The role of supraspinal, spinal and peripheral alpha-2 adrenoceptors in the regulation of gastrointestinal motility in mice was investigated using anatomically site specific administration of clonidine and adrenoceptor antagonists. Clonidine produced a dose-dependent inhibition of gastrointestinal transit when given by the i.c.v., i.th., or s.c. routes, and was most potent when given i.c.v. Yohimbine, an alpha-2 adrenoceptor antagonist, but not the alpha-1 antagonist prazosin, antagonized the antitransit effects of clonidine. Yohimbine was most potent in antagonizing i.c.v. clonidine; increased doses of the i.c.v. antagonist were required when the agonist was given s.c. After transection of the spinal cord, i.th. clonidine failed to produce an antitransit effect. Additionally, the i.c.v. potency of clonidine decreased approximately 7-fold in spinally-transected mice. The data suggest that the antitransit effects of clonidine occur through actions at alpha-2 adrenoceptors located at both supraspinal and peripheral sites.

Η οξεία αιμορραγία ανώτερου πεπτικού (ΟΑΑΠ) παραμένει ένα από τα πιο συχνά και επείγοντα περιστατικά που συνοδεύεται με αυξημένη νοσηρότητα και θνητότητα. Σκοπός της μελέτης είναι να δειχθούν αλλαγές στα κλινικο-επιδημιολογικά χαρακτηριστικά των ασθενών με ΟΑΑΠ την τελευταία δεκαετία. Συλλέχθηκαν δεδομένα από όλους τους ασθενείς που εισήχθησαν στα νοσοκομεία του Νομού Αχαΐας με ΟΑΑΠ από 1η Ιανουαρίου ως την 31η Δεκεμβρίου 2005 και έγινε αναδρομική σύγκριση με δεδομένα από ασθενείς που εισήχθησαν πριν 10 έτη στην ίδια περιοχή την περίοδο από 1η Ιανουαρίου ως τη 31η Δεκεμβρίου 1995. Η επίπτωση των ασθενών με ΟΑΑΠ και των πεπτικών ελκών και στις δυο περιόδους υπολογίσθηκε με βάση δεδομένων στοιχείων από την Εθνική Στατιστική Υπηρεσία. Παρατηρήθηκε μείωση στην επίπτωση των ασθενών με ΟΑΑΠ από 162,9/100.000 πληθυσμού το 1995, σε 108,2 /100.000 πληθυσμού (RR=0,49, CI 95%=0,37-0,63) το 2005 και στην επίπτωση των ασθενών με αιμορραγία από πεπτικό έλκος (ΑΠΕ) από 104,8 /100.000 πληθυσμού σε 72,5 /100000 (RR=0,49, CI 95%=0,35-0,68). Η μείωση αυτή οφειλόταν κυρίως στη μείωση της επίπτωσης των ασθενών με αιμορραγία από δωδεκαδακτυλικό έλκος (ΑΔΕ)(από 66,7ασθενείς/100.000 σε 35,5/100.000 πληθυσμού), ενώ η επίπτωση της αιμορραγίας από γαστρικά έλκη παρέμεινε στα ίδια επίπεδα (από 33,1 /100.000 σε 34,4 /100.000). Η μέση ηλικία των ασθενών αυξήθηκε από 59,4±17,1 έτη σε 66,1±16,1, p<0.0001, όπως και η συν-νοσηρότητα των ασθενών. Το ποσοστό χρήσης μη στεροειδών αντιφλεγμονωδών φαρμάκων (ΜΣΑΦ) σε αυτούς τους ασθενείς παρέμεινε σταθερό (49,3% vs 48,2%), ενώ η χρήση από του στόματος αντιπηκτικών και αντιαιμοπεταλιακών φαρμάκων αυξήθηκε σημαντικά (από 2,2% σε 6,8%, p=0,001 και από 1,2% σε 10,8%, p<0,0001 αντίστοιχα). Η συχνότητα υποτροπής αιμορραγίας σε ασθενείς με ΑΠΕ ,καθώς και η συχνότητα της επείγουσας χειρουργικής αιμόστασής τους μειώθηκαν σημαντικά (από 12% σε 5,9%, p=0,02 και από 8,9% σε 3,4%, p=0,009, αντίστοιχα). Δεν ανεβρέθηκε στατιστικά σημαντική διαφορά στην συνολική θνητότητα (3,9% το 1995 vs 6,5 % το 2005). Η επίπτωση της ΟΑΑΠ κατά την τελευταία δεκαετία μειώθηκε σημαντικά κυρίως λόγω της μείωσης της επίπτωσης των ασθενών με ΑΔΕ. Οι ασθενείς αυτοί είναι πιο ηλικιωμένοι με αυξημένα συνοδά νοσήματα, αλλά χωρίς να έχει μεταβληθεί στατιστικά η θνητότητά τους τα τελευταία δέκα έτη. / Acute upper gastrointestinal bleeding (AUGIB) remains a common medical emergency and an important cause of morbidity and mortality. The aim of this