Impairment of agonist-induced M2 muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia.

Previous studies showed that circulating autoantibodies against M2 muscarinic receptors (anti-M2R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M2R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M2R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced Gi protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M2R/arrestin interaction or promote M2R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.

Electrical stimulation to increase lower esophageal sphincter pressure after POEM.

INTRODUCTION: Postoperative reflux remains to be a challenge for patients with achalasia undergoing Heller myotomy. Similarly, per-oral endoscopic myotomy (POEM) is gaining rapid acceptance but the impossibility of adding a fundoplication is questioned as the main pitfall to control reflux. Electrical stimulation of the lower esophageal sphincter (LES) has emerged as a new alternative for the treatment of reflux disease. The objective of this study was to evaluate the potential benefits of combining electrical stimulation with endoscopic esophageal myotomy to prevent post procedural reflux. METHODS: Five pigs were subjected to POEM. After myotomy was completed, two electrical leads were implanted at the LES level and electrical stimulation was applied with the Endostim system with a regimen of 215 µs (5 mA amplitude), at 20 Hz for 25 min. LES pressures were recorded with manometry at pre and post-myotomy and after LES stimulation. RESULTS: Myotomy was completed successfully in all cases. Mean pre-myotomy LES pressure was 35.99 ± 8.08 mmHg. After myotomy, the LES pressure significantly dropped to 10.60 ± 3.24 mmHg (p = 0.03). Subsequent to LES-EST, LES pressure significantly increased to 21.74 ± 4.65 mmHg (p = 0.01). CONCLUSIONS: The findings of this study show that LES-EST in healthy animals increases LES pressure after POEM procedure, and could be useful tool to minimize gastroesophageal reflux.

Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders.

BACKGROUND: Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. AIMS: To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. METHODS: We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High-resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene-related peptide (CGRP)-immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. RESULTS: Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP-immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP-immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = -0.567, p < 0.001) and distal oesophagus (ρ = -0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). CONCLUSIONS: Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow.

The Brief Esophageal Dysphagia Questionnaire shows better discriminative capacity for clinical and manometric findings than the Eckardt score: Results from a multicenter study.

INTRODUCTION: Grading dysphagia is crucial for clinical management of patients. The Eckardt score (ES) is the most commonly used for this purpose. We aimed to compare the ES with the recently developed Brief Esophageal Dysphagia Questionnaire (BEDQ) in terms of their correlation and discriminative capacity for clinical and manometric findings and evaluate the effect of gastroesophageal reflux symptoms on both. METHODS: Symptomatic patients referred for high-resolution manometry (HRM) were prospectively recruited from seven centers in Spain and Latin America. Clinical data and several scores (ES, BEDQ, GERDQ) were collected and contrasted to HRM findings. Standard statistical analysis was performed. KEY RESULTS: 426 patients were recruited, 31.2% and 41.5% being referred exclusively for dysphagia and GERD symptoms, respectively. Both BEDQ and ES were independently associated with achalasia. Only BEDQ was independently associated with being referred for dysphagia and with relevant HRM findings. ROC curve analysis for achalasia diagnosis showed AUC of 0.809 for BEDQ and 0.765 for ES, with the main difference being higher BEDQ sensitivity (80.0% vs 70.8% for ES). GERDQ independently predicted ES but not BEDQ. In the absence of dysphagia (BEDQ = 0), GERD symptoms significantly determine ES. CONCLUSIONS AND INFERENCES: Our study suggests both the BEDQ and ES can complementarily describe symptomatic burden in achalasia. BEDQ has several advantages over the ES in the dysphagia evaluation, basically due to its higher sensitivity for manometric diagnosis and independence of GERD symptoms. ES should be used as an achalasia-specific metric, while BEDQ is a better symptom-generic evaluating tool.

Fundic gland polyps and association with proton pump inhibitor intake: a prospective study in 1,780 endoscopies.

