Introduction: Studies show that women living in Sweden treated for coeliac disease have lower subjective health than other women. After showing signs of remission, adults who have coeliac disease and follow a gluten-free diet, are expected to handle the treatment without any further planned follow-up by health care. Aim: The overall aim of this thesis was to study aspects of living with coeliac disease in adults in the years beyond the diagnosis. Methods: Quantitative methods were used in Studies I, II and III. A qualitative content analysis was performed in Study IV. Results: The results show that women with coeliac disease have a lower level of well-being than men with coeliac disease. The women who have coeliac disease reported a high rate of gastrointestinal symptoms, although they followed a gluten-free diet, and they visited health care services more frequently than women who did not have coeliac disease. A low rate of gastrointestinal symptoms, a positive self-image and few comorbidity emerged as factors that positively affected well-being. Worries also seemed to be a companion of women diagnosed with coeliac disease in adulthood, typically evident when socializing with others. Conclusion: This thesis may provide evidence questioning the validity of declaring all women with coeliac disease showing a normalized intestinal mucosa to be in remission, and thus leaving them to self-management. Clinical implications: Health care professionals need to be aware of that the transition to a gluten-free life may vary for individuals. It does not seem enough to follow a gluten-free diet to reach a state of good well-being for all women. A major task for health care providers is therefore to support women with CD in reaching better subjective treatment outcomes. The results may also contribute to that health care system develops routines in order to optimise the care and treatment of these patients.

In der Diagnostik der gastrointestinalen Stromatumoren (GIST) spielt neben der Histologie die Immunhistochemie eine zentrale Rolle. Die vorliegende Arbeit befasst sich mit der Fragestellung, welche Wertigkeit der Mutationsanalyse im diagnostischen Kontext zukommt und wie stabil Immunphänotyp und Mutationsstatus im Verlauf der Erkrankung tatsächlich sind. In drei Fällen rezidivierter GIST war die Histomorphologie, die Immunhistochemie und der Mutationsstatus im Vergleich zum Primärtumor stabil. Bei den untersuchten synchron auftretenden Tumoren von drei Patienten waren in der Mutationsanalyse unterschiedliche Ergebnisse zu erheben. Bei zwei Patienten unterstützte das unterschiedliche Mutationsmuster das Vorliegen synchroner Tumoren, bei einem Patienten ist das Vorliegen eines Primärtumors und einer Metastase statt einem synchronen GIST wahrscheinlich. Die Untersuchung metastasierter GIST wurde an verschiedenen Tumoren von neun Patienten durchgeführt. Acht der neun Fälle zeigten sich bezüglich der Metastasen genotypisch stabil, einer der acht Fälle wies zusätzlich einen Zugewinn einer Punktmutation auf, die als Möglichkeit eines Tumormosaiks oder als neu erworbene zusätzliche Mutation zu werten sein könnte. Zudem wurden 28 Fälle unklarer spindelzelliger Tumoren mit uneinheitlichem immunhistochemischen Profil untersucht. In Zusammenschau mit der Mutationsanalyse war eine eindeutige Bestimmung der Tumorentität möglich. Abschließend zeigt sich die Kombination aus Histomorphologie, immunhistochemischer Untersuchung und Mutationsanalyse als gutes diagnostisches Mittel zur Sicherung der Tumorentität und Entdeckung eventuell neu aufgetretener prognostisch relevanter Mutationen mit therapeutischer Konsequenz.

