Presence of Melena in Obscure Gastrointestinal Bleeding Predicts Bleeding in the Proximal Small Intestine.

BACKGROUND AND AIMS: Melena is a symptom of upper gastrointestinal bleeding and usually indicates bleeding proximal to the ligament of Treitz. However, whether melena predicts bleeding in the proximal small intestine in patients with obscure gastrointestinal bleeding (OGIB) is unknown and the objective of this study. METHODS: A retrospective cohort study of consecutive patients undergoing capsule endoscopy for OGIB between July 2009 and May 2016 was conducted. Subjects were categorized based on the presence of melena, and the primary outcome was identification of a bleeding source within the proximal 2/3 of the small intestine. Multi-variable regression was performed to control for confounders. RESULTS: During the study, 288 patients met the eligibility criteria. Subjects with melena accounted for 37.1% of the cohort and were more likely to be older (mean age 66.9 vs. 63.9, p = 0.0457), take warfarin (15.1 vs. 9.4%, p = 0.0122), and have a lower 12-month hemoglobin nadir (7.3 vs. 8.3 g/dL, p = 0.0002). On crude analysis, 56.1% of patients with melena had a bleeding source within the proximal small intestine compared to 34.8% for those without (RR 1.61, 95% CI 1.24-2.09, p = 0.0004). On multi-variable analysis, the presence of melena doubled the odds of finding a bleeding site within the proximal small intestine (OR 1.97, 95% CI 1.17-3.33, p = 0.010). CONCLUSIONS: The presence of melena doubles the odds of finding a bleeding site within the proximal small intestine among patients with OGIB, and deep enteroscopy, if performed before a capsule study, should begin with an antegrade approach in these patients.

Insertion of percutaneous endoscopic gastrostomy tubes with jejunal extensions using the "wedge" technique: a novel method to prevent retrograde tube migration into the stomach.

Background and study aim In percutaneous endoscopic gastrostomy (PEG) with jejunal extension (PEGJ) procedures, retrograde migration of the jejunal extension tube into the stomach during endoscope withdrawal is a frustrating problem. We describe the novel "wedge" technique for inserting the jejunal extension tube, utilizing single-balloon enteroscopy to anchor it in place. Patients and methods Prospective 1-year study of consecutive patients undergoing PEGJ insertion at a single tertiary care center. The primary outcome was number of pyloric intubations required to place the jejunal extension tube. Secondary outcomes included success rate, time, and complications related to jejunal extension tube insertion. Results 17 patients underwent the procedure. The jejunal extension tube was inserted at the first attempt in 15 patients (88.2 %) and 2 required another pyloric intubation. Abdominal X-ray showed that all PEGJ tubes were successfully seated in the proximal jejunum. The mean (SD) time required for jejunal extension insertion was 16.9 (8.6) minutes. Two adverse events occurred due to PEG insertion although none were related to the jejunal extension insertion itself. Conclusions: The "wedge" technique is an effective and easy method for inserting a jejunal extension tube after PEG insertion.

The utility of fecal calprotectin in predicting the need for escalation of therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: Fecal calprotectin is an important biomarker used in the evaluation of inflammatory bowel disease. It has proven to be an effective tool in initial screening as well monitoring response to therapy. The aim of this study is to examine the utility of fecal calprotectin both as a predictor for the escalation of therapy in established inflammatory bowel disease and as a predictor of de novo diagnosis. METHODS: Patients with signs and symptoms concerning for inflammatory bowel disease presenting to outpatient clinics were recruited to provide fecal calprotectin stool samples prior to endoscopic evaluation. Patients were followed up for at least one year and monitored clinically for any change in symptomatology, escalation of therapy or development of IBD, confirmed endoscopically. RESULTS: A total of 126 patients, of whom 72 were known to have underlying inflammatory bowel disease, were included in the final analysis. Among the patients with elevated fecal calprotectin levels and known inflammatory bowel disease, 66% (33/50) went on to have escalation of therapy within 12 months compared to 18% (4/22) if the fecal calprotectin levels were in the normal range (p < .0001). For the remaining patients who at baseline did not have inflammatory bowel disease and a normal endoscopic evaluation, elevated fecal calprotectin resulted in no cases (0/17) of a new diagnosis in the next 12 months. CONCLUSIONS: Fecal calprotectin is a useful test for predicting escalation of therapy in established inflammatory bowel disease.

