ERCP and SARS-COV-2: an urgent procedure that should be immune.

BACKGROUND: Radical changes to clinical and endoscopy practice have been rapidly introduced following the spread of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). Urgent endoscopies are, however, intended to proceed as normal with additional personal protective procedures. A perceived reduction in hospital attendances may suggest a number of urgently indicated endoscopic retrograde cholangio-pancreatographies (ERCPs) are being missed. Objectives and Methods: A review of all ERCPs carried out in a large tertiary referral endoscopy unit under healthcare restrictions was compared to the same time period in previous years. The intention was to determine if ERCPs are proceeding as normal or if there is a difference in referral characteristics. RESULTS: Under service restrictions (13 March to the end of April 2020), 55 ERCPs were performed compared with 87 ERCPs in 2019. Similar numbers to 2019 were also recorded in the preceding years. One case of coronavirus disease 2019 (COVID-19) was reported in a patient in the days following ERCP, with no cases notified among staff related to endoscopy. CONCLUSIONS: A reduction in ERCP referrals raises concern that a cohort of patients with significant biliary disease remain undetected. Whether this results in later, and more severe, presentation remains to be seen but a potential surge in such cases could significantly burden all future endoscopy planning services.

Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing.

BACKGROUND: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim: To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years. METHODS: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time. RESULTS: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time. CONCLUSIONS: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.

Acute hemiparesis and status epilepticus following endoscopic esophageal balloon dilation: is it really a stroke?

A 68-year-old gentleman was referred for elective upper gastrointestinal endoscopy on a background of dysphagia and esophageal candidiasis. A benign peptic stricture was noted, managed with balloon dilation without apparent immediate complication. At completion, however, the patient became confused and agitated, with no improvement despite the reversal of sedation. Two hours later, with all investigations for suspected complications including perforation, negative, he developed acute left-sided hemiparesis. Urgent computed tomography brain and angiogram were both normal. A diagnosis of acute ischemic stroke was made, and the patient was thrombolysed in the Intensive Care Unit. No improvement of the stroke was observed. Seven hours later, the patient developed generalized tonic-clonic seizures that required phenytoin infusion and subsequent intubation and ventilation. The following morning, magnetic resonance imaging brain did not reveal features of a stroke, but instead diffuse cortical and white matter edema in the right frontal lobe, consistent with atypical, unilateral Posterior Reversible Encephalopathy Syndrome (PRES). Signs and symptoms resolved rapidly over the course of several days, and after one month the patient made a complete clinical and radiological recovery. To our knowledge, this is the only case of PRES to arise in the setting of endoscopy and esophageal dilation.

A National Bowel Cancer Screening Programme using FIT: Achievements and Challenges.

Colorectal cancer accounts for 11% of all cancer-related deaths in Ireland. With the aim of diagnosing these cancers at an earlier stage, and detecting premalignant lesions, the National Screening Service (NSS) offered a fecal immunochemical test (FIT) to all individuals aged 60 to 69. All individuals in the age range were contacted by post and invited to participate in the programme. Those with a positive FIT result were offered a colonoscopy in an internationally accredited unit. From an eligible population of 488,628, 196,238 individuals participated giving an uptake of 40.2%. Commencing at a FIT threshold of 20 µg Hg/g feces, the positivity rate was 8.6%, which overwhelmed colonoscopy capacity and, thus, the threshold was increased to 45 µg, resulting in an overall 5% positivity rate. A total of 520 individuals had cancer detected (68.3% stage I or II), of which 104 were removed endoscopically (pT1s). Adenomas were present in 54.2% of all colonoscopies, 17.4% deemed high risk. Despite a lower uptake, males were twice as likely to have colorectal cancers as females and had a 59% increased rate of high-risk adenomas diagnosed. Challenges facing the programme include increasing participation, especially among males, and increasing colonoscopy capacity. The ability to alter the sensitivity of FIT to match colonoscopy capacity is a valuable option for such a programme as it ensures that the maximum public health benefit can be achieved within available resources.

