In title, [beta] is represented by the Greek letter. Copies of author's previously published articles inserted. Errata pages pasted onto back end-paper. Bibliography: leaves 104-137. Studies milk TGF-[beta] and its receptors in the post-natal gut using a rat model to investigate a link between milk TGF-[beta] and the development of the infant gut and gut mucosal immune system. Finds maternal milk may be a major source of TGF-[beta] to the immature gut and may react with receptors on the cells of the mucosal immune system along the gastro-intestinal tract, modulating infant mucosal immune responses in the transition to the post-natal enteral feeding.

Orientador: Stelio Pacca Loureiro Luna / Coorientador: Francisco José Teixeira Neto / Banca: Eduardo Raposo Monteiro / Banca: Juliana Tabarelli Brondani / Resumo:As substâncias mais potentes utilizadas para o alívio da dor conhecidas são os opioides. No entanto, estes fármacos não são amplamente utilizados em equinos, devido ao substancial estímulo simpático, excitação do sistema nervoso central e redução da motilidade do trato gastrointestinal observados quando administrados principalmente pela via intravenosa (IV). Objetivou-se avaliar os efeitos da metadona na antinocicepção, na atividade locomotora espontânea e na motilidade gastrointestinal de equinos tratados com metadona IV. Foram utilizados seis equinos adultos em um delineamento em blocos aleatorizados. Cada animal foi submetido a três tratamentos: salina (controle), metadona (0,2 mg/kg - MET0,2) e metadona (0,5 mg/kg - MET0,5) pela via IV, com intervalo mínimo de 1 semana entre cada tratamento. Foi avaliado o efeito antinociceptivo por meio da latência para o reflexo de retirada do membro (LRRM) com uma lâmpada de projeção de calor e voltagem para o reflexo de retirada do membro (VRRM) após estimulo elétrica (fase 1); atividade locomotora espontânea (ALE) em baias comportamentais por meio da interrupção de feixes de raios infravermelho (fase 2) e motilidade intestinal por meio de escores de auscultação (fase 3).As variáveis paramétricas foram analisadas pela ANOVA seguida pelos testes de Dunnett ou Tukey. Para a ALE e auscultação intestinal foi ajustado um modelo linear generalizado para medidas repetidas considerando o erro aleatório assumindo distribuição de Poisson e função de ligação log. As diferenças foram consideradas significantes quando p< 0.05. Para o estímulo nociceptivo elétrico não foram realizados os testes com a dose 0,5 mg/kg IV de metadona. No teste nociceptivo térmico, não houve aumento no tempo de LRRM no grupo MET0,2, no entanto, após a administração de 0,5 mg/kg... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract:Opioids are the most potent substances used for pain relief. However, these drugs are not widely used in horses, due to substantial sympathetic stimulation, excitement of the central nervous system and decreased of the gastrointestinal motility observed when opioids are administered intravenously. The effects of methadone on antinociception, spontaneous locomotor activity and gastrointestinal motility were investigates. Six adult horses were used in a randomized crossover design. Each animal was subjected to three treatments: saline (control), methadone (0.2 mg / kg - MET0.2) and methadone (0.5 mg / kg - MET0.5) intravenously (IV), within 1 week between each treatment. The antinociceptive effect was evaluated by the hoof- withdrawal reflex latency (HWRL) after painful stimulation with a heat lamp and voltage for the withdrawal reflex of the limb (VRRM) after electrical stimulation (phase 1). Spontaneous locomotor activity (SLA ) was investigated in a behavior box by use of infrared photoelectric sensors (phase 2) and gastrointestinal motility by abdominal auscultation (phase 3). Parametric variables were analyzed by ANOVA followed by Dunnett or Tukey test. For SLA and abdominal auscultation was fitted the generalized linear models with Poisson error and log link function for repeated data. Differences were considered significant when P <0.05.No electrical noxious stimulation test was performed with the dose of 0.5 mg/kg methadone IV. The HWRL did not increase in animals treated with MET0,2. However, after administration of 0.5 mg/kg of methadone IV, HWRL increased significantly at 15 and 30 minutes compared to baseline and control groups and MET0,2, rising from 3,21 seconds (average) to 8.61 and 9.11 seconds respectively (P <0.05). VRRM increased significantly from baseline at all... (Complete abstract click electronic access below) / Mestre

Irritable bowel syndrome (IBS), majorly characterized by irregular bowel movements and abdominal pain, is one of the most prevalent functional gastrointestinal disorders (FGIDs) in the world. Disturbance of gut microbiota, closely linking with gut dysfunction, has been regarded as one of important pathogenetic factors for IBS. However, gut microbiota-driven mechanism underlying IBS remains unclear, which leads to inefficient and non-specific effects of current microbiota-oriented therapy. In this thesis, function-based microbiota investigation with combination of metagenomic and metabolomic analyses was separately performed in IBS cohort and model to precisely link pathogenic species with disordered GI motor function. A series of microbiota manipulation studies in rodents were conducted to explore bacteria-driven molecular mechanism. Firstly, a pilot study with 'omics' analyses revealed fecal microbial structure significantly varied in IBS patients with disorder GI motility relative to healthy controls (HC). Such changed IBS enterotype was functionally characterized by disturbed metabolism of bile acids (BAs) that are previously proved to regulate GI motor function. It indicates microbiota-driven GI dysmotility relevant to disturbance of BA metabolism in IBS. Secondly, a systematic review with meta-analysis was performed to comprehensively understand existing findings related to BA metabolism and its linkage with IBS. Results showed that abnormal BA excretion, previously reported in at least one IBS subtype, is associated with dysregulation of BA synthesis, marked with abnormalities of circulating indices 7α-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19). However, what's the role of gut microbiota in abnormal BA excretion is undetermined. Thirdly, to