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The use of domperidone (DOM) for gastroparesis (GP) remains controversial and limited. We aimed to present outcomes of DOM therapy for treatment of patients participating in the multicenter National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) Registries (GpR). The GpCRC cohort consisted of patients with GP (75%) and with GP-like symptoms but with normal gastric emptying (25%). The DOM group initiated therapy during the 96 weeks of enrollment in GpR1 and GpR2. Patients who had previously taken or who were on DOM therapy at enrollment were excluded from this analysis. The control group did not use domperidone (non-DOM group) before or after enrollment. The following outcome measures were identified: change from baseline in Gastroparesis Cardinal Symptom Index total score, with 3 subscales, plus Gastroesophageal Reflux Disease and Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life scores. Overall, of 748 patients, 181 (24%) were in the DOM group, whereas 567 were in the non-DOM group. Sixty-three percent of participants had idiopathic GP. At baseline, DOM patients compared with non-DOM patients were significantly younger, had lower body mass index, non-Hispanic ethnicity, a higher annual household income, lower narcotic utilization, lower supplemental and complimentary medication use, and were more likely to have delayed gastric emptying time, as well as worse nausea and fullness scores. Compared with non-DOM patients, DOM patients experienced moderate but significantly more improvement in GP outcome measures: Gastroparesis Cardinal Symptom Index total score (P =.003), nausea (P =.003), and fullness subscales (P =.005), upper abdominal pain score (P =.04), Gastroesophageal Reflux Disease score (P =.05), and Patient Assessment of Upper Gastrointestinal Disorders–Quality of Life score (P =.05). Utilizing the method of pragmatic modeling to evaluate long-term treatment of GP in a large GpCRC database, DOM treatment resulted in moderately but significantly improved GP. This project was based on data generated by 2 GpCRC Registry studies recognized under the Clinicaltrial.gov numbers: NCT00398801 and NCT01696747 symptoms compared with a group receiving standard-of-care but not DOM. [ABSTRACT FROM AUTHOR]

The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls. A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. NCT00398801 , NCT01696747 [ABSTRACT FROM AUTHOR]

Duodenoscope contamination is associated with notable patient morbidity and mortality and can occur despite high-level disinfection protocols, requiring a solution that protects against contamination of the endoscope in the first place. We assessed a newly cleared, single-use device to seal the distal end of duodenoscopes while preserving optics and other endoscope functionality and tested its ability to protect against contamination using dye immersion tests and microbial inoculation. Dye immersion tests revealed a complete seal with no leakage. Rigorous microbial challenge tests showed the device can both protect against contamination of the endoscope by external microbes ("outside-in" protection) and shield instruments from contact with pre-existing microbial biofilm on or around the elevator that may have survived reprocessing ("inside-out" protection). Optical and mechanical performance of the endoscope was not compromised by the addition of the device. The results show that this disposable device provides 2-way protection to the duodenoscope from microbial contamination, without the potential for disrupting current equipment, technique, and workflow. [ABSTRACT FROM AUTHOR]

In June 2016, the National Institutes of Health hosted a workshop on functional bowel disorders (FBDs), particularly irritable bowel syndrome, with the objective of elucidating gaps in current knowledge and recommending strategies to address these gaps. The workshop aimed to provide a roadmap to help strategically guide research efforts during the next decade. Attendees were a diverse group of internationally recognized leaders in basic and clinical FBD research. This document summarizes the results of their deliberations, including the following general conclusions and recommendations. First, the high prevalence, economic burden, and impact on quality of life associated with FBDs necessitate an urgent need for improved understanding of FBDs. Second, preclinical discoveries are at a point that they can be realistically translated into novel diagnostic tests and treatments. Third, FBDs are broadly accepted as bidirectional disorders of the brain−gut axis, differentially affecting individuals throughout life. Research must integrate each component of the brain−gut axis and the influence of biological sex, early-life stressors, and genetic and epigenetic factors in individual patients. Fourth, research priorities to improve diagnostic and management paradigms include enhancement of the provider−patient relationship, longitudinal studies to identify risk and protective factors of FBDs, identification of biomarkers and endophenotypes in symptom severity and treatment response, and incorporation of emerging “-omics” discoveries. These paradigms can be applied by well-trained clinicians who are familiar with multimodal treatments. Fifth, essential components of a successful program will include the generation of a large, validated, broadly accessible database that is rigorously phenotyped; a parallel, linkable biorepository; dedicated resources to support peer-reviewed, hypothesis-driven research; access to dedicated bioinformatics expertise; and oversight by funding agencies to review priorities, progress, and potential synergies with relevant stakeholders. [ABSTRACT FROM AUTHOR]