Golimumab effectiveness and safety in clinical practice for moderately active ulcerative colitis.

BACKGROUND AND AIMS: Golimumab (GLB) is an antitumour necrosis factor-α (anti-TNF) therapy that has shown efficacy as induction and maintenance therapy for ulcerative colitis (UC). We aimed to describe the outcome of GLB therapy for UC in a real-world clinical practice. PATIENTS AND METHODS: Consecutive patients receiving GLB for UC in six Irish Academic Medical Centres were identified. The primary study endpoint was the 6-month corticosteroid-free remission rate. The secondary endpoints included the 3-month clinical response, time free of GLB discontinuation and adverse events. RESULTS: Seventy-two patients were identified [57% men; median (range) age of 41.4 years (20.3-76.8); disease duration 6.6 years (0-29.9); follow-up 8.7 months (0.4-39.2)]. Sixty-four percent of patients were anti-TNF naive. The 3-month clinical response and the 6-month corticosteroid-free remission rates were 55 and 39%, respectively. Forty-four percent of patients discontinued GLB during the follow-up, median (95% confidence interval) time to GLB discontinuation 18.7 months (9.2-28.1). A C-reactive protein more than 5 mg/l at baseline was associated with failure to achieve 6-month corticosteroid-free remission and a shorter time to GLB discontinuation, odds ratio 0.2 (0.1-0.7), P=0.008, and hazard ratio (95% confidence interval) 2.8 (1.3-5.7), P=0.007, respectively. Adverse events occurred in 7% of patients (n=5), all of which were minor and self-limiting. CONCLUSION: These real-world clinical data suggest that GLB is an effective and safe therapy for a UC cohort with significant previous anti-TNF exposure. An elevated baseline C-reactive protein, likely reflective of increased inflammatory burden, is associated with a reduced likelihood of a successful outcome of GLB therapy.

High-risk family colorectal cancer screening service in Ireland: Critical review of clinical outcomes.

BACKGROUND: We present the 15-year experience of a family colorectal cancer screening service in Ireland with emphasis on real life experience and outcomes. METHODS: Questionnaires were used to assess family cancer history and assign patients to risk categories; 'Moderate Risk', HNPCC, (suspected) genetic syndrome (non-HNPCC), 'Low Risk'. Screening was by full colonoscopy. We report neoplastic yield, examining effect of risk category, age, gender, and index colonoscopy findings. RESULTS: Between 1998 and 2013, 2242 individuals were referred; 57.3% female, 42.7% male, median age 46 years (range9-85yrs). Median follow up time was 7.9yrs (range 0.5-15.3yrs). Follow up data after exclusion (non-compliance, known CRC) was available in 1496 (66.7%): 'Moderate risk' 785 (52.5%), HNPCC 256 (17.1%), (suspected) genetic syndrome (non-HNPCC) 85 (5.7%), 'Low Risk' 370 (24.7%). Screening was performed in 1025(68.5%) patients; colonoscopy data available for 993 (96.9%); total 1914 colonoscopies. At index colonoscopy, 178 (18.0%) patients had adenomas; 56 (5.5%) advanced adenoma. During the entire study period, 240 (24.2%) had an adenoma; 69 (7.0%) advanced adenoma. Cancers were diagnosed on screening in 2 patients. Older age and male gender were associated with higher adenoma detection rate; p<0.001, p=0.01, respectively. Risk category did not affect adenoma yield. Adenoma and advanced adenoma detection at index colonoscopy were associated with detection of same at follow up screening; p<0.001. CONCLUSION: Male gender and age (>50) were the core identifiable risk factors for neoplasia at screening colonoscopy in this family screening setting. Our results would support less intensive surveillance in younger patients (<50), particularly where index colonoscopy is normal.

Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers.

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair-deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005-December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9-year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Changes in Presentation of Celiac Disease in Ireland From the 1960s to 2015.

