Zachary Sellers, MD, PhD

Abstract

Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent (ARP) and chronic pancreatitis (CP) in children.Data were obtained from ARP group with 1 episode of DAP and CP group with medication exposure +/- DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode.Of 726 children, 392 had ARP, 334 CP. 51 children (39 ARP and 12 CP) had 1 AP associated with a medication. 61% had 1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10/35 (28.6%) genetic, 1/48 (2.1%) autoimmune pancreatitis, 13/51 (25.5%) immune-mediated conditions, 11/50 (22.0%) obstructive/ anatomic, 28/51 (54.9%) systemic risk factors. In Med group, 24/ 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores.Medications were involved in 51/ 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive", raising questions about its reliability for DAP.

View details for DOI 10.1097/MPG.0000000000003898

View details for PubMedID 37496124

Abstract

Although it was described previously for estrogen (E2) regulation of intestinal epithelial Cl- and HCO3- secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E2-modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ER and ER subtypes in the regulation of E2-modulated colonic epithelial HCO3- and Cl- secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ER attenuated female colonic Cl- secretion but promoted Ca2+-dependent HCO3- secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ER attenuated HCO3- secretion by inhibiting Ca2+ via the SOCE and inhibiting cAMP via protein kinases. Moreover, ER but not ER promoted epithelial cell restitution via SOCE/Ca2+ signaling. ER also enhanced Cyclin D1, PCNA and -catenin expression in normal human colonic epithelial cells (HCoEpiC). All ER-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ER and ER were expressed in HCoEpiC and mouse colonic tissues. We therefore conclude that E2 modulates complex colonic epithelial HCO3- and Cl- secretion via ER subtype-dependent mechanisms and that ER is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ER and ER subtypes orchestrate functional homeostasis of normal colonic epithelial cells.

View details for DOI 10.1016/j.jbc.2023.105068

View details for PubMedID 37468102

Abstract

Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the gamma-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation towards the multiciliated lineage. Thus, gamma-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here we demonstrate therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In sum, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.

View details for DOI 10.1152/ajplung.00382.2022

View details for PubMedID 37039381

Abstract

OBJECTIVES: To investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).METHODS: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP.RESULTS: Of 689 children, 365 had ARP (53%), 324 CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP.CONCLUSIONS: Children with family history of CP, constant pain or obstructive risk factors should raise suspicion for CP.

View details for DOI 10.1097/MPG.0000000000003590

View details for PubMedID 35976273

Abstract

The negative impact of healthcare disparities, specifically low health literacy, on clinical outcomes related to Cystic Fibrosis (CF) have been described [1]. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/ppul.26071

View details for PubMedID 35811375

Abstract

Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal (GI) health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (Isc) of the intestine from wild-type, TRPV1-, and TRPV4-knockout mice were measured in Ussing chambers, and Ca2+ imaging was performed on small intestinal epithelial cells (IECs). We also performed Western blots, immunohistochemistry, and immunofluorescence on IECs and on intestinal tissues following UC induction with dextran sodium sulphate (DSS). We found that capsaicin did not affect basal intestinal Isc, but significantly inhibited carbachol- and caffeine-induced intestinal Isc in wild-type mice. Capsaicin similarly inhibited the intestinal Isc in TRPV1 knockout mice, but this inhibition was absent in TRPV4 knockout mice. We also determined that Ca2+ influx via TRPV4 was required for cholinergic signaling-mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal Isc via Na+/glucose co-transporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic Isc. Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive Isc. We therefore conclude that capsaicin inhibits intestinal Cl- secretion and promotes Na+ absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action.

View details for DOI 10.1016/j.jbc.2022.101847

View details for PubMedID 35314195

Abstract

OBJECTIVES: Chronic pancreatitis (CP) is rare in childhood, but impactful due to its high disease burden. There is limited literature regarding the management of CP in children, specifically about the various surgical approaches. Herein, we summarize the current pediatric and adult literature and provide recommendations for the surgical management of CP in children.METHODS: The literature review was performed to include the scope of the problem, indications for operation, conventional surgical options as well as total pancreatectomy with islet autotransplantation, and outcomes following operations for CP.RESULTS: Surgery is indicated for children with debilitating CP who have failed maximal medical and endoscopic interventions. Surgical management must be tailored to the patient's unique needs, considering the anatomy and morphology of their disease. A conventional surgical approach (e.g., drainage operation, partial resection, combination drainage-resection) may be considered in the presence of significant and uniform pancreatic duct dilation or an inflammatory head mass. Total pancreatectomy with islet autotransplantation is the best surgical option in patients with small duct disease. The presence of genetic risk factors often portends a suboptimal outcome following a conventional operation.CONCLUSIONS: The morphology of disease and the presence of genetic risk factors must be considered while determining the optimal surgical approach for children with CP. Surgical outcomes for CP are variable and depend on the type of intervention. A multidisciplinary team approach is needed to assure that the best possible operation is selected for each patient, their recovery is optimized, and their immediate and long-term postoperative needs are well-met.

