clinical trial --- p.54 / Chapter 3.2.2.1 --- Demographic data --- p.54 / Chapter 3.2.2.2 --- Cost analysis --- p.55 / Chapter 3.3 --- Discussion --- p.55 / Chapter 3.3.1 --- Cost analysis --- p.55 / Chapter 3.3.2 --- Sensitivity analysis --- p.59 / Chapter 3.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.59 / Chapter 3.3.4 --- Limitation --- p.60 / Chapter 3.4 --- Future study --- p.62 / Chapter 3.5 --- Conclusion --- p.62 / Chapter Chapter 4 --- Conclusion --- p.63 / Chapter Chapter 5 --- Reference --- p.65 / Appendix Data collection form --- p.75

Zhang Jie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 54-74). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.ii / ABSTRACT (Chinese) --- p.iv / ABBREVIATION --- p.vi / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Overview of the study --- p.1 / Chapter 1.2 --- Secretin --- p.3 / Chapter 1.2.1 --- Discovery / Chapter 1.2.2 --- Molecular biology / Chapter 1.2.3 --- Biosynthesis and localization / Chapter 1.2.4 --- Function / Chapter 1.3 --- Secretin receptor --- p.8 / Chapter 1.3.1 --- Molecular biology / Chapter 1.3.2 --- Localization / Chapter 1.3.3 --- Signal transduction pathway / Chapter 1.4 --- Secretin and autism --- p.13 / Chapter 1.5 --- AMPA receptor --- p.15 / Chapter 1.5.1 --- Molecular biology / Chapter 1.5.2 --- Localization / Chapter 1.5.3 --- Pharmacological property / Chapter 1.5.4 --- Function / Chapter 1.6 --- Cerebellum --- p.20 / Chapter 1.6.1 --- Structure of the cerebellar cortex / Chapter 1.6.2 --- Neurons of the cerebellar cortex / Chapter 1.6.2.1 --- Granule cells / Chapter 1.6.2.2 --- Purkinje cells / Chapter 1.6.2.3 --- Basket and stellate cells / Chapter 1.6.2.4 --- Golgi cells / Chapter 1.6.3 --- Intrinsic circuitry of the cerebellar cortex / Chapter CHAPTER 2 --- METHODS AND MATERIALS --- p.25 / Chapter 2.1 --- Brain slice preparation and maintenance --- p.25 / Chapter 2.2 --- Experimental set-up --- p.26 / Chapter 2.2.1 --- Visualization of neurons / Chapter 2.2.2 --- Electrophysiological recordings / Chapter 2.2.3 --- Evoked stimulation / Chapter 2.2.4 --- Drug preparation and administration / Chapter 2.3 --- Data analysis --- p.29 / Chapter 2.3.1 --- Construction of dose-response curve / Chapter 2.3.2 --- Analysis of synaptic currents / Chapter 2.3.3 --- Statistics / Chapter CHAPTER 3 --- RESULTS --- p.31 / Chapter 3.1 --- Basic characteristics of IPSCs recorded from PCs --- p.31 / Chapter 3.1.1 --- Spontaneous IPSCs / Chapter 3.1.2 --- Miniature IPSCs / Chapter 3.1.3 --- Evoked IPSCs / Chapter 3.1.4 --- Rundown of IPSCs / Chapter 3.2 --- Electrophysiological effects of secretin --- p.33 / Chapter 3.2.1 --- Effects of secretin on evoked IPSCs and EPSCs / Chapter 3.2.2 --- Effects of secretin on spontaneous IPSCs / Chapter 3.2.3 --- Effects of secretin on miniature IPSCs / Chapter 3.3 --- Mechanisms of secretin as a neuropeptide --- p.37 / Chapter 3.3.1 --- Non-involvement of a postsynaptic site of action / Chapter 3.3.2 --- Non-involvement of calcium influx / Chapter 3.3.3 --- Involvement of cAMP second messenger / Chapter 3.3.4 --- Involvement of presynaptic AMP A receptors / Chapter 3.3.4.1 --- Glutamate-mediated action of secretin / Chapter 3.3.4.2 --- Effects of AMPA on miniature IPSCs / Chapter 3.3.4.3 --- Pharmacological evidence / Chapter CHAPTER 4 --- DISCUSSION --- p.45 / Chapter 4.1 --- Secretin as a novel neuropeptide --- p.45 / Chapter 4.2 --- Mechanisms of secretin --- p.46 / Chapter 4.3 --- Physiological role of secretin in the cerebellum --- p.52 / Chapter 4.4 --- Secretin and autism --- p.52 / REFERENCES --- p.54