explore possible role of gut microbiota in abnormal BA excretion in IBS, BA metabolites and BA-related microbiome were simultaneously analyzed in stools of recruited subjects. Results found that total BA and microbiota-derived BAs were remarkably elevated in a quarter of IBS-D patients (BA+IBS-D) who exhibited more frequent defecation, higher level of serum C4 but lower level of serum FGF19 than those with normal BA excretion (BA-IBS-D). In line with metabolic results, abundances of BA-metabolizing bacteria, particularly Clostridium scindens (C. scindens) simultaneously expressed hdhA and bais that are responsible for BA 7α oxidation and dehydroxylation, were highly enriched in fecal metagenomes of such particular IBS-D population. These findings suggest the increased BA-metabolizing microbiome is associated with the dysregulated host BA synthesis in the subgroup of BA+IBS-D patients. Fourthly, by analyzing metabolites and bacteria related to BA metabolism, a neonatal maternal separation (NMS)-induced IBS-D rat model characterized by accelerated GI motility and excessive BA excretion were found to largely mimic gut microbial BA metabolism in BA+IBS-D patients. Specifically, intraluminal total and secondary BAs were significantly elevated in the large intestinal lumens (cecum, proximal colon and feces) of NMS rats, together with increased abundances of hdhA- and bais-expressing Clostridium species, including C. scindens. Moreover, quantitative polymerase chain reaction (PCR) analysis showed upregulated mRNA expression of cholesterol 7 α-hydroxylase (CYP7A1) whereas downregulated mRNA expression of small heterodimer partner (SHP) in the liver of NMS rats, indicating enhanced hepatic BA synthetic level. These observations based on such IBS-D model suggest the association of excessive BA-metabolizing microbiome and increased hepatic BA synthesis. Fifthly, to further clarify whether excessive BA-metabolizing bacteria contribute to enhanced hepatic BA synthesis and to explore the underlying molecular mechanism, we performed bacterial intervention in pseudo germ-free (GF) or/and specific pathogen free (SPF) mice by transplantation of human fecal microbiota and the signal strain C. scindens. Compared with GF mouse recipients of HC and BA-IBS-D fecal microbiota, BA+IBS-D fecal microbial recipients displayed shorter GI transit and increased subsistence of C. scindens in the cecal contents. In line with higher level of serum C4, taurine-conjugated BA contents and mRNA expressions of BA synthetase CYP7A1 and sterol 12α-hydroxylase (CYP8B1) were significantly elevated in the liver of BA+IBS-D recipients. These findings showed bioactive effects of BA+IBS-D fecal microbiota with enrichment of C. scindens on hepatic BA synthesis. Next, to further confirm the effects of the species C. scindens on host BA synthesis, we individually colonized C. scindens strains (ATCC 37504) to pseudo GF and SPF mice. Results showed both mice models with single strain colonization exhibited accelerated GI transit and higher contents of hepatic total and taurine-conjugated BAs compared with individual vehicles treated with PBS. Combining metabolic changes, the upregulated expressions of hepatic CYP7A1 mRNA in colonized mice indicate that C. scindens substantially promote hepatic BA synthesis in colonized mice. Furthermore, contents of taurine-conjugated BAs, served as natural antagonists of farnesoid X receptor (FXR) that negatively control of new BA synthesis, were elevated in ileal lumens of colonized mice. Expressions of FXR-targeted genes SHP and fibroblast growth factor 15 (FGF15) were consistently reduced in the liver and ileum tissues of colonized mice, respectively. Results suggest that suppression of FXR-mediated feedback signaling is involved in Clostridium-driven hepatic BA oversynthesis, which deserve the further investigation. Collectively, the works of this thesis integrating clinical and animal studies indicate that BA-metabolizing bacteria, particularly C. scindens, enhance hepatic BA synthesis and consequently leads to BA overexcretion. It provides novel bacteria-driven mechanism for enhanced GI motility, and supply a direction in precise microbiota-related pathogenesis and medication for IBS-D population in future.

Background: Growing numbers of patients with cancer are surviving following treatment with pelvic radiotherapy. Eighty per cent will experience acute gastrointestinal (GI) toxicity during treatment and 50% will subsequently have a change in their bowel habit which will affect their quality of life. The main project in this thesis aims to determine whether delivery of a gastrointestinal bundle of care will decrease GI acute toxicity and late effects of pelvic chemoradiotherapy. Additional work in the thesis evaluated the newer technique of Volumetric Modulated Arc Therapy (VMAT) which delivers decreased dose to the organs at risk on planning scans. We aimed to determine outcomes of this technique in terms of patient-reported acute toxicity and late effects. There is no internationally accepted patient reported outcome measure to capture this toxicity data and this issue was addressed using Rasch analysis in a third project. Methods: A randomised controlled trial was performed. Patients who were scheduled to undergo potentially curative chemoradiotherapy for cervix and bladder cancers were recruited and randomised. The treatment group received dietetic input and if they developed lower GI symptoms they underwent investigations and treatment for bile acid malabsorption, small bowel bacterial overgrowth and lactose intolerance. The control group received standard care. Patients who were to undergo VMAT to treat gynaecological malignancy completed patient-reported outcomes at baseline, end of treatment and one year. The rates of patient-reported toxicity were compared with those of a historical cohort and were correlated with the volume of small bowel which was irradiated. Thirdly the technique of Rasch analysis was used to evaluate the Common Terminology Criteria for Adverse Events derived patient reported outcome to measure pelvic toxicity of gynaecological cancer treatments. Results: It was feasible and acceptable to deliver a GI care bundle to patients undergoing chemotherapy and pelvic radiotherapy. All patients' data were available for analysis