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Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity - in response to gastric distention - was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a "bottom-up" pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.

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]

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 & 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]

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]

Background & Aims: The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. Methods: CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat’s nocifensive behavior to electrical stimulation of the pancreas. Results: CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. Conclusions: TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation. [Copyright &y& Elsevier]

Background & Aims: Robust chemical or mechanical irritation of the colon of neonatal rats leads to chronic visceral hypersensitivity. The clinical and physiologic relevance of such noxious stimulation in the context of human irritable bowel syndrome is questionable. The aims of this study were to determine whether mild chemical irritation of the colon of neonatal rats produced persistent changes in visceral sensitivity and to evaluate the role of transient receptor potential vanilloid 1 (TRPV1) in the initiation and maintenance of visceral hypersensitivity. Methods: Ten-day-old rat pups received an intracolonic infusion of 0.5% acetic acid in saline. TRPV1 inhibitors were administered 30 minutes before acetic acid sensitization. Sensitivity of the colon to balloon distention (CRD) in adults was measured by grading their abdominal withdrawal reflex and electromyographic responses. In adult rats, TRPV1 antagonist was injected intraperitoneally 30 minutes before CRD. Results: Neonatal acetic acid treatment resulted in higher sensitivity to CRD in adult rats compared with controls in the absence of histopathologic signs of inflammation. Treatment of colons of adult rats with acetic acid did not produce persistent sensitization. Antagonism of the TRPV1 before neonatal administration of acetic acid and after established visceral hypersensitivity attenuated sensitivity to CRD. TRPV1 expression was increased in dorsal root ganglia–containing colon afferent neurons. Conclusions: We have described a new model for persistent colonic sensory dysfunction following a transient noxious stimulus in the neonatal period and a potentially important role for TRPV1 in initiation and maintenance of persistent visceral hypersensitivity. [Copyright &y& Elsevier]

Background: Perforation is an uncommon but potentially devastating complication of colonoscopy. Surgical closure is the standard of care. Immediate endoluminal closure of a perforation would avoid the morbidity and mortality associated with general anesthesia, laparotomy, and surgical repair. Objectives: To evaluate the feasibility and safety of full-thickness endoscopic closure of colonic perforations with a prototype endoscopic suturing device, the Eagle Claw, in a porcine model. Design: Endoscopic animal experimental study of closure of colon perforation by using a porcine model. Subjects: Ten pigs were included in the study. Interventions: The Eagle Claw was used to close small perforations (1.5 to 2 cm) of the colon created by needle-knife with the animal under general anesthesia by using the endoluminal route. All animals received intravenous antibiotics and were allowed to eat after 24 hours. Main Outcome Measurements: The animals were monitored daily for signs of sepsis and peritonitis. On day 7, they were euthanized. The peritoneal cavity was examined for fecal peritonitis, and the colon perforation site was checked for wound dehiscence and pericolic abscess formation. Results: Endoscopic closure of the colon perforation was successful in 7 animals, and they recovered well without any sepsis or peritonitis. Necropsy did not reveal fecal peritonitis or pericolonic abscess formation at the site of perforation, and the perforation healed well. Closure was successful in 1 animal, but necropsy revealed dehiscence of the colon perforation site. Endoscopic closure was unsuccessful in 2 animals, and these were euthanized immediately. Conclusions: Closure of acute perforation of the colon is feasible with the Eagle Claw endoscopic suturing device in a porcine model. [Copyright &y& Elsevier]

Background: Despite several attempts to make the conventional tubular stents with a central lumen for flow less susceptible to a biofilm buildup and thereby prevent clogging, this goal has remained elusive. We hypothesized that the creation of pathways for fluid flow around the stent instead of through it would avoid this problem. The aim of our study was to report the development and the evaluation of a novel lumen-less stent. Methods: By using a software computer modeling, a 10F “winged” stent was designed. A pilot feasibility study was performed by using a prototype of this stent for endoscopic biliary drainage in 5 patients with malignant biliary obstruction. Observations: Modeling data revealed that the winged stent offers a larger surface area for flow, higher velocity of flow, and increased flow rates compared with the conventional tubular stent. In the clinical trial, there was a significant decrease of serum bilirubin after the placement of this stent (serum bilirubin before and 2 weeks after stent placement, 14.94 ± 5.7 mg/dL vs. 2.86 ± 1.4 [p < 0.004]), accompanied by radiologic evidence of decompression of the biliary system. Conclusions: We have shown that it is possible to provide adequate biliary drainage by using a stent without a lumen. Such a design may have potential clinical advantages over existing designs. [Copyright &y& Elsevier]

Background & Aims: Nitric oxide is a major inhibitory neurotransmitter in the enteric nervous system. Loss or dysfunction of nitrinergic neurons is associated with serious disruptions of motility, intractable symptoms, and long-term suffering. The aim of this study was to evaluate the effect of intrapyloric transplantation of neural stem cells (NSCs) on gastric emptying and pyloric function in nNOS−/− mice, a well-established genetic model of gastroparesis. Methods: NSCs were isolated from embryonic mice transgenically engineered to express green fluorescent protein and transplanted into the pylorus of nNOS−/− mice. Grafted cells were visualized in pyloric sections and further characterized by immunofluorescence staining. One week posttransplantation, gastric emptying to a non-nutrient meal was measured using the phenol red method and pyloric function was assessed by measuring the relaxation of pyloric strips in an organ bath in response to electrical field stimulation (EFS) under nonadrenergic, noncholinergic conditions. Results: One week following implantation, grafted NSCs differentiated into neurons and expressed neuronal nitric oxide synthase. Gastric emptying was significantly increased in mice that received NSCs as compared with vehicle-injected controls (49.67% vs 35.09%; P < .01 by Student t test). EFS-induced relaxation of pyloric strips was also significantly increased (P < .01 by 2-way analysis of variance). The nitric oxide synthase inhibitor NG -nitro-l-arginine methyl ester and the neuronal blocker tetrodotoxin blocked the EFS-induced relaxation, indicating that the observed effect is NO mediated and neuronally derived. Conclusions: Our results support the potential of NSC transplantation as a viable therapeutic option for neuroenteric disorders. [Copyright &y& Elsevier]