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Background Recent reports showed that overseas doctors were more likely than UK graduates to be referred by their employers to the General Medical Council (GMC) . We investigated the trend of medico-legal insurance awareness and uptake of medical defence organisations (MDOs) by junior doctors and to examine if there is a difference between overseas and UK graduates. Methods Online questionnaire survey sent to junior doctors within the Yorkshire and Humber Deanery. Data regarding year of graduation, country of origin of primary medical qualification, year of starting work in the National Health Service (NHS) and date of joining an MDO were collected. Participant-identifiable information was not collected. Results A total of 202 junior doctors completed the survey: 153 (76%) UK graduates and 49 (24%) overseas. Overseas doctors were less likely to know about MDO compared to UK graduates prior to working in the NHS (13 [26.5%] vs. 146 [95.4%]; p < 0.0001). At the time of starting practice, MDO uptake was still significantly lower amongst overseas graduates (4 [8.2%] vs. 144 [94.1%]; p < 0.0001). Uptake by overseas doctors increased after starting work to 33 (67.3%). However, despite improvement in MDO uptake, a significant number of overseas doctors still did not have independent cover compared with UK graduates (16 [32.7%] vs. 3 [2%]; p < 0.0001). Conclusions Overseas graduates joining the NHS are still less likely to be aware of the requirement of adequate medico-legal cover and are less likely to join an MDO compared with UK graduates. Healthcare providers and regulators should work to decrease the existing gap and increase awareness amongst newly arrived overseas doctors., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Jalal et al.)

Overseas doctors are playing an important role in the successful running of the NHS. They represent one-third of the total number of UK doctors and include doctors from the European Economic Area and international medical graduates. The main aim of this review is to explore the challenges that overseas doctors might face when they take up their first job in the UK. We conducted literature search using MEDLINE and EMBASE databases. The inclusion and exclusion criteria were designed to include published literature concerning overseas doctors in the UK and the NHS. Lack of information about the UK health system; language and communication challenges; clinical, educational and work-culture challenges; and discrimination challenges are some of the difficulties that overseas doctors might experience. Understanding these challenges and providing support are important steps in helping overseas doctors to make a smooth transition.

Our patient, aged 73 years, had background peripheral neuropathy of unknown cause, stable for several years, which caused some difficulty in walking on uneven ground. He attended for a teaching session but now staggered in, a new development. He had apparent weakness of his right arm, but there was difficulty in distinguishing motor weakness from impaired spatial awareness suggestive of parietal lobe dysfunction. With the patient seated, eyes closed, and left arm outstretched, S.A.R. lifted the patient's right arm and asked him to indicate when both were level. This confirmed motor weakness. Urgent computed tomographic scan confirmed left subdural haematoma and its urgent evacuation rapidly resolved the patient's symptoms. Intrigued by our patient's case, we explored further and learnt that in rehabilitation medicine, the awareness of limb position is commonly viewed in terms of joint position sense. We present recent literature evidence indicating that the underlying mechanisms are more subtle., Competing Interests: DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

The visibility of the colon in positron emission tomography (PET) scans of patients without gastrointestinal disease indicating the presence of 18F Fluorodeoxyglucose (18FDG) is well recognised, but unquantified and unexplained. In this paper a qualitative scoring system was applied to PET scans from 30 randomly selected patients without gastrointestinal disease to detect the presence of 18FDG in 4 different sections of the colon and then both the total pixel value and the pixel value per unit length of each section of the colon were determined to quantify the amount of 18FDG from a randomly selected subset of 10 of these patients. Analysis of the qualitative scores using a non-parametric ANOVA showed that all sections of the colon contained 18FDG but there were differences in the amount of 18FDG present between sections (p<0.05). Wilcoxon matched-pair signed-rank tests between pairs of segments showed statistically significant differences between all pairs (p<0.05) with the exception of the caecum and ascending colon and the descending colon. The same non-parametric statistical analysis of the quantitative measures showed no difference in the total amount of 18FDG between sections (p>0.05), but a difference in the amount/unit length between sections (p<0.01) with only the caecum and ascending colon and the descending colon having a statistically significant difference (p<0.05). These results are consistent since the eye is drawn to focal localisation of the 18FDG when qualitatively scoring the scans. The presence of 18FDG in the colon is counterintuitive since it must be passing from the blood to the lumen through the colonic wall. There is no active mechanism to achieve this and therefore we hypothesise that the transport is a passive process driven by the concentration gradient of 18FDG across the colonic wall. This hypothesis is consistent with the results obtained from the qualitative and quantitative measures analysed.

