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Zachary Sellers, MD, PhD

  • Zachary Michael Sellers

Especialidades médicas y/o especialidades quirúrgicas

Gastroenterology

Trabajo y educación

Educación

University of Illinois College of Medicine Urbana-Champaign, Urbana, IL, 06/1/2012

Últimos años de residencia

Stanford University Pediatric Residency, Palo Alto, CA, 6/30/2015

Subespecialidad

Stanford University Pediatric Gastroenterology, Palo Alto, CA, 6/30/2018

Todo Publicaciones

Clinical use of shear-wave elastography for detecting liver fibrosis in children and adolescents with cystic fibrosis. Pediatric radiology Levitte, S. n., Lee, L. W., Isaacson, J. n., Zucker, E. J., Milla, C. n., Barth, R. A., Sellers, Z. M. 2021

Abstract

Complications from liver cirrhosis are a leading cause of death in children with cystic fibrosis. Identifying children at risk for developing liver cirrhosis and halting its progression are critical to reducing liver-associated mortality.Quantitative US imaging, such as shear-wave elastography (SWE), might improve the detection of liver fibrosis in children with cystic fibrosis (CF) over gray-scale US alone. We incorporated SWE in our pediatric CF liver disease screening program and evaluated its performance using magnetic resonance (MR) elastography.Ninety-four children and adolescents with CF underwent 178 SWE exams, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and platelet measurements. Of these, 27 children underwent 34 MR elastography exams. We evaluated SWE performance using 6-MHz and 9-MHZ point SWE, and 9-MHz two-dimensional (2-D) SWE.The 6-MHz point SWE was the only method that correlated with MR elastography (r=0.52; 95% confidence interval [CI] 0.20-0.74; P=0.003). SWE of 1.45m/s distinguished normal from abnormal MR elastography (79% sensitivity, 100% specificity, 100% positive predictive value [PPV], 55% negative predictive value [NPV], area under the receiver operating characteristic [AUROC] curve 0.94). SWE of 1.84m/s separated mild-moderate (3.00-4.77kPa) from severe (>4.77kPa) MR elastography (88% sensitivity, 86% specificity, 78% PPV, 93% NPV, AUROC 0.79). Elevations of AST, ALT, GGT and thrombocytopenia were associated with higher SWE. AST-to-platelet ratio index of 0.42, fibrosis-4 of 0.29, and GGT-to-platelet ratio of 1.43 all had >95% NPV for SWE >1.84m/s.Given its correlation with MR elastography, SWE might be a clinically useful predictor of liver fibrosis. We identified imaging criteria delineating the use of SWE to identify increased liver stiffness in children with CF. With multicenter validation, these data might be used to improve the detection and monitoring of liver fibrosis in children with CF.

View details for DOI 10.1007/s00247-021-05015-w

View details for PubMedID 33759025

Targeted replacement of full-length CFTR in human airway stem cells by CRISPR/Cas9 for pan-mutation correction in the endogenous locus. Molecular therapy : the journal of the American Society of Gene Therapy Vaidyanathan, S. n., Baik, R. n., Chen, L. n., Bravo, D. T., Suarez, C. J., Abazari, S. M., Salahudeen, A. A., Dudek, A. M., Teran, C. A., Davis, T. H., Lee, C. M., Bao, G. n., Randell, S. H., Artandi, S. E., Wine, J. J., Kuo, C. J., Desai, T. J., Nayak, J. V., Sellers, Z. M., Porteus, M. H. 2021

Abstract

Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR/Cas9 and two adeno-associated viruses (AAV) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial basal stem cells (HBECs). The modified cells were enriched to obtain 60-80% tCD19+ UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies.

View details for DOI 10.1016/j.ymthe.2021.03.023

View details for PubMedID 33794364

Pancreatic complications in children with cystic fibrosis. Current opinion in pediatrics Sellers, Z. M. 2020

Abstract

PURPOSE OF REVIEW: The pancreas is highly affected in cystic fibrosis, with complications occurring early in childhood. This review highlights recent research in exocrine pancreatic function in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and discusses how these are affecting pancreatitis and exocrine pancreatic insufficiency (EPI) in children. Additionally, new research into exocrine--endocrine interactions sheds light on how CFTR dysfunction in ductal cells may affect beta cells.RECENT FINDINGS: Ivacaftor has disproved the hypothesis that EPI in children with cystic fibrosis is irreversible. Improvements in pancreatic function have increased pancreatitis episodes in some children and reduced them in others. Imaging advances are providing complementary methods for exocrine pancreatic function testing. New research into the interplay between the exocrine and endocrine components of the pancreas are elucidating the intertwined and complex relationship between the exocrine and endocrine pancreas.SUMMARY: Pancreatic complications contribute to the morbidity and mortality of children with cystic fibrosis. Increasing use of highly effective CFTR modulators will not only abrogate these but will also advance our understanding of pancreatic pathophysiology in cystic fibrosis. New frontiers into pancreatic gene therapy and exocrine--endocrine research will help provide new therapeutic opportunities for pancreatitis, EPI, and diabetes in cystic fibrosis.

View details for DOI 10.1097/MOP.0000000000000934

View details for PubMedID 32773577

Barrier to using APRI and GPR as identifiers of cystic fibrosis liver disease. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society Sellers, Z. M. 2020

Abstract

Cystic fibrosis-associated liver disease (CFLD) is the third most common cause of death in cystic fibrosis (CF). Poor ability to identify early, non-cirrhotic liver disease hampers interventions to mitigate complications associated with CFLD and potential early therapies that may halt the progression of cirrhosis. Liver fibrosis indices, such as APRI, FIB-4, and GPR, are minimally invasive biomarkers that may be useful for the detection and monitoring of CFLD. However, variability in the upper limit of normal values used in these calculations makes it difficult to compare results across research studies and identify appropriate indices cutoffs. Previously published APRI and GPR values are re-calculated using the same upper limit of normal values as recently published data on APRI and GPR, highlighting the importance of standardized upper limit of normal values for calculating liver fibrosis indices in CFLD detection and monitoring.

