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Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease.ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426.Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77).In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care.UK National Institute for Health and Care Research.

Background:\ud Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.\ud \ud Methods:\ud We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.

Background Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5–40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid – Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. Methods The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient’s self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. Discussion We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. Trial registration Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012. Electronic supplementary material The online version of this article (10.1186/s13063-019-3561-7) contains supplementary material, which is available to authorized users.

Background and aims: Toll-like receptors [TLRs] are potential drug targets for immunomodulation. We determined the safety and efficacy of the TLR-9 agonist DNA-based immunomodulatory sequence 0150 [DIMS0150] in ulcerative colitis [UC] patients refractory to standard therapy. Methods: In this randomized, double-blind, placebo-controlled trial, 131 patients with moderate-to-severe active UC were randomized to receive two single doses of the oligonucleotide DIMS0150 [30 mg] or placebo administered topically during lower GI endoscopy at baseline and Week 4. The primary endpoint was clinical remission, defined as Clinical Activity Index [CAI] ≤4, at Week 12. Secondary endpoints included mucosal healing and symptomatic remission of key patient-reported outcomes [absence of blood in stool and weekly stool frequency

Background Allopurinol is licensed for the prevention of gout. In recent years, several studies have suggested that allopurinol may have beneficial effects on cardiovascular parameters. The ALL-HEART study is a large outcome trial designed to investigate whether allopurinol improves cardiovascular outcomes in patients with ischaemic heart disease[.1 It is a multicentre, controlled, prospective, randomised, open-label, blinded endpoint trial of allopurinol (up to 600 mg daily) versus no treatment added to usual care in patients aged 60 and over with ischaemic heart disease. Patients are followed up by electronic record-linkage and annual questionnaires. Patient recruitment to the trial started in 2014 and completed in 2017 and follow-up is ongoing. Objectives To describe the baseline characteristics of the patients randomised into the ALL-HEART study. Methods The primary endpoint of the ALL-HEART study is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. Results 5938 patients from the UK have been randomised into the ALL-HEART study. The mean age at randomisation was 72.1±6.8 (SD) years. 75.2% of participants are male. 56.5% are former smokers and 9.4% current smokers. Mean systolic blood pressure was 133±18 mmHg and mean diastolic blood pressure 72±11 mmHg. Mean body mass index was 28.9±5.3 kg/m2. The average duration of ischaemic heart disease was 11.5±7.9 years. 47.4% of participants had a history of previous myocardial infarction, 64.2% a history of angina, 56.4% a history of coronary revascularisation and 69.3% had other evidence of ischaemic heart disease. 57.6% had a history of hypertension. 3.9% had a history of previous cerebrovascular accident, 7.6% of peripheral arterial disease, 21.8% of diabetes mellitus, 8.9% of chronic obstructive pulmonary disease and 5.2% of heart failure. Conclusions This large ongoing trial will determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Reference [1] Mackenzie IS, Ford I, Walker A, et al. Multicentre, prospective, randomised, open-label, blinded endpoint trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open2016;6:e13774. doi:10.1136/bmjopen-2016-013774. Acknowledgements This study is funded by the National Institute for Health Research, Health Technology Assessment programme (http://www.nihr.ac.uk) (HTA 11/36/41). The study is sponsored by the University of Dundee and NHS Tayside. The study is supported by the Scottish Primary Care Research Network, Support for Science in Scotland and the NIHR Local Clinical Research Networks. Disclosure of Interest None declared

Introduction There is an urgent need for superior topical therapy for mesalazine-refractory ulcerativeproctitis. Two small preliminary cohort studies have suggested good clinical efficacy data for organic arsenic derivatives such as acetarsol in refractory ulcerative proctitis. Our aim was to describe the effectiveness and tolerability of acetarsol suppositories in a cohort of inflammatory bowel disease (IBD) patients. Methods We performed a retrospective cohort study by prospectively reviewing maintained clinical records for all patients exposed to acetarsol at the IBD clinic in Nottingham University Hospitals from 2004 to 2017. Response was determined as clinical improvement or improvement in endoscopic appearance. Serum arsenic and C-reactive protein levels were reviewed when available. Non parametric statistical analysis was performed. Data are presented as median and interquartile range Results 35 patients were prescribed acetarsol suppositories (28 with proctitis, 5 with left-sided colitis, 1 with diversion colitis and 1 with chronic pouchitis). Twenty were males with median age of 44 (34) years and disease duration of 7 (19) years. Nearly all patients had failed mesalazine or corticosteroid-based topical therapy with 20 (57.1%) being refractory to immunotherapy and 3 (8.6%) to anti-TNF therapy. Acetarsol 250 mg bd for at least 4 weeks was prescribed in 75% of the cases. Median treatment duration was 56 days (28). Sixteen patients were exposed to acetarsol more than once. 76.7% of patients achieved clinical response. 3/35 patients had an endoscopic assessment with two of three patients showing endoscopic improvement. 33.3% patients required treatment escalation following acetarsol exposure with two undergoing subtotal colectomy. Five patients (14.3%) stopped acetarsol due to side effects. One patient experienced vomiting, palpitations and sweating, and the other four experienced headache, vomiting, anal itching and paresthesia. Median serum arsenic level was 728.25 (872) nmol/l ( Conclusions Acetarsol suppositories could be an effective and tolerable option in the management of refractory proctitis. A definitive study is urgently warranted to thoroughly investigate the clinical efficacy and safety of this promising drug.

