This thesis presents studies relating to the role of the gastrointestinal tract in postprandial blood pressure regulation. The areas that have been addressed include : ( i ) the methodological approaches to the evaluation of gastric emptying, blood pressure, splanchnic blood flow, intraluminal manometry and gut hormones and ( ii ) the pathophysiological mechanisms underlying postprandial hypotension, with a particular focus on ' gastric ' and ' small intestinal ' mechanisms and their potential therapeutic relevance. All of the studies have been either published or manuscripts have been prepared for publication. While scintigraphy represents the ' gold standard ' for the measurement of gastric emptying, recent studies suggest that three - dimensional ( 3D ) ultrasonography may also allow a precise measure of gastric emptying. Concurrent scintigraphic and ultrasonographic measurements of gastric emptying of liquids were performed in healthy young volunteers. There was a good correlation and agreement between scintigraphic measurements of gastric emptying and 3D ultrasonography after ingestion of both low - and high - nutrient drinks, indicating that 3D ultrasonography, provides a valid measure of gastric emptying of liquid meals in normal subjects. Postprandial hypotension, defined as a fall in systolic blood pressure of ≥ 20mmHg,occurring within two hours of a meal is now recognised as an important clinical problem, particularly in the elderly and in patients with type 2 diabetes. The mechanisms mediating postprandial hypotension are poorly understood. The effects of variations in concentration of intraduodenal glucose on the magnitude of the fall in blood pressure were evaluated in healthy elderly subjects. Blood pressure fell, and heart rate and blood glucose increased over time during infusions, however, there was no difference in blood pressure, heart rate or blood glucose concentrations between the study days. These observations suggest that glucose induced postprandial hypotension is a load rather, than concentration, dependent phenomenon. The effect of meal composition has been reported to influence the hypotensive response to a meal and information relating to the effects of triglyceride and protein on blood pressure is inconsistent. The comparative effects of isocaloric and isovolaemic intraduodenal infusions of glucose, triglyceride and protein on the magnitude of the postprandial fall in blood pressure and rise in heart rate and superior mesenteric artery blood flow were evaluated in healthy elderly subjects. There were comparable falls in systolic blood pressure and rises in heart rate, however, the maximum fall in systolic blood pressure occurred later after triglyceride and protein and the stimulation of superior mesenteric artery blood flow was less after protein. These observations suggest that the relatively slower systolic blood pressure response after triglyceride and protein may potentially reflect the time taken for digestion of triglyceride to free fatty acids and protein to amino acids. Acarbose is an antidiabetic drug that slows both gastric emptying and small intestinal glucose absorption. The effects of acarbose, on blood pressure, heart rate, gastric emptying of, and the glycaemic, insulin, glucagon - like peptide - 1 ( GLP - 1 ) and glucosedependent insulinotropic - polypeptide ( GIP ) responses to, an oral sucrose load were evaluated in healthy elderly subjects. Acarbose attenuated the fall in blood pressure and increase in heart rate induced by oral sucrose. Acarbose slowed gastric emptying and was associated with increased retention in the distal stomach. Stimulation of GLP - 1 may contribute to the slowing of gastric emptying and suppression of postprandial glycaemia by acarbose. These findings suggest that acarbose may represent a therapeutic option for the treatment of patients with postprandial hypotension. Recent studies indicate that gastric distension attenuates the postprandial fall in blood pressure. The effects of gastric distension on blood pressure and heart rate during intraduodenal infusion of glucose at a constant load and concentration were evaluated in healthy elderly subjects. Intragastric administration of water markedly attenuated the falls in systolic and diastolic blood pressure induced by intraduodenal glucose. Heart rate increased, with and without gastric distension, in response to intraduodenal glucose infusion but not after intraduodenal saline infusion. This study suggests that gastric distension may potentially be used as a simple adjunctive treatment in the management of postprandial hypotension. Studies employing nitric oxide synthase blockers have established, in animals, that nitric oxide mechanisms are important in the regulation of splanchnic blood flow and, hence, may effect postprandial blood pressure. The role of the nitric oxide synthase inhibitor, NG - nitro - L - arginine - methyl - ester ( L - NAME ), on gastric emptying, postprandial blood pressure, plasma insulin concentration and incretin hormone ( ie GIP and GLP - 1 ) release, following an oral glucose load, were evaluated in healthy elderly subjects. L - NAME attenuated the postprandial fall in blood pressure and