Identification of putative transcriptomic biomarkers in irritable bowel syndrome (IBS): Differential gene expression and regulation of TPH1 and SERT by vitamin D.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and affects approximately 4% of the global population. The diagnosis of IBS can be made based on symptoms using the validated Rome criteria and ruling out commonly occurring organic diseases. Although biomarkers exist for "IBS mimickers" such as celiac disease and inflammatory bowel disease (IBD), no such test exists for IBS. DNA microarrays of colonic tissue have been used to identify disease-associated variants in other gastrointestinal (GI) disorders. In this study, our objective was to identify biomarkers and unique gene expression patterns that may define the pathological state of IBS. Mucosal tissue samples were collected from the sigmoid colon of 29 participants (11 IBS and 18 healthy controls). DNA microarray analysis was used to assess gene expression profiling. Extraction and purification of RNA were then performed and used to synthesize cDNA. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was employed to identify differentially expressed genes in patients diagnosed with IBS compared to healthy, non-IBS patient-derived cDNA. Additional testing probed vitamin D-mediated regulation of select genes associated with serotonergic metabolism. DNA microarray analyses led to the identification of 858 differentially expressed genes that may characterize the IBS pathological state. After screening a series of genes using a combination of gene ontological analysis and RT-qPCR, this spectrum of potential IBS biomarkers was narrowed to 23 genes, some of which are regulated by vitamin D. Seven putative IBS biomarkers, including genes involved in serotonin metabolism, were identified. This work further supports the hypothesis that IBS pathophysiology is evident within the human transcriptome and that vitamin D modulates differential expression of genes in IBS patients. This suggests that IBS pathophysiology may also involve vitamin D deficiency and/or an irregularity in serotonin metabolism.

Impact of Artificial Intelligence on Miss Rate of Colorectal Neoplasia.

BACKGROUND & AIMS: Artificial intelligence (AI) may detect colorectal polyps that have been missed due to perceptual pitfalls. By reducing such miss rate, AI may increase the detection of colorectal neoplasia leading to a higher degree of colorectal cancer (CRC) prevention. METHODS: Patients undergoing CRC screening or surveillance were enrolled in 8 centers (Italy, UK, US), and randomized (1:1) to undergo 2 same-day, back-to-back colonoscopies with or without AI (deep learning computer aided diagnosis endoscopy) in 2 different arms, namely AI followed by colonoscopy without AI or vice-versa. Adenoma miss rate (AMR) was calculated as the number of histologically verified lesions detected at second colonoscopy divided by the total number of lesions detected at first and second colonoscopy. Mean number of lesions detected in the second colonoscopy and proportion of false negative subjects (no lesion at first colonoscopy and at least 1 at second) were calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted by endoscopist, age, sex, and indication for colonoscopy. Adverse events were also measured. RESULTS: A total of 230 subjects (116 AI first, 114 standard colonoscopy first) were included in the study analysis. AMR was 15.5% (38 of 246) and 32.4% (80 of 247) in the arm with AI and non-AI colonoscopy first, respectively (adjusted OR, 0.38; 95% CI, 0.23-0.62). In detail, AMR was lower for AI first for the ≤5 mm (15.9% vs 35.8%; OR, 0.34; 95% CI, 0.21-0.55) and nonpolypoid lesions (16.8% vs 45.8%; OR, 0.24; 95% CI, 0.13-0.43), and it was lower both in the proximal (18.3% vs 32.5%; OR, 0.46; 95% CI, 0.26-0.78) and distal colon (10.8% vs 32.1%; OR, 0.25; 95% CI, 0.11-0.57). Mean number of adenomas at second colonoscopy was lower in the AI-first group as compared with non-AI colonoscopy first (0.33 ± 0.63 vs 0.70 ± 0.97, P < .001). False negative rates were 6.8% (3 of 44 patients) and 29.6% (13 of 44) in the AI and non-AI first arms, respectively (OR, 0.17; 95% CI, 0.05-0.67). No difference in the rate of adverse events was found between the 2 groups. CONCLUSIONS: AI resulted in an approximately 2-fold reduction in miss rate of colorectal neoplasia, supporting AI-benefit in reducing perceptual errors for small and subtle lesions at standard colonoscopy. CLINICALTRIALS: gov, Number: NCT03954548.