BACKGROUND AND AIMS: Fundic gland polyps (FGPs) are incidentally found when an endoscopy is performed for a non-related indication. Some authors suggested a relationship with proton pump inhibitor (PPI) intake. We aimed to determine their prevalence and association with PPI intake. METHODS: We prospectively studied 1,780 patients who underwent a gastroduodenal endoscopy at our ambulatory care center between June 2007 and August 2008. PPI intake during a period of at least 12 months, female gender and age were statistically evaluated as risk factors for the presence of FGPs. Then, a multiple logistic regression analysis was applied to these variables. RESULTS: Gastric polyps were found in 129 patients (7.2%) and 77 (4.33%) were FGPs. Five patients with no available histology were excluded for the assessment of risk factors. PPI intake was detected in 49 patients with FGPs (63.6%) and 264 without FGPs (15.5%) (P < 0.0001). Fifty-nine patients with FGPs (76.7%) and 987 without FGPs (58.1%) were women (P < 0.001). The mean age was 58.91 ± 11.82 years in patients with FGPs and 50.34 ± 15.04 years in patients without FGPs (P < 0.0001). The three variables remained significant in the multiple model: PPI intake: P < 0.0001, OR 9.00 (95% CI 5.44-14.89); female gender: P = 0.0001, OR 2.95 (95% CI 1.69-5.15); age: P = 0.001, OR 1.03 (95% CI 1.01-1.05). CONCLUSIONS: In our population, the prevalence of FGPs was high. Although female gender and age were also significant, PPI intake was the strongest risk factor associated with the presence of FGPs.

The Spanish version of the esophageal hypervigilance and anxiety score shows strong psychometric properties: Results of a large prospective multicenter study in Spain and Latin America.

BACKGROUND: Anxiety is a significant modulator of sensitivity along the GI tract. The recently described Esophageal Hypervigilance and Anxiety Score (EHAS) evaluates esophageal-specific anxiety. The aims of this study were as follows: 1. translate and validate an international Spanish version of EHAS. 2. Evaluate its psychometric properties in a large Hispano-American sample of symptomatic individuals. METHODS: A Spanish EHAS version was developed by a Delphi process and reverse translation. Patients referred for high-resolution manometry (HRM) were recruited prospectively from seven Spanish and Latin American centers. Several scores were used: EHAS, Hospital Anxiety and Depression Scale (HADS), Eckardt score (ES), Gastroesophageal Reflux Questionnaire (GERDQ), and the Brief Esophageal Dysphagia Questionnaire (BEDQ). Standardized psychometric analyses were performed. KEY RESULTS: A total of 443 patients were recruited. Spanish EHAS showed excellent reliability (Cronbach´s alpha = 0.94). Factor analysis confirmed the presence of two factors, corresponding to the visceral anxiety and hypervigilance subscales. Sufficient convergent validity was shown by moderate significant correlations between EHAS and other symptomatic scores. Patients with high EHAS scores had significantly more dysphagia. There was no difference in EHAS scores when compared normal vs abnormal or major manometric diagnosis. CONCLUSIONS AND INFERENCES: A widely usable Spanish EHAS version has been validated. We confirm its excellent psychometric properties in our patients, confirming the appropriateness of its use in different populations. Our findings support the appropriateness of evaluating esophageal anxiety across the whole manometric diagnosis spectrum.

Validation and psychometric evaluation of the Spanish version of Brief Esophageal Dysphagia Questionnaire (BEDQ): Results of a multicentric study.

