Gianrico Farrugia

Mayo Clinic - Rochester, Rochester, Minnesota, United States

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Publications (275)1994.18 Total impact

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    ABSTRACT: In eukaryotic cells, DNA replication proceeds with continuous synthesis of leading-strand DNA and discontinuous synthesis of lagging-strand DNA. Here we describe a method, eSPAN (enrichment and sequencing of protein-associated nascent DNA), which reveals the genome-wide association of proteins with leading and lagging strands of DNA replication forks. Using this approach in budding yeast, we confirm the strand specificities of DNA polymerases delta and epsilon and show that the PCNA clamp is enriched at lagging strands compared with leading-strand replication. Surprisingly, at stalled forks, PCNA is unloaded specifically from lagging strands. PCNA unloading depends on the Elg1-containing alternative RFC complex, ubiquitination of PCNA, and the checkpoint kinases Mec1 and Rad53. Cells deficient in PCNA unloading exhibit increased chromosome breaks. Our studies provide a tool for studying replication-related processes and reveal a mechanism whereby checkpoint kinases regulate strand-specific unloading of PCNA from stalled replication forks to maintain genome stability. Copyright © 2014 Elsevier Inc. All rights reserved.
    Molecular cell. 11/2014; 56(4).
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    ABSTRACT: Anoctamin-1 (Ano1) is a widely expressed protein responsible for endogenous Ca(2+)-activated Cl(-) currents. Ano1 is overexpressed in cancer. Differential expression of transcriptional variants is also found in other diseases. However, the mechanisms underlying regulation of Ano1 are unknown. This study identifies the Ano1 promoter and defines a mechanism for regulating its expression. Next-generation RNA sequencing (RNA-seq) analysis in human gastric muscle found a new exon upstream of the reported exon 1 and identified a promoter proximal to this new exon. Reporter assays in human embryonic kidney 293 cells showed a 6.7 ± 2.1-fold increase in activity over empty vector. Treatment with a known regulator of Ano1 expression, IL-4, increased promoter activity by 1.6 ± 0.02-fold over untreated cells. The promoter region contained putative binding sites for multiple transcription factors including signal transducer and activator of transcription 6 (STAT6), a downstream effector of IL-4. Chromatin immunoprecipitation (ChIP) experiments on T84 cells, which endogenously express Ano1, showed a 2.1 ± 0.12-fold increase in binding of STAT6 to P0 after IL-4 treatment. These results were confirmed by mutagenesis, expression, and RNA interference techniques. This work allows deeper understanding of the regulation of Ano1 in physiology and as a potential therapeutic target in a variety of diseases-Mazzone, A., Gibbons, S. J., Bernard, C. E., Nowsheen S., Middha S., Almada, L. L., Ordog, T., Kendrick, M. L., Reid Lombardo, K., Shen, K. R., Galietta, L. J. V., Fernandez-Zapico, M. E., and Farrugia, G. Identification and characterization of a novel promoter for the human ANO1 gene regulated by the transcription factor signal transducer and activator of transcription 6 (STAT6).
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 10/2014;
  • Leila Neshatian, Simon J. Gibbons, Gianrico Farrugia
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    ABSTRACT: Background Diabetic gastroparesis results in significant morbidity for patients and major economic burden for society. Treatment options for diabetic gastroparesis are currently directed at symptom control rather than the underlying disease and are limited. The pathophysiology of diabetic gastroparesis includes damage to intrinsic and extrinsic neurons, smooth muscle, and interstitial cells of Cajal (ICC). Oxidative damage in diabetes appears to be one of the primary insults involved in the pathogenesis of several complications of diabetes, including gastroparesis. Recent studies have highlighted the potential role of macrophages as key cellular elements in the pathogenesis of diabetic gastroparesis. Macrophages are important for both homeostasis and defense against a variety of pathogens. Heme oxygenase 1 (HO1), an enzyme expressed in a subset of macrophages has emerged as a major protective mechanism against oxidative stress. Activation of macrophages with high levels of HO1 expression protects against development of delayed gastric emptying in animal models of diabetes, while activation of macrophages that do not express HO1 are linked to neuromuscular cell injury. Targeting macrophages and HO1 may therefore be a therapeutic option in diabetic gastroparesis.PurposeThis report briefly reviews the pathophysiology of diabetic gastroparesis with a focus on oxidative damage and how activation and polarization of different subtypes of macrophages in the muscularis propria determines development of delay in gastric emptying or protects against its development.