View details for DOI 10.1016/j.jcf.2020.07.018

View details for PubMedID 32747194

Patient Passport for Pediatric Acute Recurrent and Chronic Pancreatitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Sellers, Z. M., Piester, T., Mark, J., Khalaf, R., Abu-El-Haija, M., Husain, S. Z. 2020; 71 (1): E51E53
Endoscopic Pancreatic Function Testing (ePFT) in Children: A Position Paper From the Naspghan Pancreas Committee. Journal of pediatric gastroenterology and nutrition Patel, N. n., Sellers, Z. M., Grover, A. n., Liu, Q. Y., Maqbool, A. n., Morinville, V. D., Abu-El-Haija, M. n., Husain, S. Z. 2020

Abstract

Endoscopic pancreatic function testing is one of the few ways to directly diagnose exocrine pancreatic insufficiency, and considerable confusion regarding indications, utility and interpretation of the test remains. This position paper of the Pancreas Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) reviews the history and indications for endoscopic pancreatic function testing (ePFT) in children. We compare various methods in current practice and determine their strengths and limitations, and based on data from children and adults we provide guidance on a protocol on how to perform ePFT in children. Lastly, we pose areas in need of further research relating to ePFT in children.

View details for DOI 10.1097/MPG.0000000000002931

View details for PubMedID 32910088

Web-based cognitive-behavioral intervention for pain in pediatric acute recurrent and chronic pancreatitis: Protocol of a multicenter randomized controlled trial from the study of chronic pancreatitis, diabetes and pancreatic cancer (CPDPC). Contemporary clinical trials Palermo, T. M., Murray, C., Aalfs, H., Abu-El-Haija, M., Barth, B., Bellin, M. D., Ellery, K., Fishman, D. S., Gariepy, C. E., Giefer, M. J., Goday, P., Gonska, T., Heyman, M. B., Husain, S. Z., Lin, T. K., Liu, Q. Y., Mascarenhas, M. R., Maqbool, A., McFerron, B., Morinville, V. D., Nathan, J. D., Ooi, C. Y., Perito, E. R., Pohl, J. F., Schwarzenberg, S. J., Sellers, Z. M., Serrano, J., Shah, U., Troendle, D., Zheng, Y., Yuan, Y., Lowe, M., Uc, A., Consortium for the Study of Chronic Pancreatitis, D. a. 2019: 105898

Abstract

INTRODUCTION: Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response.METHODS: This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10-18) with ARP/CP and their parents from twenty-one INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N=130) or to a web-based pain education program (WebED; N=130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization.CONCLUSIONS: This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431.

View details for DOI 10.1016/j.cct.2019.105898

View details for PubMedID 31756383

A Unified Treatment Algorithm and Admission Order Set for Pediatric Acute Pancreatitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Sellers, Z. M., Dike, C., Zhang, K., Giefer, M. J., Uc, A., Abu-El-Haija, M. 2019; 68 (6): E109E111
A multi-disciplinary approach to pre and post-transplant management of cystic fibrosis associated liver disease. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Freeman, A. J., Sellers, Z. M., Mazariegos, G., Kelly, A., Saiman, L., Mallory, G., Ling, S. C., Narkewicz, M. R., Leung, D. H. 2019

Abstract

Approximately 5 to 10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the 3rd leading cause of death among patients with CF. CF liver disease (CFLD) represents the most significant risk to patient mortality second only to pulmonary or lung transplant complications in patients with CF. Currently there is no medical therapy to treat or reverse CFLD. Liver transplantation in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT, as well as disease specific transplant considerations are notably absent. The goal of this comprehensive and multi-disciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face. This article is protected by copyright. All rights reserved.

View details for PubMedID 30697907

High-Efficiency, Selection-free Gene Repair in Airway Stem Cells from Cystic Fibrosis Patients Rescues CFTR Function in Differentiated Epithelia. Cell stem cell Vaidyanathan, S. n., Salahudeen, A. A., Sellers, Z. M., Bravo, D. T., Choi, S. S., Batish, A. n., Le, W. n., Baik, R. n., de la O, S. n., Kaushik, M. P., Galper, N. n., Lee, C. M., Teran, C. A., Yoo, J. H., Bao, G. n., Chang, E. H., Patel, Z. M., Hwang, P. H., Wine, J. J., Milla, C. E., Desai, T. J., Nayak, J. V., Kuo, C. J., Porteus, M. H. 2019

Abstract

Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mortality in CF patients is mostly due to respiratory sequelae. Challenges with gene delivery have limited attempts to treat CF using invivo gene therapy, and low correction levels have hindered exvivo gene therapy efforts. We have used Cas9 and adeno-associated virus 6 to correct the F508 mutation in readily accessible upper-airway basal stem cells (UABCs) obtained from CF patients. On average, we achieved 30%-50% allelic correction in UABCs and bronchial epithelial cells (HBECs) from 10 CF patients andobserved 20%-50% CFTR function relative to non-CF controls in differentiated epithelia. Furthermore, we successfully embedded the corrected UABCs on an FDA-approved porcine small intestinal submucosal membrane (pSIS), and they retained differentiation capacity. This study supports further development of genetically corrected autologous airway stem cell transplant as a treatment for CF.

View details for DOI 10.1016/j.stem.2019.11.002

View details for PubMedID 31839569

New Algorithm for the Integration of Ultrasound Into Cystic Fibrosis Liver Disease Screening. Journal of pediatric gastroenterology and nutrition Sellers, Z. M., Lee, L. W., Barth, R. A., Milla, C. n. 2019; 69 (4): 40410

Abstract

Liver nodularity occurs across the spectrum of cystic fibrosis liver disease (CFLD), from regenerative nodules to cirrhosis, and can occur without liver enzyme abnormalities. Our aims were to determine if incorporating abdominal ultrasound (US) with annual laboratory testing improves the detection of CFLD and establish CF-specific thresholds for liver screening labs.CF patients at least 6 years old who were exocrine pancreatic-insufficient had an US with Doppler and shear wave elastography. Patients were divided into Normal, Echogenic, or Nodular groups, based on US findings. Results were compared with aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, AST to platelet ratio index (APRI), Fibrosis 4 (FIB-4), and gamma-glutamyl transferase (GGT) to platelet ratio (GPR). Receiver operator curve, sensitivity, specificity, positive predictive value, negative predictive value, and optimal cut-off with Youden Index were calculated.From 82 patients, incorporation of US identified more nodular livers than using labs alone. The Nodular group had significantly greater median AST (44), ALT (48), GGT (46), APRI (0.619), FIB-4 (0.286), GPR (1.431). Optimal cut-offs to detect liver nodularity in CF were AST >33, ALT >45, GGT >21, Platelets <230, APRI >0.367, FIB-4 >0.222, GPR >0.682. Using GGT, APRI, and GPR, we generated an algorithm to direct the use of US in CFLD screening.Using modified serum lab thresholds, addition of liver fibrosis indices, and/or abdominal US can increase detection of liver nodularity in CF. A combination of GGT, GPR, and APRI can help direct which CF children should undergo US evaluation. These tools may improve earlier identification of fibrosis and/or cirrhosis in CF patients.