BACKGROUND & AIMS: Celiac disease is an immune-mediated enteropathy characterized with high heterogeneity in presentation among genetically predisposed individuals. In recent years, a change in the phenotypic presentation of celiac disease has been reported. We studied clinical presentation, from 1960 through 2015, in Ireland, which has a high incidence of celiac disease. METHODS: We performed a retrospective analysis of medical charts from patients diagnosed with celiac disease at 5 secondary referral centers in Ireland from 1960 through 2015 (n = 749; median age, 56 years; age range, 18-91 years). The cohort was divided into 5 groups based on year of diagnosis (≤1985, 1986-1995, 1996-2005, 2006-2010, or 2011 and later). We collected findings from clinical presentation at diagnosis; serology tests; small intestinal biopsy analyses; and patients' demographic, clinical, and family data. Presentations at diagnosis were classified according to the Oslo criteria as follows: classical (patients presenting with malabsorption), nonclassical (no signs or symptoms of malabsorption at presentation), or subclinical (below the threshold of clinical detection). The primary outcome was change in clinical presentation of celiac disease over time. RESULTS: Of the 749 patients studied, 512 were female and 237 were male (ratio of 2.2:1). Female patients were diagnosed at younger ages than male patients (42 vs 47 years, respectively; P = .004), and had more immune-mediated conditions than male patients (35.7% for female patients vs 21.5% for male patients; P < .001). For patients diagnosed as adults (after the age of 18 years), the median age of diagnosis increased from 34.0 years during the period ≤1985 to median ages of 44-46 years after 1985 (P < .002). A smaller proportion of patients presented with classical features of celiac disease after 2010 (48.4%) than ≤1985 (85.2%); the proportion of patients with nonclassical or subclinical celiac disease increased from 14.8% ≤1985 to 51.6% after 2010 (P = .006 for each). Biopsies categorized as Marsh 3c decreased, from 52.2% in the period 1996-2005 to 22.5% in the period after 2010 (P = .003). The prevalence of associated thyroid disease has decreased during the study period, from 36.6% ≤1985 to 17.1% after 2010 (P = .039), whereas body mass index at diagnosis increased from 21.5 kg/m2 ≤1985 to 24.8 kg/m2 after 2010 (P < .001). CONCLUSIONS: We found the clinical presentation of celiac disease changed significantly in Ireland from 1960 through 2015. The age of presentation in adulthood increased over this time period, as did the proportions of patients with nonclassical or subclinical disease.

Water-enhanced antegrade MR pyelography in pregnancy: a novel radiation-free approach.

Our aim was to determine if water-enhanced antegrade magnetic resonance (MR) pyelography can be an alternative to conventional antegrade pyelography in pregnant patients who require percutaneous nephrostomy placement for urosepsis and/or obstructive uropathy. The pregnant patient was placed supine in a 1.5-T MRI scanner seven days after percutaneous nephrostomy placement using ultrasound. Serial axial and coronal T2-weighted echo-planar fast spin-echo sequences were performed before and after injection of the catheter. The right nephrostomy catheter hub was sterilised using chlorhexidine. Sixty millilitres of sterile water were slowly injected. No Gd-based contrast agent was utilised due to safety concerns for the foetus. MR antegrade pyelography demonstrated the level of ureteric obstruction and the absence of renal calculi using sterile water as a contrast medium injected through a percutaneous nephrostomy followed by T2-weighted imaging. Air bubbles in the injected solution were differentiated from calculi due to their mobility on serial scans and their anti-dependent position. Water-enhanced antegrade MR pyelography was a safe and effective method of imaging the pregnant patient. It served as an alternative to conventional antegrade pyelography and minimised potential risks to the foetus.

Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.

Endoscopic pneumatic dilation versus botulinum toxin injection in the management of primary achalasia.