Cannabis Use in Patients With Inflammatory Bowel Disease Following Legalization of Cannabis in Canada.

Background: Cannabis is used by patients with Crohn's disease (CD) and ulcerative colitis (UC) as an alternative to, or in combination with, conventional therapies to treat symptoms such as abdominal pain, poor sleep, and reduced appetite. The clinical efficacy of cannabis for these disorders is controversial, with some studies showing harmful outcomes associated with its use. Previous studies suggest that cannabis is used by ~12% of patients with UC and ~16% of patients with CD in the USA despite legal prohibition. Methods: We conducted a prospective cohort study of adult patients with inflammatory bowel diseases (IBD) followed in a Canadian tertiary care center. Patients completed an online 40-question survey that included demographics, IBD disease history, cannabis use, and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Results: Completed surveys were obtained from 254 participants (148 with CD, 90 with UC, and 16 with indeterminate colitis). Recent cannabis use was reported by 41% of CD and 31% of UC participants. Interestingly, only 46% of participants who used cannabis discussed their use with their physician. Participants who recently used cannabis reported more abdominal pain, poor appetite, and flatulence, and importantly this was associated with lower SIBDQ scores (recent use 37 vs non-recent use 40). Conclusions: Cannabis use among patients with IBD has more than doubled since its legalization. Cannabis use is associated with worse abdominal symptoms and quality of life. Physicians should inquire about cannabis use and optimize symptom control with evidence-based therapies.

Prevalence of stricturing, penetrating complications and extraintestinal manifestations in inflammatory bowel disease detected on cross-sectional imaging in a tertiary care setting.

BACKGROUND: Stricturing, penetrating complications and extraintestinal manifestations (EIMs) are frequent in patients with inflammatory bowel disease (IBD). There is limited data on the prevalence of these complications in patients with IBD. Therefore, we aimed to assess the burden of these complications detected incidentally on cross-sectional imaging. METHODS: A retrospective study conducted at two tertiary care centers in London, Ontario. Patients (≥18 years) with a confirmed diagnosis of IBD who underwent CT enterography (CTE) or MR enterography (MRE) between 1 Jan 2010 and 31 Dec 2018 were included. Categorical variables were reported as proportions and the mean and standard deviations were reported for continuous variables. RESULTS: A total of 615 imaging tests (MRE: 67.3% [414/615]) were performed in 557 IBD patients (CD: 91.4% [509/557], UC: 8.6% [48/557]). 38.2% (213/557) of patients were male, with mean age of 45.6 years (±15.8), and median disease duration of 11.0 years (±12.5). Among patients with CD, 33.2% (169/509) had strictures, with 7.8% having two or more strictures and 66.3% considered inflammatory. A fistula was reported in 10.6% (54/509), the most common being perianal fistula (27.8% [15/54]), followed by enterocutaneous fistula (16.8% [9/54]), and enteroenteric fistula (16.8% [9/54]). Additionally, 7.4% (41/557) of patients with IBD were found to have an EIM on cross-sectional imaging, with the most prevalent EIM being cholelithiasis (63.4% [26/41]), followed by sacroiliitis (24.4% [10/41]), primary sclerosing cholangitis (4.8% [2/41]) and nephrolithiasis (4.8% [2/41]). CONCLUSIONS: Approximately 40% of patients with CD undergoing cross-sectional imaging had evidence of a stricture or fistulizing disease, with 7% of patients with IBD having a detectable EIM. These results highlight the burden of disease and the need for specific therapies for these disease phenotypes.

Initiation of vedolizumab did not provoke new-onset spondylarthritis in patients with inflammatory bowel disease: A prospective 24-week study with imaging assessments.

BACKGROUND: A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested. AIMS: We evaluated the relationship between vedolizumab initiation and development of new-onset SpA in patients with inflammatory bowel disease (IBD) through serial clinical evaluation and magnetic resonance imaging (MRI). METHODS: A single-centre prospective observational study of 24 patients with IBD. Patients were eligible if they had active ulcerative colitis or Crohn's disease (CD), were initiating vedolizumab, had no prior history of arthritis or SpA and were suitable for serial MRI. A rheumatologist performed clinical evaluation prior to the first dose and 8 and 24 weeks. Axial MRI was evaluated by a blinded central reader and performed at baseline 8 and 24 weeks. RESULTS: Nine tumor necrosis factor (TNF) inhibitor-naïve patients (4 male; mean age 53.2 years; 6 UC; 3 CD) and eight TNF inhibitor-experienced patients (7 male; mean age 48 years; 3 UC; 5 CD) completed all assessments. No patients developed new features of axial arthritis or features of peripheral SpA (inflammatory oligoarthritis, enthesitis, dactylitis, or psoriasis (nail, body, or scalp)). Both groups demonstrated a good intestinal response. CONCLUSION: Vedolizumab initiation did not induce new features of axial or peripheral SpA after 24 weeks of treatment in TNF inhibitor-experienced or TNF inhibitor-naive patients with IBD.

