Computational analysis to define efficacy & molecular mechanisms of 7, 4'- Dihydroxyflavone on eosinophilic esophagitis: Ex-vivo validation in human esophagus biopsies.

Introduction: Eosinophilic Esophagitis (EoE) is a chronic condition characterized by eosinophilic inflammation of the esophagus which leads to esophageal dysfunction with common symptoms including vomiting, feeding difficulty, dysphagia, abdominal pain. Current main treatment options of EoE include dietary elimination and swallowed steroids. Diet elimination approach could lead to identifying the trigger food(s), but it often requires repeated upper endoscopy with general anesthesia and potentially could negatively affect nutrition intake and growth of the child and individuals' quality of life. Although the swallowed steroid treatment of effective, the EoE will universally recur after discontinuation of the treatment. Digestive Tea formula (DTF) has been used by the Traditional Chinese Medicine (TCM) practice to improve GI symptoms in EoE patients, including abdominal pain, GE reflux, and abnormal bowel movement. Previously, a flavonoid small molecule compound 7, 4 dihydroxy flavone (DHF) from Glycyrrhiza uralensis in DTF inhibited eotaxin, Th2 cytokine and IgE production in vitro and in vivo. Method: This study comprehensively evaluates the potential therapeutic and immunological mechanisms underlying DHF improvement of symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses, in silico molecular docking and dynamic simulation followed by ex-vivo target validation by qRT-PCR using cultured human esophagus biopsy specimen with or without DHF from patients with EoE. Results: Computational analyses defined 29 common targets of DHF on EoE, among which TNF-α, IL-6, IL1ß, MAPK1, MAPK3 and AKT1 were most important. Docking analysis and dynamic simulation revealed that DHF directly binds TNF-α with a free binding energy of -7.7 kcal/mol with greater stability and flexibility. Subsequently, in the human esophagus biopsy culture system, significant reduction in levels of TNF-α, IL-6, IL-8 and IL1-ß was found in the supernatant of biopsy sample cultured with DHF. Furthermore, the gene expression profile showed significant reduction in levels of TNF-α, IL1-ß, IL-6, CCND and MAPK1 in the esophagus biopsy sample cultured with DHF. Discussion: Taken together, the current study provides us an insight into the molecular mechanisms underlying multi-targeted benefits of DHF in the treatment of EoE and paves the way for facilitating more effective EoE therapies.

Severe scurvy in a patient with eosinophilicoesophagitis.

While scurvy is considered to be a rare disease in the modern era, the disease still presents in certain populations with nutritional deficiencies such as those with poor nutritional absorption secondary to gastrointestinal disorders and in patients with poor nutritional intake. We present a case of scurvy in a patient who had eosinophilic oesophagitis which limited his oral intake. He presented with the classic symptoms of scurvy including a perifollicular rash, arthralgia, gingivitis and anaemia. He was treated with intravenous vitamin C initially followed by an oral course after which he showed improvement. This case demonstrates that it is important to consider vitamin C deficiency in patients with who present with anaemia and bleeding stigmata specifically in those who have poor nutritional intake. Furthermore, additional consideration should be given to patients with malnutrition as part of the preoperative evaluation.

Ingesta dietética de pacientes adultos con esofagitis eosinofílica que siguen una dieta de exclusión de seis grupos de alimentos / Dietary intake for adult eosinophilic esophagitis patients following a six-food-groups elimination diet

Introducción: la esofagitis eosinofílica (EEo) es una enfermedad inmunoalérgica crónica emergente en adultos. Surge como respuesta disfuncional frente a los antígenos de los alimentos y se caracteriza por síntomas recurrentes de disfunción esofágica e inflamación. El tratamiento farmacológico y dietético se basa en su patogénesis y debe ser individualizado. Uno de los posibles abordajes dietéticos se basa en la eliminación empírica de alimentos que con mayor frecuencia causan EEo. Objetivo: evaluar la ingesta dietética de los pacientes con EEo que siguen la dieta de exclusión de los seis grupos de alimentos (DESGA) y conocer sus posibles carencias nutricionales. Métodos: estudio transversal descriptivo en un grupo de pacientes con EEo que inició tratamiento con DESGA durante el periodo de marzo del 2013 hasta marzo del 2015. Se evaluó la ingesta mediante registro de 72 h. Se compararon los resultados con las referencias para población adulta sana española Moreiras, 2013. Para el análisis estadístico se usaron los test de Mann-Whitney, Krhuskall-Wallis y chi cuadrado. Signifi cación p < 0,05. Resultados: se incluyeron en el estudio 14 pacientes. En algunos de ellos, la ingesta dietética siguiendo DESGA fue deficitaria en energía, proteínas y fibra. Tampoco consiguieron cubrir las ingestas de micronutrientes de calcio, zinc, magnesio, ácido fólico, niacina y vitaminas B2 y D, teniendo en cuenta edad y sexo, el 60% de la muestra. Conclusiones: el abordaje terapéutico mediante DESGA, teniendo en cuenta las características de la dieta, debe acompañarse de una evaluación periódica del estado nutricional, que incluya micronutrientes y una pauta de suplementación específica (AU)