    Neurogastroenterology and Motility 08/2014; · 2.94 Impact Factor
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    ABSTRACT: Background There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC.Methods Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer.Key ResultsSignificantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types.Conclusions & InferencesDepletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages.
    Neurogastroenterology and Motility 07/2014; · 2.94 Impact Factor
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    ABSTRACT: Interstitial cells of Cajal (ICC) are pacemaker cells that generate electrical activity to drive contractility in the gastrointestinal tract via ion channels. Ano1 (Tmem16a), a Ca2+ -activated Cl− channel is an ion channel expressed in ICC. Genetic deletion of Ano1 in mice resulted in loss of slow waves in smooth muscle of small intestine. In this study, we show that Ano1 is required to maintain coordinated Ca2+ transients between myenteric ICC (ICC-MY) of small intestine. First, we found spontaneous Ca2+ transients in ICC-MY in both Ano1 WT and KO mice. However, Ca2+ transients within the ICC-MY network in Ano1 KO mice were uncoordinated, while ICC-MY Ca2+ transients in Ano1 WT mice were rhythmic and coordinated. To confirm the role of Ano1 in the loss of Ca2+ transient coordination, we used pharmacological inhibitors of Ano1 activity and shRNA-mediated knock down of Ano1 expression in organotypic cultures of Ano1 WT small intestine. We found that coordinated Ca2+ transients became uncoordinated using both these approaches supporting the conclusion that Ano1 is required to maintain coordination/rhythmicity of Ca2+ transients. We next determined the effect on smooth muscle contractility using spatio-temporal maps of contractile activity in Ano1 KO and -WT tissues. Significantly decreased contractility that appeared non-rhythmic and uncoordinated was observed in Ano1 KO jejunum. In conclusion, Ano1 has a previously unidentified role in the regulation of coordinated gastrointestinal smooth muscle function through coordination of Ca2+ transients in ICC-MY.This article is protected by copyright. All rights reserved
    The Journal of Physiology 07/2014; · 4.38 Impact Factor
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    ABSTRACT: Background Heme oxygenase 1 (HO-1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO-1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO-1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α-lipoic acid, on HO-1 protein concentration and activity in humans.Methods This randomized, double-blind, placebo-controlled study compared the effects of three oral regimens administered for 7 days, i.e., placebo; aspirin (325 mg twice daily) and simvastatin (40 mg twice daily); aspirin, simvastatin, and the sodium salt of R- α-lipoic acid (NaRLA, 600 mg three times daily) on markers of HO-1 activation (i.e., plasma HO-1 protein concentration and venous monocyte HO-1 protein activity) in 18 healthy subjects (14 females). Markers of HO-1 activation were evaluated at baseline, days 2, and 7.Key ResultsBaseline HO-1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO-1 protein concentration or activity at 2 or 7 days. HO-1 protein concentrations and activity were correlated on day 7 (r = 0.75, p = 0.0004) but not at baseline and on day 2.Conclusions & InferencesAt therapeutic doses, aspirin, simvastatin, and α-lipoic acid do not increase plasma HO-1 protein concentration or venous monocyte HO-1 activity in healthy humans.
    Neurogastroenterology and Motility 07/2014; · 2.94 Impact Factor
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  • Mayo Clinic Proceedings 06/2014; 89(6):718–721. · 5.79 Impact Factor
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    ABSTRACT: See Covering the Cover synopsis on page 1583. BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na V 1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether pa-tients with IBS have SCN5A variants that affect the function of Na V 1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na V 1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na V 1.5 had the greatest effect in reducing Na V 1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na V 1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    06/2014;
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    ABSTRACT: Our aim was to conduct a pilot case-control study of RNA expression profile using RNA sequencing of rectosigmoid mucosa of 9 females with irritable bowel syndrome-diarrhea [IBS-D] with accelerated colonic transit and 9 female healthy controls. Mucosal total RNA was isolated, purified, and next generation pair-end sequencing was performed using Illumina TruSeq. Analysis was carried out using: a targeted approach towards 12 genes previously associated with IBS, and a hypothesis-generating approach. Of the 12 targeted genes tested, patients with IBS-D had decreased mRNA expression of TNFSF15 (fold change controls to IBS-D: 1.53, p=0.01). Overall, up- and downregulated mRNA expressions of 21 genes (p values 10(-5) to 10(-8); p values with FDR shown) were potentially relevant to IBS-D: neurotransmitters [P2RY4 (p=0.001), VIP (p=0.02)]; cytokines [CCL20 (p=0.019)]; immune function [C4BPA complement cascade (p=0.0187)], and IFIT3 [interferon-related, p=0.016]; mucosal repair and cell adhesion [TFF1 (trefoil protein, p= 0.012)], RBP2 (retinol binding protein, p=0.017), FN1 (fibronectin, p=0.009)]; and ion channel functions [GUCA2B (guanylate cyclase, p= 0.017), PDZD3 (PDZ domain-containing protein 3, p=0.029)]. Ten genes associated with functions related to pathobiology of IBS-D were validated by RT-PCR: There was significant correlation in fold changes of the selected genes (Rs=0.73, p=0.013). Up- or downregulation of P2RY4, GUC2AB, RBP2, FNI and C4BPA genes were confirmed on RT-PCR, which also revealed upregulation of FXR and ASBT. RNA seq and RT-PCR analysis of rectosigmoid mucosa in IBS-D show transcriptome changes that provide the rationale for validation studies to explore the role of mucosal factors in the pathobiology of IBS-D.