study was to evaluate changes in clinico-epidemiologic characteristics of patients who presented with AUGIB during the last 10 years. Data from all patients admitted with AUGIB in a defined geographical area in Greece from January 1 to December 31, 2005 (period B) were compared with retrospectively collected data from all patients admitted with AUGIB in the same area 10 years ago, from January 1 to December 31, 1995 (period A). The estimated incidence of AUGIB and peptic ulcer bleeding (PUB) in both periods was calculated using data from the population of this area according to the National Statistical Service. A reduction in the incidence of AUGIB from 162.9/100,000 population in 1995, to 108.2/100,000 population (rate ratio=0.49, confidence interval 95%=0.37-0.63) in 2005 and in the incidence of PUB from 104.8/100,000 population to 72.5/100,000 (rate ratio=0.49, confidence interval 95%=0.35-0.68) were, respectively, observed. This reduction was mainly due to the reduction in the incidence of duodenal ulcer bleeding (from 66.7 cases/100,000 to 35.5/100,000 population), whereas gastric ulcer bleeding incidence remained unchanged (33.1/100,000 vs. 34.4/100,000 cases). Mean age of patients increased from 59.4+/-17.1 years to 66.1+/-16.1, P<0.0001, and the patients' comorbidity. The percentage of NSAIDs' use remained stable (49.3% vs. 48.2%), whereas the use of oral anticoagulants and antiplatelets drugs increased significantly (from 2.2% to 6.8%, P=0.001 and from 1.2% to 10.8%, P<0.0001, respectively). Blood transfusion requirements per patient significantly decreased (from 2.5+/-2 to 2+/-2.4, P=0.009). The rate of rebleeding in PUB patients and emergency surgical hemostasis statistically decreased (from 12% to 5.9%, P=0.02 and from 8.9% to 3.4%, P=0.009, respectively). No significant difference in the overall mortality was observed (3.9% in 1995 vs. 6.5% in 2005). The incidence of AUGIB during the past 10 years significantly decreased, mainly due to the decline in the incidence of bleeding duodenal ulcers. Nowadays, patients are older with more comorbidities, but mortality remains unchanged.

Η λοίμωξη με Helicobacter pylori (Ελικοβακτήριο του πυλωρού, ΕΠ) αυξάνει τις πιθανότητες ανάπτυξης καρκίνου του στομάχου. Η εξέλιξη σε αδενοκαρκίνωμα περνάει από το προκαρκινικό στάδιο της εντερικής μεταπλασίας, η οποία ακολουθεί τη γαστρίτιδα που προκαλείται από το ΕΠ. Ένας από τους πιθανούς μηχανισμούς καρκινογένεσης είναι η απορύθμιση της ισορροπίας ανάμεσα στη απόπτωση και τον πολλαπλασιασμό κυττάρων του γαστρικού επιθηλίου. Στην εργασία αυτή μελετήθηκαν η απόπτωση και ο πολλαπλασιασμός του γαστρικού επιθήλιου σε ομάδα ασθενών χωρίς λοίμωξη με ΕΠ, ομάδα ασθενών με γαστρίτιδα από ΕΠ και, τέλος, ομάδα ασθενών με γαστρίτιδα που περιείχε εστίες εντερικής μεταπλασίας. Η απόπτωση αξιολογήθηκε με τη μέθοδο TUNEL και εκφράστηκε με τον Δείκτη Απόπτωσης (Apoptotic Index, AI). Ο πολλαπλασιασμός αξιολογήθηκε με την ανοσοϊστοχημική χρώση του αντιγόνου Ki-67 και εκφράστηκε με τον Δείκτη Πολλαπλασιασμού (Proliferation Index, PI). Στους ΕΠ- θετικούς ασθενείς, η απόπτωση και ο πολλαπλασιασμός ήταν σημαντικά αυξημένες σε σύγκριση με τους ΕΠ-αρνητικούς ασθενείς (AI=1,22 +/- 0,13% έναντι 0,15 +/- 0,03%, p<0,0001; PI=24 +/- 1% έναντι 13 +/- 2%, p<0,0001). Η αύξηση ήταν ανάλογη με τη βαρύτητα της γαστρίτιδας. Μέσα στις εστίες εντερικής μεταπλασίας, όμως, η απόπτωση ήταν σημαντικά μειωμένη σε σύγκριση με την γαστρίτιδα που τις περιέβαλλε (AI=0,20 +/- 0,06% έναντι 1,34 +/- 0,23%, p=0,0014), ενώ ο πολλαπλασιασμός διατηρούνταν σε ψηλά επίπεδα (PI=25,4 +/- 4% έναντι 24,7 +/- 2%, p=0,87). Αυτό είχε σαν αποτέλεσμα τη μείωση στη σχέση απόπτωσης-πολλαπλασιασμού στις εστίες εντερικής μεταπλασίας σε σύγκριση με τη περιβάλλουσα γαστρίτιδα (Λόγος ΑΙ/ΡΙ=0,008 +/- 0,005 vs. 0,054 +/- 0,009, 63 p<0,02). Έτσι, η γαστρίτιδα στη λοίμωξη με ΕΠ σχετίζεται με ταυτόχρονη αύξηση στην απόπτωση και τον πολλαπλασιασμό επιθηλιακών κυττάρων, ενώ η μετάβαση σε εντερική μεταπλασία οδηγεί σε υποχώρηση της απόπτωσης σε φυσιολογικά επίπεδα και διατήρηση του αυξημένου πολλαπλασιασμού. Αυτή η διαταραχή στη σχέση απόπτωσης και πολλαπλασιασμού είναι πιθανό να αποτελεί σημαντικό παράγοντα στην καρκινογενετική δράση του ΕΠ. / Infection with Helicobacter pylori (HP) has been recognized as a risk factor for the development of gastric cancer. In the histologic progression to cancer, adenocarcinoma is preceded by the precursor lesion of intestinal metaplasia, which may follow HP-induced gastritis. An imbalance between the competing processes of apoptosis and proliferation in the gastric epithelium has been postulated to play a role in this sequence of events. This study compared apoptosis and proliferation in antral epithelium from a group of individuals not infected with HP, a group of individuals with HP-induced gastritis, and a group of individuals with HP-induced gastritis containing foci of intestinal metaplasia. Apoptosis was evaluated by the TUNEL assay and expressed as Apoptotic Index (AI), while proliferation was assessed by Ki-67 immunohistochemistry and expressed as Proliferation Index (PI). In the HP-positive group, apoptosis and proliferation were increased compared with the HP-negative group (AI=1,22 +/- 0,13% vs. 0,15 +/- 0,03%, p<0,0001; PI=24 +/- 1% vs. 13 +/- 2%, p<0,0001). Increases were proportional to the severity of the gastritis. Within foci of intestinal metaplasia, apoptosis was significantly reduced compared with surrounding gastritis (AI=0,20 +/- 0,06% vs. 1,34 +/- 0,23%, p=0,0014), whereas proliferation was not altered (PI=25,4 +/- 4% vs. 24,7 +/- 2%, p=0,87). This resulted in a lower AI/PI ratio in intestinal metaplasia than in surrounding gastritis (0,008 +/- 0,005 vs. 0,054 +/- 0,009, p<0,02). HP-induced gastritis was thus associated with increased epithelial apoptosis and proliferation compared with uninfected controls. In intestinal metaplasia, proliferation remained increased but apoptosis reverted to normal levels. This imbalance may contribute to HP-associated gastric carcinogenesis.

Humans harbour a diverse suite of microorganisms in and on their bodies. These microorganisms collectively amount to 10 times more cells than human cells in the body, and their combined genomes have more than 100 times more genes than the human genome does. Despite our understanding of the composition, diversity, and abundance of microorganisms of the human body, it is surprising how little we know about the structure and function of the human microbiome. Here, I use network structure to describe interactions among human-associated microbiota and the human body by exploring differences in structure of human microbiomes across five regions of the body and the robustness of these networks to perturbations. My results show that positive interactions among microbiota are extremely important in structuring microbiome networks and those structural aspects of microbiome networks play a major role in their response to perturbations.

