In-vivo oesophageal regeneration in a human being by use of a non-biological scaffold and extracellular matrix.

BACKGROUND: Tissue-engineered extracellular matrix populated with autologous pluripotent cells can result in de-novo organogenesis, but the technique is complex, not widely available, and has not yet been used to repair large oesophageal defects in human beings. We aimed to use readily available stents and extracellular matrix to regenerate the oesophagus in vivo in a human being to re-establish swallowing function. METHODS: In a patient aged 24 years, we endoscopically placed a readily available, fully covered, self-expanding, metal stent (diameter 18 mm, length 120 mm) to bridge a 5 cm full-thickness oesophageal segment destroyed by a mediastinal abscess and leading to direct communication between the hypopharynx and the mediastinum. A commercially available extracellular matrix was used to cover the stent and was sprayed with autologous platelet-rich plasma adhesive gel. The sternocleidomastoid muscle was placed over the matrix. After 4 weeks, stent removal was needed due to stent migration, and was replaced with three stents telescopically aligned to improve anchoring. The stents were removed after 3·5 years and the oesophagus was assessed by endoscopy, biopsy, endoscopic ultrasonography, and high-resolution impedance manometry. FINDINGS: After stent removal we saw full-thickness regeneration of the oesophagus with stratified squamous epithelium, a normal five-layer wall, and peristaltic motility with bolus transit. 4 years after stent removal, the patient was eating a normal diet and maintaining a steady weight. INTERPRETATION: Maintenance of the structural morphology of the oesophagus with off-the-shelf non-biological scaffold and stimulation of regeneration with commercially available extracellular matrix led to de-novo structural and functional regeneration of the oesophagus. FUNDING: None.

An Internet survey of marijuana and hot shower use in adults with cyclic vomiting syndrome (CVS).

Cyclic vomiting syndrome (CVS) is a chronic disorder characterized by episodic nausea and vomiting. A large proportion of patients use marijuana to control their symptoms. Several case reports implicate marijuana as a cause of intractable vomiting with compulsive hot water bathing considered pathognomonic of "cannabinoid hyperemesis." We sought to examine the relationship between marijuana use and CVS. Patients >18 years of age diagnosed by a health care provider were invited to participate in an anonymous internet-based survey. A total of 514 patients participated and 437 completed questions about marijuana use. Mean age was 34 ± 12 years with patients being predominantly female (63%), Caucasian (92%) and from the USA (82%). Nineteen percent never used marijuana and 81% did. Fifty-four percent used marijuana for health issues and 43% for recreational purposes. Users stated that it improved nausea, appetite, general well-being, stress levels and vomiting. Users were more likely to be male and have an associated anxiety disorder. Sixty-seven percent of patients reported taking hot showers/baths for symptom relief, and this was associated with marijuana use. (OR 2.54, CI 1.50-4.31, P = 0.0006). Eighty-one percent of patients with CVS who completed an internet survey reported frequent use of marijuana. With marijuana use, patients noted the greatest improvement with stress levels, appetite and nausea. Marijuana users were more likely to be male and have associated anxiety. Hot showers were not pathognomonic of marijuana use though they were more likely to be associated with its use.

Cyclic Vomiting Syndrome (CVS): is there a difference based on onset of symptoms--pediatric versus adult?