Endoscopic Skipping, Stricturing, and Penetrating Complications in Crohn's Disease on Tandem Ileo-colonoscopy and Cross-sectional Imaging: A Retrospective Cohort Study.

BACKGROUND: Crohn's disease (CD) is characterized by discontinuous inflammation. Failure to identify skipping lesions of the terminal ileum (TI) or transmural changes can lead to incorrect management. METHODS: Eligible adult patients with CD undergoing ileo-colonoscopy and computed tomography enterography or magnetic resonance enterography within 6 months. We determined the prevalence of endoscopic skipping (normal ileum on colonoscopy but proximal small bowel inflammation on cross-sectional imaging), skip lesions (discontinuous inflammation along the gastrointestinal tract identified on cross-sectional imaging), structuring, and penetrating complications. RESULTS: Among 202 patients, 45 (22.3%) had endoscopic skipping proximal to TI intubation. Fifty patients (24.5%) had small bowel skip lesions, primarily in the ileum. Strictures were identified in 34 patients (16.8%) through both imaging and ileo-colonoscopy, in 21 patients (10.4%) solely through cross-sectional imaging, and in 3 patients (1.5%) solely through ileo-colonoscopy. Approximately 36.2% of stricturing cases would be missed without cross-sectional imaging. Penetrating complications, including abscesses (2.5%) and various fistula types (4.9%), were detected in 15 (7.4%) patients. CONCLUSIONS: Ileo-colonoscopy missed detection of active CD in approximately one-fifth of cases due to more proximal disease location. Stricturing disease might be missed in more than a third of cases if cross-sectional imaging is not performed.

Crohn's disease often presents with discontinuous inflammation, with endoscopic evaluation sometimes missing proximal lesions. This study highlights the importance of cross-sectional imaging, which identifies skip lesions and strictures missed by endoscopy, crucial for accurate management.

Transcutaneous bowel sonography for inflammatory bowel disease is sensitive and specific when performed in a nonexpert low-volume North American center.

OBJECTIVES: Transcutaneous bowel sonography is a nonionizing imaging modality used in inflammatory bowel disease. Although available in Europe, its uptake in North America has been limited. Since the accuracy of bowel sonography is highly operator dependent, low-volume centers in North America may not achieve the same diagnostic accuracy reported in the European literature. Our objective was to determine the diagnostic accuracy of bowel sonography in a nonexpert low-volume center. METHODS: All cases of bowel sonography at a single tertiary care center during an 18-month period were reviewed. Bowel sonography was compared with reference standards, including small-bowel follow-through, computed tomography, magnetic resonance imaging, colonoscopy, and surgical findings. RESULTS: A total of 103 cases were included for analysis during the study period. The final diagnoses included Crohn disease (72), ulcerative colitis (8), hemolytic uremic syndrome (1), and normal (22). The sensitivity and specificity of bowel sonography for intestinal wall inflammation were 87.8% and 92.6%, respectively. In the subset of patients who had complications of Crohn disease, the sensitivity and specificity were 50% and 100% for fistulas and 14% and 100% for strictures. One patient had an abscess, which was detected by bowel sonography. Abnormal bowel sonographic findings contributed to the escalation of treatment in 55% of cases. CONCLUSIONS: Bowel sonography for inflammatory bowel disease can be performed in low-volume centers and provides diagnostic accuracy for luminal disease comparable with published data, although it is less sensitive for complications of Crohn disease.

Clinical, Endoscopic, and Radiological Effectiveness of Ustekinumab in Bio-naïve Versus Bio-experienced Patients With Crohn's Disease: Real-world Experience From a Large Canadian Center.