for the primary outcome and 29 patients' data were available at the 1 year time point. GI toxicity at 6 weeks was predicted by the trial group, suggesting that the intervention benefited the patients in terms of GI toxicity at 6 weeks. It is not yet clear whether this benefit is maintained at the 1 year time point. The frequencies of acute and late GI toxicity reported by patients undergoing VMAT were similar to that of a historical cohort who received conformal therapy. There was not a strong association between the volume of small bowel which was irradiated and the toxicity which was reported suggesting that other factors are involved in the development of toxicity. Rasch analysis of the pelvic symptom questionnaire demonstrated the main issue to be response dependency. When this was accounted for by grouping items into sub-tests the questionnaire could be made to be unidimensional and showed high reliability in a symptomatic population. Conclusion: GI intervention holds promise as a measure to reduce the acute toxicity and late effects of pelvic radiotherapy. Although newer radiotherapy techniques appear to decrease the dose delivered to the small bowel this does not translate to a reduction in patient-reported toxicity. The measurement of toxicity is complex and patient-reported outcome measures should be developed with techniques such as Rasch analysis to ensure meaningful data is available to guide further developments to reduce GI toxicity secondary to pelvic radiotherapy.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmácia, Florianópolis, 2011 / Made available in DSpace on 2012-10-25T16:31:35Z (GMT). No. of bitstreams: 1 289039.pdf: 1645045 bytes, checksum: 04fc5f82cc2565abe48b6acb5256d1ff (MD5) / O ensaio PAMPA tem demonstrado sua versatilidade desde 1998, sendo utilizado para avaliar a permeabilidade passiva transcellular de fármacos/compostos, e tem ganhado espaço por ser de baixo custo, muito rápido e por auxiliar, particularmente, na elucidação dos mecanismos de transporte, em conjunto com os ensaios que utilizam células Caco-2. Para padronizar este ensaio no Laboratório de Virologia Aplicada da UFSC, dois modelos: o PAMPA TGI, variante Double-Sink e o PAMPA Pele foram selecionados por mimetizar, respectivamente, a absorção de fármacos/compostos através do trato gastrointestinal e da pele,sendo que estas duas vias foram escolhidas pela fácil adesão do paciente aos tratamentos por via oral e tópica. Inicialmente, para demonstrar a funcionalidade dos modelos em estudo, foram selecionados fármacos de alta e baixa permeabilidade, classificados segundo o Sistema de Classificação Biofarmacêutica. Além dos fármacos utilizados para a padronização, alguns cardenolídeos e o composto galato de pentila foram selecionados para testar os modelos padronizados. Para a quantificação das amostras nos compartimentos aceptores e doadores das placas usadas nos experimentos, foram desenvolvidos e validados métodos analíticos por espectrofotometria no UV, segundo critérios preconizados pela ANVISA e ICH. Os resultados obtidos na validação analítica demonstraram que tais métodos foram suficientemente específicos, lineares, precisos e exatos para quantificar as amostras. A partir dos resultados obtidos nos modelos PAMPA TGI, variante Double-Sink e PAMPA Pele, foram calculados os coeficientes de permeabilidade efetiva (Log Pe) para os fármacos/compostos testados, que permearam através das membranas lipídicas usadas e, desta forma, foi possível correlacioná-los com dados da literatura, quando existentes. O galato de pentila apresentou alta permeabilidade nos dois modelos avaliados; já os cardenolídeos apresentaram baixa permeabilidade nos dois modelos, exceto a digitoxigenina, que permeou através da membrana usada no ensaio PAMPA TGI, variante Double-Sink. A integridade das membranas lipídicas usadas nos dois modelos foi avaliada com corantes marcadores de baixa permeabilidade, Azul de Cresil Brilhante (ACB) e Lucifer Yellow (LY), e foi possível demonstrar a integridade e a uniformidade destas membranas, pela baixa passagem do ACB e pela rejeição do LY. / PAMPA assay has demonstrated its versatility since 1998, and it has been used to assess the passive transcellular permeability of drug/compounds, and has gained importance because of its low cost, fast making profile, and also for its particularly help on the elucidation of transport mechanisms together with the assays that make use of caco-2 cells. In order to standardize this assay in the Laboratorio de Virologia Aplicada UFSC, two models: variant Double-Sink PAMPA-GIT and Skin PAMPA were selected by its mimetizing effect on drugs absorption through the gastrointestinal tract and skin, respectively. These two routes were chosen because of easy patient adherence to topical and oral treatment. Initially, to demonstrate the studying models functionality, drugs with high and low permeability were selected, as classified by the Biopharmaceutics Classification System. In addition to the drugs used for standardization, some cardenolide compounds and pentyl gallate were selected to test the standard models. To quantify the samples in compartment acceptors and donors of the plates used in the experiments were developed and analytical methods were validated by UV spectrophotometry, according to the criteria recommended by ICH and ANVISA. The results obtained in the analytical validation showed that these methods were sufficiently specific, linear, precise and accurate to quantify the samples. From the results obtained in PAMPA GIT model, variant Double-Sink PAMPA and skin, the effective permeability coefficients were calculated (log pe) for the drugs / compounds tested that permeated through the lipid membranes used and thus could correlate them with the literature data. The pentyl gallate showed high permeability in the two models evaluated, the cardenolide already had low permeability in the two models, except the digitoxigenin, that permeated through the membrane used in the PAMPA assay TGI, variant Double-Sink. The integrity of the lipid membranes used in both models was assessed with colored markers of low permeability, brilliant cresyl blue (ACB) and Lucifer Yellow (LY), and it was possible to demonstrate the integrity and uniformity of these membranes, the low pass and the ACB rejection of LY.