BACKGROUND: Achalasia is an oesophageal motility disorder, of unknown cause, which results in increased lower oesophageal sphincter (LOS) tone and symptoms of difficulty swallowing. Treatments are aimed at reducing the LOS tone. Current endoscopic therapeutic options include pneumatic dilation (PD) or botulinum toxin (BTX) injection. OBJECTIVES: To undertake a systematic review comparing the efficacy and safety of two endoscopic treatments, PD and intrasphincteric BTX injection, in the treatment of oesophageal achalasia. SEARCH METHODS: Trials were initially identified by searching MEDLINE (1966 to August 2008), EMBASE (1980 to September 2008), ISI Web of Science (1955 to September 2008), The Cochrane Library Issue 3, 2008.  Searches in all databases were conducted in October 2005 and updated in September 2008 and April 2014. The Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE, sensitivity maximising version in the Ovid format, was combined with specific search terms to identify randomised controlled trials in MEDLINE. The MEDLINE search strategy was adapted for use in the other databases that were searched. SELECTION CRITERIA: Randomised controlled trials comparing PD to BTX injection in individuals with primary achalasia. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study quality assessment and data extraction. MAIN RESULTS: Seven studies involving 178 participants were included. Two studies were excluded from the meta-analysis of remission rates on the basis of clinical heterogeneity of the initial endoscopic protocols. There was no significant difference between PD or BTX treatment in remission within four weeks of the initial intervention; with a risk ratio of remission of 1.11 (95% CI 0.97 to 1.27). There was also no significant difference in the mean oesophageal pressures between the treatment groups; with a weighted mean difference for PD of -0.77 (95% CI -2.44 to 0.91, P = 0.37). Data on remission rates following the initial endoscopic treatment were available for three studies at six months and four studies at 12 months. At six months 46 of 57 PD participants were in remission compared to 29 of 56 in the BTX group, giving a risk ratio of 1.57 (95% CI 1.19 to 2.08, P = 0.0015); whilst at 12 months 55 of 75 PD participants were in remission compared to 27 of 72 BTX participants, with a risk ratio of 1.88 (95% CI 1.35 to 2.61, P = 0.0002). No serious adverse outcomes occurred in participants receiving BTX, whilst PD was complicated by perforation in three cases. AUTHORS' CONCLUSIONS: The results of this meta-analysis suggest that PD is the more effective endoscopic treatment in the long term (greater than six months) for patients with achalasia.

Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype.

INTRODUCTION: Neuroepithelial Transforming Gene 1 (NET1) is a well characterised oncoprotein and a proven marker of an aggressive phenotype in a number of cancers, including gastric adenocarcinoma. We aimed to investigate whether NET1 plays a functional role in oesophageal cancer (OAC) and its pre-malignant phenotype Barrett's oesophagus. METHODS: Baseline NET1 mRNA levels were determined by qPCR across a panel of six cell lines, including normal oesophageal, Barrett's and OAC derived cells. Quantification of NET1 protein in OAC cells was performed using Western blot and immunofluorescence. NET1 expression was modulated by treating with lysophosphatidic acid (LPA) and NET1-specific siRNA. The functional effects of NET1 knockdown were assessed in vitro using proliferation, migration and invasion assays. RESULTS: NET1 expression was increased in Barrett's and in OAC-derived cells in comparison to normal oesophageal cells. The highest expression was observed in OE33 a Barrett's-related OAC cell line. NET1 protein and mRNA expression was enhanced by LPA treatment in OAC and furthermore LPA treatment caused increased proliferation, migration and invasion in a NET1-dependent manner. NET1 knockdown resulted in reduced OAC cell proliferation and invasion. CONCLUSIONS: As found in other malignancies, NET1 expression is elevated in OAC and its pre-malignant phenotype, Barrett's oesophagus. NET1 promotes OAC cell invasion and proliferation and it mediates LPA-induced OAC cell migration.

The diagnostic accuracy of endoscopic ultrasound in suspected biliary obstruction and its impact on endoscopic retrograde cholangiopancreatography burden in real clinical practice: a consecutive analysis.