INTRODUCTION: With the expanding therapeutic armamentarium for inflammatory bowel disease (IBD), real-world data may help inform drug positioning. We assessed clinical, endoscopic, imaging, and biochemical response/remission outcomes in patients with Crohn's disease (CD) treated with ustekinumab in a large Canadian IBD center. METHODS: A retrospective cohort study of CD patients was treated with ustekinumab. Clinical, endoscopic, radiological, and biochemical response and remission outcomes were stratified by prior biologic exposure status. Hazard ratios for biologic exposure status were estimated using Cox proportional hazard models and subgroup-specific incidence rates for healing. RESULTS: A total of 231 patients (55.9% female, median 45.8 years) were identified as receiving ustekinumab during the study period, with 2 patients subsequently excluded (N = 229). Of these patients, 79.0% (181 of 229) were bio-experienced, with 38.7% (70 of 181) having failed 1 biologic and 61.3% (111 of 181) having failed ≥2 biologics. At 3 months of follow-up after induction, clinical remission (Harvey-Bradshaw Index ≤4) was achieved by 59.1% (62 of 105) of bio-experienced patients and 79.4% (27 of 34) of bio-naïve patients (relative risk [RR], 1.34; 95% CI, 1.06-1.70; P = .013). Endoscopic remission (absence of mucosal ulcers) was achieved in 37.9% (33 of 87) cases. Rate of endoscopic healing (either endoscopic response or remission) per 1000 person-months was 72.7 (95% CI, 42.4-125.1) and 50.2 (37.9-66.4); and the median time to endoscopic response was 8.4 months (95% CI, 6.4-9.8) and 15.4 months (95% CI, 10.3-17.9) in bio-naïve vs bio-experienced patients, respectively. Imaging response/remission and steroid-free remission rates were higher in bio-naïve patients. CONCLUSION: In this large real-world cohort of CD patients with complex phenotypes and high rates of prior biologic exposure, we observed that ustekinumab was effective and safe with higher rates of improvement in bio-naïve subjects across a range of end points.

In this large real-world study of patients with Crohn's Disease treated with ustekinumab, we observed high rates of clinical, endoscopic, radiological, and biochemical response and remission rates. Effectiveness was greater in bio-naïve compared with bio-experienced patients.

Severity of coeliac disease and clinical management study when using a non-metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: The non-metabolised antihistamine fexofenadine has oral absorption resulting from transporter activity. Uptake by enterocyte organic anion transporting polypeptides and efflux by an ATP-binding cassette transporter (P-glycoprotein) are primary determinants. Coeliac disease-mediated lesions to the small intestinal mucosa may alter oral absorption of the drug probe, fexofenadine. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study SETTING: London, Ontario, Canada PARTICIPANTS: Patients with coeliac disease (n=41) with positive serology and healthy individuals (n=48). MAIN OUTCOME MEASURES: Patients with coeliac disease-duodenal histology and oral fexofenadine pharmacokinetics within a 3-week period. Healthy individuals-oral fexofenadine pharmacokinetics with water and grapefruit juice. RESULTS: Patients with coeliac disease were stratified by disease severity: Group A (n=15, normal), B+C (n=14, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=12, moderate to severe villous blunting). Patients with coeliac disease in groups A, B+C and D and healthy individuals receiving water had similar fexofenadine AUC0-8 (2038±304, 2259±367, 2128±410, 1954±138 ng.h/mL; p>0.05; mean±SEM) and Cmax (440±73, 513±96, 523±104, 453±32 ng/mL; p>0.05), respectively. These four groups all had higher fexofenadine AUC0-8 (1063±59; p<0.01) and Cmax (253±18; p<0.05) compared with those for healthy individuals receiving grapefruit juice. Coeliac groups had a positive linear trend between disease severity and fexofenadine Tmax (2.0±0.3, 2.7±0.4, 3.1±0.5 hours; p<0.05). CONCLUSIONS: Coeliac disease severity based on duodenal histopathology did not affect oral fexofenadine bioavailability. Increased Tmax suggested absorption distal to the duodenum (jejunum + ileum), where histology seems more normal which may be the key determinant. Patients with coeliac disease may not require consideration for alternative clinical drug management for a number of non-metabolised and transport-mediated medications.

Nonutility of routine testing of stool for ova and parasites in a tertiary care Canadian centre.