BACKGROUND AND AIMS: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial. METHODS: We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries. RESULTS: Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56. CONCLUSIONS: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted. ispartof: JOURNAL OF CROHNS & COLITIS vol:12 issue:9 pages:1097-1103 ispartof: location:England status: published

Background Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users. Methods The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (≥ 60 years, on chronic aspirin ≤ 325 mg daily, not on anti-ulcer therapy or non-steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data. Results HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date. Discussion HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK., Highlights • HEAT, a large clinical trial investigating effects of H. pylori eradication on incidence of ulcer bleeding in aspirin users • HEAT methodology allows large-scale trials of important clinical outcomes to be conducted at low cost affordable to the NHS • As the largest CRN-supported drug study, HEAT has currently invited participation from over 115,000 patients countrywide

Adverse drug effects on the gastrointestinal (GI) tract can occur as a predictable result of a drug's mode of action, by direct injury, through compromising GI defences, or as a consequence of changes in colonic bacterial flora. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of gastroduodenal injury, owing to inhibition of prostaglandin synthesis, and increase the risk of serious GI complications between twofold and fourfold. Low doses of aspirin are associated with an increased risk of upper GI haemorrhage. COX-2 inhibitors largely spare the GI mucosa from injury. Advancing technology for investigating the small bowel now allows identification of subtle changes to the small bowel mucosa (such as ulceration and erosions) secondary to drugs. This can lead to occult iron deficiency anaemia, hypoalbuminaemia and protein-losing enteropathy. Drug-induced colitis is an important problem, with antibiotics the most common drug cause. Drugs can also exacerbate pre-existing inflammatory bowel disease. Strategies to minimize the adverse GI effects of drugs include drug avoidance or minimization, using lowest doses for the shortest time, selective COX-2 inhibitors for high-GI/low-cardiovascular risk patients, and upper GI mucosal protection by co-prescription of proton pump inhibitors with GI irritants.

The incidence of gastro-oesophageal reflux disease and Barrett's oesophagus is increasing. Barrett's oesophagus is the main precursor to oesophageal adenocarcinoma, which has a poor prognosis. In view of the vast potential burden of these diseases on patients and health-care resources, there is a real need to define and focus research efforts. This priority setting exercise aimed to produce a list of the top ten uncertainties in the field that reflect the priorities of patients and health-care providers. We adopted the robust and transparent methodologies previously outlined by the James Lind Alliance. This qualitative approach firstly involves an ideas gathering survey that, once distilled, generates a longlist of research uncertainties. These uncertainties are then prioritised via an interim ranking survey and a final workshop to achieve consensus agreement. The initial 629 uncertainties, generated from a survey of 170 individual respondents (47% professional, 53% non-professional) and one workshop, were narrowed down to the final top ten uncertainties of priority for future research. These priorities covered a range of issues, including a need for improved patient risk stratification, alternative diagnostic and surveillance tests, efficacy of a dedicated service for Barrett's oesophagus, cost-effectiveness and appropriateness of current surveillance, advances in development of non-drug treatments for gastro-oesophageal reflux disease, safety of long-term drug treatment, and questions regarding the durability and role of different endoscopic therapies for dysplastic Barrett's oesophagus. This is the first patient-centred assessment of priorities for researchers in this chronic disease setting. We hope that recognition and dissemination of these results will shape the future direction of research and translate into meaningful gains for patients.

