The existence of a stimulatory intestinal phase of gastric acid secretion has been suspected for some time, and recently the importance of this phase has been recognized. The intestinal phase is of particular interest in relation to the profound gastric hypersecretion associated with portacaval anastomosis. The results of many studies in dogs, and recently in man, have demonstrated conclusively that shunt-related gastric hyper-secretion is due to unmasking of the intestinal phase by hepatic bypass of a humoral stimulant that is normally inactivated by the liver. Definitive experiments have shown that this humoral agent is a hormone that arises in the jejunum. Elaboration of the hormone is triggered both by the entry of food into the jejunum and by a brief period of jejunal distension with a balloon.

There is a need for a simple, safe, reproducible and non-invasive method for studying upper gastrointestinal motility in humans. Existing methods, measuring electrical contractions and intraluminal pressure changes have limitations in their correlation with the physiology of what is actually happening to ingested food. Transit time has been suggested as a more physiologic means of studying gut motility; therefore a method was developed to measure transit time and secretory changes in response to ingested liquids, using ileostomy patients. 2.5 gm of polyethylene glycol (PEG) was added to 500 ml of normal saline, and given orally to volunteers with ileostomies. The ileostomy effluent was collected for 2 hours in 10 minute aliquots. PEG assay was performed by the turbidimetric method of Hyden, using Malawer's modification with an emulsifier. The following were measured: most rapid, mode, median, mean and total transit t imes. A study was then performed to determine if different foodstuffs -carbohydrate, fat, and protein - produce measurable changes in transit time. 2.5 gm of PEG was added to 500 ml of (a) 90 ml Lipomul in 410 ml normal saline (b) 5% dextrose (c) 100 ml of Travasol 10% in 400 ml distilled water. The volumes were chosen to produce isoosmolar test feeds. Validating studies showed satisfactory reproducibility and individual variation (r = 0.68 for volume recovery, r = 0.69 for PEG recovery, p = < 0.5) The recovery pattern of a test feed of 500 ml normal saline was found to follow a skew distribution, with mode, median and mean transit times all different. The most reproducible and easily measured was mode, or peak, transit time (average 40 minutes for volume and PEG recovery). Significant delays in all transit times were found (p = < 0.01) using each of the test feeds: (a) for Lipomul a peak volume recovery of 60 minutes and PEG recovery of 70 minutes; (b) for 5% dextrose a peak volume recovery of 90 minutes and PEG recovery of 90 minutes; (c) with Travasol, negligible amounts of ileostomy output were obtained over 2 hours. The most rapid transit time was consistently less than 10 minutes, as measured by PEG appearance from the ileostomy. This is far less than previously described by standard methods, but is in accordance with transit times measured to the ileocaecal valve in intact gastrointestinal tracts using the recently-introduced breath hydrogen method following lactulose ingestion. Comparison of total volume recovery with total PEG recovery over 2 hours indicates whether net absorption or secretion has occurred: (a) with normal saline a volume recovery of 62% and PEG recovery of 48% indicates net secretion; (b) with Lipomul a volume recovery of 66% and PEG recovery of 58% also indicates net secretion, with no significant difference from normal saline (p = < 0.05); (c) with 5% dextrose a volume recovery of 4% and PEG recovery of 13% indicates net absorption, significantly different from normal saline (p = < 0.01); (d) for Travasol a volume recovery of 1% and PEG recovery of 1% indicates no net absorption or secretion, but confirms the above finding of a very large delay in transit time. These studies have shown that isotonic solutions of normal saline, glucose, fat and protein result in widely different peak transit times in ileostomy patients. They also result in widely different fluid outputs from the ileostomy due to net absorption or secretion. These differences have not been described before. / Surgery, Department of / Medicine, Faculty of / Graduate