BACKGROUND: In many clinical situations, stool examinations for ova and parasites (O&P) are routine in the work-up of patients with acute or chronic diarrhea. Frequently, these tests are found to be negative for pathogens. The purpose of this study was to examine the diagnostic yield of routine stool testing for O&P in a Canadian tertiary care centre and to estimate the potential clinical benefit of a positive result. PATIENTS AND METHODS: All stool samples sent to the central microbiology laboratory at London Health Sciences Centre were reviewed over a 5-year period ending January 2010. Initial screening was done by direct antigen testing using an enzyme immunoassay (EIA) technique followed by direct microscopy for negative results where there was a high index of suspicion and for positive results to rule out any concurrent parasites not included in the EIA kit. Pathogens identified were categorized and their potential susceptibility to metronidazole was estimated. No clinical data were available, as this was purely a utilization study. RESULTS: A total of 5812 stool tests were ordered. Of these, 5681 (97.7%) were completed. The most common reasons for an incomplete test were sample leakage (n = 38) and use of the incorrect collection kit (n = 32). Direct microscopy identified white blood cells in 17% of patients with positive testing. The most common pathogen was Giardia lamblia , which was detected in 45/83 (54%) of positive specimens. Entamoeba histolytica/Entamoeba dispar was identified in 16/83 (19%) and Cryptosporidium spp. in 10/83 (12%) of positive specimens. Microorganisms not thought to be pathogenic were identified in 7/83 (8%). Direct laboratory costs independent of labor were estimated at $1836 per clinically significant organism identified. Of the 77 specimens positive for pathogenic organisms, 62 (81%) were likely to be sensitive to treatment with metronidazole. CONCLUSION: In a tertiary care centre, the diagnostic yield of routine testing of stool for O&P during the evaluation of patients with acute or chronic diarrhea is low. Most clinically significant positive results should be responsive to metronidazole, but empirical treatment is not encouraged. Strategies to identify patients with a higher likelihood of harboring pathogenic parasites and consideration of empiric metronidazole therapy for patients at highest risk merit further research.

Wait times for diagnostic colonoscopy among outpatients with colorectal cancer: a comparison with Canadian Association of Gastroenterology targets.

BACKGROUND: Timely access to colonoscopy is a nationally recognized issue in Canada, with previous studies documenting significant wait times for a variety of indications. However, specific wait times for colonoscopy among patients diagnosed with colorectal cancer remain unknown. METHODS: A review of all outpatient cases of colorectal cancer diagnosed at colonoscopy in London, Ontario, in 2010 was performed. Wait times from the date of referral to colonoscopy were reviewed and compared with maximal wait times established by the Canadian Association of Gastroenterology (CAG) stratified according to indication. Cancer stage at the time of diagnosis was compared with colonoscopy wait times. RESULTS: A total of 106 colorectal cancer patients meeting the inclusion and exclusion criteria were included in the study. Forty-six per cent of patients waited longer than CAG targets, with a mean (± SD) wait time of 79 ± 101 days. Higher cancer stage was associated with shorter wait time, likely as a result of triaging. CONCLUSION: Long wait times for diagnostic colonoscopy among patients with colorectal cancer remain an issue, with a significant proportion of cases not meeting maximal CAG wait time targets.

High oncostatin M predicts lack of clinical remission for patients with inflammatory bowel disease on tumor necrosis factor α antagonists.

The interleukin-6 family cytokine, oncostatin-M (OSM) has been associated with response to tumor necrosis factor-α antagonists (anti-TNFs) in small cohorts of patients with inflammatory bowel disease (IBD). We aimed to evaluate the association between plasma OSM concentrations and response to anti-TNFs (infliximab and adalimumab) in both ulcerative colitis (UC) and Crohn's disease (CD). A retrospective cohort study was conducted in patients with IBD with a history of anti-TNF exposure. Blood samples, collected prior to anti-TNF exposure, were analyzed by enzyme-linked immunosorbent assay for the presence and quantity of OSM. Clinical remission was assessed at 1-year post anti-TNF exposure in addition to the occurrence of surgery, hospitalization, corticosteroid use, and adverse drug events. Lastly the threshold OSM plasma concentration associated with anti-TNF non-response was assessed by receiver operator characteristic (ROC) curve analysis. Patients with IBD (CD, n = 82; UC, n = 40) were assessed. In both UC and CD, mean pre-treatment OSM concentrations were significantly lower in those who achieved clinical remission at 1-year (p < 0.0001). A threshold plasma OSM concentration of 168.7 pg/ml and 233.6 pg/ml respectively separated those who achieved clinical remission at 1-year on an anti-TNF from those who did not in CD and UC respectively (CD: area under the receiver operator characteristic curve, AUROC = 0.880, 95% CI 0.79-0.96; UC: AUROC = 0.938, 95% CI 0.87-1.00). High OSM concentrations were associated with anti-TNF discontinuation and use of rescue steroids in CD and UC. High pre-treatment OSM concentrations identify IBD patients at-risk of anti-TNF non-response at 1-year as well as other deleterious clinical outcomes.