Gastroparesis continues to represent a large unmet clinical need and a major opportunity for new drug development. This has led to increasing interest by federal funding agencies, regulatory bodies, and industry. This article summarizes the proceedings of the gastroparesis section of the “Drug Development Conference: Clinical Endpoints in Upper GI Disorders” organized by the American Gastroenterological Association in Washington, DC, on October 27–28, 2016. The presentation, diagnosis, and current therapeutic strategies are briefly reviewed, followed by a detailed discussion of the regulatory strategy, recommended endpoints, and future directions. [ABSTRACT FROM AUTHOR]

The Gastroparesis Clinical Research Consortium is a multicenter coalition created and funded by the National Institutes of Diabetes and Digestive and Kidney Disorders, with a mission to advance understanding of the pathophysiology of gastroparesis and develop an effective treatment for patients with symptomatic gastroparesis. In this review, we summarize the results of the published Gastroparesis Clinical Research Consortium studies as a ready and convenient resource for gastroenterologists and others to provide a clear understanding of the consortium's experience and perspective on gastroparesis and related disorders. [ABSTRACT FROM AUTHOR]

Background and Aims The safety and efficacy of peroral endoscopic myotomy (POEM) when performed by gastroenterologists in the endoscopy unit are currently unknown. The aims of this study were to assess (1) the safety and efficacy of POEM in which all procedures were performed by 1 gastroenterologist in the endoscopy unit, and (2) the predictors of adverse events and nonresponse. Methods All consecutive patients who underwent POEM at 1 tertiary center were included. Clinical response was defined by a decrease in the Eckardt score to 3 or lower. Adverse events were graded according to the American Society for Gastrointestinal Endoscopy lexicon’s severity grading system. Results A total of 60 consecutive patients underwent POEM in the endoscopy suite with a mean procedure length of 99 minutes. The mean length of submucosal tunnel was 14 cm and the mean myotomy length was 11 cm. The median length of hospital stay was 1 day. Among 52 patients with a mean follow-up period of 118 days (range 30-750), clinical response was observed in 48 patients (92.3%). There was a significant decrease in Eckardt score after POEM (8 vs 1.19, P < .0001). The mean lower esophageal sphincter pressure decreased significantly after POEM (29 mm Hg vs 11 mm Hg, P < .0001). A total of 10 adverse events occurred in 10 patients (16.7%): 7 rated as mild, 3 as moderate, and none as severe. Procedure length was the only predictor of adverse events ( P = .01). pH impedance testing was completed in 25 patients, and 22 (88%) had abnormal acid exposure, but positive symptom correlation was present in only 6 patients. All patients with symptomatic reflux were successfully treated with proton pump inhibitors. Conclusions POEM can be effectively and safely performed by experienced gastroenterologists at a tertiary care endoscopy unit. Adverse events are infrequent, and most can be managed intraprocedurally. Post-POEM reflux is frequent but can be successfully managed medically. [ABSTRACT FROM AUTHOR]

The development of and adherence to quality indicators in gastroenterology, as in all of medicine, is increasing in importance to ensure that patients receive consistent high-quality care. In addition, government-based and private insurers will be expecting documentation of the parameters by which we measure quality, which will likely affect reimbursements. Barrett’s esophagus remains a particularly important disease entity for which we should maintain up-to-date guidelines, given its commonality, potentially lethal outcomes, and controversies regarding screening and surveillance. To achieve this goal, a relatively large group of international experts was assembled and, using the modified Delphi method, evaluated the validity of multiple candidate quality indicators for the diagnosis and management of Barrett’s esophagus. Several candidate quality indicators achieved >80% agreement. These statements are intended to serve as a consensus on candidate quality indicators for those who treat patients with Barrett’s esophagus. [ABSTRACT FROM AUTHOR]

