Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE.

Mutations in the plectin gene (PLEC1) cause epidermolysis bullosa simplex (EBS), which may associate with muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). The association of EBS with congenital myasthenic syndrome (CMS) is also suspected to result from PLEC1 mutations. We report here a consanguineous patient with EBS and CMS for whom mutational analysis of PLEC1 revealed a homozygous 36 nucleotide insertion (1506_1507ins36) that results in a reduced expression of PLEC1 mRNA and plectin in the patient muscle. In addition, mutational analysis of CHRNE revealed a homozygous 1293insG, which is a well-known low-expressor receptor mutation. A skin biopsy revealed signs of EBS, and an anconeus muscle biopsy showed signs of a mild myopathy. Endplate studies showed fragmentation of endplates, postsynaptic simplification, and large collections of thread-like mitochondria. Amplitudes of miniature endplate potentials were diminished, but the endplate quantal content was actually increased. The complex phenotype presented here results from mutations in two separate genes. While the skin manifestations are because of the PLEC1 mutation, footprints of mutations in PLEC1 and CHRNE are present at the neuromuscular junction of the patient indicating that abnormalities in both genes contribute to the CMS phenotype.

Mechanisms involved in the recent large reductions in US road fatalities.

Road fatalities in the USA have recently decreased, and these reductions are greater than the corresponding reductions in the amount of driving. A multiple regression analysis was performed on monthly data from January 2007 through December 2008. The dependent variable was the number of road fatalities. The independent variables were distance driven, proportion of driving on rural roads, and the average price of unleaded gasoline as a proxy for the proportion of leisure driving. The results suggest that the larger-than-expected fall in road fatalities is partly a consequence of the disproportional decreases in rural driving (which is more risky than urban driving) and leisure driving (which is more risky than commuter driving).

A CD40 Kozak sequence polymorphism and susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific expression.

Previously, we and others have demonstrated the association of a C/T single nucleotide polymorphism (SNP), in the Kozak sequence of CD40, with Graves' disease (GD). Here, using an expanded data set of patients, we confirm the association of the CD40 SNP with GD (n=210, P=0.002, odds ratio (OR)=1.8). Subset analysis of patients with persistently elevated thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies (Abs), (TPO/Tg Abs), after treatment (n=126), revealed a significantly stronger association of the SNP with disease (P=5.2 x 10(-5), OR=2.5) than in GD patients who were thyroid antibody-negative. However, the CD40 SNP was not associated with TPO/Tg Abs in healthy individuals. Next, we tested the CD40 SNP for association with Myasthenia Gravis (MG), which, like GD is an antibody-mediated autoimmune condition. Analysis of 81 MG patients found no association of the SNP with disease. Functional studies revealed significant expression of CD40 mRNA and protein in the thyroid (target tissue in GD) but not in skeletal muscle (target tissue in MG). Combined, our genetic and tissue expression data suggest that the CD40 Kozak SNP is specific for thyroid antibody production involved in the etiology of GD. Increased thyroidal expression of CD40 driven by the SNP may contribute to this disease specificity.

Sleeping more as a way to lose weight.

Caloric consumption in a society with readily available food is likely to be approximately proportional to the number of hours of being awake. Thus, replacing 1 h of inactive wakefulness (e.g. watching TV), with sleeping is likely to result in a substantial reduction in caloric intake. Calculations are presented to illustrate the possible benefits of such a switch on weight reduction.

Gastrointestinal endoscopy: past and future.

The former editor of Gastrointestinal Endoscopy reflects on the history of endoscopy, which reveals much about the mechanisms whereby innovation occurred, and attempts to forecast the future. Endoscopic technological development in most industrialised countries will be determined largely by various combinations of many external factors together with the further development of virtual imaging.

Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults.