The medical profession is becoming ever more interested in the use of gas-phase biomarkers for disease identification and monitoring. This is due in part to its rapid analysis time and low test cost, which makes it attractive for many different clinical arenas. One technology that is showing promise for analyzing these gas-phase biomarkers is the electronic nose--an instrument designed to replicate the biological olfactory system. Of the possible biological media available to "sniff", urine is becoming ever more important as it is easy to collect and to store for batch testing. However, this raises the question of sample storage shelf-life, even at -80 °C. Here we investigated the effect of storage time (years) on stability and reproducibility of total gas/vapour emissions from urine samples. Urine samples from 87 patients with Type 2 Diabetes Mellitus were collected over a four-year period and stored at -80 °C. These samples were then analyzed using FAIMS (field-asymmetric ion mobility spectrometry--a type of electronic nose). It was discovered that gas emissions (concentration and diversity) reduced over time. However, there was less variation in the initial nine months of storage with greater uniformity and stability of concentrations together with tighter clustering of the total number of chemicals released. This suggests that nine months could be considered a general guide to a sample shelf-life.

Introduction. Abdominal adhesions can cause serious morbidity and complicate subsequent operations. Their diagnosis is often one of exclusion due to a lack of a reliable, non-invasive diagnostic technique. Development and testing of a candidate technique are described below. Method. During respiration, smooth visceral sliding motion occurs between the abdominal contents and the walls of the abdominal cavity. We describe a technique involving image segmentation and registration to calculate shear as an analogue for visceral slide based on the tracking of structures throughout the respiratory cycle. The presence of an adhesion is attributed to a resistance to visceral slide resulting in a discernible reduction in shear. The abdominal movement due to respiration is captured in sagittal dynamic MR images. Results. Clinical images were selected for analysis, including a patient with a surgically confirmed adhesion. Discernible reduction in shear was observed at the location of the adhesion while a consistent, gradually changing shear was observed in the healthy volunteers. Conclusion. The technique and its validation show encouraging results for adhesion detection but a larger study is now required to confirm its potential.

Background & Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is the commonest cause of chronic liver disease in the western world. Current diagnostic methods including Fibroscan have limitations, thus there is a need for more robust non-invasive screening methods. The gut microbiome is altered in several gastrointestinal and hepatic disorders resulting in altered, unique gut fermentation patterns, detectable by analysis of volatile organic compounds (VOCs) in urine, breath and faeces. We performed a proof of principle pilot study to determine if progressive fatty liver disease produced an altered urinary VOC pattern; specifically NAFLD and Non-Alcoholic Steatohepatitis (NASH)., Methods: 34 patients were recruited: 8 NASH cirrhotics (NASH-C); 7 non-cirrhotic NASH; 4 NAFLD and 15 controls. Urine was collected and stored frozen. For assay, the samples were defrosted and aliquoted into vials, which were heated to 40±0.1°C and the headspace analyzed by FAIMS (Field Asymmetric Ion Mobility Spectroscopy). A previously used data processing pipeline employing a Random Forrest classification algorithm and using a 10 fold cross validation method was applied., Results: Urinary VOC results demonstrated sensitivity of 0.58 (0.33 - 0.88), but specificity of 0.93 (0.68 - 1.00) and an Area Under Curve (AUC) 0.73 (0.55 - 0.90) to distinguish between liver disease and controls. However, NASH/NASH-C was separated from the NAFLD/controls with a sensitivity of 0.73 (0.45 - 0.92), specificity of 0.79 (0.54 - 0.94) and AUC of 0.79 (0.64 - 0.95), respectively., Conclusions: This pilot study suggests that urinary VOCs detection may offer the potential for early non-invasive characterisation of liver disease using 'smell prints' to distinguish between NASH and NAFLD.