A Pain in the Butt: Hemorrhoids, Fissures, Fistulas, and Other Anorectal Syndromes.

Painful and bothersome anorectal syndromes can be a diagnostic and therapeutic challenge for clinicians because structural and functional abnormalities may often coexist and require a multidisciplinary approach to management. Although it is often difficult to attribute all of a patient's anorectal symptoms to a singular disorder with definitive intervention and cure, improving quality of life, treating coexistent conditions such as functional constipation and/or defecation disorders, addressing psychological comorbidities if present, and confirming there is no evidence of inflammatory or malignant conditions are top priorities.

Timing of Resumption of Anticoagulation After Polypectomy and Frequency of Post-procedural Complications: A Post-hoc Analysis.

BACKGROUND: Optimal timing for anticoagulation resumption after polypectomy is unclear. We explored the association between timing of anticoagulation resumption and occurrence of delayed post-polypectomy bleeding (PPB) and thromboembolic (TE) events. METHODS: We performed a post-hoc analysis of patients in an earlier study whose anticoagulants were interrupted for polypectomy. We compared rates of clinically important delayed PPB and TE events in relationship to timing of anticoagulant resumption. Late resumption was defined as > 2 days after polypectomy. RESULTS: Among 437 patients, 351 had early and 86 late resumption. Compared to early resumers, late resumers had greater polypectomy complexity. PPB rate was higher (but not significantly) in the late versus early resumers (2.3% vs. 0.9%, 1.47% greater, 95% CI [- 2.58 to 5.52], p = 0.26). TE events were more frequent in late versus early resumers [0% vs. 1.2% at 30 days, 0% vs. 2.3%, 95% CI 0.3-8, (p = 0.04) at 90 days]. On multivariate analysis, timing of restarting anticoagulation was not a significant predictor of PPB (OR 0.97, 95% CI 0.61-1.44, p = 0.897). Significant predictors were number of polyps ≥ 1 cm (OR 4.14, 95% CI 1.27-13.66, p = 0.014) and use of fulguration (OR 11.43, 95% CI 1.35-80.80, p = 0.014). CONCLUSIONS: Physicians delayed anticoagulation resumption more commonly after complex polypectomies. The timing of restarting anticoagulation was not a significant risk factor for PPB and late resumers had significantly higher rates of TE events within 90 days. Considering the potentially catastrophic consequences of TE events and the generally benign outcome of PPBs, clinicians should be cautious about delaying resumption of anticoagulation after polypectomy.

Diagnostic Evaluation of Gastric Motor and Sensory Disorders.

Disorders of gastric motor and sensory function affect 10%-20% of the world's population and adversely impact nutrition, quality of life, work productivity, and health care costs. Classifying these disorders can be challenging given the heterogeneity of symptom presentation, the presence of symptoms unexplained by endoscopic, radiographic and/or laboratory evaluation, and overlap with other luminal gastrointestinal disorders. Accurately diagnosing these highly prevalent disorders relies upon an understanding of epidemiology and risk factors, the ability to take a careful clinical history focused on symptoms, and the presence of predisposing medical, surgical, and psychological conditions. A variety of diagnostic studies are now available to assess gastric motor function and identify maladaptive relaxation, accommodation, and abnormal sensation. FDA-approved treatment options are limited and thus many patients undergo a series of empirical treatment trials that target individual symptoms, often without much benefit. This article provides updated recommendations for identifying and classifying the most common gastric motor and sensory disorders using currently accepted diagnostic tests, and provides a brief supplemental overview on treatment options. "Things sweet to taste prove in digestion sour." -Shakespeare, Richard II, 1595.

