Showing papers in "Gut in 2008"

Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis

Abstract: 34 and the only effective treatment is liver transplantation. During the 56th Meeting of the American Association for the Study of Liver Diseases, the International Ascites Club held a Focused Study Group (FSG) on HRS for the purpose of reporting the results of an international workshop and to reach a consensus on a new definition, criteria for diagnosis and recommendations on HRS treatment. A similar workshop was held in Chicago in 1994 in which standardised nomenclature and diagnostic criteria for refractory ascites and HRS were established. 5 The introduction of innovative treatments and improvements in our understanding of the pathogenesis of HRS during the previous decade led to an increasing need to undertake a new consensus meeting. This paper reports the scientific rationale behind the new definitions and recommendations.

Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease

Abstract: Background: Clinical predictors of advanced non-alcoholic liver disease (NAFLD) are needed to guide diagnostic evaluation and treatment. Methods: To better understand the demographics of NAFLD and risk factors for advanced disease, this study analysed 827 patients with NAFLD at two geographically separate tertiary medical centres. Results: The cohort was 51% female and had a median body mass index (BMI) of 33 kg/m 2 ; 3% had a normal BMI. Common co-morbidities included hypertension (60%) and diabetes (35%); insulin resistance was present in 91% and advanced fibrosis in 24% of patients. When comparing patients with no fibrosis or mild fibrosis to those with advanced fibrosis, BMI ⩾28 kg/m 2 , age >50 years, and aspartate transaminase/alanine aminotransferase (AST/ALT) ratio ⩾0.8, a quantitative assessment check index (QUICKI) score 6.2) and the presence of diabetes mellitus (DM) were individually associated by univariate analysis with odds ratios (ORs) of ⩾2.4 for advanced fibrosis. Based on the results of forced entry logistic regression analysis, three variables were combined in a weighted sum ( B MI ⩾28 = 1 point, A AR of ⩾0.8 = 2 points, D M = 1 point) to form an easily calculated composite score for predicting advanced fibrosis called the BARD score. A score of 2–4 was associated with an OR for advanced fibrosis of 17 (confidence interval 9.2 to 31.9) and a negative predictive value of 96%. Conclusions: Insulin resistance and its co-morbidities are often present in patients with NAFLD. An easily calculated score based on readily available clinical data can reliably exclude the presence of advanced fibrosis in these patients, particularly among non-diabetics.

High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota

Abstract: The human gastrointestinal (GI) tract microbiota plays a pivotal role in our health. For more than a decade a major input for describing the diversity of the GI tract microbiota has been derived from the application of small subunit ribosomal RNA (SSU rRNA)-based technologies. These not only provided a phylogenetic framework of the GI tract microbiota, the majority of which has not yet been cultured, but also advanced insights into the impact of host and environmental factors on the microbiota community structure and dynamics. In addition, it emerged that GI tract microbial communities are host and GI tract location-specific. This complicates establishing relevant links between the host’s health and the presence or abundance of specific microbial populations and argues for the implementation of novel high-throughput technologies in studying the diversity and functionality of the GI tract microbiota. Here, we focus on the recent developments and applications of phylogenetic microarrays based on SSU rRNA sequences and metagenomics approaches exploiting rapid sequencing technologies in unravelling the secrets of our GI tract microbiota.

Guidelines for the clinical management of familial adenomatous polyposis (FAP)

Abstract: BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Long-term results and risk factor analysis for recurrence after curative endoscopic therapy in 349 patients with high-grade intraepithelial neoplasia and mucosal adenocarcinoma in Barrett’s oesophagus

Abstract: Objective: Endoscopic therapy is increasingly being used in the treatment of high-grade intraepithelial neoplasia (HGIN) and mucosal adenocarcinoma (BC) in patients with Barrett’s oesophagus. This report provides 5 year follow-up data from a large prospective study investigating the efficacy and safety of endoscopic treatment in these patients and analysing risk factors for recurrence. Design: Prospective case series. Setting: Academic tertiary care centre. Patients: Between October 1996 and September 2002, 61 patients with HGIN and 288 with BC were included (173 with short-segment and 176 with long-segment Barrett’s oesophagus) from a total of 486 patients presenting with Barrett’s neoplasia. Patients with submucosal or more advanced cancer were excluded. Interventions: Endoscopic therapy. Main outcome measures: Rate of complete remission and recurrence rate, tumour-associated death. Results: Endoscopic resection was performed in 279 patients, photodynamic therapy in 55, and both procedures in 13; two patients received argon plasma coagulation. The mean follow-up period was 63.6 (SD 23.1) months. Complete response (CR) was achieved in 337 patients (96.6%); surgery was necessary in 13 (3.7%) after endoscopic therapy failed. Metachronous lesions developed during the follow-up in 74 patients (21.5%); 56 died of concomitant disease, but none died of BC. The calculated 5 year survival rate was 84%. The risk factors most frequently associated with recurrence were piecemeal resection, long-segment Barrett’s oesophagus, no ablative therapy of Barrett’s oesophagus after CR, time until CR achieved >10 months and multifocal neoplasia. Conclusions: This study showed that endoscopic therapy was highly effective and safe, with an excellent long-term survival rate. The risk factors identified may help stratify patients who are at risk for recurrence and those requiring more intensified follow-up.