The human colonic carcinoma cell lines HT-29 and Caco-2 both exhibit structural and functional differentiation under appropriate culture conditions. HT-29 can be induced to differentiate by treatment with short-chain fatty acids or acetoacetate. Caco-2 cells differentiate spontaneously upon contact inhibition. In this study HT-29 cells were treated with 5 mM acetate, propionate, butyrate and acetoacetate (physiological inducers) to assess their effects on the expression of carbonic anhydrase 1, sucrase-isomaltase and alkaline phosphatase which are reported to be markers of gastrointestinal differentiation. The maturation induction observed was compared to that of the spontaneous differentiation observed in Caco-2 cells. Assays were performed over an 18 day period. Results showed a close correlation (p < 0.05) between HT-29 and Caco-2 cell on days 4 and 12. These results indicate that differentiation reported in both cell lines is comparable and can be used as a basis for further comparative studies. In addition, parallel experiments to the above were conducted using a selection of nine rationally designed cyclic dipeptides (CDPs) potential drug entities which were chosen as non-physiological inducers. The results showed that the cyclic dipeptides were able to induce the gastrointestinal phenotype as observed in HT-29 cells treated with physiological inducers. Studies on the effects of energy-related metabolism in HT-29 and Caco-2 cells as induced by physiological and non-physiological inducers indicated that energy metabolism is a significant role player in gastrointestinal differentiation. The results reported show a decrease in ATP concentrations indicating that the cyclic dipeptides, like physiological inducers, affect the energy state of the HT-29 cells and thus may effect the differentiation of these cells. A positive correlation was found between histone phsophorylation and differentiation confirming that histone phsophorylation was partly responsible for the decrease in ATP concentrations. It is suggested that the induction of differentiation in HT- 29 cells could be either due to non-specific transcription of genes by activation of a chromatin switch or specific by the activation of signal transduction pathways based on the flux of ATP through the cells. Differential display RT-PCR is probably the most sensitive method that could be used to validate the suggestion of either a nonspecific transcription of genes or a specific differentiation reported for HT-29 cells.

Systemic hydration, plasma electrolytes, ingesta and fecal hydration and gastrointestinal passage of cobalt (after CoEDTA administration via nasogastric tube) in horses fed large grain meals or treated with enteral fluid therapy, IV fluid therapy and enteral laxatives were investigated. In the first study, 0.9% NaCl (10 L/h/8h) was administered slowly via a small-bore nasogastric tube or as 10 L boluses via a large-bore nasogastric tube to four normal horses. In the other studies, horses with a right dorsal colon fistula were used. To create the right dorsal colon fistula, a cannula with 5 cm internal diameter was implanted 2 to 6 weeks after a right dorsal colopexy had been created. Six horses with the right dorsal colostomy were alternately used to test three feeding regimes for 48 h: 1- hay free choice; 2- hay free choice plus 4.5 kg of sweet feed twice daily after a period of 5 days of adaptation; 3- sudden change from hay to hay plus sweet feed. Seven horses with the right dorsal colostomy were alternately used to test 6 experimental conditions while fasted for 24 h: 1- control (no treatment), 2- enteral MgSO4 (1 g/kg), 3- enteral Na2SO4 (1 g/kg), 4- IV lactated Ringer's solution (5 L/h/12 h), 5- enteral water (5 L/h/12 h), 6- enteral electrolyte solution (5 L/h/12 h). In the last study, four horses with the right dorsal colostomy were alternately treated with enteral electrolyte solution (10 L/h/6h) and enteral MgSO4 (1 g/kg) plus IV fluid therapy (10 L/h/6h). Despite the administration regimen, enteral administration of 0.9% NaCl produced diarrhea, hypernatremia and hyperchloremia. Colostomy allowed serial collection of large ingesta samples. Grain ingestion did not change PCV or plasma protein, but affected plasma electrolytes and produced dehydration of ingesta and formation of frothy ingesta. Fasting delayed gastrointestinal transit. Enteral fluid therapy was the most effective treatment in promoting ingesta hydration. Enteral water, MgSO4, Na2SO4, IV fluid therapy and enteral MgSO4 plus IV fluid therapy were either ineffective in promoting ingesta hydration or produced marked plasma electrolyte imbalance. These findings support the use of enteral fluid therapy in horses with gastrointestinal impaction. / Ph. D.