As neoplasias gastrintestinais de cães são incomuns e desconhece-se a sua ocorrência em São Paulo. O objetivo foi avaliar do ponto de vista epidemiológico, clínico, anatomopatológico e imuno-histoquímico cães portadores de neoplasias gastrintestinais. Para tanto foram analisadas as fichas clínicas e os resultados anatomopatológicos de 62 cães atendidos no Hospital Veterinário da Universidade de São Paulo no período de janeiro de 1998 a dezembro de 2008. As neoplasias foram 92% malignas, das quais as epiteliais corresponderam a 42% dos casos, hematopoéticas, 32% e mesenquimais, 26%. Todos os animais eram adultos com média de idade igual a 9 ± 3 anos, de porte pequeno a médio, 37,1% não tinham raça definida e 58% eram machos. A sintomatologia clínica foi correlacionada com a localização topográfica do tumor. Êmese, prostração, perda de peso e anorexia foram relatadas nas neoplasias do esôfago, estômago e intestino delgado, enquanto os quadros de hematoquesia, prolapso de reto, disquesia e tenesmo foram relatados nos tumores localizados na válvula íleoceco-cólica e no intestino grosso. As localizações mais freqüentes dos tumores foram o reto, 35,5 %, e o jejuno, 17,7%. As neoplasias mais freqüentes foram o adenocarcinoma tubular mucinoso, o linfoma T alimentar e os sarcomas de células alongadas. Os linfonodos mesentéricos e o fígado foram os principias sítios metastáticos. A sobrevida média dos cães foi 12 meses após o diagnóstico e não variou entre as neoplasias. O tamanho da neoplasia, grau histológico de malignidade e os escores de proliferação celular nas neoplasias não mostraram associação com a presença de metástases e com o período de sobrevida dos cães, exceto nos casos de linfoma alimentar. O estudo multidisciplinar na medicina veterinária mostrou ser importante para melhor caracterizar as neoplasias gastrintestinais de cães e estabelecer o melhor tratamento para esses animais. / Gastrointestinal neoplasias of dogs are unusual and its occurrence is unknown in São Paulo. The aim was to assess dogs affected by gastrointestinal neoplasias undertaken clinical, pathological and immunohistochemical aspects. It was analyzed the medical files and pathological diagnosis of 62 animals attended at the Veterinary Hospital of the University of São Paulo from January 1998 to December 2008. The tumors were 92% cancer and epithelial neoplasias corresponded to 42% of the cases, hematopoietic neoplasias, 32% and mesenchymal neoplasias, 26%. All of the animals were adults with an average age of 9 ± 03 years, small to medium sizes and 37,1% were mixed breed and 58% were males. The clinical signs were directly related to the anatomical location of the tumors. Emesis, weight loss and anorexia were reported in esophageal, gastric and small intestinal tumors; while hematochezia, rectal prolapse, dyschezia and tenesmus were described in the ileo-ceco-colic valve and large intestine. The most frequent local of tumors were rectum 35,5%, and jejunum, 17,7%. Mucinous tubular adenocarcinoma, T cell tumors and spindle cells sarcomas were the most common diagnosed. Mesenteric lymph nodes and liver were the main sites of metastasis. The average of survival rate was 12 months and had no differences among neoplasias. The sizes of tumors, histological grading and scores of cell proliferation had no statistic association with the presence of metastasis and reduced survival period of dogs, except the cases of alimentary lymphoma. The multidisciplinary approach in veterinary medicine is important to establish the definitive diagnosis and proper treatment of gastrointestinal tumors of dogs.