The early prediction of mortality in acute pancreatitis: a large population-based study

Abstract: Background: Identification of patients at risk for mortality early in the course of acute pancreatitis (AP) is an important step in improving outcome. Methods: Using Classification and Regression Tree (CART) analysis, a clinical scoring system was developed for prediction of in-hospital mortality in AP. The scoring system was derived on data collected from 17 992 cases of AP from 212 hospitals in 2000–2001. The new scoring system was validated on data collected from 18 256 AP cases from 177 hospitals in 2004–2005. The accuracy of the scoring system for prediction of mortality was measured by the area under the receiver operating characteristic curve (AUC). The performance of the new scoring system was further validated by comparing its predictive accuracy with that of Acute Physiology and Chronic Health Examination (APACHE) II. Results: CART analysis identified five variables for prediction of in-hospital mortality. One point is assigned for the presence of each of the following during the first 24 h: blood urea nitrogen (BUN) >25 mg/dl; impaired mental status; systemic inflammatory response syndrome (SIRS); age >60 years; or the presence of a pleural effusion (BISAP). Mortality ranged from >20% in the highest risk group to Conclusions: A new mortality-based prognostic scoring system for use in AP has been derived and validated. The BISAP is a simple and accurate method for the early identification of patients at increased risk for in-hospital mortality.

Guidelines on the management of common bile duct stones (CBDS).

Abstract: The last 30 years have seen major developments in the management of gallstone-related disease, which in the United States alone costs over 6 billion dollars per annum to treat. Endoscopic retrograde cholangiopancreatography (ERCP) has become a widely available and routine procedure, whilst open cholecystectomy has largely been replaced by a laparoscopic approach, which may or may not include laparoscopic exploration of the common bile duct (LCBDE). In addition, new imaging techniques such as magnetic resonance cholangiography (MR) and endoscopic ultrasound (EUS) offer the opportunity to accurately visualise the biliary system without instrumentation of the ducts. As a consequence clinicians are now faced with a number of potentially valid options for managing patients with suspected CBDS. It is with this in mind that the following guidelines have been written.

IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease

Abstract: Background: A novel T helper (Th) cell lineage, Th17, that exclusively produces the proinflammatory cytokine interleukin 17 (IL17) has been reported to play important roles in various inflammatory diseases. IL23 is also focused upon for its potential to promote Th17. Here, the roles of the IL23/IL17 axis in inflammatory bowel diseases such as ulcerative colitis (UC) and Crohn’s disease (CD) were investigated. Methods: Mucosal samples were obtained from surgically resected specimens (controls, n = 12; UC, n = 17; CD, n = 22). IL17 production by isolated peripheral blood (PB) and lamina propria (LP) CD4 + cells was examined. Quantitative PCR amplification was performed to determine the mRNA expression levels of IL17, interferon γ (IFNγ), IL23 receptor (IL23R) and retinoic acid-related orphan receptor γ (RORC) in LP CD4 + cells, and IL12 family members, such as IL12p40, IL12p35 and IL23p19, in whole mucosal specimens. The effects of exogenous IL23 on IL17 production by LP CD4 + cells were also examined. Results: IL17 production was higher in LP CD4 + cells than in PB. Significant IL17 mRNA upregulation in LP CD4 + cells was found in UC, while IFNγ was increased in CD. IL23R and RORC were upregulated in LP CD4 + cells isolated from both UC and CD. IL17 production was significantly increased by IL23 in LP CD4 + cells from UC but not CD. Upregulated IL23p19 mRNA expression was correlated with IL17 in UC and IFNγ in CD. Conclusions: IL23 may play important roles in controlling the differential Th1/Th17 balance in both UC and CD, although Th17 cells may exist in both diseases.

Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain

Abstract: Objective: The capsaicin receptor TRPV1 (transient receptor potential vanilloid type-1) may play an important role in visceral pain and hypersensitivity states. In irritable bowel syndrome (IBS), abdominal pain is a common and distressing symptom where the pathophysiology is still not clearly defined. TRPV1-immunoreactive nerve fibres were investigated in colonic biopsies from patients with IBS, and this was related to abdominal pain. Methods: Rectosigmoid biopsies were collected from 23 IBS patients fulfilling Rome II criteria, and from 22 controls. Abdominal pain scores were recorded using a validated questionnaire. TRPV1-, substance P- and neuronal marker protein gene product (PGP) 9.5-expressing nerve fibres, mast cells (c-kit) and lymphocytes (CD3 and CD4) were quantified, following immunohistochemistry with specific antibodies. The biopsy findings were related to the abdominal pain scores. Results: A significant 3.5-fold increase in median numbers of TRPV1-immunoreactive fibres was found in biopsies from IBS patients compared with controls (p Conclusions: Increased TRPV1 nerve fibres are observed in IBS, together with a low-grade inflammatory response. The increased TRPV1 nerve fibres may contribute to visceral hypersensitivity and pain in IBS, and provide a novel therapeutic target.

Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis

Abstract: Background: Needle biopsy of a suspicious liver lesion could guide management in the setting of equivocal imaging and serology, although it is not recommended generally because there is the possibility of tumour dissemination outside the liver. The incidence of needle track seeding following biopsy of a suspicious liver lesion is ill-defined, however. Methods: A systematic review and meta-analysis of observational studies published before March 2007 was performed. Studies that reported on needle tract seeding following biopsy of suspicious liver lesions were identified. Lesions suspected of being hepatocelleular cancer (HCC) were considered. Data on the type of needle biopsy, diagnosis, incidence of needle track seeding duration to seeding, follow-up and impact on outcome were tabulated. Results: Eight studies identified by systematic review on biopsy of HCC were included in a meta-analysis. The pooled estimate of a patient with seeding per 100 patients with HCC was 0.027 (95% confidence interval (CI) 0.018 to 0.040). There was no difference whether a fixed or random effects model was used. Q was 4.802 with 7 degrees of freedom, p = 0.684; thus the observed heterogeneity was compatible with variation by chance alone. The pooled estimate of a patient with seeding per 100 patients per year was 0.009 (95% CI 0.006 to 0.013), p = 0.686. Conclusions: In this systematic review we have shown that the incidence of needle tract tumour seeding following biopsy of a HCC is 2.7% overall, or 0.9% per year.

Biology and management of pancreatic cancer

Abstract: Pancreatic cancer continues to pose an enormous challenge to clinicians and cancer scientists. With a more affluent world the global incidence of pancreatic cancer is rising. For the first time significant advances are now being made into the management of the disease. There is a more sophisticated approach to palliative care and the centralisation of pancreatic cancer services is leading to greater tumour resection rates. Newer adjuvant modalities are also greatly increasing the 5 year survival rates. The molecular basis of pancreatic cancer is now better understood than ever before, leading to the development of new diagnostic approaches and the introduction of mechanistic based treatments. Technical advances in imaging and great improvements in conventional and molecular pathology have led to a deeper understanding of the pathological variables of the disease. This is now an important time for making big inroads into what still remains the most lethal of the common cancers. Pancreatic ductal adenocarcinoma remains one of the most difficult cancers to treat. It is the commonest cancer affecting the exocrine pancreas. In 2000, there were 217 000 new cases of pancreatic cancer and 213 000 deaths world wide and in Europe 60 139 new patients (10.4% of all digestive tract cancers) and 64 801 deaths.1 In 2002 there were 7152 new cases in the UK, with similar numbers in men and women.2 In the USA in 2006 there were 33 730 new cases and 32 300 deaths.3 Without active treatment, metastatic pancreatic cancer has a median survival of 3–5 months and 6–10 months for locally advanced disease, which increases to around 11–15 months with resectional surgery.4 The late presentation and aggressive tumour biology of this disease mean that only a minority (10–15%) of patients can undergo potentially curative surgery. Major advances in the past decade …

Gastro-oesophageal reflux symptoms, oesophagitis and Barrett’s oesophagus in the general population: the Loiano–Monghidoro study

Abstract: OBJECTIVE Existing endoscopy-based data on gastro-oesophageal reflux disease (GORD) in the general population are scarce. This study aimed to evaluate typical symptoms and complications of GORD, and their associated risk factors, in a representative sample of the Italian population. METHODS 1533 adults from two Italian villages were approached to undergo symptom assessment using a validated questionnaire and upper gastrointestinal endoscopy. Data were obtained from 1033 individuals (67.4% response rate). RESULTS The prevalence of reflux symptoms was 44.3%; 23.7% of the population experienced such symptoms on at least 2 days per week (frequent symptoms). The prevalence rates of oesophagitis and Barrett's oesophagus in the population were 11.8% and 1.3%, respectively. Both frequent (relative risk (RR) 2.6; 95% confidence interval (CI) 1.7 to 3.9) and infrequent (RR 1.9; 95% CI 1.2 to 3.0) reflux symptoms were associated with the presence of oesophagitis. No reflux symptoms were reported by 32.8% of individuals with oesophagitis and 46.2% of those with Barrett's oesophagus. Hiatus hernia was associated with frequent reflux symptoms and oesophagitis, and was present in 76.9% of those with Barrett's oesophagus. We found no association between body mass index and reflux symptoms or oesophagitis. CONCLUSIONS GORD is common in Italy, but the prevalence of Barrett's oesophagus in the community is lower than has been reported in selected populations. Both frequent and infrequent reflux symptoms are associated with an increased risk of oesophagitis. Individuals with oesophagitis and Barrett's oesophagus often have no reflux symptoms.

Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease

Abstract: Background: Clostridium difficile is an important cause of diarrhoea in hospitalised patients. An increasing number of cases of C difficile colitis occur in patients with inflammatory bowel disease (IBD)—Crohn’s disease (CD), ulcerative colitis (UC). Objective: To estimate the potential excess morbidity and mortality associated with C difficile in hospitalised patients with IBD. Methods: Data from the Nationwide Inpatient Sample (2003) were analysed and outcomes were examined of patients hospitalised with both C difficile colitis and IBD compared with those hospitalised for either condition alone. The primary outcome was in-hospital mortality. A subgroup analysis was also performed comparing outcomes of C difficile infection in patients with CD and UC. Results: 2804 discharges were diagnosed as having both C difficile and IBD, 44 400 as having C difficile alone, and 77 366 as having IBD alone. On multivariate analysis, patients in the C difficile –IBD group had a four times greater mortality than patients admitted to hospital for IBD alone (aOR = 4.7, 95% CI 2.9 to 7.9) or C difficile alone (aOR = 2.2, 95% CI 1.4 to 3.4), and stayed in the hospital for three days longer (95% CI 2.3 to 3.7 days). Significantly higher mortality, endoscopy and surgery rates were found in patients with UC compared with CD (p Conclusions: C difficile colitis is associated with a significant healthcare burden in hospitalised patients with IBD and carries a higher mortality than in patients with C difficile without underlying IBD.

Cardiovascular complications of cirrhosis

Abstract: Cardiovascular complications of cirrhosis include cardiac dysfunction and abnormalities in the central, splanchnic and peripheral circulation, and haemodynamic changes caused by humoral and nervous dysregulation. Cirrhotic cardiomyopathy implies systolic and diastolic dysfunction and electrophysiological abnormalities, an entity that is different from alcoholic heart muscle disease. Being clinically latent, cirrhotic cardiomyopathy can be unmasked by physical or pharmacological strain. Consequently, caution should be exercised in the case of stressful procedures, such as large volume paracentesis without adequate plasma volume expansion, transjugular intrahepatic portosystemic shunt (TIPS) insertion, peritoneovenous shunting and surgery. Cardiac failure is an important cause of mortality after liver transplantation, but improved liver function has also been shown to reverse the cardiac abnormalities. No specific treatment can be recommended, and cardiac failure should be treated as in non-cirrhotic patients with sodium restriction, diuretics, and oxygen therapy when necessary. Special care should be taken with the use of ACE inhibitors and angiotensin antagonists in these patients. The clinical significance of cardiovascular complications and cirrhotic cardiomyopathy is an important topic for future research, and the initiation of new randomised studies of potential treatments for these complications is needed.

C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study

Abstract: Background and aims: C-reactive protein (CRP) levels are often used in the follow-up of patients with inflammatory bowel disease (IBD). The aims of this study were to establish the relationship of CRP levels to disease extent in patients with ulcerative colitis and to phenotype in patients with Crohn’s disease, and to investigate the predictive value of CRP levels for disease outcome. Methods: CRP was measured at diagnosis and after 1 and 5 years in patients diagnosed with IBD in south-eastern Norway. After 5 years, 454 patients with ulcerative colitis and 200 with Crohn’s disease were alive and provided sufficient data for analysis. Results: Patients with Crohn’s disease had a stronger CRP response than did those with ulcerative colitis. In patients with ulcerative colitis, CRP levels at diagnosis increased with increasing extent of disease. No differences in CRP levels at diagnosis were found between subgroups of patients with Crohn’s disease as defined according to the Vienna classification. In patients with ulcerative colitis with extensive colitis, CRP levels above 23 mg/l at diagnosis predicted an increased risk of surgery (odds ratio (OR) 4.8, 95% confidence interval (CI) 1.5 to 15.1, p = 0.02). In patients with ulcerative colitis, CRP levels above 10 mg/l after 1 year predicted an increased risk of surgery during the subsequent 4 years (OR 3.0, 95% CI 1.1 to 7.8, p = 0.02). A significant association between CRP levels at diagnosis and risk of surgery was found in patients with Crohn’s disease and terminal ileitis (L1), and the risk increased when CRP levels were above 53 mg/l in this subgroup (OR 6.0, 95% CI 1.1 to 31.9, p = 0.03). Conclusions: CRP levels at diagnosis were related to the extent of disease in patients with ulcerative colitis. Phenotype had no influence on CRP levels in patients with Crohn’s disease. CRP is a predictor of surgery in subgroups of patients with either ulcerative colitis or Crohn’s disease.

Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis

Abstract: Introduction Several studies have suggested that microsatellite instability (MSI) resulting from defective DNA mismatch repair confers a better prognosis in colorectal cancer (CRC). Recently, however, data have suggested this is secondary to the effects of ploidy/chromosomal instability (CIN). To estimate the prognostic significance of CIN for survival, we have reviewed and pooled data from published studies. Methods Studies stratifying survival in CRC by CIN status were identified by searching PubMed and hand-searching bibliographies of identified studies. Two reviewers confirmed study eligibility and extracted data independently, and data were pooled using a fixed-effects model. The principal outcome measure was the hazard ratio for death (HR). Results Sixty-three eligible studies reported outcome in 10,126 patients, 60.0% of whom had CIN+ (aneuploid/polyploid) tumours. The overall HR associated with CIN was 1.45 (95% CI of 1.35-1.55, p Conclusion CIN is associated with a worse prognosis in CRC, and should be evaluated as a prognostic marker, together with MSI status, in all clinical trials, particularly those involving adjuvant therapies.