Background The Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct®) is a promising therapeutic option for ulcerative colitis (UC) patients. Aims The objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes (PRO) defined endpoints. Methods Dual topical administration of cobitolimod was studied in a randomised, multicentre clinical trial named COLLECT in moderate-to-severe UC patients. Symptomatic remission (SR) was studied in 104 patients based on their e-diary records and was defined as absence of blood in stool and a mean daily stool frequency (SF) Results SR was achieved at week 4 in 17.1% of cobitolimod vs. 5.9% of placebo treated patients (p = 0.13), at week 8 in 35.7% vs. 17.6% (p = 0.07), and at week 12 in 38.6% vs. 17.6% (p = 0.04) of the patients, respectively. SR rates with cobitolimod and placebo in anti-TNFα experienced patients were smaller but with a broadly similar relative effect-size to anti-TNFα naive patients. Clinical efficacy was higher in patients with moderate compared to severe disease. Conclusions Application of the Toll-like-receptor 9 (TLR-9) agonist cobitolimod is able to induce remission as assessed by PRO measures in UC patients with moderate-to-severe activity as well as in anti-TNFα experienced and naive patients supporting the overall efficacy of the substance.

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

BACKGROUND: The randomised controlled ASTIC trial showed no benefit of mobilisation and autologous haematopoietic stem-cell transplantation (HSCT) compared with mobilisation followed by conventional therapy using a stringent primary endpoint (steroid-free clinical remission for 3 months with no endoscopic or radiological evidence of intestinal inflammation) in patients with treatment-refractory Crohn's disease. We now assess HSCT in patients enrolled in the ASTIC trial using endpoints that are traditional for clinical trials in Crohn's disease, and identify factors that predict benefit or harm.METHODS: Patients who underwent mobilisation and were randomly assigned to conventional therapy in the ASTIC trial were offered HSCT at 1 year and underwent complete assessment for a further year. We report analyses of the combined cohort of patients who underwent HSCT at any time during the ASTIC trial programme. The primary outcome for this analysis was 3-month steroid-free clinical remission at 1 year after HSCT (Crohn's Disease Activity Index [CDAI] FINDINGS: Between June 28, 2007, and Sept 1, 2011, 45 patients were enrolled in the ASTIC trial from 11 European transplant units. 23 patients were randomly assigned to immediate HSCT, and 22 patients were assigned to mobilisation followed by conventional care. After completion of the ASTIC trial, 17 patients from the conventional care group received HSCT. In the combined cohort, data were available for 40 patients at baseline and 38 patients at 1 year after HSCT (one patient died, one withdrew). At 1 year after HSCT, 3-month steroid-free clinical remission was seen in 13 (38%, 95% CI 22-55) of 34 patients with available data for the whole year. Complete endoscopic healting was noted in 19 (50%, 34-66) of 38 patients. On multivariate analyses, factors associated with the primary outcome were short disease duration (odds ratio [OR] 0·64, 95% CI 0·41-0·997 per year; p=0·048) and low baseline CDAI (0·82, 0·74-0·98 per 10 units; p=0·031). 76 serious adverse events occurred in 23 of 40 patients with available data. The most common serious adverse event was infection, most of which were treatment related. Smoking and perianal disease at baseline were independent factors associated with the number of serious adverse events (OR 3·07 [95% CI 1·75-5·38; p=0·0001] for smoking and 3·97 [2·17-7·25; pINTERPRETATION: When assessed using endpoints traditional for clinical trials of conventional therapy in Crohn's disease, HSCT resulted in clinical and endoscopic benefit, although it was associated with a high burden of adverse events. The prognostic factors identified could allow the therapy to be targeted to patients most likely to benefit and not experience serious adverse events.FUNDING: Broad Medical Research Program, National Institute for Health Research Senior Investigator Award, The University of Nottingham Medical School Dean's Fund, and The Nottingham University Hospitals NHS Trust Research and Development Fund.

Introduction Dysplasia in colonic inflammatory bowel disease (IBD) is often multifocal and flat, making it easy for significant lesions to be overlooked. Dye spraying the mucosal surface is believed to enhance visualisation of subtle mucosal abnormalities, but is cumbersome and messy and has poor uptake among endoscopists. High definition (HD) colonoscopy improves adenoma detection rates by improving the ability to detect subtle mucosal changes and is as good as chromoendoscopy in polyp detection. The utility of high definition colonoscopy in dysplasia detection in patients with IBD has not been reported so far. The authors aimed to compare the yield of dysplastic lesions detected by standard definition white light endoscopy (SD) with high definition endoscopy (HD). Methods Details of consecutive patients with long standing (>7 years) colonic IBD who underwent surveillance colonoscopy at Nottingham University Hospitals between September 2008 and February 2010 were extracted from the endoscopy database. Details of diagnosis, duration of disease and outcomes of the colonoscopy were then collected from the electronic patient records and patient notes. The colonoscopies were done at 2 sites, of which one had only HD systems and the other SD. SPSS v17 was used for the data analysis. Results 360 colonoscopies were done on 353 patients. There were 162 colonoscopies (102 UC and 60 CD) in the SD group and 208 colonoscopies (146 UC and 62 CD), in the HD group. The groups were well matched for mean age of patients, duration of disease, gender and number of biopsies taken. Table 1 gives information on the number and characterisation of dysplastic lesions detected. Conclusion HD colonoscopy is superior to SD colonoscopy in targeted detection of dysplastic lesions during surveillance colonoscopy of patients with colonic IBD in routine clinical practice. HD colonoscopy could facilitate endoscopic resection in these patients. Randomised controlled studies are required to confirm these findings.