increase in heart rate but had no effect on gastric emptying of glucose. L - NAME attenuated the glucose - induced rise in plasma insulin but had no effect on the incretin ( GIP and GLP - 1 ) hormone response to oral glucose. The study indicates that the magnitude of the fall in blood pressure and increase in heart rate and stimulation of insulin secretion induced by oral glucose in healthy elderly subjects are mediated by nitric oxide mechanisms by an effect unrelated to changes in gastric emptying, or the secretion of GIP and GLP - 1. Studies utilising 5 - hydroxytryptamine ( 5 - HT ) infusions in animals have demonstrated regional variations in intestinal blood flow suggesting a role for 5 - HT in postprandial haemodynamic responses. The effects of the 5 - hydroxytryptamine 3 ( 5 - HT3 ) antagonist, granisetron, on the blood pressure, heart rate, antropyloroduodenal motility and glycaemic responses to intraduodenal glucose infusion were assessed in healthy elderly subjects. Granisetron had no effect on blood pressure, heart rate or antral and pyloric motor responses but modulated the duodenal motor response, to intraduodenal glucose. This study indicates that while the cardiovascular response to intraduodenal glucose does not appear to be influenced by the stimulation of 5 - HT3 receptors, this receptor may be involved in the modulation of the duodenal motor activity. / Thesis (Ph.D.)--School of Medicine, 2006.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Ο στόχος της παρούσας μελέτης ήταν η σύγκριση των αποτελεσμάτων και των μεταβολικών επιπλοκών της γαστρικής παράκαμψης Roux-en-Y και μιας εκδοχής της χολοπαγκρεατικής εκτροπής σε έναν αποκλειστικά non-superobese πληθυσμό. Τα κύρια χαρακτηριστικά της χολοπαγκρεατικής εκτροπής ήταν: γαστρικός θύλακος 15 ± 5 pml, χολοπαγκρεατική έλικα 200 cm, κοινό κανάλι 100 cm και διατροφική έλικα το λοιπό λεπτό έντερο. Τα κύρια χαρακτηριστικά της RYGBP ήταν: γαστρικός θύλακος 15 ± 5 ml, χολοπαγκρεατική έλικα 60 cm, Roux έλικα 100 cm και κοινό κανάλι το υπόλοιπο μήκος του λεπτού εντέρου. Από 130 ασθενείς με BMI 35-50 kg/m2, οι 65 υποβλήθηκαν σε RYGBP και οι 65 σε BPD. ΄Ολοι οι ασθενείς ολοκλήρωσαν το δεύτερο μετεγχειρητικό έτος. Η μέση απώλεια υπερβάλλοντος βάρους (excess weight loss, %EWL) ήταν καλύτερη μετά από BPD καθόλη τη διάρκεια του follow-up, ενώ στα 2 χρόνια η EWL ήταν > 50% στο 100% των ασθενών της BPD σε σύγκριση με το 88.7% της RYGBP. Η παθολογική ανοχή γλυκόζης, η υπερχοληστερολαιμία, η υπερτριγλυκεριδαιμία και η υπνική άπνοια παρουσίασαν πλήρη ύφεση και στις δύο ομάδες, αλλά τα μέσα επίπεδα ολικής χοληστερόλης ήταν σημαντικά χαμηλότερα μετά από BPD στα 2 χρόνια. Ο διαβήτης υποχώρησε πλήρως σε όλους τους ασθενείς της BPD και σε 7 στους 10 ασθενείς της RYGBP. Δεν παρατηρήθηκαν στατιστικά σημαντικές διαφορές στις πρώιμες και όψιμες μη μεταβολικές επιπλοκές. Υποαλβουμιναιμία παρατηρήθηκε σε 1 ασθενή της RYGBP (1.5%) και σε 6 ασθενείς της BPD (9.2%). Μόνο ένας ασθενής από κάθε ομάδα χρειάστηκε νοσηλεία και ολική παρεντερική διατροφή. Συμπεραίνουμε πως οι μεταβολικές επιπλοκές μετά από BPD δεν ήταν σοβαρές και δεν παρουσίαζαν στατιστικά σημαντική διαφορά ανάμεσα στις δύο ομάδες, οπότε και οι δύο επεμβάσεις είναι ασφαλείς και αποτελεσματικές σε non-superobese πληθυσμούς, αλλά η BPD είναι πιο αποτελεσματική στην απώλεια βάρους και στην επίλυση του διαβήτη και της υπερχοληστερολαιμίας. / The aim of the present study was the comparison of the effectiveness and the metabolic complications of Roux-en-Y gastric bypass (RYGBP) versus a variant of biliopancreatic diversion (BPD) in an exclusively non-superobese population. The main characteristics of the BPD were: gastric pouch 15 ± 5 ml, biliopancreatic limb 200 cm, common channel 100 cm and alimentary limb the remainder of the small intestine. The main characteristics of the RYGBP were: gastric pouch 15 ± 5 ml, biliopancreatic limb 60 cm, Roux limb 100 cm and common channel the remainder of the small intestine. Of 130 patients with BMI 35-50 kg/m2, 65 underwent RYGBP and 65 underwent BPD. All patients completed their second postoperative year. Mean excess weight loss (EWL) was better after BPD at all time periods, and the %EWL was > 50% in all BPD patients compared to 88.7% of RYGBP patients. Glucose intolerance, hypercholesterolemia, hypertriglyceridemia and sleep apnea completely resolved in all patients in both groups, although mean total cholesterol level was significantly lower in BPD patients at second year. Diabetes completely resolved in all BPD patients and in 7 of the 10 RYGBP patients. No statistically significant differences were observed between the two groups in early and late non-metabolic complications. Hypoalbuminemia occured in only 1 patient after RYGBP (1.5%) and in 6 patients after BPD (9.2%). Only 1 patient from each group was hospitalized and received total parenteral nutrition. We conclude that the metabolic complications that occured following this type of BPD were not severe nor significantly different between the two groups, therefore both operations can be considered safe and effective for non-superobese patients, but BPD is more effective in weight loss as well as the resolution of diabetes and hypercholesterolemia.

