Broad detection of bacterial type III secretion system and flagellin proteins by the human NAIP/NLRC4 inflammasome.

Inflammasomes are cytosolic multiprotein complexes that initiate host defense against bacterial pathogens by activating caspase-1-dependent cytokine secretion and cell death. In mice, specific nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs) activate the nucleotide-binding domain, leucine-rich repeat-containing family, CARD domain-containing protein 4 (NLRC4) inflammasome upon sensing components of the type III secretion system (T3SS) and flagellar apparatus. NAIP1 recognizes the T3SS needle protein, NAIP2 recognizes the T3SS inner rod protein, and NAIP5 and NAIP6 recognize flagellin. In contrast, humans encode a single functional NAIP, raising the question of whether human NAIP senses one or multiple bacterial ligands. Previous studies found that human NAIP detects both flagellin and the T3SS needle protein and suggested that the ability to detect both ligands was achieved by multiple isoforms encoded by the single human NAIP gene. Here, we show that human NAIP also senses the Salmonella Typhimurium T3SS inner rod protein PrgJ and that T3SS inner rod proteins from multiple bacterial species are also detected. Furthermore, we show that a single human NAIP isoform is capable of sensing the T3SS inner rod, needle, and flagellin. Our findings indicate that, in contrast to murine NAIPs, promiscuous recognition of multiple bacterial ligands is conferred by a single human NAIP.

Postoperative Opioid-Prescribing Practices in Nasal Surgery: A Prospective Study.

Importance: There has been a greater awareness of the opioid epidemic. Studies are needed to better characterize opioid usage after outpatient nasal surgery. Objective: Provide data to guide prescription management for nasal procedures and investigate opioid prescription and subsequent consumption, with the aim of offering analysis to build evidence-based guidelines for postoperative pain management. Design, Setting, and Participants: In this prospective single-center study, morphine milligram equivalents (MME) consumption and pain scores were collected in 69 patients who underwent nasal surgery. Main Measures and Outcomes: Patient demographics, MME use, and pain scores were examined. MME use was compared with patient demographics, surgical procedure type, and postoperative pain scores. Results: In total, 3302 MME were prescribed: 2012 MME (61%) were used, leaving 1290 MME (39%). Patients were prescribed a total average of 47.8 ± 24.0 MME. Four (6%) patients required a second prescription. History of opioid use, benzodiazepine use, and obesity were negative predictors of opioid consumption (p ≤ 0.001). Conclusion and Relevance: Assessing opioid consumption for nasal procedures will guide prescribing practices. Our results indicate that prescription practices can likely be down titrated in patients with a history of certain medication consumption.

Reliability of the Endoscopic Ultrasound Ulcerative Colitis (EUS-UC) score for assessment of inflammation in patients with ulcerative colitis.

Background and study aims Endoscopic ultrasound (EUS) may be a useful modality for disease assessment and risk stratification in ulcerative colitis. We assessed the reliability of a newly developed EUS index of inflammation called the EUS-Ulcerative Colitis (EUS-UC) score. Patients and methods The EUS-UC score components include total wall thickness, hyperemia, and depth of inflammation (DOI). Three blinded expert endosonographers assessed EUS videos of 58 patients with UC in triplicate. Intra- and inter-rater reliability of the hyperemia and DOI component scores were estimated using intra-class correlation coefficients (ICCs). Total wall thickness reliability estimates could not be assessed in this study. The ICCs were compared to the original indices from which they were derived. Results For hyperemia, the inter-class ICC was "moderate" at 0.556 (95 % CI = 0.434-0.651) and the intra class ICC was "almost perfect" at 0.884 (95 % CI = 0.835-0.920). The newly defined hyperemia score performed better than the original index from which is was derived. The DOI inter-class ICC was "fair" at 0.335 (95 % CI = 0.201-0.464), and the intra-class ICC was "substantial" at 0.732 (95 % CI = 0.642-0.802). The DOI reliability estimates were similar to the original index from which it was derived. Conclusions The hyperemia component of the EUS-UC score performed significantly better than the original index from which it was derived, but the reliability of the DOI component was suboptimal. Intra-class correlation was excellent for both components. The EUS-UC score is a promising instrument for assessment of UC and further validation is required.