BACKGROUND: Although familial clusters of Barrett's oesophagus and oesophageal adenocarcinoma have been reported, a familial predisposition to these diseases has not been systematically investigated. AIMS: To determine whether Barrett's oesophagus and oesophageal (or oesophagogastric junctional) adenocarcinoma aggregate in families. PATIENTS AND METHODS: A structured questionnaire eliciting details on reflux symptoms, exposure history, and family history was given to Caucasian case (n=58) subjects with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma, and to Caucasian control (n=106) subjects with symptomatic gastro-oesophageal reflux disease without Barrett's oesophagus. Reported diagnoses of family members were confirmed by review of medical records. RESULTS: The presence of a positive family history (that is, first or second degree relative with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma) was significantly higher among case subjects compared with controls (24% v 5%; p<0.005). Case subjects were more likely to be older (p<0.001) and male (74% v 43% male; p<0.0005) compared with control subjects. In a multivariate logistic regression analysis, family history was independently associated with the presence of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma (odds ratio 12.23, 95% confidence interval 3.34-44.76) after adjusting for age, sex, and the presence of obesity 10 or more years prior to study enrollment. CONCLUSIONS: Individuals with Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma are more likely to have a positive family history of Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma than individuals without Barrett's oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma. A positive family history should be considered when making decisions about screening endoscopy in patients with symptoms of gastro-oesophageal reflux.

Evaluation of a rapid urine amylase test using post-ERCP hyperamylasemia as a model.

OBJECTIVE: The initial diagnosis of acute pancreatitis is often based on clinical criteria together with elevations of serum amylase and lipase. A reliable bedside urine test could facilitate the early diagnosis of pancreatitis. We evaluated a rapid urine amylase test (Rapignost) by using post-ERCP hyperamylasemia as a human model of acute development of hyperamylasemia suggestive of pancreatitis. METHODS: Seventy-five patients undergoing ERCP were prospectively evaluated. Patients with renal insufficiency, hyperlipidemia, or hyperglycemia were excluded. Before ERCP, patients had serum amylase and lipase measured, and urine amylase tested with the Rapignost test strip. At 4 and 16-24 h post-ERCP, a serum and urine (test strip) amylase were measured again; the adequacy of urine collection was verified by measuring a 2-h creatinine clearance. Patients were clinically assessed for the development of clinical pancreatitis. The concordance of the strip result with post-ERCP hyperamylasemia was assessed. RESULTS: The sensitivity of the test strip for the detection of hyperamylasemia was greatest at 16-24 h post-ERCP (78%). Specificity was uniformally high (100% specificity at 16-24 h post-procedure). The test strip was positive in all cases of clinical pancreatitis. Of three cases of clinically evident ERCP-induced pancreatitis, only one was urine test strip positive by 4 h post-procedure. CONCLUSIONS: Using post-ERCP hyperamylasemia as a model, the Rapignost rapid urine amylase test strip was only marginally sensitive but highly specific for hyperamylasemia. The urine test strip was positive in all cases of clinical pancreatitis and may be a useful bedside test for the diagnosis of acute pancreatitis.

High-resolution endoscopic imaging of the GI tract: a comparative study of optical coherence tomography versus high-frequency catheter probe EUS.

BACKGROUND: Both optical coherence tomography (OCT) and catheter probe EUS (CPEUS) are candidates for high-resolution imaging of the GI wall, but their potential roles in this clinical context have not been investigated. METHODS: OCT and CPEUS were used to image normal-appearing portions of the GI tract at the same sites. CPEUS was performed with a 20-MHz or a new 30-MHz catheter probe. RESULTS: Forty-four histologically confirmed normal sites in 27 patients were evaluated. With OCT, mucosa and muscularis mucosa were clearly seen at all sites. Except for stomach, OCT demonstrated the submucosa in all sites. OCT penetration ranged from 0.7 to 0.9 mm. Microscopic structures such as esophageal glands, intestinal villi, colonic crypts, and blood vessels were easily identified. CPEUS penetration ranged from 10 mm to 20 mm, and 5 to 7 distinct layers were discernible. However, both mucosa and submucosa were seen as thin layers without microscopic detail. CONCLUSION: OCT resolution is superior to high-frequency CPEUS, but depth of penetration is limited to mucosa and submucosa. OCT images the major structural components of the mucosa and submucosa whereas CPEUS does not. Potentially, OCT and high-frequency CPEUS may be complementary for clinical imaging.