Made available in DSpace on 2014-06-11T19:32:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-03-11Bitstream added on 2014-06-13T21:05:19Z : No. of bitstreams: 1 fogaca_kcp_dr_arafcf.pdf: 1112291 bytes, checksum: f3c51513471a3c93b2a06295152462f4 (MD5) / Unimep / A cirurgia bariátrica é apontada como um dos mais efetivos, se não o único recurso terapêutico para obesidade mórbida. Entretanto, a recuperação de peso vem sendo foco de atenção nesses pacientes, especialmente após um ou mais anos de cirurgia; sendo que seus efeitos, magnitude e causas necessitam ser estudados. Esta pesquisa teve como objetivo avaliar a relação de fatores ligados ao consumo e gasto energético com a variação do peso corporal de mulheres em pós-cirúrgico tardio de Derivação Gástrica em Y-de-Roux (DGYR). Foi realizado um estudo transversal do qual participaram 45 mulheres, com idades entre 26 e 61 anos, operadas por derivação gástrica em Y-de-Roux há mais de 24 meses, assistidas na Clínica Bariátrica do Hospital Fornecedores de Cana, Piracicaba – SP. Foi avaliado o consumo alimentar e o gasto energético com atividades físicas a partir do recordatório de 3 dias, a taxa de metabolismo em repouso (TMR) por calorimetria indireta e as concentrações séricas de glicose, insulina e leptina. Para efeito de análise, as mulheres foram agrupadas quanto à recuperação de peso corporal (NR = não recuperação; R = recuperação > 10% do menor peso após a cirurgia), ao índice de massa corporal (IMC) em Não Obesas (NO - IMC < 30 kg/m²) e Obesas (O - IMC > 30 kg/m²) e pela percentagem da Perda do Excesso de Peso (PPEP) Baixa (PPEP < 50%), Moderada (PPEP entre 50% e 75%) e Alta (PPEP > 75%). Para a comparação dos resultados entre os grupos foram utilizados os testes de Mann-Whitney e Kruskal-Wallis, seguido do teste de Dunn. As correlações entre as variáveis foram testadas pelo coeficiente de Spearman. As análises foram realizadas considerando um nível de significância de 5%. Não foi encontrada relação dos indicadores de perda e manutenção de peso (recuperação de peso, IMC e PPEP) e o consumo de nutrientes. O perfil geral de consumo... / Bariatric surgery is pointed out as one of the most effective, if not the only therapeutic resource to treat morbid obesity. However, there has been growing attention to the weight regain seen in bariatric surgery patients, especially one or more years after surgery. The objective of this study was to assess the factors associated with energy consumption and expenditure and body weight variation in the late postoperative period of women who had undergone Roux-en-Y gastric bypass (RYGB). A cross-sectional study was done with 45 women aged 26 to 61 years who had undergone Roux-en-Y gastric bypass at least 24 months earlier, being treated at the Bariatric Clinic of the Hospital Fornecedores de Cana, Piracicaba, SP. The following were investigated: food intake and energy expenditure with physical activities (3-day recall), resting energy expenditure - REE (indirect calorimetry) and serum concentrations of glucose, insulin and leptin. The women were grouped according to the following for analysis: amount of weight regained (NR = no regain; R = regained >10% of the lowest weight achieved after surgery); body mass index (BMI) into non-obese (NO-BMI < 30kg/m2) and Obese (O – BMI > 30 kg/m2); and percentage of excess weight lost (PEWL) into Low (PEWL < 50%), Moderate (50% < PEWL < 75%) and High (PEWL > 75%). The results of the groups were compared with the Mann-Whitney and Kruskal-Wallis tests, followed by the Dunn test. The correlations between the variables were tested with the Spearman’s coefficient. The level of significance was set at 5%. There was no relationship between weight loss and maintenance indicators (weight regain, BMI and PEWL) and nutrient intake. The general food intake profile did not vary among the volunteers but there was a positive correlation between carbohydrate intake... (Complete abstract click electronic access below)

Made available in DSpace on 2015-05-14T12:59:36Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2369002 bytes, checksum: fd2cf79c752c71fa1e3b1bb348116a42 (MD5) Previous issue date: 2011-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Combretum duarteanum Cambess is popularly known as mofumbo, a unique species from Latin America, usually associated with arid environments. This species belongs to Combretaceae family, known in various continents of the world for its popular use in treatment of inflammation and infections, its effects are usually associated with its major constituents, flavonoids, tannins and terpenes. The crude ethanol extract (Cd-EtOHE) and the hexane phase (Cd-HexP) obtained from the leaves of C. duarteanum Cambess were evaluated for toxicity and pharmacological effects against gastroprotective activity and healing, as well as the likely mechanisms of related actions. Oral administration (p.o.) 2000 mg/Kg of Cd-EtOHE, in mice did not show behavioral changes. Regarding water intake, was observed that the extract did not cause significant changes in both the groups, both in males and in females. However the feed intake was observed to decrease significantly in the group of males treated. No animal died and no significant macroscopic changes in daily body or organ weight were observed, making it impossible to determine the LD50. The Cd-EtOHE and Cd-HexP were assessed for their gastroprotective activity in models of acute ulcer induced by