Introduction: Gastric cancer (GC) is ranked as the second most common fatal malignancy worldwide. Although Helicobacter pylori is recognized as a major predisposing factor for non-cardia GC, infection alone is not sufficient to cause cancer. This thesis aimed to determine the variation in host genetic polymorphisms in subjects from Malaysia and Singapore and to examine the role of H. pylori infection, host genetic factors and dietary factors in the etiology of non-cardia GC in Chinese subjects resident in Malaysia. Methods: Functional dyspepsia (FD) controls from three ethnic groups in Malaysia, Chinese (123), Indian (110) and Malay (84) and Singaporean Chinese (127) plus Malaysian Chinese gastric cancer cases (55)were examined. Polymorphisms in IL-1B-511, IL-1RN, IL-10 cluster, TNFA-308 and TLR5+1174 were determined by PCR-RFLP or PCR; H. pylori status by serology, dietary intake by questionnaire and gastric IL-1b levels by real time PCR. Results: 1) Significant differences existed in the frequency of all polymorphisms, except IL-1B-1473 and TNFA-308, in the three Malaysian ethnic groups and in the IL-1B-511 polymorphism in Malaysian and Singaporean Chinese FD 2) Globally, two distinct patterns of IL-1B-511, IL-1RN, IL-10-1082, IL-10-592 and TNFA-308 exist, Western and East-Asian 3) In Malaysian Malays, the IL-10 ATA haplotype was associated with H. pylori susceptibility 4) In Malaysian Chinese an increased risk of GC was associated with carriage of the IL-1B-1473 G allele {OR=4.4(1.3-15.3)} and the IL-1B-511 C allele {OR=1.8(0.8-4.1)} 5) Increased levels of IL-1b were observed in Singaporean and Malaysian Chinese FD subjects carrying the IL-1-511C and IL-1-1473G alleles 6) Malaysian Chinese not consuming fresh fruit and vegetables had the highest risk of GC {OR=10.2 (3.4-30.6)} 7) The highest risk of GC {OR=37.3(3.3-424.8)} was observed in H. pylori positive Malaysian Chinese who carried both the IL-1B-511C and IL-1B-1473G alleles and did not consume fresh fruit and vegetables. Conclusions: In Malaysian Chinese, H. pylori infection, host genetic and dietary factors all contribute to the risk of GC. However the significant difference observed in the frequency of host genetic polymorphisms within and between ethnic groups suggests that a single group of risk factors cannot be used to determine GC risk across all populations.

Bibliography :leaves 250-302. / xix, 302, [19] leaves, [4] leaves of plates : ill. (chiefly col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Results suggest that IGF-I peptides significantly influence gastrointestinal growth in normal adult and suckling rats and indicate they may have therapeutic implications both in conditions of impaired gut function in the adult gastrointestinal tract and in the treatment of gut disease in the immature intestine. / Thesis (Ph.D.)--University of Adelaide, Dept. of Obstetrics & Gynaecology, 1995?

Bibliography: leaves 227-260. / xiv, 260 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / To identify some of the motor mechanisms involved in emptying of gastric contents, the disturbances to these mechanisms caused by various therapeutic gastric surgical procedures, and possible new techniques to minimize such disturbances. The work was conducted on human subjects and conscious pigs. / Thesis (Ph.D.)--University of Adelaide, Dept. of Surgery, 1996?

Bibliography: leaves 282-354 / 354 leaves : ill ; 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 Physiology, 1986

Bibliography: leaves 133-148 / x, 148 leaves, [3] leaves of plates : ill ; 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, 1984

A review of the literature revealed that diet plays an important role in serious human noninfectious large bowel diseases including cancer and inflammatory bowel diseases. Dietary protein (especially as red and processed meats) has been implicated as a positive risk factor for colorectal cancer while starch which is not digested in the small intestine (resistant starch, RS) appears to be protective. The series of experiments described in this thesis were aimed to determine the effects of dietary proteins and RS on indices of colon health in an animal model, the laboratory rat. Genetic damage is a prerequisite for carcinogenesis and this was assessed by a specific assay (the comet assay) which gives a measure of DNA strand breaks. Loss of mucus barrier function is thought to contribute to inflammatory bowel disease by permitting bacterial translocation and this was measured optically using a microscope micrometer. Other biomarkers were measured as described below. There were four major experiments. 