Pathogenetic mechanisms of hepatic encephalopathy

Abstract: Hepatic encephalopathy (HE) in liver cirrhosis is a clinical manifestation of a low-grade cerebral oedema, which is exacerbated in response to ammonia and other precipitating factors. This low-grade cerebral oedema is accompanied by an increased production of reactive oxygen and nitrogen oxide species (ROS/RNOS), which trigger multiple protein and RNA modifications, thereby affecting brain function. The action of ammonia, inflammatory cytokines, benzodiazepines and hyponatraemia integrates at the level of astrocyte swelling and oxidative stress. This explains why heterogenous clinical conditions can precipitate HE episodes. Oxidised RNA species, which are formed in response to oxidative stress, also participate in local postsynaptic protein synthesis in neurons, which is required for memory formation. Although the functional consequences of RNA oxidation in this context remain to be established, these findings bear a potential biochemical explanation for the multiple alterations of neurotransmitter receptor systems and of synaptic plasticity. Such changes may in part also underlie the pathologically altered oscillatory networks in the brain of HE patients in vivo, as detected by magnetencephalography. These disturbances of oscillatory networks, which in part are triggered by hypothalamic structures, can explain the motor and cognitive deficits in patients with HE. Current therapeutic strategies aim at the elimination of precipitating factors. The potential of therapies targeting downstream pathophysiological events in HE has not yet been explored, but offers novel potential sites of therapeutic intervention.

Asia Pacific consensus recommendations for colorectal cancer screening

Abstract: Colorectal cancer (CRC) is rapidly increasing in Asia, but screening guidelines are lacking. Through reviewing the literature and regional data, and using the modified Delphi process, the Asia Pacific Working Group on Colorectal Cancer and international experts launch consensus recommendations aiming to improve the awareness of healthcare providers of the changing epidemiology and screening tests available. The incidence, anatomical distribution and mortality of CRC among Asian populations are not different compared with Western countries. There is a trend of proximal migration of colonic polyps. Flat or depressed lesions are not uncommon. Screening for CRC should be started at the age of 50 years. Male gender, smoking, obesity and family history are risk factors for colorectal neoplasia. Faecal occult blood test (FOBT, guaiac-based and immunochemical tests), flexible sigmoidoscopy and colonoscopy are recommended for CRC screening. Double-contrast barium enema and CT colonography are not preferred. In resource-limited countries, FOBT is the first choice for CRC screening. Polyps 5-9 mm in diameter should be removed endoscopically and, following a negative colonoscopy, a repeat examination should be performed in 10 years. Screening for CRC should be a national health priority in most Asian countries. Studies on barriers to CRC screening, education for the public and engagement of primary care physicians should be undertaken. There is no consensus on whether nurses should be trained to perform endoscopic procedures for screening of colorectal neoplasia.

Oesophageal high-resolution manometry - moving from research into clinical practice

Abstract: Manometry measures pressure within the oesophageal lumen and sphincters, and provides an assessment of the neuromuscular activity that dictates function in health and disease. It is performed to investigate the cause of functional dysphagia, unexplained “non-cardiac” chest pain, and in the pre-operative work-up of patients referred for anti-reflux surgery. Manometric techniques have improved in a step-wise fashion from a single pressure channel to the development of high-resolution manometry (HRM) with up to 36 pressure sensors. At the same time, advances in computer processing allow pressure data to be presented in real time as a compact, visually intuitive “spatiotemporal plot” of oesophageal pressure activity. HRM recordings reveal the complex functional anatomy of the oesophagus and its sphincters. Spatiotemporal plots provide objective measurements of the forces that move food and fluid from the pharynx to the stomach and determine the risk of reflux events. The introduction of commercially available HRM has been followed by rapid uptake of the technique. This review examines the current evidence that supports the move of HRM from the research setting into clinical practice. It is assessed whether a detailed description of pressure activity identifies clinically relevant oesophageal dysfunction that is missed by conventional investigation, increasing diagnostic yield and accuracy. The need for a new classification system for oesophageal motor activity based on HRM recordings is discussed. Looking ahead the potential of this technology to guide more effective medical and surgical treatment of oesophageal disease is considered because, ultimately, it is this that will define the success of HRM in clinical practice.

Crohn's disease: factors associated with exposure to high levels of diagnostic radiation

Abstract: Aims: Exposure to diagnostic radiation may be associated with increased risk of malignancy. The aims of this study were: (a) to examine patterns of use of imaging in Crohn9s disease; (b) to quantify the cumulative effective dose (CED) of diagnostic radiation received by patients; and (c) to identify patients at greatest risk of exposure to high levels of diagnostic radiation. Methods: 409 patients with Crohn9s disease were identified at a tertiary centre. CED was calculated retrospectively from imaging performed between July 1992 and June 2007. High exposure was defined as CED>75 milli-Sieverts (mSv), an exposure level which has been reported to increase cancer mortality by 7.3%. Complete data were available for 399 patients. 45 were excluded (20 attended outside study period, 25 primarily managed at other centres). Results: Use of computed tomography increased significantly and accounted for 77.2% of diagnostic radiation. Mean CED was 36.1mSv and exceeded 75mSv in 15.5% of patients. Factors associated with high cumulative exposure were: age 1) surgeries (OR 2.7, CI 1.4-5.4). Conclusions: Identifiable subsets of patients with Crohn9s disease are at risk of exposure to significant amounts of diagnostic radiation. Given the background risk of neoplasia and exposure to potentially synergistic agents such as purine analogues and other immune-modulators, specialist centres should develop low-radiation imaging protocols.

