Visceral hypersensitivity is the heightened response to sensory stimuli. Visceral sensations are transmitted through primary afferent neurons in the dorsal root ganglion (DRG) and the sensitization of the neural pathway leads to modification in spinal ascending and descending neurons. The aim of this investigation is to determine the effects of brain-derived neurotrophic factor (BDNF) and its signaling pathway on sensory neuronal activation during colitis. In order to evaluate this, levels of calcitonin-gene related peptide (CGRP), a neuropeptide marker for nociceptive transmission, and phosphorylated cAMP-response element binding protein (pCREB), a molecular switch in neuronal plasticity, were studied in response to BDNF in vivo and in vitro. Colitis caused an increase in the levels of CGRP and pCREB in thoracolumbar DRG, which was attenuated by BDNF neutralizing antibody and PLC inhibitor, U73122, but not PI3K inhibitor, LY294002. BDNF-induced CGRP expression and CREB activation in DRG culture was also blocked by PLC inhibitor, U73122, but not PI3K inhibitor, LY294002, or MEK kinase inhibitor, PD98059. These results suggest a unique signaling pathway, i.e. the PLC-γ pathway, is mediating BDNF action on sensory neuronal activation during colitis.

<p>Abstract Redacted.</p> / Master of Science (MSc)

Inflammatory bowel disease (IBD) is a group of diseases in the gastrointestinal field that is becoming more commonly diagnosed among patients. IBD is usually characterized as a group of chronic diseases affecting the digestive tract that are caused by a multitude of factors including genetic, environmental, mucosal, and immune contributors. One of the subgroups of IBD is very early onset IBD (VEO-IBD), which is diagnosed in children under the age of 6. VEO-IBD is a rare yet unique case of IBD, which reports poor response to conventional adult-onset IBD treatments. Nutrition is an alternative treatment that can decrease inflammation and allow IBD patients to achieve remission. This proposed study explores whether formula-based diets, which have been strongly correlated with reduced IBD inflammation and symptoms, will impact VEO-IBD patients. A mouse model will be set up with one control group of healthy mice and two variable groups of VEO-IBD characteristic mice, with 60 mice in each group. The mice will be fed three formula-based dietary regiments including camel’s milk, Pediasure, and liquid vitamin D3 twice daily for 90 days. All three of these dietary treatments have been proven to decrease inflammation in adult-onset IBD patients. The inflammation and severity of symptoms will be monitored every two days through Western blotting protein levels of IL10 (a genetic marker for VEO-IBD) and physiological tests. If nutrition has a positive effect on the VEO-IBD induced mice, then a decrease in inflammation and VEO-IBD symptoms should be observed. This study is vital to future treatment plans by determining the influence of formula-based diets in alleviating symptoms of VEO-IBD patients.

The aim of the present study was to assess whether the changes in the epithelial glycoproteins seen in the mucosa adjacent to tumors are specific premalignant markers or secondary reactive phenomena. A secondary objective was to assess whether ulcerative colitis and Crohn's Disease could be distinguished from one another histochemically. The carbohydrate prosthetic groups from colonic epithelial glycoproteins were characterized histologically and histochemically from 17 cases of ulcerative colitis, 21 cases of Crohn's Disease and 19 cases of diverticular disease. Two histochemical parameters - the relative proportion of sulpho- and sialomucin and the side-chain substitution pattern of O-acetylated sialic acid - were assessed using a battery of seven histochemical techniques. Serial sections from each specimen were also evaluated morphologically, using hematoxylin and eosin. In addition, the patterns of O-acetylated side-chain sialic acid from the three inflammatory bowel diseases were compared to data previously acquired from the mucosa adjacent to colonic tumors. Results indicate that neither focal changes nor the predominance of sialomucins are specific to the mucosa adjacent to tumors. As well, changes in one histochemical parameter were independent of changes in the other parameter. No histochemical class of epithelial glycoproteins was specific to any of the inflammatory bowel diseases and, therefore, it was not possible to distinguish between ulcerative colitis and Crohn's Disease on the basis of the histochemical techniques used in the present study. It was also noted that the histochemical changes in ulcerative colitis, Crohn's Disease and diverticular specimens were not related to the degree of inflammation. Finally, as a group, Crohn's Disease specimens showed a loss of sulphomucin-sialomucin gradient along the length of the crypts. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Stomal varices are a rare phenomenon that can infrequently develop in patients with enterostomies and portal hypertension. Acute gastrointestinal bleeding from stomal varices can be life threatening and is often a diagnostic challenge. We present a case of severe gastrointestinal hemorrhage from stomal varices requiring emergent intervention with transjugular intrahepatic portosystemic shunt (TIPS) and plug embolization. A 61 year old male patient with a history of colorectal adenocarcinoma status post chemotherapy, radiation, along with low anterior colon resection with ostomy creation presented with a one day history of sudden onset of bright red blood from his colostomy site. He had a known history of decompensated cirrhosis related to hepatitis C and alcohol abuse. On arrival, the patient was tachycardic with borderline low blood pressure with evidence of bright red bleeding from his ostomy site. After initial resuscitation, a colonoscopy through the stoma revealed active bleeding from what appeared to be submucosal colonic varices. The patient continued to experience large volumes of blood loss and became more hemodynamically unstable. Cross sectional imaging showed colonic varices being fed by a branch of the inferior mesenteric vein. The patient underwent TIPS followed by Amplatzer plug embolization of the branch of the interior mesenteric vein that was feeding the colonic stomal varices. The patient’s bleeding was stopped by the combination of these therapeutic modalities and he recovered without complication. The current standard of care for treatment of such varices is with either (1) local therapy with ligation or sclerotherapy, (2) surgical interventions such as stomal manipulation or vessel shunting, either transhepatic or portosystemic to reduce portal pressures, or (3) liver transplantation. Our patient required an unusual combination of TIPS and Amplatzer plug embolization to control his massive hemorrhage. This combination of therapies has been shown effective for the management of select cases of esophageal or gastric variceal bleeding; however, our case demonstrates that the application of the TIPS plus Amplatzer plug embolization can be applied more broadly to the rare scenario of colonic stomal varices.