1. Effects of dietary red meat and casein on colonic DNA damage and interaction with resistant starch Previous studies had shown that higher dietary protein (as casein) induced genetic damage in rat colonocytes and that RS (fed as a high amylose maize starch) was protective. This study was aimed at establishing whether a high protein diet fed as cooked red meat had similar effects and whether RS was protective. Rats were fed diets containing either 15 % or 25% casein or 25% barbecued lean red beef, each with or without 48% high amylose maize starch (as a source of RS) for 4 weeks. As expected, high dietary casein caused a 2-fold increase in colonic single-strand DNA breaks compared with a low casein diet and reduced the thickness of the colonic mucus layer by 41%. High levels of cooked meat caused 26% more DNA damage than the high casein diet but reduced mucus thickness to a similar degree as casein. Addition of RS to the diet abolished the increase in DNA damage and the loss of colonic mucus thickness induced by either high protein diet. It is thought that RS promotes large bowel health through the SCFA produced by the large bowel bacteria. One acid in particular (butyrate) has been associated particularly with promotion of normal large bowel function and protection against disease. In keeping with this hypothesis, caecal and faecal short chain fatty acid pools (including those of butyrate) were increased by inclusion of RS in the diet. DNA damage is an early step in the initiation of cancer and these findings agree with the population data which suggest that total dietary protein and red meat promote risk of colorectal cancer. However, inclusion of resistant starch in the diet could significantly reduce that risk. 2. Differential effects of dietary whey, soy and casein on colonic DNA damage and interaction with resistant starch The preceding experiments showed that high levels of animal-derived proteins increased colonocyte genetic damage and loss of the mucus barrier in rats. This second experiment was designed to determine whether diets high in different types of dairy protein (casein or whey) or a plant protein isolate (soy) had similar adverse effects on colonic DNA and mucus barrier function and whether inclusion of RS in the diet was protective. Adult male Sprague Dawley rats were fed a diet containing 15 % or 25 % casein, whey or soy protein, each with or without 48 % high amylose maize starch for 4 weeks. In confirmation of the earlier studies, higher levels of dietary casein increased colonocyte DNA damage significantly. However, whey did not increase genetic damage. Colonic DNA damage was highest for soy when fed at both 15% and 25% protein in the absence of RS. Inclusion of RS in the diet attenuated colonocyte DNA damage due to higher dietary protein in all three groups. The colonic mucus barrier was thinner in rats fed higher dietary protein but the effect was reversed by feeding RS. Caecal total SCFA and butyrate pools were low in rats fed the digestible starch and were higher in rats fed RS. However, there was no relationship between caecal or faecal SCFA and genetic damage or mucus thickness. Caecal and colonic tissue weight and colon length were higher in rats fed RS, consistent with greater SCFA supply. These data confirm that higher dietary protein of animal (casein) or plant (soy) origin increases genetic damage and loss of the mucus barrier indicating that this is an effect of protein and not its source. These findings accord with the epidemiological data which link dietary protein to greater risk of colorectal cancer and inflammatory bowel disease. However, the data show also that dietary proteins differ in their specific actions on genetic damage and mucus thickness. Further, the data from the feeding of whey suggest that not all proteins are equivalent in their capacity to provoke adverse changes in colonic integrity. While the data show that RS raised large bowel and faecal SCFA, they indicate their levels were not related directly to these biomarkers. 