Cell-cell communication between bacteria, belonging to the same species or to different species (Intra-kingdom signaling), or communication between bacteria and their animal host (Inter-kingdom signaling) is mediated through different chemical signals that are synthesized and secreted by bacteria or the host and is crucial for the survival of bacteria inside their host. The overall goal of this work was to understand the role of inter- and intra-kingdom signaling in phenotypes such as chemotaxis, colonization and biofilm formation, and virulence that are associated with infections caused by the human gastrointestinal (GI) tract pathogens. A part of our work also aimed at developing microfluidics-based models to study inter- and intra-kingdom signaling in biofilm formation, inhibition, and dispersal. We showed that norepinephrine (NE), an important host signal produced during stress, increases human opportunistic pathogen Pseudomonas aeruginosa growth, motility, attachment, and virulence, and also showed that the actions of NE are mediated primarily through the LasR, and not the RhlR QS system. We investigated the molecular mechanism underlying the chemo-sensing of the intra-kingdom signal autoinducer-2 (AI-2) by pathogens Escherichia coli and Salmonella typhimurium by performing different chemotaxis assays (capillary, microPlug and microFlow assays), and discovered that AI-2 is a potent attractant for E. coli and S. typhimurium, and that the Tsr chemoreceptor and periplasmic AI-2 binding protein LsrB are necessary for sensing AI-2, although uptake of AI-2 into the cytoplasm is not required. We concluded that LsrB, when bound to AI-2, interacts directly with the periplasmic domain of Tsr primarily at the Thr-61 and Asp-63 residues of LsrB, making LsrB the first known periplasmic-protein partner for Tsr. We fabricated a simple user-friendly microfluidic flow cell (microBF) device that can precisely measure the effect of a wide range of concentrations of single or combinations of two or more soluble signals on bacterial biofilm formation and development. We also constructed a synthetic biofilm circuit that utilizes the Hha and BdcA dispersal proteins of E. coli along with a quorum sensing (QS) switch that works based on the accumulation of the signal N-(3-oxo-dodecanoyl)-L-homoserine lactone (3-o-C12HSL) and implemented it in an upgraded �BF device. We showed that a QS system may be utilized with biofilm dispersal proteins to control consortial biofilm formation by removing an existing biofilm and then removing the biofilm that displaced the first one. These types of synthetic QS circuits may be used to pattern biofilms by facilitating the re-use of platforms and to create sophisticated reactor systems that will be used to form bio-refineries.

The gastrointestinal (GI) tract of cats and dogs is inhabited by many different types of microorganisms, known as the GI microbiota. Mounting evidence suggests that the administration of certain dietary and/or therapeutic agents can alter the composition and activity of the GI microbiota, thus influencing gastrointestinal health and disease. The aim of this study was to evaluate the gastrointestinal microbiota in response to dietary and therapeutic interventions in cats and dogs. A multi-species synbiotic formulation, containing a total of 5x109 colony forming units of a mixture of seven probiotic bacterial strains and a blend of prebiotics, was administered daily for 21 days to healthy cats and dogs. Fecal samples were collected before, during, and up to three weeks after discontinuation of the administration of the synbiotic. The fecal microbiota was analyzed using 454-pyrosequencing, denaturing gradient gel electrophoresis, quantitative real-time PCR, and 16S rRNA gene clone libraries. The results showed that the synbiotic led to increased concentrations of probiotic bacteria in the feces but did not alter the predominant bacterial phyla. Additionally, we investigated the effect of age, body weight, and baseline abundance of probiotic related bacterial genera, as potential predictors of intestinal colonization by the ingested microorganisms. The results suggested that cats having a low abundance of fecal probiotic genera before consuming probiotics may have a higher concentration of the probiotic groups in feces during consumption of the symbiotic formulation. Also, a proton-pump inhibitor, aimed at suppressing the secretion of gastric acid, was administered daily for 15 days to healthy dogs. Changes in the GI microbiota were analyzed using 454-pyrosequencing, fluorescent in situ hybridization, and quantitative real-time PCR. The results suggested that inhibition of gastric acid secretion can alter the abundance of several gastric, duodenal, and fecal bacterial groups. However, these changes were not associated with major qualitative modifications of the overall composition of the GI microbiota. These studies showed that dietary and therapeutic agents can alter the composition of the GI microbiota and suggest that these changes could be associated with particular characteristics of the host. The clinical significance of these results needs further investigation.