Endoscopic Tri-Modal Imaging for Detection of Early Neoplasia in Barrett’s Oesophagus; A multi-centre feasibility study using high-resolution endoscopy, autofluorescence imaging and narrow band imaging incorporated in one endoscopy system.

Abstract: Objective: To investigate the diagnostic potential of endoscopic tri-modal imaging and the relative contribution of each imaging modality (i.e. high-resolution endoscopy (HRE), autofluorescence imaging (AFI) and narrow-band imaging (NBI)) for the detection of early neoplasia in Barrett’s oesophagus. Design: Prospective multi-centre study. Setting: Tertiary referral centres. Patients: 84 Patients with Barrett’s oesophagus. Interventions: The Barrett’s oesophagus was inspected with HRE followed by AFI. All lesions detected with HRE and/or AFI were subsequently inspected in detail by NBI for the presence of abnormal mucosal and/or microvascular patterns. Biopsies were obtained from all suspicious lesions for blinded histopathological assessment followed by random biopsies. Main outcome measures: (1) Number of patients with early neoplasia diagnosed by HRE and AFI; (2) number of lesions with early neoplasia detected with HRE and AFI; and (3) reduction of false positive AFI findings after NBI. Results: Per patient analysis: AFI identified all 16 patients with early neoplasia identified with HRE and detected an additional 11 patients with early neoplasia that were not identified with HRE. In three patients no abnormalities were seen but random biopsies revealed HGIN. After HRE inspection, AFI detected an additional 102 lesions; 19 contained HGIN/EC (false positive rate of AFI after HRE: 81%). Detailed inspection with NBI reduced this false positive rate to 26%. Conclusions: In this international multi-centre study, the addition of AFI to HRE increased the detection of both the number of patients and the number of lesions with early neoplasia in patients with Barrett’s oesophagus. The false positive rate of AFI was reduced after detailed inspection with NBI.

Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C

Abstract: Background: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. Aim: To assess the value of TE for predicting the stage of fibrosis. Methods: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. Results: The areas under the curve for the prediction of significant fibrosis (>F2), advanced fibrosis (>F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE , 6o r>12, , 9o r>12, and ,12 or >18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p,0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. Conclusions: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.

Disorders of a modern lifestyle-reconciling the epidemiology of inflammatory bowel diseases

Abstract: Few would contest that advances in uncovering genetic risk factors for Crohn’s disease and ulcerative colitis over the past decade have changed the way we think about inflammatory bowel diseases (IBDs). Perhaps the most important message has been that much of the genetically determined risk lies in how the host interprets its microbial environment.1–3 However, the primacy of environmental factors was already evident from several sources; notably, studies of genetically identical twins showing a relatively low concordance rate for both Crohn’s disease (<50%) and ulcerative colitis (<10%), and the increased frequency of both disorders in many countries during a period too short to involve significant changes in the population gene pool.4 What are the environmental or lifestyle risk factors for IBD? How do they collude with genetic susceptibility? The lesson of Helicobacter pylori and peptic ulcer disease was that the solution to some chronic disorders cannot be found by studying the human host alone. Rather, the answer may lie at the interface with the microbial environment. A more sobering lesson was the failure of conventional epidemiological studies to recognise that peptic ulcer disease is caused by a transmissible agent. How did disparate epidemiological observations miss this association and fail to guide medical scientists toward this conclusion? Could IBDs (or a subset thereof) be due to an infectious agent, waiting to be identified? Or is the relationship between host susceptibility and the microbial environment a more subtle one? While the complexity and heterogeneity of these diseases surely accounts for some of this dilemma, it seems reasonable to ask whether several decades of epidemiological studies have directed or distracted researchers seeking clues to the cause of IBD. Some of the false leads and false promises of epidemiology have been highlighted elsewhere, with the most vigorous attacks in the …

Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential

Abstract: Background and aim: Mesenchymal stem cells from bone marrow (MSCs) may have the potential to differentiate in vitro and in vivo into hepatocytes. We investigated whether transplanted human MSCs (hMSCs) may engraft the liver of non-obese diabetic severe combined immuno-deficient (NOD/SCID) mice and differentiate into cells of hepatic lineage. Methods: Ex vivo expanded, highly purified and functionally active hMSCs from bone marrow were transplanted (caudal vein) in sublethally irradiated NOD/SCID mice that were either exposed or not to acute liver injury or submitted to a protocol of chronic injury (single or chronic intraperitoneal injection of CCl 4 , respectively). Chimeric livers were analysed for expression of human transcripts and antigens. Results: Liver engraftment of cells of human origin was very low in normal and acutely injured NOD/SCID mice with significantly higher numbers found in chronically injured livers. However, hepatocellular differentiation was relatively rare, limited to a low number of cells (ranging from less than 0.1% to 0.23%) as confirmed by very low or not detectable levels of human transcripts for α-fetoprotein, CK18, CK19 and albumin in either normal or injured livers. Finally, a significant number of cells of human origin exhibited a myofibroblast-like morphology. Conclusions: Transplanted hMSCs have the potential to migrate into normal and injured liver parenchyma, particularly under conditions of chronic injury, but differentiation into hepatocyte-like cells is a rare event and pro-fibrogenic potential of hMSC transplant should be not under-evaluated.

Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus. Commentary

Abstract: Objective: To measure the relative risks of adenocarcinomas of the oesophagus and gastro-oesophageal junction associated with measures of obesity, and their interactions with age, sex, gastro-oesophageal reflux symptoms and smoking. Design and setting: Population-based case-control study in Australia. Patients: Patients with adenocarcinomas of the oesophagus (n = 367) or gastro-oesophageal junction (n = 426) were compared with control participants (n = 1580) sampled from a population register. Main outcome measure: Relative risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction. Results: Risks of oesophageal adenocarcinoma increased monotonically with body mass index (BMI) (Ptrend <0.001). Highest risks were seen for BMI ≥40 kg/m 2 (odds ratio (OR) = 6.1, 95% Cl 2.7 to 13.6) compared with "healthy" BMI (18.5-24.9 kg/m 2 ). Adjustment for gastro-oesophageal reflux and other factors modestly attenuated risks. Risks associated with obesity were substantially higher among men (OR = 2.6, 95% Cl 1.8 to 3.9) than women (OR = 1.4, 95% Cl 0.5 to 3.5), and among those aged <50 years (OR = 7.5, 95% Cl 1.7 to 33.0) than those aged ≥50 years (OR = 2.2, 95% Cl 1.5 to 3.1). Obese people with frequent symptoms of gastro-oesophageal reflux had significantly higher risks (OR = 16.5, 95% Cl 8.9 to 30.6) than people with obesity but no reflux (OR = 2.2, 95% Cl 1.1 to 4.3) or reflux but no obesity (OR - 5.6, 95% 2.8 to 11.3), consistent with a synergistic interaction between these factors. Similar associations, but of smaller magnitude, were seen for gastro-oesophageal junction adenocarcinomas. Conclusions: Obesity increases the risk of oesophageal adenocarcinoma independently of other factors, particularly among men. From a clinical perspective, these data suggest that patients with obesity and frequent symptoms of gastro-oesophageal reflux are at especially increased risk of adenocarcinoma.

Combined effects of obesity, acid reflux and smoking on the risk of adenocarcinomas of the oesophagus.

Abstract: Objective: To measure the relative risks of adenocarcinomas of the oesophagus and gastro-oesophageal junction associated with measures of obesity, and their interactions with age, sex, gastro-oesophageal reflux symptoms and smoking. Design and setting: Population-based case-control study in Australia. Patients: Patients with adenocarcinomas of the oesophagus (n = 367) or gastro-oesophageal junction (n = 426) were compared with control participants (n = 1580) sampled from a population register. Main outcome measure: Relative risk of adenocarcinoma of the oesophagus or gastro-oesophageal junction. Results: Risks of oesophageal adenocarcinoma increased monotonically with body mass index (BMI) (p(trend) = 40 kg/m(2) (odds ratio (OR) = 6.1, 95% Cl 2.7 to 13.6) compared with "healthy'' BMI (18.5-24.9 kg/m(2)). Adjustment for gastro-oesophageal reflux and other factors modestly attenuated risks. Risks associated with obesity were substantially higher among men (OR = 2.6, 95% Cl 1.8 to 3.9) than women (OR = 1.4, 95% Cl 0.5 to 3.5), and among those aged = 50 years (OR = 2.2, 95% Cl 1.5 to 3.1). Obese people with frequent symptoms of gastro-oesophageal reflux had significantly higher risks (OR = 16.5, 95% Cl 8.9 to 30.6) than people with obesity but no reflux (OR = 2.2, 95% Cl 1.1 to 4.3) or reflux but no obesity (OR = 5.6, 95% 2.8 to 11.3), consistent with a synergistic interaction between these factors. Similar associations, but of smaller magnitude, were seen for gastro-oesophageal junction adenocarcinomas. Conclusions: Obesity increases the risk of oesophageal adenocarcinoma independently of other factors, particularly among men. From a clinical perspective, these data suggest that patients with obesity and frequent symptoms of gastro-oesophageal reflux are at especially increased risk of adenocarcinoma.

Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity

Abstract: Objectives: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is characterised by elevated colonic lumenal serine protease activity. The aims of this study were (1) to investigate the origin of this elevated serine protease activity, (2) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity, and (3) to examine the role of the proteinase-activated receptor-2 (PAR-2) activation and signalling cascade in this process. Patients and methods: Faecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhoea. Following mucosal exposure to supernatants from control subjects and IBS-D patients, electromyographic response to colorectal balloon distension was recorded in wild-type and PAR-2 –/– mice, and CPP was evaluated on colonic strips in Ussing chambers. Zonula occludens-1 (ZO-1) and phosphorylated myosin light chain were detected by immunohistochemistry. Results: The threefold increase in faecal serine protease activity seen in IBS-D patients compared with constipation-predominant IBS (IBS-C) or infectious diarrhoea is of neither epithelial nor inflammatory cell origin, nor is it coupled with antiprotease activity of endogenous origin. Mucosal application of faecal supernatants from IBS-D patients in mice evoked allodynia and increased CPP by 92%, both of which effects were prevented by serine protease inhibitors and dependent on PAR-2 expression. In mice, colonic exposure to supernatants from IBS-D patients resulted in a rapid increase in the phosphorylation of myosin light chain and delayed redistribution of ZO-1 in colonocytes. Conclusions: Elevated colonic lumenal serine protease activity of IBS-D patients evokes a PAR-2-mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS.

Gut, inflammation and osteoporosis: basic and clinical concepts

Abstract: Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the immune system such as the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-6, or interferon-gamma. TNF-α, a master cytokine in human IBD, causes bone erosions in experimental models and these effects are exerted by osteoclasts. Other TNF-related cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin are important mediators in inflammatory processes in the gut and are critically involved in the pathophysiology of bone loss. The awareness and early diagnosis of osteoporosis in states of chronic inflammation, together with applied therapies such as bisphosphonates, may be beneficial in inflammation-associated osteoporosis. Although several mechanisms may contribute to osteoporosis in patients with IBD and coeliac disease, inflammation as an important factor has so far been neglected. As key inflammatory mediators in IBD such as TNF-α are involved in the disease process both in gut and bone, we hypothesise that neutralisation of TNF-α could prove an efficient strategy in the treatment of inflammation-related osteoporosis in the future.

Secreted enteric antimicrobial activity localises to the mucus surface layer

Abstract: Objectives: The intestinal mucosa is constantly exposed to a dense and highly dynamic microbial flora and challenged by a variety of enteropathogenic bacteria. Antibacterial protection is provided in part by Paneth cell-derived antibacterial peptides such as the α-defensins. The mechanism of peptide-mediated antibacterial control and its functional importance for gut homeostasis has recently been appreciated in patients with Crohn’s ileitis. In the present study, the spatial distribution of antimicrobial peptides was analysed within the small intestinal anatomical compartments such as the intestinal crypts, the overlaying mucus and the luminal content. Methods: Preparations from the different intestinal locations as well as whole mouse small intestine were extracted and separated by reversed-phase high-performance liquid chromatography. Antibacterial activity was determined in extracts, and the presence of antimicrobial peptides/proteins was confirmed by N-terminal sequencing, mass spectrometry analysis and immunodetection. Results: The secreted antibacterial activity was largely confined to the layer of mucus, whereas only minute amounts of activity were noted in the luminal content. The extractable activity originating from either crypt/mucus/lumen compartments respectively (given as a percentage) was for Listeria monocytogenes , 48 (4)/44 (4)/8 (8); Enterococcus faecalis , 44 (10)/49 (3)/7 (7); Bacterium megaterium , 56 (4)/42 (3)/2 (1); Streptococcus pyogenes , 48 (4)/46 (3)/6 (6); Escherichia coli , 46 (4)/47 (3)/7 (7); and Salmonella enterica sv. Typhimurium, 38 (3)/43 (7)/19 (10). A spectrum of antimicrobial peptides was identified in isolated mucus, which exhibited strong and contact-dependent antibacterial activity against both commensal and pathogenic bacteria. Conclusion: These findings show that secreted antimicrobial peptides are retained by the surface-overlaying mucus and thereby provide a combined physical and antibacterial barrier to prevent bacterial attachment and invasion. This distribution facilitates high local peptide concentration on vulnerable mucosal surfaces, while still allowing the presence of an enteric microbiota.

Development of ductal carcinoma of the pancreas during follow-up of branch duct intraductal papillary mucinous neoplasm of the pancreas

Abstract: Background: Synchronous occurrence of intraductal papillary mucinous neoplasm (IPMN) and ductal carcinoma of the pancreas has been reported. Branch duct IPMNs with lower likelihood of malignancy are not submitted to resection but are followed-up, so ductal carcinoma may develop during the follow-up. The development of ductal carcinoma of the pancreas during follow-up of branch duct IPMNs was investigated. Methods: 60 patients with branch duct IPMN who had an intraductal tumour of Results: Ductal carcinoma of the pancreas distinct from IPMN developed in 5 of 60 (8%) branch duct IPMNs during follow-up. The 5-year rate of development of ductal carcinoma was 6.9% (95% CI 0.4% to 13.4%), the incidence of ductal carcinoma was 1.1% (95% CI 0.1% to 2.2%) per year and the standardised incidence ratio of development of ductal carcinoma was 26 (95% CI 3 to 48). Patients >70 years old developed ductal carcinoma significantly more frequently than those under 69. Four of five ductal carcinomas identified during follow-up were resectable. Cancer developed in IPMN in 2 of 60 (3%) branch duct IPMNs during follow-up. Conclusions: During follow-up of branch duct IPMNs, ductal carcinoma of the pancreas not infrequently developed distinct from IPMN. In the follow-up of IPMN, special attention should be paid to the development of ductal carcinoma of the pancreas.