Colorectal cancer is a leading cause of cancer death in the USA and Europe with symptoms that mimick other far more common lower gastrointestinal (GI) disorders. This difficulty in separating colorectal cancer from these other diseases has driven researchers to search for an effective, non-invasive screening technique. Current state-of-the-art method of Faecal Immunochemical Testing achieving sensitivity ~90%, unfortunately the take-up in the western world is low due to the low patient acceptability of stool samples. However, a wide range of cancers have been distinguished from each-other and healthy controls by detecting the gas/volatile content emanating patient biological media. Dysbiosis afforded by certain disease states may be expressed in the volatile content of urine - a reflection of the gut bacteria's metabolic processes. A new electronic nose instrument was developed at the University of Warwick to measure the gas/volatile content of urine headspace, based on an array of 13 commercial electro-chemical and optical sensors. An experimental setup was arranged for a cohort of 92 urine samples from patients of colorectal cancer (CRC), irritable bowel syndrome (IBS) and controls to be run through the machine. Features were extracted from response data and used in Linear Discriminant Analysis (LDA) plots, including a full 3-disease classification and one focussing on distinguishing CRC from IBS. The latter case was tested by the success of re-classification using an (n-1) K-nearest neighbour algorithm, showing 78% sensitivity and 79% specificity to CRC., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To determine the best faecal calprotectin (FCP) cut-off level for differentiating between irritable bowel syndrome (IBS) and organic disease, particularly inflammatory bowel disease (IBD), in patients presenting with chronic diarrhoea., Design: Retrospective analysis of patients who had colonoscopy, histology and FCP completed within 2 months., Setting: District general hospital., Patients: Consecutive new patients with chronic diarrhoea lasting longer than 4 weeks., Interventions: Patients were seen by a single experienced gastroenterologist and listed for colonoscopy with histology. Laboratory investigations included a single faecal specimen for calprotectin assay (lower limit of detection: 8 µg/g), the results used for information only., Main Outcome Measures: Six FCP cut-off levels (range 8-150 µg/g) were compared against the 'gold standard' of histology: inflammation 'present' or 'absent'., Results: Of 119 patients studied, 98 had normal colonoscopy and histology. The sensitivity of FCP to detect IBD at cut-off levels 8, 25 and 50 µg/g was 100% (with corresponding specificity 51%, 51%, 60%). In contrast, the lowest FCP cut-off, 8 µg/g, had 100% sensitivity to detect colonic inflammation, irrespective of cause (with negative predictive value (NPV) 100%). Importantly, 50/119 patients (42%) with FCP <8 µg/g had normal colonoscopy and histology., Conclusions: Our results suggest that using FCP to screen patients newly referred for chronic diarrhoea could exclude all without IBD and, at a lower cut-off, all without colonic inflammation, thus avoiding the need for colonoscopy. Such a major reduction has implications for resource allocation.