Introduction: Eosinophilic esophagitis (EoE) is an emerging chronic immune/antigen mediated inflammatory disease in adults. It develops as a dysfunctional response to food antigens and is characterized by recurrent symptoms of esophageal dysfunction and inflammation. Drug and dietary treatment are based on its pathogenesis and should be individualized. One of the possible dietary approaches is based on empirical elimination of foods which most commonly cause EoE. Objective: To evaluate dietary intake of patients who follow the diet consisting of the exclusion of six food groups (DESGA) and to know its potential nutritional deficiencies. Methods: Cross-sectional study of patients who started treatment with DESGA diet between March 2013 and March 2015. A 72 h dietary record was completed. The results were compared with the references for the Spanish healthy adult population Moreiras, 2013. Statistical analysis included Mann-Whitney, Kruskal-Wallis and Chi-square tests. Significance was set at p < 0.05. Results: The study included 14 patients. For some of them, the DESGA diet was defi cient inenergy, protein and fiber. Taking into account age and sex, sixty percent of the sample did not get adequate amount of calcium, zinc, magnesium, folic acid, niacin, vitamin B2 and vitamin D. Conclusions: Considering the characteristics of the DESGA diet, this therapeutic approach must be accompanied by a periodic assessment of nutritional status, including micronutrients and a pattern of specific supplementation (AU)

Multimodality evaluation of patients with gastroesophageal reflux disease symptoms who have failed empiric proton pump inhibitor therapy.

Patients with symptoms suggestive of gastroesophageal reflux disease (GERD), such as chest pain, heartburn, regurgitation, and dysphagia, are typically treated initially with a course of proton pump inhibitors (PPIs). The evaluation of patients who have either not responded at all or partially and inadequately responded to such therapy requires a more detailed history and may involve an endoscopy and esophageal biopsies, followed by esophageal manometry, ambulatory esophageal pH monitoring, and gastric emptying scanning. To assess the merits of a multimodality 'structural' and 'functional' assessment of the esophagus in patients who have inadequately controlled GERD symptoms despite using empiric PPI, a retrospective cohort study of patients without any response or with poor symptomatic control to empiric PPI (>2 months duration) who were referred to an Esophageal Studies Unit was conducted. Patients were studied using symptom questionnaires, endoscopy (+ or - for erosive disease, or Barrett's metaplasia) and multilevel esophageal biopsies (eosinophilia, metaplasia), esophageal motility (aperistalsis, dysmotility), 24-hour ambulatory esophageal pH monitoring (+ if % total time pH < 4 > 5%), and gastric emptying scanning (+ if >10% retention at 4 hours and >70% at 2 hours). Over 3 years, 275 patients (147 men and 128 women) aged 16-89 years underwent complete multimodality testing. Forty percent (n= 109) had nonerosive reflux disease (esophagogastroduodenoscopy [EGD]-, biopsy-, pH+); 19.3% (n= 53) had erosive esophagitis (EGD+); 5.5% (n= 15) Barrett's esophagus (EGD+, metaplasia+); 5.5% (n= 15) eosinophilic esophagitis (biopsy+); 2.5% (n= 7) had achalasia and 5.8% (n= 16) other dysmotility (motility+, pH-); 16% (n= 44) had functional heartburn (EGD-, pH-), and 5.8% (n= 16) had gastroparesis (gastric scan+). Cumulative symptom scores for chest pain, heartburn, regurgitation, and dysphagia were similar among the groups (mean range 1.1-1.35 on a 0-3 scale). Multimodality evaluation changed the diagnosis of GERD in 34.5% of cases and led to or guided alternative therapies in 42%. Overlap diagnoses were frequent: 10/15 (67%) of patients with eosinophilic esophagitis, 12/16 (75%) of patients with gastroparesis, and 11/23 (48%) of patients with achalasia or dysmotility had concomitant pathologic acid reflux by pH studies. Patients with persistent GERD symptoms despite empiric PPI therapy benefit from multimodality evaluation that may change the diagnosis and guide therapy in more than one third of such cases. Because symptoms are not specific and overlap diagnoses are frequent and multifaceted, objective evidence-driven therapies should be considered in such patients.