HCl/ ethanol, absolute ethanol, stress (immobilization and cold), nonsteroidal anti-inflammatory drug (piroxicam) at doses with 62.5, 125, 250 and 500 mg / kg (p.o.) and pylorus ligature (250 mg/kg v.o. and i.d.) in Swiss mice and male Wistar rats. In the model HCl / ethanol, Cd-EtOHE (62.5 125, 250 and 500 mg / kg, p.o.) significantly reduced the ULI the ulcerative lesion index in 28, 36, 55 and 63% respectively. It was also observed in the ethanol model Cd-EtOHE and Cd-HexP (62.5 125, 250 and 500 mg/kg, p.o.) significantly inhibited the ULI in 51, 48, 61, 45 and 37, 44, 79, 86 %, respectively. In the stress model Cd-EtOHE (125, 250 and 500 mg / kg, po) reduced the ULI in 44, 54 and 69% and Cd-HexP (62.5, 125, 250 and 500 mg / kg po) was about 55, 56, 69 and 79%.In the NSAID-induced ulcers, the percentages of protection for Cd-EtOHE (125, 250 and 500 mg / kg, po) and Cd-HexP (250 and 500 mg / kg, po) were 30, 42, 49 and 43%, 52% , respectively. The results obtained front of the restraint of gastric secretion (pylorus ligation) have shown that Cd-EtOHE (250 mg/kg) or Cd-HexP (250 mg/kg), showed protection both given orally (p.o.) (66 and 39%) or by intraduodenal route (i.d.) (41 and 45%), respectively. The data showed that the Cd-EtOHE and Cd-HexP, did not promote changes in pH and the volume of gastric juice. To evaluate the gastroprotective activity and the likely mechanisms of related actions of the Cd-EtOHE (250 mg / kg) and Cd-HexP (250 mg / kg) were carried out experimental protocols to assess the contribution of mucus, nitric oxide and sulfhydryl groups. According to the obtained results, it is possible to suggest that the gastroprotective effect does not include the mucus participation, but is dependent on the nitric oxide and sulfhydryl compounds participation. In the model of acetic acid induced ulcer, chronic treatment with Cd-EtOHE (250 mg / kg, po) and Cd-HexP (250 mg / kg, p.o.) significantly reduced the ulcerative area in 38 and 48%, respectively. During the 14 days of treatment, we observed that the Cd-EtOHE increased the water and food intake, but for Cd-HexP this effect was not observed. These results suggest that the Cd-EtOHE and Cd-HexP displays gastroprotective activity, which are related the participation of NO, an increase in endogenous SH compounds, as well as the growth factors involvement in the healing process induced by the chemical constituents present in the vegetable samples tested. / Combretum duarteanum Cambess, popularmente conhecida como mofumbo, é uma espécie exclusiva da América Latina, geralmente associada a ambientes da caatinga, com uso popular para fins medicinais, dentre elas para o tratamento de inflamação e infecções. Tais efeitos geralmente estão associados aos seus principais constituintes, dentre eles os flavonóides, taninos e terpenos. O extrato etanólico bruto (EEtOH-Cd) e a fase hexânica (FaHex-Cd) obtidos das folhas de C. duarteanum Cambess, foram avaliados quanto a sua toxicidade e efeitos farmacológicos frente a atividade gastroprotetora e cicatrizante, assim como os prováveis mecanismos de ação relacionados. A administração oral (v.o.) de 2000 mg/Kg do EEtOH-Cd, não provocou alterações no comportamento, nos pesos corporais e nos órgãos, bem como não ocorreram alterações no consumo de água, entretanto, o consumo de ração, foi reduzido no grupo dos animais machos. Não foram observadas alterações macroscópicas nos órgãos, sem ocorrência de mortes, sendo portanto, impossível determinar a DL50. O EEtOH-Cd e FaHex-Cd foram avaliados quanto à sua atividade gastroprotetora nos modelos de indução aguda de úlcera HCl/Etanol, etanol absoluto, estresse (imobilização e frio) e antiinflamatório não esteroidal (piroxicam) nas doses 62,5, 125, 250 e 500 mg/Kg (v.o.) e contensão do suco gástrico ( 250 mg/Kg v.o. e i.d.) em camundongos Swiss e ratos Wistar machos. No modelo HCl/etanol, o EEtOH-Cd (62,5 125, 250 e 500 mg/kg, v.o.) reduziu o índice de lesão ulcerativa (ILU) em 28, 36, 55 e 63 %, respectivamente. Também foi observado no modelo de etanol que o EEtOH-Cd e a FaHex-Cd (62,5 125, 250 e 500 mg/kg, v.o.) inibiram o ILU em 51, 48, 61, 45 e 37, 44, 79, 86 %, respectivamente. No modelo de estresse o EEtOH-Cd ( 125, 250 e 500 mg/kg, v.o.) reduziu o ILU em cerca de 44, 54 e 69% e a FaHex-Cd (62,5, 125, 250 e 500 mg/kg, v.o.) em cerca de 55, 56, 69 e 79 %. Na indução aguda de úlcera por AINE, as porcentagens de proteção para EEtOH-Cd ( 125, 250 e 500 mg/kg, v.o.) e FaHex-Cd ( 250 e 500 mg/kg, v.o.) foram 30, 42, 49 % e 43, 52 %, respectivamente. Nas úlceras induzidas por contensão do suco gástrico (ligadura de piloro) o EEtOH-Cd (250 mg/kg) e a FaHex-Cd (250 mg/kg) apresentaram proteção gástrica tanto por via oral (v.o.) (66 e 39 %) quanto por via intraduodenal (i.d.) (41 e 45 %), respectivamente. Tanto o EEtOH-Cd e FaHex-Cd não provocaram alterarações no volume e pH do suco gástrico. Na perspectiva de elucidar os prováveis mecanismos de ação envolvidos com a atividade gastroprotetora do EEtOH-Cd (250 mg/kg) e da FaHex-Cd (250 mg/kg), foram avaliadas as participações do muco aderido a mucosa, do óxido nítrico e dos grupamentos sulfidrílicos. De acordo com os resultados obtidos o efeito gastroprotetor não inclui a participação do muco, porém é dependente da participação do óxido nítrico e dos compostos sulfidrílicos. No modelo de úlcera induzida por ácido acético, o tratamento crônico com o EEtOH-Cd (250 mg/kg, v.o.) ou FaHex-Cd (250 mg/kg, v.o.) reduziu a área de lesão ulcerativa em 38 e 48 %, respectivamente. Neste modelo, durante os 14 dias de tratamento, foi observado que o EEtOH-Cd promoveu aumento na ingesta de água e ração. Portanto, estes dados indicam C. duarteanum apresenta atividade gastroprotetora podendo ter a participação dos grupamentos sulfidrilas e da via do óxido nítrico, bem como o envolvimento de fatores de crescimento no processo de cicatrização induzido pelos constituintes químicos presentes nas amostras vegetais testadas.