Coeliac disease (CD), a T-cell-mediated gluten sensitive enteropathy, affects ∼ 1% of the UK population and can present with wide ranging clinical features, often being mistaken for Irritable Bowel Syndrome (IBS). Heightened clinical awareness and serological screening identifies those with potential coeliac disease; the diagnosis is confirmed with duodenal biopsies, and symptom improvement with a gluten-free diet. Limitations to diagnosis are false negative serology and reluctance to undergo biopsy. The gut microbiome is altered in several gastrointestinal disorders, causing altered gut fermentation patterns recognisable by volatile organic compounds (VOC) analysis in urine, breath and faeces. We aimed to determine if CD alters the urinary VOC pattern, distinguishing it from IBS. 47 patients were recruited, 27 with established CD, on gluten free diets, and 20 with diarrhoea-predominant IBS (D-IBS). Collected urine was stored frozen in 10 ml aliquots. For assay, the specimens were heated to 40 ± 0.1°C and the headspace analysed by Field Asymmetric Ion Mobility Spectrometry (FAIMS). Machine learning algorithms were used for statistical evaluation. Samples were also analysed using Gas chromatography and mass spectroscopy (GC-MS). Sparse logistic regression showed that FAIMS distinguishes VOCs in CD vs D-IBS with ROC curve AUC of 0.91 (0.83-0.99), sensitivity and specificity of 85% respectively. GCMS showed a unique peak at 4'67 found only in CD, not D-IBS, which correlated with the compound 1,3,5,7 cyclooctatetraene. This study suggests that FAIMS offers a novel, non-invasive approach to identify those with possible CD, and distinguishes from D-IBS. It offers the potential for monitoring compliance with a gluten-free diet at home. The presence of cyclooctatetraene in CD specimens will need further validation.

Colorectal cancer (CRC) is a leading cause of cancer related death in Europe and the USA. There is no universally accepted effective non-invasive screening test for CRC. Guaiac based faecal occult blood (gFOB) testing has largely been superseded by Faecal Immunochemical testing (FIT), but sensitivity still remains poor. The uptake of population based FOBt testing in the UK is also low at around 50%. The detection of volatile organic compounds (VOCs) signature(s) for many cancer subtypes is receiving increasing interest using a variety of gas phase analytical instruments. One such example is FAIMS (Field Asymmetric Ion Mobility Spectrometer). FAIMS is able to identify Inflammatory Bowel disease (IBD) patients by analysing shifts in VOCs patterns in both urine and faeces. This study extends this concept to determine whether CRC patients can be identified through non-invasive analysis of urine, using FAIMS. 133 patients were recruited; 83 CRC patients and 50 healthy controls. Urine was collected at the time of CRC diagnosis and headspace analysis undertaken using a FAIMS instrument (Owlstone, Lonestar, UK). Data was processed using Fisher Discriminant Analysis (FDA) after feature extraction from the raw data. FAIMS analyses demonstrated that the VOC profiles of CRC patients were tightly clustered and could be distinguished from healthy controls. Sensitivity and specificity for CRC detection with FAIMS were 88% and 60% respectively. This study suggests that VOC signatures emanating from urine can be detected in patients with CRC using ion mobility spectroscopy technology (FAIMS) with potential as a novel screening tool.

Background & Aims: Celiac disease shares features of other disorders. It can be diagnosed conclusively only based on duodenal histology analysis, which is not practical for screening purposes. Serologic analysis might be used to identify candidates for biopsy analysis. We aimed to develop a simple diagnostic approach that all clinicians could follow to increase the percentage of patients accurately diagnosed with celiac disease at initial presentation., Methods: We performed a retrospective analysis of data from 752 patients (88 with celiac disease, none were IgA deficient) who attended a UK district general hospital from January 2007 through December 2008 and underwent biopsy analysis and serologic tests to measure endomyseal antibodies and IgA antibodies against tissue transglutaminase (tTG). Patients avoiding gluten in their diet were excluded. Patients were assigned to 1 of 4 groups: high-risk (based on presence of anemia, chronic diarrhea, unintentional weight loss, or dermatitis herpetiformis), low-risk (based on such factors as dyspepsia, abnormal liver function, ataxia, or chronic cough), nutrient deficiency (based on levels of iron, vitamins B12 and D, or folate), or screening (because they had type 1 diabetes or a family history of celiac disease). Patients with celiac disease were identified using the modified Marsh criteria (grades 1-3) for interpreting duodenal histology. We compared clinical category, serology profiles, and biopsy results between patients with and without celiac disease., Results: Celiac disease was diagnosed in 64 of 565 patients in the high-risk group (11%), 14 of 156 patients in the low-risk group (9%; P = .47 compared with high-risk group), 7 of 28 patients in the nutrient-deficiency group, and 3 of 3 patients in the screening group. Among 71 patients who tested positive for both antibodies (tTG and endomyseal antibodies), the positive predictive value for celiac disease was 97%; a negative test result for tTG had a negative predictive value of 98%. Among 708 patients with normal-looking biopsy samples, only 62 had celiac disease (9%). Among 44 patients with abnormal biopsy samples, 26 had celiac disease (59%)., Conclusions: Based on a retrospective analysis, patients with and without celiac disease cannot be distinguished based on clinical features. Patients who present with symptoms of celiac disease should be tested for tTG, to identify candidates for duodenal biopsy analysis., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis., Aim: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea., Methods: One hundred and fifty-two consecutive patients were grouped according to (75) Se-homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; ≤15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7α-hydroxy-4-cholesten-3-one (C4) and total bile acids., Results: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 ≤ 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy., Conclusions: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy., (© 2013 John Wiley & Sons Ltd.)