Wire-guided intraductal US: an adjunct to ERCP in the management of bile duct stones.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) may misdiagnose bile duct stones if air bubbles are introduced during contrast injection, and it may also fail to diagnose stones in the presence of bile duct dilation. METHODS: Our aim was to determine whether intraductal US (IDUS) improves the accuracy of cholangiography and whether it is a useful adjunct in the management of bile duct stones. IDUS with a wire-guided US probe was performed after initial ERC in patients in whom bile duct stones were suspected. The diagnostic accuracy of ERC alone was compared with that of ERC plus IDUS. RESULTS: ERC with IDUS was performed in 62 patients who were suspected to have bile duct stones. Both IDUS and ERC were performed by the same endoscopist, and ERC was performed with a C-arm fluoroscope. The presence of bile duct stones and/or sludge were confirmed after sphincterotomy and extraction in 34 patients. Overall, the accuracy of ERC combined with IDUS in the diagnosis of bile duct stone and/or sludge was higher than that of ERC alone (97% vs. 87%, p < 0.05). With dilated bile ducts, the diagnostic accuracy of ERC combined with IDUS was also higher than that of ERC alone (95.5% vs. 72.7%, p < 0.05). Additional diagnostic information provided by IDUS included identification of cystic duct stones in 5 patients, characterization of bile duct strictures in 2 patients, and choledochal varices in 1 patient. Performance of wire-guided IDUS required 5% of the total procedure time. CONCLUSIONS: IDUS improves diagnostic accuracy of ERC and is a useful adjunct to ERC when bile duct stones are suspected.

Methylene blue staining of dysplastic and nondysplastic Barrett's esophagus: an in vivo and ex vivo study.

BACKGROUND AND STUDY AIMS: Methylene blue selectively stains specialized columnar epithelium in Barrett's esophagus with high accuracy. We prospectively evaluated the methylene blue staining properties of dysplastic and nondysplastic Barrett's esophagus and the association of these properties with the risk for dysplasia and cancer. PATIENTS AND METHODS: In a ex vivo study, we mapped, photographed, and sampled esophagectomy specimens with high grade dysplasia and/or early adenocarcinoma before and after methylene blue staining. In a concurrent in vivo study, we performed methylene blue staining and characterized methylene blue stain characteristics. Pathologists estimated the proportion of specialized columnar epithelium in each specimen and graded dysplasia. RESULTS: We examined 551 biopsies from 47 patients with biopsy-proven Barrett's esophagus and 48 sections from five surgical specimens with Barrett's esophagus and dysplasia and early adenocarcinoma. The accuracy of ex vivo and in vivo methylene blue staining for specialized columnar epithelium was 87% and 90%, respectively. It was influenced by the length of Barrett's esophagus, biopsy location, and the presence of esophagitis and/or dysplasia. Light to absent staining (p = 0.01) and moderate to marked heterogeneity (p = 0.01) were significantly associated with high grade dysplasia or cancer in the univariate analysis and in a multivariate model that adjusted for the length of Barrett's esophagus and the presence of a lesion. These staining characteristics were present in all patients with severe dysplasia and/or adenocarcinoma. CONCLUSIONS: Highly dysplastic or malignant Barrett's esophagus stains differently with methylene blue. Increased heterogeneity and decreased methylene blue stain intensity are significant independent predictors of high grade dysplasia and/or cancer. These features may help to direct biopsies in patients without a lesion.

Potential new endoscopic techniques for the earlier diagnosis of pre-malignancy.

