Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial.

Noncardiac chest pain is associated with poor quality of life and high care expenditure. The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders, and the rest are considered functional chest pain (FCP) due to central and peripheral hypersensitivity. Current treatment of FCP improves 40-50% of patients. Cannabinoid receptors 1 (CB1) and 2 (CB2) modulate release of neurotransmitters; CB1 is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity. We performed a prospective study to evaluate its effects on pain threshold, frequency, and intensity in FCP. Subjects with FCP received dronabinol (5 mg, twice daily; n = 7; average age, 44 years; mean body mass index, 26.7) or placebo (n = 6; average age, 42 years; mean body mass index, 25.9) for 28 days (4 weeks). Chest pain, general health, and anxiety/depression questionnaires were assessed at baseline and at 4 weeks. Subjects underwent an esophageal balloon distention test prior to treatment and on last day of the study. Dronabinol increased pain thresholds significantly (3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04). Depression and anxiety scores did not differ between the groups at baseline or after treatment. No significant adverse effects were observed. In this novel study, dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP. Further, large scale studies are needed to substantiate these findings.

Gastroesophageal reflux disease-related symptom recurrence in patients discontinuing proton pump inhibitors for Bravo® wireless esophageal pH monitoring study. / Recurrencia sintomática relacionada con la enfermedad por reflujo gastroesofágico en pacientes que descontinúan los inhibidores de la bomba de protones durante el estudio inalámbrico de monitorización de pH esofágico Bravo®.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) are treated with proton pump inhibitors (PPIs). Those that do not achieve symptom relief, or non-responders, usually undergo esophageal pH monitoring off PPIs in order to confirm the presence of GERD. AIMS: To assess the efficacy of the reverse-PPI trial in evaluating the presence of GERD or its recurrence rates, as well as to identify a correlation between the symptom recurrence rates and GERD severity determined by 48-hour Bravo® esophageal pH-monitor testing. METHODS: A final total of 205 patients that underwent the 48-hour Bravo® esophageal pH-monitoring study were retrospectively included. Patients discontinued PPI usage for at least 7 days prior to testing, and completed symptom questionnaires during the 2-day test. The Bravo® test was considered positive if the percentage of time with esophageal pH <4 was >4.4%. RESULTS: A total of 363 patients underwent 48-hour Bravo® testing and of those patients, 205 were eligible for the study. Ninety-two patients reported symptoms as being «same/better¼ and 113 as being «worse¼ after stopping PPIs. Of the 92 patients with improved symptoms, 44 (48%) had documented acid reflux during the Bravo® study, compared with 65 of 113 (58%) patients with worsening symptoms that also complained of acid reflux. Of the 109 patients found to have confirmed GERD upon pH monitoring, 65 (59.6%) reported a worsening of symptoms, compared with 48 of 96 (50.0%) patients without GERD (p=0.043). Main symptoms stated to be worse included heartburn, chest pain, regurgitation, nausea, and belching (p<0.05). Of the 205 patients, 103 were off PPIs for 7 days. Seventy-two of them (68.9%) reported a worsening of symptoms, compared with 40 of the 102 (41.2%) patients that were off PPIs for>7 days (p=0.042) CONCLUSION: Symptom exacerbation following PPI cessation for at least 7 days correlated with acid reflux severity assessed by Bravo® testing. Patients off PPIs for 7 days had a higher likelihood of experiencing worsening symptoms, compared with those off PPIs for more than 7 days. These findings suggest that when PPIs are held for 7 days or less prior to Bravo® testing, acute worsening of upper GI symptoms due to the abrupt discontinuation of therapy may influence the Bravo® results. The etiology of this may be related to rebound acid hypersecretion and needs to be further elucidated in future studies.

Comparison of clinical features in patients with eosinophilic esophagitis living in an urban and rural environment.

Eosinophilic esophagitis (EoE) has been associated with exposure to aeroallergens. Living in different locations (urban vs. rural) could potentially expose individuals to different environmental factors. Currently, there is limited data on the matter, and all was based on small population studies that did not exclude proton pump inhibitor (PPI)-responsive esophageal eosinophilia in their cohort. The primary aim of this study was to determine the prevalence of EoE in an urban versus rural population and compare demographic and clinical characteristics in patients that had been treated with high-dose PPI prior to diagnosis. Esophageal biopsies were obtained from a cohort of patients who presented with symptoms of dysphagia, odynophagia, globus sensation, and heartburn during a 10-year period. Only patients who had biopsies from the mid and distal esophagus with ≥20 eosinophils per high-power field while on high-dose PPI treatment during endoscopy were included. Urban population was defined as >1000 people/square mile, and rural population was defined as ≤1000 people/square mile (U.S. Census Bureau). Demographic data from each group was analyzed for age, sex, body mass index, duration of symptoms, and tobacco use. Chi-square analysis was used for frequencies with statistical significance defined as P ≤ 0.05. A total of 20 718 patients were identified and their records evaluated. From this cohort, 57 (0.28%) symptomatic patients (male/female: 39/18, mean age = 29.5 years) had biopsy-proven EoE (≥20 eosinophils/hpf) while on PPI treatment. Of those EoE patients, 29 (50.9%) reported living in rural area versus 28 (49.1%) living in the urban area. The most common medical history components included asthma (12.3%), and the most common presenting symptoms included dysphagia (50.9%), heartburn (26.3%), and nausea/vomiting (22.8%). The average duration of symptoms, body mass index, and smoking habits did not differ between the groups. Dysphagia was significantly more prevalent in the urban population (37.9% vs. 64.3% P = 0.047), while heartburn and reflux were more prevalent in the rural population (37.9% vs. 14.3 P = 0.043). Asthma was prevalent in both populations without a significant difference (P = not significant). There is no residential variation in the incidence of EoE among patients with non-PPI-responsive esophageal eosinophilia. Dysphagia was more prevalent in the urban population, while heartburn and reflux symptoms were more prevalent in the rural environment. Further exploration of environmental factors and specific allergens may help explain the varying symptoms and causes of EoE.