This research investigated the role of the intestinal microbiota in shaping host food intake and body weight through immunomodulation, the impact of refined and unrefined diets, and though fermentable fibre induced gastrointestinal hormone secretion. Gut-derived lipopolysaccharide activating TLR4 has been proposed to contribute to obesity. To investigate this, TLR4-/- or CD14-/- mice and C57BL/6J controls were fed a high-fat or low-fat diet. Neither TLR4-/- or CD14-/- were protected against high-fat diet-induced obesity. High-fat diet increased hypothalamic expression of SerpinA3N and SOCS3 regardless of genotype; however, inflammatory gene expression was not increased. To investigate the use of chow control diets in obesity-associated microbiota changes, C57BL/6J mice were fed a chow diet, refined high-fat, or low-fat diet. Both high-fat and low-fat refined diets resulted in similar dramatic alterations in the composition of the intestinal microbiota at the phylum, family, and species level compared to chow, while only high-fat diet feeding resulted in obesity and glucose intolerance. The roles of colonic GLP-1 and PYY in mediating fermentable fibre in reducing food intake and body fat were investigated using GLP-1R-/- and PYY-/- mice fed a high-fat diet supplemented with inulin or cellulose. Inulin supplementation reduced body fat and food intake in C57BL/6J control mice while GLP-1R-/- and PYY-/- mice showed an attenuated response to dietary inulin. In summary, this research questions the role of TLR4 and LPS in diet-induced obesity. These results demonstrate the importance of the control diet used in studies of obesity in mice and indicate that many of the obesity-associated changes in the gut microbiota are due to comparing refined high-fat diets with chow diets. These results also provide evidence for an essential role for both GLP-1 and PYY in mediating the food intake and bodyweight-reducing effects of fermentable fibre.

MACEDO, Geraldo Munguba. A hipovolemia por doação de sangue aumenta a complacência gástrica e eleva o limiar de saciedade em humanos sadios. 2010. 67 f. Dissertação (Mestrado em Cirurgia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2010. / Submitted by denise santos (denise.santos@ufc.br) on 2014-02-20T12:06:38Z No. of bitstreams: 1 2010_dis_gmmacedo.pdf: 614774 bytes, checksum: 2c1fa32d0990c863e2e9d39711cb2b01 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2014-02-20T12:07:30Z (GMT) No. of bitstreams: 1 2010_dis_gmmacedo.pdf: 614774 bytes, checksum: 2c1fa32d0990c863e2e9d39711cb2b01 (MD5) / Made available in DSpace on 2014-02-20T12:07:30Z (GMT). No. of bitstreams: 1 2010_dis_gmmacedo.pdf: 614774 bytes, checksum: 2c1fa32d0990c863e2e9d39711cb2b01 (MD5) Previous issue date: 2010 / Introduction: We have shown that blood shedding reduces tonus and increases gastric compliance in animals. Since satiety to a drinking test is affected by gastric tonus and compliance, we investigated the effect of blood donation (BD) and saline infusion in gastric tonus, compliance and sensitivity in healthy volunteers. Method: After approval of local ethics committee, 23 healthy male volunteers were studied. After an overnight fast (8-10h), followed by a light meal, and a 2h interval, one of the following procedures was performed. Tonus and compliance study. A PVC bag (1.6L) attached to a catheter was placed into the proximal stomach. Gastric volume (GV, ml) was continuously measured by an electronic barostat (Synectics®), with the intrabag pressure fixed at 12mmHg. After 30-min basal recording, the subjects (n=18) were randomly submitted to either BD (450 ml) or venous puncture site manipulation only, and GV was recorded for further 30-min. Small IP increments (until mild pain report) were also performed; before the basal period and at the end of the study. In 5 volunteers, saline infusion (1.3L) was performed 15-min after BD. Satiety. Volunteers were studied in two different occasions, 1 to 2 weeks apart. They were submitted to a blood donation or venous puncture only, before a modified satiety drinking test with a caloric meal was performed. Results: BD caused a rapid increase in GV (values above basal levels: 154 ± 62 ml at 5 minutes after shedding start and 152 ± 66 ml at the end of study, p<0.05). Volume x pressure slope increased (53.7 ± 4.2 vs. 45.1 ± 4.2ml.mmHg-1 basal, P=0.01) after BD. Saline infusion brought GV back to basal levels (0±1 ml basal vs -14 ± 6 ml at 30 min). BD increased the maximum volume ingested by the volunteers (790±56,7 vs. 1327±127ml, p<0.05). The time to reach the maximum score was also increased. (52.8±4 vs. 95.8±8min, p<0.05). The time to elicit the first (beginning to feel full) and third (full) sensations was also increased after BD (19.2±1.3 vs. 41.6 ±4.2min e 37.8±3.5 vs. 67.5 ±6.6min, respectively, p<0.05). BD did not change blood pressure and cardiac rate. Conclusions: BD decreases gastric tonus and increases gastric compliance. Saline infusion reverted such phenomena. Furthermore BD increases the time and volume sensitivity threshold in a satiety drinking test. This might explain dyspeptic complains in individuals under acute volemic imbalance. / Objetivos: A hipovolemia aguda reduz o tônus e aumenta a complacência gástrica em animais. A complacência do estômago proximal é o principal determinante da saciedade no teste de saciedade (drinking