Background: Not only does IBD lead to nutritional deficiencies, but also nutrients influence its pathophysiology: exclusive enteral nutrition (EEN) is an effective primary treatment in Crohn's disease; and vitamin D (VitD) is involved in its pathogenesis and course. Aims: We hypothesised that nutrients impact on the course of IBD. We therefore studied the effect of EEN i) on long term clinical course in children; ii) on CD58, a costimulatory molecule at the intestinal epithelial cell (IEC) lines, iii) adults with Crohn's disease. We examined the possible effect of serum vitamin D levels on the course of IBD and also the possible role of ethnicity in our paediatric and adult populations that were treated with EEN but also in our general adult population. Results Chapter II: 56 paediatric patients with Crohn's disesase were followed up for 5 years. 57% of patients achieved remission after 6 weeks of EEN. Achievement of clinical remission within 6 weeks of EEN was significantly associated with a longer time to relapse and to treatment escalation. VitD deficiency was common; and those patients who were deficient were significantly more likely to require corticosteroids and also needed thiopurines sooner. Chapter III: CD58 was expressed in the IEC isolated from IBD patients and healthy controls. EN down-regulated the expression of CD58 on IEC lines. Chapter IV: 22 adult patients with Crohn's disease with a mean age of 30.8 years were given EEN and followed up for a mean time of 1.9 years. 22.7% of patients went into clinical remission and 77.3% experienced a clinical response. By the end of follow up 63.6% (14/22) of patients had clinically relapsed and 36.4% required surgery during their follow up. There was no difference between South Asian and Caucasian patients in the disease outcomes after administration of EEN. Chapter V: Bangladeshis were more often vitamin D deficient than white Caucasian patients; however vitamin D status was not associated with the course of IBD. Bangladeshis developed perianal disease and required thiopurines earlier in their disease course. Bangladeshi patients with UC had more extensive disease. Conclusions: EEN, when successful, improves the long term outcome of Crohn's disease in children, possibly in part, by down-regulating CD58 on the IEC. VitD deficiency may influence the clinical course of IBD; however our results were contradictory between children and adults and significantly limited by the assessment of the vitamin D level at a single time point.

Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide characterized by the accumulation of lipids within the liver, inflammation and the possibility of progressing to cirrhosis and liver failure. More importantly, there are currently no effective treatments for ALD and liver transplantation remains the only therapeutic option for end-stage liver disease. Previous studies have shown that ALD is a result of a combination of endoplasmic reticulum (ER) stress, lipid metabolism dysregulation and inflammation. It has been previously reported that alcohol disrupts gut microbiota homeostasis and causes increased endotoxins that contribute to the pathology of ALD. However, the detailed mechanism(s) underlying ALD and disease progression is poorly understood. We have discovered that sphingosine kinase 2 (SphK2) deficient (SphK2-/-) mice on an alcohol diet exhibit increased steatosis and inflammation compared to wild type mice. Sphingosine 1-phosphate receptor 2 (S1PR2) and SphK2 have been previously shown to play a key role in nutrient metabolism and signaling. However, their roles in alcohol-induced liver injury have not been characterized. The overall objective of this study is to determine the molecular mechanism(s) by which disruption of S1PR2-mediated SphK2 signaling contributes to ALD. The effects of alcohol on mouse primary hepatocytes and cultured RAW264.7 macrophages were examined. The acute on chronic alcohol mouse model from NIAAA that recapitulates the drinking pattern of human ALD patients was used to study the effects of SphK2 deficiency in ALD. In addition, 60-day chronic alcohol mouse model was used to determine whether a more severe form of ALD was present in SphK2-/- mice. The results indicated that SphK2-/- mice on an alcohol diet exhibited an increased amount of hepatic steatosis compared to wild type mice. Genes regulating lipid metabolism were also dysregulated in SphK2-/- mice. SphK2-/- mice also had increased inflammation and liver injury as shown by an upregulation of inflammatory markers and increased levels of liver enzymes. Moreover, SphK2 protein expression levels were downregulated in the human livers of alcoholic cirrhotic and hepatocellular carcinoma (HCC) patients. These findings contribute to a greater understanding of the pathophysiology of ALD and could provide information on the development of novel therapeutics against ALD.