    AJP Gastrointestinal and Liver Physiology 04/2014; · 3.65 Impact Factor
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    ABSTRACT: There is increasing recognition that genomic medicine as part of individualized medicine has a defined role in patient care. Rapid advances in technology and decreasing cost combine to bring genomic medicine closer to the clinical practice. There is also growing evidence that genomic-based medicine can advance patient outcomes, tailor therapy and decrease side effects. However the challenges to integrate genomics into the workflow involved in patient care remain vast, stalling assimilation of genomic medicine into mainstream medical practice. In this review we describe the approach taken by one institution to further individualize medicine by offering, executing and interpreting whole exome sequencing on a clinical basis through an enterprise-wide, standalone individualized medicine clinic. We present our experience designing and executing such an individualized medicine clinic, sharing lessons learned and describing early implementation outcomes. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 03/2014; · 4.44 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    Gastroenterology 03/2014; 146(7):1659-1668. · 12.82 Impact Factor
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    ABSTRACT: Gastrointestinal (GI) infections resulting from bacterial, viral, and parasitic pathogens predispose to postinfectious irritable bowel syndrome (PI-IBS) and other functional GI disorders. Existing literature supports the role of enterochromaffin cell hyperplasia, serotonin synthesis and reuptake, impaired barrier function, altered immune activation, and potentially mast cell activation in the pathophysiology of PI-IBS. The objective of this review was to summarize from the literature the characteristics of the pathogens commonly implicated in PI-IBS, their acute enteritis phases, and the changes seen in the postinfectious phase that may contribute toward development of IBS. A limitation of our current understanding is that the postinfectious GI sequelae reported in prior studies followed epidemic diarrheal outbreaks often involving more than one pathogen, or the studies focused on highly selected, tertiary referral patients. Understanding the mechanisms, natural history, and optimized management of individuals suffering PI-IBS following the more typical sporadic infection requires larger studies of PI-IBS following GI infections encountered in community settings. These studies should include genetic, physiological, and molecular studies to provide more generalizable information that can ultimately be used to diagnose, manage, and potentially prevent the development of PI-IBS.
    Neurogastroenterology and Motility 02/2014; 26(2):156-167. · 2.94 Impact Factor
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    ABSTRACT: Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca(2+) oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca(2+)-activated Cl(-) channel, anoctamin 1 (Ano1). In this paper we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca(2+) entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl(-) current in ICC, and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca(2+) channel, but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca(2+) current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl(-) equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl(-) dynamics in ICC.
    AJP Gastrointestinal and Liver Physiology 01/2014; · 3.65 Impact Factor
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    ABSTRACT: To report the design and implementation of the Right Drug, Right Dose, Right Time-Using Genomic Data to Individualize Treatment protocol that was developed to test the concept that prescribers can deliver genome-guided therapy at the point of care by using preemptive pharmacogenomics (PGx) data and clinical decision support (CDS) integrated into the electronic medical record (EMR). We used a multivariate prediction model to identify patients with a high risk of initiating statin therapy within 3 years. The model was used to target a study cohort most likely to benefit from preemptive PGx testing among the Mayo Clinic Biobank participants, with a recruitment goal of 1000 patients. We used a Cox proportional hazards model with variables selected through the Lasso shrinkage method. An operational CDS model was adapted to implement PGx rules within the EMR. The prediction model included age, sex, race, and 6 chronic diseases categorized by the Clinical Classifications Software for International Classification of Diseases, Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). Of the 2000 Biobank participants invited, 1013 (51%) provided blood samples, 256 (13%) declined participation, 555 (28%) did not respond, and 176 (9%) consented but did not provide a blood sample within the recruitment window (October 4, 2012, through March 20, 2013). Preemptive PGx testing included CYP2D6 genotyping and targeted sequencing of 84 PGx genes. Synchronous real-time CDS was integrated into the EMR and flagged potential patient-specific drug-gene interactions and provided therapeutic guidance. This translational project provides an opportunity to begin to evaluate the impact of preemptive sequencing and EMR-driven genome-guided therapy. These interventions will improve understanding and implementation of genomic data in clinical practice.