Biomarkers in Migraine.

BACKGROUND: Disability from migraine has a profound impact on the world's economy. Research has been ongoing to identify biomarkers to aid in diagnosis and treatment. OBJECTIVE: The aim of this study was to highlight the purported diagnostic and therapeutic migraine biomarkers and their role in precision medicine. METHODS: A comprehensive literature search was conducted using PubMed, Google Scholar, and clinicaltrials.gov using keywords: "migraine" OR "headache" combined with "biomarkers" OR "marker." Other keywords included "serum," "cerebral spinal fluid," "inflammatory," and "neuroimaging." RESULTS: After a review of 88 papers, we find the literature supports numerous biomarkers in the diagnosis of migraine. Therapeutic biomarkers, while not as extensively published, highlight calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide-38 (PACAP-38) as biomarkers with the most substantiated clinical relevance. Genetic markers mainly focusing on gene mutations with resultant biochemical alterations continue to be studied and show promise. CONCLUSION: Although there are several proposed biomarkers for migraine, continued research is needed to substantiate their role in clinical practice.

EUS-guided gold fiducial insertion for image-guided radiation therapy of pancreatic cancer: 50 successful cases without fluoroscopy.

BACKGROUND: Image-guided radiation therapy (IGRT) accurately delivers a high dose of potentially tumoricidal radiation to its target while sparing adjacent healthy tissue. Application of IGRT to unresectable pancreatic cancer requires the use of fiducials to track the precise location of the tumor. Fiducial markers have been successfully placed endoscopically. OBJECTIVE: To determine the feasibility of EUS-guided gold fiducial placement for IGRT. DESIGN: Prospective case series. SETTING: Tertiary medical center. PATIENTS: Consecutively referred patients with locally advanced unresectable pancreatic adenocarcinoma for EUS-guided insertion of gold fiducials from December 2006 to February 2009. INTERVENTIONS: Under only EUS guidance, fiducial markers were deployed into or near the tumor by using a 19-gauge needle. In most cases, a sterile water injection technique was used to insert the fiducials. Fluoroscopy was not used in any case. MAIN OUTCOME MEASUREMENTS: Successful placement of an adequate number of fiducials to proceed with IGRT as determined by CT. RESULTS: Fifty-seven consecutive patients were included. Fifty cases (88%) were successful. Of the cases in which fiducial placement was attempted and follow-up was adequate, 94% (50 of 53) of cases were successful. LIMITATIONS: Single-center, nonrandomized study. CONCLUSIONS: EUS-guided fine-needle insertion was safe and effective in delivering gold fiducial markers for image-guided radiation therapy. Fluoroscopy was not required for successful fiducial placement.

Endoscopic ultrasound-guided intratumoural therapy for pancreatic cancer.

Pancreatic cancer is the second most frequent gastrointestinal malignancy and carries a dismal prognosis. The current standard of care includes resection, if possible, as well as systemic chemoradiation therapy. Endoscopic ultrasound (EUS) is an established technique for the diagnosis and staging of pancreatic adenocarcinoma. Interventional EUS via fine needle injection (FNI) for the treatment of pancreatic cancer is a rapidly expanding field. The present article reviews the up-to-date developments in EUS FNI for intratumoural pancreatic cancer therapy, including antitumoural agents, immunotherapy, ablative techniques and new delivery systems. The therapeutic modalities discussed are currently under development and will hopefully reach clinical practice if benefit is demonstrated through clinical trials. EUS FNI may be an exciting new technique for the delivery of desperately needed novel therapies for pancreatic cancer.

Diagnosis of pancreatic gastrointestinal stromal tumor by EUS guided FNA.

