WJGP|www.wjgnet.com

ISSN 2150-5330 (online)

World J Gastrointest Pathophysiol 2010 August 15; 1(3): 91-114

Triglyceride (intramuscular droplet)Prothrombotic state

FibrinogenPAI-1 Adiponectin

FFA

FFA CO2

Glycogen

Insulin

InsulinFFA

C-reactive protein

Interleukin 6

Sympathetic nervous system

Glucose

TNF-a interleukin 6

VLDL

↓ HDL cholesterol↑ Small dense LDL

Hypertension

C-ⅡC-ⅢB-100 and

Triglyceride

-

-

-

-

-

-

Role of insulin resistance in metabolic syndrome.

PRESIDENT AND EDITOR-IN-CHIEFLian-Sheng Ma, Beijing

STRATEGY ASSOCIATE EDITORS-IN-CHIEFJean François Beaulieu, QuebecHirotada Akiho, FukuokaSharon DeMorrow, Texas

GUEST EDITORIAL BOARD MEMBERSJin-Town Wang, Taipei

MEMBERS OF THE EDITORIAL BOARD

ArgentinaMarcelo G Roma, Rosario

Australia

Shu-Feng Zhou, Victoria

AustriaMichael Trauner, Graz

BelgiumRobaeys Geert, Genk

Michael HJ Maes, Wilrijk Theodoor A Niewold, HeverleeMathieu Vinken, Roeselare

BrazilNiels OS Câmara, São PauloJuarez Quaresma, Belem

CanadaFernando Alvarez, QuebecFrancois Boudreau, QuebecWang-Xue Chen, OttawaWolfgang Kunze, OntarioJian-Jun Li, Ontario Nathalie Rivard, QuebecEldon A Shaffer, AlbertaManuela Santos, QuebecJean Sévigny, Quebec

ChinaCH Cho, Hong KongZhong-Hong Gao, Wuhan Jing-Yan Han, BeijingWei Wei, Hefei Hua Yang, ChongqingXiao Yang, Beijing

Czech RepublicMartin Vokurka, Praha

DenmarkLars Arendt Nielsen, Aalborg

Egypt

Ram I Mahato, Memphis

France

Pascale Plaisancié, Lyon

Germany

Carsten Bergmann, IngelheimElke Cario, EssenNikolaus Gassler, AachenWerner Hartwig, HeidelbergChristoph Michalski, MunichFrank Tacke, AachenBrigitte Vollmar, Rostock

Greece

George V Papatheodoridis, Athens

India

Uday Bandyopadhyay, Kolkata Nilesh M Dagia, Maharashtra

The World Journal of Gastrointestinal Pathophysiology Editorial Board consists of 154 members, representing a team of worldwide experts in gastrointestinal pathophysiology. They are from 27 countries, including Argentina (1), Australia (1), Austria (1), Belgium (4), Brazil (2), Canada (10), China (8), Czech Republic (1), Denmark (1), Egypt (1), France (1), Germany (7), Greece (1), India (2), Iran (1), Ireland (1), Israel (2), Italy (11), Japan (11), Netherlands (1), Singapore (3), South Korea (5), Spain (8), Sweden (2), Switzerland (2), United Kingdom (4), and United States (61).

Editorial Board2010-2015

August 15, 2010ⅠWJGP|www.wjgnet.com

Iran

Shahram Shahabi, Urmia

Ireland

Stephen J Keely, Dublin

Israel Yosefa Avraham, Jerusalem Yaakov M Kendler, Tel-Hashomer

Italy

Alessandro Antonelli, PisaRosaria Acquaviva, CataniaSalvatore Auricchio, NaplesGiuseppe Calamita, BariIgnazio Castagliuolo, PadovaWalter Fries, MessinaEnzo Ierardi, FoggiaPietro Invernizzi, Rozzano Anna Kohn, RomeAnnamaria Staiano, NaplesClaudio Tiribelli, Trieste

Japan

Haruki Kitazawa, Sendai Xiao Kang Li, TokyoAtsushi Nakajima, KanagawaKoji Nomoto, Tokyo Hidekazu Suzuki, TokyoIkuo Shoji, Hyogo Toru Takahashi, Okayama Yoshihisa Takahashi, TokyoTakato Ueno, Kurume Hitoshi Yoshiji, Nara