Bile acid diarrhoea (BAD) is a common disease that requires expensive imaging to diagnose. We have tested the efficacy of a new method to identify BAD, based on the detection of differences in volatile organic compounds (VOC) in urine headspace of BAD vs. ulcerative colitis and healthy controls. A total of 110 patients were recruited; 23 with BAD, 42 with ulcerative colitis (UC) and 45 controls. Patients with BAD also received standard imaging (Se75HCAT) for confirmation. Urine samples were collected and the headspace analysed using an AlphaMOS Fox 4000 electronic nose in combination with an Owlstone Lonestar Field Asymmetric Ion Mobility Spectrometer (FAIMS). A subset was also tested by gas chromatography, mass spectrometry (GCMS). Linear Discriminant Analysis (LDA) was used to explore both the electronic nose and FAIMS data. LDA showed statistical differences between the groups, with reclassification success rates (using an n-1 approach) at typically 83%. GCMS experiments confirmed these results and showed that patients with BAD had two chemical compounds, 2-propanol and acetamide, that were either not present or were in much reduced quantities in the ulcerative colitis and control samples. We believe that this work may lead to a new tool to diagnose BAD, which is cheaper, quicker and easier that current methods.

It is well known that the electronic nose can be used to identify differences between human health and disease for a range of disorders. We present a pilot study to investigate if the electronic nose and a newer technology, FAIMS (Field Asymmetric Ion Mobility Spectrometry), can be used to identify and help inform the treatment pathway for patients receiving pelvic radiotherapy, which frequently causes gastrointestinal side-effects, severe in some. From a larger group, 23 radiotherapy patients were selected where half had the highest levels of toxicity and the others the lowest. Stool samples were obtained before and four weeks after radiotherapy and the volatiles and gases emitted analysed by both methods; these chemicals are products of fermentation caused by gut microflora. Principal component analysis of the electronic nose data and wavelet transform followed by Fisher discriminant analysis of FAIMS data indicated that it was possible to separate patients after treatment by their toxicity levels. More interestingly, differences were also identified in their pre-treatment samples. We believe these patterns arise from differences in gut microflora where some combinations of bacteria result to give this olfactory signature. In the future our approach may result in a technique that will help identify patients at "high risk" even before radiation treatment is started.

Gastroesophageal reflux disease is mediated principally by acid. Today, we recognise reflux reaches beyond the esophagus, where pepsin, not acid, causes damage. Extraesophageal reflux occurs both as liquid and probably aerosol, the latter with a further reach. Pepsin is stable up to pH 7 and regains activity after reacidification. The enzyme adheres to laryngeal cells, depletes its defences, and causes further damage internally after its endocytosis. Extraesophageal reflux can today be detected by recognising pharyngeal acidification using a miniaturised pH probe and by the identification of pepsin in saliva and in exhaled breath condensate by a rapid, sensitive, and specific immunoassay. Proton pump inhibitors do not help the majority with extraesophageal reflux but specifically formulated alginates, which sieve pepsin, give benefit. These new insights may lead to the development of novel drugs that dramatically reduce pepsinogen secretion, block the effects of adherent pepsin, and give corresponding clinical benefit."For now we see through a glass, darkly."-First epistle, Chapter 13, Corinthians.

