No description available.

<p> Knowledge into uptake rate and interactions of the metals via the gastrointestinal tract of freshwater fish is vital, in order to provide tools to protect and to sustain aquatic biota. An in vitro stomach and gut sac technique was utilized to investigate uptake rates of essential metals (copper, zinc and nickel) and non-essential metals (cadmium, lead and nickel) at luminal concentrations of 50fJ.M via the gastrointestinal tract Metals had no effect on the fluid transport rates via the gastrointestinal tract except for copper at the stomach. The stomach emerged as small but important site for metal absorption and interaction. Essential metals were absorbed at approximately the same rate as nonessential metals via the gastrointestinal tract. Copper, zinc, nickel, silver, and lead showed statistical correlation between rate of absorption and mucus binding via gastrointestinal tract, an important first finding for the development of a Biotic Ligand Model (BLM) for the gastrointestinal tract of trout. </p> <p> There was an antagonistic effect of calcium on cadmium uptake at the stomach but not at the intestine. Zinc and calcium exhibited synergistic interaction at the stomach but no interaction at the intestine. These results showed the possibility of the transporters DMTl to mediate copper and cadmium uptake via the intestine; hZip 2 to mediate copper and zinc uptake at the stomach; and Mzip 4 or ZTLl to mediate zinc uptake via the gastrointestinal tract of trout. These results can be used to develop a BLM for the gastrointestinal tract of fish. </p> / Thesis / Master of Science (MSc)

Obsessive-Compulsive Disorder (OCD) is a debilitating, chronic neuropsychiatric disorder estimated to effect approximately 1-2% of the Canadian population. Our understanding of the pathophysiological mechanisms involved in OCD is unclear, as evidenced by the moderate response associated with treatments targeting these putative pathways. As such, there is a need to explore novel mechanisms of disease. Recent research has focused on the gut-brain axis and highlighted the potential role of the gut microbiota in psychiatric conditions. Further, the role of inflammation is also gaining traction in psychiatric research. This thesis investigates the role of these commensal gut bacteria in OCD, by examining stool samples of unmedicated, non-depressed OCD outpatients and healthy community controls. Given that systemic inflammation is a suggested pathway by which gut bacteria effect behaviour, morning levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor-necrosis factors-α (TNF-α) were also examined. To our knowledge, this thesis is the first investigation of the gut microbiome in OCD. This thesis describes: (1) a critical review of the literature developing a theoretical basis for a role of microbial dysbiosis in OCD; that (2) three specific genera and species richness/diversity are lower in OCD patients compared to controls; (3) mean CRP, but not IL-6 and TNF-α, is elevated in this sample of OCD patients; and (4) gastrointestinal symptom severity and prevalence of irritable bowel syndrome is higher in OCD. Taken together, this thesis is the first study to provide evidence for microbial dysbiosis in OCD. Although systemic inflammation may not mediate the relationship between reduced diversity and OCD symptomatology, these results provide evidence for mild systemic inflammation. Further gastrointestinal and psychiatric symptom severity are positively correlated, but not specific to patients with IBS. These results suggest the gut microbiome may be a potential pathway of interest for future OCD research, clinical implications are also made. / Thesis / Doctor of Philosophy (PhD)

Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability. This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition. A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test. NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms. Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle. Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

Complex medication regimens have major implications on patient therapy. When we consider that these regimen therapies can also be further convoluted by co-morbidity, it is then seen as an essential opportunity to research possible solutions to alleviate such complications. Globally identified conditions such as the Human Immuno-deficiency Virus (HIV) and Tuberculosis (TB) are known to have such complications within their respective regimens. In many cases, the regimental therapies themselves are overbearing with high pill burdens having to be taken in segregated manners throughout the day. Within a standard TB regimen, isoniazid and rifampicin are seen to have a deleterious drug-drug interaction in which the bioavailability is compromised through formation of an insoluble complex. Despite this interaction, the 2 active drugs must be taken concurrently for successful TB therapy. No true solution exists as fixed dose combinations of isoniazid and rifampicin (Rifinah®) are still in production despite the