Netherlands

Aldo Grefhorst, Groningen

SingaporeMadhav Bhatia, SingaporeBrian KP Goh, Singapore Cliff KS Ong, Singapore

South KoreaMyung Haing Cho, SeoulHo Jae Han, GwangjuSang Geon Kim, SeoulWon-Jae Lee, SeoulKwan Kyu Park, Daegu

SpainFernando Azpiroz, BarcelonaMarçal P Anglada, BarcelonaRamón Bataller, Barcelona Dariao A Castroviejo, GranadaJoan Clària, BarcelonaMaría Eugenia Sáez, SevilleYolanda Sanz, ValenciaMaria D Yago, Granada

SwedenBob Roger Olsson, GöteborgHenrik Thorlacius, Malmö

Switzerland Jyrki J Eloranta, Zurich

Catherine Pastor, Geneva

United Kingdom

Geoffrey Burnstock, LondonGirish Gupte, Birmingham Vadim Sumbayev, KentAndrea Varro, Liverpool

United States

Gianfranco D Alpini, TempleGyorgy Baffy, Massachusetts

Michael T Bailey, ColumbusDavid H Berger, Texas Wei-Biao Cao, Rhode Island Jiande Chen, Texas Mashkoor A Choudhry, Illinois Parimal Chowdhury, Arkansas Edwin A Deitch, New Jersey H Henry Dong, PittsburghHui Dong, Carolina Ashkan Farhadi, IrvineMitchell P Fink, Pennsylvania Robert Armour Forse, OmahaYan-Fang Guan, Ohio Hartmut Jaeschke, Kansas Chris Kevil, Los Angeles Pawel R Kiela, Arizona Tammy Lyn Kindel, Ohio Ashok Kumar, DetroitSuthat Liangpunsakul, Indiana Feng-Xin Lu, Massachusetts Guang-Xiang Luo, LexingtonKenneth Maiese, New YorkAdhip PN Majumdar, Michigan José E Manautou, Connecticut Craig J McClain, Kentucky Douglas S Merrell, BethesdaMurielle Mimeault, OmahaAdam Moeser, North Carolina Chung Owyang, Michigan Helieh S Oz, LexingtonsNicholas C Popescu, BethesdaChao Qin, Oklahoma P Rafiee, Wisconsin Sigrid A Rajasekaran, Wilmington Ramesh M Ray, Tennessee Yehuda Ringel, Chapel HillRichard A Rippe, Maryland Chantal A Rivera, Los Angeles Paul A Rufo, BostonSanjaya K Satapathy, New Hyde ParkMuhammad Y Sheikh, FresnoLe Shen, Illinois Frank A Simmen, Little RockNed Snyder, TexasStuart Jon Spechler, Texas Catia Sternini, California Yvette Taché, California George C Tsokos, Massachusetts Arnold Wald, MadisonGuo-Yao Wu, TexasChristian Wunder, BethesdaGuo-Rong Xu, New Jersey Chiang John YL, Ohio Jay A Yelon, ValhallaShao-Yong Yu, Pennsylvania Joerg Zehetner, Los AngelesJian X Zhang, North Carolina Zhi Zhong, CharlestonQing Zhu, Maryland

ⅡWJGP|www.wjgnet.com August 15, 2010

91   Metabolic syndrome and gastro-esophageal reflux: A link towards a growing 

interest in developed countries

Ierardi E, Rosania R, Zotti M, Principe S, Laonigro G, Giorgio F, de Francesco V, Panella C

97Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in

irritable bowel syndrome

Akiho H, Ihara E, Nakamura K

106Colo-renal fistula: An unusual cause of hematochezia

Wysocki JD, Joshi V, Eiser JW, Gil N

109Isolated splenic tuberculosis: A case report

Zhan F, Wang CJ, Lin JZ, Zhong PJ, Qiu WZ, Lin HH, Liu YH, Zhao ZJ

112Syphilitic proctitis mimicking rectal cancer: A case report

Zhao WT, Liu J, Li YY

Contents

EDITORIAL

BimonthlyVolume1Number3August15,2010

August 15, 2010|Volume 1|Issue 3|WJGP|www.wjgnet.com I

REVIEW

CASE REPORT

ContentsWorld Journal of Gastrointestinal Pathophysiology

Volume1Number3August15,2010

IAcknowledgments to reviewers of World Journal of Gastrointestinal  Pathophysiology