Association of Trainee Participation in Colonoscopy Procedures With Quality Metrics.

Importance: Trainees routinely participate in colonoscopy procedures, yet whether their involvement is positively or negatively associated with procedural quality is unknown because prior studies involved small number of trainees and/or supervisors, lacked generalizability, and/or failed to adjust for potential confounders. Objective: To assess the association between trainee participation and colonoscopy quality metrics. Design, Setting, and Participants: This multicenter population-based cohort study was conducted at 21 academic and community hospitals between April 1, 2017, and October 31, 2018, among consecutive adult patients undergoing colonoscopy. Procedures performed by endoscopists who did not supervise trainees were excluded. Statistical analysis was performed from April 3, 2017, to October 31, 2018. Exposure: Participation by a trainee, defined as a resident or fellow enrolled in a gastroenterology or general surgery training program. Main Outcomes and Measures: The primary outcome was the adenoma detection rate (ADR), and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Results: A total of 35 499 colonoscopies (18 989 women [53.5%]; mean [SD] patient age, 60.0 [14.1] years) were performed by 71 physicians (mean [SD] time in practice, 14.0 [9.3] years); 5941 colonoscopies (16.7%) involved trainees. There were no significant differences in the ADR (26.4% vs 27.3%; P = .19), CIR (96.7% vs 97.2%; P = .07), and perforation rate (0.05% vs 0.06%; P = .82) when trainees participated vs when they did not participate, whereas the the ssPDR (4.4% vs 5.2%; P = .009) and PDR (39.2% vs 42.0%; P < .001) were significantly lower when trainees participated vs when they did not. After adjustment for potential confounders, the ADR (risk ratio [RR], 0.97; 95% CI, 0.91-1.03; P = .30), PDR (RR, 0.98; 95% CI, 0.93-1.04; P = .47), and CIR (RR, 0.93; 95% CI, 0.78-1.10; P = .38) were not associated with trainee participation, although the ssPDR remained significantly lower (RR, 0.79; 95% CI, 0.64-0.98; P = .03). Conclusions and Relevance: This study suggests that trainee involvement during colonoscopy was associated with reduced ssPDR but not other colonoscopy outcome measures. Extra care should be exercised when examining the right colon when trainees are involved.

Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2).

BACKGROUND AND AIM: The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity. METHODS: Single nucleotide polymorphisms in SLC10A2 from genomic DNA of ethnically-defined healthy individuals were identified using a polymerase chain reaction (PCR)-based temperature gradient capillary electrophoresis (TGCE) system. A heterologous gene expression system was used to assess transport activity of SLC10A2 nonsynonymous variants and missense mutations. Total and cell surface protein expression of wild-type and variant ASBT was assessed by Western blot analysis and immunofluorescence confocal microscopy. Expression of ASBT mRNA and protein was also measured in human intestinal samples. RESULTS: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. A novel variant, 790A>G, was also shown to exhibit near complete loss of taurocholate transport, similar to the previously identified ASBT missense mutations. Examination of ASBT protein expression revealed no significant differences in expression or trafficking to the cell surface among variants versus wild-type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples revealed modest intersubject variability. CONCLUSIONS: Genome sequencing and in vitro studies reveal the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology.

The Tricky Trachea: Tracheitis and Mediastinitis Treated With Infliximab and Steroids in a Patient With Ulcerative Colitis.

Pulmonary extra-intestinal manifestations of inflammatory bowel disease are rare, comprising 0.21% to 0.4% of the inflammatory bowel disease population. Common symptoms include cough, chest pain, and dyspnea. Abnormal pulmonary function tests are common in these patients, with restrictive, obstructive, and diffusion capacity defects. CT scanning remains the most sensitive imaging technique to detect abnormalities. Pulmonary manifestations are diverse and include airway, parenchymal, and pleural disease. Large airway disease predominates, particularly bronchiectasis. Upper airway disease is rare but concerning for the development of acute airway compromise. To our knowledge, there are no reports of concurrent mediastinitis with tracheitis in the setting of inflammatory bowel disease. We present a case of a patient with ulcerative proctitis who experienced the development of inflammatory tracheitis and mediastinitis. Her disease responded to systemic steroids and biologic therapy. In addition to our case, we reviewed the literature and provide an approach to pulmonary complications as extra-intestinal manifestation of inflammatory bowel disease.