test). No entanto, não há relatos de eventuais alterações de complacência, tônus, saciedade e de plenitude gástricas frente a uma redução aguda do volume sangüíneo em humanos. Método: Após aprovação pelo Comitê de Ética, e seguido de jejum noturno de 8 horas, estudou-se 23 voluntários sadios. Tônus e complacência: Após obtenção de um acesso venoso, uma sonda-balão (12F, saco de PVC de 1600ml) foi afixada no estômago proximal dos voluntários (n=17). O volume gástrico foi medido continuamente por um sistema computadorizado de barostato (Synectics®), com a pressão intragástrica fixada em 12mmHg. Após um período basal de 30min os voluntários foram submetidos aleatoriamente a sangria (doação padrão de sangue, 450 ml) ou apenas a punção venosa. Foram realizados também pequenos aumentos da pressão intra-balão até o relato de leve desconforto, antes do período basal e ao final do estudo. Em sete voluntários foi realizada infusão de salina 15min após a sangria. Saciedade e plenitude: Avaliou-se seis voluntários sadios (homens, 28,5±3,5 anos) em duas ocasiões (intervalo de 1 a 2 semanas). Após jejum noturno de 8h, os voluntários ingeriram refeição padronizada. Decorridas 2h, foram submetidos à punção venosa seguida (condição experimental) ou não (controle) por doação padrão de sangue. Logo após, avaliou-se a saciedade e a plenitude gástricas pelo drinking test modificado mediante a ingestão de refeição líquida, achocolatada sem lactose, num ritmo fixo de 15 ml/min. A cada 5min da refeição teste, avaliou-se a plenitude utilizando escala de 0 a 5 (0-não sinto nada, 5-não agüento mais) e a saciedade com escala de descritores. Resultados: A sangria causou um aumento no volume gástrico (incremento sobre o período basal: 154 ± 62ml aos 5min e 152 ± 66ml aos 30min, p < 0,05). A inclinação da curva volume vs pressão aumentou após doação de sangue (53,7 ± 4,2 vs 45,1 ± 4,2ml.mmHg-1 basal, p = 0,01). A infusão de salina trouxe os valores de volta ao nível basal (0 ml basal vs -14 ± 6 ml aos 30min, p > 0,05). A doação padrão de sangue aumentou o volume máximo ingerido em relação à condição controle (790±56,7 vs 1327±127ml, p<0,05). O tempo para chegar ao valor 5 (plenitude máxima) foi maior após doação de sangue (52,8±4 vs 95,8±8min, p<0,05). O tempo para a primeira sensação (“começando a encher”) e o tempo para a terceira sensação (“cheio”) foram maiores após a doação de sangue (19,2±1,3 vs 41,6 ±4,2min e 37,8±3,5 vs 67,5 ± 6,6min, respectivamente, p<0,05). A doação de sangue não alterou significativamente a pressão arterial e a freqüência cardíaca. Conclusão: A doação de sangue diminuiu o tônus e aumentou a complacência gástrica. A infusão de salina reverteu esse fenômeno. A redução da volemia aumentou o limiar para a percepção da plenitude gástrica. Isto pode corresponder a um novo fator determinante de sintomas relacionados à plenitude gástrica.

CRISTINO FILHO, Gerardo. Efeito da hipertensão intracraniana sobre a complacência gástrica de ratos anestesiados : cauterização do fenômeno e dos mecanismos neurais. 2004. 148 f. Tese (Doutorado em Cirurgia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2004. / Submitted by denise santos (denise.santos@ufc.br) on 2014-03-17T16:32:41Z No. of bitstreams: 1 2004_tese_gcristinofilho.pdf: 1531055 bytes, checksum: 2e841345892a86682b24f2602fa990f0 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2014-03-17T16:33:22Z (GMT) No. of bitstreams: 1 2004_tese_gcristinofilho.pdf: 1531055 bytes, checksum: 2e841345892a86682b24f2602fa990f0 (MD5) / Made available in DSpace on 2014-03-17T16:33:22Z (GMT). No. of bitstreams: 1 2004_tese_gcristinofilho.pdf: 1531055 bytes, checksum: 2e841345892a86682b24f2602fa990f0 (MD5) Previous issue date: 2004 / In humans, intracranial hypertension (ICH) disturbs cardiovascular function and also modifies gastrointestinal physiology as clinically manifested by nausea and vomiting symptoms. Since gastric compliance drives the gastric emptying of liquid which is inhibited by ICH, it was studied the ICH effect on gastric compliance behavior in anesthetized rats and the neuropathways possibly serving this phenomenon. Anesthetized male Wistar rats (N=65, 280-320g) received a carotid cannula to monitor arterial pressure (AP) and heart rate (HR). Under stereotactic guidance a cannula was positioned into each lateral ventricule: one for cerebrospinal fluid simile infusion and the other to record intracranial pressure (ICP in mmHg). All animals received a catheter balloon that was positioned in the proximal stomach and connected to a U shaped barostat filled with standard ionic solution set 4cm above the animals xyphoid appendix. Gastric volume changes transmitted to this communicant vessel system were sensed and recorded by a plethysmometer for 80min After a basal period of 20min the animals were randomly allocated to either experimental protocols: control or ICH. In controls the animals remained untouched while in ICH the ICP was increased from basal to 10, 20, 40, or 60 mmHg, for 30min. In crescent ICP, the pressure was increased in the same animal, at every 20min, from basal to 20, 40 and then 60 mmHg. Separate groups of animals also underwent neurotomy or respective sham operation: subdiafragmatic vagotomy, splancnotomy plus bilateral ganglionectomy and after the basal period were submitted to 10 mmHg of ICP. Brains from other animals (control ICP 10 