    Mayo Clinic Proceedings 01/2014; 89(1):25-33. · 5.79 Impact Factor
  • Gianrico Farrugia, Joseph H. Szurszewski
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    ABSTRACT: Carbon monoxide (CO) and hydrogen sulfide (H2S) used to be thought of simply as lethal and (for H2S) smelly gaseous molecules; now they are known to have important signaling functions in the gastrointestinal tract. CO and H2S, which are produced in the gastrointestinal tract by different enzymes, regulate smooth muscle membrane potential and tone, transmit signals from enteric nerves and can regulate the immune system. The pathways that produce nitric oxide (NO) H2S and CO interact—each can inhibit and potentiate the level and activity of the other. However, there are significant differences between these molecules, such as in half-lives; CO is more stable and therefore able to have effects distal to the site of production, whereas NO and H2S are short lived and act only close to sites of production. We review their signaling functions in the luminal gastrointestinal tract and discuss how their pathways interact. We also describe other physiologic functions of CO and H2S and how they might be used as therapeutic agents.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: Background & Aims SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. Methods We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P<.05). Electrophysiologic analysis showed that 10/13 detected mutations disrupted NaV1.5 function (9 reduced and 1 increased function); p.A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current; administration of mexiletine to 1 carrier of this mutation (who had IBS-C) normalized their bowel habits. In the GWAS and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: IMPORTANCE Gastroparesis remains a challenging syndrome to manage, with few effective treatments and a lack of rigorously controlled trials. Tricyclic antidepressants are often used to treat refractory symptoms of nausea, vomiting, and abdominal pain. Evidence from well-designed studies for this use is lacking. OBJECTIVE To determine whether treatment with nortriptyline results in symptomatic improvement in patients with idiopathic gastroparesis. DESIGN, SETTING, AND PARTICIPANTS The NORIG (Nortriptyline for Idiopathic Gastroparesis) trial, a 15-week multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC), comparing nortriptyline with placebo for symptomatic relief in idiopathic gastroparesis. One hundred thirty patients with idiopathic gastroparesis were enrolled between March 2009 and June 2012 at 7 US academic medical centers. Patient follow-up was completed in October 2012. Inclusion criteria included delayed gastric emptying and moderate to severe symptom scores using the Gastroparesis Cardinal Symptom Index (GCSI). INTERVENTIONS Nortriptyline vs placebo. Study drug dose was increased at 3-week intervals (10, 25, 50, 75 mg) up to 75 mg at 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure of symptomatic improvement was a decrease from the patient's baseline GCSI score of at least 50% on 2 consecutive 3-week GCSI assessments during 15 weeks of treatment. RESULTS The primary symptomatic improvement outcome did not differ between 65 patients randomized to nortriptyline vs 65 patients randomized to placebo: 15 (23% [95% CI, 14%-35%]) in the nortriptyline group vs 14 (21% [95% CI, 12%-34%]) in the placebo group (P = .86). Treatment was stopped more often in the nortriptyline group (19 [29% {95% CI, 19%-42%}]) than in the placebo group (6 [9%] {95% CI, 3%-19%}]) (P = .007), but numbers of adverse events were not different (27 [95% CI, 18-39] vs 28 [95% CI, 19-40]) (P = .89). CONCLUSIONS AND RELEVANCE Among patients with idiopathic gastroparesis, the use of nortriptyline compared with placebo for 15 weeks did not result in improvement in overall symptoms. These findings do not support the use of nortriptyline for idiopathic gastroparesis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00765895.