BACKGROUND: Cyclic Vomiting Syndrome (CVS) is a well-recognized functional gastrointestinal disorder in children but its presentation is poorly understood in adults. Genetic differences in pediatric-onset (presentation before age 18) and adult-onset CVS have been reported recently but their clinical features and possible differences in response to therapy have not been well studied. METHODS: This was a retrospective review of 101 CVS patients seen at the Medical College of Wisconsin between 2006 and 2008. Rome III criteria were utilized to make the diagnosis of CVS. RESULTS: Our study population comprised of 29(29%) pediatric-onset and 72 (71%) adult-onset CVS patients. Pediatric-onset CVS patients were more likely to be female (86% vs. 57%, p = 0.005) and had a higher prevalence of CVS plus (CVS + neurocognitive disorders) as compared to adult-onset CVS patients (14% vs. 3%, p = 0.05). There was a longer delay in diagnosis (10 ± 7 years) in the pediatric-onset group when compared to (5 ± 7 years) adult-onset CVS group (p = 0.001). Chronic opiate use was less frequent in the pediatric-onset group compared to adult-onset patients (0% vs. 23%, p = 0.004). Aside from these differences, the two groups were similar with regards to their clinical features and the time of onset of symptoms did not predict response to standard treatment. The majority of patients (86%) responded to treatment with tricyclic antidepressants, anticonvulsants (topiramate), coenzyme Q-10, and L-carnitine. Non-response to therapy was associated with coalescence of symptoms, chronic opiate use and more severe disease as characterized by longer episodes, greater number of emergency department visits in the year prior to presentation, presence of disability and non-compliance on univariate analysis. On multivariate analysis, only compliance to therapy was associated with a response. (88% vs. 38%, Odds Ratio, OR 9.6; 95% Confidence Interval [CI], 1.18-77.05). CONCLUSION: Despite reported genetic differences, the clinical features and response to standard therapy in pediatric- and adult-onset CVS were mostly similar. Most patients (86%) responded to therapy and compliance was the only factor associated with a response.

Physiology and pathophysiology of glottic reflexes and pulmonary aspiration: from neonates to adults.

Pulmonary aspiration is the consequence of abnormal entry of fluid, particulate material, or endogenous secretions into the airway. The two main types of aspiration scenarios include anterograde aspiration, which occurs during swallowing, and retrograde aspiration, which can occur during gastroesophageal reflux (GER) events. The important structures that protect against aspiration include the aerodigestive apparatus: pharynx, upper esophageal sphincter, esophageal body, glottis and vocal cords, and airway. In this article we review the neuroanatomy, physiology, and pathophysiology pertinent to glottic reflexes and airway aspiration across the age spectrum from neonates to adults. We also discuss recent advances in our understanding of glottal reflexes and the relationship of these reflexes to developmental anatomy and physiology, the pathophysiology of aspiration, and aerodigestive interactions.

A survey of emergency department use in patients with cyclic vomiting syndrome.

BACKGROUND: Cyclic vomiting syndrome (CVS), a chronic disorder characterized by recurrent episodes of vomiting, is frequently unrecognized and is associated with high utilization of emergency department (ED) services. METHODS: A web-based survey was posted on the Cyclic Vomiting Syndrome Association (CVSA) website to assess utilization of ED services in patients with CVS. RESULTS: Of 251 respondents, 104 (41.4%) were adult CVS patients and 147 (58.6%) were caregivers of pediatric and adult patients. In the adult group, the median number of ED visits for CVS symptoms was 15(range 1 - 200), with a median of 7 ED visits prior to a diagnosis of CVS (range 0 - 150). In the caregiver group, the median number of ED visits was 10 (range 1 - 175) and the median number of ED visits prior to a diagnosis of CVS was 5 (range 0 - 65). CVS was not diagnosed in the ED in 89/104 (93%) adults and 119/147 (93%) patients in the caregiver group. CVS was not recognized in the ED in 84/95 (88%) of adults and 97/122 (80%) of patients in the caregiver group, despite an established diagnosis of CVS. CONCLUSION: There is a sub-group of adult and pediatric CVS patients who are high utilizers of ED services and CVS is not recognized in the ED in the majority of patients. Improved efforts to educate ED physicians are indicated to optimize treatment of patients with CVS and to decrease potential overuse of ED services.

Normal physiology of the aerodigestive tract and its effect on the upper gut.