View details for DOI 10.1097/MPG.0000000000002412

View details for PubMedID 31181020

Reply to "The National Trends in Acute and Chronic Pancreatitis Needs to be Improved," (Manuscript GASTRO-D-18-00901). Gastroenterology Sellers, Z. M. 2018

View details for PubMedID 30472228

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas Fisher, W. E., Cruz-Monserrate, Z., McElhany, A. L., Lesinski, G. B., Hart, P. A., Ghosh, R., Van Buren, G., Fishman, D. S., Rinaudo, J. A., Serrano, J., Srivastava, S., Mace, T., Topazian, M., Feng, Z., Yadav, D., Pandol, S. J., Hughes, S. J., Liu, R. Y., Lu, E., Orr, R., Whitcomb, D. C., Abouhamze, A. S., Steen, H., Sellers, Z. M., Troendle, D. M., Uc, A., Lowe, M. E., Conwell, D. L., Consortium for the Study of Chronic Pancreatitis, D. 2018; 47 (10): 121321

Abstract

High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

View details for PubMedID 30325860

INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study: Design and Rationale for INSPPIRE 2 From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas Uc, A., Perito, E. R., Pohl, J. F., Shah, U., Abu-El-Haija, M., Barth, B., Bellin, M. D., Ellery, K. M., Fishman, D. S., Gariepy, C. E., Giefer, M. J., Gonska, T., Heyman, M. B., Himes, R. W., Husain, S. Z., Maqbool, A., Mascarenhas, M. R., McFerron, B. A., Morinville, V. D., Lin, T. K., Liu, Q. Y., Nathan, J. D., Rhee, S. J., Ooi, C. Y., Sellers, Z. M., Schwarzenberg, S. J., Serrano, J., Troendle, D. M., Werlin, S. L., Wilschanski, M., Zheng, Y., Yuan, Y., Lowe, M. E., Consortium for the Study of Chronic Pancreatitis, D. 2018; 47 (10): 122228

Abstract

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

View details for PubMedID 30325861

Depression and Healthcare Utilization in Patients with Inflammatory Bowel Disease. Journal of Crohn's & colitis Wong, J. J., Sceats, L., Dehghan, M., Wren, A. A., Sellers, Z. M., Limketkai, B. N., Bensen, R., Kin, C., Park, K. T. 2018

Abstract

Background: Depression frequently co-occurs in patients with inflammatory bowel disease (IBD) and is a driver in health care costs and utilization.Aim: This study examined the associations between depression and total health care costs, emergency department (ED) visits, computed tomography (CT) scans during ED/inpatient visits, and IBD-related surgery among IBD patients.Methods: Our sample included 331,772 IBD patients from a national administrative claims database (Truven Health MarketScan Database). Gamma and Poisson regression analyses assessed differences related to depression controlling for key variables.Results: Approximately 16% of the IBD cohort was classified as having depression. Depression was associated with a $17,706 (95% CI [$16,892, 18,521]) increase in mean annual IBD-related health care costs and an increased incidence of ED visits (aIRR of 1.5; 95% CI [1.5, 1.6]). Among patients who had 1 ED/inpatient visits, depression was associated with an increased probability of receiving repeated CT scans (1-4 CT scans aOR of 1.6; 95% CI [1.5, 1.7]; 5 CT scans aOR 4.6; 95% CI [2.9, 7.3]) and increased odds of undergoing an IBD-related surgery (aOR of 1.2; 95% CI [1.1, 1.2]). Secondary analysis with a pediatric subsample revealed approximately 12% of this cohort was classified as having depression, and depression was associated with increased costs and incidence rates of ED visits and CT scans, but not IBD-related surgery.Conclusion: Quantifiable differences in healthcare costs and patterns of utilization exist among patients with IBD and depression. Integration of mental health services within IBD care may improve overall health outcomes and costs of care.

View details for PubMedID 30256923

New Management Guidelines for Both Children and Adults With Acute Pancreatitis. Gastroenterology Sellers, Z. M., Abu-El-Haija, M., Husain, S. Z., Morinville, V. 2018

View details for PubMedID 29890113

Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee. Journal of pediatric gastroenterology and nutrition Abu-El-Haija, M. n., Kumar, S. n., Quiros, J. A., Balakrishnan, K. n., Barth, B. n., Bitton, S. n., Eisses, J. F., Foglio, E. J., Fox, V. n., Francis, D. n., Freeman, A. J., Gonska, T. n., Grover, A. S., Husain, S. Z., Kumar, R. n., Lapsia, S. n., Lin, T. n., Liu, Q. Y., Maqbool, A. n., Sellers, Z. M., Szabo, F. n., Uc, A. n., Werlin, S. L., Morinville, V. D. 2018; 66 (1): 15976

Abstract

Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed.The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation.The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values 3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP.This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP.

View details for PubMedID 29280782

Starting Young: Trends in Opioid Therapy Among US Adolescents and Young Adults With Inflammatory Bowel Disease in the Truven MarketScan Database Between 2007 and 2015. Inflammatory bowel diseases Wren, A. A., Bensen, R. n., Sceats, L. n., Dehghan, M. n., Yu, H. n., Wong, J. J., MacIsaac, D. n., Sellers, Z. M., Kin, C. n., Park, K. T. 2018

Abstract

Opioids are commonly prescribed for relief in inflammatory bowel disease (IBD). Emerging evidence suggests that adolescents and young adults are a vulnerable population at particular risk of becoming chronic opioid users and experiencing adverse effects.This study evaluates trends in the prevalence and persistence of chronic opioid therapy in adolescents and young adults with IBD in the United States.A longitudinal retrospective cohort analysis was conducted with the Truven MarketScan Database from 2007 to 2015. Study subjects were 15-29 years old with 2 IBD diagnoses (Crohn's: 555/K50; ulcerative colitis: 556/K51). Opioid therapy was identified with prescription claims within the Truven therapeutic class 60: opioid agonists. Persistence of opioid use was evaluated by survival analysis for patients who remained in the database for at least 3 years following index chronic opioid therapy use.In a cohort containing 93,668 patients, 18.2% received chronic opioid therapy. The annual prevalence of chronic opioid therapy increased from 9.3% in 2007 to 10.8% in 2015 (P < 0.01), peaking at 12.2% in 2011. Opioid prescriptions per patient per year were stable (approximately 5). Post hoc Poisson regression analyses demonstrated that the number of opioid pills dispensed per year increased with age and was higher among males. Among the 2503 patients receiving chronic opioid therapy and followed longitudinally, 30.5% were maintained on chronic opioid therapy for 2 years, and 5.3% for all 4 years.Sustained chronic opioid use in adolescents and young adults with IBD is increasingly common, underscoring the need for screening and intervention for this vulnerable population.