Background: In developing countries the prevalence of duodenal ulceration is related to the staple diet and not to the prevalence of Helicobacter pylori. Experiments using animal peptic ulcer models show that the lipid fraction in foods from the staple diets of low prevalence areas gives protection against ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promotes healing of ulceration. The lipid from the pulse Dolichos biflorus (Horse gram) was highly active and used for further investigations. Further experiments showed the phospholipids, sterol esters and sterols present in Horse gram lipid were gastroprotective. Dietary phospholipids are known to be protective, but the nature of protective sterols in staple diets is not known. The present research investigates the nature of the protective phytosterols., Methods: Sterol fractions were extracted from the lipid in Dolichos biflorus and tested for gastroprotection using the rat ethanol model. The fractions showing protective activity were isolated and identification of the components was investigated by Gas Chromatography-Mass Spectrometry (GC-MS)., Results: The protective phytosterol fraction was shown to consist of stigmasterol, β-sitosterol and a third as yet unidentified sterol, isomeric with β-sitosterol., Conclusions: Dietary changes, affecting the intake of protective phospholipids and phytosterols, may reduce the prevalence of duodenal ulceration in areas of high prevalence and may reduce the incidence of recurrent duodenal ulceration after healing and elimination of Helicobacter pylori infection. A combination of phospholipids and phytosterols, such as found in the lipid fraction of ulceroprotecive foods, may be of value in giving protection against the ulcerogenic effect of NSAIDs.

Spinal afferent neurons, with endings in the intestinal mesenteries, have been shown to respond to changes in vascular perfusion rates. The mechanisms underlying this sensitivity were investigated in an in vitro preparation of the mesenteric fan devoid of connections with the gut wall. Afferent discharge increased when vascular perfusion was stopped ("flow off"), a response localized to the terminal vessels just prior to where they entered the gut wall. The flow-off response was compared following pharmacological manipulations designed to determine direct mechanical activation from indirect mechanisms via the vascular endothelium or muscle. Under Ca(2+)-free conditions, responses to flow off were significantly augmented. In contrast, the myosin light chain kinase inhibitor wortmannin (1 microM, 20 min) did not affect the flow-off response despite blocking the vasoconstriction evoked by 10 microM l-phenylephrine. This ruled out active tension, generated by vascular smooth muscle, in the response to flow off. Passive changes caused by vessel collapse during flow off were speculated to affect sensory nerve terminals directly. The flow-off response was not affected by the N-, P-, and Q-type Ca(2+) channel blocker omega-conotoxin MVIIC (1 muM intra-arterially) or the P2X receptor/ion channel blocker PPADS (50 microM). However, ruthenium red (50 microM), a blocker of nonselective cation channels, greatly reduced the flow-off response and also abolished the vasodilator response to capsaicin. Our data support the concept that mesenteric afferents sense changes in vascular flow during flow off through direct mechanisms, possibly involving nonselective cation channels. Passive distortion in the fan, caused by changes in blood flow, may represent a natural stimulus for these afferents in vivo.

Background and Aim: The outcome of gastro-oesophageal reflux disease treatment is traditionally assessed by measuring endoscopically confirmed healing and symptom relief separately. Both terms together, indicating complete remission, are intuitively a more realistic clinical endpoint but are assessed less often., Aim: To explore this concept, we formally compared the efficacy of the proton pump inhibitors (PPIs) pantoprazole and esomeprazole using rates of complete remission judged against rates of healing and symptom relief separately., Methods: Five hundred and eighty-two patients with erosive gastro-oesophageal reflux disease were randomized to treatment for 4, 8, or 12 weeks with either pantoprazole or esomeprazole 40 mg daily. Symptom relief was assessed with the validated ReQuesttrade mark-GI subscale., Results: Approximately 75% of patients were free of symptoms or had no oesophageal lesions after 4 weeks' treatment, rising to about 93% and 96%, respectively, at 12 weeks. Complete remission rates were, however, lower at these time points; approximately 60% and about 90%, respectively. Both PPIs had similar efficacy., Conclusions: Endoscopically confirmed healing and symptom relief assessed separately over-estimated the benefits of both drugs. In contrast, complete remission indicates that patients may be treated inadequately when given the standard 4- to 8-week treatment. We suggest that complete remission is a more reliable and clinically relevant endpoint of treatment.