Background: The prevalence and factors associated with delayed gastric emptying (DGE) in patients undergoing total pancreatectomy with islet auto transplantation (TP-IAT) for chronic pancreatitis are unknown. Methods: A retrospective study of all patients who underwent TP-IAT at Johns Hopkins Hospital (JHH) from August 2011 to November 2014 was performed. The International Study Group of Pancreatic Surgery (ISGPS) clinical grading of DGE was used in this study. Key Results: A total of 39 patients with chronic pancreatitis underwent TP-IAT during the study period. The prevalence of DGE following TP-IAT was 35.9 %. Twenty-five patients (64.1 %) had no DGE, 10 (25.6 %) had grade A, 2 (5.1 %) had grade B, and 2 patients (5.1 %) had grade C DGE. Patients with DGE had 5.7-fold higher odds of having a hospital length of stay (LOS) greater than 14 days (OR 5.70, 95 % CI 1.37-23.76, p = 0.02). Patients undergoing laparoscopic TP-IAT had significantly shorter LOS (10.5 vs. 14 days, p = 0.02) and lower need for prokinetics (0.01) during the postoperative course. Conclusions and Inferences: DGE is common after TP-IAT and can prolong LOS. Laparoscopic TP-IAT lowers LOS and need for prokinetics postoperatively. Further studies are needed to determine if laparoscopic approaches will improve long-term dysmotility. [ABSTRACT FROM AUTHOR]

Background & Aims: As in other tumor types, progression of pancreatic cancer may require a functionally unique population of cancer stem cells. Although such cells have been identified in many invasive cancers, it is not clear whether they emerge during early or late stages of tumorigenesis. Using mouse models and human pancreatic cancer cell lines, we investigated whether preinvasive pancreatic neoplasia contains a subpopulation of cells with distinct morphologies and cancer stem cell–like properties. Methods: Pancreatic tissue samples were collected from the KCPdx1, KPCPdx1, and KCiMist1 mouse models of pancreatic intraepithelial neoplasia (PanIN) and analyzed by confocal and electron microscopy, lineage tracing, and fluorescence-activated cell sorting. Subpopulations of human pancreatic ductal adenocarcinoma (PDAC) cells were similarly analyzed and also used in complementary DNA microarray analyses. Results: The microtubule regulator DCLK1 marked a morphologically distinct and functionally unique population of pancreatic cancer–initiating cells. These cells displayed morphological and molecular features of gastrointestinal tuft cells. Cells that expressed DCLK1 also expressed high levels of ATAT1, HES1, HEY1, IGF1R, and ABL1, and manipulation of these pathways in PDAC cell lines inhibited their clonogenic potential. Pharmacological inhibition of γ-secretase activity reduced the abundance of these cells in murine PanIN in a manner that correlated with inhibition of PanIN progression. Conclusions: Human PDAC cells and pancreatic neoplasms in mice contain morphologically and functionally distinct subpopulations that have cancer stem cell–like properties. These populations can be identified at the earliest stages of pancreatic tumorigenesis and provide new cellular and molecular targets for pancreatic cancer treatment and/or chemoprevention. [Copyright &y& Elsevier]

Constipation can be an important symptom in some patients with gastroparesis. The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; and 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and wireless motility capsule (WMC). Patients with symptoms of gastroparesis underwent gastric emptying scintigraphy (GES), wireless motility capsule (WMC) assessing gastric emptying, small bowel transit, and colonic transit, and questionnaires assessing symptoms using a modified Patient Assessment of Upper GI Symptoms [PAGI-SYM] and Rome III functional GI disorder questionnaire. Of 338 patients with symptoms of gastroparesis, 242 (71.5%) had delayed gastric emptying by scintigraphy; 298 (88.2%) also met criteria for functional dyspepsia. Severity of constipation was severe/very severe in 34% patients, moderate in 24%, and none/very mild/mild in 42%. Increasing severity of constipation was associated with increasing symptoms of gastroparesis and presence of irritable bowel syndrome (IBS). Severity of constipation was not associated with gastric retention on GES or WMC. Delayed colonic transit was present in 108 patients (32% of patients). Increasing severity of constipation was associated with increasing small bowel transit time, colonic transit time, and whole gut transit time. Severe/very severe constipation and delayed colon transit occurs in a third of patients with symptoms of gastroparesis. The severity of constipation is associated with severity of gastroparesis symptoms, presence of IBS, small bowel and colon transit delay, but not delay in gastric emptying. ClinicalTrials.gov Identifier: NCT01696747 [ABSTRACT FROM AUTHOR]