View details for PubMedID 29986015

Nationwide Trends in Acute and Chronic Pancreatitis Among Privately Insured Children and Non-Elderly Adults in the United States, 2007-2014. Gastroenterology Sellers, Z. M., MacIsaac, D. n., Yu, H. n., Dehghan, M. n., Zhang, K. Y., Bensen, R. n., Wong, J. J., Kin, C. n., Park, K. T. 2018

Abstract

Epidemiologic analyses of acute and chronic pancreatitis (AP and CP) provide insight into causes and strategies for prevention, and affect allocation of resources to its study and treatment. We sought to determine current and accurate incidences of AP and CP, along with the prevalence of CP, in children and adults in the United States.We collected data from the Truven MarketScan Research Databases of commercial inpatient and outpatient insurance claims in the United States from 2007 through 2014 (patients 0-64 years old). We calculated the incidences of AP and CP, and prevalence of CP, based on International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Children were defined as 18 years or younger and adults as 19 to 64 years old.The incidence of pediatric AP was stable from 2007 through 2014, remaining at 12.3/100,000 persons in 2014. Meanwhile the incidence for adult AP decreased from 123.7/100,000 persons in 2007 to 111.2/100,000 persons in 2014. The incidence of CP decreased over time in children (2.2/100,000 persons in 2007 to 1.9/100,000 persons in 2014) and adults (31.7/100,000 persons in 2007 to 24.7/100,000 persons in 2014). The prevalence of pediatric and adult CP was 5.8/100,000 persons and 91.9/100,000 persons, respectively in 2014. Incidences of AP and CP increased with age; we found little change in incidence during the first decade of life, but linear increases starting in the second decade.We performed a comprehensive epidemiologic analysis of privately insured non-elderly adults and children with AP and CP in the United States. Changes in gallstone formation, smoking, and alcohol consumption, along with advances in pancreatitis management, may be responsible for the stabilization and even decrease in the incidences of AP and CP.

View details for PubMedID 29660323

Plasmapheresis for Hypertriglyceridemia-Induced Acute Pancreatitis in a Child A Case Report and Brief Review of the Literature PANCREAS Zhang, K., Cox, K. L., Sellers, Z. M. 2017; 46 (7): E58E59

View details for PubMedID 28697142

Feeling the Impact of Long-Term Total Parenteral Nutrition. Digestive diseases and sciences Sellers, Z. M., Thorson, C., Co, S., Schaberg, K. B., Kerner, J. A. 2017

View details for DOI 10.1007/s10620-017-4588-9

View details for PubMedID 28455563

Technological advances shed light on left ventricular cardiac disturbances in cystic fibrosis. Journal of cystic fibrosis Sayyid, Z. N., Sellers, Z. M. 2017

Abstract

Cystic fibrosis (CF), the most common autosomal recessive lethal disease in Caucasians, causes chronic pulmonary disease and can lead to cor pulmonale with right ventricular dysfunction. The presence of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiac myocardia has prompted debate regarding possible defective ion channel-induced cardiomyopathy. Clinical heart disease in CF is considered rare and is restricted to case reports. It has been unclear if this is due to the lack of physiological importance of CFTR in the heart, the relatively short lifespan of those with CF, or a technical inability to detect subclinical disease. Extensive echocardiographic investigations have yielded contradictory results, leading to the dogma that left ventricular defects in CF occur secondary to lung disease. In this review, we consider why studies examining heart function in CF have not provided clarity on this topic. We then focus on data from new echocardiographic and magnetic resonance imaging technology, which are providing greater insight into cardiac function in CF and demonstrating that, in addition to secondary effects from pulmonary disease, there may be an intrinsic primary defect in the CF heart. With advancing lifespans and activity levels, understanding the risk of cardiac disease is vital to minimizing morbidity in adults with CF.

View details for DOI 10.1016/j.jcf.2017.02.013

View details for PubMedID 28314540

Market share and costs of biologic therapies for inflammatory bowel disease in the USA. Alimentary pharmacology & therapeutics Yu, H. n., MacIsaac, D. n., Wong, J. J., Sellers, Z. M., Wren, A. A., Bensen, R. n., Kin, C. n., Park, K. T. 2017

Abstract

Real-world data quantifying the costs of increasing use of biologics in inflammatory bowel disease (IBD) are unknown.To determine the outpatient IBD drug utilization trends, relative market share, and costs in the USA during a 9-year period.The Truven MarketScan Database was analysed for patients with Crohn's disease (CD) and ulcerative colitis (UC) during 2007-2015. National drug codes were used to identify prescription drugs; Healthcare Common Procedure Coding System J-codes were used to capture biologic out-patient infusions. Proportion of drug usage, relative market share and per-member per-year (PMPY) costs were analysed for biologics, immunomodulators, 5-ASAs and corticosteroids.In 415405 patients (188842 CD; 195183 UC; 31380 indeterminate colitis; 54.67% female), utilization trends show a consistent rise in the market share of biologics during the 9-year study period. The proportion of patients using biologics increased from 21.8% to 43.8% for CD and 5.1%-16.2% for UC. This contrasts a small decrease in immunomodulator and 5-ASA use for CD and relative constancy of other classes including corticosteroids-only use as primary IBD medication from 2007 to 2015. The average biologic-taking patient accounted for $25275 PMPY in 2007 and $36051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23616 PMPY in 2007 and $41109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics).The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients.

View details for PubMedID 29164650

Impaired PGE2-stimulated Cl- and HCO3- secretion contributes to cystic fibrosis airway disease. PloS one Sellers, Z. M., Illek, B. n., Figueira, M. F., Hari, G. n., Joo, N. S., Sibley, E. n., Souza-Menezes, J. n., Morales, M. M., Fischer, H. n., Wine, J. J. 2017; 12 (12): e0189894