and ICP 60 mmHg) were removed for histological studies. Data (mean ± SEM) were compared to respective basal values after ANOVA and Bonferroni’s test. In controls, hemodynamic parameters and GV remained within stable levels. In ICP 10 mmHg, GV decreased (P<0.05) from basal levels (2.70±0.12ml) to 2.30±0.14ml at 30min to remain decreased afterwards, while at ICP 20, 40 and 60mmHg decreased early at 20min of ICH (2.36±0.18 vs 2.03±0.19, 2.69±0.27 vs 2.03±0.25 e 2.83±0.12 vs 1.95±0.11ml, respectively), remaining as such up to the end (P<0.05). In crescent ICP, GV decreased from basal levels (2.94±0.04ml) at ICP 40mmHg to 2.70±0.07ml as well as at ICP 60 mmHg to 2.67±0.06ml (P<0.05). In all groups were observed arterial hypertension and bradycardia, typical findings of Cushing’s reflex. In animals without vagal connection, GV despite beginning from lower basal values (1.82±0.18ml) decreased (P<0.05) at 30min to 1.69±0.18ml. After sympathectomy, GV remained stable (P>0.05) throughout the experiment (2.29±0.21ml vs 2.11±0.23ml). Moderate meningeal edema-coroid plexus- was observed moreover at brains from ICP 60mmHg subset. In conclusion, experimental ICH besides inducing Cushing’s reflex (arterial hypertension and bradycardia) also decreases gastric compliance in anesthetized rats in an ICP dependent manner. Vagotomy had no effect and this phenomenon is likely to be mediated by sympathetic neuropathways. / Em humanos, a hipertensão intracraniana (HIC) além de promover distúrbios hemodinâmicos, também provoca alterações na função gastrintestinal, apresentadas clinicamente com náuseas e vômitos. Como a HIC em ratos acordados inibe o esvaziamento gástrico de líquido e este é influenciado pela complacência gástrica (CG), estudou-se o efeito da HIC sobre a CG e os mecanismos neurais envolvidos no fenômeno. Ratos Wistar (N=65, 280-320g) anestesiados com uretana tiveram a artéria carótida canulada para registro hemodinâmico. Mediante estereotaxia, cânulas-guias foram implantadas bilateralmente nos ventrículos laterais, para registro simultâneo da PIC e compressão do sistema ventricular por infusão de líquido cefalorraquidiano-símile (LCR-símile). Um catéter com um balão na extremidade foi posicionado no estômago proximal e conectado a um sistema de vasos comunicantes com barostato. Variações do volume do balão gástrico (VG) transmitidas ao barostato foram detectadas por um sensor eletrônico de volume e registradas continuamente por 80min num pletismômetro. Após um período basal de 20min, os ratos foram aleatoriamente submetidos às seguintes condições: Controle (PIC espontânea), PIC 10mmHg, PIC 20mmHg, PIC 40mmHg, PIC 60mmHg e PIC Crescente. Após a compressão ventricular, os animais foram monitorados por mais 30min. Para o estudo dos mecanismos neurais, grupos de ratos, previamente submetidos a laparotomia seguida ou não (falsa cirurgia) de vagotomia subdiafragmática ou esplancnicectomia+gangliectomia celíaca bilaterais, foram estudados sob PIC de 10mmHg. Um grupo à parte de animais (n=9) PIC controle, PIC 10mmHg e PIC 60mmHg tiveram seus encéfalos retirados para avaliação histológica. Os dados foram expressos em média±EPM e analisados pela ANOVA seguido pelo teste de Bonferroni. No grupo controle, os parâmetros hemodinâmicos e de VG se mantiveram constantes. No grupo PIC 10mmHg, em relação ao período basal (2.70±0.12ml), o VG diminuiu para 2.30±0.14ml aos 30min de HIC, assim permanecendo por todo o experimento (P<0.05). Já nos grupos PIC 20mmHg, PIC 40mmHg e PIC 60mmHg, o VG diminuiu em relação ao período basal aos 20min de HIC (2.36±0.18 vs 2.03±0.19, 2.69±0.27 vs 2.03±0.25 e 2.83±0.12 vs 1.95±0.11ml, respectivamente), assim permanecendo até o final (P<0.05). No grupo PIC crescente, em relação ao período basal (2.94±0.04ml), o VG diminuiu para 2.70±0.07ml com PIC 40 mmHg e para 2.67±0.06ml com PIC 60mmHg (P<0.05). Em todos os grupos observou-se hipertensão arterial e bradicardia, efeitos típicos do reflexo de Cushing. Nos animais sem conexão vagal, o VG embora partindo de níveis basais menores (1.82±0.18ml) diminuiu (P<0.05) aos 30min para 1.69±0.18ml. Nos animais submetidos a esplacnicectomia, em relação ao período basal (2.29±0.21ml), o VG permaneceu inalterado (P>0.05) durante (2.11±0.23ml) e após a compressão ventricular. Nas lâminas analisadas identificou-se edema parenquimatoso e congestões meníngea, do plexo coróide e parenquimatosa de graus leve a moderado, principalmente nos animais submetidos a PIC de 60 mmHg. A HIC diminui a CG de ratos anestesiados, sendo o fenômeno PIC dependente e possivelmente mediado por via esplâncnica.