CONTEXT: Gastrointestinal stromal tumors of the pancreas are very rare. Only two case reports have been published, both with diagnoses made on surgical pathology. We present the first case of pancreatic stromal tumor diagnosed by endoscopic ultrasound guided fine needle aspiration. CASE REPORT: A 47-year-old male presented with self limited nausea and vomiting. A CT scan revealed a subtle, hypervascular mass in the uncinate process of the pancreas. Endoscopic ultrasound confirmed the pancreatic mass and fine needle aspiration was performed giving a bloody sample. Cytology showed spindle cell proliferation with CD117 positive immunohistochemistry, confirming a pancreatic gastrointestinal stromal tumor. CONCLUSION: We present a case of pancreatic stromal tumor diagnosed by endoscopic ultrasound guided fine needle aspiration. Although very rare in the pancreas, gastrointestinal stromal tumors should be considered in the differential diagnosis of solid pancreatic masses and blood aspirates.

Epidemiology of gastrointestinal stromal tumors in a defined Canadian Health Region: a population-based study.

The aim of this study was to determine the incidence and the clinical and pathological features of gastrointestinal stromal tumors within a nonselected, well-defined Canadian Health Region. A population-based cohort study of all adult patients diagnosed with gastrointestinal stromal tumors was conducted in the Calgary Health Region from April 2000 to March 2004. All charts and pathological specimens were reviewed for clinical, histological, and antigenic features. The age-adjusted and gender-adjusted annual incidence rate was 0.91/10(5) person-years. There was a trend for increased incidence with routine use of CD117. The only identified risk was advancing age (age >or=50; rate ratio = 4.6; P = .0006). All samples were positive for CD117. At presentation, 19% were at intermediate and 19% were at high risk of becoming malignant, with 14% being overtly metastatic. This is the first North American study to define the incidence and the clinical and pathologic features of gastrointestinal stromal tumors based on current diagnostic criteria.

Eosinophilic esophagitis: an overlooked entity in chronic dysphagia.

BACKGROUND: A 40-year-old white male with atopy presented to our department in March 2004 with a history of chronic heartburn and solid-food dysphagia since 1994. The patient was taking on-demand salbutamol for asthma and ranitidine for mild heartburn, occurring less than once per week. Eight years previously, he had undergone esophageal dilatation for a Schatzki's ring. INVESTIGATIONS: Physical examination, laboratory investigations, video esophagram, upper endoscopy with mid-esophageal biopsies, and skin testing for a number of food and environmental allergens. Diagnosis Eosinophilic esophagitis. MANAGEMENT: Topical steroids with a fluticasone 220 microg multiple-dose inhaler, four puffs swallowed twice a day for 6 weeks.

Eosinophilic esophagitis: a newly established cause of dysphagia.

Eosinophilic esophagitis has rapidly become a recognized entity causing dysphagia in young adults. This review summarizes the current knowledge of eosinophilic esophagitis including the epidemiology, clinical presentation, diagnostic criteria, pathophysiology, treatment, and prognosis. An extensive search of PubMed/Medline (1966-December 2005) for available English literature in humans for eosinophilic esophagitis was completed. Appropriate articles listed in the bibliographies were also attained. The estimated incidence is 43/10(5) in children and 2.5/10(5) in adults. Clinically, patients have a long history of intermittent solid food dysphagia or food impaction. Some have a history of atopy. Subtle endoscopic features may be easily overlooked, including a "feline" or corrugated esophagus with fine rings, a diffusely narrowed esophagus that may have proximal strictures, the presence of linear furrows, adherent white plaques, or a friable (crepe paper) mucosa, prone to tearing with minimal contact. Although no pathologic consensus has been established, a histologic diagnosis is critical. The accepted criteria are a dense eosinophilic infiltrate (>20/high power field) within the superficial esophageal mucosa. In contrast, the esophagitis associated with acid reflux disease can also possess eosinophils but they are fewer in number. Once the diagnosis is established, treatment options may include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, or biologic treatment. The long-term prognosis of EE is uncertain; however available data suggests a benign, albeit inconvenient, course. With increasing recognition, this entity is taking its place as an established cause of solid food dysphagia.

Emergency management of bleeding esophageal varices: drugs, bands or sleep?