Influence of everyday bolus consistencies in different body positions on high-resolution esophageal pressure topography (HREPT) parameters.

The standard protocol for esophageal manometry involves placing the patient in the supine position with head turned to left (supine head left [SHL]) while evaluating liquid bolus swallows. Routinely, semisolid or solid boluses are not evaluated. Currently, the daily American diet includes up to 40% solid or semisolid texture. Thus far, the data on the effect of different bolus on high-resolution esophageal pressure topography (HREPT) parameters are scarce. This study aims to evaluate the effect of every day bolus consistencies in different body positions on HREPT variables. HREPT was performed on healthy volunteers with a modified protocol including liquid swallows in the SHL position followed by applesauce (semisolid), cracker (solid), and marshmallow (soft solid) in three different positions (SHL, sitting, and standing). A total of 38 healthy adult subjects (22 males and 16 females, median age = 27, and mean body mass index = 25) were evaluated. The resting upper esophageal sphincter pressure was significantly different while subjects swallowed crackers, applesauce, and marshmallows in most positions compared with liquid SHL (P < 0.05). The lower esophageal sphincter, contractile front velocity, and distal contractile integral pressures did not differ in all different consistencies compared with SHL. The integrated relaxation period was significantly higher with solid bolus compared with liquid bolus only in SHL position. The intrabolus pressure was significantly different with solid and soft solid boluses in all postures compared to liquid SHL. The American diet consistency affects upper esophageal sphincter pressure and partially integrated relaxation period and intrabolus pressure in various positions. Semisolid bolus swallows do not cause substantial pressure changes and are safe for evaluation and maintaining adequate caloric intake in patients with dysphagia who cannot tolerate solids.

Esophageal motility in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is characterized by eosinophilic infiltration of the esophagus and is a potential cause of dysphagia and food impaction, most commonly affecting young men. Esophageal manometry findings vary from normal motility to aperistalsis, simultaneous contractions, diffuse esophageal spasm, nutcracker esophagus or hypotonic lower esophageal sphincter (LES). It remains unclear whether esophageal dysmotility plays a significant role in the clinical symptoms of EoE. AIM: Our aim is to review the pathogenesis, diagnosis, and effect of treatment on esophageal dysmotility in EoE. METHODS: A literature search utilizing the PubMed database was performed using keywords: eosinophilic esophagitis, esophageal dysmotility, motility, manometry, impedance planimetry, barium esophagogram, endoscopic ultrasound, and dysphagia. RESULTS: Fifteen studies, totaling 387 patients with eosinophilic esophagitis were identified as keeping in accordance with the aim of this study and included in this review. The occurrence of abnormal esophageal manometry was reported to be between 4 and 87% among patients with EoE. Esophageal motility studies have shown reduced distensibility, abnormal peristalsis, and hypotonicity of the LES in patients with EoE, which may also mimic other esophageal motility disorders such as achalasia or nutcracker esophagus. Studies have shown conflicting results regarding the presence of esophageal dysmotility and symptoms with some reports suggesting a higher rate of food impaction, while others report no correlation between motor function and dysphagia. CONCLUSIONS: Motility dysfunction of the esophagus in EoE has not been well reported in the literature and studies have reported conflicting evidence regarding the clinical significance of dysmotility seen in EoE. The correlation between esophageal dysmotility and symptoms of EoE remains unclear. Larger studies are needed to investigate the incidence of esophageal dysmotility, clinical implications, and effect of treatment on patients with EoE.

Pyloric sphincter characteristics using EndoFLIP® in gastroparesis. / Características del esfínter pilórico utilizando EndoFLIP® en gastroparesia.