    JAMA The Journal of the American Medical Association 12/2013; 310(24):2640-9. · 29.98 Impact Factor
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    ABSTRACT: A transwall gradient in RMP exists across the circular muscle layer in the mouse colon. This gradient is dependent on endogenous generation of CO. H2S also is generated in muscle layers of the mouse colon. The effect of endogenously generated H2S on the transwall gradient is not known. The aim was to investigate the role of endogenous H2S. Result: The CSE inhibitor DL-propargylglycine (PAG, 500 µM) had no effect on the transwall gradient. However, in preparations pre-treated with the nitric oxide synthase inhibitor N-nitro-L-Arginine (L-NNA, 200 µM) and in nNOS-KO mouse preparations, PAG shifted the transwall gradient in the depolarizing direction. In CSE-KO/nNOS-KO mice, the gradient was shifted in the depolarizing direction. Endogenous generation of NO was significantly higher in muscle preparations of CSE-KO mice compared to WT mice. The amplitude of NO mediated S-IJPs evoked by electric field stimulation was significantly higher in CSE-KO mouse preparations compared to the amplitude of S-IJPs in wild type mouse preparations. CSE was present in all submucosal ganglion neurons and in almost all myenteric ganglion neurons. Eleven percent of CSE positive neurons in the submucosal plexus and fifty percent of CSE positive neurons in the myenteric plexus also contained nNOS. Our results suggest that endogenously generated H2S acts as a stealth hyperpolarizing factor on smooth muscle cells to maintain the CO-dependent transwall gradient and inhibits NO production from nNOS.
    The Journal of Physiology 12/2013; · 4.38 Impact Factor
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    ABSTRACT: A 26-year-old patient was diagnosed as having chronic intestinal pseudo-obstruction with manometric and histopathologic features suggestive of an intestinal myopathy. Histology was characterized by smooth muscle degeneration without inflammatory or immune cells. The severe gut dysfunction required full parenteral nutritional support. After a few months, the patient developed symptomatic tachy-brady arrhythmia episodes with syncopes. A thorough diagnostic work-up led to a diagnosis of sick sinus syndrome, which was managed by pacemaker implantation and administration of β-blockers. This led to a partial improvement in tachy-brady arrhythmia episodes. Nonetheless, the patient continued to experience sustained supraventricular tachyarrhythmia runs, poorly responsive to increasing β-blocker doses. To investigate the origin of the cardiologic impairment, the patient was tested for anticonductive tissue autoantibodies, which were positive, thus supporting a possible autoimmune origin of the dysrhythmia. Other autoantibodies were negative. On the basis of these findings, the patient was treated with high-dose steroids, which were then tapered. The patient responded to the steroid treatment and did not experience further episodes of syncope and tachyarrhythmias. The severe gut dysfunction remained unchanged. This case highlights an association between severe gut dysfunction and cardiac conductive tissue abnormalities, with autoantibodies to conductive tissue possibly causing the dysrhythmia. The severe gut and heart (likely autoimmune-mediated) dysfunction presented in this case provides a basis to further assess a link between intestinal and cardiac abnormal rhythmicity.
    European journal of gastroenterology & hepatology 11/2013; 25(11):1358-1363. · 1.66 Impact Factor

Publication Stats

4k Citations
1,994.18 Total Impact Points

Institutions

  • 1993–2014
    • Mayo Clinic - Rochester
      • • Department of Gastroenterology and Hepatology
      • • Department of Surgery
      Rochester, Minnesota, United States
  • 2013
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
    • State University of New York College at Brockport
      • Department of Biology
      Brockport, NY, United States
  • 2010–2013
    • Temple University
      • • Section of Gastroenterology
      • • Department of Medicine
      Philadelphia, PA, United States
    • University of Auckland
      • • Auckland Bioengineering Institute
      • • Department of Surgery
      • • Auckland Bioengineering Institute
      Auckland, Auckland, New Zealand
  • 1999–2013
    • Mayo Foundation for Medical Education and Research
      • • Division of Gastroenterology and Hepatology
      • • Department of Physiology and Biomedical Engineering
      Rochester, Michigan, United States
  • 2011
    • University of Florence
      Florens, Tuscany, Italy
    • Wake Forest University
      Winston-Salem, North Carolina, United States
    • Wayne State University
      Detroit, Michigan, United States
  • 2010–2011
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 2008–2011
    • Stanford University
      • • Division of Gastroenterology and Hepatology
      • • Department of Medicine
      Stanford, CA, United States
  • 2009
    • Universidad de Extremadura
      Ara Pacis Augustalis, Extremadura, Spain
    • McMaster University
      • Farncombe Family Digestive Health Research Institute
      Hamilton, Ontario, Canada
  • 2007
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
    • Chung-Ang University
      Sŏul, Seoul, South Korea
  • 2003
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 2001
    • Vanderbilt University
      Nashville, Michigan, United States