Abstract

Airway mucociliary clearance (MCC) is an important defense mechanism against pulmonary infections and is compromised in cystic fibrosis (CF). Cl- and HCO3- epithelial transport are integral to MCC. During pulmonary infections prostaglandin E2 (PGE2) production is abundant.To determine the effect of PGE2 on airway Cl- and HCO3- secretion and MCC in normal and CF airways.We examined PGE2 stimulated MCC, Cl- and HCO3- secretion using ferret trachea, human bronchial epithelial cell cultures (CFBE41o- with wildtype CFTR (CFBE41 WT) or homozygous F508del CFTR (CFBE41 CF) and human normal bronchial submucosal gland cell line (Calu-3) in Ussing chambers with or without pH-stat.PGE2 stimulated MCC in a dose-dependent manner and was partially impaired by CFTRinh-172. PGE2-stimulated Cl- current in ferret trachea was partially inhibited by CFTRinh-172, with niflumic acid eliminating the residual current. CFBE41 WT cell monolayers produced a robust Cl- and HCO3- secretory response to PGE2, both of which were completely inhibited by CFTRinh-172. CFBE41 CF cells exhibited no response to PGE2. In Calu-3 cells, PGE2 stimulated Cl- and HCO3- secretion. Cl- secretion was partially inhibited by CFTRinh-172, with additional inhibition by niflumic acid. HCO3- secretion was completely inhibited by CFTRinh-172.PGE2 stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE2-stimulated Cl- and HCO3- conductance is impaired and may contribute to decreased MCC. There remains a CFTR-independent Cl- current in submucosal glands, which if exploited, could represent a means of improving airway Cl- secretion and MCC in CF.

View details for PubMedID 29281691

View details for PubMedCentralID PMC5744969

Strain rate echocardiography uncovers subclinical left ventricular dysfunction in cystic fibrosis. Journal of cystic fibrosis Sellers, Z. M., McGlocklin, L., Brasch, A. 2015; 14 (5): 654-660

Abstract

CFTR is expressed in cardiac myocytes. In mice, lack of CFTR alters cardiomyocyte contraction and Ca(2+) signaling, and decreases cardiac reserve. We undertook a pilot study evaluating left ventricular (LV) function in CF patients using strain and strain rate echocardiography.Echocardiography with tissue Doppler and strain and strain rate imaging were performed in 8 CF adults following pulmonary function tests. Results were compared to literature values obtained in healthy subjects.All CF individuals had normal LV ejection fractions. In contrast, 50% of men and 100% of women with CF had decreased LV systolic strain. Strain rates were significantly decreased in 100% of CF individuals. RV function was normal and LV function did not correlate with lung function.Strain and strain rate echocardiography identified LV systolic abnormalities in CF individuals not detected by conventional echocardiography. We propose that this echocardiography modality may identify subclinical cardiac dysfunction in CF.

View details for DOI 10.1016/j.jcf.2015.03.010

View details for PubMedID 25866147

Left ventricular and aortic dysfunction in cystic fibrosis mice. Journal of cystic fibrosis Sellers, Z. M., Kovacs, A., Weinheimer, C. J., Best, P. M. 2013; 12 (5): 517-524

Abstract

Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease.Using gut-corrected F508del CFTR mutant mice (F508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization.F508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (-dP/dt, Tau). Aortas displayed increased stiffness and altered diastolic flow. -adrenergic stimulation revealed diminished cardiac reserve (attenuated +dP/dt,-dP/dt, LV pressure).In a mouse model of CF, CFTR mutation leads to LV remodeling with alteration of cardiac and aortic functions in the absence of lung disease. As CF patients live longer, more active lives, their risk for cardiovascular disease should be considered.

View details for DOI 10.1016/j.jcf.2012.11.012

View details for PubMedID 23269368

MRP4 and CFTR in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes EUROPEAN JOURNAL OF PHARMACOLOGY Sellers, Z. M., Naren, A. P., Xiang, Y., Best, P. M. 2012; 681 (1-3): 80-87

Abstract

Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of -adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR (cystic fibrosis transmembrane conductance regulator). In the current study we investigated the potential role of MRP4 in regulating intracellular cAMP and -adrenergic stimulated contraction rate in cardiac myocytes. Cultured neonatal ventricular myocytes were used for all experiments. In addition to wildtype mice, (1)-, (2)-, and (1)/(2)-adrenoceptor, and CFTR knockout mice were used. MRP4 expression was probed via Western blot, intracellular cAMP was measured by fluorescence resonance energy transfer, while the functional role of MRP4 was assayed via monitoring of isoproterenol-stimulated contraction rate. We found that MRP4 is expressed in mouse neonatal ventricular myocytes. A pharmacological inhibitor of MRP4, MK571, potentiated submaximal isoproterenol-stimulated cAMP accumulation and cardiomyocyte contraction rate via (1)-adrenoceptors. CFTR expression was critical for submaximal isoproterenol-stimulated contraction rate. Interestingly, MRP4-dependent changes in contraction rate were CFTR-dependent, however, PDE4-dependent potentiation of contraction rate was CFTR-independent. We have shown, for the first time, a role for MRP4 in the regulation of cAMP in cardiac myocytes and involvement of CFTR in -adrenergic stimulated contraction. Together with phosphodiesterases, MRP4 must be considered when examining cAMP regulation in cardiac myocytes.

View details for DOI 10.1016/j.ejphar.2012.02.018

View details for Web of Science ID 000301799400012

View details for PubMedID 22381067

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca2+-activated Cl- channel activity to maintain contraction rate JOURNAL OF PHYSIOLOGY-LONDON Sellers, Z. M., De Arcangelis, V., Xiang, Y., Best, P. M. 2010; 588 (13): 2417-2429

Abstract

The physiological role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiomyocytes remains unclear. Using spontaneously beating neonatal ventricular cardiomyocytes from wild-type (WT) or CFTR knockout (KO) mice, we examined the role of CFTR in the modulation of cardiomyocyte contraction rate. Contraction rates of spontaneously beating myocytes were captured by video imaging. Real-time changes in intracellular ([Ca(2+)](i)) and protein kinase A (PKA) activity were measured by fura-2 and fluorescence resonance energy transfer, respectively. Acute inhibition of CFTR in WT cardiomyocytes using the CFTR inhibitor CFTR(inh)-172 transiently inhibited the contraction rate. By contrast, cardiomyocytes from CFTR KO mice displayed normal contraction rates. Further investigation revealed that acute inhibition of CFTR activity in WT cardiomyocytes activated L-type Ca(2+) channels, leading to a transient increase of [Ca(2+)](i) and inhibition of PKA activity. Additionally, we found that contraction rate normalization following acute CFTR inhibition in WT cardiomyocytes or chronic deletion in cardiomyocytes from CFTR KO mice requires the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) and Ca(2+)-activated Cl(-) channels (CaCC) because simultaneous addition of myristoylated-autocamtide-2-related inhibitory peptide or niflumic acid and CFTR(inh)-172 to WT cardiomyocytes or treatment of cardiomyoctes from CFTR KO mice with these agents caused sustained attenuation of contraction rates. Our results demonstrate that regulation of cardiomyocyte contraction involves CFTR. They also reveal that activation of CaMKII and CaCC compensates for loss of CFTR function. Increased dependence on CaMKII upon loss of CFTR function might leave cystic fibrosis patients at increased risk of heart dysfunction and disease.