<p>Inflammatoriska tarmsjukdomar (IBD) är en av samhällets nya folksjukdomar och ses som ett stort problem. IBD innefattar flera olika sjukdomar som påverkar mag- tarm kanalen, där Ulcerös kolit och Morbus crohn är de största och vanligast förkommande sjukdomarna, dessa kommer att belysas i denna litteraturstudie. IBD sjukdomarna är kroniska, inflammatoriska och uppträder i skov. Syftet med denna studie var att undersöka hur dessa tarmsjukdomar påverkar vuxna individers livskvalitet både psykiskt och fysiskt. Resultatet visar att sjukdomarna påverkar individernas livskvalitet och kan bidra till ångest, depression och social isolering. Mer individanpassad omvårdnad och information borde ges och är viktiga faktorer för hälso- och sjukvården att tänka på vid mötet med individer med dessa diagnoser. Fortsatt forskning kring området bör innefatta just hur stöd kan ges för att individen skall uppleva tillfredställande livskvalitet.</p> / <p>Inflammatory bowel disease (IBD) is a group of widespread diseases and is to be considered a rising problem. IBD involve several gastrointestinal diseases, where Ulcerative colitis and Crohn disease are the most common. These will be illuminated in this literature review. IBD is chronical, involves inflammation and appears in relapsing episodes. The aim of this literature review was to investigate how these gastrointestinal diseases affect the adult individual, both physical and psychological, regarding quality of life. The result showed how IBD might cause anxiety, depression and social isolation. It is of importance that the healthcare system provides individual nursing care and adequate information to individuals suffering from these conditions. Continuing research regarding what way of support these individuals need in order to improve quality of life, ought to be carried out.</p>

Inflammatoriska tarmsjukdomar (IBD) är en av samhällets nya folksjukdomar och ses som ett stort problem. IBD innefattar flera olika sjukdomar som påverkar mag- tarm kanalen, där Ulcerös kolit och Morbus crohn är de största och vanligast förkommande sjukdomarna, dessa kommer att belysas i denna litteraturstudie. IBD sjukdomarna är kroniska, inflammatoriska och uppträder i skov. Syftet med denna studie var att undersöka hur dessa tarmsjukdomar påverkar vuxna individers livskvalitet både psykiskt och fysiskt. Resultatet visar att sjukdomarna påverkar individernas livskvalitet och kan bidra till ångest, depression och social isolering. Mer individanpassad omvårdnad och information borde ges och är viktiga faktorer för hälso- och sjukvården att tänka på vid mötet med individer med dessa diagnoser. Fortsatt forskning kring området bör innefatta just hur stöd kan ges för att individen skall uppleva tillfredställande livskvalitet. / Inflammatory bowel disease (IBD) is a group of widespread diseases and is to be considered a rising problem. IBD involve several gastrointestinal diseases, where Ulcerative colitis and Crohn disease are the most common. These will be illuminated in this literature review. IBD is chronical, involves inflammation and appears in relapsing episodes. The aim of this literature review was to investigate how these gastrointestinal diseases affect the adult individual, both physical and psychological, regarding quality of life. The result showed how IBD might cause anxiety, depression and social isolation. It is of importance that the healthcare system provides individual nursing care and adequate information to individuals suffering from these conditions. Continuing research regarding what way of support these individuals need in order to improve quality of life, ought to be carried out.