Introduction Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. Methods and analysis The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. Ethics and dissemination The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups. Trial registration number 32017426, pre-results.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) DK064869 DK062432 National Human Genome Research Institute (NHGRI) DK064869 DK043351 HG005923 Crohns and Colitis Foundation 3765 Leona M. & Harry B. Helmsley Charitable Trust 2015PG-IBD001 Amgen 2013583217 CCFA 3765 Cedars-Sinai F. Widjaja Foundation, info:eu-repo/grantAgreement/EC/FP7/305479, European Union DK062413 AI067068 U54DE023789-01 Leona M. and Harry B. Helmsley Charitable Trust Crohn's and Colitis Foundation of America NIH DK062431 U01 DK062429 U01 DK062422 R01 DK092235 U01 DK062420 Medical Research Council, UK MR/J00314X/1 Wellcome Trust WT091310 098051 Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh PO1DK046763

Genetic association studies have identified 210 risk loci for inflammatory bowel disease1–7, which have revealed fundamental aspects of the molecular biology of the disease, including the roles of autophagy and Th17 cell signaling and development. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 26 new genome-wide significant loci, three of which contain integrin genes that encode molecules in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are also correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at two previously implicated integrin loci (ITGAL, ICAM1). In all four cases, the stimulus-dependent expression increasing allele also increases disease risk. We applied summary statistic fine-mapping and identified likely causal missense variants in the primary immune deficiency genePLCG2and the negative regulator of inflammation,SLAMF8. Our results demonstrate that new common variant associations continue to identify genes and pathways of relevance to therapeutic target identification and prioritization.

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.

To compare the efficacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain.A randomised, double-blind, four-arm, parallel-group, active controlled trial investigating short-term (day 10) and long-term (week 13) benefits and side-effects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fixed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg).There were 892 participants (mean age 60.6, range 40-84 years); 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p0.001; paracetamol, 20.3%; ibuprofen, 19.6%; one or two combination tablets, 24.1%, 38.4%, respectively).Ibuprofen/paracetamol combination analgesia, at non-prescription doses, confers modest short-term benefits for knee pain/osteoarthritis. However, in this population, paracetamol 3 g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. Study no ISRCTN77199439.

IBD is a lifelong condition that can impose a substantial physical, psychological and social burden on individuals. In this article, Joanne Cooper, Jacqueline Collier, Veronica James and Christopher J Hawkey present a case study of one person's diagnosis of IBD during pregnancy. Taken from a larger qualitative research project exploring beliefs about personal control and self-management in inflammatory bowel disease (IBD), the challenges faced when developing symptoms of IBD during pregnancy are discussed. This offers new insight into the needs of pregnant women developing IBD and identifies the important role played by gastrointestinal nurses in supporting patients and educating non-IBD specialist staff.

Aliment Pharmacol Ther 2011; 33: 304–312 Summary Background Dysplasia in inflammatory bowel disease (IBD) is often multifocal and flat. Dye spraying is believed to enhance visualisation of subtle mucosal abnormalities. Aim To perform a meta-analysis of the published studies to compare the diagnostic yield of dysplastic lesions in patients with IBD undergoing surveillance colonoscopy between chromoendoscopy and standard white light endoscopy. Methods We searched electronic databases for full journal articles reporting on chromoendoscopy in patients with IBD. Pooled incremental yield of chromoendoscopy over white light endoscopy for dysplasia detection was determined. A fixed effects model was used unless there was significant heterogeneity. Publication bias was assessed using Funnel plots or Egger’s test. Results Six studies involving 1277 patients provided data on a number of dysplastic lesions detected. The difference in yield of dysplasia between chromoendoscopy and white light endoscopy was 7% (95% CI 3.2–11.3) on a per patient analysis with an NNT of 14.3. The difference in proportion of lesions detected by targeted biopsies was 44% (95% CI 28.6–59.1) and flat lesions was 27% (95% CI 11.2–41.9) in favour of chromoendoscopy. Conclusions Chromoendoscopy is significantly better than white light endoscopy in detecting dysplasia in patients with colonic IBD. This holds true for all dysplastic lesions, proportion of targeted lesions and proportion of flat lesions detected.