Background: Better pancreatic cyst fluid biomarkers are needed. Objective: To determine whether metabolomic profiling of pancreatic cyst fluid would yield clinically useful cyst fluid biomarkers. Design: Retrospective study. Setting: Tertiary-care referral center. Patients: Two independent cohorts of patients (n = 26 and n = 19) with histologically defined pancreatic cysts. Intervention: Exploratory analysis for differentially expressed metabolites between (1) nonmucinous and mucinous cysts and (2) malignant and premalignant cysts was performed in the first cohort. With the second cohort, a validation analysis of promising identified metabolites was performed. Main Outcome Measurements: Identification of differentially expressed metabolites between clinically relevant cyst categories and their diagnostic performance (receiver operating characteristic [ROC] curve). Results: Two metabolites had diagnostic significance--glucose and kynurenine. Metabolomic abundances for both were significantly lower in mucinous cysts compared with nonmucinous cysts in both cohorts (glucose first cohort P = .002, validation/5 = .006; and kynurenine first cohort F = .002, validation P = .002). The ROC curve for glucose was 0.92 (95% confidence interval [CI], 0.81-1.00) and 0.88 (95% CI, 0.72-1.00) in the first and validation cohorts, respectively. The ROC for kynurenine was 0.94 (95% CI, 0.81-1.00) and 0.92 (95% CI, 0.76- 1.00) in the first and validation cohorts, respectively. Neither could differentiate premalignant from malignant cysts. Glucose and kynurenine levels were significantly elevated for serous cystadenomas in both cohorts. Limitations: Small sample sizes. Conclusion: Metabolomic profiling identified glucose and kynurenine to have potential clinical utility for differentiating mucinous from nonmucinous pancreatic cysts. These markers also may diagnose serous cystadenomas. [ABSTRACT FROM AUTHOR]

Background & Aims: Diet has major effects on the intestinal microbiota, but the exact mechanisms that alter complex microbial communities have been difficult to elucidate. In addition to the direct influence that diet exerts on microbes, changes in microbiota composition and function can alter host functions such as gastrointestinal (GI) transit time, which in turn can further affect the microbiota. Methods: We investigated the relationships among diet, GI motility, and the intestinal microbiota using mice that are germ-free (GF) or humanized (ex-GF mice colonized with human fecal microbiota). Results: Analysis of gut motility revealed that humanized mice fed a standard polysaccharide-rich diet had faster GI transit and increased colonic contractility compared with GF mice. Humanized mice with faster transit due to administration of polyethylene glycol or a nonfermentable cellulose-based diet had similar changes in gut microbiota composition, indicating that diet can modify GI transit, which then affects the composition of the microbial community. However, altered transit in mice fed a diet of fermentable fructooligosaccharide indicates that diet can change gut microbial function, which can affect GI transit. Conclusions: Based on studies in humanized mice, diet can affect GI transit through microbiota-dependent or microbiota-independent pathways, depending on the type of dietary change. The effect of the microbiota on transit largely depends on the amount and type (fermentable vs nonfermentable) of polysaccharides present in the diet. These results have implications for disorders that affect GI transit and gut microbial communities, including irritable bowel syndrome and inflammatory bowel disease. [Copyright &y& Elsevier]