There is a close functional relation between the aerodigestive tract and the upper gastrointestinal tract. The pharynx and larynx are involved in respiration, speech, and deglutition. This article reviews the effects of reflexes emanating from the pharynx and larynx on the esophagus and its sphincters, as well as the effects of reflexes emanating from the esophagus on the larynx. Principally, reciprocal reflexes within these 2 regions result in protection of the airway against aspiration from above and below, either by swallowed or refluxed material. However, other reflexes appear to facilitate reflux of gastric content into the esophagus and inhibit esophageal motor function.

A critical review of endoscopic therapy for gastroesophageal reflux disease.

The US Food and Drug Administration has approved 2 endoscopic devices for treating gastroesophageal reflux disease, and several thousand procedures have been performed to date. At least 6 other endoscopic devices designed to treat gastroesophageal reflux are in various stages of testing and may soon obtain approval for clinical use. Short-term follow-up studies uniformly report improvement in heartburn symptoms and quality-of-life scores, as well as decreases in use of antisecretory medications. However, esophageal acid reflux is not normalized after these treatments, nor is esophagitis improved. Although troubling efficacy and safety issues are currently unresolved, these techniques are becoming routine clinical procedures outside of clinical trials. Unless there is rigorous attention to scientific validation of these techniques, including comparative trials versus conventional treatments, there will remain a cloud of doubt and concern about their role and usefulness in clinical medicine. The rapid incursion of these devices into the clinical marketplace before they have undergone critical scientific scrutiny magnifies the urgency of addressing these issues.

Clinical trials evaluating endoscopic GERD treatments: is it time for a moratorium on the clinical use of these procedures?

Perendoscopic treatments of gastroesophageal reflux have been used in clinical practice following FDA approval of the first two devices in 2000. A number of clinical trials predominantly short-term have been performed almost uniformly demonstrating patient improvement in GERD symptomatology and reduction or elimination of antacids. However, only two of these endo reflux treatment trials have included the essential elements of strict patient entry criteria, randomization, attempts at blending, and intention-to-treat analysis. Two new endoscopic antireflux trials are published in this issue of the journal. The first study compares the EndoCinch sewing device to the Enteryx copolymer injection procedure. The second report compares the EndoCinch technique to the laparoscopic fundoplication procedure. Unfortunately, both studies lack a sham-control population and have other important flaws in design. Basically, all these techniques improved GERD symptoms and well-being and decreased the patients PPI requirement during follow-up period. However, none of the endoscopic procedures reduced acid reflux impressively or improved lower esophageal sphincter tone, a consistent negative outcome with all these techniques. Morbidity was associated with all the procedures and Enteryx has been withdrawn recently from clinical use by the manufacturer because of significant complications. The efficacy durability and safety of these devices in treating GERD patients is in question. A moratorium on the continued use of the procedures in clinical practice seems appropriate at this time.

Dickkopf homologs in squamous mucosa of esophagitis patients are overexpressed compared with Barrett's patients and healthy controls.

OBJECTIVES: Esophageal mucosal response to acid exposure varies from minimal changes to erosions/ulcerations and Barrett's metaplasia. While differences in acid contact time have been suggested, the reason for these different responses is not completely understood. The aim of this study was to identify and compare gene expression differences between normal distal and proximal squamous esophageal mucosa (SM) in esophagitis patients with that of healthy controls and Barrett's patients. METHODS: Gene microarray was performed on laser-capture microdissected epithelial cells isolated from biopsy specimens followed by real-time PCR. The effect of acidic pH (pH 4.5) on Dickkopf Homolog 1 (Dkk-1) expression in the human esophageal epithelial cell line (Het-1A) was determined. RESULTS: Gene microarray analysis demonstrated that the upregulation of five genes in the distal compared with the proximal SM in esophagitis patients was greater than the healthy controls and Barrett's patients. Overexpression of Dkk-1 and Dkk-4 was further confirmed by real-time PCR. Dkk-1 and Dkk-4 mRNA levels in the distal SM of the esophagitis patients were 7.0- and 3.1-fold higher, respectively, than in the distal SM of the Barrett's patients and 4.1- and 4.1-fold higher than in healthy controls, respectively. Dkk-1 protein expression in the distal esophagitis SM was also higher than the Barrett's patients and healthy controls. Acidic pH exposure of Het-1A cells resulted in Dkk-1 upregulation at the level of both mRNA and protein. CONCLUSIONS: Dkk-1 and Dkk-4 may potentially be involved in the development of different injuries in response to pathological gastroesophageal acid reflux.