detrimental interaction that impedes successful bioavailability. The once daily multi-unit drug delivery system (ODMUS) has the benefits of superseding the described problems and aiding in therapeutic outcomes. Preliminary studies utilized preliminary testing to ascertain the science surrounding the 2 components of the ODMUS, the memblet and the multiparticulate components. pH-sensitive polymers (Eudragit® L100-55 and E 100) were of critical importance to the success of the system and were individually manipulated for each component to produce a novel memblet and multiparticulate system through a unique salting out approach. Primary studies focused on drug release testing and drug entrapment for the multiparticulate component. Testing of the memblet system addressed dissolution and thermal analysis. Utilizing this data, a series of process variables were used to achieve an optimized formulation through a Box- Behnken statistical design. Optimized formulations used response testing to establish the optimal characteristics of both components. Multiparticulates achieved controlled release for 12 hours with an enhanced 71% drug entrapment efficiency. Memblet release profiles were confirmed over 2 hours with a maximal Tg of 56°C. Molecular modeling corroborated release understanding for both components. Surface area and porosity analysis, surface morphology, fourier transform infrared spectroscopy as well as thermal, rheological and mechanical analysis were additional tests undertaken on the optimized formulations. In vivo analysis was the final testing to verify validity of the ODMUS components and utilized a pig model for the investigation. UPLC blood analysis revealed increase blood levels of INH (CmaxINH= 0.0138ng/mL) and RIF (CmaxRIF= 0.052ng/mL) in relation to conventional dosage forms validating segregated site-specific release and increased bioavailability. Ideally, a segregated means of drug delivery throughout the gastrointestinal tract was achieved such that an enhanced bioavailability, a more controlled release and a simplified medication regimen was produced. This study aimed to achieve said goals through novel technique analysis, innovation and globally approved science to critically assess the success of the ODMUS as a potential means to reduce the complexities of medication regimen therapy.

Le titre de la thèse concernant le succès des nématodes peut sembler extremement vaste. Notre projet était pourtant bien d’avoir une vue d’ensemble de l’ensemble des acteurs, à savoir les nématodes parasites du tube digestif mais également l’hôte et certains aspects de sa réponse, et enfin l’éleveur qui est celui qui décide du mode d’élevage et des traitements antiparasitaires. Nous avons essentiellement travaillé en conditions expérimentales et sur une espèce de ces strongles. En ce qui concerne les traits de vie des nématodes plusieurs grands phénomènes conditionnent leur succès : a) leur capacité assez variable selon les isolats à infester un hôte, b) l’interaction entre résistance aux antiparasitaires et cette capacité à infester, c) enfin leur aptitude à survivre aux stress climatiques au cours de leur phase non-parasitaire. / The success of gastrointestinal nematodes in their sheep hosts is so extensive that they present one of the leading threats to ruminant health and production throughout the globe. This thesis research identified three key factors which influence their success including the gastrointestinal nematode biology, the sheep host protective response and the farmers control decisions. Using Haemonchus contortus as a model species, we demonstrated that the success of GIN biology is aided by their capacity to overcome numerous selective pressures that target both parasitic and free-living stages in their life cycle. This was achieved by amplifying life-history traits following challenge to recoup any costs in survival and reproduction. In turn, high levels of fitness were maintained and they remained stable in the face of numerous selective pressures. Sheep have the capacity to exert almost perfect control over GIN success by blocking their life cycle through via protective responses.

Trata-se de um estudo observacional, retrospectivo, cujo objetivo foi descrever o perfil dos pacientes e características da Terapia Nutricional Enteral (TNE) bem como analisar as complicações dessa terapia e os fatores associados em pacientes adultos hospitalizados. O estudo constituiu-se de uma amostra de 214 pacientes internados, no período de 2008 e 2009, em um hospital universitário do Município de São Paulo. Os dados foram coletados dos prontuários e das fichas de avaliação nutricional, em um formulário elaborado para o estudo. Os resultados permitiram verificar que: 1 a-) em relação ao perfil dos pacientes e terapia nutricional enteral, houve predominância do sexo masculino (55,6%), com média de idade de 64,8 anos; internados em unidades de semi-intensiva e UTI (66,8%). b-) Referente à terapia nutricional enteral, a média de dias de nutrição enteral foi de 13,2 dias, e 43,5% dos pacientes receberam-na em até uma semana. Quanto à via de acesso enteral, predominaram as sondas nasoenterais (96,3%) e o método de administração contínuo da dieta (67,3%). 