Background & Aims: Antibodies against the water channel protein aquaporin (AQP)-4 cause a spectrum of inflammatory, demyelinating, central nervous system disorders called neuromyelitis optica spectrum disorders (NMOSDs); these primarily affect the optic nerves and spinal cord but also the brain. Symptoms of intractable nausea, vomiting, and hiccups reflect involvement of AQP4 in the brainstem area postrema and account for gastroenterological presentations. We investigated the frequency of intractable nausea, vomiting, or hiccups in patients with NMOSD who tested positive for immunoglobulin G against AQP4 (AQP4-IgG). We also analyzed sera from patients with idiopathic nausea or vomiting for the presence of AQP4-IgG. Methods: We reviewed the Mayo Clinic AQP4-IgG positive NMOSD database (n = 70) to identify patients who presented with vomiting, focusing on results from gastroenterological evaluations. We also tested serum samples (from the Gastroparesis Clinical Research Consortium repository) from patients who presented with idiopathic nausea or vomiting for AQP4-IgG (controls, n = 318 with gastroparesis and 117 without gastroparesis). Results: Ten AQP4-IgG–positive patients diagnosed with NMOSD (14% of patients in the database) initially presented with intractable vomiting. Extensive gastroenterological evaluation was noninformative. AQP4-IgG was not detected in any of the controls. Conclusions: Although NMOSDs are rare, tests for AQP4-IgG should be considered for patients who present with unexplained, intractable vomiting. Detection of the antibody before the development of optic neuritis or transverse myelitis allows patients to receive immunosuppressive therapy before the development of neurologic disabilities. [ABSTRACT FROM AUTHOR]

Gastrointestinal endoscopy has had a spectacular run in the last few decades with advances in technology that have redefined both gastroenterology and gastrointestinal surgery. Going forward, its contributions are likely to be even more meaningful as new procedures expand both the indications as well as the user base and contribute to bending the curve of healthcare costs. In this essay, I will describe some of what I believe to be the most important future developments with the greatest potential for impact across the spectrum of digestive disorders. [ABSTRACT FROM AUTHOR]

Background: Peroral endoscopic myotomy (POEM) was developed to reduce lower esophageal sphincter pressure in patients with achalasia. POEM is technically challenging and time consuming. The creation of an esophageal submucosal tunnel is a major and integral part of the procedure. Dissection of the submucosal fibers is a lengthy task. Objective: To present our initial experience with the use of a novel gel with dissecting properties for facilitating submucosal tunneling during POEM. Setting: Johns Hopkins Hospital. Intervention: POEM. Results: The gastroscope was successfully introduced into the submucosal space in all pigs. The gel in the submucosal space was easily suctioned through the working channel of the gastroscope and did not interfere with endoscopic visualization. The esophageal submucosal tunnel was noted to be already formed upon entry into the submucosal space in all 5 pigs. Esophageal submucosal dissection was not required in any case. “Auto-tunneling” by the dissecting gel stopped at the level of the lower esophageal sphincter. Further tunneling into the gastric cardia was needed in all pigs. The average procedure (including myotomy) time was 28 minutes. Limitations: Animal experiments. Conclusion: Gel consistently resulted in efficient auto-tunneling without any complications. This gel has the potential to revolutionize POEM and endoscopic submucosal dissection if its safety and efficacy are replicated in other animal studies and subsequently in human trials. [ABSTRACT FROM AUTHOR]

Background & Aims: Gastroparesis can be diabetic or idiopathic, yet little is known about differences in their presentation. We compared clinical characteristics, symptoms, and gastric emptying in patients with type 1 or type 2 diabetic (DG) or idiopathic (IG) gastroparesis. Methods: We analyzed data from 416 patients with gastroparesis who were enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Registry; 254 had IG (most were female and white), and 137 had DG (78 had type 1 and 59 had type 2). Registry data included detailed histories, physical examinations, results from gastric emptying scintigraphy, and responses to validated symptom questionnaires. Results: Patients with type 2 diabetes mellitus (DM) were an average of 13 years older at the onset of symptoms of gastroparesis and heavier than patients with IG. Patients with type 1 DM had more hospitalizations in the past year than patients with IG. Symptoms that prompted evaluation more often included vomiting for DG and abdominal pain for IG. Patients with DG had more severe retching and vomiting than those with IG, whereas patients with IG had more severe early satiety and postprandial fullness subscores. Compared with IG, gastric retention was greater in patients with type 1 DM. More than 50% of patients with type 1 DM had severe retention (>35% at 4 hours); they took prokinetic agents more frequently and were more likely to receive gastric electric stimulation. Conclusions: There are similarities and differences in clinical characteristics of DG and IG. Gastroparesis is a heterogeneous disorder; its etiology affects symptoms and severity. Long-term studies are needed to determine whether the differences in symptoms and gastric emptying affect progression and treatment responses. [ABSTRACT FROM AUTHOR]