Background and aim: Persistent stress and life events affect the course of ulcerative colitis (UC) by largely unknown mechanisms. Regulation of epithelial permeability to antigens is crucial for the balance between inflammation and immuno-surveillance, and increased intestinal permeability has been shown in patients with ulcerative colitis. Corticotropin releasing hormone (CRH) has been implicated as an important mediator of stress-induced abnormalities in intestinal mucosal function in animal models. Further cholinergic signalling during stress has been reported to increase bowel ion secretion in humans and uptake of HRP in rodents via activation of mast cells. The overall aim of this thesis was to examine the role of CRH-mediated and cholinergic signalling, and their interaction with mast cells and eosinophils, in the regulation of the mucosal barrier function in the normal human colon and in UC. In vivo studies or the use of surgical specimens for such studies have major shortcomings. Therefore a method with endoscopic biopsies in Ussing chambers was established for studies of protein antigen uptake and electrophysiology in human colonic biopsies, and used in subsequent investigations. Materials and methods: In the four studies a total of 91 healthy volunteers, 3 patients with rectal cancer, and 15 UC patients were included. Biopsies from the sigmoid colon were assessed for macromolecular permeability (Horseradish peroxidase (HRP), and 51Cr-EDTA), and electrophysiology during challenge with sodium caprate (C10), CRH or carbachol. Experiments were repeated with CRH receptor antagonists, carbachol receptor antagonists, mast cell stabilizers and nerve conductance blockers in Ussing chambers. The biopsies were examined by electron and light microscopy for endocytosis of HRP, morphological changes and receptor expression. Moreover, the human mast cell line, HMC-1; was used in studying expression of CRH receptors on mast cells. Results: Endoscopic biopsies of human colon were viable in Ussing chambers, and the technique was shown to be a reliable tool for studies of mucosal permeability to HRP. CRH stimulates transcellular uptake of HRP in human colon via CRH receptor subtypes R1 and R2 on subepithelial mast cells. Further, carbachol acts on muscarinic receptors, located on subepithelial eosinophils. Activated muscarinic M2 and M3 receptors on increased numbers of CRHproducing eosinophils in UC, lead to activation of mast cells and increased macromolecular uptake across the colonic mucosa. This signalling cascade is previously unrecognized, and may be involved in the inflammatory process in UC. Conclusions: In conclusion, we have demonstrated a chain of events leading to increased permeability to the protein antigen HRP in biopsies from healthy volunteers and patients with UC. The important steps begin with a cholinergic signal to muscarinic receptors on the CRH containing eosinophils. The next step includes activation of CRH receptors on mast cells leading to degranulation and increased macromolecular uptake across the epithelium. This explanatory model will have implications for understanding of the pathogenesis of UC and future treatment of the disease.

To examine the relationship between liver injury and the appearance of bone marrow derived hepatic cells we performed sex-mismatched bone marrow transplants in mice, with subsequent liver injury. Co-labeling for a marker of donor bone marrow origin and a marker of liver epithelial phenotype allowed us to identify rare marrow-derived hepatocytes at various time points following liver damage. The number of marrow-derived hepatocytes was low, however, and did not allow us to determine if liver-specific injury upregulated this process from baseline. We conclude that while marrow-derived hepatocytes are found, the low level of occurrence in this study makes it impossible to draw a clear temporal relationship between liver damage, recovery and the appearance of donor-derived cells. In addition, we cannot say whether liver-specific damage upregulates this phenomenon.

Some mounted ill. / Bibliography: leaves 203-263 / vii, 263, [52], [29] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1984

INTRODUCTION: Abdominal pain and diarrhea are two of the most common pediatric complaints. They are often associated with a diagnosis of Crohn Disease or Ulcerative Colitis, collectively known as inflammatory bowel disease (IBD). IBD is set of diseases with ill-defined pathogenesis but similar clinical presentation. Clinicians rely on colonoscopic evaluation to distinguish between the two disorders, and the rate of colonoscopies has been increasing over the past several years. With the risks and costs associated with colonoscopic evaluation, our study sought to identify physiologic variables with significant predictive value in order to better determine those most likely to have an abnormal colonoscopy. Those variables could then be incorporated into a predictive model to stratify the risk of a patient having an abnormal colonoscopy and be used as a decision assist tool for physicians. METHODS: We conducted a retrospective cohort study examining 443 patients who underwent a colonoscopy between the years of 2012 and 2016 at Boston Children’s Hospital. Data on demographics, lab work, and stool studies was collected into an online database for three separate data sets. It was analyzed using SAS 9.4 and logistic regression was performed to identify four variables with the most predictive value relating to abnormal colonoscopy. Those variables were incorporated into a predictive model. RESULTS: Several variables were determined to be statistically significant in the prediction of abnormal colonoscopy. The four variables with the most predictive value based on calculated odds ratios were family history of IBD in a first-degree relative, serum albumin, fecal lactoferrin, and platelet count. When ROC curves were generated to validate the model using the four variables for each of the data sets, the area under the ROC curve was used to assess the robustness of the predictive model. The area under the curve (AUC) for the training data set was .81, the first validation set was .79, and the second validation set was .6. DISCUSSION: ROC curves were generated for each of the data sets in order to assess the predictive ability of the model, and the AUCS were calculated. An AUC of 1.0 would indicate a predictive model with perfect predictability. The AUC of the model building set at .81 and the first validation set at .79 are indicative of a predictive model with strong predictive value. The second validation set, used to assess the success of the model on an external data set, had an AUC of .6, which is less robust in its predictive value but is of more predictive utility than a coin flip. CONCLUSION: Logistic regression yielded a parsimonious model consisting of four variables with the strongest predictive value in terms of having an abnormal colonoscopy. The variables are metrics that are routinely collected as part of ambulatory and inpatient clinic visits. When the model was validated using an external data set, it did not perform as well as expected based on the results of the training and first validation set. If the robustness of the model can be improved when validated using an external data set, it could be of great clinical utility to physicians as a decision assist tool and help to limit the number of less clinically indicated colonoscopies being performed in the future.

