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Background: Hephaestin is a multicopper ferroxidase required for basolateral transport of iron from enterocytes. Sex linked anaemia (sla) mice have a defect in the release of iron from intestinal enterocytes into the circulation due to an interstitial deletion in the hephaestin gene (heph). Results: We have demonstrated that hephaestin is primarily localised to a supranuclear compartment in both intestinal enterocytes and in cultured cells. In normal intestinal enterocytes, hephaestin was also present on the basolateral surface. In sla mice, hephaestin was present only in the supranuclear compartment. In contrast, the iron permease Ireg1 localised to the basolateral membrane in both control and sla mice. Conclusion: We suggest that mislocalisation of hephaestin likely contributes to the functional defect in sla intestinal epithelium.

Background: A large oral dose of iron will reduce the absorption of a subsequent smaller dose of iron in a phenomenon known as mucosal block. Molecular analysis of this process may provide insights into the regulation of intestinal iron absorption. Aims: To determine the effect of an oral bolus of iron on duodenal expression of molecules associated with intestinal iron transport in rats and to relate this to changes in iron absorption. Methods: Rats were given an oral dose of iron and duodenal expression of divalent metal transporter 1 (DMT1), Dcytb, Ireg1, and hephaestin (Hp) was determined using the ribonuclease protection assay, western blotting, and immunofluorescence. Iron absorption was measured using radioactive 59Fe. Results: A decrease in intestinal iron absorption occurred following an oral dose of iron and this was associated with increased enterocyte iron levels, as assessed by iron regulatory protein activity and immunoblotting for ferritin. Reduced absorption was also accompanied by a rapid decrease in expression of the mRNAs encoding the brush border iron transport molecules Dcytb and the iron responsive element (IRE) containing the splice variant of DMT1. No such change was seen in expression of the non-IRE splice variant of DMT1 or the basolateral iron transport molecules Ireg1 and Hp. Similar changes were observed at the protein level. Conclusions: These data indicate that brush border, but not basolateral, iron transport components are regulated locally by enterocyte iron levels and support the hypothesis that systemic stimuli exert their primary effect on basolateral transport molecules.

BACKGROUND—Paracellular permeability to solutes across the descending colon is much higher in cattle than sheep. This is a possible route for transmission of infective materials, such as scrapie prion. AIMS—To compare the permeabilities of labelled scrapie prion protein and other macromolecules in bovine and ovine descending colons in vitro. METHODS—Using fresh slaughterhouse material, transepithelial fluxes of macromolecules across colonic mucosae mounted in Ussing chambers were measured by monitoring transport of either enzyme activity or radioactivity. RESULTS—The comparative bovine to ovine permeability ratio of the probes increased with molecular weight: from 3.1 (0.13) for PEG400 to 10.67 (0.20) (p

Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

Introduction Administration of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide reduces food intake and induces weight loss. GLP-1 receptors are located throughout the body including the brain and vagal afferent neurones. Although exenatide slows gastric emptying (GE), it is believed the main mechanism behind exenatide-induced weight loss may be related to activation of central pathways that mediate satiety. However, research in humans is lacking. Brain activation can be indirectly measured by quantifying changes in the blood oxygen level dependent (BOLD) signal measured during functional magnetic resonance imaging (fMRI). Methods To confirm a gastric inhibitory effect of exenatide, 12 healthy volunteers received a subcutaneous injection of 5 µg exenatide or placebo on separate occasions 60min prior to consumption of a 0.5 M carbohydrate test drink (500 mL). Over 45 min GE was non-invasively measured using breath tests. Then, to examine brain activation using fMRI, 15 healthy volunteers received 5 µg exenatide or placebo after ~10 h fast and underwent 70 min scanning (3T Philips scanner). Wholebrain analysis was conducted (data for the hypothalamus only are reported). For each volunteer the difference in mean%BOLD signal change from baseline between exenatide and placebo was extracted and analysed in 5min blocks using T-tests. Two volunteers were excluded due to excessive movement during scans. Results Repeated measures ANOVA revealed that exenatide significantly slowed GE of the test drink with the area under the curve for exenatide being 31% lower than placebo (p Conclusion Our data confirms that a single dose of exenatide potently delays GE. Furthermore, most regions of the hypothalamus, a key appetite regulatory brain area, were progressively activated 45 min after exenatide administration. Those volunteers were fasted which suggests that the anorectic effects of exenatide in humans could be mediated via activation of central GLP-1 receptors, either directly or via vagal inputs. Further analysis will now be conducted to examine the effect of exenatide on areas in the brain associated with food reward such as the insula and orbitofrontal cortex. Disclosure of Interest None Declared.