Swallow syncope in association with Schatzki ring and hypertensive esophageal peristalsis: report of three cases and review of the literature.

Syncope caused by swallowing-induced cardiac arrhythmia is an uncommon condition. The recognition of this syndrome is paramount but often difficult. We report three cases of deglutition syncope evaluated at our institution over a three-year period. Two patients had distal esophageal (Schatzki) ring and two had hypertensive peristaltic waves (commonly referred to as "nutcracker esophagus"), neither of which had been described before in association with deglutition syncope. Two patients underwent placement of a demand cardiac pacemaker with subsequent resolution of their syncopal symptoms, while the third patient refused any further intervention. Swallow syncope usually follows a benign course from a cardiac standpoint. Placement of a demand cardiac pacemaker can prevent recurrence of presyncopal and syncopal attacks and their untoward consequences.

Endoscopic techniques for treatment of gastroesophageal reflux disease: a review of abstracts from Digestive Disease Week 2003.

Endoscopic treatments of gastroesophageal reflux disease (GERD) are a new and potentially useful form of therapy for reflux disorders. This type of treatment was first introduced at Digestive Disease Week (DDW) in 2000, and the most recent DDW, in 2003, included a growing number of abstracts describing further experience with endoscopic GERD treatments. The studies are still generally open-label trials involving relatively small patient groups given a variety of unique endoscopic GERD treatments, including radiofrequency, thermal ablation, plication suturing, and polymer injection and implantation techniques. Longer patient follow-up after Stretta (Curon Medical, Sunnyvale, CA) procedures, the permanency rate of EndoCinch (Bard Interventional Products, Billerica, MA) plication sutures, and new experiences with Enteryx (Boston Scientific, Natick, MA) and Gatekeeper (Medtronic, Minneapolis, MN) procedures were highlighted at DDW 2003. Despite these unique devices with significant potential for treatment of GERD, caution was expressed concerning their clinical use in anything other than appropriately designed, scientifically validated clinical trials.

Endoscopic therapy for gastroesophageal reflux disease.

Many new and developing endoscopic techniques for treatment of gastroesophageal reflux disease (GERD) are now or will soon be available for clinical use. These new therapies are directed to the gastroesophageal junction and include three basic techniques, which are outlined in this review: thermal remodeling and neurolysis of the lower esophageal sphincter (LES) zone; bulking or reinforcing of the LES; and plicating gastric folds at the gastric cardia. Only two of these treatments, radiofrequency ablation and fundic fold plication, have been approved by the US Food and Drug Administration (FDA). Published clinical research on endoscopic treatment is reviewed, although it is mostly comprised of open-label trials and anecdotal clinical reports. Complications of endoscopic GERD treatments are described as well as real and potential pitfalls of these techniques. Problems caused by premature introduction of endoscopic GERD treatments into the marketplace are also discussed, along with the rationale for FDA approval of similar devices.

Sphincter of Oddi dysfunction and other functional biliary disorders: evaluation and treatment.

Functional biliary disorders encompass the conditions of SOD and gallbladder dysmotility, both of which result in clinical pain syndromes. Obtaining objective diagnostic and outcomes data for both disorders has been an ongoing challenge over the last two decades. SOD, although initially believed to be strictly a biliary disorder, has now been implicated in recurrent pancreatitis. The biliary-type classification allows a clinician to stratify patients who would benefit from SOM and endoscopic sphincterotomy. Further study into the impact of endoscopic therapy for recurrent pancreatitis is needed. By the same token, the dilemma of postcholecystectomy abdominal pain, whether classified as biliary or pancreatic type III, remains challenging. The current limitations of knowledge highlight the need for prospective randomized studies to evaluate the clinical significance of SOM abnormalities to facilitate treatment of these patients.