Contexto: A hemorragia digestiva alta (HDA) resulta em 200 a 300 mil internações por ano nos Estados Unidos, com uma mortalidade de 2,5% a 10%. A úlcera péptica representa a causa mais comum de HDA, correspondendo por um terço a metade de todos os casos. Apesar das melhorias na compreensão de sua etiologia, a incidência de sangramento da úlcera péptica, sua complicação mais comum, não se alterou nas últimas décadas. A terapia endoscópica para HDA pode reduzir drasticamente o risco de ressangramento ou sangramento contínuo, a necessidade de cirurgia de urgência, o número de unidades de concentrado de hemácias para transfusão, o tempo de internação hospitalar e a mortalidade. O tratamento endoscópico da úlcera hemorrágica já percorreu um longo caminho desde injeções de adrenalina e outras soluções, o uso da termocoagulação, até a aplicação de dispositivos mecânicos, como o clipe metálico e a ligadura elástica. Objetivo: Permanece por esclarecer qual é a modalidade endoscópica (ou combinação de modalidades) que apresenta os melhores resultados no tratamento da hemorragia digestiva decorrente da úlcera péptica. Portanto, o objetivo desta revisão sistemática é comparar as diferentes modalidades de tratamento endoscópico da HDA decorrente da úlcera péptica, utilizando ensaios clínicos randomizados. Fontes de dados: Os estudos foram identificados através de pesquisa em bases de dados eletrônicas e listas de referência de artigos. As bases de dados pesquisadas foram Medline, Embase, Cochrane, LILACS, Dare e CINAHL. Critérios de elegibilidade de estudo, participantes e intervenções: Os estudos selecionados foram os ensaios clínicos randomizados comparando as diferentes modalidades endoscópicas para o tratamento de pacientes com hemorragia digestiva alta causada por úlcera péptica. Os estudos incluídos avaliaram técnicas endoscópicas contemporâneas de hemostasia: terapia de injeção endoscópica (todas as soluções, simples ou múltiplas), termocoagulação (heater probe, coagulação com plasma de argônio, coagulação com micro-ondas, eletrocoagulação monopolar, bipolar e multipolar), aplicação de clipes metálicos e tratamento combinado. Os desfechos avaliados foram as taxas de hemostasia inicial, ressangramento, cirurgia de urgência e de mortalidade. Avaliação de vieses: Ao nível de cada estudo, os revisores determinaram a adequação da randomização e da alocação; cegamento de pacientes, profissionais de saúde, coletores de dados e avaliadores de resultados; bem como o relato e a extensão das perdas de seguimento. Também foi avaliado se as técnicas de hemostasia endoscópica foram devidamente descritas e, se os desfechos foram adequadamente definidos em cada estudo. A análise de sensibilidade foi realizada quando a heterogeneidade (I2) foi superior a 50% e uma nova meta-análise foi calculada excluindo o(s) estudo(s) discrepante(s). Uma análise adicional foi realizada em cada comparação, incluindo apenas os ensaios de qualidade metodológica mais elevada. Resultados principais: Um total de 28 ensaios clínicos randomizados (envolvendo 2988 pacientes) foram avaliados nesta revisão, eles foram divididos em sete grupos de comparação de acordo com as modalidades estudadas em cada estudo. A terapia de injeção endoscópica como modalidade única foi inferior à sua combinação com o clipe metálico e com a termocoagulação na avaliação de taxa de ressangramento (diferença dos riscos [DR] = -0,10, intervalo de confiança de 95% [IC95%] = -0,18 a -0,03 e [DR] = -0,08, [IC95%] = -0,14 a -0,02, respectivamente) e na necessidade de cirurgia de urgência ([DR] = -0,11, [IC95%] = -0,18 a -0,04 e [DR] = -0,06, [IC95%] = -0,12 para -0,00, respectivamente). A aplicação de clipes metálicos foi superior à terapia de injeção endoscópica na avaliação da taxa de ressangramento ([DR] = -0,13, [IC95%] = -0,19 para -0,08), e os resultados da comparação entre a aplicação de clipes metálicos como monoterapia e a sua combinação com a terapia de injeção endoscópica não apresentaram diferenças estatísticas. A comparação entre o clipe metálico e a termocoagulação encontrou uma considerável heterogeneidade entre as intervenções utilizadas em cada estudo e nos resultados encontrados das meta-análises. A comparação da termocoagulação com a terapia de injeção endoscópica não evidenciou qualquer diferença estatística entre as modalidades, e a combinação delas é superior à técnica de termocoagulação sozinha ao avaliar a taxa de ressangramento ([DR] = -0,11, [IC95%] = -0,21 para - 0,02). Conclusões: A terapia de injeção endoscópica não deve ser empregada isoladamente. A aplicação de clipes metálicos é superior à terapia de injeção endoscópica, e a associação da injeção endoscópica não melhora a eficácia hemostática do uso isolado do clipe metálico. Como modalidade única, uma técnica de termocoagulação tem uma eficácia hemostática semelhante à terapia de injeção endoscópica, e estas modalidades combinadas parecem ser superiores à técnica de termocoagulação sozinha. Portanto, recomendamos