This Thesis examined the contributions of gastrointestinal and/or sensory influences to the control of food intake in everyday life. The postingestional effects at first exposure to an unfamiliar variant of a familiar food were measured by correcting the observed satiating effects with what the eater expected them to be. Physical forms of fat or chemical compositions of carbohydrate in familiar foods differed in the timing of these postingestional satiating effects. Cream, which is hypothesised to empty rapidly from the stomach into the intestine, satiated rapidly but transiently. Conversely, oil that was liable to separation in the stomach produced a delayed and more prolonged satiating effect. Learning about the postprandial effects of foods containing unfamiliar levels of a form of nutrient occurred at first exposure to the after-effects of that variant: that is, sensory recognition of that variant at the second exposure resulted in participants' predictions of its satiating effect becoming more realistic. A more prolonged satiating effect was expected from yoghurts containing a higher amount of fat. At the same time, repeated exposure to a particular flavour of yoghurt induced more accurate predictions of the postprandial effects of the amount of fat associated with that flavour. Expected duration of hunger suppression by familiar and identifiable foods was related to some extent to the observed differences in the duration of postingestional satiating effects of a particular nutrient preparation. Pasta with an oily salad dressing was believed to satiate the eater for longer than a pasta with a creamy salad dressing. Breakfast cereal labelled as high in fibre was expected to produce a more prolonged satiating effect than protein and so on in order for starch, fat or sugar. These differences in expected postingestional satiating after-effects of a food or meal may contribute to the planning of meal contents and perhaps timing. Unexpected timing of a meal or a `surprise' in the postingestional effects of a food altered the composition of the next meal of another sort from the participant's usual choice towards one giving the appropriate after-effects.

published_or_final_version / abstract / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Master / Master of Public Health

No description available.

No description available.

The effects of cholecystokinin octapeptide (CCK-8), and its antagonist proglumide, upon conditioned behavior in the rat was studied. First, the effects of CCK-8 and proglumide upon passive avoidance behavior was investigated. Rats were trained to avoid a darkened chamber by presenting electrical footshock (two seconds of intensity levels) inside the chamber. Directly following the footshock, injections of CCK-8 or proglumide were given, with avoidance behavior measured 24 hours following the injection. CCK-8 was found to produce reductions in the passive avoidance latency at doses ranging from 30 ug/Kg to 500 ug/Kg. This effect was found to be dependent upon the current intensity used during conditioning. The CCK-8 effect was found when the current was at 0.25 mA, but at no other current setting tested. Proglumide (5 mg/Kg) was found to block the CCK-8 effect upon passive avoidance behavior. A lower dose of proglumide (2 mg/Kg) was found to produce reductions in the passive avoidance latency. These results suggest that CCK-8 may play a role in passive avoidance conditioning in rats. The effects of CCK-8 upon an appetitively conditioned behavior were then investigated. Rats were trained to locate and drink from a drinking tube that contained a 10 percent sucrose solution. Following 30 seconds exposure to the solution, injections of CCK-8 were given, with the latency to begin drinking from the tube measured 24 hours later. CCK-8 was found to produce increases in the latency to begin drinking, at doses of 20 ug/Kg and 100 ug/Kg. CCK-8 also produced a reduction in the amount of sucrose solution consumed during the test period. When CCK-8 was given following exposure to regular tap water, no increase in drinking latency or reduction in consumption was found. These results suggest that CCK-8 can act as an aversive stimulus and is capable of producing conditioned taste aversions. The results of this dissertation project demonstrate that CCK-8 can influence the acquisition of conditioned behavior in the rat when the octapeptide is paired with the presentation of an unconditioned stimulus (shock or sucrose).