Orientador: Joel Mesa Hormaza / Resumo: A úlcera péptica é provocada pelo desequilíbrio entre fatores lesivos e protetores das mucosas gástrica e duodenal, em consequência a fatores endógenos ou exógenos aos tecidos. Para seu tratamento, algumas plantas são popularmente empregadas e demonstram eficácia semelhante ou superior aos fármacos geralmente utilizados, ocasionando menores efeitos adversos. Apesar de várias pesquisas na área, a compreensão do mecanismo gastroprotetor dos compostos fitoterápicos ainda não é completa. Assim, com o objetivo de contribuir para a compreensão da ação farmacológica dos extratos de três plantas medicinais (Alchornea glandulosa, Davilla elliptica e Davilla nitida), foi realizada uma análise da distribuição elementar dos constituintes das amostras de mucosas gástricas de ratos tratados com os extratos vegetais e que tiveram úlceras gástricas induzidas por álcool ou por droga anti-inflamatória não-esteroidal (DAINE). O experimento foi realizado no Laboratório Nacional de Luz Síncrotron (LNLS) e permitiu a análise dos elementos Cl, Ca, Mn, Fe, Cu e Zn que contem relação com a formação ou neutralização das úlceras pépticas. De acordo com os mapas da distribuição dos elementos, foi possível detectar alta concentração de Fe, Cu e Zn no interior da lesão das amostras de úlcera induzida por DAINE, e de Cu, Zn e Cl no interior da lesão das amostras induzidas por álcool. Nas amostras de úlcera induzida por DAINE e tratadas com Alchornea glandulosa, as concentrações de Ca, Cu e Fe aumentaram. N... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The peptic ulcer is caused by the imbalance between harmful and protective factors of the gastric and duodenal mucosa, as a consequence of factors endogenous or exogenous to the tissues. For its treatment, some plants are popularly employed and demonstrate efficacy akin or superior to the drugs normally used, leading to less adverse effects. Although much research has been conducted in the field, the understanding of the gastroprotective mechanism of phytotherapic compounds is still not complete. Therefore, aiming to advance the understanding of the pharmacological action of the extracts of three medicinal plants (Alchornea glandulosa, Davilla elliptica e Davilla nitida), we conducted an analysis of the elemental distribution of constituents within samples of gastric mucosa from rats treated with phytoterapic extracts and affected with peptic ulcers induced by alcohol or nonsteroidal anti-inflammatory drugs (NSAIDs). The experiment was performed at the Brazilian Synchrotron Light Laboratory (LNLS) and allowed for the analysis of the elements Cl, Ca, Mn, Fe, Cu and Zn that are connected to peptic ulcers development or inhibition. According to the elemental distribution maps, it was possible to detect high concentrations of Fe, Cu and Zn inside the lesion from the NSAID-induced ulcer samples, and of Cu, Zn and Cl inside the lesion from the alcohol-induced ulcer samples. In NSAID-induced ulcer samples treated with Alchornea glandulosa, Ca, Cu and Fe concentrations were augmented... (Complete abstract click electronic access below) / Doutor

Introdução: O Fator de Crescimento Endotelial Vascular - A (VEGF) é um dos principais promotores da angiogênese e demonstra relação com prognóstico no câncer gástrico (CG). Objetivos: Correlacionar a expressão imunoistoquímica do VEGF com o estadiamento e sobrevida no câncer gástrico. Métodos: 45 espécimes de adenocarcinomas foram avaliados para expressão imunoistoquímica do VEGF. O estadiamento patológico (pTNM), características histológicas e sobrevida foram avaliados empregando os testes ANOVA, análise multivariada e curva de Kaplan-Meier. Resultados: Foi observada maior expressão do VEGF na comparação entre os estadiamentos IA e IB vs II,III e IV (p<0,001). O VEGF menos expresso estava relacionado com maior penetração do tumor na parede gástrica (p<0,003) e presença de comprometimento linfonodal (p<0,001). Pacientes apresentando tumores com maior expressão de VEGF tiveram maior sobrevida (HR 0,37; IC 95%: 0,17-0,79). Conclusão: Houve associação inversa na expressão do VEGF com o estadiamento dos tumores gástricos. A análise multivariada demonstra a expressão do VEGF como fator prognóstico independente na sobrevida dos pacientes com câncer gástrico. / Background: Vascular endothelial growth factor A (VEGF) is one of the main promoters of angiogenesis and correlates with gastric cancer (GC) prognosis. Aims: To evaluate the correlation between immunohistochemical VEGF expression and the gastric cancer stage and survival rate. Methods: VEGF expression was evaluated by immunohistochemistry in 45 adenocarcinoma specimens. Pathologic staging (pTNM), histological characteristics and survival were assessed using an ANOVA test, a multivariate analysis and the Kaplan-Meier method. Results: A higher VEGF expression level was observed in stages IA and IB compared with II, III and IV (p<0.001). A lower VEGF expression level correlated with a greater tumor penetration level in the gastric wall (p<0.003) and the extent of tumor spread to the lymph nodes (p<0.001). Higher VEGF scores correlated with a longer survival time (HR 0.37; 95% CI: 0.17 - 0.79). Conclusion: An inverse correlation was observed between VEGF expression and gastric tumor stage. A multivariate analysis demonstrates that VEGF expression is an independent prognostic factor for survival in gastric cancer.