BACKGROUND AND AIMS: Performing endoscopic ultrasound (EUS) before endoscopic retrograde cholangiopancreatography (ERCP) has been described to be useful in cases of suspected biliary obstruction where EUS can triage patients for ERCP. We aimed to determine the diagnostic accuracy of EUS and its impact on ERCP burden in real clinical practice. We also evaluated the safety and efficacy of EUS+ERCP in a single endoscopic session. PATIENTS AND METHODS: Four hundred and eighteen consecutive patients with suspected but unexplained biliary obstruction referred for EUS before possible ERCP were evaluated. The diagnostic accuracy of EUS and its value in predicting the need for ERCP were determined. EUS established whether pancreaticobiliary disorder (PBD) was present and whether therapeutic ERCP was required. These decisions were matched with ERCP findings, histology, clinical course, and follow-up. Where ERCP was indicated, it was performed in the same endoscopic session. RESULTS: EUS was performed in 412/418 patients (feasibility 98.5%), and ERCP was considered necessary in 64% (ERCP avoided in 36%). The single-session EUS and ERCP was safe and effective (264 patients). The diagnostic accuracy of EUS was as follows: choledocholithiasis 99%, malignant strictures 90%, and benign strictures 92%. EUS showed pathology in 42% of patients who had a nondilated biliary system at initial investigations. When EUS indicated a normal common bile duct (n=119), this had a 100% positive predictive value for non-necessity for ERCP. The median overall follow-up period was 12 months (range 6-34 months). CONCLUSION: EUS demonstrated high diagnostic accuracy in this mixed group of PBD. This accurately guided ERCP need and avoided unnecessary ERCP in 36%. EUS and ERCP in the same endoscopic session for the evaluation and management of PBD is technically feasible, with safety and efficacy profiles equivalent to that of each procedure performed independently in different sessions.

A functional and transcriptomic analysis of NET1 bioactivity in gastric cancer.

BACKGROUND: NET1, a RhoA guanine exchange factor, is up-regulated in gastric cancer (GC) tissue and drives the invasive phenotype of this disease. In this study, we aimed to determine the role of NET1 in GC by monitoring the proliferation, motility and invasion of GC cells in which NET1 has been stably knocked down. Additionally, we aimed to determine NET1-dependent transcriptomic events that occur in GC. METHODS: An in vitro model of stable knockdown of NET1 was achieved in AGS human gastric adenocarcinoma cells via lentiviral mediated transduction of short-hairpin (sh) RNA targeting NET1. Knockdown was assessed using quantitative PCR. Cell proliferation was assessed using an MTS assay and cell migration was assessed using a wound healing scratch assay. Cell invasion was assessed using a transwell matrigel invasion assay. Gene expression profiles were examined using affymetrix oligonucleotide U133A expression arrays. A student's t test was used to determine changes of statistical significance. RESULTS: GC cells were transduced with NET1 shRNA resulting in a 97% reduction in NET1 mRNA (p < 0.0001). NET1 knockdown significantly reduced the invasion and migration of GC cells by 94% (p < 0.05) and 24% (p < 0.001) respectively, while cell proliferation was not significantly altered following NET1 knockdown. Microarray analysis was performed on non-target and knockdown cell lines, treated with and without 10 µM lysophosphatidic acid (LPA) allowing us to identify NET1-dependent, LPA-dependent and NET1-mediated LPA-induced gene transcription. Differential gene expression was confirmed by quantitative PCR. Shortlisted NET1-dependent genes included STAT1, TSPAN1, TGFBi and CCL5 all of which were downregulatd upon NET1 downregulation. Shortlisted LPA-dependent genes included EGFR and PPARD where EGFR was upregulated and PPARD was downregulated upon LPA stimulation. Shortlisted NET1 and LPA dependent genes included IGFR1 and PIP5K3. These LPA induced genes were downregulated in NET1 knockdown cells. CONCLUSIONS: NET1 plays an important role in GC cell migration and invasion, key aspects of GC progression. Furthermore, the gene expression profile further elucidates the molecular mechanisms underpinning NET1-mediated aggressive GC cell behaviour.