3. Dose response effects of resistant starch on protein induced colonic DNA damage The accumulated data linking greater protein intakes to adverse changes in the colon were obtained at dietary levels which were not unreasonable in terms of animal or human consumption. However, the dietary level of RS which were fed were relatively high (48% by weight) so this study was conducted to determine its effectiveness at lower levels of dietary inclusion. It was also important to ascertain whether there was a dose-response relationship between RS intake and the observed effects. One of the mechanisms proposed for the induction of colorectal cancer by high dietary protein intakes is oxidative damage to DNA. In this experiment, this was done by assaying with endonuclease III. Adult male rats were fed a diet containing 25% casein with 0%, 10%, 20%, 30% or 40% high amylose maize starch for 4 weeks. As in the preceding studies comet tail moment was greatest and the mucus barrier thinnest in rats fed 0% RS. DNA damage was reduced and the mucus barrier thickened in a logarithmic dose-dependent manner by RS. There was no significant difference between dietary groups associated with oxidative DNA damage as measured by endonuclease III. Caecal and faecal short chain fatty acid (SCFA) pools rose with the increased level of dietary RS. DNA damage of colonocytes correlated negatively with caecal SCFA but the strongest correlation was with caecal butyrate, which is consistent with the proposed role of this SCFA in promoting a normal cell phenotype. The data show that RS prevents protein induced colonic DNA damage in a dose-dependent manner. Inclusion of 10% high amylose maize starch was found to be sufficient to oppose colonocyte DNA damage, and to increase caecal and faecal SCFA pools. Intakes of this order are not unreasonable in terms of human consumption of RS. 4. Dose response effects of red and white meat on colonic DNA damage and interaction with resistant starch The accumulated evidence from large prospective human studies links diet to colorectal cancer risk strongly. The evidence from the animal studies described in this thesis that dietary protein induces colonocyte genetic damage supports a role for high protein intakes in increasing risk. Recently, several large epidemiological studies and a meta-analysis of prospective studies have found that consumption of dietary red or processed meats, but not white (poultry) meat, is associated with increased risk of colorectal cancer. This is consistent with the data from the preceding studies that specific proteins affected colonic integrity differentially. A large prospective European study (European Prospective Investigation into Cancer and Nutrition) has reported that dietary fibre was protective. The findings reported in this thesis that RS opposes the effects of high dietary protein accord with that conclusion. This study aimed to compare the effects of cooked red (beef) or white (chicken) meat on DNA damage and mucus barrier thickness in rats. The study was designed to determine whether the relationship between the intakes of these meats was dose-dependent. Double-strand DNA breaks are thought to relate more closely to carcinogenesis than single-strand breaks so both were measured. Adult male Sprague-Dawley rats were fed a diet containing 15%, 25% or 35% cooked beef or cooked chicken each with or without 20% high amylose maize starch for four weeks. Both red and white meat increased colonic DNA damage dose-dependently. However, both single and double strand breaks were significantly greater when the rats were fed the red meat diets compared to those fed the white meat. Colonocyte DNA damage was reduced by the consumption of RS while large bowel SCFA were increased. The findings of this study are consistent with the epidemiological data which show that red meat consumption is associated with greater risk of colorectal cancer but that white meat is not. Summary The data reported in this thesis support the findings of prospective population studies that high dietary protein, red meat in particular, appears to be harmful to the health of the large bowel. However, the data demonstrate also that different protein types have differential effects on the integrity of the colonocyte DNA. Furthermore, the addition of RS to the diet protects against protein-induced colonic DNA damage and maintenance of the colonic mucus barrier, apparently through increased SCFA production by colonic fermentation. The results of these experiments indicate a strong potential for RS to be effective in maintenance of large bowel integrity in the face of high dietary protein. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1292858 / Thesis(Ph.D.)-- School of Molecular and Biomedical Science, 2007.

