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Background Staple-line leak following laparoscopic sleeve gastrectomy is a dire adverse event. While the treatment of acute and early leaks is well established, there is still dispute regarding late and chronic leaks. We describe an endoscopic approach combining septotomy and sleeve stricture dilation for treating late/chronic leaks. Methods Ten consecutive patients with late/chronic proximal leaks were treated at our center. The septum separating the sleeve lumen from the perigastric cavity was progressively dissected over several sessions and the downstream stricture was pneumatically dilated. The technical and clinical success rates were evaluated. Results: All ten patients were treated successfully. Eight patients had sleeve strictures that were dilated in conjunction with septotomy. A mean of five sessions over the course of 43 days was needed to complete treatment. In two patients with a small perigastric cavity and no stricture, septotomy was achieved with through-the-scope balloon dilation of the fistula. No adverse events were encountered. Conclusions Septotomy accompanied by stricture dilation seems highly effective and safe in late and chronic leaks following sleeve gastrectomy.

Background Biliary strictures (BS) are a common complication of liver transplantation. The standard treatment is sequential insertion of increasing numbers of plastic stents by endoscopic retrograde cholangiopancreatography (ERCP). Despite high success rates, some strictures fail to resolve and require surgery as definitive treatment. Goals To identify predictors of response or failure of standard endoscopic treatment, allowing earlier referral to alternative modalities when needed and avoiding unnecessary procedures. Study Database of Gastroenterology Department at Tel Aviv Medical Center was retrospectively reviewed, and data regarding patients who underwent liver transplantation and developed BS were analyzed. Results Thirty-one patients met the study criteria. Twenty-four (77.4%) resolved with plastic stenting and 7 ultimately required surgery. There were no significant differences between stent responders and nonresponders regarding demographics, transplant and postoperative hospitalization data, time from transplantation to presentation with stricture, total number of ERCP sessions, or maximal number of stents.A trend toward difference was noted in the time elapsed between the first and the second ERCP, whereby ERCP nonresponders required a second procedure sooner than responders. Patients presenting to their second procedure as scheduled ultimately had a 95% endoscopic success rate, whereas those presenting urgently with acute cholangitis had a 55% failure rate (P=0.02). Conclusions Urgent repeat ERCP is a harbinger of ultimate failure of plastic stent treatment for BS after liver transplant. This finding may assist earlier triage of these patients toward alternative treatment such as metal stents or surgery, thus sparing needless procedures and complications.

Cullin RING ligases (CRLs), the most prolific class of ubiquitin ligase enzymes, are multimeric complexes that regulate a wide range of cellular processes. CRL activity is regulated by CAND1 (Cullin-associated Nedd8-dissociated protein 1), an inhibitor that promotes the dissociation of substrate receptor components from the CRL. We demonstrate here that COMMD1 (copper metabolism MURR1 domain-containing 1), a factor previously found to promote ubiquitination of various substrates, regulates CRL activation by antagonizing CAND1 binding. We show that COMMD1 interacts with multiple Cullins, that the COMMD1-Cul2 complex cannot bind CAND1, and that, conversely, COMMD1 can actively displace CAND1 from CRLs. These findings highlight a novel mechanism of CRL activation and suggest that CRL regulation may underlie the pleiotropic activities of COMMD1.

Introduction Tumor-associated eosinophilia has been first described more than 120 years ago, and is frequently observed in many types of cancer. Yet, fundamental knowledge is missing regarding the roles of tumor-associated eosinophils. Since gastrointestinal (GI) tract is the largest eosinophil reservoir in the body and a main organ for eosinophil-mediated diseases, we focused our studies on colorectal cancer (CRC) as a model system to define the roles of eosinophils in the tumour microenvironment (TME). Material and methods Eosinophil infiltration and function were studied in two independent models of colorectal cancer (CRC), representing the genetically driven and inflammation-driven CRC models (i.e. Apcmin/+ model and AOM+DSS treatment, respectively). Results and discussions We report that eosinophils are an integral part of the TME in CRC. Eosinophils are actively and specifically recruited to the TME in both models, where they undergo degranulation. Moreover, we show that a single intravenous injection of eosinophils into eosinophil deficient mice (ΔdblGATA mice) undergoing colitis-associated colorectal cancer (CAC) or ΔdblGATA/Apcmin/+ mice resulted in substantial recruitment of eosinophils to the TME, which fosters prolonged eosinophils survival likely via secretion of GM-CSF, IL-3 and IL-5. Eosinophil-deficient ΔdblGATA mice undergoing CAC displayed significantly decreased survival, which was associated with increased tumour number and size. Similarly, generation of ΔdblGATA/Apcmin/+ mice revealed significantly decreased survival, which was associated with increased tumour burden, thereby suggesting an anti-tumorigenic role for eosinophils. Importantly, the anti-tumorigenic effects of eosinophils were independent of changes in CD8+ T cells or MDSCs and were accompanied with a specific decrease in anti-active caspase 3+ cells. No changes were observed in the numbers of Ki-67+ or CD31+ cells. Thus, supporting eosinophil-mediated cytotoxicity in-vivo. Indeed, eosinophils were capable of killing CRC cell lines in vitro. Conclusion Our data establish key anti-tumorigenic roles for eosinophils in CRC. These findings may facilitate the development of new pharmacological treatments unleashing robust anti-tumour responses by eosinophils and will hopefully lead to the development of innovative eosinophil-oriented ‘checkpoint inhibitors’.