Evaluation and Treatment of Constipation in the Geriatric Population.

Chronic constipation affects one-third of the US population and occurs disproportionately in the elderly and female individuals, increasing in older individuals who are institutionalized. This condition has a significant impact on health care costs and quality of life. Clinicians need to consider primary as well as secondary causes of constipation in elderly individuals because the cause is often multifactorial. Diagnostic algorithms should eliminate red-flag symptoms that may indicate a malignancy but also consider pelvic floor dysfunction, which is more common in this age group. An appropriate treatment plan is tailored to the severity of the patient's symptoms.

A Prospective Multicenter Study Evaluating Endoscopy Competence Among Gastroenterology Trainees in the Era of the Next Accreditation System.

PURPOSE: The Next Accreditation System requires training programs to demonstrate competence among trainees. Within gastroenterology (GI), there are limited data describing learning curves and structured assessment of competence in esophagogastroduodenoscopy (EGD) and colonoscopy. In this study, the authors aimed to demonstrate the feasibility of a centralized feedback system to assess endoscopy learning curves among GI trainees in EGD and colonoscopy. METHOD: During academic year 2016-2017, the authors performed a prospective multicenter cohort study, inviting participants from multiple GI training programs. Trainee technical and cognitive skills were assessed using a validated competence assessment tool. An integrated, comprehensive data collection and reporting system was created to apply cumulative sum analysis to generate learning curves that were shared with program directors and trainees on a quarterly basis. RESULTS: Out of 183 fellowships invited, 129 trainees from 12 GI fellowships participated, with an overall trainee participation rate of 72.1% (93/129); the highest participation level was among first-year trainees (90.9%; 80/88), and the lowest was among third-year trainees (51.2%; 27/53). In all, 1,385 EGDs and 1,293 colonoscopies were assessed. On aggregate learning curve analysis, third-year trainees achieved competence in overall technical and cognitive skills, while first- and second-year trainees demonstrated the need for ongoing supervision and training in the majority of technical and cognitive skills. CONCLUSIONS: This study demonstrated the feasibility of using a centralized feedback system for the evaluation and documentation of trainee performance in EGD and colonoscopy. Furthermore, third-year trainees achieved competence in both endoscopic procedures, validating the effectiveness of current training programs.

Effect of individualized feedback on learning curves in EGD and colonoscopy: a cluster randomized controlled trial.

BACKGROUND AND AIMS: Gastroenterology fellowships need to ensure that trainees achieve competence in upper endoscopy (EGD) and colonoscopy. Because the impact of structured feedback remains unknown in endoscopy training, this study compared the effect of structured feedback with standard feedback on trainee learning curves for EGD and colonoscopy. METHODS: In this multicenter, cluster, randomized controlled trial, trainees received either individualized quarterly learning curves or feedback standard to their fellowship. Assessment was performed in all trainees using the Assessment of Competency in Endoscopy tool on 5 consecutive procedures after every 25 EGDs and colonoscopies. Individual learning curves were created using cumulative sum (CUSUM) analysis. The primary outcome was the mean CUSUM score in overall technical and overall cognitive skills. RESULTS: In all, 13 programs including 132 trainees participated. The intervention arm (6 programs, 51 trainees) contributed 558 EGD and 600 colonoscopy assessments. The control arm (7 programs, 81 trainees) provided 305 EGD and 468 colonoscopy assessments. For EGD, the intervention arm (-.7 [standard deviation {SD}, 1.3]) had a superior mean CUSUM score in overall cognitive skills compared with the control arm (1.6 [SD, .8], P = .03) but not in overall technical skills (intervention, -.26 [SD, 1.4]; control, 1.76 [SD, .7]; P = .06). For colonoscopy, no differences were found between the 2 arms in overall cognitive skills (intervention, -.7 [SD, 1.3]; control, .7 [SD, 1.3]; P = .95) or overall technical skills (intervention, .1 [SD, 1.5]; control, -.1 [SD, 1.5]; P = .77). CONCLUSIONS: Quarterly feedback in the form of individualized learning curves did not affect learning curves for EGD and colonoscopy in a clinically meaningful manner. (Clinical trial registration number: NCT02891304.).