BACKGROUND: The recently developed Brief Esophageal Dysphagia Questionnaire (BEDQ) evaluates esophageal obstructive symptoms. Its initial evaluation showed strong psychometric properties. The aims of this study were to (a) translate and validate an international Spanish version of BEDQ and (b) evaluate its psychometric properties in a large Hispano-American sample of symptomatic individuals. METHODS: A Spanish BEDQ version was performed by Hispano-American experts using a Delphi process and reverse translation. Patients were prospectively recruited from seven centers in Spain and Latin America among individuals referred for high-resolution manometry (HRM). Patients completed several scores: Hospital Anxiety & Depression Scale (HADS), Eckardt score (ES), Gastroesophageal Reflux Questionnaire (GERDQ), and the BEDQ. Standardized psychometric analyses were performed. KEY RESULTS: A total of 426 patients were recruited. Spanish BEDQ showed excellent reliability (Cronbach's alpha = 0.91). Factor analysis confirmed its unidimensional character. Moderate significant correlations between BEDQ and other symptomatic scores were found, suggesting sufficient convergent validity. Patients with abnormal or obstructive HRM findings scored significantly higher when compared to normal or non-obstructive findings, respectively. Using a cutoff of 10, BEDQ showed a sensitivity of 65.38% and a specificity of 66.21% and an area under the curve of 0.71 for obstructive or major manometric diagnosis. CONCLUSIONS AND INFERENCES: A widely usable Spanish BEDQ version has been validated. We confirm its excellent psychometric properties in our patients, confirming the appropriateness of its use in different populations.

Fair reliability of eckardt scores in achalasia and non-achalasia patients: Psychometric properties of the eckardt spanish version in a multicentric study.

BACKGROUND: Eckardt symptom score (ESS) is the most used tool for the evaluation of esophageal symptoms. Recent data suggest that it might have suboptimal reliability and validity. The aims of this study were as follows: (a) Develop and validate an international Spanish ESS version. (b) Perform psychometric ESS evaluation in patients with achalasia and non-achalasia patients. METHODS: Eckardt symptom score translation was performed by Delphi process. ESS psychometric evaluation was done in two different samples of patients referred for manometry. First sample: 430 dysphagia non-achalasia patients. Second sample: 161 achalasia patients. Internal consistency was evaluated using Cronbach's α and Guttman coefficient (<0.5 = unacceptable. 0.5-0.7 = fair. >0.7 = acceptable). KEY RESULTS: Our data show that in patients without and with achalasia, ESS behaves similarly. Both show a fair reliability with Cronbach's α of 0.57 and 0.65, respectively. Based on our results, we recommend interpretation of the Spanish ESS be done with caution. The psychometric quality of the ESS could not be improved by removal of any items based on the single-factor structure of the scale and no items meeting criteria for elimination. CONCLUSIONS AND INFERENCES: Eckardt symptom score Spanish translation was developed. ESS showed a fair reliability for the evaluation of patients with any causes of dysphagia. Our results highlight the need for development and psychometric validation of new dysphagia scoring tools.

The enteric nervous system in chagasic and idiopathic megacolon.

Chagas disease frequently causes megacolon. We investigated the enteric nervous systems in patients with chagasic megacolon compared to idiopathic megacolon and controls. Surgical specimens were obtained from 12 patients with chagasic megacolon (1 woman, 11 men, age range 41 to 72 y) and 9 patients with idiopathic megacolon (3 women, 6 men, age range 39 to 68 y), undergoing surgery for intractable constipation. A control group of 10 patients (9 women, 1 man, age range 43 to 75 y) undergoing left hemicolectomy for nonobstructing colorectal cancer was also studied. Colonic sections were investigated by conventional and immunohistochemical methods, also taking into consideration the presence of lymphocytes. Compared to controls, the 2 megacolon groups showed a decrease of enteric neurons (not due to increased apoptosis) and of enteric glial cells (all more important in chagasic patients). The interstitial cells of Cajal subtypes were decreased but not absent in megacolons, although an increase of the intramuscular subtype was found, suggesting a possible compensative mechanism. An increased amount of fibrosis was found in the smooth muscle and the myenteric plexus of chagasic patients compared to the idiopathic megacolon and the control group. A mild lymphocytic infiltration of the enteric plexuses (more evident in Chagas disease) was also found in megacolons but not in controls. Patients with chagasic megacolon display important abnormalities of several components of the enteric nervous system. Similar alterations, although of lesser severity, may be found in patients with idiopathic megacolon.

[Diagnostic and therapeutic algorithm in functional dyspepsia]. / Algoritmo diagnóstico y terapéutico para la dispepsia funcional.