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / The South African economy relies heavily on mining. The residues of these activities contain harmful metals that are discharged into the environment as industrial wastes, contaminating the air, soil, surface and ground water. A lot of people who live in remote areas in South Africa rely on ground water to drink and cook. They also cultivate their own vegetables increasing the risk of metal toxicity. Some of these metals are very toxic and can cause adverse effects upon being ingested. Toxic metals are well known to be harmful to humans. Some of these metals are carcinogenic or nephrotoxic when a large amount is accumulated in the human body causing cancer and destroying tissues such as the kidneys. The detrimental health effects of these metals may take months to years before manifestation causing people to sideline them as hazards. One of the major toxic elements that are discharged into the environment is lead. A natural zeolite called clinoptilolite has been widely used as an adsorbent for toxic metals from contaminated water and from the human body because of its properties such as ion-exchange capacity and pore size. However, this natural zeolite clinoptilolite is not pure and may contain traces of toxic elements of which the nature and concentration depend on the origin of clinoptilolite. The structural stability of clinoptilolite in acidic or alkaline media is not well documented. The lack of documented information about the leachates of clinoptilolite and their long term effects on the human body may cause harm to people who ingest this zeolite. This has led to investigation of synthetic zeolites such as faujasite which has already been used for decontamination of sludge, industrial effluents and other waste water by removing toxic metals such as Pb, Cd, Cu, Zn and As. This study focuses on comparing the toxic metal removal efficiency of natural zeolite clinoptilolite (C), clinoptilolite-based faujasite (FAU3) and clinoptilolite-based ultrastable Y zeolite (USY3), from contaminated water and simulated gastric juice containing lead and cadmium and to evaluate the extent of leaching of other elements from these zeolites. Clinoptilolite was used as a starting material for the synthesis of faujasite (FAU3) which was further treated with oxalic acid to get an ultrastable Y zeolite (USY3). Various techniques were used to characterise the as-received clinoptilolite, faujasite zeolite and USY, namely XRD, SEMEDS, FTIR, solid state NMR (27Al and 29Si) and BET-N2. These characterisation techniques confirmed that clinoptilolite was successfully transformed into faujasite and that the treatment of faujasite with oxalic acid yielded USY3. A comparative adsorption study was conducted using three zeolite samples: namely Clinoptilolite (C), clinoptilolite-based faujasite (FAU3) and ultrastable Y zeolite (USY3). ICP was used to characterise the liquid samples and it was concluded that zeolites were efficient in removing lead and cadmium from contaminated water samples as well as from simulated gastric juice. Some leachates from these zeolites were also observed. A contaminated water sample containing lead and cadmium was used as a medium where the removal capacity and percentage removal with C, FAU3 and USY3 was investigated. It was observed that the optimum dosage varied from one zeolite to the other and also from one metal to the other. The optimum dosage for C, FAU3 and USY3 for the uptake of lead was found to be 0.2 g, 0.2 g and 0.05 g respectively while for cadmium it was 0.4 g, 005 g and 0.1 g, respectively. It was also shown in this study that the removal capacity for lead and cadmium could be hindered by the Na content in FAU3 and USY3 due to the fact that these metals could be in an uptake competition with Na and other cations that leached out or exchanged from the zeolites. It was observed that the optimum metal concentration for lead uptake as well as for cadmium with few metals being released back into the solution was 0.1 mg/L. The optimum contact time for both lead and cadmium was 15 minutes. The factor that varied depending on the type of metal was pH, which was at its optimum at 3.5 for lead and at 5.5 for cadmium. A simulated gastric juice was contaminated with toxic metals (lead and cadmium) and the zeolites were used to treat the contaminated samples. It was shown that the removal capacity of these zeolites increased with the increase in initial concentration of the metal. Time proved to be one factor that affected the behaviour of zeolites. The modification of the synthesised faujasite into an ultrastable Y zeolite proved to have played a role in increasing the removal of toxic metals and in preventing the high leaching of some elements out of the zeolite. / 2018-12-14