2-) em relação às complicações da TNE e os eventos observados - dos 214 pacientes da amostra, em 200 deles houve complicações durante o uso da nutrição enteral. Verificou-se a ocorrência de complicações: gastrointestinal (90,5%), metabólica (55,0%), mecânica (41,5%) e pulmonar (13,0%). Os eventos observados mais frequentes da complicação gastrointestinal foram: distensão abdominal (33,4%), constipação (17,5%) e alto volume residual gástrico (14,6%). Na complicação metabólica, o evento observado foi hiperglicemia (55,0%), com valor médio de 174,2 mg/dL. Os eventos observados predominantes da complicação mecânica foram: saída não programada da sonda enteral (70,5%), seguida de obstrução da sonda enteral (19,0%). Na complicação pulmonar, a aspiração pulmonar (13,0%) foi o evento observado. 5-) Quanto ao método de infusão houve associação significativa da infusão contínua com os seguintes eventos observados na complicação gastrointestinal: alto VRG (p=0,000), constipação (p=0,010), distensão abdominal (p=0,037). Na complicação mecânica, houve associação significativa com a infusão intermitente nos seguintes eventos: saída não programada da sonda enteral (p=0,005) e deslocamento da sonda enteral (p=0,040). 6-) Quanto à terapia medicamentosa, houve associação significativa da complicação metabólica (hiperglicemia) e o uso de sedativos/opioides (p=0,000) e drogas vasoativas (p=0,000). Este estudo demonstrou que as complicações coexistentes com a TNE são muito prevalentes nesta população (93,5%). Além disso, verificou-se que existe elevada ocorrência de eventos observados (617), sendo as complicações (400) que apresentaram intersecções significativas com outras variáveis acima descritas. Portanto, investigações das condições clínicas, as terapêuticas e os cuidados no uso da sonda enteral devem ser reiteradamente indicadas, sobretudo para os enfermeiros que são responsáveis pela administração e monitoramento da nutrição enteral. / This observational and retrospective study aimed to describe the profile of patients and the characteristics of the Enteral Nutrition Therapy (ENT), as well as to analyze the complications of this therapy and the associated factors in hospitalized adult patients. The study consisted of a sample of 214 patients, hospitalized between 2008 and 2009 at a university hospital in the city of São Paulo. Data were collected from medical records and of nutritional assessment sheets, using a form developed for the study. Results showed that: 1 a-) in relation to patient profiles and enteral nutrition therapy participants were predominantly male (55.6%), with an average age of 64.8 years, hospitalized in semi-intensive and intensive care units (66.8%); b-) Concerning enteral nutrition therapy, the average days of enteral nutrition was 13.2 days, and 43.5% of the patients received it for up to one week. As for the route of enteral access, nasoenteric feeding tube (96.3%) and continuous feeding administration (67.3%) were the most common. 2 -) regarding the complications of ENT and the observed events of the 214 patients of the sample, 200 had complications during the use of enteral nutrition. There was occurrence of gastrointestinal (90.5%), metabolic (55.0%), mechanical (41.5%) and pulmonary (13.0%) complications. The most frequently observed events among gastrointestinal complication were: abdominal distention (33.4%), constipation (17.5%) and high gastric residual volume (GRV) (14.6%). Among the metabolic complication, hyperglycemia (55.0%) was observed, with average of 174.2 mg/dL. The predominant events resulting from mechanical complication were unexpected withdrawal of enteral feeding tube (70.5%), followed by obstruction of enteral feeding tube (19.0%). As for pulmonary complication, pulmonary aspiration (13.0%) was the observed event. 5-) Concerning the method of infusion, there was significant association of continuous infusion with the following events observed in gastrointestinal complication: high GRV (p=0.000), constipation (p=0.010) and abdominal distension (p=0.037). Among the mechanical complication, there was significant association with intermittent infusion at the following events: unexpected withdrawal of enteral feeding tube (p=0.005) and displacement of enteral feeding tube (p=0.040). 6-) Regarding drug therapy, there was significant association of metabolic complication (hyperglycemia) and use of sedatives/opioids (p=0.000) and vasoactive drugs (p=0.000). This study evidenced that complications concomitant with ENT are very prevalent in this population (93.5%). Moreover, it was found that there is a high occurrence of observed events (617), with complications (400) presenting significant intersections with other variables described above. Therefore, research on the clinical conditions, treatments and care to the use of enteral feeding tubes should be constantly indicated, particularly for nurses who are responsible for the administration and monitoring of enteral nutrition.