Variceal bleeding is a severe complication of cirrhosis leading to significant morbidity and mortality. Treatment of acute variceal bleeding has improved dramatically since the era of the mechanical balloon tamponade. These advances include endoscopic band ligation or sclerotherapy, and vasoactive pharmacological options such as somatostatin, octreotide, vasopressin and terlipressin. Evidence from a multitude of clinical trials and meta-analyses comparing endoscopic and pharmacological treatments suggests near equivalence in efficacy for initial hemostasis, mortality and rate of rebleeding. This raises the question of whether on-call gastroenterologists should be performing emergency endoscopic treatment in the middle of the night or start pharmacological treatment and delay endoscopy until optimal patient and working conditions the next morning. The present review analyzes the available comparative data between endoscopic and pharmacological treatment options. Although the literature cannot yet definitively answer the question posed, the authors suggest that delaying endoscopic treatment until the next morning may be the most reasonable practical approach.

Acute coinfection with hepatitis B and hepatitis C viruses.

Acute coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) is rare. The few previously reported cases all describe acute HBV followed by acute HCV, leading to HBV clearance but chronic HCV. This is the first reported case of acute concurrent infection and spontaneous clearance of both HBV and HCV.

Defining quality indicators for best-practice management of inflammatory bowel disease in Canada.

BACKGROUND: There is a paucity of published data regarding the quality of care of inflammatory bowel disease (IBD) in Canada. Clinical quality indicators are quantitative end points used to guide, monitor and improve the quality of patient care. In Canada, where universal health care can vary significantly among provinces, quality indicators can be used to identify potential gaps in the delivery of IBD care and standardize the approach to interprovincial management. METHODS: The Emerging Practice in IBD Collaborative (EPIC) group generated a shortlist of IBD quality indicators based on a comprehensive literature review. An iterative voting process was used to select quality indicators to take forward. In a face-to-face meeting with the EPIC group, available evidence to support each quality indicator was presented by the EPIC member aligned to it, followed by group discussion to agree on the wording of the statements. The selected quality indicators were then ratified in a final vote by all EPIC members. RESULTS: Eleven quality indicators for the management of IBD within the single-payer health care system of Canada were developed. These focus on accurate diagnosis, appropriate and timely management, disease monitoring, and prevention or treatment of complications of IBD or its therapy. CONCLUSIONS: These quality indicators are measurable, reflective of the evidence base and expert opinion, and define a standard of care that is at least a minimum that should be expected for IBD management in Canada. The next steps for the EPIC group involve conducting research to assess current practice across Canada as it pertains to these quality indicators and to measure the impact of each of these indicators on patient outcomes.

Ultra high magnification endoscopy: Is seeing really believing?

Endoscopy is an indispensible diagnostic and therapeutic instrument for gastrointestinal diseases. Endocytoscopy and confocal endomicroscopy are two types of ultra high magnification endoscopy techniques. Standard endoscopy allows for 50 × magnification, whereas endocytoscopy can magnify up to 1400 × and confocal endomicroscopy can magnify up to 1000 ×. These methods open the realm of real time microscopic evaluation of the GI tract, including cellular and subcellular structures. Confocal endomicroscopy has the additional advantage of being able to visualize subsurface structures. The use of high magnification endoscopy in conjunction with standard endoscopy allows for a real-time microscopic assessment of areas with macroscopic abnormalities, providing "virtual biopsies" with valuable information about cellular and subcellular changes. This can minimize the number of biopsies taken at the time of endoscopy. The use of this technology may assist in detecting pre-malignant or malignant changes at an earlier state, allowing for earlier intervention and treatment. High magnification endoscopy has shown promising results in clinical trials for Barrett's esophagus, esophageal adenocarcinoma, esophageal squamous cell cancer, gastric cancer, celiac disease, colorectal cancer, and inflammatory bowel disease. As the use of high magnification endoscopy techniques increases, the clinical applications will increase as well. Of the two systems, only confocal endomicroscopy is currently commercially available. Like all new technologies there will be an initial learning curve before operators become proficient in obtaining high quality images and discerning abnormal from normal pathology. Validated criteria for the diagnosis of the various gastrointestinal diseases will need to be developed for each method. In this review, the basic principles of both modalities are discussed, along with their clinical applicability and limitations.