MYEOV (myeloma overexpressed gene) drives colon cancer cell migration and is regulated by PGE2.

INTRODUCTION: We have previously reported that Myeov (MYEloma OVerexpressed gene) expression is enhanced in colorectal cancer (CRC) and that it promotes CRC cell proliferation and invasion. The role of Myeov in CRC migration is unclear. ProstaglandinE2 (PGE 2) is a known factor in promoting CRC carcinogenesis. The role of PGE 2 in modulating Myeov expression has also not been defined. AIM: To assess the role of Myeov expression in CRC cell migration and to evaluate the role of PGE 2 in Myeov bioactivity. METHODS: siRNA mediated Myeov knockdown was achieved in T84 CRC cells. Knockdown was assessed using quantitative real time PCR. The effect of knockdown on CRC cell migration was assessed using a scratch wound healing assay. Separately, T84 cells were treated with PGE 2 (0.00025 micro M, 0.1 micro M and 1 micro M) from 30 min to 3 hours and the effect on Myeov gene expression was assessed using real time PCR. RESULTS: Myeov knockdown resulted in a significant reduction in CRC cell migration, observable as early as 12 hours (P < 0.05) with a 39% reduction compared to control at 36 hours (p < 0.01). Myeov expression was enhanced after treatment with PGE 2, with the greatest effect seen at 60 mins for all 3 PGE 2 doses. This response was dose dependent with a 290%, 550% & 1,000% increase in Myeov expression for 0.00025 micro M, 0.1 micro M and 1 micro M PGE 2 respectively. CONCLUSION: In addition to promoting CRC proliferation and invasion, our findings indicate that Myeov stimulates CRC cell migration, and its expression may be PGE 2 dependant.

Evaluation of 6 candidate genes on chromosome 11q23 for coeliac disease susceptibility: a case control study.

BACKGROUND: Recent whole genome analysis and follow-up studies have identified many new risk variants for coeliac disease (CD, gluten intolerance). The majority of newly associated regions encode candidate genes with a clear functional role in T-cell regulation. Furthermore, the newly discovered risk loci, together with the well established HLA locus, account for less than 50% of the heritability of CD, suggesting that numerous additional loci remain undiscovered. Linkage studies have identified some well-replicated risk regions, most notably chromosome 5q31 and 11q23. METHODS: We have evaluated six candidate genes in one of these regions (11q23), namely CD3E, CD3D, CD3G, IL10RA, THY1 and IL18, as risk factors for CD using a 2-phase candidate gene approach directed at chromosome 11q. 377 CD cases and 349 ethnically matched controls were used in the initial screening, followed by an extended sample of 171 additional coeliac cases and 536 additional controls. RESULTS: Promotor SNPs (-607, -137) in the IL18 gene, which has shown association with several autoimmune diseases, initially suggested association with CD (P < 0.05). Follow-up analyses of an extended sample supported the same, moderate effect (P < 0.05) for one of these. Haplotype analysis of IL18-137/-607 also supported this effect, primarily due to one relatively rare haplotype IL18-607C/-137C (P < 0.0001), which was independently associated in two case-control comparisons. This same haplotype has been noted in rheumatoid arthritis. CONCLUSION: Haplotypes of the IL18 promotor region may contribute to CD risk, consistent with this cytokine's role in maintaining inflammation in active CD.

Multiple common variants for celiac disease influencing immune gene expression.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Do the benefits of metal stents justify the costs? A systematic review and meta-analysis of trials comparing endoscopic stents for malignant biliary obstruction.