Background Inflammatory Bowel Disease is a collective term for two distinct long term conditions: Ulcerative Colitis and Crohn's disease. There is increasing emphasis on patients taking greater personal control and self-management of this condition, reflecting earlier research into the management of chronic illness. Nurses play a pivotal role in this process, yet how optimal personal control is self-assessed and self-managed in Inflammatory Bowel Disease is poorly understood. Objectives This study set out to explore beliefs about personal control and self-management of Inflammatory Bowel Disease. It focused on the role of physical, psychological and socio-economic factors within the individual's life experience. Design A qualitative approach was used comprising 24, one-to-one, semi-structured interviews with participants aged 30–40 years. Participants with a histological diagnosis of Inflammatory Bowel Disease for at least 12 months were eligible and recruited by gastrointestinal specialist staff from outpatient clinics at a large National Health Service Trust in the United Kingdom. Interviews were transcribed verbatim. Data analysis was informed by existing theories of personal control and used the ‘systematic framework analysis' approach. Results In addition to existing theories of personal control, self-discrepancy theory helped to explain how people viewed the control and self-management of Inflammatory Bowel Disease. One main theme emerged from the findings: ‘Reconciliation of the self in IBD', this was supported by three sub-themes and eight basic themes. Some participants found that being unable to control and predict the course of their condition was distressing, however for others this limited control was not viewed as a negative outcome. Being able to share control of IBD with specialist health care staff was beneficial, and participants stated that other priorities in life were as equally important to manage and control. A key barrier to ensuring greater personal control and self-management was a lack of knowledge and awareness by non-specialist health care staff, employers and the wider society. Conclusions Nurses involved in the care of individuals with Inflammatory Bowel Disease should support and prepare patients for the discrepancies and uncertainties of living with the condition. Greater training about Inflammatory Bowel Disease is recommended, specifically for non-specialist health care staff and employers.

Summary Background Gastroduodenal ulcers are common in patients taking low-dose aspirin. However, the factors predisposing to mucosal erosions, the precursor lesions, are not well known. Aims To examine the potential risk factors for the development of erosions in patients chronically taking low-dose aspirin. Methods Patients included were taking aspirin 75–325 mg daily for >28 days. Exclusion criteria included use of nonsteroidal anti-inflammatory and ulcer-healing drugs. Demographic data were collected at baseline, prior to endoscopy to determine the frequency and number of erosions and Helicobacter pylori status. In those without ulcer or other exclusions, endoscopy was repeated at 3 months. Results Fewer patients had gastric erosions if they were H. pylori +ve (48.5% vs. 66.4% in H. pylori−ve patients at baseline, P = 0.17; 40.0% vs. 64.1% at 3 months, P = 0.029). If gastric erosions were present, they were also less numerous in H. pylori +ve patients (3.61 ± 0.83 vs. 4.90 ± 0.53 at baseline, P = 0.026; 2.17 ± 0.68 vs. 5.68 ± 0.86 at 3 months, P = 0.029). There was a trend (0.1 > P > 0.05) for more gastric erosions in those taking >100 mg/day aspirin. Males had more duodenal erosions at baseline (25.2% vs. 7.5%, P = 0.016). Patient age did not affect the presence or number of erosions. H. Pylori was not significantly associated with duodenal erosion numbers. Conclusions Helicobacter pylori infection may partially protect against low-dose aspirin-induced gastric erosions; damage to the stomach appears weakly dose-related; and older age does not increase the risk of erosions.

Low-dose acetylsalicylic acid (ASA; aspirin; 75-325 mg/day) is effective for the prevention of cardiovascular events, and its use in this indication is rapidly increasing. However, the use of ASA and, indeed, other non-steroidal anti-inflammatory drugs (NSAIDs) is limited by the incidence of adverse gastroduodenal events. OBJECTIVES AND SCOPE: To review the clinical evidence for, and the pharmacodynamic basis of, ASA-induced gastroduodenal toxicity in comparison with NSAIDs, and address the question of whether low-dose ASA is 'safe' from a gastroduodenal perspective. This was a narrative, descriptive review, rather than a formal systematic review.Adverse gastroduodenal effects, which are well known to occur with NSAIDs, are also prevalent in patients receiving low-dose ASA for cardiovascular protection even at doses as low as 75 mg/day. The risk of gastroduodenal toxicity is particularly high among 'at-risk' low-dose ASA patients (aged70 years, previous ulcer or upper gastrointestinal bleeding and users of antiplatelets or NSAIDs). There are important differences in the mechanism of ASA-induced gastroduodenal toxicity, relative to NSAIDs. These differences include the effects on the cyclooxygenase (COX)-1 isoenzyme, local effects on the gastroduodenal mucosa specific to ASA and a reduction in platelet aggregation.Data suggest that ASA causes significant gastroduodenal damage even at the low doses used for cardiovascular protection. These effects (both systemic and possibly local) may be pharmacodynamically distinct from the gastroduodenal toxicity seen with NSAIDs. Studies are required to establish strategies for improving the tolerability of low-dose ASA, allowing patients to continue to benefit from the cardiovascular protection associated with such therapy.