The triple antibiotic formulation, known as anti-MAP therapy, exhibits unique synergistic antimicrobial activity and should be effective for treatment of Crohn's disease (CD) associated with Mycobacterium avium subspecies paratuberculosis (MAP). The absence of MAP detection in some CD cases may be linked to poor diagnostics or lack of association with the disease. To understand the therapeutic response of some CD patients to anti-MAP therapy in absence of MAP detection, the immunomodulatory potency of anti-MAP therapy and its major ingredients, clarithromycin (CLA) and rifabutin (RIF), in THP-1, Caco-2, and Jurkat T-cells were investigated. Anti-MAP formulation at 2.0 µg/mL decreased MAP viability in macrophages by 18-fold over 72 h. Additionally, M1/M2 macrophage polarization ratio was reduced by 6.7-fold, and expression and protein levels of TNF-a and IL-6 were reduced by 2.9-fold, whereas IL-10 increased by 5.0-fold in these cells. Mechanistically, the effect of anti-MAP formulation on NF-kB activation was dose-dependent and decreased to 13.4% at 2.0 µg/mL. Anti-MAP therapy also reversed the pro-inflammatory response in lipopolysaccharide (LPS)-induced macrophages, which shows that the anti-inflammatory effect of the treatment is not just due to a decrease in MAP viability. Furthermore, this study shows that anti-MAP therapy exhibits anti-cytotoxic effects in Caco-2 monolayers infected with MAP or treated with dextran sodium sulfate (DSS). Anti-MAP therapy decreased T-cell proliferation by up to 4.8-fold following treatment with phytohemagglutinin (PHA) or MAP purified protein derivative (PPD). Overall, the data demonstrate that anti-MAP therapy plays a significant role in modulating and eliciting a protective immune response in macrophages, endothelial cells, and T lymphocytes, even in absence of infection. This may explain the therapeutic response of some CD patients to treatment, even in absence of MAP detection, infection, or total eradication. The study supports anti-MAP therapy as an alternate treatment option for CD, especially in absence of reliable MAP diagnostics.

Upper gastrointestinal symptoms can be caused by many different diseases and can present themselves in many different forms and range in intensity depending on the person. In previous research, upper gastrointestinal symptoms have been correlated with stress, smoking, alcohol intake, and nonsteroidal anti-inflammatory drugs (NSAIDs), among others. The purpose of this study will be focusing on finding any association between these risk factors mention and symptoms of upper gastrointestinal disease among college students. The study will utilize an Izumo scale questionnaire for the assessment of abdominal symptoms and Quality of Life (QOL). The questionnaire was built using Survey Monkey and distributed via email to students at the University of Central Florida (UCF). The main hypothesis was that the more the student’s advancement in their college career, stress load, alcohol consumption, smoking, poor diet and a high consumption of some over the counter medication (specifically Non-Steroidal Anti Inflammatory Drugs), the more prone the students will be to present symptoms of upper gastrointestinal disease. The results were analyzed using Statistical Package for the Social Science (SPSS), and Analysis of Variance (ANOVA) were used to find any associations. The One-Way ANOVA tests showed an association between gender, ethnicity, student status, major, cigarette smoking habits, alcohol consumption, binge drinking, diet, stress, sleeping, and overall health. The results of this study present clear evidence that among college students, their demographics as well as lifestyle and school choices have significant associations to the amount of gastrointestinal symptoms they present with.