Made available in DSpace on 2016-08-12T18:48:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-02. Added 1 bitstream(s) on 2016-08-12T18:50:52Z : No. of bitstreams: 1 000863846.pdf: 3298954 bytes, checksum: ce489642320e67c302a1d66485a0e563 (MD5) / Alterações da motilidade gastrintestinal estão envolvidas na etiologia da dispepsia funcional (DF) que apresenta sintomatologia vasta sem qualquer causa orgânica que a justifique, enquadrando-se no grupo de doenças funcionais do trato gastrintestinal. A cintilografia é técnica padrão-ouro para a avaliação da DF, todavia não há uma padronização para sua utilização na avaliação motora gástrica. O objetivo deste trabalho foi avaliar, na cintilografia, o esvaziamento gástrico (EG) total, regional e a distribuição intragástrica de refeição (DIR) empregando duas segmentações e analisar a frequência e amplitude das contrações nas segmentações propostas na dispepsia por meio dos sinais cintilográficos dinâmicos. Foram avaliados 34 indivíduos, 20 normais e 14 dispépticos, selecionados de acordo com Roma III. A refeição-teste e o protocolo de aquisição das imagens estáticas adquiridas imediatamente e em intervalos de 60, 120 e 240 minutos após a ingestão da refeição-teste foram preconizados pelo consenso de 2008; ademais, imagens dinâmicas de 1 Hz foram adquiridas após a imagem imediata e antes daquela referente a 60 minutos da ingestão. Os dados foram analisados em MatLab® com segmentação das imagens em regiões proximal e distal. O EG total em dispépticos foi semelhante àquele de indivíduos normais. Todavia, o EG regional e a DIR mostraram-se alterados na dispepsia, independente da segmentação, sinalizando que o EG não deve ser avaliado unicamente por meio de quantificações de retenção da refeição-teste, devendo-se também considerar parâmetros clássicos de avaliação e a análise visual das imagens. A aquisição dinâmica associada às estáticas mostrou-se como uma ferramenta de avaliação do EG regional, permitindo quantificações da DIR e das frequências dominantes (FD) e amplitudes das contrações regionais. Diferenças entre os grupos foram observadas independente da... / Gastrointestinal motility abnormalities are involved in the etiology of functional dyspepsia (FD), which is characterized by several manifestations with no organic disease that explain the symptoms; it fits into the functional gastrointestinal disorders. Scintigraphy is the gold standard technique to FD assessment; however there is no standard application for evaluate gastric motility alterations. The aim of this study was to evaluate, by scintigraphy, gastric total emptying (GE), regional and intragastric distribution of meal (IDM) using two segmentations and to assess frequency and amplitude of contractions in proposed segmentations in dyspepsia by dynamic scintigraphic. Thirty four individuals, 20 normal and 14 dyspeptics were evaluated, selected according to Rome III. The test meal and protocols of static images acquisition obtained immediately and at intervals of 60, 120 and 240 minutes after ingestion of the test meal were recommended by consensus; in addition, dynamic images of 1 Hz were acquired after immediate image and before image referent to 60 minutes of ingestion. Data were analyzed in MatLab® with images segmentation in proximal and distal regions. Total GE in dyspepsia was similar to normal individuals. However, the regional GE and the IMD were altered in dyspepsia, independently of segmentation, indicating GE should be evaluated not only by the test meal retention, but also considering classical parameters and visual image analysis. Dynamic acquisition in associated with statics images represented a tool to measure regional GE, allowing quantification of the IMD and dominant frequencies (DF) and amplitudes of regional gastric contractions. Differences between groups were observed independently of segmentation, encouraging the use of segmentation according to half of gastric area due to minor proximal regional influence. Although DF hasn't differed in both regions between groups, smaller amplitude of contraction ...