Efficacy of Prophylactic Hemoclips in Prevention of Delayed Post-Polypectomy Bleeding in Patients With Large Colonic Polyps.

BACKGROUND & AIMS: The efficacy of prophylactic placement of hemoclips to prevent delayed bleeding after removal of large colonic polyps has not been established. We conducted a randomized equivalence study to determine whether prophylactic placement of hemoclips affects incidence of delayed post-polypectomy bleeding (PPB). METHODS: During elective colonoscopy performed at 4 Veterans Affairs Medical Centers, 1098 patients who had polyps ≥1 cm removed were randomly assigned to groups that received prophylactic hemoclips (n = 547) or no hemoclips (n = 551), from September 2011 through September 2018. Data on PPB (rectal bleeding resulting in hemoglobin decreases ≥2 g/dL, hemodynamic instability, colonoscopy, angiography, or surgery) within 30 days of colonoscopy (called delayed PPB) were collected during telephone interviews or hospital visits 7 and 30 days after colonoscopy. The primary outcome was the incidence of important post-polypectomy bleeding. RESULTS: Twelve patients in the hemoclip group (2.3%) and 15 patients in the no hemoclip group (2.9%) had important delayed PPB. There were no deaths, and no patients in either group required angiography or surgery. In intention-to-treat analysis, two 1-sided test's lower and upper confidence interval limits were -2.07 and 1.01, indicating that the data approached but did not meet equivalence criteria. On multiple logistic regression analysis, significant predictors of PPB included use of warfarin with bridging, thienopyridines, polyp size, and polyp location, but hemoclip placement did not associate with important delayed PPB. CONCLUSIONS: In a randomized trial, we found that prophylactic placement of hemoclips after removal of large colon polyps does not affect the proportion of important delayed PPB events, compared with no hemoclip placement. These findings call into question the widespread, expensive practice of routinely placing prophylactic hemoclips after polypectomy. ClinicalTrials.gov ID: NCT01647581.

Ascites Module for Third-Year Medical Students: Group-Based Learning Workshop on the Diagnosis, Workup, and Management of Ascites.

INTRODUCTION: As medical students transition from didactic courses to clinical rotations, they will frequently encounter patients with cirrhosis and ascites. It is paramount that they have a firm foundation of how to diagnose ascites and perform a proper diagnostic workup in order to understand the etiology and therefore the proper management. This module is designed as a group-based, interactive learning workshop for those transitioning students. METHODS: The session begins with the students obtaining a pertinent history of a standardized patient case. The students are then divided into four groups and rotate through four stations: physical examination, diagnostic studies, paracentesis, and ascitic fluid analysis. Each station is designed for up to 10-12 students and typically lasts 20 minutes. After all of the students have rotated through each station, they reconvene to review ascites management, case conclusions, and summary. The total time allocated for this module is 125 minutes for 40-48 students. RESULTS: Postmodule evaluations by the students showed a high level of satisfaction and improvement in the students' fund of knowledge and clinical skills. Evaluations completed by the students after each workshop revealed more than 95% either agreeing or strongly agreeing with the learning objectives being clear, the learning materials being effective, overall satisfaction with the learning material and teaching, and having a better understanding of the evaluation, diagnosis, and management of ascites. DISCUSSION: Through this team-based interactive module, students obtain clinical and hands-on experience that better prepares them for their clinical rotations.

YouTube™ as a Source of Instructional Videos on Bowel Preparation: a Content Analysis.