Nitric oxide, a short-lived free radical and neurotransmitter, is responsible for decreased smooth muscle contractility in vitro. When in excess, NO can cause hypotension and is believed to mediate altered intestinal motility. Not enough evidence is available for morphological changes in gastrointestinal smooth muscle and its correlation with motility disorders caused by Escherichia coli-induced NO production. Male Lewis rats were treated with injections of 10 mg/kg LPS from E. coli with or without 12.5 mg/kg of NOS inhibitor, LNMMA. Eighteen to 24 hours following injection, duodenum, ileum, colon, liver, and spleen were harvested for histological analysis. Urine and fecal analysis assessed functional aspects in control and treatment groups. Muscularis externa measurements revealed significant increase in muscle thickness of LPS + LNMMA injected group compared to control and LPS group. However, the average values in control and LPS group were not significantly different. Fecal consistency was significant in all 3 groups. Mean urinary nitrite in the LPS group was 44 times higher than control and 52 times higher than the inhibitor-treated group. / Department of Physiology and Health Science

The intent of this study was to compare the rate of gastric emptying of three commercially available athletic drinks (GA, BT, and BP) against water, and in doing so to assess the exchange of water, carbohydrate and electrolytes 15 minutes after ingestion. Nine men and three women reported to the laboratory after having fasted for 12 hours.' A No. 20 French Levine Tube was inserted through the nasal passage and into the stomach. The subjects drank down 400 ml of the test solution containing 25 mg of phenol red which was used as a volume indicator. Fifteen minutes after ingestion, the gastric contents were aspirated via the tube by means of a 50 ml syringe. The 4 conditions were tested in one morning, with the order of feedings rotated between subjects. The recovered gastric contents were measured for total volume, volume of original drink, carbohydrate content and gastric electrolyte exchange. Student t values were used to test the difference between means set at the P < .05 level of confidence. BT and BP were found to empty statistically the same volume of fluid in 15 minutes as did water, while GA emptied 39% less volume than did water. BT, BP, and GA contributed 1.9, 4.5 and 6.8 gm of carbohydrate respectively in 15 minutes. These data are in agreement with previous findings that high glucose concentrations (GA - 4.5 gam) cause a slowing of gastric emptying.

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. / viii, 137, [22] leaves, [1] leaf 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. / 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. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 2000

Mucositis is the damage that occurs to the alimentary canal from anti - cancer therapies. It is caused by chemotherapy, radiotherapy and combination therapy and affects a large proportion of patients. Despite its prevalence, an effective anti - mucositis agent has yet to be developed that protects the whole tube, although the use of keratinocyte growth factor ( Amgen ' s Palifermin ) has recently been approved for the prevention of oral mucositis. It is important to understand mechanisms controlling mucositis so that treatment can be targeted appropriately. This thesis has investigated some of the key components identified as being involved in mucositis as well as identifying new genes which contribute to chemotherapy - induced intestinal injury. The research chapters investigated : 1 ) Gene expression of the apoptosis - regulating Bcl - 2 family, p53 and caspase - 3, and the changes which occur in the intestine following chemotherapy treatment for cancer. 2 ) The effect of different chemotherapeutic agents on intestinal cells in vitro and the role p53 plays. 3 ) The mucositis caused by single dose irinotecan in the rat with breast cancer and the role of p53 in induction of intestinal damage. 4 ) The early gene changes that occur in the small intestine of the rat with breast cancer following irinotecan treatment. Firstly, to investigate the difference in susceptibility to damage between the small and large intestine, the protein expression of 8 members of the Bcl - 2 family ( 4 pro - apoptotic ; Bax, Bak, Bid, Bim and 4 anti - apoptotic ; Bcl - 2, Bcl - xL, Bcl - w, Mcl - 1 ) was quantified in jejunal and colonic sections taken from rats inoculated with breast cancer. It was found that there was significantly higher expression of the pro - apoptotic proteins, Bax, Bak, Bim and Bid, in the crypts of the jejunum compared to the colon. Furthermore, expression of the anti - apoptotic proteins, Bcl - 2, Bcl - xL and Bcl - w, was significantly lower in jejunal crypts compared to colonic crypts. Mcl - 1 expression was similar in both regions. Thus, the small intestine is an environment balanced to favour apoptosis through specific Bcl - 2 family protein expression profiles. The Bcl - 2 family regulates apoptosis in response to a variety of chemotherapy agents. However, it is unknown how Bcl - 2 family gene expression changes along with other apoptogenic factors following cytotoxic therapy in the normal intestine. To investigate this, sections of rat jejunum treated with methotrexate and duodenal biopsies from chemotherapy patients treated with various regimens for cancer were subjected to