Eosinophilic esophagitis in adults: an emerging problem with unique esophageal features.

BACKGROUND: Eosinophilic esophagitis is an inflammatory condition in which there is dense eosinophilic infiltration of the surface lining of the esophagus. Reports of eosinophilic esophagitis pertain almost exclusively to pediatric populations. However, eosinophilic esophagitis is emerging as a clinical affliction of adults. This report describes the clinical and endoscopic findings of eosinophilic esophagitis in the largest cohort of adult patients reported to date. METHODS: Twenty-nine patients (21 men, 8 women; mean age 35 years) with documented eosinophilic esophagitis (>/=15 eosinophils per high-power field in biopsy specimens) and a significant history of chronic dysphagia for solid food (24 patients) were evaluated clinically and endoscopically during a 3-year period (1999-2002). Fourteen patients (48%) had a history of asthma, environmental allergy, or atopy. In a subset of 15 patients, the diagnostic accuracy of endoscopy was compared with that of barium contrast esophagography. RESULTS: Twenty-seven patients (93%) had abnormal endoscopic findings; 25 (86%) had unique esophageal structural changes, associated with a preserved mucosal surface, that were highly atypical for acid reflux injury. Structural alterations seen in adult patients with eosinophilic esophagitis may occur in combination or as a primary characteristic, e.g., uniform small-caliber esophagus, single or multiple corrugations (rings), proximal esophageal stenosis, or 1 to 2 mm whitish vesicles scattered over the mucosal surface. Barium contrast radiography combined with swallow of a barium-coated marshmallow identified 10 (67%) of the primary features observed endoscopically in 15 patients. However, radiography failed to detect other features noted at endoscopy (e.g., only 3/6 patients with proximal stenosis, 5/9 patients with concentric rings and none of 4 patients with small caliber esophagus). Eight of the 29 patients (20%) had a history of chronic heartburn. Twelve patients had been treated with a proton pump inhibitor and only 3 reported some improvement in the severity of dysphagia. CONCLUSIONS: Relatively young age, a history of chronic dysphagia for solid food, and endoscopic detection of unique structural alterations atypical for GERD in an adult patient should prompt a suspicion of EE and subsequent biopsy confirmation. Acid reflux appears to have a secondary role in eosinophilic esophagitis. In an uncontrolled comparison, endoscopy was superior to barium contrast radiography for the diagnosis of eosinophilic esophagitis. The incidence of eosinophilic esophagitis in adults appears to be increasing.

Effect of lower esophageal sphincter tone and crural diaphragm contraction on distensibility of the gastroesophageal junction in humans.

Previous studies of distensibility of the gastroesophageal junction (GEJ) in humans have not tried to distinguish between the effects of muscle action and passive elastic tissue properties of the GEJ. We studied 15 healthy subjects (ages 23-67 yr, 11 men/4 women) by using a catheter with a highly complaint bag positioned manometrically at the GEJ. The bag was distended with air at a rate of 20 ml/min while intrabag pressure was recorded. Distensions were performed during normal breathing, with breath held at maximum inspiration (MI) to activate the diaphragmatic crura, and with midesophageal balloon distension (BD) to relax the lower esophageal sphincter. In 10 subjects, distensions were performed after atropine injection (12 microg/kg iv). Pressure-volume curves and incremental distensibility values were calculated and compared among the different conditions. Both MI and BD significantly altered the slopes of the pressure-volume curves, whereas no effect was seen with atropine. Maximum distensibility was seen at the volume increment of 5-10 ml and was reduced with larger volumes. Distensibility measurements for the various test conditions tended to converge at the largest volume increment, suggesting that distensibility at this degree of distension was more related to the passive elastic properties of the GEJ. On the basis of these findings, we conclude that there can be significant active muscular contributions to recordings of distensibility at the GEJ, variations that must be controlled for during different study conditions.