Instructional videos on bowel preparation have been shown to improve bowel preparation scores during colonoscopy. YouTube™ is one of the most frequently visited website on the internet and contains videos on bowel preparation. In an era where patients are increasingly turning to social media for guidance on their health, the content of these videos merits further investigation. We assessed the content of bowel preparation videos available on YouTube™ to determine the proportion of YouTube™ videos on bowel preparation that are high-content videos and the characteristics of these videos. YouTube™ videos were assessed for the following content: (1) definition of bowel preparation, (2) importance of bowel preparation, (3) instructions on home medications, (4) name of bowel cleansing agent (BCA), (5) instructions on when to start taking BCA, (6) instructions on volume and frequency of BCA intake, (7) diet instructions, (8) instructions on fluid intake, (9) adverse events associated with BCA, and (10) rectal effluent. Each content parameter was given 1 point for a total of 10 points. Videos with ≥5 points were considered by our group to be high-content videos. Videos with ≤4 points were considered low-content videos. Forty-nine (59 %) videos were low-content videos while 34 (41 %) were high-content videos. There was no association between number of views, number of comments, thumbs up, thumbs down or engagement score, and videos deemed high-content. Multiple regression analysis revealed bowel preparation videos on YouTube™ with length >4 minutes and non-patient authorship to be associated with high-content videos.

C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians.

The measurement of C-reactive protein (CRP) using both standard and high-sensitivity CRP (hs-CRP) assays is becoming common in clinical practice. This article addresses the causes of CRP elevation and the use of different CRP assays in internal medicine, including cardiology, gastroenterology, rheumatology, infectious diseases, and oncology. We focus on the recent medical literature on the use of hs-CRP in cardiovascular disease risk stratification and management, including updated screening guidelines on the use of hs-CRP, such as those issued in 2009 by the Canadian Cardiovascular Society. We also discuss the Reynolds Risk Score, which incorporates hs-CRP and family history with more standard cardiovascular risk factors (eg, tobacco use, hypertension, and dyslipidemia) and frequently leads to improved recategorization of cardiovascular disease risk levels. As the recently completed Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial indicated that statin therapy decreases the vascular events among persons with elevated hs-CRP by half, even when cholesterol levels are low, the inclusion of information on hs-CRP values with other cardiovascular risk factors may assist physicians in medical decision making for patients.

Lubiprostone: evaluation of the newest medication for the treatment of adult women with constipation-predominant irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a chronic disorder that affects primarily female patients and is thought also to afflict approximately 7%-10% of the population of the Western World. Although bowel habits may change over the course of years, patients with IBS are characterized according to their predominant bowel habit, constipation (IBS-C), diarrhea (IBS-D), or mixed type (IBS-M), and treatments are focused toward the predominant symptom. Current treatments for IBS-C have included fiber, antispasmodics, osmotic and stimulant laxatives, and the now severely limited 5-HT(4) agonist tegaserod. No one agent has been universally successful in the treatment of this bothersome syndrome and the search for new agents continues. Lubiprostone (Amitiza(®)), a novel compound, is a member of a new class of agents called prostones and was approved for the treatment of chronic idiopathic constipation in 2006 at a dose of 24 µg twice daily and then in 2008 for the treatment of IBS-C in women only at a dose of 8 µg twice daily. Its purported mechanism is as a type 2 chloride channel activator, but recent evidence suggests that it may also work at the cystic fibrosis transport receptor. This article will compare the newly proposed mechanism of action of this compound to the purported mechanism and review the structure, pharmacology, safety, efficacy, and tolerability of this new therapeutic option. Clinical trial data leading to the approval of this agent for the treatment of IBS-C and the gender-based understanding of IBS, as well as this agent's place among existing and emerging therapies, will be examined.

Tract disruption and external displacement following gastrostomy tube exchange in adults.