Background & Aims: The pathogenesis of pain in chronic pancreatitis (CP) is poorly understood and treatment remains difficult. We hypothesized that nerve growth factor (NGF) plays a key role in this process via its effects on the transient receptor potential vanilloid 1, TRPV1. Methods: CP was induced by intraductal injection of trinitrobenzene sulfonic acid in rats. After 3 weeks, anti-NGF antibody or control serum was administered daily for 1 week. Pancreatic hyperalgesia was assessed by nocifensive behavioral response to electrical stimulation of the pancreas as well as by referred somatic pain assessed by von Frey filament testing. TRPV1 currents in pancreatic sensory neurons were examined by patch-clamp. The expression and function of TRPV1 in pancreas-specific nociceptors was examined by immunostaining and quantification of messenger RNA levels. Results: Blockade of NGF significantly attenuated pancreatic hyperalgesia and referred somatic pain compared with controls. It also decreased TRPV1 current density and open probability and reduced the proportion of pancreatic sensory neurons that expressed TRPV1 as well as levels of TRPV1 in these neurons. Conclusions: These findings emphasize a key role for NGF in pancreatic pain and highlight the role it plays in the modulation of TRPV1 expression and activity in CP. [ABSTRACT FROM AUTHOR]

Introduction: Sphincter function is a common problem in gastroenterology and leads to disorders such as GERD and fecal incontinence. Objective: We hypothesized that transplantation of skeletal muscle–derived cells (MDCs) into GI sphincters may improve their function, leading to a more physiological approach to treating these disorders. Design: We performed experiments to test the potential of MDCs to survive and differentiate within the GI smooth muscle in order to gain further knowledge on the biology of skeletal muscle transplantation in GI smooth muscle sphincters as well as to test the safety and feasibility of endoscopic injection of MDCs in a large animal model. Setting: Animal laboratory. Interventions: Adult male Sprague-Dawley rats and adult male beagle dogs were used. Rat-derived and dog-derived MDCs were prepared in vitro and labeled with DiI. DiI-labeled, rat-derived MDCs (200,000/4 μL phosphate buffered saline solution) were injected bilaterally in the pyloric wall of rats, and survival, differentiation, and in vitro contractility were assessed 1 month after transplantation. Dog-derived MDCs (4.0 × 106 cells) were also injected into the lower esophageal sphincter of 3 beagle dogs by using a standard variceal sclerotherapy needle after baseline esophageal manometry and pH monitoring. The dogs were treated with daily cyclosporine, and 2 weeks later esophageal manometry was repeated and the esophagus was examined histologically. Differentiation of grafted cells was assessed by immunofluorescence, using specific antibodies to markers of the smooth muscle phenotype (smooth muscle actin) and of the skeletal muscle phenotype (skeletal muscle myosin). Results: In rats, grafted MDCs were visualized based on DiI fluorescence and were found to be localized within the muscle wall and in the muscularis mucosa. In vitro organ bath studies showed a significant increase in the contractile response of the pyloric sphincter to exogenous acetylcholine. In dogs, MDC injection resulted in a significant increase in baseline lower esophageal sphincter pressure. Further, in 1 dog with significant baseline acid reflux, MDC injection resulted in a reduction of acid reflux, with the fraction of time with pH <4 decreasing from 26.5% to 1.5%. Transplanted MDCs were seen adding bulk to the lower esophageal area and were well-integrated into the surrounding tissue. Immunofluorescence analysis revealed weak expression of skeletal muscle myosin in grafted MDCs and no expression of smooth muscle actin in either rats or dogs. Limitations: Animal study. Conclusion: MDCs can survive and integrate into GI smooth muscle and augment their contractile response. Thus, they may have potential for the treatment of a variety of conditions. [Copyright &y& Elsevier]

The American Gastroenterological Association (AGA) Institute Future Trends Committee (FTC) developed this report based on a consensus conference it convened on March 8–9, 2008, in Washington, DC. The report was prepared for the FTC by Carol Regueiro, MD, MSc, a medical writer under contract to the AGA Institute, and Michael Stolar, PhD, staff liaison to the FTC. This report was approved by the FTC on July 1, 2008, and accepted by the AGA Institute Governing Board on July 26, 2008. [Copyright &y& Elsevier]