View details for DOI 10.1113/jphysiol.2010.188334

View details for Web of Science ID 000279406600015

View details for PubMedID 20442264

View details for PubMedCentralID PMC2915517

A critical GxxxA motif in the gamma(6) calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current JOURNAL OF PHYSIOLOGY-LONDON Lin, Z., Witschas, K., Garcia, T., Chen, R., Hansen, J. P., Sellers, Z. M., Kuzmenkina, E., Herzig, S., Best, P. M. 2008; 586 (22): 5349-5366

Abstract

The eight members of the calcium channel gamma subunit family are integral membrane proteins that regulate the expression and behaviour of voltage and ligand gated ion channels. While a subgroup consisting of gamma(2), gamma(3), gamma(4) and gamma(8) (the TARPs) modulate AMPA receptor localization and function, the gamma(1) and gamma(6) subunits conform to the original description of these proteins as regulators of voltage gated calcium channels. We have previously shown that the gamma(6) subunit is highly expressed in atrial myocytes and that it is capable of acting as a negative modulator of low voltage activated calcium current. In this study we extend our understanding of gamma(6) subunit modulation of low voltage activated calcium current. Using engineered chimeric constructs, we demonstrate that the first transmembrane domain (TM1) of gamma(6) is necessary for its inhibitory effect on Cav3.1 current. Mutational analysis is then used to identify a unique GxxxA motif within TM1 that is required for the function of the subunit strongly suggesting the involvement of helix-helix interactions in its effects. Results from co-immunoprecipitation experiments confirm a physical association of gamma(6) with the Cav3.1 channel in both HEK cells and atrial myocytes. Single channel analysis reveals that binding of gamma(6) reduces channel availability for activation. Taken together, the results of this study provide both a molecular and a mechanistic framework for understanding the unique ability of the gamma(6) calcium channel subunit to modulate low voltage activated (Cav3.1) calcium current density.

View details for DOI 10.1113/jphysiol.2008.159111

View details for Web of Science ID 000261274600012

View details for PubMedID 18818244

Heat-stable enterotoxin of Escherichia coli (STa) can stimulate duodenal HCO3- secretion via a novel GC-C- and CFTR-independent pathway FASEB JOURNAL Sellers, Z. M., Mann, E., Smith, A., Ko, K. H., Giannella, R., Cohen, M. B., Barrett, K. E., Dong, H. 2008; 22 (5): 1306-1316

Abstract

The heat-stable enterotoxin of Escherichia coli (STa) is a potent stimulant of intestinal chloride and bicarbonate secretion. Guanylyl cyclase C (GC-C) has been shown to be the primary receptor involved in mediating this response. However, numerous studies have suggested the existence of an alternative STa-binding receptor. The aims of this study were to determine whether a non-GC-C receptor exists for STa and what is the functional relevance of this for intestinal bicarbonate secretion in mice. (125)I-STa-binding experiments were performed with intestinal mucosae from GC-C knockout (KO) and wild type (WT) mice. Subsequently, the functional relevance of an alternative STa-binding receptor was explored by examining STa-, uroguanylin-, and guanylin-stimulated duodenal bicarbonate secretion (DBS) in GC-C KO mice in vitro and in vivo. Significant (125)I-STa-binding occurred in the proximal small intestines of GC-C KO and WT mice. Analysis of binding coefficients and pH dependence showed that (125)I-STa-binding in GC-C KO mice involved a receptor distinct from that of WT mice. Functionally, STa, uroguanylin, and guanylin all stimulated a significant increase in DBS in GC-C KO mice. Uroguanylin- and guanylin-stimulated DBS were significantly inhibited by glibenclamide, but not by 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS). However, STa-stimulated DBS was unaffected by glibenclamide but inhibited by DIDS. Taken together, our results suggest that alternative, non-GC-C, receptors likely exist for STa, uroguanylin, and guanylin in the intestines of mice. While uroguanylin- and guanylin-stimulated DBS are cystic fibrosis transmembrane conductance regulator (CFTR) dependent, STa-stimulated DBS is CFTR independent. Further understanding of this alternative receptor and its signaling pathway may provide important insights into rectification of intestinal bicarbonate secretion in cystic fibrosis.

View details for DOI 10.1096/fj.06-7540com

View details for Web of Science ID 000255898700004

View details for PubMedID 18096816

Calcium channel gamma subunits: a functionally diverse protein family CELL BIOCHEMISTRY AND BIOPHYSICS Chen, R., Deng, T., Garcia, T., Sellers, Z. M., Best, P. M. 2007; 47 (2): 178-186

Abstract

The calcium channel gamma subunits comprise an eight-member protein family that share a common topology consisting of four transmembrane domains and intracellular N- and C-termini. Although the first gamma subunit was identified as an auxiliary subunit of a voltage-dependent calcium channel, a review of phylogenetic, bioinformatic, and functional studies indicates that they are a functionally diverse protein family. A cluster containing gamma1 and gamma6 conforms to the original description of the protein family as they seem to act primarily as subunits of calcium channels expressed in muscle. Members of a second cluster (gamma2, gamma3, gamma4, gamma8) function as regulators of AMPA receptor localization and function in the brain and are collectively known as TARPs. The function of members of the third cluster (gamma5, gamma7) remains unclear. Our analysis shows that the members of each cluster contain conserved regulatory motifs that help to differentiate the groups. However, the physiological significance of these motifs in many cases remains to be demonstrated.

View details for DOI 10.1007/s12013-007-0002-0

View details for Web of Science ID 000247447800002

View details for PubMedID 17652770

Esomeprazole therapy for gastric acid hypersecretion in children with cystinosis PEDIATRIC NEPHROLOGY Dohil, R., Fidler, M., Barshop, B., Newbury, R., Sellers, Z., Deutsch, R., Schneider, J. 2005; 20 (12): 1786-1793

Abstract

Oral cysteamine therapy prevents natural disease progression in children with cystinosis, but it may cause severe gastrointestinal (GI) symptoms through gastric acid-hypersecretion. The purpose of this study was to assess the value of esomeprazole in controlling cysteamine-induced acid-hypersecretion and GI symptoms in children with cystinosis. Subjects underwent upper GI endoscopy and biopsy, serum gastrin and cysteamine measurements as well as acid secretion studies (basal, maximal and peak acid output, BAO, MAO, PAO) before and during esomeprazole therapy. A symptom score (maximum 14 points) was devised to monitor symptoms. Twelve children (mean age 5.8 years) were studied. Cysteamine ingestion resulted in mean MAO and PAO significantly higher than mean BAO, both before and during esomeprazole therapy. PAO was usually within 60 min of cysteamine ingestion. Esomeprazole therapy significantly reduced MAO (P<0.01) and PAO (P<0.01). The mean symptom score fell from 6.4 to 0.7 (P<0.0001) during esomeprazole therapy. The mean final dose of esomeprazole was 1.7 mg/kg per day (range 0.7 mg/kg per day to 2.75 mg/kg per day). Plasma cysteamine levels were not affected by acid-suppression therapy. One child had multi-nucleated parietal cells. Cysteamine-induced gastric acid-hypersecretion and GI symptoms are dramatically reduced with esomeprazole therapy. Esomeprazole does not alter cysteamine absorption and is very well tolerated in children.