BACKGROUND: Anecdotal reports, mostly in children, indicate that disruption of the gastrostomy tract may occur during gastrostomy tube exchange and cause serious complications. The aim of our study was to determine the rate of tract disruption occurring in adults requiring long-term enteral nutrition who had an original gastrostomy tube replaced and to evaluate factors contributing to this complication. METHODS: We retrospectively reviewed the medical records of all patients who underwent replacement of their gastrostomy tube over a 3-year period. Information was collected relating to patient demographics, underlying diagnosis, method of insertion and tube type used for initial gastrostomy tube and subsequent tube replacement, staff involved in tube replacement, patient nutritional status at the time of tube change, and the number of days from initial tube placement to replacement. For comparative purposes, the patients were divided into 2 groups: those with tract disruption and those without tract disruption. RESULTS: A total of 182 tube changes in 108 adults were performed; 55 were initial tube changes. Four (7.3%) tract disruptions occurred, all with skin-level replacement devices and only with the initial replacement of the original gastrostomy tube. There were no significant differences in patient demographics, principal diagnosis, method of insertion and tube type used for initial gastrostomy tube, staff involved in tube replacement, patient nutritional status at the time of tube change, or the number of days from initial tube placement to replacement. CONCLUSION: Tract disruption occurs infrequently during replacement of gastrostomy tubes and appears to be an issue primarily during the initial tube exchange when using a skin-level device.

Personality traits and impaired health-related quality of life in patients with functional gastrointestinal disorders.

BACKGROUND & AIMS: Negative affectivity and social isolation (Type D personality) are personality traits associated with poor health-related quality of life (HRQoL). We hypothesized these traits would be associated with impaired HRQoL and increased gastrointestinal symptom severity in functional gastrointestinal disorders. METHODS: Data were collected from patients undergoing breath testing. Patients completed the Type D Scale-14, Gastrointestinal Symptoms Severity Index and Short-Form Health Survey 12. RESULTS: Of 230 patients evaluated, 37% met criteria for Type D personality. Type D was associated with a decreased Mental Component score on the Short-Form Health Survey 12 (mean difference = -8.29; 95% confidence interval, 5.2-11.4; P < .001). On the Gastrointestinal Symptoms Severity Index, severity of symptoms was significantly higher in Type D patients compared with non Type D patients (P < .001). CONCLUSIONS: Type D personality was associated with decreased perceived HRQoL and reporting of more severe gastrointestinal symptoms. Type D personality construct may be an important consideration when assessing HRQoL outcomes. Consideration of personality traits could improve risk stratification in research and clinical practice in this patient group.

Emerging drugs for chronic constipation.

Chronic constipation (CC) is one of the most common functional gastrointestinal disorders. CC is estimated to affect up to 27% of the North American population. Although not life-threatening, CC can have profoundly negatively affects on quality of life and result in significant economic burden in terms of both direct and indirect healthcare costs. Possible etiologies for CC include alterations in gastrointestinal motility and secretion. Research efforts in CC have begun to identify multifactorial and often overlapping etiologies including abnormalities in myenteric neurons, alterations in neurotransmitters and their receptors, and incoordination of the muscles of the pelvic floor or anorectum. CC may be influenced by genetic predisposition, environmental factors and stress. In this article, the safety and efficacy of traditional and emerging therapies for CC are examined.

A novel histologic scoring system to evaluate mucosal biopsies from patients with eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is characterized by medically/surgically-resistant gastroesophageal reflux symptoms and dense squamous eosinophilia. Studies suggest that histologic assessment of esophageal eosinophilia alone cannot reliably separate patients with EoE from those with gastroesophageal reflux disease (GERD). Our goal was to develop an assay to identify EoE patients and perhaps differentiate EoE from other causes of esophageal eosinophilia. METHODS: A monoclonal antibody specific for an eosinophil secondary granule protein (eosinophil peroxidase [EPX]) was developed and shown to specifically identify intact eosinophils and detect eosinophil degranulation in formalin-fixed specimens. A histopathologic scoring algorithm was developed to analyze data from patient evaluations; the utility of this algorithm was assessed by using archived esophageal tissues from patients with known diagnoses of EoE and GERD as well as controls from 2 tertiary care centers. RESULTS: Intraobserver/interobserver blinded evaluations demonstrated a significant difference (P < .001) between scores of samples taken from control subjects, from patients with esophageal eosinophilia who had a diagnosis of EoE, and from patients with GERD (P < .001). This algorithm also was able to identify patients whose clinical course was suggestive of a diagnosis of EoE, but that nonetheless failed to reach the critical threshold number of > or =15 eosinophils in a high-power (40x) microscopy field. CONCLUSIONS: A novel immunohistochemical scoring system was developed to address an unmet medical need to differentiate histologic specimens from patients with EoE relative to those with GERD. The availability of a unique anti-EPX-specific monoclonal antibody, combined with the ease/rapidity of this staining method and scoring system, will provide a valuable strategy for the assessment of esophageal eosinophilia.