INTRODUCTION: Dyspepsia is a word that means bad digestion. In the conviction of which it is a question of an entity that it includes different disciplines, we realize a meeting consensus to discuss and to resolve a diagnostic and therapeutic algorithm of national order. OBJECTIVE: To agree on a national algorithm applicable to the functional dyspepsia. MATERIAL AND METHODS: In June 2005 a multidisciplinary group met to design and to propose a diagnostic and therapeutic algorithm for the functional dyspepsia. RESULTS: Priority gives to the medical-patient relationship and to the reinsurance. Then we divide the patients if they have signs of alarm. If they are present we studied them, if not we divide them, in accordance to the principal symptoms, in pain or epigastric discomfort. If they have pain we realized an endoscopy and a abdominal ultrasound scan. If they are positive, treatment of the disease. If the studies are negative or it has epigastric discomfort we propose a therapeutic test. Pain: H2 bloquers, wait 4 to 6 weeks, if it not response we propose a PPI, wait for 4 to 6 weeks, if there is no response psychiatric or psychological consultation. Discomfort: proquinetics, wait for 4 to 6 weeks if there are no answers, antidepressants in low doses, wait for 4 to 6 weeks if there are no answers, ca. bloquers, sumatriptan or trimebutina. In all cases we can add tranquillizers in anxious personality. CONCLUSIONS: A multidisciplinary dignostic and therapeutic consensus of national order for the patients with functional dyspepsia was obtained.

Altered Esophageal Mucosal Structure in Patients with Celiac Disease.

Background/Aim. Reflux symptoms (RS) are common in patients with celiac disease (CD), a chronic enteropathy that affects primarily the small intestine. We evaluated mucosal integrity and motility of the lower esophagus as mechanisms contributing to RS generation in patients with CD. Methods. We enrolled newly diagnosed CD patients with and without RS, nonceliac patients with classical reflux disease (GERD), and controls (without RS). Endoscopic biopsies from the distal esophagus were assessed for dilated intercellular space (DIS) by light microscopy and electron microscopy. Tight junction (TJ) mRNA proteins expression for zonula occludens-1 (ZO-1) and claudin-2 and claudin-3 (CLDN-2; CLDN-3) was determined using qRT-PCR. Results. DIS scores were higher in patients with active CD than in controls, but similar to GERD patients. The altered DIS was found even in CD patients without RS and normalized after one year of a gluten-free diet. CD patients with and without RS had lower expression of ZO-1 than controls. The expression of CLDN-2 and CLDN-3 was similar in CD and GERD patients. Conclusions. Our study shows that patients with active CD have altered esophageal mucosal integrity, independently of the presence of RS. The altered expression of ZO-1 may underlie loss of TJ integrity in the esophageal mucosa and may contribute to RS generation.

Encuesta piloto virtual a médicos argentinos (usuarios de la red intramed) sobre conocimientos, conductas diagnósticas y terapéuticas referidas a la dispepsia funcional / Virtual Pilot survey to Argentinian physicians (users from IntraMed), knowledge, diagnostic approach and therapeutic related to functional dyspepsia

La dispepsia funcional es una entidad muy frecuente en la práctica diaria tanto del gastroenterólogo como de médicos clínicos y aún de los que practican otras especialidades, pero continúa siendo muy polémica desde el punto de vista de su definición, clasificación, diagnóstico y su enfoque terapéutico. Para conocer el punto de vista y los conocimientos que los médicos argentinos tienen del tema hemos realizado una encuesta virtual. Objetivos: 1) Determinar creencias, criterios y conductas édicas diagnósticas y terapéuticas más frecuentes asociadas al cuadro clínico de dispepsia funcional. 2) Determinar (estimativamente) por los médicos que respondieron, la prevalencia de dispépticos en la consulta diaria y mensual. 3) Determinar (estimativamente) por los médicos que respondieron, la prevalencia de enfermedad orgánica dentro de los pacientes que consultaron por dispepsia funcional. Población y muestra: Médicos residentes en Argentina, usuarios de red virtual IntraMed (expuestos: n=12.849). Respondieron voluntariamente 622 médicos de las siguientes especialidades: generalistas, de familia, gastroenterólogos, erontólogos, cirujanos generales y “otras” (muestreo no probabilístico). Fueron excluidos 43 especialistas que respondieron por no constituir una especialidad que reciba este tipo de consultas con mayor frecuencia. Fueron eliminadas las respuestas de pediatras por ser de bajísima frecuencia (3 pediatras). Lugar y período de exposición a la encuesta: Buenos Aires, Red virtual IntraMed, desde enero de 2005 a enero de 2006, encuesta colgada on-line desde el 2 al 31 de mayo de 2005. Metodología: Invitación electrónica a participar luego de una breve difusión previa. Exhibición de la encuesta on-line durante mayo de 2005. Diseño: exploratorio, prospectivo, observacional, transversal, de cuantificación. Instrumento: Cuestionario que exploróentre médicos de diferentes especialidades de la Argentina: a) Dificultades y preferencias acerca de la definición...