View details for DOI 10.1007/s00467-005-2027-1

View details for Web of Science ID 000233349900017

View details for PubMedID 16133039

Heat-stable enterotoxin of Escherichia coli stimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Sellers, Z. M., Childs, D., Chow, J. Y., SMITH, A. J., Hogan, D. L., Isenberg, J. I., Dong, H., Barrett, K. E., Pratha, V. S. 2005; 288 (4): G654-G663

Abstract

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is an important pathway for duodenal mucosal bicarbonate secretion. Duodenal biopsies from CF patients secrete bicarbonate in response to heat-stable enterotoxin from Escherichia coli (STa) but not cAMP. To explore the mechanism of STa-induced bicarbonate secretion in CF more fully, we examined the role of CFTR in STa-stimulated duodenal bicarbonate secretion in mice. In vivo, the duodenum of CFTR (-/-) or control mice was perfused with forskolin (10(-4) M), STa (10(-7) M), uroguanylin (10(-7) M), 8-bromoguanosine 3',5'-cGMP (8-Br-cGMP) (10(-3) M), genistein (10(-6) M) plus STa, or herbimycin A (10(-6) M) plus STa. In vitro, duodenal mucosae were voltage-clamped in Ussing chambers, and bicarbonate secretion was measured by pH-stat. The effect of genistein, DIDS (10(-4) M), and chloride removal was also studied in vitro. Control, but not CF, mice produced a significant increase in duodenal bicarbonate secretion after perfusion with forskolin, uroguanylin, or 8-Br-cGMP. However, both control and CF animals responded to STa with significant increases in bicarbonate output. Genistein and herbimycin A abolished this response in CF mice but not in controls. In vitro, STa-stimulated bicarbonate secretion in CF tissues was inhibited by genistein, DIDS, and chloride-free conditions, whereas bicarbonate secretion persisted in control mice. In the CF duodenum, STa can stimulate bicarbonate secretion via tyrosine kinase activity resulting in apical Cl(-)/HCO(3)(-) exchange. Further studies elucidating the intracellular mechanisms responsible for such non-CFTR mediated bicarbonate secretion may lead to important therapies for CF.

View details for DOI 10.1152/ajpgi.00386.2004

View details for Web of Science ID 000227564400009

View details for PubMedID 15513951

Na+/Ca2+ exchange regulates Ca2+-dependent duodenal mucosal ion transport and HCO3- secretion in mice AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Dong, H., Sellers, Z. M., Smith, A., Chow, J. Y., Barrett, K. E. 2005; 288 (3): G457-G465

Abstract

Stimulation of muscarinic receptors in duodenal mucosa raises intracellular Ca(2+), which regulates ion transport, including HCO(3)(-) secretion. However, the underlying Ca(2+) handling mechanisms are poorly understood. The aim of the present study was to determine whether Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of duodenal mucosal ion transport and HCO(3)(-) secretion by controlling Ca(2+) homeostasis. Mouse duodenal mucosa was mounted in Ussing chambers. Net ion transport was assessed as short-circuit current (I(sc)), and HCO(3)(-) secretion was determined by pH-stat. Expression of NCX in duodenal mucosae was analyzed by Western blot, and cytosolic Ca(2+) in duodenocytes was measured by fura 2. Carbachol (100 muM) increased I(sc) in a biphasic manner: an initial transient peak within 2 min and a later sustained plateau starting at 10 min. Carbachol-induced HCO(3)(-) secretion peaked at 10 min. 2-Aminoethoxydiphenylborate (2-APB, 100 muM) or LiCl (30 mM) significantly reduced the initial peak in I(sc) by 51 or 47%, respectively, and abolished the plateau phase of I(sc) without affecting HCO(3)(-) secretion induced by carbachol. Ryanodine (100 muM), caffeine (10 mM), and nifedipine (10 muM) had no effect on either response to carbachol. In contrast, nickel (5 mM) and KB-R7943 (10-30 muM) significantly inhibited carbachol-induced increases in duodenal mucosal I(sc) and HCO(3)(-) secretion. Western blot analysis showed expression of NCX1 proteins in duodenal mucosae, and functional NCX in duodenocytes was demonstrated in Ca(2+) imaging experiments where Na(+) depletion elicited Ca(2+) entry via the reversed mode of NCX. These results indicate that NCX contributes to the regulation of Ca(2+)-dependent duodenal mucosal ion transport and HCO(3)(-) secretion that results from stimulation of muscarinic receptors.

View details for DOI 10.1152/ajpgi.00381.2004

View details for Web of Science ID 000226833100007

View details for PubMedID 15499079

A role for CagA/VacA in Helicobacter pylori inhibition of murine duodenal mucosal bicarbonate secretion DIGESTIVE DISEASES AND SCIENCES Tuo, B. G., Sellers, Z. M., SMITH, A. J., Barrett, K. E., Isenberg, J. I., Dong, H. 2004; 49 (11-12): 1845-1852

Abstract

Duodenal mucosal bicarbonate secretion is diminished in patients with Helicobacter pylori (HP)-associated duodenal ulcer disease. We examined whether HP water extracts inhibit murine duodenal mucosal bicarbonate secretion in vitro, and the mechanisms involved. Murine duodenal mucosae were mounted in Ussing chambers. Short-circuit current and bicarbonate secretion was measured. CagA/VacA-positive HP water extract (HPWE+/+) markedly inhibited PGE2-, carbachol-, or the calcium ionophore A23187-stimulated bicarbonate secretion in a dose-dependent manner. While 3-isobutyl-1-methylxanthine-stimulated bicarbonate secretion was not affected by HPWE+/+, HPWE+/+ did diminish forskolin-stimulated bicarbonate secretion. HPWE+/+ markedly diminished PGE2-induced increases in duodenal mucosal cAMP. CagA/VacA of HP decreases Ca2+-mediated bicarbonate secretion downstream of increases in intracellular Ca2+. Dimunition of PGE2-stimulated bicarbonate secretion occurs, in part, by inhibition of adenylate cyclase, which leads to decreased cAMP levels. The ability of virulent HP strains to inhibit duodenal bicarbonate secretion through multiple intracellular pathways likely contributes to the pathogenesis of HP-associated duodenal ulcer disease.