quantitative immunohistochemistry to detect Bcl - 2 family proteins, p53 and caspase - 3. Treatment caused expression of p53 and caspase - 3 to increase within the crypts and follow a similar pattern to apoptosis levels. Pro - apoptotic Bcl - 2 family members, Bax and Bak, were increased, while the anti - apoptotic protein, Mcl - 1, was significantly reduced. A significant increase in mRNA expression for Bax and Bak was noticed at 6 h, without a concurrent decrease in Mcl - 1. Thus, Bcl - 2 family genes were altered in the small intestine in both humans and rats, and this was irrespective of chemotherapy agent or regimen used. The best characterised changes which occur during chemotherapy - induced damage in the intestine are in the epithelial layer, although it is thought that pan #45 mucosal alterations are involved. Two intestinal cell lines were chosen to investigate changes in apoptosis, proliferation and protein expression following cytotoxic treatment with various chemotherapeutic agents. These were the rat IEC - 6 and human FHs 74 cell lines, which represent untransformed epithelial cells. The human breast carcinoma cell line, MCF - 7, was also used as a positive control. Intestinal cells were resistant to the occurrence of methotrexate toxicities within 24 h of treatment, modestly affected by irinotecan and extremely sensitive to doxorubicin. Doxorubicin caused a marked increase in p53 and p21 expression, which for irinotecan was less pronounced. The effect of cytotoxic treatment on Bcl - 2 family expression in intestinal cells varied, however the pro - apoptotic proteins, Bax and Bak, were generally upregulated following doxorubicin. Temporary inhibition of p53 using pifithrin alpha resulted in a significant improvement in cell survival in cancerous cell only and did not alter Bcl - 2 family expression. It was concluded that cultured epithelial cells exhibit varying sensitivities to different chemotherapeutic agents which is dependent on induction of p53 gene expression. The topoisomerase I inhibitor, irinotecan, is a chemotherapeutic agent commonly used in the treatment of colorectal cancer. It often induces severe mucositis with the most common symptom being diarrhoea. Previous research has shown that irinotecan damages the small and large bowel equally, which is unusual. This is characterised by an increase in apoptosis and a reduction in proliferation within epithelial crypts, an increase in inflammatory cell infiltrate in the lamina propria and excess mucin production. These investigations used two sequential doses of irinotecan. The early effect of a single dose of irinotecan on the intestine have yet to be studied. Thus the primary aim of this experiment was to examine in detail the changes caused by irinotecan at 6 and 48 h in the rat. A secondary aim was to investigate the role of p53 on induction of apoptosis and cell cycle arrest within intestinal crypts and the effect of temporary inhibition of the protein. Single dose irinotecan caused a decrease in body and small intestinal weight by 48 h after treatment. This was accompanied by crypt and villous degeneration, increased apoptosis and reduced proliferation within crypt epithelium as well as inflammatory infiltrate throughout lamina propria. An increase in Bax expression was seen at 6 h, however p53 protein levels remained relatively low until 48 h. Rats also treated with pifithrin alpha to inhibit p53 and had a significantly lower peak in apoptosis in the colon at 6 h, however did not show improvements in any other parameters tested. It was concluded that irinotecaninduced damage in the rat intestine is primarily p53 - independent, and that pifithrin alpha acts to inhibit apoptosis in the large intestine via a p53 - independent pathway. A study was designed to investigate the early genome - wide changes which occur following irinotecan treatment in the rat small intestine. Microarray analysis found that regulation of many genes was altered at 6 h following dual dose irinotecan. These genes were involved in apoptosis, cell cycle regulation, immune function, calcium homeostasis and protein turnover. Multiple genes from the MAP kinase pathway were also activated by irinotecan. The cystine protease, caspase - 1 was upregulated and was chosen for further investigations due to its role in apoptosis and inflammation. Real time PCR analysis confirmed the increase in gene expression at 6 h and also showed a return to baseline levels by 24 h which was followed by another modest increase at 48 h. It was concluded that irinotecan induces a wide range of gene changes within the intestine and that apoptosis and inflammatory damage pathways are activated during treatment. This thesis described key molecules in apoptosis and their role in induction of chemotherapy - induced intestinal mucositis. It has provided evidence of the importance of apoptosis in mucosal injury and also highlighted areas requiring further research. Results presented herein show that the Bcl - 2 family is involved in intestinal damage following many chemotherapy agents, whereas p53 is agent - specific. It has also shown that irinotecan causes intestinal damage via a mainly p53 - independent manner in the rat. It can be concluded that gastrointestinal mucositis is complex and activates multiple pathways to induce damage. Findings from this thesis will aid targeting of new anti - mucotoxic agents. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2006.