INTRODUÇÂO: O termo lesão subepitelial se refere a qualquer protrusão ao lúmen do trato gastrointestinal recoberta por mucosa de aspecto normal. A realização de biópsias endoscópicas apresenta rendimento diagnóstico limitado. A ecoendoscopia é considerada o teste diagnóstico de escolha para avaliar diversas características da lesão subepitelial. OBJETIVO: Em relação às lesões subepiteliais gástricas, avaliar dados clínicos, topográficos e ecoendoscópicos como fatores preditores do diagnóstico histopatológico. MÉTODOS: selecionados 55 pacientes adultos atendidos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no período de outubro de 2003 a agosto de 2011 com diagnóstico de lesão subepitelial gástrica à endoscopia digestiva alta, submetidos à ecoendoscopia, com diagnóstico histopatológico, utilizando-se como procedimentos de investigação a ecoendoscopia e a análise histológica/imuno-histoquímica do material obtido por punção ecoguiada e/ou ressecção/biópsia endoscópica/cirúrgica. As seguintes variáveis foram incluídas para análise, relacionando-as ao diagnóstico histopatológico: tamanho; camada ecoendoscópica; aspecto ecográfico; limites; detecção de fluxo ao Doppler e distribuição topográfica gástrica. RESULTADO: Utilizando modelo logístico para variáveis associadas aos diagnósticos (p <,05), observamos que no caso do tumor gastrointestinal estromal (GIST) a probabilidade da lesão localizar-se na cárdia é baixa (4,5%); há maior risco de GIST em pacientes acima de 57 anos (RC=8,9, IC95%7.6,10.2), lesão >= 21mm (RC=7,15, IC95%5.88, 8.43), com fluxo ao Doppler (RC =9, IC95%6.6, 11.4), limite irregular (RC= 7,75, IC95%6, 9.4) e inserida na 4ª. camada parietal (RC=18,8 IC95% 16.7, 20.94); o leiomioma apresentou alta probabilidade (95%) para cárdia com RC = 390 (IC95% 387, 394); o modelo de regressão múltipla indicou as variáveis dimensão, distribuição topográfica gástrica e camada parietal como significativas para GIST, e distribuição topográfica gástrica (cárdia) para leiomioma. CONCLUSÃO: Existe associação entre a localização da lesão subepitelial gástrica na topografia da cárdia e os diagnósticos de Leiomioma e GIST, com comportamento inverso, sendo o leiomioma o diagnóstico mais provável nesta situação.O modelo logístico de regressão múltipla indica que as variáveis significativas para afastar o diagnóstico de GIST são localização na cárdia, fora da 4a. camada parietal ecoendoscópica e diâmetro da lesão de até 20mm / BACKGROUND: The term subepithelial mass (SEM) refers to any protrusion of the lumen of the gastrointestinal tract covered by a normal appearance mucosa. The performance of endoscopic biopsies has limited diagnostic yield. Endoscopic ultrasonography (EUS) is considered the diagnostic test of choice to assess various characteristics of SEM. AIM: to investigate the association between patients\' clinical characteristics, EUS features and gastric topography with the histopathological diagnosis of gastric SEM, using as diagnostic gold standard the histological and immunohistochemical analysis of the material obtained by fine-needle aspiration and/or surgical resection. METHODS: fifty-five patients selected at the Clinics Hospital - University of São Paulo, from October 2003 to August 2011 with a endoscopic diagnosis of gastric SEM, who underwent EUS, with histopathologic confirmed diagnosis. The following variables were included for analysis: size, echoendoscopic layer, sonographic appearance, echogenicity, irregular outer limits, Doppler flow signal and topographic distribution. RESULTS: Applying logistic regression for variables associated with the diagnoses (P < .05), we found that in the case of gastrointestinal stromal tumor (GIST) the probability of the lesion to be located in the cardia is low (4.5%); there is greater risk of GIST in patients older than 57 years (OR = 8.9, 95% CI 7.6,10.2), with lesion >= 21mm (OR = 7.15, 95% CI 5.88, 8:43), positive Doppler (OR = 9, 95% CI 6.6, 11.4), irregular outer limits (OR = 7.75, 95% CI 6, 9.4) and located at 4th. parietal layer (OR = 18.8 95% CI16.7, 20.94); if leiomyoma, the likelihood of this lesion in the cardia was high (greater than 95%) with odds ratio of 390; multiple regression model indicated the size, topographic distribution and gastric parietal layer as significant for GIST, and gastric topographic distribution (cardia) for leiomyoma. CONCLUSION: There is an association between the location of gastric subepithelial lesion in the topography of cardia and diagnostics of leiomyoma and GIST, with opposite behavior, being leiomyoma the most likely diagnosis. Multiple regression analysis indicates cardia location, lesion outside 4th. parietal layer and diameter of up to 20mm as significant variables to exclude GIST diagnosis