View details for Web of Science ID 000225971000022

View details for PubMedID 15628715

5-HT induces duodenal mucosal bicarbonate secretion via cAMP- and Ca2+-dependent signaling pathways and 5-HT4 receptors in mice AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Tuo, B. G., Sellers, Z., Paulus, P., Barrett, K. E., Isenberg, J. I. 2004; 286 (3): G444-G451

Abstract

In previous studies, we have found that 5-hydroxytryptamine (5-HT) is a potent stimulant of duodenal mucosal bicarbonate secretion (DMBS) in mice. The aim of the present study was to determine the intracellular signaling pathways and 5-HT receptor subtypes involved in 5-HT-induced DMBS. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. 5-HT receptor involvement in DMBS was inferred from pharmacological studies by using selective 5-HT receptor antagonists and agonists. The expression of 5-HT(4) receptor mRNA in duodenal mucosa and epithelial cells was analyzed by RT-PCR. cAMP-dependent signaling pathway inhibitors MDL-12330A, Rp-cAMP, and H-89 and Ca(2+)-dependent signaling pathway inhibitors verapamil and W-13 markedly reduced 5-HT-stimulated duodenal bicarbonate secretion and short-circuit current (I(sc)), whereas cGMP-dependent signaling pathway inhibitors NS-2028 and KT-5823 failed to alter these responses. Both SB-204070 and high-dose ICS-205930 (selective 5-HT(4) receptor antagonists) markedly inhibited 5-HT-stimulated bicarbonate secretion and I(sc), whereas methiothepine (5-HT(1) receptor antagonist), ketanserin (5-HT(2) receptor antagonist), and a low concentration of ICS-205930 (5-HT(3) receptor antagonist) had no effect. RS-67506 (partial 5-HT(4) receptor agonist) concentration-dependently increased bicarbonate secretion and I(sc), whereas 5-carboxamidotryptamine (5-HT(1) receptor agonist), alpha-methyl-5-HT (5-HT(2) receptor agonist), and phenylbiguanide (5-HT(3) receptor agonist) did not significantly increase bicarbonate secretion or I(sc). RT-PCR analysis confirmed the expression of 5-HT(4) receptor mRNA in murine duodenal mucosa and epithelial cells. These results demonstrate that 5-HT regulates DMBS via both cAMP- and Ca(2+)-dependent signaling pathways and 5-HT(4) receptors located in the duodenal mucosa and/or epithelial cells.

View details for DOI 10.1152/ajpgi.00105.2003

View details for Web of Science ID 000188783400011

View details for PubMedID 14576083

A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY Rao, S. P., Sellers, Z., Crombie, D. L., Hogan, D. L., Mann, E. A., Childs, D., Keely, S., Sheil-Puopolo, M., Giannella, R. A., Barrett, K. E., Isenberg, J. I., Pratha, V. S. 2004; 286 (1): G95-G101

Abstract

Luminal acidification provides the strongest physiological stimulus for duodenal HCO3- secretion. Various neurohumoral mechanisms are believed to play a role in acid-stimulated HCO3- secretion. Previous studies in the rat and human duodenum have shown that guanylin and Escherichia coli heat-stable toxin, both ligands of the transmembrane guanylyl cyclase receptor [guanylate cyclase C (GC-C)], are potent stimulators for duodenal HCO3- secretion. We postulated that the GC-C receptor plays an important role in acid-stimulated HCO3- secretion. In vivo perfusion studies performed in wild-type (WT) and GC-C knockout (KO) mice indicated that acid-stimulated duodenal HCO3- secretion was significantly decreased in the GC-C KO animals compared with the WT counterparts. Pretreatment with PD-98059, an MEK inhibitor, resulted in attenuation of duodenal HCO3- secretion in response to acid stimulation in the WT mice with no further effect in the KO mice. In vitro cGMP generation studies demonstrated a significant and comparable increase in cGMP levels on acid exposure in the duodenum of both WT and KO mice. In addition, a rapid, time-dependent phosphorylation of ERK was observed with acid exposure in the duodenum of WT mice, whereas a marked attenuation in ERK phosphorylation was observed in the KO animals despite equivalent levels of ERK in both groups of animals. On the basis of these studies, we conclude that transmembrane GC-C is a key mediator of acid-stimulated duodenal HCO3- secretion. Furthermore, ERK phosphorylation may be an important intracellular mediator of duodenal HCO3- secretion.

View details for DOI 10.1152/ajpgi.00087.2003

View details for Web of Science ID 000187118600013

View details for PubMedID 12881226

The evaluation and treatment of gastrointestinal disease in children with cystinosis receiving cysteamine JOURNAL OF PEDIATRICS Dohil, R., Newbury, R. O., Sellers, Z. M., Deutsch, R., Schneider, J. A. 2003; 143 (2): 224-230

Abstract

Cysteamine prevents organ damage in children with cystinosis, but may cause gastrointestinal (GI) symptoms. In this study we evaluated the nature of GI disease, and the value of omeprazole in controlling GI symptoms in these children.Upper GI disease was evaluated with endoscopy, gastrin levels, and acid secretion studies after oral administration of cysteamine, before and after 16 weeks of therapy with omeprazole. A symptom score was devised.Eleven children (mean age, 5.7 years) were studied. After cysteamine ingestion, before and after omeprazole therapy, the mean maximum acid output was significantly higher than the mean basal acid output. The maximum acid output was measured within 60 minutes of cysteamine ingestion and was reduced by omeprazole therapy (P<.01). The mean peak gastrin level was 30 minutes postcysteamine and was higher than baseline (P<.01). The initial mean symptom score (maximum score, 14) was 6.9 and fell to 0.7 (P<.0001) after 16 weeks of omeprazole therapy. At endoscopy, two children had diffuse gastric nodularity, and nearly all had cystine crystal deposits.GI symptoms in children with cystinosis receiving cysteamine are often acid-mediated and improve with omeprazole. Cystine crystals were detected in the GI tract and may signify inadequate treatment with cysteamine.

View details for DOI 10.1067/S0022-3476(03)00281-6

View details for Web of Science ID 000185118300018

View details for PubMedID 12970638