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Trikudanathan G.,University of Connecticut | Navaneethan U.,Cleveland Clinic | Vege S.S.,Miles and Shirley Fiterman Center for Digestive Diseases
American Journal of Gastroenterology

Intra-abdominal infections of pancreatic or peripancreatic necrotic tissue complicate the clinical course of severe acute pancreatitis (SAP) and are associated with significant morbidity. Fungal infection of necrotic pancreatic tissue is increasingly being reported. The incidence of intra-abdominal pancreatic fungal infection (PFI) varies from 5% to 68.5%. Candida albicans is the most frequently isolated fungus in patients with necrotizing pancreatitis. Prolonged use of prophylactic antibiotics, prolonged placement of chronic indwelling devices, and minimally invasive or surgical interventions for pancreatic fluid collections further increase the risk of PFI. Computed tomography- or ultrasound-guided fine-needle aspiration of pancreatic necrosis is a safe, reliable method for establishing pancreatic infection. Amphotericin B appears to be the most effective antifungal treatment. Drainage and debridement of infected necrosis are also critical for eradication of fungi from the poorly perfused pancreatic or peripancreatic tissues where the antifungal agents may not reach to achieve therapeutic levels. Fungal infection adversely affects the outcome of patients with SAP and is associated with increased morbidity, although the mortality rate is not increased specifically because of PFI. Although antifungal prophylaxis has been suggested for patients on broad-spectrum antibiotics, no randomized controlled trials have yet studied its efficacy in preventing PFI. © 2011 by the American College of Gastroenterology. Source

Sah R.P.,Miles and Shirley Fiterman Center for Digestive Diseases | Chari S.T.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Immunology Reviews

IgG4-related Systemic Disease (ISD) is a chronic fibro-inflammatory disorder affecting exocrine and several other organs characterized by the presence of IgG4-positive cellular infiltrates in affected organs and elevated serum IgG4 levels. Autoimmune Pancreatitis (AIP) is the pancreatic manifestation of ISD. Responsiveness to steroid is a characteristic feature ISD and consistently leads to improvement of most lesions including AIP, at least in the short term. However, relapse is common in ISD though there is lack of agreement among different studies on the rates of relapse and factors predicting relapse, with estimates from 25% to upto 50%. Proximal bile duct involvement appears to be predictive of relapse in several studies. Corticosteroids are effective in treating relapses as well and long term maintenance therapy may be necessary in patients who relapse. The role of maintenance of corticosteroid therapy for primary prevention of relapses and utility of immunosuppressive drugs like azathioprine in refractory cases remain to be studied in controlled studies, though there is some experience with successful use of immunosuppressive drugs in refractory cases with frequent relapses. In light of several reports of malignancies, long term follow-up of patients is recommended. Long term survival is currently unknown in ISD due to short-term follow-up and preponderance in older population, and as more follow-up data become available, it will be clear if the consequence of ISD and AIP decreases patient survival. © 2011 Bentham Science Publishers Ltd. Source

Sah R.P.,Fiterman Center for Digestive Diseases | Chari S.T.,Fiterman Center for Digestive Diseases | Chari S.T.,Miles and Shirley Fiterman Center for Digestive Diseases
Current Gastroenterology Reports

Autoimmune Pancreatitis (AIP) is a recently recognized chronic fibro-inflammatory disease of the pancreas. Although rare, its recognition continues to increase worldwide. Patients often present with painless obstructive jaundice mimicking pancreatic cancer. Two subtypes of AIP are known-type 1 is a multi-organ disease associated with IgG4; type 2 appears to be a pancreas-specific disorder. Dramatic response to steroid treatment is characteristic of both forms. A non-invasive diagnosis of type 1 AIP may be possible using diagnostic criteria (in ~70% cases) while diagnosis of type 2 requires histology. These subtypes differ in natural history- type 1 often relapses while initial reports suggest that type 2 does not. Long term complications include endocrine and exocrine insufficiency and in case of type 1, disease relapses and complications from extra-pancreatic involvement. Neither form affects long term survival. The treatment and follow-up guidelines continue to evolve with our increasing experience in AIP. © Springer Science+Business Media, LLC 2012. Source

O'Hara S.P.,Miles and Shirley Fiterman Center for Digestive Diseases | Splinter P.L.,Miles and Shirley Fiterman Center for Digestive Diseases | Gajdos G.B.,Miles and Shirley Fiterman Center for Digestive Diseases | Trussoni C.E.,Miles and Shirley Fiterman Center for Digestive Diseases | And 4 more authors.
Journal of Biological Chemistry

MicroRNAs, central players of numerous cellular processes, regulate mRNA stability or translational efficiency. Although these molecular events are established, the mechanisms regulating microRNA function and expression remain largely unknown. The microRNA let-7i regulates Toll-like receptor 4 expression. Here, we identify a novel transcriptional mechanism induced by the protozoan parasite Cryptosporidium parvum and Gram(-) bacteria-derived lipopolysaccharide (LPS) mediating let-7i promoter silencing in human biliary epithelial cells (cholangiocytes). Using cultured cholangiocytes, we show that microbial stimulus decreased let-7i expression, and promoter activity. Analysis of the mechanism revealed that microbial infection promotes the formation of a NFκB p50-C/EBPβ silencer complex in the regulatory sequence. Chromatin immunoprecipitation assays (ChIP) demonstrated that the repressor complex binds to the let-7i promoter following microbial stimulus and promotes histone-H3 deacetylation. Our results provide a novel mechanism of transcriptional regulation of cholangiocyte let-7i expression following microbial insult, a process with potential implications for epithelial innate immune responses in general. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Peyrin-Biroulet L.,Miles and Shirley Fiterman Center for Digestive Diseases | Loftus E.V.,Miles and Shirley Fiterman Center for Digestive Diseases | Colombel J.-F.,Lille University Hospital Center | Sandborn W.J.,Miles and Shirley Fiterman Center for Digestive Diseases
American Journal of Gastroenterology

Objectives: Natural history studies provide invaluable data on the disease course. First, they help define the end points for clinical trials that are designed to test drugs for the end point of disease modification in chronic disabling diseases. Natural history studies can also help to identify subsets of patients in whom the disease prognosis can be stratified according to clinical features. This comprehensive review summarizes our current knowledge of the natural history of Crohn's disease in adults as reported in population-based studies that include long-term follow-up results. Methods: We conducted a literature search of English and non-English language publications listed in the electronic databases of MEDLINE (source PUBMED, 1935 to December 2008). Results: One-third of the patients had ileitis, colitis, or ileocolitis at the time of diagnosis. Disease location remained broadly stable over time. Up to one-third of the patients had evidence of a stricturing or penetrating intestinal complication at diagnosis, and half of all patients had experienced an intestinal complication within 20 years after diagnosis. Ten percent of the patients had prolonged clinical remission. Steroid dependency occurred in one-third of the patients, and surgery was required in one-third after initiation of steroid therapy. The annual incidence of hospitalizations was 20%. Half of the patients required surgery within 10 years after diagnosis. The risk of postoperative recurrence was 44-55% after 10 years. Conclusions: Crohn's disease is a disabling condition over time. The impact of changing treatment paradigms with increased use of immunosuppressants and biological agents on its natural history is poorly known. © 2010 by the American College of Gastroenterology. Source

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