Multilayered epithelium in mucosal biopsy specimens from the gastroesophageal junction region is a histologic marker of gastroesophageal reflux disease.

Barrett esophagus (BE) is defined as a columnar metaplasia of the distal esophagus that develops as a result of chronic gastroesophageal reflux disease (GERD). A distinctive type of multilayered epithelium (ME) that exhibits features of both squamous and columnar epithelium has been hypothesized to represent an early, or intermediate, phase in the development of BE. The aim of this prospective study was to evaluate the prevalence and specificity of ME in mucosal biopsies of the squamocolumnar junction (SCJ) from patients who had GERD, either with or without BE. During endoscopic examination of the esophagus, 2 biopsy specimens were obtained from across the SCJ from 27 patients with BE, 12 patients who had GERD without BE, and 14 controls who had no symptoms or endoscopic or histologic signs of GERD. ME was present at the SCJ in 33%, 33%, and 0% of BE, GERD, and control patients, respectively. Compared with control subjects, the prevalence of ME was significantly higher in both GERD and BE patients (P<0.05). In GERD patients without BE, ME was always detected adjacent to areas of cardia-type mucosa composed of mucous glands. ME from GERD patients and BE patients had a similar immunophenotype, showing expression of the intestinal markers MUC2 and cdx-2 in 38% and 77% of cases, respectively. The prevalence of expression of these markers in ME was significantly different from nongoblet epithelium in control patients. Our results provide further evidence that ME may represent an early, transitional form of columnar metaplasia, and that ME may be used as a histologic marker of reflux disease in mucosal biopsies from the gastroesophageal junction region.

GERD is associated with shortened telomeres in the squamous epithelium of the distal esophagus.

Telomeres are repetitive DNA sequences located at the ends of chromosomes. Telomeres are shortened by repeated cell divisions and by oxidative DNA damage, and cells with critically shortened telomeres cannot divide. We hypothesized that chronic gastroesophageal reflux disease (GERD)-induced injury of the esophageal squamous epithelium results in progressive telomeric shortening that eventually might interfere with mucosal healing. To address our hypothesis, we compared telomere length and telomerase activity in biopsy specimens of esophageal squamous epithelium from GERD patients and control patients. Endoscopic biopsies were taken from the esophageal squamous epithelium of 38 patients with GERD [10 long-segment Barrett's esophagus (LSBE), 15 short-segment (SSBE), 13 GERD without Barrett's esophagus] and 16 control patients without GERD. Telomere length was assessed using the terminal restriction fragment assay, and telomerase activity was studied by the PCR-based telomeric repeat amplification protocol assay. Patients with GERD had significantly shorter telomeres in the distal esophagus than controls [8.3 +/- 0.5 vs. 10.9 +/- 1.5 (SE) Kbp, P = 0.043]. Among the patients with GERD, telomere length in the distal esophagus did not differ significantly in those with and without Barrett's esophagus (LSBE 7.9 +/- 0.8, SSBE 8.6 +/- 0.9, GERD without BE 8.7 +/- 1.0 Kbp). No significant differences in telomerase activity in the distal esophagus were noted between patients with GERD and controls (4.0 +/- 0.39 vs. 5.2 +/- 0.53 RIUs). Telomeres in the squamous epithelium of the distal esophagus of patients who have GERD, with and without Barrett's esophagus, are significantly shorter than those of patients without GERD despite similar levels of telomerase activity.