Light interacts with tissue in a variety of ways, including absorption, fluorescence, elastic scattering and Raman scattering. These interactions enable a number of promising technologies for endoscopic diagnosis of pre-malignancy, including chromoscopy; fluorescence, scattering and Raman spectroscopies; and optical coherence tomography. Although still in various stages of technical development and clinical trials, these optical diagnostic techniques are demonstrating strong potential to significantly enhance the clinical endoscopist's ability to detect dysplasia in gastrointestinal mucosae.

Prospective evaluation of balloon-sheathed catheter US system.

BACKGROUND: Catheter US probes must rely on luminal water to create images because they do not incorporate a water-filled balloon such as that used with a designated echoendoscope. The purpose of this study is to determine the effectiveness and safety of a balloon sheath for the US catheter system. METHODS: Catheter EUS was performed on 50 patients by using a 2.3 mm 12 MHz or 20 MHz catheter probe. Catheter EUS was used in 47 cases, and a newly developed water-filled balloon sheath was used in 41 cases. Both devices were used in 39 cases. Procedure time, depth of ultrasound penetration, and a subjective assessment of image quality and ease of use were recorded, along with TMN stage as applicable. Catheter EUS findings were confirmed with a standard radial scanning echoendoscopy (S-EUS) in 18 cases. RESULTS: Catheter probe EUS (C-EUS) and catheter probe plus balloon (CB-EUS) imaging was obtained of 25 esophageal, 8 gastric, 4 rectal, 1 biliary, and 1 duodenal lesion. Time required for the ultrasound portion of the examination was identical with C-EUS and CB-EUS. Depth of penetration increased with CB-EUS with both the 12 MHz and 20 MHz probes (p < 0.05). Subjective assessment of image clarity improved when CB-EUS was used in the esophagus. C-EUS failed to identify 2 esophageal cancers and 2 sets of paraesophageal lymph nodes, and understaged 1 esophageal cancer. The remaining 14 cancers were staged identically by both modalities. The catheter probes with and without the balloon sheath were easy to use, even in markedly narrow esophageal strictures. CB-EUS did not significantly improve resolution in the stomach or rectum. S-EUS confirmed findings of CB-EUS in all 18 cases in which both instruments were used. There were no procedure-related complications. CONCLUSIONS: For esophageal lesions, CB-EUS improves images compared with C-EUS, and enhances depth of penetration without prolonging or encumbering the examination. CB-EUS offers no advantage over C-EUS in organs other than the esophagus. S-EUS, when possible, remains the preferred imaging modality for esophageal cancers because of the ability to image the celiac axis and other deep structures.

Cervical esophageal perforation during EUS: a national survey.

BACKGROUND: EUS is considered to be as safe a procedure as EGD. However, the longer, rigid tip of the echoendoscopes raises concern about cervical esophageal perforation during intubation. Our aim was to determine the rate of this complication. METHODS: Members of the American Endosonography Club were surveyed by questionnaire to determine the number of EUS examinations performed and the number of cervical esophageal perforations encountered up to June 1999. Each questionnaire was coded to avoid duplicate reporting. RESULTS: Questionnaires were mailed to 203 members; 86 (42.4%) responded. Cervical esophageal perforation occurred in 16 of 43,852 reported upper EUS procedures at a frequency of 0.03%. Fifteen (94%) patients were elderly. A history of difficult intubation with prior endoscopic procedures was present in 7 (44%) patients. Three patients had large cervical osteophytes. In 9 (56%) patients, the procedure was done by an endosonographer with less than 1 year of experience. Two patients required surgery. One patient died as a result of the perforation and the other 13 (81%) patients were managed successfully with conservative treatment. CONCLUSIONS: The incidence of cervical perforation during upper EUS may be higher than during EGD. Advanced patient age, difficult intubation during prior upper endoscopy, operator inexperience, and the presence of large cervical osteophytes may contribute to cervical perforation during upper EUS examination.

Endoscopic palliation for inoperable pancreatic cancer.