I Meetings

I-V   Instructions to authors

Ierardi E, Rosania R, Zotti M, Principe S, Laonigro G, Giorgio F, de Francesco V, 

Panella C. Metabolic syndrome and gastroesophageal reflux: A  link towards a 

growing interest in developed countries

World J Gastrointest Pathophysiol  2010; 1(3): 91-96  http://www.wjgnet.com/2150-5330/full/v1/i3/91.htm 

World Journal of Gastrointestinal Pathophysiology (World J Gastrointest Pathophysiol, WJGP, online ISSN 2150-5330, DOI: 10.4291), is a bimonthly, open-access, peer-reviewed journal supported by an editorial board of 154 experts in gastrointestinal pathophysiology from 27 countries.

The major task of WJGP is to report rapidly the most recent results in basic and clinical research on gastrointestinal pathophysiology, including all aspects of normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. WJGP specifically covers growth and development, digestion, secretion, absorption, metabolism and motility relative to the gastrointestinal organs, as well as immune and inflammatory processes, and neural, endocrine and circulatory control mechanisms that affect these organs. This journal will also report new methods and techniques in gastrointestinal pathophysiological research.

I-II Editorial BoardFLYLEAF

ACKNOWLEDGMENTS

APPENDIX

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Na Liu Responsible Science Editor: Hai-Ning ZhangResponsible Electronic Editor: Na Liu Proofing Editorial Office Director: Hai-Ning ZhangProofing Editor-in-Chief: Lian-Sheng Ma

NAME OF JOURNAL World Journal of Gastrointestinal Pathophysiology

LAUNCH DATEApril 15, 2010

SPONSOR Beijing Baishideng BioMed Scientific Co., Ltd., Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, China Telephone: 0086-10-8538-1892Fax: 0086-10-8538-1893E-mail: baishideng@wjgnet.comhttp://www.wjgnet.com

EDITINGEditorial Board of World Journal of Gastrointestinal Pathophysiology, Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: 0086-10-5908-0038Fax: 0086-10-8538-1893E-mail: wjgp@wjgnet.comhttp://www.wjgnet.com

PUBLISHINGBaishideng Publishing Group Co., Limited,Room 1701, 17/F, Henan Bulding, No.90 Jaffe Road, Wanchai, Hong Kong, ChinaFax: 00852-3115-8812

Telephone: 00852-5804-2046E-mail: baishideng@wjgnet.comhttp://www.wjgnet.com

SUBSCRIPTIONBeijing Baishideng BioMed Scientific Co., Ltd., Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: 0086-10-8538-1892Fax: 0086-10-8538-1893E-mail: baishideng@wjgnet.comhttp://www.wjgnet.com

ONLINE SUBSCRIPTION One-Year Price 108.00 USD

PUBLICATION DATEAugust 15, 2010

CSSNISSN 2150-5330 (online)

PRESIDENT AND EDITOR-IN-CHIEFLian-Sheng Ma, Beijing

STRATEGY ASSOCIATE EDITORS-IN-CHIEFJean François Beaulieu, QuebecHirotada Akiho, FukuokaSharon DeMorrow, Texas

EDITORIAL OFFICEHai-Ning Zhang, Director

World Journal of Gastrointestinal PathophysiologyRoom 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: 0086-10-5908-0038Fax: 0086-10-8538-1893E-mail: wjgp@wjgnet.comhttp://www.wjgnet.com

COPYRIGHT© 2010 Baishideng. All rights reserved; no part of this publication may be commercially reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise without the prior permission of Baishideng. Authors are required to grant World Journal of Gastrointestinal Pathophysiology an exclusive license to publish.

SPECIAL STATEMENT All articles published in this journal represent the viewpoints of the authors except where indicated otherwise.

INSTRUCTIONS TO AUTHORSFull instructions are available online at http://www.wjgnet.com/2150-5330/g_info_20100316080008.htm. If you do not have web access please contact the editorial office.

