William J. Ravich

Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells

Objectives Long non-coding RNAs (lncRNA) have been shown to play important roles in the development and progression of cancer. However, functional lncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of oesophageal adenocarcinoma (EAC) and its progression. Design lncRNAs that are abnormally upregulated in EACs were identified by RNA-sequencing analysis, followed by quantitative RT-PCR (qRTPCR) validation using tissues from 25 EAC patients. Cell biological assays in combination with small interfering RNA-mediated knockdown were performed in order to probe the functional relevance of these lncRNAs. Results We discovered that a lncRNA, HNF1A-AS1, is markedly upregulated in human primary EACs relative to their corresponding normal oesophageal tissues (mean fold change 10.6, p<0.01). We further discovered that HNF1A-AS1 knockdown significantly inhibited cell proliferation and anchorage-independent growth, suppressed S-phase entry, and inhibited cell migration and invasion in multiple in vitro EAC models (p<0.05). A gene ontological analysis revealed that HNF1A-AS1 knockdown preferentially affected genes that are linked to assembly of chromatin and the nucleosome, a mechanism essential to cell cycle progression. The well known cancer-related lncRNA, H19, was the gene most markedly inhibited by HNF1A-AS1 knockdown. Consistent to this finding, there was a significant positive correlation between HNF1A-AS1 and H19 expression in primary EACs (p<0.01). Conclusions We have discovered abnormal upregulation of a lncRNA, HNF1A-AS1, in human EAC. Our findings suggest that dysregulation of HNF1A-AS1 participates in oesophageal tumorigenesis, and that this participation may be mediated, at least in part, by modulation of chromatin and nucleosome assembly as well as by H19 induction.

Brainstorming about next-generation computer-based documentation: an AMIA clinical working group survey

UNLABELLEDnComputer-based software to record histories, physical exams, and progress or procedure notes, known as computer-based documentation (CBD) software, has been touted as an important addition to the electronic health record. The functionality of CBD systems has remained static over the past 30 years, which may have contributed to the limited adoption of these tools. Early users of this technology, who have tried multiple products, may have insight into important features to be considered in next-generation CBD systems.nnnOBJECTIVE AND METHODSnWe conducted a cross-sectional, observational study of the clinical working group membership of the American Medical Informatics Association (AMIA) to generate a set of features that might improve adoption of next-generation systems. The study was conducted online over a 4-month period; 57% of the working group members completed the survey.nnnRESULTSnAs anticipated, CBD tool use was higher (53%) in this population than in the US physician offices. The most common methods of data entry employed keyboard and mouse, with agreement that these modalities worked well. Many respondents had experience with pre-printed data collection forms before interacting with a CBD system. Respondents noted that CBD improved their ability to document large amounts of information, allowed timely sharing of information, enhanced patient care, and enhanced medical information with other clinicians (all P < 0.001). Respondents also noted some important but absent features in CBD, including the ability to add images, get help, and generate billing information.nnnCONCLUSIONSnThe latest generation of CBD systems is being used successfully by early adopters, who find that these tools confer many advantages over the approaches to documentation that they replaced. These users provide insights that may improve successive generations of CBD tools. Additional surveys of CBD non-users and failed adopters will be necessary to provide other useful insights that can address barriers to the adoption of CBD by less computer literate physicians.

Accuracy and reliability of the endoscopic classification of portal hypertensive gastropathy