Thrombin is a potent stimulant of smooth muscle cell (SMC) proliferation in inflammatory conditions, leading to pathological thickening of vascular walls in atherosclerosis and airway remodeling in asthma. Cell proliferation requires the formation and remodeling of cell membrane phospholipids (PLs), involving the activation of PL-metabolizing enzymes. Yet, the role of specific PL-metabolizing enzymes in SMC proliferation has hardly been studied. To bridge this gap, in the present study, we investigated the role of key enzymes involved in PL metabolism, the PL-hydrolyzing enzyme phospholipase A2 (PLA2) and the PL-synthesizing enzyme lysophosphatidic acid-fatty acid transacylase (LPAAT), in thrombin-induced proliferation of bovine aortic SMCs (BASMCs). Concomitantly with the induction of BASMC proliferation, thrombin activated cytosolic PLA2 (cPLA2-α), expressed by selective release of arachidonic acid and mRNA expression, as well as LPAAT, expressed by nonselective incorporation of fatty acid and mRNA expression. Specific inhibitors of these enzymes, arachidonyl-trifluoromethyl-ketone for cPLA2 and thimerosal for LPAAT, suppressed their activities, concomitantly with suppression of BASMC proliferation, suggesting a mandatory requirement for cPLA2 and LPAAT activation in thrombin-induced SMC proliferation. Thrombin acts through the protease-activated receptor (PAR-1), and, accordingly, we found that thrombin-induced BASMC proliferation was suppressed by the PAR-1 inhibitor SCH-79797. However, the PAR-1 inhibitor did not prevent thrombin-induced mRNA expression of cPLA2 and LPAAT, implying that the activation of cPLA2 and LPAAT is essential but not sufficient for thrombin-induced proliferation of BASMCs.

Background and study aims: The Aer-O-Scope™ Colonoscope System (AOS) combines panoramic 360° view with standard forward view. We assessed the AOS’s ability to identify lesions implanted in live swine, compared to conventional colonoscopy (CC). Patients and methods: Twelve swine colons were surgically ligated and beads sewn within. Five procedures (3 AOS and 2 CC) were performed on each swine and findings reported. Physicians were blinded to number, size, and color of beads. The sequence of procedures and physicians was randomized. Pigs, physicians, and colonoscopes were randomly alternated between examination rooms, maintaining physician blindness. Two independent blinded physicians interpreted procedure videos offline. Results: A total of 259 /273 (94.9 %) of lesions were visualized by AOS compared to 158 /182 with CC (86.8 %) (P = 0.002). Miss rates of lesions ≥ 6 mm were 2.6 % and 10.5 %, respectively (P = 0.022), and 6.9 % and 15.1 %, respectively, for lesions

Background Patients with familial adenomatous polyposis (FAP) are prone to developing duodenal adenoma and cancer. Optimal surveillance and management of these adenomas are not well established. Objective We assessed the outcome of FAP patients undergoing intense multimodal surveillance and subsequent endoscopic resection of advanced lesions. Patients Eighty consecutive FAP patients enrolled during 2001 to 2011 from the Familial Cancer Clinic of a tertiary hospital as part of routine surveillance. Design Case series, prospective in years 2006 to 2011 and retrospective in years 2001 to 2006. Setting and Intervention Patients were followed by annual forward-view and/or side-view upper endoscopy. A biopsy sample was obtained from visible lesions and normal papillae. Ampullary adenomas were further assessed by EUS to determine dimensions and resectability. Advanced adenomas (size ≥ 10 mm, villous type, high-grade dysplasia) underwent endoscopic ampullectomy or polypectomy and continued surveillance. Main Outcome Measurements Detection of advanced adenomas by endoscopy and EUS, endoscopic maintenance of duodenum free of advanced adenoma and cancer. Results Patients (38 men and 42 women, mean age 32.68 ± 13.60) were followed 7.2 years and underwent 5.36 diagnostic studies on average. Thirty-eight patients had ampullary adenomas. Advanced adenoma was diagnosed by endoscopy in 10 patients. Importantly, EUS upstaged 9 additional patients to advanced adenoma and downstaged 1, thus altering the treatment course in 36% of patients performing EUS. Endoscopic ampullectomy was performed in 15 patients. Adenoma recurred in 10. Five remained nonadvanced and 5 in advanced stages: 3 were successfully retreated endoscopically and 2 ultimately required surgery for residual adenoma. Advanced nonampullary adenomas were successfully resected endoscopically in 23 patients. No patient had duodenal cancer during the study period. Limitations Limited follow-up period, young age group, uncontrolled study. Conclusions In an intense surveillance program for FAP patients, both endoscopy and EUS were key in accurate selection of advanced adenomas for endoscopic resection. During a 10-year period, only 2 patients required elective surgery and no cancer was observed.