To evaluate whether there is any appreciable difference in imaging characteristics between high-resolution magnification white-light endoscopy (WLE-Z) and narrow-band imaging (NBI-Z) in Barrett's oesophagus (BE) and if this translates into superior prediction of histology.This was a prospective single-centre study involving 21 patients (75 areas, corresponding NBI-Z and WLE-Z images) with BE. Mucosal patterns (pit pattern and microvascular morphology) were evaluated for their image quality on a visual analogue scale (VAS) of 1-10 by five expert endoscopists. The endoscopists then predicted mucosal morphology based on four subtypes which can be visualized in BE. Type A: round pits, regular microvasculature; type B: villous/ridge pits, regular microvasculature; type C: absent pits, regular microvasculature; type D: distorted pits, irregular microvasculature. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were then compared with the final histopathological analysis and the interobserver variability calculated.The overall pit and microvasculature quality was significantly higher for NBI-Z, pit: NBI-Z=6, WLE-Z=4.5, p0.001; microvasculature: NBI-Z=7.3, WLE-Z=4.9, p0.001. This translated into a superior prediction of histology (Sn: NBI-Z: 88.9, WLE-Z: 71.9, p0.001). For the prediction of dysplasia, NBI-Z was superior to WLE-Z (chi(2)=10.3, p0.05). The overall kappa agreement among the five endoscopists for NBI-Z and WLE-Z, respectively, was 0.59 and 0.31 (p0.001).NBI-Z is superior to WLE-Z in the prediction of histology in BE, with good reproducibility. This novel imaging modality could be an important tool for surveillance of patients with BE.

Low-dose aspirin is standard treatment for prevention of cardiovascular events in at-risk patients. However, long-term administration of low-dose aspirin is associated with a greater risk of adverse events, including gastroduodenal ulcers. This study determined the efficacy of esomeprazole for reducing the risk of gastric and/or duodenal ulcers and dyspeptic symptoms in patients receiving continuous, low-dose aspirin therapy.Patients agedor =60 yr, without baseline gastroduodenal ulcer at endoscopy, who were receiving aspirin 75-325 mg once daily, were randomized to esomeprazole 20 mg once daily or placebo for 26 wk. The presence of endoscopic gastric and/or duodenal ulcers and esophageal lesions was assessed at weeks 8 and 26. Upper gastrointestinal symptoms were assessed at weeks 8, 16, and 26.The intention-to-treat population comprised 991 patients (esomeprazole, N = 493; placebo, N = 498). Twenty-seven patients (5.4%) in the placebo group developed a gastric or duodenal ulcer during 26 weeks' treatment compared with eight patients (1.6%) in the esomeprazole group (life-table estimates: 6.2%vs 1.8%; P= 0.0007). At 26 wk, the cumulative proportion of patients with erosive esophagitis was significantly lower for esomeprazole versus placebo (4.4% and 18.3%, respectively; P0.0001). At 26 wk, esomeprazole-treated patients were more likely to experience resolution of heartburn, acid regurgitation, and epigastric pain (P0.05).Esomeprazole 20 mg once daily reduces the risk of developing gastric and/or duodenal ulcers and symptoms associated with the continuous use of low-dose aspirin in patients agedor =60 yr without preexisting gastroduodenal ulcers.

Background: Information sheets for clinical research are becoming increasingly complex but the extent to which they are understood is uncertain. Aims: To assess, as our primary outcome, recall by healthy volunteers of key facts in a patient information sheet in a phase 3 clinical trial. As secondary outcomes, we examined whether there was a difference between medical student and non-medically trained volunteers. Design: Questionnaire to determine recall by healthy volunteers of informed consent information. Methods: Eighty-two healthy volunteers participating in a capsule endoscopy study were given a 13 page written information sheet and allowed to asked questions. After indicating they were ready to give consent they were asked to complete a 6-item questionnaire covering the identity and adverse effects of trial treatments and of the procedure, the duration of the trial and value of the inconvenience allowance. Results: All 82 healthy volunteers were questioned. Of the volunteers, 74 (90%) had university level education and 49 (60%) were clinical medical students. However, only 10 subjects (12%) could name the three trial drugs. The maximum number of risks remembered was 6 ( n = 2) of 23. Only 14 (17%) could name three or more potential risks of the medication they might be exposed to, whilst 17 (20%) could identify none. Most subjects (77/82, 90%) identified capsule endoscopy as the trial procedure and impaction/obstruction as its main risk (52/82, 64%). All but one subject (98.8%) could recall the exact value of the inconvenience payment. Conclusion: A comprehensive information sheet resulted in limited recall of trial risks. Shorter information sheets with a test and feedback session should be trialled so that informed consent becomes valid informed consent.