BACKGROUNDnThere is no consensus regarding the endoscopic classification of the severity of portal hypertensive gastropathy. This study compared the accuracy and reproducibility of the 2-category classification system (2-CCS) with the 3-category classification system (3-CCS).nnnMETHODSnNinety-eight endoscopic pictures of portal hypertensive gastropathy and 22 of nonspecific gastritis were selected. Eight duplicate sets were generated, each in a different random order. These were shown to 6 experienced endoscopists during 2 sessions 1 week apart with 4 slide sets at each session. Each picture was scored by using either the 2-CCS or 3-CCS. Kappa statistics and percent agreement were used to estimate the reproducibility and agreement.nnnRESULTSnThe mean percentage agreement among the 4 separate readings for each observer was significantly lower for the 3-CCS compared with the 2-CCS (mean [standard deviation] = 33.5% [8.9%] vs. 64.9% [9.1%]; p = 0.0001). The mean (SD) interobserver kappa values were 0.44 (0.03) for the 3-CCS and 0.52 (0.04) for the 2-CCS (p = 0.02), and the respective intraobserver kappa values were 0.43 (0.1) and 0.63 (0.06) (p = 0.002).nnnCONCLUSIONSnEven though both the 2-CCS and 3-CCS have substantial limitations with regard to specificity and reliability, there were better agreement and reproducibility with the simpler classification system for portal hypertensive gastropathy.

Neuromuscular diseases and disorders of the alimentary system.

This review outlines the relationship and interaction between neuromuscular diseases and disorders of the alimentary system. Neuromuscular manifestations of gastrointestinal and hepatobiliary diseases are first considered. Such diseases may cause neuromuscular disorders by leading to nutritional deficiency or by more direct mechanisms. The pathogenesis, clinical features, and treatment of these various neuromuscular manifestations are discussed. The impact of disorders of nerve, neuromuscular transmission, and muscle on the alimentary system is then reviewed. The main sequelae are impaired deglutition and gastrointestinal dysmotility. The management of these complications is considered.

Endoscopic Management of Benign Esophageal Strictures

Purpose of ReviewThis paper presents the author’s approach to esophageal dilation. It offers a tailored approach to the application of dilation to specific types of esophageal stenotic lesions.Recent FindingsIn patients with inflammatory stricture, recent studies confirm the importance of treating the underlying inflammatory condition in order to decrease the rate of recurrence. The paper reviews some of the novel techniques that have been suggested for the treatment of refractory benign esophageal strictures, including incisional therapy, stenting, or the injection steroids or antifibrotic agents.SummaryThe endoscopist who treats esophageal strictures must be familiar with the tools of the dilation and how they are best applied to specific types of stenotic lesions. If inflammation is present, effective management requires treatment of the inflammatory process in addition to mechanical dilation of the stenotic lesion. Controlled trials of novel approaches to treatment of refractory benign esophageal strictures are limited and will be necessary to determine efficacy.

Endoscopic balloon catheter dilatation via retrograde or static technique is safe and effective for cricopharyngeal dysfunction

AIM To evaluate the safety and efficacy of upper esophageal sphincter (UES) dilatation for cricopharyngeal (CP) dysfunction. To determine if: (1) indication for dilatation; or (2) technique of dilatation correlated with symptom improvement. METHODS All balloon dilatations performed at our institution from over a 3-year period were retrospectively analyzed for demographics, indication and dilatation site. All dilatations involving the UES underwent further review to determine efficacy, complications, and factors that predict success. Dilatation technique was separated into static (stationary balloon distention) and retrograde (brusque pull-back of a fully distended balloon across the UES). RESULTS Four hundred and eighty-eight dilatations were reviewed. Thirty-one patients were identified who underwent UES dilatation. Median age was 63 years (range 27-81) and 55% of patients were male. Indications included dysphagia (28 patients), globus sensation with evidence of UES dysfunction (2 patients) and obstruction to echocardiography probe with cricopharyngeal (CP) bar (1 patient). There was evidence of concurrent oropharyngeal dysfunction in 16 patients (52%) and a small Zenker’s diverticula (≤ 2 cm) in 7 patients (23%). Dilator size ranged from 15 mm to 20 mm. Of the 31 patients, 11 had dilatation of other esophageal segments concurrently with UES dilatation and 20 had UES dilatation alone. Follow-up was available for 24 patients for a median of 2.5 mo (interquartile range 1-10 mo), of whom 19 reported symptomatic improvement (79%). For patients undergoing UES dilatation alone, follow-up was available for 15 patients, 12 of whom reported improvement (80%). Nineteen patients underwent retrograde dilatation (84% response) while 5 patients had static dilatation (60% response); however, there was no significant difference in symptom improvement between the techniques (P = 0.5). Successful symptom resolution was also not significantly affected by dilator size, oropharyngeal dysfunction, Zenker’s diverticulum, age or gender (P > 0.05). The only complication noted was uvular edema and a shallow ulcer after static dilatation in one patient, which resolved spontaneously and did not require hospital admission. CONCLUSION UES dilatation with a through-the-scope balloon by either static or retrograde technique is safe and effective for the treatment of dysphagia due to CP dysfunction. To our knowledge, this is the first study evaluating retrograde balloon dilatation of the UES.