BACKGROUND: The majority of patients with pancreatic cancer are not candidates for surgical resection. Palliative therapy remains the cornerstone of management of this population. METHODS: We reviewed recent clinical and experimental studies on endoscopic palliative therapy of inoperable pancreatic cancer. RESULTS: Endoscopic placement of a biliary stent is the preferred mode of palliation of obstructive jaundice in patients with pancreatic cancer. The techniques of endoscopic stent insertion are briefly described. Episodic recurrence of jaundice and cholangitis due to stent occlusion is a major drawback of biliary polyethylene stents. Self-expandable metal stents with large diameters have lower rates of stent occlusion and are cost effective in patients who are expected to survive beyond 3 months. Palliation of duodenal obstruction with self-expandable enteral stents and endosonography-guided celiac plexus neurolysis are emerging options for the treatment of patients with advanced pancreatic cancer. CONCLUSIONS: Endoscopic therapy offers safe and effective management options for palliation of major symptoms associated with inoperable pancreatic cancer.

Role of Doppler US in acute peptic ulcer hemorrhage: can it predict failure of endoscopic therapy?

BACKGROUND: Recurrent bleeding after successful primary endoscopic hemostasis of acutely bleeding ulcers is a significant problem. This study evaluates endoscopic Doppler ultrasound (US) in assessing risk of recurrent bleeding in patients presenting with acute peptic ulcer hemorrhage. METHODS: In this prospective, double-blind, nonrandomized trial, patients were enrolled from a single academic institution. Only patients with endoscopically confirmed gastric, duodenal, pyloric, or anastomotic ulcers were enrolled. The therapeutic endoscopist was blinded to the Doppler US signal from the ulcer and based treatment decisions on standard guidelines. A 16 MHz pulsed-wave, linear scanning, US probe was used through the accessory channel of an endoscope to assess for the presence of a Doppler signal. RESULTS: Fifty-two of 139 screened patients entered the trial (55 Doppler sessions). Endoscopic therapy was performed in 42% (30-day recurrent bleeding rate of 17%). Ulcers that remained persistently Doppler positive immediately after endoscopic therapy had a significantly higher rate of recurrent bleeding than ulcers where the Doppler signal was abolished: 100% versus 11% (p = 0.003). There were no bleeding-related deaths. CONCLUSIONS: A persistently positive Doppler US signal appears to be a marker of inadequate endoscopic therapy in patients with acutely bleeding peptic ulcers.

Methylene blue-directed biopsies improve detection of intestinal metaplasia and dysplasia in Barrett's esophagus.

BACKGROUND: Endoscopically applied methylene blue selectively stains specialized columnar epithelium in Barrett's esophagus. METHODS: The diagnostic yield and cost of cancer surveillance in patients with Barrett's esophagus using methylene blue-directed biopsies (MBDB) were compared with surveillance using a "jumbo" random biopsy technique in a prospective, sequential, controlled trial. Esophagogastroduodenoscopy was performed with either MBDB or random biopsy in a randomized sequence. The proportions of various types of epithelia in each biopsy were estimated and dysplasia was graded in a blinded fashion. RESULTS: Forty-three patients with short- (n = 8), limited- (n = 10), and long-segment (n = 25) Barrett's esophagus were studied. Using MBDB technique, the average number of biopsies obtained per patient was significantly lower and the proportion of specialized columnar epithelium in each specimen was significantly higher compared with random biopsy. Dysplasia or cancer was diagnosed in significantly more MBDB specimens (12% vs. 6%, p = 0.004). Despite fewer biopsies per patient using MBDB, dysplasia or cancer was diagnosed in significantly more patients (44% vs. 28%, p = 0.03) than by random biopsy technique. MBDB cost less and detected more cancers than random biopsy. CONCLUSIONS: MBDB is a more accurate and cost-effective technique than random biopsy for diagnosing specialized columnar epithelium and dysplasia/cancer, particularly in long-segment Barrett's esophagus.