Summary Background The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development. Methods This multicentre, randomized, double-blind, parallel-group trial compared endoscopic healing rates at 4 and 8 weeks after treatment with oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice daily, in patients with 1 baseline GU ≥5 mm but no GUs or duodenal ulcers >25 mm in diameter who received continued cyclooxygenase-2–selective or non-selective NSAID therapies. The primary outcome was the percentage of patients in each treatment group who had no GUs at week 8. Results Four hundred and forty patients were randomized to treatment. At week 8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole 20 mg and ranitidine were 85.7 (79.8–91.7)%, 84.8 (78.8–90.8)% and 76.3 (69.2–83.3)%, respectively; between-group differences were not statistically significant. Week-4 GU healing rates were 70.7 (62.9–78.4)% and 72.5 (65.0–79.9)% with esomeprazole 40 and 20 mg, respectively, and were significantly higher (P

Background Therapy targeted at tumour necrosis factor-alpha has an established role in Crohn's disease. Lenalidomide, an analogue of thalidomide, is an oral immunomodulatory agent with powerful antitumour necrosis factor-alpha properties. It is licensed for myeloma and myelodysplastic syndrome. Based upon reports of thalidomide efficacy, lenalidomide was evaluated in Crohn's disease.Aim To evaluate the efficacy and safety of lenalidomide in subjects with moderately severe active Crohn's disease.Methods In a multicentre, double-blind, placebo-controlled parallel group study 89 subjects were randomized to lenalidomide 25 mg daily, 5 mg daily or placebo. Subjects were treated for 12 weeks. The primary end point was a 70-point reduction in Crohn's Disease Activity Index.Results The overall clinical response rate was not significantly different between the three groups: lenalidomide 25 mg 26%, lenalidomide 5 mg 48% and placebo 39%. Lenalidomide was generally well tolerated with only one serious adverse event, a deep vein thrombosis, being attributed to treatment.Conclusion Lenalidomide, an oral agent with antitumour necrosis factor-alpha properties, was not effective in active Crohn's disease in contrast to reports of benefit from thalidomide. The reasons for this lack of efficacy are speculative, other physiological activities may offset its action on inflammatory cytokines, or its antitumour necrosis factor-alpha action without apoptosis may be insufficient for activity in Crohn's disease.

Summary Background High resolution magnification endoscopy with narrow band imaging (NBI) may improve the detection of specialised intestinal metaplasia (SIM) and dysplasia in Barrett’s oesophagus. Aims To describe the magnified endoscopic features with the use of NBI in Barrett’s oesophagus. Methods Three hundred and forty-four areas from 50 patients with Barrett’s oesophagus were studied using high resolution magnification endoscopy (HRME) with NBI and targeted biopsies were obtained. The sensitivity, specificity, predictive values of the various patterns for the prediction of SIM and dysplasia were calculated. Results The magnified endoscopic features of Barrett’s oesophagus with the use of NBI consist of microstructural/microvascular patterns. The yield of SIM according to the patterns was: (i) Regular microstructural pattern with tubular/linear/villous pattern 90.6% and with circular pattern 0%; and (ii) Absent microstructural pattern 98.9%. The sensitivity, specificity, positive and negative predictive values of the combination of regular microstructural pattern (tubular/villous/linear) and absent microstructural pattern to detect SIM were 100%, 78.8%, 93.5% and 100%, respectively. The sensitivity, specificity, positive and negative predictive values of the irregular microvascular/microstructural pattern for the prediction of high grade dysplasia were 90%, 100%, 99.2% and 100%, respectively. Conclusion High resolution magnification endoscopy with NBI allows clear visualisation of microstructural and microvascular patterns within Barrett’s oesophagus, and allows targeted biopsy with a high yield of SIM and high grade dysplasia.