ONLINE SUBMISSION http://www.wjgnet.com/2150-5330office

ABOUT COVER

August 15, 2010|Volume 1|Issue 3|WJGP|www.wjgnet.com II

AIM AND SCOPE

EDITORIAL

Metabolic syndrome and gastro-esophageal reflux: A link towards a growing interest in developed countries

Enzo Ierardi, Rosa Rosania, Mariangela Zotti, Simonetta Principe, Giulio Laonigro, Floriana Giorgio, Vincenzo de Francesco, Carmine Panella

Enzo Ierardi, Rosa Rosania, Mariangela Zotti, Simonetta Principe, Giulio Laonigro, Floriana Giorgio, Vincenzo de Francesco, Carmine Panella, Gastroenterology Section, De­partment of Medical Sciences, University of Foggia, Foggia 71100, ItalyAuthor contributions: Ierardi E and Panella C designed the study, revised the manuscript and approved the final version; Rosania R, Zotti M, Prencipe S and Laonigro G collected the data; De Francesco V, Giorgio F and Ierardi E analyzed the data; and Rosania R, Zotti M, Prencipe S and Giorgio F drafted the manuscript.Correspondence to: Enzo Ierardi, MD, Profesor, Section of Gastroenterology, Department of Medical Sciences, University of Foggia, Ospedali Riuniti, Viale L. Pinto, Foggia 71100, Italy. enzo.ierardi@fastwebnet.itTelephone: +39­0881­733848 Fax: +39­0881­733849 Received: May 21, 2010 Revised: July 23, 2010Accepted: July 30, 2010Published online: August 15, 2010

AbstractThe aim of this Editorial is to describe the growing possibility of a link between gastro-esophageal reflux disease (GERD) and metabolic syndrome on the light of recent epidemiological and pathophysiological evidence. The state of the art of GERD is described, based on recent definitions, pathophysiological evidence, epi-demiology in developed countries, clinical subtypes together with a diagnostic approach specifically focussed on the appropriateness of endoscopy. Metabolic syn-drome is accurately defined and the pivotal role of in­sulin resistance is emphasized. The strong relationship between GERD and metabolic syndrome has been pathophysiologically analyzed, taking into account the role of obesity, mechanical factors and metabolic changes. Data collected by our group regarding eating habits and GERD are briefly summarized at the end of a pathophysiological analysis. The literature on the subject strongly supports the possibility that lifestyle and eating habits may be involved in both GERD and metabolic syndrome in developed countries.

© 2010 Baishideng. All rights reserved.

Key words: Gastroesophageal reflux disease; Metabolic syndrome; Obesity; Insulin resistance

Peer reviewers: Jing­Bo Zhao, Associate Professor, Depart­ment of Abdominal Surgery, Aalborg Hospital, Aalborg, DK 9000, Denmark; Shouji Shimoyama, MD, Department of Gas­trointestinal Surgery, University of Tokyo, Bunkyo­ku, Tokyo 113­8655, Japan; Ilse Hoffman, Professor, Division of Pediatrics, University Hospitals Leuven, Leuven 3000, Belgium

Ierardi E, Rosania R, Zotti M, Principe S, Laonigro G, Giorgio F, de Francesco V, Panella C. Metabolic syndrome and gastro­esophageal reflux: A link towards a growing interest in deve loped countries. World J Gastrointest Pathophysiol 2010; 1(3): 91­96 Available from: URL: http://www.wjgnet.com/2150­5330/full/v1/i3/91.htm DOI: http://dx.doi.org/10.4291/wjgp.v1.i3.91

INTRODUCTIONGastroesophageal reflux disease (GERD) was compared by Castell in 1985[1] as an “iceberg”, in which only a small part is visible and requiring a medical intervention.Since then, the visible part of the “iceberg” has been growing steadily, until it has affected, at least sporadically, about half of people living in developed countries.

Metabolic syndrome is another relevant disorder which has been shown to be strongly linked to environmental conditions and the normal habits of people in developed countries, and is invoked to explain some disorders in­volving different apparatus with a particular regard to the digestive tract.

In this Editorial, the growing link between the above­mentioned two conditions is analyzed in the light of re­cent epidemiological and pathophysiological evidence.

GASTROESOPHAGEAL REFUX DISEASEDefinition, epidemiology, pathogenesisGastroesophageal refux disease (GERD) is defined as an

Online Submissions: http://www.wjgnet.com/2150-5330officewjgp@wjgnet.comdoi:10.4291/wjgp.v1.i3.91

91

World J Gastrointest Pathophysiol 2010 August 15; 1(3): 91-96ISSN 2150-5330 (online)

© 2010 Baishideng. All rights reserved.