Algoritmo diagnóstico y terapéutico para la dispepsia funcional / Diagnostic and therapeutic algorithm in functional dyspepsia

Introducción. “Dispepsia” deriva del griego y significa “mala digestión”. Dado que se trata de una entidad que abarca distintas disciplinas, se realizó una reunión de consenso para discutir y acordar un algoritmo diagnóstico y terapéutico nacional. Objetivo: Consensuar un algoritmo nacional aplicable a la dispepsia funcional. Material y métodos: En junio de 2005 un grupo multidisciplinario se reunió para diseñar y proponer un algoritmo diagnóstico y terapéutico para dispepsia funcional. Resultados: Darle prioridad a la relación médico-paciente, a las medidas higiénicos dietéticas y al reaseguro. Luego dividimos a los pacientes de acuerdo a si tienen o no signos de alarma. Si están presentes, se los estudia, si no, se los divide de acuerdo a los síntomas principales en dolor o malestar epigástrico. Si tienen dolor, se realiza VEDA y ecografía abdominal. Si son positivos, tratamiento de la enfermedad. Si los estudios son negativos o tiene malestar epigástrico: prueba terapéutica. La pruebas serían: Dolor: Antagonistas H2, esperar 4 a 6 semanas, respuesta negativa: IBP, esperar 4 a 6 semanas, sin no hay mejoría: consulta Psiquiátrica o Psicológica. Malestar: Proquinéticos y esperar 4 a 6 semanas. Si no hay respuestas: Antidepresivos a bajas dosis, esperar 4 a 6 semanas y si no responde: Bloqueantes Cálcicos, Sumatriptan o Trimebutina. En todos los casos se pueden sumar ansiolíticos en personalidad ansiosa. Conclusiones: Se logró un consenso diagnóstico y terapéutico multidisciplinario de orden nacional para los pacientes con dispepsia funcional.

Introduction. Dyspepsia is a word that means bad digestion. In the conviction of which it is a question of an entity that it includes different disciplines, we realize a meeting consensus to discuss and to resolve a diagnostic and therapeutic algorithm of national order. Objetive: To agree on a national algorithm applicable to the functional dyspepsia. Material and methods: In June 2005 a multidisciplinary group met to design and to propose a diagnostic and therapeutic algorithm for the functional dyspepsia. Results: Priority gives to the medical-patient relationship and to the reinsurance. Then we divide the patients if they have signs of alarm. If they are present we studied them, if not we divide them, in accordance to the principal symptoms, in pain or epigastric discomfort. If they have pain we realized an endoscopy and a abdominal ultrasound scan. If they are positive, treatment of the disease. If the studies are negative or it has epigastric discomfort we propose a therapeutic test. Pain: H2 bloquers, wait 4 to 6 weeks, if it not response we propose a PPI, wait for 4 to 6 weeks, if there is no response psychiatric or psychological consultation. Discomfort: proquinetics, wait for 4 to 6 weeks if there are no answers, antidepressants in low doses, wait for 4 to 6 weeks if there are no answers, ca. bloquers, sumatriptan or trimebutina. In all cases we can add tranquillizers in anxious personality. Conclusions: A multidisciplinary dignostic and therapeutic consensus of national order for the patients with functional dyspepsia was obtained.