INTRODUCTION AND AIMS: Pyloric sphincter abnormalities may be detected in gastroparesis. Botulinum toxin A (BoNT/A) injection into the pylorus has been used to treat gastroparesis with varying results. The aim of the present article was to assess whether pyloric sphincter characteristics using the endoscopic functional lumen imaging probe (EndoFLIP®) with impedance planimetry in patients with gastroparesis correlated with symptoms, gastric emptying, and therapeutic response to pyloric sphincter BoNT/A injection. METHODS: EndoFLIP® study was performed on patients undergoing gastroparesis treatment with BoNT/A. The gastroparesis cardinal symptom index (GCSI) was applied prior to treatment and at post-treatment weeks 2, 4, 8, and 12. RESULTS: Forty-four patients were enrolled (30 with idiopathic gastroparesis, 14 with diabetic gastroparesis). Smaller pyloric diameter, cross-sectional area (CSA), and distensibility correlated with worse vomiting and retching severity at baseline. Greater gastric retention tended to correlate with decreased CSA and pyloric distensibility. BoNT/A treatment resulted in a significant decrease in the GCSI score at 2 and 4 weeks after treatment, but not at post-treatment weeks 8 or 12. Nausea, early satiety, postprandial fullness, and upper abdominal pain improved up to 12 weeks, whereas loss of appetite, stomach fullness, and stomach visibly larger improved only up to 4 weeks. Retching and vomiting failed to improve. Greater pyloric compliance at baseline correlated with greater improvement in early satiety and náusea at 8 weeks and greater pyloric distensibility correlated with improvement in upper abdominal pain. CONCLUSIONS: EndoFLIP® characteristics of the pylorus provided important pathophysiologic information in patients with gastroparesis, in relation to symptoms, gastric emptying, and predicting the response to treatment directed at the pylorus.

Difference of achalasia subtypes based on clinical symptoms, radiographic findings, and stasis scores. / Diferencia de subtipos de acalasia basados en síntomas clínicos, hallazgos radiográficos y puntajes de estasis.

INTRODUCTION: Three subtypes of achalasia have been defined through high-resolution esophageal manometry: subtype i shows no pressurization with swallows, subtype ii has increased isobaric panesophageal pressure, and subtype iii has distal esophageal spastic non-isobaric contractions. Studies describing the subtypes based on radiographic findings, clinical symptoms, and stasis scores are limited. AIM: To determine the differences in clinical symptoms, radiographic findings, and stasis scores for the 3 achalasia subtypes. METHODS: Patients undergoing high-resolution esophageal manometry received a questionnaire about current symptoms and previous treatments. The questions included the presence of symptoms and their severity. Barium swallow tests were performed before the high-resolution esophageal manometry study to evaluate the maximum esophageal diameter. Stasis scores were calculated using the transit patterns on high-resolution esophageal manometry. RESULTS: One hundred and eight patients with high-resolution esophageal manometry diagnosis of achalasia (n=8, subtype i; n=84, subtype ii; n=16, subtype iii) within the time frame of 1/2012-6/2015 were included in the study. Sex distribution was similar between the subtypes. Patient age was younger for subtype i (38±16 years), compared with subtypes ii (55±17 years) and iii (63±17 years) (P=.03). Esophageal symptoms did not differ between subtypes regarding the severity of nausea, chest pain, coughing, and heartburn, except for increased vomiting severity in subtype i (2.8±1.4 vs. 1.4±1.4 vs. 1.2±1.2, P<.01). A significant radiographic difference in esophageal dilation was seen between subtypes ii and iii (35.1±14.4 vs. 24.0±7.2mm, P=.023). Stasis scores did not significantly differ between the subtypes. CONCLUSIONS: Achalasia subtypes had similar clinical symptoms, except for increased vomiting severity in subtype i. The maximum esophageal diameter in subtype ii was significantly greater than in subtype iii. Esophageal stasis scores were similar. Thus, high-resolution esophageal manometry remains essential in assessing achalasia subtypes.

CD101 inhibits the expansion of colitogenic T cells.

CD101 exerts negative-costimulatory effects in vitro, but its function in vivo remains poorly defined. CD101 is abundantly expressed on lymphoid and myeloid cells in intestinal tissues, but absent from naïve splenic T cells. Here, we assessed the impact of CD101 on the course of inflammatory bowel disease (IBD). Using a T-cell transfer model of chronic colitis, we found that in recipients of naïve T cells from CD101(+/+) donors up to 30% of the recovered lymphocytes expressed CD101, correlating with an increased interleukin (IL)-2-mediated FoxP3 expression. Transfer of CD101(-/-) T cells caused more severe colitis and was associated with an expansion of IL-17-producing T cells and an enhanced expression of IL-2Rα/ß independently of FoxP3. The co-transfer of naïve and regulatory T cells (Treg) protected most effectively from colitis, when both donor and recipient mice expressed CD101. Although the expression of CD101 on T cells was sufficient for Treg-function and the inhibition of T-cell proliferation, sustained IL-10 production required additional CD101 expression by myeloid cells. Finally, in patients with IBD a reduced CD101 expression on peripheral and intestinal monocytes and CD4(+) T cells correlated with enhanced IL-17 production and disease activity. Thus, CD101 deficiency is a novel marker for progressive colitis and potential target for therapeutic intervention.