MORAIS, Talita Cavalcante. Efeito pró-cinético da Mangiferina, isolada de Mangifera indica L., em camundongos. 2015. 115 f. Tese (Doutorado em Farmacologia) – Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2015. / Submitted by denise santos (denise.santos@ufc.br) on 2015-06-17T11:05:37Z No. of bitstreams: 1 2015_tese_tcmorais.pdf: 1855659 bytes, checksum: 7f3244a6cf2d7fe9de0964bb33c0e092 (MD5) / Approved for entry into archive by denise santos(denise.santos@ufc.br) on 2015-06-17T11:20:21Z (GMT) No. of bitstreams: 1 2015_tese_tcmorais.pdf: 1855659 bytes, checksum: 7f3244a6cf2d7fe9de0964bb33c0e092 (MD5) / Made available in DSpace on 2015-06-17T11:20:21Z (GMT). No. of bitstreams: 1 2015_tese_tcmorais.pdf: 1855659 bytes, checksum: 7f3244a6cf2d7fe9de0964bb33c0e092 (MD5) Previous issue date: 2015 / Mangiferin is a glucosylxanthone encountered in several traditionally used medicinal plants that has been shown to exhibit multiple pharmacological effects that include antioxidant, anti-inflammatory and gastroprotective. Mangiferin used in this study was extracted and isolated from the stem bark of Mangifera indica L. (mango), and its prokinetic effect was investigated using experimental models of gastrointestinal motility in mice. Mangiferin significantly accelerated gastrointestinal transit at oral doses of 30 and 100 mg/kg (89% and 93%, respectively), compared with the vehicle control (63%). Tegaserod (1mg/kg, i.p.), a known prokinetic, stimulated gastrointestinal transit (81%). In the second series of experiments, mice were used to study the effect of mangiferin (30 mg/kg, po) on gastrointestinal transit delay caused by morphine, clonidine, capsaicin, verapamil, ondansetron or atropine. While co-administered mangiferin totally reversed the inhibitory effects of morphine, ondansetron and capsaicin on gastrointestinal transit, the transit delays caused by clonidine and verapamil were only partially reversed. Atropine completely blocked the stimulant effect of mangiferin, suggesting the involvement of muscarinic acetylcholine receptor. Also, mangiferin (30 and 100 mg/kg, po) significantly increase gastric emptying in mice. Mangiferin at doses of 100 mg/kg and 300 mg/kg, and tegaserod at 1 mg/kg significantly enhanced the fecal pellets output by 52%, 40%, and 80%, respectively, when compared to fecal output in vehicle treated mice. Tegaserod group elevated water content (59%) relative to the vehicle-treated control (51%). Postoperative ileus (POI) in mice was characterized by decreased gastrointestinal transit accompanied by an intestinal inflammatory response. POI caused a significant decrease (46,46 ± 4,56%) of gastrointestinal transit when compared to sham control (75,09 ± 1,88%). The oral treatment with mangiferin (30 and 100 mg/kg) accelerated gastrointestinal transit, reduced myeloperoxidase activity, reduced nitrate/nitrite and inflammatory mediators (TNF-α, IL-1β, IL-6, MCP-1) levels in mice compared to respective vehicle control. Treatment with mangiferin reduced the inflammation and protected the ileus from histological damage induced by POI, and reduced the NF-κB and iNOS immunoreactivity in the ileum. This study indicate the prokinetic action of mangiferin and suggests that could be an alternative to available prokinetic drugs for the treatment of gastrointestinal disturbances such as constipation, dyspepsia and postoperative ileus. / A mangiferina é uma glicosilxantona encontrada em algumas plantas medicinais utilizadas tradicionalmente, que tem mostrado múltiplos efeitos farmacológicos, como antioxidante, anti-inflamatório e gastroprotetor. A mangiferina utilizada neste trabalho foi extraída e isolada a partir das cascas do caule de Mangifera indica L. (mangueira), e seu efeito pró-cinético foi investigado utilizando-se modelos experimentais de motilidade gastrintestinal em camundongos. Mangiferina acelerou significativamente o trânsito gastrintestinal nas doses orais de 30 e 100 mg/kg (89% e 93%, respectivamente), comparada ao controle veículo (63%). Tegaserode (1mg/kg, i.p.), um pró-cinético conhecido, estimulou o trânsito gastrintestinal (81%). Em uma segunda série de experimentos, camundongos foram usados para estudar o efeito da mangiferina (30 mg/kg, v.o.) no retardo do trânsito gastrintestinal causado por morfina, clonidina, capsaicina, verapamil, ondansetrona ou atropina. Enquanto a co-administração de mangiferina reverteu totalmente os efeitos inibitórios de morfina, ondansetrona e capsaicina no trânsito gastrintestinal, o retardo no trânsito causado por clonidina e verapamil foram apenas revertidos parcialmente. A atropina bloqueou completamente o efeito estimulante da mangiferina, sugerindo o envolvimento de receptores muscarínicos de acetilcolina. Além disso, a mangiferina (30 e 100 mg/kg, v.o.) aumentou significativamente o esvaziamento gástrico em camundongos. Mangiferina, nas doses de 100 mg/kg e 300 mg/kg, e tegaserode 1 mg/kg aumentaram significativamente a saída de pelotas fecais em 52%, 40% e 80%, respectivamente, quando comparado à produção fecal em camundongos tratados com veículo. O grupo tegaserode elevou o conteúdo de água nas fezes (59%) em relação ao controle veículo (51%). O Íleo Pós-Operatório (IPO) em camundongos foi caracterizado por redução do trânsito gastrintestinal acompanhada por uma resposta inflamatória intestinal. IPO causou uma redução significativa do trânsito gastrintestinal (46,46 ± 4,56%) quando comparado ao grupo sham (75,09 ± 1,88%). O tratamento oral com mangiferina (30 e 100 mg/kg) acelerou o trânsito gastrintestinal, reduziu a atividade da mieloperoxidase, reduziu os níveis de nitrato/nitrito e de mediadores inflamatórios (TNF-α, IL-1β, IL-6, MCP-1) em camundongos, comparado ao controle veículo respectivo. O tratamento com mangiferina reduziu a inflamação e protegeu o íleo do dano histológico induzido por IPO, além de reduzir a imunoreatividade de NF-κB e iNOS no íleo. Este estudo indica o efeito pró-cinético da mangiferina, sugerindo que a droga venha a ser uma alternativa às drogas pró-cinéticas disponíveis para o tratamento de distúrbios gastrintestinais, como constipação, dispepsia e íleo pós-operatório.