Content removed due to copyright restrictions: E I-Sherbiny, I.M., Lins, R.l , Abdel-Bary, E.M., Harding, D.R.K. Preparation, characterization, swelling and in vitro drug release behaviour of poly[Nacryloylglycine- chitosan] interpolymeric pH and thermally-responsive hydrogels. Eur. Polym. J. 41 (2005) 2584. E I-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R.K. Preparation and swelling study of a pH-dependent interpolymeric hydrogel based on chitosan for controlled drug release. Inl. J. Polym. Mater. 55 (2006) 789. El-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R. K. Swelling characteristics and in-vitro drug release study with pH and thermo-sensitive hydro gels based on modified chitosan. J. Appl. Polym. Sci. 102 (2006) 977. Abdelaal, M.Y., Abdel-Razik, E . A , Abdel-Bary, E.M., El-Sherbiny, I.M. Study on chitosan-poly(vinyl alcohol) interpolymeric pH-responsive hydrogel films for controlled drug delivery. J. Appl. Polym. Sci. (2006) in press. El-Sherbiny, I. M., Abdel-Bary, E.M., Harding, D. R. K. In-vitro investigation of new biodegradable pH-responsive hydrogel beads for oral delivery of protein drugs in the small intestine. New Zealand Institute of Chemistry Conference (NZIC), (2006) Rotorua, New Zealand, 2-6 December. / Controlled drug release enhances the safety, efficacy and reliability of drug therapy. Regulation of the drug release rate results in a reduction in the frequency of drug administration and should encourage patients to comply with dosing instructions. Hydrogels are crosslinked, three-dimensional hydrophilic polymers, which swell without dissolving when brought into contact with water or other biological fluids. The number of polymers suitable for the controlled release of viable therapeutics is quite limited because of inherent toxicity or lack of certain properties such as biodegradability. In this thesis, chitosan was chosen as the base polymer for the development of new hydrogels that can be tailored for use in the site-specific delivery of drugs to the gastrointestinal tract. Chitosan is a non-toxic and biodegradable polymer obtained through the alkaline deacetylation of natural chitin. The interesting characteristics of chitosan make it an ideal candidate for use in controlled drug release formulations. However, chitosan exhibits some shortcomings such as hydrophobicity and a high pH-dependency for its physical properties. Hence, it is very difficult to control drug release with chitosan itself because of the various pH values of the internal organs of the human body. This may negatively affect the human body because of drug under- or over-release. In a structured programme, some new chitosan-based hydrogels have been prepared for controlled drug release investigations by applying three main approaches to overcome the shortcomings of chitosan. The first approach was the incorporation of chitosan into interpenetrating polymer network hydrogels with either a hydrophilic polymer or with hydrophilic monomers treated to bring about in situ copolymerization in the presence of chitosan and a suitable crosslinking agent. The second approach was the chemical modification of chitosan by grafting of a suitable vinyl macromer such as poly(ethylene glycol)-diacrylate, then crosslinking this modified chitosan. The equilibrium swelling studies were carried out for the hydrogels prepared using these two approaches at 37 °C at pH 2.1 (simulated gastric fluid, SGF) and at pH 7.4 (simulated intestinal fluid, SIF). The swelling results showed a pH-responsive nature of these hydrogels. They attained higher swelling values in SGF than in SIF. 5-Fluorouracil (5-FU), an anti cancer drug, was entrapped as a model drug in all the hydrogels prepared using these two approaches. The in-vitro drug release studies were carried out at 37 °C in SGF and SIF. From the preliminary investigations of the prepared hydrogels, they may be customized and used to expand the utilization of these systems in drug delivery applications. In the third approach, chitosan was modified in such a fashion that the hydrogels produced were also pH-responsive but attained limited swelling in SGF and higher swelling in SIF. Hence, the resulting hydrogels could be tailored for utilization for intestine-targeted delivery of peptide and protein drugs with a potential protection of the drugs from the harsh acidity of the stomach. In this third approach the ionotropic gelation was used for the preparation of the hydrogels based on the modified chitosan with another natural polymer (sodium alginate) in the presence of a divalent ion. Bovine serum albumin (BSA) was entrapped as a model protein drug and the in-vitro drug release profiles were established at 37 °C in SGF and SIF. The results showed promising release profiles of BSA. However, this hydrogel study requires more effort to limit the swelling and consequently the loss of drug in the SGF, to act as an excellent candidate for intestine-specific delivery of peptide and protein drugs.