The small-caliber esophagus: an unappreciated cause of dysphagia for solids in patients with eosinophilic esophagitis.

BACKGROUND: Dysphagia for solids usually indicates a structural esophageal abnormality. This article is a description of a group of 5 young men referred with chronic dysphagia for solids. Esophagoscopy and barium esophagogram failed to show a cause. Our evaluation showed that these patients had eosinophilic esophagitis and a "small-caliber esophagus." This article describes the clinical features, diagnosis, and management of the small-caliber esophagus. METHODS: Patients were evaluated by barium esophagogram with marshmallow challenge, esophageal manometry, Bernstein test, and EGD with biopsies. All patients underwent empiric esophageal dilation with wire-guided dilators. OBSERVATIONS: A diffusely narrow esophagus was appreciated in 3 of 5 patients radiographically, endoscopically, or both. However, the latter studies showed normal findings in 2 patients. Eosinophilic esophagitis was found in all 4 patients in whom biopsy specimens were obtained. Esophageal manometry was performed in 4 patients and showed normal findings in all. The feature that most confirmed the diagnosis of small-caliber esophagus in all patients was the unusually long rents (8 to 17 cm) in the esophageal wall after empiric dilation. Dilation relieved the symptoms in all cases. CONCLUSIONS: The small-caliber esophagus is a cause of dysphagia for solids in young men with eosinophilic esophagitis. It frequently defies detection by routine diagnostic studies. The clue to diagnosis lies in endoscopic reinspection after dilation and the finding of unusually long rents in the esophageal wall.

Volume and yield of screening colonoscopy at a tertiary medical center after change in medicare reimbursement.

OBJECTIVE: Starting July 1, 2001, Medicare began to reimburse for screening colonoscopy in asymptomatic adults older than 50 yr with no risk factors for colorectal cancer. We sought to determine the short-term impact of the change in Medicare reimbursement on the demand for and yield of screening colonoscopy at our tertiary institution. METHODS: Asymptomatic patients older than 50 referred for first screening colonoscopy after the change in Medicare reimbursement from July 1, 2001 to December 31, 2001 were compared with a similar cohort screened before Medicare coverage for a family history of cancer or polyps during the same months the previous year (July 1, 2000 to December 31, 2000). Patient demographics, number, size, location, and histology of polyps/cancers for these screening colonoscopies were collected. RESULTS: A total of 1282 colonoscopies were performed in our institution from July 1, 2001 to December 31, 2001, 257 (20%) for screening. During the same months in the previous year, 121 of 938 colonoscopies (12.9%) were for screening (p < 0.01). This was a 55% increase in the percentage of colonoscopies performed for screening, and a 112% increase in the number of screening colonoscopies. Patients screened after the change in Medicare reimbursement were on average 5 yr older compared with patients of the previous year (62 +/- 10 [mean +/- SD] vs 56 +/- 9 yr; p < 0.01). A total of 61 screening colonoscopies (24%) performed after the change in Medicare reimbursement had adenomatous lesions, compared with 25 (21%) screened for family history (p = ns). The number of adenomas 10 mm or larger or cancers did not differ significantly between the two groups (17 in 2001 vs 12 in 2000; p = ns). Age of 65 or older was associated with detection of adenomatous lesions (OR = 1.7; 95% CI = 1.01-2.9013). CONCLUSIONS: Since the change in Medicare reimbursement, there has been a significant increase in the number and proportion of colonoscopies performed for screening at our institution. Patients screened since this change are older, and the detection rate of neoplastic lesions is similar to those previously screened for a family history of colorectal cancer or polyps.