BACKGROUND: A variety of stent designs has been studied for endoscopic stenting of the bile duct in patients with malignant biliary obstruction. Although metal stents are associated with longer patency, their costs are significantly higher than plastic stents. AIMS: To compare clinical outcome and cost-effectiveness of endoscopic metal and plastic stents for malignant biliary obstruction by a systematic review and meta-analysis of all randomized controlled trials in this area. METHODS: We conducted searches to identify all randomized controlled trials in any language from 1966 to 2006 using electronic databases and hand-searching of conference abstracts. Meta-analysis was performed with RevMan software [Review Manager (RevMan) version 4.2 for Windows. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2003]. RESULTS: Seven randomized controlled trials were identified that met the inclusion criteria, and 724 participants were randomized to either metal or plastic endoscopic stents. No significant difference between the two stent types in terms of technical success, therapeutic success, 30-day mortality or complications was observed. Metal stents were associated with a significantly less relative risk (RR) of stent occlusion at 4 months than plastic stents [RR, 0.44; 95% confidence interval (CI) 0.3, 0.63; P<0.01]. The overall risk of recurrent biliary obstruction was also significantly lower in patients treated with metal stents (RR, 0.52; 95% confidence interval 0.39, 0.69; P<0.01). The median incremental cost-effectiveness ratio of metal stents was $1820 per endoscopic retrograde cholangiopancreatography prevented. CONCLUSION: Endoscopic metal stents for malignant biliary obstruction are associated with significantly higher patency rates than plastic stents as early as 4 months after insertion. Metal stents will be cost-effective if the unit cost of additional endoscopic retrograde cholangiopancreatographies per patient exceeds $1820.

In silico gene expression analysis--an overview.

Efforts aimed at deciphering the molecular basis of complex disease are underpinned by the availability of high throughput strategies for the identification of biomolecules that drive the disease process. The completion of the human genome-sequencing project, coupled to major technological developments, has afforded investigators myriad opportunities for multidimensional analysis of biological systems. Nowhere has this research explosion been more evident than in the field of transcriptomics. Affordable access and availability to the technology that supports such investigations has led to a significant increase in the amount of data generated. As most biological distinctions are now observed at a genomic level, a large amount of expression information is now openly available via public databases. Furthermore, numerous computational based methods have been developed to harness the power of these data. In this review we provide a brief overview of in silico methodologies for the analysis of differential gene expression such as Serial Analysis of Gene Expression and Digital Differential Display. The performance of these strategies, at both an operational and result/output level is assessed and compared. The key considerations that must be made when completing an in silico expression analysis are also presented as a roadmap to facilitate biologists. Furthermore, to highlight the importance of these in silico methodologies in contemporary biomedical research, examples of current studies using these approaches are discussed. The overriding goal of this review is to present the scientific community with a critical overview of these strategies, so that they can be effectively added to the tool box of biomedical researchers focused on identifying the molecular mechanisms of disease.

Malignant distal biliary obstruction: a systematic review and meta-analysis of endoscopic and surgical bypass results.

BACKGROUND: Surgical bypass and endoscopic stents are available for palliative bypass of malignant distal biliary obstruction. AIM: Comparison of reported outcomes in randomized controlled trials (RCTs) which included surgery, endoscopic plastic stents or endoscopic metal stents in palliative relief of malignant distal biliary obstruction. METHODS: Systematic review and meta-analysis of published literature and conference proceedings review to June 2006. RESULTS: We found 24 studies, containing 2436 patients, which met our inclusion criteria. Endoscopic stenting with plastic stents (three studies) is associated with a lower risk of complications (RR 0.60, 95% CI 0.45-0.81), but a higher risk of recurrent biliary obstruction (RR 18.59, 95% CI 5.33 -64.86) than traditional surgical bypass. Self-expanding metal stents (seven studies) are associated with a significantly reduced risk of recurrent biliary obstruction at 4 months (RR 0.44, 95% CI 0.3, 0.63), or prior to death or end of study (RR 0.52, 95% CI 0.39-0.69), but are not superior to plastic stents in terms of technical success, therapeutic success, mortality or complications. Cost-effectiveness outcomes were not suitable for meta-analysis. No other plastic stent designs have been demonstrated to be superior to polyethylene stents (12 studies). CONCLUSIONS: Endoscopic metal stents are the intervention of choice in patients with malignant distal biliary obstruction, producing similar outcomes to plastic stents, but with improved patency rates.