Content removed due to copyright restrictions: E I-Sherbiny, I.M., Lins, R.l , Abdel-Bary, E.M., Harding, D.R.K. Preparation, characterization, swelling and in vitro drug release behaviour of poly[Nacryloylglycine- chitosan] interpolymeric pH and thermally-responsive hydrogels. Eur. Polym. J. 41 (2005) 2584. E I-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R.K. Preparation and swelling study of a pH-dependent interpolymeric hydrogel based on chitosan for controlled drug release. Inl. J. Polym. Mater. 55 (2006) 789. El-Sherbiny, I.M., Abdel-Bary, E.M., Harding, D. R. K. Swelling characteristics and in-vitro drug release study with pH and thermo-sensitive hydro gels based on modified chitosan. J. Appl. Polym. Sci. 102 (2006) 977. Abdelaal, M.Y., Abdel-Razik, E . A , Abdel-Bary, E.M., El-Sherbiny, I.M. Study on chitosan-poly(vinyl alcohol) interpolymeric pH-responsive hydrogel films for controlled drug delivery. J. Appl. Polym. Sci. (2006) in press. El-Sherbiny, I. M., Abdel-Bary, E.M., Harding, D. R. K. In-vitro investigation of new biodegradable pH-responsive hydrogel beads for oral delivery of protein drugs in the small intestine. New Zealand Institute of Chemistry Conference (NZIC), (2006) Rotorua, New Zealand, 2-6 December. / Controlled drug release enhances the safety, efficacy and reliability of drug therapy. Regulation of the drug release rate results in a reduction in the frequency of drug administration and should encourage patients to comply with dosing instructions. Hydrogels are crosslinked, three-dimensional hydrophilic polymers, which swell without dissolving when brought into contact with water or other biological fluids. The number of polymers suitable for the controlled release of viable therapeutics is quite limited because of inherent toxicity or lack of certain properties such as biodegradability. In this thesis, chitosan was chosen as the base polymer for the development of new hydrogels that can be tailored for use in the site-specific delivery of drugs to the gastrointestinal tract. Chitosan is a non-toxic and biodegradable polymer obtained through the alkaline deacetylation of natural chitin. The interesting characteristics of chitosan make it an ideal candidate for use in controlled drug release formulations. However, chitosan exhibits some shortcomings such as hydrophobicity and a high pH-dependency for its physical properties. Hence, it is very difficult to control drug release with chitosan itself because of the various pH values of the internal organs of the human body. This may negatively affect the human body because of drug under- or over-release. In a structured programme, some new chitosan-based hydrogels have been prepared for controlled drug release investigations by applying three main approaches to overcome the shortcomings of chitosan. The first approach was the incorporation of chitosan into interpenetrating polymer network hydrogels with either a hydrophilic polymer or with hydrophilic monomers treated to bring about in situ copolymerization in the presence of chitosan and a suitable crosslinking agent. The second approach was the chemical modification of chitosan by grafting of a suitable vinyl macromer such as poly(ethylene glycol)-diacrylate, then crosslinking this modified chitosan. The equilibrium swelling studies were carried out for the hydrogels prepared using these two approaches at 37 °C at pH 2.1 (simulated gastric fluid, SGF) and at pH 7.4 (simulated intestinal fluid, SIF). The swelling results showed a pH-responsive nature of these hydrogels. They attained higher swelling values in SGF than in SIF. 5-Fluorouracil (5-FU), an anti cancer drug, was entrapped as a model drug in all the hydrogels prepared using these two approaches. The in-vitro drug release studies were carried out at 37 °C in SGF and SIF. From the preliminary investigations of the prepared hydrogels, they may be customized and used to expand the utilization of these systems in drug delivery applications. In the third approach, chitosan was modified in such a fashion that the hydrogels produced were also pH-responsive but attained limited swelling in SGF and higher swelling in SIF. Hence, the resulting hydrogels could be tailored for utilization for intestine-targeted delivery of peptide and protein drugs with a potential protection of the drugs from the harsh acidity of the stomach. In this third approach the ionotropic gelation was used for the preparation of the hydrogels based on the modified chitosan with another natural polymer (sodium alginate) in the presence of a divalent ion. Bovine serum albumin (BSA) was entrapped as a model protein drug and the in-vitro drug release profiles were established at 37 °C in SGF and SIF. The results showed promising release profiles of BSA. However, this hydrogel study requires more effort to limit the swelling and consequently the loss of drug in the SGF, to act as an excellent candidate for intestine-specific delivery of peptide and protein drugs.