Determination of the relationship between gastric wall thickness and body mass index with endoscopic ultrasound.

BACKGROUND: The aim of this study was to determine the relationship between gastric wall thickness and BMI. METHODS: Bariatric surgery patients undergoing a pre-operative screening EGD and patients undergoing endoscopic ultrasound for non-gastric pathology were prospectively enrolled in the study. Patients underwent endoscopic ultrasound evaluation with measurements of gastric wall thickness at six areas of the stomach. The primary outcome was the correlation of BMI and mean gastric wall thickness. RESULTS: Twenty-four patients were enrolled in the study. Eight patients were excluded due to endoscopic abnormalities of the stomach (five) or intolerance to the procedure (three). Ten patients with a normal BMI and six obese patients were included in the analysis. BMI in the non-obese group was 23.8 ± 2.5 kg/m(2) compared to 54.7 ± 14.6 kg/m(2) in the obese population. The average gastric wall thickness amongst all subjects was 3.27 ± 0.42 mm. Mean gastric thickness in the non-obese group was 3.25 ± 0.45 mm compared to 3.30 ± 0.39 mm in the obese group (p = 0.41). When both groups were combined, there did not appear to be a linear relationship between mean thickness and BMI (R (2) = 0.005). There was no linear relationship between gastric wall thickness and waist circumference (R (2) = 0.02). CONCLUSION: There was no significant correlation between gastric wall thickness and BMI. Mean gastric wall thickness of endoscopically normal stomachs was in the range of 3-4 mm.

Contrast enhanced endoscopic ultrasound: More than just a fancy Doppler.

Contrast enhanced endoscopic ultrasound (CEUS) is a new modality that takes advantage of vascular structure and blood flow to distinguish different clinical entities. Contrast agents are microbubbles that oscillate when exposed to ultrasonographic waves resulting in characteristic acoustic signals that are then converted to colour images. This permits exquisite imaging of macro- and microvasculature, providing information to help delineate malignant from non-malignant processes. The use of CEUS may significantly increase the sensitivity and specificity over conventional endoscopic ultrasound. Currently available contrast agents are safe, with infrequent adverse effects. This review summarizes the theory and technique behind CEUS and the current and future clinical applications.

Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer.

BACKGROUND: A major focus of palliation in patients with unresectable pancreatic cancer is pain control. The aim of this systematic review was to examine the efficacy and safety of neurolytic celiac plexus blockade (NCPB) compared with standard treatment in randomized controlled trials (RCTs) involving patients with unresectable pancreatic cancer. METHODS: An electronic search was completed (1966 through August, 2005) for RCTs comparing NCPB versus control (standard treatment and/or sham NCPB) in patients with unresectable pancreatic cancer. The primary outcome was pain measured on a 10-point visual analogue scale (VAS). Secondary outcomes included opioid usage, adverse effects, quality of life (QOL), and survival. All outcomes were assessed at 2, 4, and 8 wk. RESULTS: Five RCTs involving 302 patients (NCPB, N = 147; control, N = 155) met the inclusion criteria. Mean age was 61.0 +/- 4.3 yr. Compared with control, NCPB was associated with lower VAS scores for pain at 2, 4, and 8 wk (weighted mean difference [WMD]-0.60, 95% CI -0.82 to -0.37). Opioid usage (in mg/d oral morphine) was also reduced at 2, 4, and 8 wk (WMD -85.9, 95% CI -144.0 to -27.9). NCPB was associated with a reduction in constipation (relative risk 0.67, 95% CI 0.49-0.91), but not other adverse events. No differences in survival were observed. QOL could not be adequately analyzed due to differences in outcome scales among studies. CONCLUSIONS: In patients with unresectable pancreatic cancer, NCPB is associated with improved pain control, and reduced narcotic usage and constipation compared with standard treatment, albeit with minimal clinical significance.