View details for DOI 10.1097/MPG.0000000000003439

View details for PubMedID 35258494

Abstract

OBJECTIVES: The aim of this article is to provide guidance to centers and organizations on the personnel (both physician and nonphysician) needed to create and sustain an optimal team, along with potential alternatives, to provide care to children with acute recurrent pancreatitis and chronic pancreatitis.METHODS: This document was developed in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Pancreas Committee and the National Pancreas Foundation (NPF) after several meetings.RESULTS: This document highlights both physician and nonphysician personnel needed to provide multidisciplinary care to children with pancreatitis per the recommendation of the NASPGHAN Pancreas Committee members in year 2021 and added to the currently published NPF criteria. We summarize how the NPF criteria would fit with the recently published pediatric pancreatitis society articles from the NASPGHAN.CONCLUSIONS: It is important to manage children with acute recurrent pancreatitis and chronic pancreatitis in a multidisciplinary setting. There is need to study the impact of these personnel on the outcomes of children with pancreatitis.

View details for DOI 10.1097/MPA.0000000000002008

View details for PubMedID 35584383

Abstract

OBJECTIVES: Abdominal pain, emergency department visits and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). However, data on health-related quality of life (HRQOL) in this population remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL.METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment.RESULTS: The sample included 368 children (54.3% females, mean age=12.7years, SD=3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M=38.5, SD=16.0) was demonstrated while psychosocial HRQOL (M=49.5, SD=10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B=-10.28, p<.001), episodic and constant abdominal pain (B=-4.66, p=.03; B=-13.25, p<.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine and endocrine disease (F (9, 271)=8.34, p<.001). Borderline and clinical levels of emotional and behavioral problems (B=-10.18, p<.001; B=-15.98, p<.001), and constant pain (B=-4.46, p<.001) were associated with low psychosocial HRQOL (F (9, 271)=17.18, p<.001).CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.An infographic is available for this article at:http://links.lww.com/MPG/C712.

View details for DOI 10.1097/MPG.0000000000003420

View details for PubMedID 35192575

Abstract

OBJECTIVES: It is unknown to what extent coronavirus 2019 (COVID-19) may co-occur with acute pancreatitis (AP) in children and how their clinical course may differ from children with AP alone.METHODS: An online survey was sent to pediatric gastroenterologists to report on COVID-19 and AP cases from December 11, 2020, to February 26, 2021.RESULTS: From 72 respondents (20 countries, 5 continents), 22 cases of positive COVID-19 infection and AP were reported. Patients were predominantly White or Hispanic/Latinx (73%), female (68%), and adolescents (68%). For 86% of patients, this was their first episode of AP. Sixty-eight percent of positive COVID-19 tests were polymerase chain reaction based. There was significant morbidity; 60% required intensive care, 45% had multiorgan involvement, and 24% developed shock. Eleven percent had pancreatic necrosis. Abnormal clotting and systemic inflammatory laboratories were common (31%-92% and 93%, respectively). Median length of symptomatic pancreatitis recovery was 1.8* longer than AP without COVID-19.CONCLUSIONS: Coronavirus 2019 infection and AP co-occur primarily in children without a prior history of pancreatitis. Given the increased need for intensive care, multiorgan involvement, and potentially higher risk for pancreatic necrosis, pediatric providers should have a high level of suspicion for AP in children with COVID-19 infection.

View details for DOI 10.1097/MPA.0000000000001923

View details for PubMedID 34860816

Abstract

Acute pancreatitis (AP) is associated with significant morbidity and mortality, and it substantially contributes to the healthcare burden of gastrointestinal disease and quality of life in children and adults. AP across the lifespan is characterized by similarities and differences in epidemiology, diagnostic modality, etiologies, management, adverse events, long-term outcomes, and areas in greatest need of research. In this review, we touch on each of these shared and distinctive features of AP in children and adults, with an emphasis on recent advances in the conceptualization and management of AP.

View details for DOI 10.3390/jcm10122545

View details for PubMedID 34201374

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

View details for Web of Science ID 000546375600039

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

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

View details for PubMedID 30472228

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

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

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

View details for PubMedID 29890113

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

View details for PubMedID 28697142

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

View details for PubMedID 28455563

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

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

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

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

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

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

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

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

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

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

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

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

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