BACKGROUND & AIMS: Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-kappa B activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. METHODS: We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-kappa B. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. RESULTS: In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. CONCLUSIONS: Expression of COMMD1 by myeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

The subcranial approach has emerged as a safe and effective procedure for resection of tumors of the anterior skull base. This approach allows excellent exposure of the nasal cavities, the paranasal sinuses, and the orbit 1 I also enables a wide approach to the anterior cranial fossa, while applying minimal retraction of the frontal lobes. Complications of this procedure are acceptable and comparable to the classical transfacial transcranial approac 2

Background and Aims The self-propelled disposable colonoscope (SPDC) with a 360° view is designed to enhance visualization, minimize risks of perforation and infection transmission, and shorten operator training time associated with conventional colonoscopy (CC). We evaluated SPDC efficacy for cecal intubation and safety. Methods Prospective patients presenting for colorectal cancer screening underwent SPDC immediately followed by CC. Initial patients necessary for SPDC operators to achieve proficiency comprised the training cohort. Subsequent enrolled patients comprised the study cohort. SPDC colonoscopy was performed up to the cecum, where anatomic landmarks were photographed and mucosal suction marks were placed. During SPDC withdrawal, polyps were recorded and similarly marked. On the second pass (by using CC), any potential mucosal damage and suction marks from the SPDC as well as polyps were recorded. Main endpoints included SPDC cecal intubation rates, confirmed by anatomic landmarks and residual marks seen on subsequent CC, and frequency and severity of adverse events and mucosal damage with SPDC. The secondary endpoint was subjective procedure proficiency, evaluated by the operator based on the training cohort. The tertiary endpoint was documenting pathologies visualized with SPDC. Results Fifty-six of 58 enrolled subjects completed the study. Proficiency with SPDC was attained after 8 to 10 procedures. Cecal intubation was successful in 98.2% (55/56 subjects; 95% confidence interval [CI], 90.4%-99.9%), including 100% (95% CI, 90.7%-100%) of the study cohort and 94.4% (95% CI, 72.7%-99.9%) of the training cohort. No mucosal damage or adverse events were reported. SPDC detected 87.5% of polyps seen in tandem CC, including all polyps larger than 5 mm. Conclusions SPDC was highly successful, simple to use, and safe in achieving complete colonoscopy (cecal intubation). (Clinical trial registration number: 0692-12-TLV.)

Hepatotoxicity due to intravenous amiodarone (HIVAD) is a rare side effect with a distinct pattern of enzyme disturbances compared to liver damage from oral amiodarone. Intravenous amiodarone is administered for acute arrhythmias often causing heart failure. The enzyme abnormalities and clinical setting are very similar to that of ischemic hepatitis, a far more common condition.To ascertain if acute HIVAD exists as a separate entity or whether reported cases may be explained by ischemic hepatitisIn this case-control retrospective study the files of hospitalized patients with markedly elevated aminotransferases were reviewed for the diagnoses of HIVAD or ischemic hepatitis. Medline was searched for published cases of HIVAD. Pooled data of all patients with HIVAD were compared to a control group with ischemic hepatitis.There were no significant differences in the clinical characteristics, laboratory results or histological findings between HIVAD and ischemic hepatitis patients.In our opinion, there is currently insufficient data to support the existence of distinct HIVAD, and ischemic hepatitis is a more probable diagnosis in most reported cases. Withdrawing amiodarone because of assumed hepatic damage could deprive patients of a life-saving therapy.

Pericardial effusion from any cause may lead to decreased cardiac output and blood pressure, causing heart failure and reduced renal blood flow. Although pericardial effusion is not uncommon, it is usually not associated with hemodynamic compromise unless the effusion causes cardiac tamponade. Acute renal failure resulting from pericardial effusion is surprisingly rare, with only six cases described to date. We describe the first case known to us of pericardial effusion without tamponade causing acute anuric renal failure. The case was characterized initially by non-specific symptoms and signs; anuria dominated the clinical picture, and was completely reversed after pericardiocentesis.

INTRODUCTIONThe tandem affinity purification (TAP) procedure was pioneered in yeast for the purpose of purifying and characterizing protein complexes. While affinity purification is relatively easy to perform, nonspecific protein interactions can plague the identification of true interacting partners of the given bait utilized in the purification. To alleviate this problem, two sequential affinity purification steps are employed in the TAP procedure. Since its inception in yeast, TAP has gone through many adaptations and has been employed multiple times in diverse organisms, including mammalian systems. In all these approaches, two out of many possible affinity moieties are employed and are usually expressed as a fusion polypeptide in the amino or carboxyl-terminal region of the protein bait. In this protocol, we describe a variation on the TAP procedure in which the affinity moieties are placed on two different proteins of a molecular complex to isolate or detect components present in the complex. This variation, which we refer to as bimolecular affinity purification (BAP), is suited for the identification of specific molecular complexes marked by the presence of two known components.

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, ‎poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by subclinical infiltration of immune cells bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.