Cullin-based E3 ligases are a large family of ubiquitin ligases with diverse cellular functions. They are composed of one of six mammalian cullin homologues, the Ring finger containing protein Roc1/Rbx1 and cullin homologue-specific adapter and substrate recognition subunits. To be active, cullin-based ligases require the covalent modification of a conserved lysine residue in the cullin protein with the ubiquitin-like protein Nedd8. To characterize this family of E3 ligases in intact cells, we generated a cell line with tetracycline-inducible expression of a dominant-negative mutant of the Nedd8-conjugating enzyme Ubc12, a reported inhibitor of cullin neddylation. Using this cell line, we demonstrate that the substrate recognition subunit Skp2 and the adaptor protein Skp1 are subject to Ubc12-dependent autoubiquitination and degradation. In contrast, cullin protein stability is not regulated by neddylation in mammalian cells. We also provide evidence that Cul1 and Cul3, as well as their associated substrate recognition subunits Skp2 and Keap1, respectively, homooligomerize in intact cells, suggesting that cullin-based ligases are dimeric. Cul3, but not Cul1 homooligomerization is dependent on substrate recognition subunit dimer formation. As shown for other E3 ubiquitin ligases, dimerization may play a role in regulating the activity of cullin-based E3 ligases.

SUMMARY Background: Adaptation to gastric damage from nonsteroidal anti-inflammatory drugs (NSAID) has been observed during ongoing dosage in rats and humans. However, this does not always occur, and our previous data suggest that NSAID half-life may be a determining factor. Aim: To investigate whether adaptation occurs during 1 week of naproxen administration in humans. Subjects: Thirteen healthy volunteers were studied at baseline, and after me or seven daily doses of naproxen 750 mg. Gastric microbleeding was measured 4 h after naproxen in gastric washings collected during a 30-min period. Serum thromboxane B concentrations were also assayed, as a marker of cyclo-oxygenase inhibition. Results: Mean blood loss after placebo was 0.60, μL/10 min (95% CI: 0.21–0.98). This rose to 2.15 (0.73–3.57) and 1.75 (0.74–2.76) μL/10 min after one and seven daily doses of naproxen, respectively (P < 0.05 vs. baseline: day 1 vs. 7 not significant). Thromboxane B concentrations were < 10% of control at both day 1 and 7 of dosing. Conclusion: In accord with our findings in rats, adaptation to this moderately long acting NSAID in humans was not apparent. We conclude that any adaptation to naproxen is unlikely to be clinically important.

SUMMARY Roxatidine acetate is a new histamine H2-antagonist of about twice the potency of ranitidine on a weight-for-weight basis. Two hundred and thirty-two patients participated in a double-blind randomized trial of duodenal ulcer healing comparing 300 mg ranitidine nocte with 150 mg roxatidine nocte. Endoscopy was repeated fortnightly to 4 weeks in each of four participating centres. Usual exclusion criteria applied but NSAID users were allowed. There were no important demographic differences between treatment recipients. Three analyses were used: protocol (dropouts and violators not included), intention-to-treat I (dropouts considered failures), and intention-to-treat II (dropouts considered failures, but violators outcome included). Healing rates differed markedly (but not significantly) with each analysis. After 2 weeks of treatment ulcers had healed in 51% versus 45% using the intention to treat I analysis with roxatidine and ranitidine, respectively; by the protocol analysis the healing proportions were 60% and 55%. These differences between treatments were not significant. After 4 weeks of treatment healing rates ranged from 71% to 83% on roxatidine and between 69% and 84% on ranitidine depending on the analysis. Differential healing proportions of smokers and non-smokers were nonsignificant (83% vs. 79%). Both drugs were well tolerated and adverse events were similar with each agent. Roxatidine should prove as effective as ranitidine for acute duodenal ulcer treatment.

SUMMARY Aim: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane. Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay. Results: Dialysate thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29 % of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers. Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.

The aim of this study was to investigate the protective action of a new compound, ranitidine bismuth citrate, in the prevention of aspirin-induced acute mucosal injury to the upper gastrointestinal tract of healthy human volunteers. In a double-blind randomized three-way cross-over study 24 male volunteers received placebo, 900 mg aspirin or 900 mg aspirin and 800 mg ranitidine bismuth citrate at 12-h intervals for nine doses with a 2-week wash-out period between each treatment. The median (interquartile range) number of erosions seen at endoscopy when ranitidine bismuth citrate was given with aspirin (1 [0-4]) was significantly lower than aspirin alone (24 [16-32]) (P < 0.001) and not significantly different from either baseline or placebo (0 [0-2]). These findings were similarly reflected in the effects on microbleeding following the ninth dose: 12.1 (7.1-21.0) microL/10 min following aspirin alone compared to levels with placebo of 1.2 (0.4-2.9), and with aspirin and ranitidine bismuth citrate of 1.6 (0.8-2.6) (P < 0.005). Ranitidine bismuth citrate conferred substantial protection from aspirin-induced injury to the gastric and duodenal mucosa as determined by both endoscopic assessment and microbleeding rates, reducing injury to placebo levels.