The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs.

Folic acid is a vitamin essential for thymidylate and purine synthesis. The human proton-coupled folate transporter (hPCFT) has recently been identified as a pH-dependent folic acid transporter, and mutations in this transporter have been linked to hereditary folic acid malabsorption. In this study, we assessed hPCFT-mediated transport activity in vitro, intersubject variability of intestinal expression in relation to blood folates, and the relationship of proton-pump inhibitor (PPI) therapy on hPCFT expression in vivo. We created a Madin-Darby canine kidney strain II (MDCKII) cell line stably expressing hPCFT to evaluate its drug substrates and inhibitors. Intestinal pinch biopsies (duodenum, ileum, colon) were collected from patients undergoing routine endoscopy procedures, and expressed levels of hPCFT were determined by RT-PCR. When assessed using MDCKII-hPCFT cells, folic acid and methotrexate were found to be high-affinity hPCFT substrates. Sulfasalazine and pyrimethamine were noted to inhibit hPCFT activity with Ki values of 42.3 and 161.7 micromol/l, respectively. hPCFT was localized to the brush-border membrane of enterocytes with highest expression in the duodenum and reduced levels in the ileum and colon. When we assessed hPCFT expression in a subset of patients who were receiving PPI therapy, a near 50% reduction in duodenal hPCFT mRNA expression was noted. These results suggest that hPCFT transporter activity can be modulated by many drugs in clinical use, and expression of this transporter in the gastrointestinal tract is higher in the duodenum than more distal sites (duodenum > ileum > colon). Importantly, we note that PPI drug use appears to be associated with reduced hPCFT expression in vivo.

Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study. SETTING: London, Ontario, Canada. PARTICIPANTS: Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). MAIN OUTCOME MEASURES: Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice. RESULTS: Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0-8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. CONCLUSIONS: Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.

Simple clinical predictors may obviate urgent endoscopy in selected patients with nonvariceal upper gastrointestinal tract bleeding.

BACKGROUND: The validated Blatchford risk score (BRS) predicts outcomes in patients with nonvariceal upper gastrointestinal tract bleeding, before endoscopy; completion of the Rockall score requires endoscopy. The aims of this study were to predict whether the modified BRS (mBRS) can predict (1) endoscopic high-risk stigmata (HRS) and (2) rebleeding and mortality. METHODS: Clinical and demographic characteristics on 1869 patients from 6 Canadian provinces were prospectively entered into the Registry for Upper GI Bleeding and Endoscopy database, recording 30-day rebleeding and mortality. The Rockall score and mBRS (hemoglobin level, hemodynamic instability, and presence of melena, liver disease, or cardiac failure; urea and syncope were not recorded) were calculated. Logistic regression was used to assess the association between an mBRS of 1 or less with HRS and with rebleeding and mortality. RESULTS: The mean (SD) age of the patients was 66 (17) years, with 62% men and a mean of 2.5 comorbidities. Of the 1860 patients with 30-day rebleeding data, 334 (18.0%) rebled; 5.3% died. The mBRS was 0 in 3% and 1 or less in 9.8% of patients; HRS were seen in 31.0% of patients. An mBRS of 1 or less was associated with lower rebleeding (5% vs 19%; P<.001) and mortality (0.5% vs 5.8%; P=.003), and was significant in multivariate analysis for rebleeding (odds ratio, 0.24; 95% confidence interval, 0.12-0.48) and mortality (odds ratio, 0.12; 95% confidence interval, 0.02-0.90). The HRS were less frequent when the mBRS was 1 or less (16.9% vs 32.7%; odds ratio, 0.4; 95% confidence interval, 0.3-0.6). Patients with a low mBRS with HRS had a low rebleeding rate (3.3%) and a lower apparent benefit from endoscopic therapy. CONCLUSIONS: An mBRS of 1 or less identifies approximately 10% of patients with gastrointestinal tract bleeding with a low likelihood of having HRS and a low risk of adverse outcomes. A prospective randomized study is required to examine whether this subgroup of patients presenting after hours could be discharged safely from emergency departments with arrangements for (urgent) outpatient endoscopy.