Establishing a Comprehensive Center for Diagnosis and Therapy of Swallowing Disorders

This chapter discuses some historical facts relating to the development of the multidisciplinary Swallowing Center concept. It also offers a perspective of the Swallowing Center concept 25 years after its original inception. The developments and changes in the world of swallowing disorders e.g. the establishment of a Journal devoted to swallowing and its disorders and the formation of a Dysphagia Research Society, to name just two of the many developments, are presented and discussed. The advantages and limitations of a multidisciplinary Swallowing Center are also discussed.

Endoluminal reflux therapy: what do “FDA clearance” and “FDA approval” mean?

In the current issue of Gastroinestinal Endoscopy, von Renteln et al describe a modification of the technique for the application of the NDO Plicator (NDO Surgical Inc, Mansfield, Mass), one of a number of devices that have been introduced to the market over the last decade for endoluminal reflux therapy (ERT). The modification involves the use of multiple sutures (either 2 or 3) instead of the standard single suture to create a tighter closure at the esophagogastric (EG) junction. The study population is small (n Z 41). As with most reports on ERTs, this one intentionally excluded patients with severe reflux. Also in keeping with most previously published reports, it focused primarily on the symptomatic response to intervention. The study demonstrates a superficially impressive response to intervention. At 6-month follow-up, the median GERD quality-of-life (GERD-QOL) score improved 76% (P!.001); with improvement in both heartburn and regurgitation (P ! .001 for each). Seventy percent of the patients were no longer taking daily proton pump inhibitors (PPIs); 40% were no longer taking any medication, and an additional 25% were taking medication on an intermittent basis. Although statistically significant, the improvement in acid reflux by pH studies and of lower esophageal sphincter (LES) resting pressure can at best be described as modest. Also, the response of the endoscopic findings of esophagitis was variable. I said that the results were ‘‘superficially impressive’’ because of the limitations of the study design. A major concern is the subjective nature of the criteria used for determining the need for additional suture. If the space around the 5.8-mm videoendoscope as seen on retroflexed view was deemed insufficiently tight, the endoscopist placed 1 or 2 additional sutures between the last suture and the scope until a satisfactory closure was achieved. However, the most important problem is the absence of a randomized control group. Without a control, it is difficult for the reader to come to a meaningful conclusion about whether the modification in technique offers any advantage over the standard single-suture approach. The absence of a control group relegates this study to the ‘‘proof of concept’’ category of clinical trial. It demonstrates that skilled endoscopists can technically perform the modification of the standard full-thickness

Quantitative size measurement of features viewed through a video endoscope

Quantitative size measurements of gastrointestinal tract lesions (i.e., ulcers and polyps) viewed during endoscopy are helpful in assessing the rate of healing or growth. We report a novel technique for quantitatively measuring the two-dimensional size of a feature viewed remotely via a video imager. Our instruments small size makes it a suitable candidate for use in endoscopes. Computing the size of a feature displayed on a two-dimensional video monitor necessitates measuring the distance between the imager and the surface under observation because an undistorted video image preserves the angular content of a scene. We have developed a prototype ranging system that exploits the tendency of light emerging from the tip of an optical fiber to diverge. Our device uses two fibers with different divergence characteristics. The separation between the imaging sensor and the viewed surface is determined by inspecting the relative sizes of the spots cast by each of the fibers. Our device, which measures distances between 2 and 8 cm, is sufficiently small to be accommodated in an endoscopes accessory channel.