A doença do refluxo gastroesofágico (DRGE), apresenta significativa variedade de sintomas e sinais esofagianos ou extra-esofagianas. Entre suas complicações, embora pouco freqüentes, estão o esôfago de Barrett e o adenocarcinoma, sendo, portanto, fundamental reconhecer os fatores implicados na etiologia e agravamento da DRGE. Nos últimos anos, tem sido dada maior importância à influência da atividade física na DRGE. Investigações recentes, embora com resultados conflitantes, em sua maioria, apontam para a exacerbação do refluxo gastroesofágico (RGE) durante o exercício físico. OBJETIVOS: Avaliar a influência da atividade física na DRGE, por meio do teste ergométrico de esforço (TE), em pacientes portadores de doença erosiva, bem como a relevância do tônus do esfíncter inferior do esôfago (EIE) e do índice de massa corporal (IMC), comparando com um grupo de pacientes portadores da forma não erosiva da doença. MÉTODOS: Foram avaliados prospectivamente 29 pacientes portadores de DRGE erosiva e, como grupo controle, 10 pacientes com a doença não erosiva. Todos foram submetidos à avaliação clínica, realização de endoscopia digestiva alta, manometria e pHmetria esofágica. Também realizaram TE precedendo a retirada da sonda de pH-metria. As seguintes variáveis foram avaliadas: eficácia do TE, consumo máximo de oxigênio (VO2max), tempo de refluxo ácido (TRA) e sintomas de RGE durante o TE, influência do tônus do EIE e do IMC na ocorrência de RGE no TE. RESULTADOS: A VO2max demonstrou correlação significativa somente no grupo de pacientes com esofagite erosiva quando esta foi maior ou igual a 70% (p=0,032) durante a realização do TE. As demais variáveis analisadas não demonstraram influência significativa entre a ocorrência de RGE e atividade física (p>0,05). CONCLUSÕES: 1) Atividade física de alta intensidade pode predispor a ocorrência de episódios de refluxo gastroesofágico em portadores de DRGE erosiva; 2) Atividade física de baixa intensidade ou de curta duração não exercem influencia, independentemente do IMC; 3) O tônus do EIE não exerce influência na ocorrência de episódios de RGE durante realização de TE / Gastroesophageal Reflux Disease (GERD) is a worldwide prevalent condition that exhibits a large variety of signs and symptoms of esophageal or extraesophageal nature and can be related to the adenocarcinoma of the esophagus. Therefore, its of crucial importance to recognize the etiologic and aggravating factors of GERD. In the last few years, greater importance has been given to the influence of physical exercises on GERD. Some recent investigations, though showing conflicting results, point to an exacerbation of gastroesophageal reflux during physical exercises. Objectives: To evaluate the influence that physical activities can have on GERD patients presenting with erosive and non erosive disease by means of an ergometric stress test and evaluate the influence of the lower esophageal sphincter tonus and body mass index (BMI) during this situation. METHODS: Twenty-nine GERD patients with erosive disease (group I) and 10 patients with non-erosive disease (group II) were prospectively evaluated. All the subjects were submitted to clinical evaluation, followed by upper digestive endoscopy, manometry and 24h esophageal pH monitoring. A stress test was performed 1 hour before removing the esophageal pH probe. During the ergometric stress test, the following variables were analyzed: test efficacy, maximum oxygen uptake (VO2 max), duration of acid reflux and gastroesophaeal reflux symptoms and the influence of the lower esophageal sphincter tonus and influence of body mass index (BMI) in the occurrence of GER during these physical stress. RESULTS: VO2 max showed significant correlation when it was 70% or higher only in the group of erosive disease, evaluating the patients with or without acid reflux during the stress test (p = 0,032). The other variables considered didnt show significant correlations between gastroesophageal reflux and physical activity (p > 0,05). CONCLUSIONS: 1) Highly intensive physical activity can predispose the occurrence of gastroesophageal reflux episodes in GERD patients with erosive disease. 2) Light or short sessions of physical activity have no influence on reflux, regardless of BMI. 3) The tonus of the lower esophageal sphincter does not influence the occurrence of episodes of GER during exercise testing