Small duct primary sclerosing cholangitis: A discrete variant or a bridge to large duct disease, a practical review.

The natural history, associations with inflammatory bowel disease (IBD), and long-term outcomes of large duct primary sclerosing cholangitis (ldPSC) have been well documented. Small duct primary sclerosing cholangitis (sdPSC) is a much less common and relatively more benign variant. The natural history of sdPSC has been difficult to characterize given the limited number of studies in the literature especially with regards to the subset of patients who progress to large duct involvement. It has been unclear whether sdPSC represented a subset of ldPSC, an earlier staging of ldPSC, or a completely separate and distinct entity of its own. Strong associations between sdPSC and IBD have been established with suspicion that concurrent sdPSC-IBD may be a key prognostic factor in determining which patients are at risk of progression to ldPSC. Little is known regarding the discrete circumstances that predisposes some patients with sdPSC to progress to ldPSC. It has been suspected that progression to large biliary duct involvement subjects this subset of patients to potentially developing life-threatening complications. Here the authors conducted a thorough review of the published sdPSC literature using Pubmed searches and cross-referencing to compile all accessible studies regarding cohorts of sdPSC patients in order better characterize the subset of sdPSC patients who progress to ldPSC and the associated outcomes.

Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart.

Ulcerative colitis and Crohn's disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1ß as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1ß neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1ß→miR-155→BDNF signaling axis.

Restarting elective endoscopy safely amidst an evolving pandemic and the impact of patient perception.

BACKGROUND: The COVID-19 pandemic has led to disruptions in elective and outpatient procedures. Guidance from the Centers for Medicare and Medicaid Services provided a framework for gradual reopening of outpatient clinical operations. As the infrastructure to restart endoscopy has been more clearly described, patient concerns regarding viral transmission during the procedure have been identified. Moreover, the efficacy of the measures in preventing transmission have not been clearly delineated. METHODS: We identified patients with pandemic-related procedure cancellations from 3/16/2020 to 4/20/2020. Patients were stratified into tier groups (1-4) by urgency. Procedures were performed using our hospital risk mitigation strategies to minimize transmission risk. Patients who subsequently developed symptoms or tested for COVID-19 were recorded. RESULTS: Among patients requiring emergent procedures, 57.14% could be scheduled at their originally intended interval. COVID-19 concerns represented the most common rescheduling barrier. No patients who underwent post-procedure testing were positive for COVID-19. No cases of endoscopy staff transmission were identified. CONCLUSIONS: Non-COVID-19 related patient care during the pandemic is a challenging process that evolved with the spread of infection, requiring dynamic monitoring and protocol optimization. We describe our successful model for reopening endoscopy suites using a tier-based system for safe reintroduction of elective procedures while minimizing transmission to patients and staff. Important barriers included financial and transmission concerns that need to be addressed to enable the return to pre-pandemic utilization of elective endoscopic procedures.

Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood.

Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

Trends in same-admission cholecystectomy and endoscopic retrograde cholangiopancreatography for acute gallstone pancreatitis: A nationwide analysis across a decade.

BACKGROUND/OBJECTIVES: Gallstones are the leading cause of acute pancreatitis in developed countries. National and international guidelines recommend that a cholecystectomy should be performed during the index hospitalization for acute gallstone pancreatitis. We aimed to delineate the national trends for same-admission cholecystectomy and ERCP for acute gallstone pancreatitis over the last ten years. METHODS: We used the 2004, 2009 and 2014 National Inpatient Sample database including patients with a principal diagnosis of acute pancreatitis and a secondary diagnosis of choledocholithiasis or cholelithiasis. Exclusion criteria were age <18 years and elective admission. Primary outcome was the trend in incidence rate of same admission cholecystectomy from 2004 to 2014. The secondary outcomes were: 10-year trend in 1) Incidence of gallstone pancreatitis, 2) proportion of gallstone pancreatitis compared to all other etiologies of acute pancreatitis, 3) incidence rate of same-admission ERCP, 4) length of hospital stay, and 5) total hospitalization costs and charges. RESULTS: The proportion of admissions during which a same-admission cholecystectomy was performed decreased from 48.7% in 2004 to 46.9% in 2009 to 45% in 2014 (trend p < 0.01). During the same time interval, the percentage of admissions during which an ERCP was performed decreased from 25.1% to 18.7% (Trend p < 0.01). CONCLUSIONS: Adherence to the guidelines for same-admission cholecystectomy for patients admitted with acute gallstone pancreatitis have been declining over the past decade. On the other hand, decline in rate of ERCP in patients with acute gallstone pancreatitis and no signs of cholangitis demonstrates adherence to guidelines in this regard.

Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life.

BACKGROUND & AIMS: Early life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1ß. METHODS: We developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid. RESULTS: Aggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1ß and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a ß-blocker, markedly ameliorated the inflammatory response and IL1ß overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1ß than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a ß2-agonist, induced a greater IL1ß expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1ß activation in human THP-1-derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol. CONCLUSIONS: NI sensitizes the colon epithelium for exacerbated IL1ß activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that ß blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.