August 15, 2010|Volume 1|Issue 3|WJGP|www.wjgnet.com

abnormal reflux of gastric contents into the esophagus at least once a week, leading to symptoms such as heartburn and/or acid regurgitation, and/or esophageal mucosal damage, which may also provoke long­term complica­tions, such as Barrett’s esophagus[2­3]. According to the Montreal definition and classification of the disease[4], GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.

GERD is the most common upper gastrointestinal disease in the Western countries, with 10%­20% of the population experiencing weekly symptoms[5­8]. Its pre­valence is also increasing in the Far East (Japan) and other areas in Asia[9].

GERD is a multifactorial disease in which anatomical and functional factors both play a pathogenetic role. Ge­nerally it is grouped into two types: the primitive type and the secondary type.

In the primitive type the main pathogenetic mechanism is considered to be a transient lower esophageal sphincter relaxation[10] that is a visceral reflex occurring mainly in response to gastric distension.

The secondary type has been correlated with a heter­ogeneous group of disorders, such as metabolic or en­docrine diseases, collagenopathies, systemic neuropathies, asthma, abdominal surgery, drugs and pregnancy.

The esophageal expression could include the typical reflux syndrome, the reflux chest pain syndrome and the syndrome with esophageal injury.

GERD is often associated with a hiatal hernia, espe­cially a sliding hernia (Type Ⅰ hernia). In this type, the cardia of the stomach is allowed to migrate back and forth between the posterior mediastinum and the peritoneal cavity. The gastro­esophageal junction is thus incompetent and large volumes of gastric contents pass unimpeded into the hiatal sac[11­12].

GERD encompasses a large spectrum of clinical fea­tures, generally characterized as esophageal and extra­esophageal expressions.

Gastroesophageal refux disease subtypesThe esophageal expression includes the typical reflux syn­drome, the reflux chest pain syndrome and the syndrome with esophageal injury, further divided into non­erosive reflux disease, reflux esophagitis, reflux stricture, Barrett’s esophagus and esophageal adenocarcinoma. In summary, GERD is a categorical disease which manifests itself in three distinct ways: non­erosive or erosive esophagitis, and Barrett’s esophagus. These three phenotypes represent different disorders. A cange from one condition to an­other condition is limited, thus suggesting that these, once established, remain distinct entities[13­14]. Moreover, when after discontinuing treatment, reflux symptoms tend to recur, the patient presenting one of the 3 entities at the onset will very often relapse in the same manner. Accor­ding to this information, GERD is a chronic disease, probably without progression, and reflux symptoms do not tend to recur in relation to endoscopic findings[15]. However, some studies state that the progression of NERD to erosive esophagitis is possible in only 10% of

GERD patients, thus indirectly confirming the hypothesis of a respective phenotypic presentation.

Gastroesophageal refux disease diagnostic approach: The appropriateness of endoscopyAlthough many tools are available for the diagnosis of GERD, such as endoscopy, manometry, ambulatory pH monitoring and esophagograms, none of them is con­sidered to be the gold standard.

The main use of upper gastrointestinal endoscopy in patients with GERD should be limited to the evaluation of treatment failures and esophageal injury. However endoscopic esophageal mucosal breaks, erosion or ulce­rationare absent in more than 50% of individuals who have had heartburn two or more times 1 wk for 6 mo. Even the recognition of minor endoscopic mucosal chan­ges, such as erythema, edema or mucosal friability attri­buted to GERD is so unreliable that these findings are of not useful for the diagnosis of reflux esophagitis[15­16]. Endoscopy plays a key role in the presence of alarm sym­ptoms, including vomiting, weight loss, dysphagia, anemia, blood loss, chest pain or epigastric mass[17]. The American Society for Gastrointestinal Endoscopic guidelines con­sider endoscopy appropriate for evaluating esophageal reflux symptoms which are persistent or recurrent, despite appropriate therapy, which needs to be given to a patient with typical symptoms without further investigation[18]. Indeed, a response is a diagnostic investigation “per se” (proton pump inhibitor test). Sequential or periodic endo­scopy may be indicated, moreover, for the surveillance of patients with Barrett’s esophagus[19].

