Achalasia: Current therapeutic options.

Achalasia is an esophageal motor disorder characterized by impaired relaxation of the lower esophageal sphincter (LES) and absent peristalsis in the smooth muscle esophageal body. As a result, patients typically experience dysphagia, regurgitation, chest pain, and weight loss. Over the past 10-15 years, there has been a resurgence of interest in the evaluation of therapies for achalasia. Unfortunately, little progress in the development of effective pharmacological treatments has been made. Botulinum toxin injection provides some relief of symptoms in many patients but requires periodic reinjection that may provide progressively less benefit over time. There are now three well-established, safe, and effective therapies for the treatment of achalasia: pneumatic dilation (PD), laparoscopic Heller myotomy (LHM), and peroral endoscopic myotomy (POEM) which can lead to marked symptom improvement in most patients. Each treatment has a specific constellation of risks, benefits, and recurrence rate. The first-line treatment used will depend on patient preference, achalasia subtype, and local expertise. The recent impressive advances in both the art and science of achalasia therapy are explored with a comprehensive review of the various treatment modalities and comparative controlled clinical trials. In addition, key technical pearls of the procedural treatments are demonstrated.

Necrotizing Esophagitis: A Big Squeeze?

Necrotizing esophagitis is rare and poorly understood. The etiologies reported in what little has been published (i.e., gastroesophageal reflux exacerbated by gastric outlet obstruction and low-flow ischemia) seem somewhat simplistic and lack any direct evidence. The following paper illustrates a recent clinical case while laying out arguments supporting esophageal spasm as a possible contributing factor.

Changes in signalling from faecal neuroactive metabolites following dietary modulation of IBS pain.

OBJECTIVE: Dietary therapies for irritable bowel syndrome (IBS) have received increasing interest but predicting which patients will benefit remains a challenge due to a lack of mechanistic insight. We recently found evidence of a role for the microbiota in dietary modulation of pain signalling in a humanised mouse model of IBS. This randomised cross-over study aimed to test the hypothesis that pain relief following reduced consumption of fermentable carbohydrates is the result of changes in luminal neuroactive metabolites. DESIGN: IBS (Rome IV) participants underwent four trial periods: two non-intervention periods, followed by a diet low (LFD) and high in fermentable carbohydrates for 3 weeks each. At the end of each period, participants completed questionnaires and provided stool. The effects of faecal supernatants (FS) collected before (IBS FS) and after a LFD (LFD FS) on nociceptive afferent neurons were assessed in mice using patch-clamp and ex vivo colonic afferent nerve recording techniques. RESULTS: Total IBS symptom severity score and abdominal pain were reduced by the LFD (N=25; p<0.01). Excitability of neurons was increased in response to IBS FS, but this effect was reduced (p<0.01) with LFD FS from pain-responders. IBS FS from pain-responders increased mechanosensitivity of nociceptive afferent nerve axons (p<0.001), an effect lost following LFD FS administration (p=NS) or when IBS FS was administered in the presence of antagonists of histamine receptors or protease inhibitors. CONCLUSIONS: In a subset of IBS patients with improvement in abdominal pain following a LFD, there is a decrease in pronociceptive signalling from FS, suggesting that changes in luminal mediators may contribute to symptom response.

Meyerson phenomenon in children: observation in five cases of congenital melanocytic nevi.

To describe the characteristics of five pediatric patients with the Meyerson phenomenon associated with congenital melanocytic nevi, five cases were reviewed to retrieve information relating to clinical presentation, treatment and evolution of the eczematous phenomenon and of the nevi. Three of five patients were male. Mean age at presentation of the Meyerson phenomenon was 23 months (range: 4 mos-4 yrs). Three patients presented with only one halo eczematous lesion, while two patients presented with more then one halo eczematous lesions. The halo eczematous lesions were located on the leg, arm, and trunk in four, two, and two patients, respectively. All were associated with congenital melanocytic nevi with overlying hypertrichosis. Four were treated with topical corticosteroids, and five developed some degree of hypopigmentation within the nevic lesion. In children with Meyerson phenomenon associated with congenital hairy melanocytic nevi, neither trigger to the eczematous eruption nor preferential gender or anatomical site location was identified. The Meyerson phenomenon evolved towards hypopigmentation of the congenital melanocytic nevic lesions in all patients but no other cutaneous changes were observed on follow-up.

Involvement of the IkappaB kinase (IKK)-related kinases tank-binding kinase 1/IKKi and cullin-based ubiquitin ligases in IFN regulatory factor-3 degradation.

Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1(-/-) mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IkappaB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.