After a meal the activity of the gut increases markedly as digestion takes place. Associated with this increase in activity is an increase in blood flow, which has been shown to be dependent on factors such as caloric content and constitution of the meal. Much qualitative work has been carried out regarding mechanisms for the presence of food in a section of gut producing increased blood flow to that section, but there are still many aspects of this process that are not fully understood. In this paper we briefly review current knowledge on several relevant areas relating to gut blood flow, focusing on quantitative data where available and highlighting areas where further research is needed. We then present new data on the effect of feeding on flow in the superior mesenteric artery. Finally, we describe a framework for combining this data to produce a single model describing the mechanisms involved in postprandial hyperaemia. For a section of the model, where appropriate data are available, preliminary results are presented.

Background: While overall hospital admission rates for peptic ulcer declined in England in the 1990 s, they increased among the elderly, especially for complicated ulcer. However, peptic ulcer admissions fell for all age groups in the United States., Aim: To examine time trends in the incidence of hospital admissions, mortality and operations because of peptic ulcer in Scotland from 1982 to 2002, and the use of various drugs relevant to the aetiology and treatment of peptic ulcer from 1992 to 2002., Results: There was a general decrease in admission rates, especially for younger individuals. For individuals aged above 74 years, admission rates actually increased for gastric ulcer with haemorrhage among men, and for duodenal ulcer haemorrhage between both sexes. The number of operations fell dramatically, especially for younger patients. Mortality rates generally declined. Case fatality rates were greater for women than men, and declined over the study period for gastric ulcer, but increased for duodenal ulcer. The use of low-dose aspirin, oral anticoagulants, selective serotonin reuptake inhibitors and proton-pump inhibitors increased while those of non-steroidal anti-inflammatory drugs and histamine-2 antagonists declined., Conclusions: Admission rates for peptic ulcer generally fell for younger individuals, but increased for older people with haemorrhage.

Background: Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms., Aim: International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease., Methods: In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients., Results: Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale -0.6; Psychological General Well-being -0.4)., Conclusion: ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.

Background: The post-withdrawal characteristics of tegaserod treatment in patients with irritable bowel syndrome with constipation remain undefined., Aim: To evaluate the effects of continuous tegaserod treatment, versus intermittent or withdrawal of treatment in patients with irritable bowel syndrome with constipation., Methods: In a randomized, open-label trial, all patients initially received tegaserod 6 mg b.d. Responders were randomized to continue or withdraw from treatment for 8 weeks and symptom recurrence was assessed. Tegaserod was re-introduced in withdrawal patients who experienced symptom recurrence, allowing an assessment of intermittent treatment. Two separate analyses assessed the effects of intermittent and withdrawal of treatment on symptom recurrence., Results: Five hundred irritable bowel syndrome with constipation patients initially received tegaserod; 410 completed treatment. Time to symptom recurrence was shorter in withdrawal patients than those maintained on tegaserod. Significantly more patients maintained on tegaserod had not experienced symptom recurrence by week 8, compared with intermittent (86.5% vs. 58.1%, respectively) or withdrawal of treatment (69.2% vs. 11.3%, respectively) (P < 0.0001 for both). Significant treatment effects were observed for bloating (P < 0.01) and abdominal pain/discomfort (P < 0.02). Most adverse events were mild to moderate., Conclusions: Irritable bowel syndrome with constipation patients who receive continuous or intermittent tegaserod are less likely to experience symptom recurrence than patients withdrawn from treatment.