Orientador: José Ricardo Arruda Miranda / Banca: Kátia Hiromoto Koga / Banca: Fernando Gomes Romeiro / Banca: Wellington Monteiro Machado / Banca: Eder Rezende Moraes / Resumo: Alterações da motilidade gastrintestinal estão envolvidas na etiologia da dispepsia funcional (DF) que apresenta sintomatologia vasta sem qualquer causa orgânica que a justifique, enquadrando-se no grupo de doenças funcionais do trato gastrintestinal. A cintilografia é técnica padrão-ouro para a avaliação da DF, todavia não há uma padronização para sua utilização na avaliação motora gástrica. O objetivo deste trabalho foi avaliar, na cintilografia, o esvaziamento gástrico (EG) total, regional e a distribuição intragástrica de refeição (DIR) empregando duas segmentações e analisar a frequência e amplitude das contrações nas segmentações propostas na dispepsia por meio dos sinais cintilográficos dinâmicos. Foram avaliados 34 indivíduos, 20 normais e 14 dispépticos, selecionados de acordo com Roma III. A refeição-teste e o protocolo de aquisição das imagens estáticas adquiridas imediatamente e em intervalos de 60, 120 e 240 minutos após a ingestão da refeição-teste foram preconizados pelo consenso de 2008; ademais, imagens dinâmicas de 1 Hz foram adquiridas após a imagem imediata e antes daquela referente a 60 minutos da ingestão. Os dados foram analisados em MatLab® com segmentação das imagens em regiões proximal e distal. O EG total em dispépticos foi semelhante àquele de indivíduos normais. Todavia, o EG regional e a DIR mostraram-se alterados na dispepsia, independente da segmentação, sinalizando que o EG não deve ser avaliado unicamente por meio de quantificações de retenção da refeição-teste, devendo-se também considerar parâmetros clássicos de avaliação e a análise visual das imagens. A aquisição dinâmica associada às estáticas mostrou-se como uma ferramenta de avaliação do EG regional, permitindo quantificações da DIR e das frequências dominantes (FD) e amplitudes das contrações regionais. Diferenças entre os grupos foram observadas independente da... / Abstract: Gastrointestinal motility abnormalities are involved in the etiology of functional dyspepsia (FD), which is characterized by several manifestations with no organic disease that explain the symptoms; it fits into the functional gastrointestinal disorders. Scintigraphy is the gold standard technique to FD assessment; however there is no standard application for evaluate gastric motility alterations. The aim of this study was to evaluate, by scintigraphy, gastric total emptying (GE), regional and intragastric distribution of meal (IDM) using two segmentations and to assess frequency and amplitude of contractions in proposed segmentations in dyspepsia by dynamic scintigraphic. Thirty four individuals, 20 normal and 14 dyspeptics were evaluated, selected according to Rome III. The test meal and protocols of static images acquisition obtained immediately and at intervals of 60, 120 and 240 minutes after ingestion of the test meal were recommended by consensus; in addition, dynamic images of 1 Hz were acquired after immediate image and before image referent to 60 minutes of ingestion. Data were analyzed in MatLab® with images segmentation in proximal and distal regions. Total GE in dyspepsia was similar to normal individuals. However, the regional GE and the IMD were altered in dyspepsia, independently of segmentation, indicating GE should be evaluated not only by the test meal retention, but also considering classical parameters and visual image analysis. Dynamic acquisition in associated with statics images represented a tool to measure regional GE, allowing quantification of the IMD and dominant frequencies (DF) and amplitudes of regional gastric contractions. Differences between groups were observed independently of segmentation, encouraging the use of segmentation according to half of gastric area due to minor proximal regional influence. Although DF hasn't differed in both regions between groups, smaller amplitude of contraction ... / Doutor