PALHETA JÚNIOR, Raimundo Campos. Caracterização das vias neuro-humorais no retarde do esvaziamento gástrico de líquidos advindo da distensão mecânica atrial direta em ratos acordados. 2010. 212 f. Tese (Doutorado em Farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2010. / Submitted by denise santos (denise.santos@ufc.br) on 2012-09-06T12:38:28Z No. of bitstreams: 1 2010_rcpalhetajúnior.pdf: 2107863 bytes, checksum: d4847c9105cbc1422cb7ee501adfbd64 (MD5) / Approved for entry into archive by Eliene Nascimento(elienegvn@hotmail.com) on 2012-09-06T13:43:37Z (GMT) No. of bitstreams: 1 2010_rcpalhetajúnior.pdf: 2107863 bytes, checksum: d4847c9105cbc1422cb7ee501adfbd64 (MD5) / Made available in DSpace on 2012-09-06T13:43:37Z (GMT). No. of bitstreams: 1 2010_rcpalhetajúnior.pdf: 2107863 bytes, checksum: d4847c9105cbc1422cb7ee501adfbd64 (MD5) Previous issue date: 2010 / Right atrium mechanical stretch (AS) increases gastric motility in anesthetized rats. We aimed to study the effect of AS on gastric emptying (GE) in awake rats and the related neuro-humoral pathways ivolved. Male albino rats (N=361, 250-280g) had a silicone balloon inserted in the right atrium. After 24-h, the central venous pressure (CVP), heart rate (HR) and the mean arterial pressure (MAP) were monitored and after the initial 20-min, animals were randomly pre-treated with: saline (S, 0.1 ml/100g, i.v.), Atropine (A, 0.5mg/kg, i.v.), Guanethidine (GT, 10mg/kg, i.p.), hexamethonium (H, 10mg/kg, i.v.), L-NAME (3mg/kg, i.v.), L-Arginine (100mg/kg, i.v.)+L-NAME (3mg/kg, i.v.), Methylene Blue (MB, 3mg/kg, i.v.), Glibenclamide (GB, 1mg/kg, i.p) or Glibenclamide+Diazoxide (3mg/kg, i.v.) [GB+D], Dexamethazone (DEX, 1mg/kg, i.p.), Anantin (ANT, 5g, i.v.) or Atosiban (AT, 40g/kg/h, i.v.). Besides, in a separate group, we realized vagotomy (V), or splanchnotomy + celiac gangliectomy (SC) or afferent cardiac denervation with capsaicin (ACD) 72h before AS. In another set of animals, we realized right appendectomy (AX) one week before AS. Next, AS with saline zero (sham) or 50L was performed during 5min. In this group, rats were gavage fed with a test meal 20-min after AS and euthanized 10-min afterwards to study GE. Moreover we determined plasmatic levels of Ocytocin (OT), Atrial Natriuretic Peptide (ANP) and Corticosterone (CORT), and determined the neuronal activity in the paraventricular (PVN) or supraoptic (SON) hypothalamic regions by measuring expressed double-labeled c-fos-OT. Comparing to Sham, AS decreased GE (p<0.05). Besides, AS increased CVP and HR. AS decreased GE (p <0.05) in S, A, GT, L-Arginine+L-NAME, MB and GB+D groups. However pre-treatment with, H, L-NAME, GB, DEX, ANT or AT, as well as SV, SC, ACD or AX prevented the effect of AS on GE. AS increased OT and CORT plasmatic levels, but did not alter ANP. In spite of AS increasing the number of c-fos expressing neurons in the parvocellular region, we did not observe this finding in the magnocellular regions of PVN or SON. Besides, AS did not alter the number of fos-OT double-labeled neurons. Therefore the decrease of GE of fluids after AS in awake rats depends on an afferent pathway mediated by cardiac low pressure receptors, and both sympathetic and parasympathetic neurons participate in the cascade mediated by OT, ANP and NO through K +-ATP dependent channels. / A distensão mecânica do átrio direito (DA) aumenta a motilidade gástrica em ratos anestesiados (Palheta et al., 2010). Resolvemos avaliar o efeito da DA sobre o esvaziamento gástrico (EG) de líquido em ratos acordados e as eventuais vias neuro-humorais relacionadas ao fenômeno. Utilizamos ratos albinos machos (n=361, 250-280g) que receberam um balão de silicone posicionado no átrio direito. Decorridos 24h, monitoramos a pressão venosa central (PVC), freqüência cardíaca (FC) e a pressão arterial média (PAM) e após os 20-min iniciais os animais foram aleatoriamente pré-tratados com: Salina (S, 0,1 ml/100g, i.v.), Atropina (A, 0,5 mg/kg, i.v.), Guanetidina (GT, 10 mg/kg, i.p.), Hexametônio (H, 10mg/kg, i.v.), L-NAME (3mg/kg, i.v.), L-Arg (100mg/kg, i.v.) + L-NAME (3 mg/kg, i.v.), Azul de metileno (MB, 3 mg/kg, i.v.), Glibenclamida (GB, 1 mg/kg, i.p.) ou Glibenclamida + Diazóxido (3mg/kg, i.v.) [GB + D], Dexametasona (DEX, 1mg/kg, i.p.), Anantin (ANT, 5 g, i.v.) ou Atosibana (AT, 40  g/kg/h, i.v.). Além disto, em grupos separados realizamos 72h antes da DA à vagotomia (V), ou esplancnotomia+ gangliectomia celíaca (SC) ou denervação cardíaca aferente com capsaicina (ACD). Em outro conjunto de animais realizamos aurilectomia direita uma semana antes da DA (AX). Em seguida ao tratamento farmacológico realizamos protocolo de falsa DA (controle) ou DA com 50L do balão intra-atrial durante 5min. Decorridos 20 min. da DA, os ratos foram alimentados por via oral com solução teste e, após 10-min sacrificados para estudo do EG. Além disto, determinamos os níveis plasmáticos de ocitocina (OT), Peptídeo Natriurético Atrial (ANP) e corticosterona (CORT). Para verificação da atividade neuronal avaliamos a expressão da proteína Fos e OT nas regiões hipotalâmicas do núcleo paraventricular (PVN) ou supra-óptico (SON). Comparado ao controle, a DA diminuiu o EG (p <0,05). Além disso, a DA aumentou a PVC e a FC. A DA diminuiu o EG (p<0,05) nos grupos S, A, GT, L-arginina + L-NAME, MB e GB+D. Já o pré-tratamento com H, L-NAME, GB, DEX, ANT ou AT, bem como a SV, SC, ACD ou AX preveniu o efeito do DA sobre o EG. Além disso, a DA aumentou os níveis plasmáticos de OT e CORT, mas não alterou o de ANP. Apesar da DA aumentar o número de neurônios imunorreativos para c-fos nas regiões parvocellular medial e posterior do PVN, não observamos tal achado nas regiões magnocellular do PVN ou do SON, também não houve diferença significativa para o número de neurônios imunorreativos para Fos-OT após DA. Portanto a diminuição do EG de líquidos após a DA em ratos acordados depende de uma via aferente cardíaca mediada por receptores de baixa pressão, sendo que tanto neurônios simpáticos como parassimpáticos participam da cascata mediada pela OT, ANP e NO através de canais para K+-ATP dependentes.