<p>Parasite infections around the world are a huge economic burden and decrease the quality of life for many people. Probiotic bacteria are being investigated as a possible treatment for many enteric issues due to their beneficial effects by altering the immune system. Goblet cells are the main source of mucins in the gut, and play an important role in host defense. Alterations in goblet cells and mucin have been implicated in a number of gastrointestinal (GI) diseases and infections. The aim of this study is to develop a probiotic based strategy to modulate goblet cell function in relation to host defense in enteric infection. Utilizing a murine model of parasite infection, <em>Trichuris muris</em>,<em> </em>we examined the effect of daily administration with probiotic <em>Lactobacillus reuteri</em> in different strains of mice and investigation of goblet cell alterations, immune and inflammatory responses in gut, and host defense mechanisms.</p> <p>Treatment with<strong> </strong>live <em>L. reuteri</em> significantly enhanced worm expulsion in resistant C57BL/6 mice and this was associated with significant increase in goblet cells numbers and an increase in IL-10. This lead to investigation of the probiotic effects in IL-10 knock out (KO) and Muc2 KO mice during the infection. There was no difference of worm burden or goblet cell amounts in infected IL-10 KO mice infected treated with probiotic or medium. In infected Muc2 KO mice treated with <em>L. reuteri</em>, there was an earlier increase of goblet cells, and a corresponding decrease in worm numbers. Finally, assessment of this probiotic in susceptible ARK mice revealed no alterations in worm burden, but the treatment prevented the increase in IFN-γ and IL-1β and significantly increased goblet cell numbers.</p> <p>These data demonstrate that altering the flora with probiotic <em>L. reuteri</em> treatment can modulate intestinal goblet cell biology and immune responses in gut, and promote worm expulsion, possibly through an IL-10 mediated mechanism. The increases in goblet cell numbers may also play a role in the early expulsion of the parasite. In addition to enhancing our understanding on the beneficial effect of probiotics in host defense in enteric infection, this research provides new information on gut function in the context of goblet cells and mucins.</p> / Master of Science (MSc)

<p>Colorectal cancer leads to more than 600,000 deaths worldwide per year. An abundance of research has shown that several non-steroidal anti-inflammatory drugs (NSAIDs) can exert chemotherapeutic and chemo-preventative effects in colorectal cancer patients. It is important to note, that use of many different NSAIDs carries a significant risk for cardiovascular and gastrointestinal (GI) complications. A recently developed group of NSAIDs, which release hydrogen sulfide (H₂S), has been shown to have greatly reduced these side effects as compared to conventional NSAIDs. This is likely attributable to the ability of H₂S to increase the resistance of the GI mucosa to injury, as well as to accelerate repair of injury when it occurs. Moreover, H₂S has been shown to be a vasodilator, and therefore may offset some of the hypertensive effects of NSAIDs.</p> <p>We assessed the chemotherapeutic actions of two of these newly developed NSAIDs. ATB-346 is an H₂S-releasing derivative of naproxen and ATB-352 is an H₂S-releasing derivative of ketoprofen. These drugs were tested in the azoxymethane mouse model and in the APC^Min/+mouse model of Colorectal cancer.</p> <p>In the azoxymethane model of colorectal cancer ATB-346 caused a significant reduction in number aberrant crypt foci (ACF), which are pre-neoplastic lesions used as markers of colorectal cancer. The reduction was superior to naproxen at all doses tested. ATB-352 also caused a significant reduction in the number of ACF, however the reduction was not superior to that produced by ketoprofen. In APC^Min/+mice treated with ATB-346 for 14 days (14.5 mg/kg) we observed a complete inhibition of the formation of colonic polyps/tumours and a 97.5% reduction in total polyp score. Shorter treatment with ATB-346 also produced similar reduction in total polyp score. We found that ATB-346-treated mice had lower levels of b-catenin and cmyc without significant changes in APC or p53 levels. <strong></strong></p> <p>These results demonstrate ATB-346 can exert superior chemo-preventative effects in mice models of colon cancer while leading to no gastric or intestinal damage.</p> / Master of Science (MSc)

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2005. / Härtill 4 uppsatser.