a aplicação de clipes metálicos ou o uso combinado de uma terapia de injeção endoscópica com um método de termocoagulação para o tratamento de pacientes com hemorragia digestiva alta por úlcera péptica / Background: Upper Gastrointestinal bleeding (UGIB) results in 200,00 to 300,000 hospital admissions annually in the United States, with a mortality of 2,5% to 10%. Peptic ulcer disease represents the most common cause of UGIB, accounting for a third to a half of all episodes. Despite improvements in the understanding of its etiology, the incidence of bleeding from peptic ulcer disease, the most common complication, has not changed. Endoscopic therapy for active UGIB can dramatically reduce the risk of rebleeding or continued bleeding, the need for surgery, the number of units of packed erythrocytes required for transfusion, the length of hospital stay and mortality. Endoscopic treatment for ulcer bleeding has come a long way from injections of epinephrine and other solutions, the use of thermocoagulation, to the application of mechanical devices such as hemoclips and banding ligator. Objective: It remains unclear which is the endoscopic modality (or combination of modalities) that presents the best results in the treatment of peptic ulcer bleeding. Therefore, the objective of this systematic review is to compare the different modalities of endoscopic hemostatic therapy, using randomized clinical trials. Data sources: Studies were identified by searching electronic databases and scanning reference lists of articles. The searched databases were Medline, Embase, Cochrane, LILACS, DARE and CINAHL. Study eligibility criteria, participants and interventions: The studies selected were the randomized clinical trials comparing different endoscopic modalities for the treatment of patients presenting with acute upper gastrointestinal bleeding caused by peptic ulcer disease. The included trials assessed contemporary endoscopic hemostatic techniques: endoscopic injection therapy (all injectates, single or multiple), thermal coagulation (heater probe, argon plasma and microwave coagulation, monopolar, bipolar and multipolar electrocoagulations), hemoclip placement and combination treatment. The outcomes measured were the rates of initial hemostasis, rebleeding, emergency surgery and overall mortality. Risk of bias assessment: At the study level, the reviewers determined the adequacy of randomization and concealment of allocation; blinding of patients, of health care providers, of data collectors, and of outcome assessors; and the correct report and extent of loss to follow-up. It was also evaluated whether the endoscopic hemostatic techniques were properly described and if the outcomes were appropriately defined in each study. A sensitivity analysis was held when the heterogeneity (I2) was over 50% and a new meta-analysis was calculated excluding the outlier(s). An additional analysis was made at each comparison, including only the higher methodological quality trials. Main results: A total of 28 trials, involving 2988 patients were evaluated in this review, they were divided into seven comparison groups according to the modalities studied in each trial. Injection Therapy as single modality was inferior to its combination with Hemoclip and with Thermal Coagulation Therapy when evaluating rebleeding rate (risk difference [RD] = -0.10, 95% confidence interval [95%CI] = -0.18 to -0.03 and [RD] = -0.08, [95%CI] = -0.14 to -0.02, respectively) and need for emergency surgery ([RD] = -0.11, [95%CI] = -0.18 to -0.04 and [RD] = -0.06, [95%CI] = -0.12 to -0.00, respectively). Hemoclip was superior to Injection Therapy in the evaluation of rebleeding rate ([RD] = -0.13, [95%CI] = -0.19 to -0.08), and the results of the comparison between Hemoclip alone versus its combination with Injection Therapy did not present any statistical differences. The comparison between Hemoclip and Thermal Coagulation encountered a considerable heterogeneity between the trials in the interventions used and in the results found. The comparison of Thermal Coagulation versus Injection Therapy did not evidence any statistical difference between the modalities, and the combination of these is superior to the Thermal Coagulation alone when evaluating rebleeding rate ([RD] = -0.11, [95%CI] = -0.21 to -0.02. Conclusions: Injection therapy should not be used as single modality. The application of Hemoclip is superior to injection therapy, and the combined application of an injectate does not improve the hemostatic efficacy of the use of Hemoclip alone. As single modality, a thermal coagulation technique has a similar hemostatic efficacy as injection therapy, and these combined modalities appear to be superior to thermal coagulation technique alone. Therefore, we recommend the application of Hemoclips or the combined use of an Injection Therapy with a Thermal Coagulation method for the treatment of patients presenting with acute peptic ulcer bleeding