Les cancers gastro-intestinaux, en particulier les cancers colorectaux (CCR) et les cancers gastriques (CG), sont des pathologies agressives avec des taux de mortalité élevés dans le monde. Ces cancers sont caractérisés par la dérégulation de voies de signalisation cellulaire telles que les voies Wnt, Notch et Hippo qui jouent un rôle très important dans la tumorigenèse gastro-intestinale. L’activité des différents facteurs de transcription impliqués dans ces voies de signalisation nucléaire est contrôlée par de nombreux corégulateurs transcriptionnels. Ces travaux de thèse ont porté sur deux corégulateurs transcriptionnels initialement identifiés comme des partenaires des récepteurs nucléaires, à savoir RIP140 et LCoR. L’objectif a été d’explorer l’expression de ces deux facteurs de transcription dans les cancers gastro-intestinaux ainsi que leur rôle dans les cancers gastriques principalement au travers du dialogue avec la voie de signalisation Hippo. L’analyse par immunohistochimie de l'expression de RIP140 et LCoR dans les cancers colorectaux et gastriques a montré que les niveaux d’expression de ces deux corégulateurs transcriptionnels sont fortement corrélés. Dans les CCRs, leur expression tend à diminuer dans le tissu tumoral par rapport au tissu normal adjacent, alors que dans les CGs, les niveaux d’expression de RIP140 et LCoR sont significativement plus élevés dans la tumeur que dans l’épithélium sain. Des corrélations significatives ont été observées avec les paramètres clinicopathologiques des patients (stade TNM et différenciation tumorale) ainsi qu’avec d’autres protéines clés impliquées dans la progression et l'invasion tumorale (incluant E-cadhérine et Cox-2). L'analyse de la survie a montré que les patients atteints de CCR avec des tumeurs LCoRlow/RIP140high ont une durée de survie plus longue. Dans le CG, l'expression élevée de RIP140 ou de LCoR a été identifiée comme un marqueur de mauvais pronostic suggérant un rôle clé de ces deux gènes dans cette malignité.Pour mieux cerner le rôle de RIP140 dans le CG, nous avons utilisé les lignées cellulaires MKN45 et MKN74 de cancer de l’estomac humain avec une surexpression ectopique du gène RIP140 ou au contraire avec une diminution de son expression. Nos résultats ont montré que l'expression de RIP140 est associée à un effet anti-prolifératif à travers une régulation positive de l'expression du gène p21WAF1/CIP1. Nous avons également démontré que RIP140 réduit la migration des cellules MKN45 et MKN74 et augmente l'expression du gène E-cadhérine au niveau transcriptionnel. D’une manière intéressante, nos résultats suggèrent aussi que RIP140 régule la voie de signalisation Hippo à travers l’activation de TEAD.Dans l'ensemble, ces résultats suggèrent que les gènes RIP140 et LCoR participent à la régulation de la tumorigenèse gastro-intestinale et que leurs niveaux d'expression ont une valeur pronostique dans ces cancers et pourraient servir de nouveaux biomarqueurs dans la caractérisation moléculaire de ces tumeurs. / Gastrointestinal cancers, particularly colorectal cancer (CRC) and gastric cancer (GC), are aggressive pathologies with a high mortality rate worldwide. These cancers are characterized by the deregulation of cellular signaling pathways such as the Wnt, Notch and Hippo pathways which play a very important role in gastrointestinal tumorigenesis. Moreover, it’s well established that the activity of the transcriptionnel factors involved in these nuclear signaling pathways is controlled by many transcriptionnel coregulators. This work focused on two transcriptional coregulators initially identified as partners of nuclear receptors, namely RIP140 and LCoR. The objective was to explore the expression of these two transcription factors in gastrointestinal cancers and their role in gastric cancers mainly through the dialogue with the Hippo signaling pathway.Immunohistochemical analysis of RIP140 and LCoR expression in colorectal and gastric cancers showed that the expression levels of these two transcriptional regulators are strongly correlated. In CRCs, their expression tends to decrease in tumor tissue compared to adjacent normal tissue, whereas in GCs, RIP140 and LCoR expression levels are significantly higher in the tumor as compared to normal stomach. Significant correlations were observed with clinicopathological parameters (TNM stage and tumor differentiation) as well as the expression levels of key proteins involved in tumor progression and invasion (E-cadherin and Cox-2). Survival analysis showed that CRC patients with LCoRlow/RIP140high tumors have a significant prolonged OS and DFS. In GC, high RIP140 or LCoR expression was identified as an independent marker of poor prognosis suggesting a key role in this malignancy.Further, we investigated the role of RIP140 in gastric cancer cell lines using human epithelial GC cell lines overexpressing or not RIP140. In both MKN45 and MKN74 cells we showed that RIP140 exerted an anti-proliferative effect through the induction of p21WAF1/CIP1 gene expression. We also demonstrated that RIP140 reduced GC cell migration and increased E-cadherin expression at the transcriptional level. Interestingly, our results also suggest that RIP140 regulates the Hippo signaling pathway through TEAD activation.In conclusion, our findings suggest that RIP140 and LCoR genes contribute to the regulation of gastrointestinal cancers and that their expression levels have a prognostic value in these pathologies. Moreover, both RIP140 and LCoR transcriptional coregulaters could serve as novel biomarkers in the molecular characterization of colorectal and gastric cancers.