Introduction Liver is the most common site of metastatic spread in colorectal cancer, and its management has significantly evolved in recent decades with liver resection now being the optimal treatment. Aims/Background This study aimed to assess referral patterns from colorectal multidisciplinary meetings (MDMs) throughout Northern Ireland to the Regional HPB Unit. Method Over a 6 week period all colorectal MDMs throughout the five health and social care trusts were reviewed. Patients with colorectal liver metastases (CRLMs) were included in the study. The following data were included: patient demographics, details of the health and social care trust, date of MDM discussion, primary tumour pathology, and the MDM outcome. These findings were subsequently compared with regional guidelines for the referral of CRLMs to assess if the decision was deemed appropriate. Results 21 discussions were recorded, which involved 20 patients, with a mean age of 69 years and 13 were male. 40% of patients were from the Belfast trust, while the remainder was evenly distributed between the 4 remaining trusts. All CRLMs discussed were confirmed by computerised tomography scanning, and the MDM decision was deemed to be appropriate in 85% of patients. Only 15% of patients had KRAS testing performed and 20% were subsequently referred for PET-CT scanning. Conclusion The majority of potentially resectable colorectal liver metastases had an appropriate outcome in terms of management and referral to the Regional HPB unit. However, this could still be further streamlined through both education, and highlighting the role of PET-CT and KRAS testing.

Aims/Background The aim of this study was to evaluate the outcomes following open biliary bypass for benign biliary and pancreatic diseases. Method Sixty-four patients (M: F=34:30) aged 15 to 89 years (median age: 54 years) underwent biliary bypass for benign diseases between 2001 and 2011. Indications for surgery were choledocholithiasis (n=18), chronic pancreatitis (n=18), iatrogenic bile duct injury (n=12), distal bile duct strictures (n=11), choledochal cyst (n=2) and other causes (n=3). Thirty-eight patients (60%) had prior surgical or endoscopic intervention. Results Sixty hepaticojejunostomies and four choledochoduodenostomies were performed. Additional procedures during the same surgery included cholecystectomy (n=25), drainage of pseudocyst (n=4), gastroenterostomy (n=4), pancreatic biopsy (n=4), liver biopsy (n=4), cyst gastrostomy (n=2) and pancreatic necrosectomy (n=2). Postoperative complications were encountered in 12 patients – bile leak (n=2), bleeding (n=2), chest infection (n=2), MI (n =1), superficial surgical site infection (n=4) and superficial wound dehiscence (n=1). Three patients required further surgery–bile leak (n=1), bleeding (n=2). Two patients (3%) died of organ failure-one following biliary bypass for cholangitis; and one following ligation of a bleeding pseudo aneurysm. Five patients developed recurrent cholangitis requiring oral antibiotics. Conclusion In the era of minimally invasive options, open biliary bypass remains a very effective, reliable and safe option in the management of benign conditions of the biliary system and pancreas.

Introduction Laparoscopic Cholecystectomy is the gold standard treatment of symptomatic gallstone disease. Incidental gallbladder cancer is found in 0.6–2.1% of cases. Patients with Tis or T1a tumours generally undergo no further intervention. We present a case report and suggest the need for an aggressive management approach in patients with incidental Tis or T1a gallbladder cancer who had spilled stones at primary laparoscopic cholecystectomy. Method A 37 year-old lady underwent a laparoscopic cholecystectomy for symptomatic gallstone disease. At operation, a number of gallstones were spilled into the peritoneal cavity. Subsequent histological examination showed an incidental pT1a gallbladder cancer, with areas of high grade dysplasia. HPB MDM discussion agreed on regular six-monthly outpatient follow-up. The patient re-presented to outpatient clinic 2 years later with recurrent right upper quadrant pain. Computed Tomography imaging revealed a small lesion in segment 6 of the liver. The patient underwent a diagnostic laparotomy which found multiple metastatic deposits, which on histological examination, were felt to have derived from the spilled gallstones at initial laparoscopic cholecystectomy. Due to the multiple metastatic deposits, the disease was un-resectable and she is to be treated with palliative chemotherapy. Results Spilled gallstones occur in around 5-7% of laparoscopic cholecystectomies. There is a paucity of literature on the management of patients with spilled gallstones who subsequently are found to have incidental gallbladder cancer. Gallbladder cancers stage Tis or T1a have a favourable prognosis and are normally treated with simple cholecystectomy alone but this case has demonstrated a devastating outcome to this management approach. Conclusion We suggest an aggressive management approach to patients with spilled gallstones who are subsequently found to have low grade Gallbladder Cancer.