Background: Gastric electrical stimulation has been used for the treatment of drug refractory GI motility disorders and for the treatment of obesity. Both these indications have involved surgical placement of gastric electrodes, which adds to the complexity and cost of the procedure. Endoscopic placement is therefore an attractive alternative approach for this therapy. Objective: Our purpose was to investigate the feasibility, safety, and efficacy of percutaneous endoscopic electrodes for gastric electrical stimulation. Design and Setting: Experimental animal study in hound dogs. Interventions: Percutaneous endoscopic transgastric electrode (PETE) placement was carried out by using a pair of gastric pacing wires attached to a percutaneous endoscopic gastrostomy tube. In addition, 4 pairs of gastric serosal electrodes were implanted surgically for comparison. The efficacy of the percutaneous endoscopic electrodes was defined by their ability to entrain gastric slow waves and the induction of dysrhythmia. Results: (1) The PETE recorded gastric slow waves comparable to the serosal electrodes. (2) Gastric electrical stimulation with long pulses delivered by the PETE, at a frequency of 10% higher than the intrinsic gastric slow wave frequency, entrained gastric slow waves. (3) Gastric electrical stimulation delivered by the PETE, at a tachygastric frequency, induced gastric dysrhythmia. Limitations: This was an animal study; however, its results are expected to be reproducible in humans, with PETE kept in place for even a longer duration than 6 to 8 weeks. Conclusion: PETE placement is both feasible and safe. PETEs are effective, having a potential for use in treatment of both gastroparesis and obesity. [Copyright &y& Elsevier]

Background & Aims: Despite being widely used in more than 20 countries for the treatment of diabetic gastroparesis for several decades, domperidone is approved only on an investigational basis in the United States. However, because its use is increasing, it is important for gastroenterologists in this country to understand its effectiveness in this condition. The literature on this subject varies considerably with respect to the methods and outcome measures, making a meta-analysis unfeasible. Methods: Our objective was to systematically analyze studies of the efficacy of domperidone in diabetic gastroparesis, with a focus on their methodologic and scientific merit. Information from 28 trials (11 full articles and 17 abstracts) from 1981 to 2007 was analyzed. Results: The average study quality score was 8.3 out of a possible 15 and the total sample size equaled 1016. Overall, 64% of the studies showed significant efficacy of domperidone on the improvement of symptoms. Sixty percent of the studies showed an efficacy in gastric emptying and 67% of the studies proved the drug effective in reducing hospital admissions. Conclusions: Overall, our assessment is that there is level 3 evidence for the efficacy of domperidone in diabetic gastroparesis, leading to a grade C recommendation for its use in this condition. These results need to be interpreted very cautiously because of significant methodologic limitations of these studies, including the fact that most positive studies lacked a control arm. It is clear that larger and better-designed studies are needed to further validate the use of this drug in diabetic gastroparesis. [Copyright &y& Elsevier]

Background & Aims: Although several pathophysiologic abnormalities have been noted in functional dyspepsia (FD), their pathogenesis is poorly understood. We hypothesized that chronic gastric hypersensitivity and gastric motor dysfunction seen in FD patients can be modeled in rats by transient gastric irritation during the neonatal period, a time of known neuronal vulnerability to long-term plasticity. Methods: Ten-day-old male rats received 0.2 mL 0.1% iodoacetamide (IA) in 2% sucrose daily by oral gavages for 6 days; controls received 2% sucrose. Rats in both groups were then followed to adulthood (8–10 weeks) at which point behavioral, visceromotor, and great splanchnic nerve responses to graded gastric balloon distention (GD; 20–80 mm Hg) and gastric motor function were tested. Results: IA-treated rats exhibited hypersensitivity to GD in a dose-dependent manner, as compared with the control group. The threshold of afferent nerve activation was lower and nerve responses to GD were significantly increased in IA-treated rats. Although IA-treated rats ingested food at a lower rate, gastric emptying was not significantly different between IA and control groups. However, gastric accommodation was significantly reduced in the IA group. No significant gastric pathology was seen in hypersensitive adult rats compared with controls. Conclusions: These studies demonstrate that gastric irritation in the neonatal period can result in chronic gastric hypersensitivity and gastric motor dysfunction in adults even in the absence of significant detectable gastric pathology. Our results offer insight into the pathogenesis of chronic functional dyspepsia and provide a potential model for further study to this important clinical problem. [Copyright &y& Elsevier]