Submitted by FERNANDO CHRISTIANO GABRIEL MORELLI null (fcgmorelli@yahoo.com.br) on 2016-02-12T17:49:35Z No. of bitstreams: 1 Fernando - Tese versão final Repositório UNESP.pdf: 1900802 bytes, checksum: a8c9044a1f5a46e203d3432398fc0a07 (MD5) / Approved for entry into archive by Sandra Manzano de Almeida (smanzano@marilia.unesp.br) on 2016-02-15T11:32:07Z (GMT) No. of bitstreams: 1 morelli_fcg_dr_araca.pdf: 1900802 bytes, checksum: a8c9044a1f5a46e203d3432398fc0a07 (MD5) / Made available in DSpace on 2016-02-15T11:32:07Z (GMT). No. of bitstreams: 1 morelli_fcg_dr_araca.pdf: 1900802 bytes, checksum: a8c9044a1f5a46e203d3432398fc0a07 (MD5) Previous issue date: 2016-02-01 / Erosões e úlceras são achados comuns no abomaso e causam preocupação econômica nos mais variados sistemas de produção de gado. Muitos fatores podem predispor ao aparecimento de úlceras e acúmulo de gases no abomaso, incluindo alimentos grosseiros, estresse ambiental, deficiências de vitaminas e minerais e infecções bacterianas. Essas úlceras podem ser subclínicas, sendo descobertas nas necropsias ou após o abate do animal, ou levarem à redução da motilidade do órgão, prejudicando o fluxo do seu conteúdo e causando transtornos digestivos graves e até ao aparecimento de síndromes semelhantes à indigestão vagal. Existem informações a respeito da resposta do sistema imune na maior parte das mucosas do trato gastrintestinal de não-ruminantes e ruminantes, porém são raras a respeito do abomaso. Os objetivos desse estudo foram detectar os níveis de citocinas (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) no conteúdo abomasal em bovinos de corte, determinar o perfil Th1 ou Th2 dessas citocinas em animais com úlceras de grau 1 e 2 na região cárdica abomasal e comparar esses valores com os níveis de citocinas de animais sem úlceras (controle), em amostras colhidas em abatedouro, para auxiliar na compreensão da fisiopatologia do processo inflamatório local. A avaliação macroscópica e a classificação das úlceras foi realizada por meio de exames visual e histológico em amostras de tecidos da parede da região cárdica abomasal ulcerada. Os níveis de citocinas produzidas do líquido abomasal dos animais com ou sem úlceras foram avaliados por citometria de fluxo (método Cytometric Bead Array). As citocinas citadas foram detectadas no líquido do abomaso dos bovinos. Não houve diferença na liberação das citocinas entre os grupos com úlceras e o grupo sem úlcera, indicando um equilíbrio entre perfis Th1 e Th2 da resposta inflamatória. / Erosions and ulcers are common findings in the abomasum and cause economic concern in several livestock production systems. Many factors may predispose to ulcers and bloat in the abomasum, including roughage, environmental stress, deficiencies of vitamins and minerals and bacterial infections. These ulcers may be subclinical and are found during necropsy or after slaughter, or lead to reduction of abomasal motility, hindering the flow of your content and causing serious digestive disorders and even the appearance of syndromes similar to vagal indigestion. There are some studies evaluating the immune system response in most of the mucous membranes of the gastrointestinal tract of non-ruminants and ruminants, but rarely related to the abomasum. The aims of this study were to investigate the levels of cytokines (IL-17A, IFN-γ, TNF-α, IL-10, IL-6, IL-4, IL-2) in the abomasal fluid of beef cattle, to determine the Th1 or Th2 profile of these cytokines in animals with types 1 or 2 ulcers located in the abomasal cardic region and to compare these levels with those of animals without ulcers (controls), in samples collected in an abbatoir, to help to the understand the pathophysiology of the local inflammatory process. Ulcers from the abomasal cardic region were macroscopicaly evaluated, then classified by histology. Cytokine levels in the abomasal fluid from animals with or without ulcers were evaluated by flow cytometry (Cytometric Bead Array). Cytokines were detected in the abomasum fluid of cattle. There was no difference in the release of cytokines between groups, indicating a balance between Th1 and Th2 profiles of the inflammatory response.