The above reported diagnostic approach is summa­rized in the flow­chart in Figure 1[20].

A very promising diagnostic tool is offered by pH impedance testing, which allows the recognition of every intraesophageal regurgitation independently by its source (acid, bile, air, food etc.), even if its real use in clinical practice remains to be recorded only in the next few years.

METABOLIC SYNDROMEDefinitionMetabolic syndrome is a cluster of metabolic abnorma­lities that has been highlighted as a risk factor for car­diovascular and other chronic diseases. It affects one fifth of the population in the developed world and its preva lence increases with the age. Some studies estimate the pre­valence in the USA to be up to 25% of the population[21] .

The International Diabetes Federation (IDF) consen­sus in 2006 defined the metabolic syndrome as the asso­ciation of central obesity. Central obesity is, in turn, de­fined as waist circumference with ethnicity specific values as reported in Table 1 with two of the following altered parameters: triglycerides > 150 mg/dL (1.7 mmol/L) or a specific treatment for this lipid abnormality, reduced HDL cholesterol < 40 mg/dL (1.03 mmol/L) in males and < 50 mg/dL (1.29 mmol/L) in females or a specific treatment for this lipid abnormality, raised blood systolic (> 130) or diastolic pressure (> 85 mm Hg) or treatment of previously diagnosed hypertension and raised fasting

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Ierardi E et al . Metabolic syndrome and gastro­esophageal reflux

plasma glucose > 100 mg/dL (5.6 mmol/L) or previ­ously diagnosed type 2 diabetes[22].

Role of insulin resistanceThe pathophysiology of metabolic syndrome is extremely complex, and has been only partially elucidated. Most patients are old and obese with a sedentary lifestyle and a variable degree of insulin resistance. Stress can also be a contributing factor[23].

A relevant pathogenetic factor is represented by insu­lin resistance (IR), a condition in which body cells become less sensitive to the hormone[24]. This phenomenon is frequent in people with visceral adiposity, hypertension, hyperglycemia and dyslipidemia. IR in fat cells results in elevated hydrolysis of stored triglycerides which increases the mobilization of free fatty acids into the plasma. IR reduces glucose uptake in skeletal muscle, and in hepato­cytes it impairs glycogen synthesis and storage, suppress­ing glucose production and release into the blood. The main effects of IR are reported in Figure 2[25].

Various diseases make body tissues more resistant to the actions of insulin,for example, infections mediated by the tumour necrosis factor­alpha (TNF­α) and acidosis. In the presence of IR, the visceral adipose cells in par­ticular produce significant amounts of proinflammatory cytokines, such as TNF­α, IL1 and IL6. In experimental models, these proinflammatory cytokines disrupt normal insulin action in fat and muscle cells, and this may be the

major factor in causing the whole­body insulin resistance observed in patients with visceral adiposity[26]. Further, vis­ceral adiposity is related to an accumulation of fat in the liver, a condition known as nonalcoholic fatty liver disease (NAFLD)[27]. The result of NAFLD is an excessive release of free fatty acids into the bloodstream, and an increase in hepatic glucose production, both of which have the effect of exacerbating peripheral insulin resistance and increas­ing the likelihood of Type 2 diabetes.

GASTROESOPHAGEAL REFUX DISEASE AND METABOLIC SYNDROMERelationship between gastroesophageal refux disease and metabolic syndromeA strong relationship between the two disorders has been accurately described in an original study that reported the transition rates between each state of esophagitis as a natural history in patients with metabolic syndrome[28]. The study was a voluntary health promotion program that used a standard protocol, including physical examination, blood chemistry, plain radiography, abdominal ultrasono­graphy and endoscopy. The population studied included 3669 subjects undergoing four upper endoscopies (en­doscopy 1 at baseline, endoscopy 2 after 528 d, endos­copy 3 after 392 d, and endoscopy after 352 d). Data were analysed using a three­state Markov model to estimate transition rates (according to the Los Angeles classifi­cation) regarding the natural course of the disease. During these three consecutive study periods, only 84 patients progressed from non­erosive to erosive disease, whereas 256 regressed to the non­erosive stage. Multivariate ana­lysis showed that the clinical weight of an individual is af fected by gender, smoking, metabolic syndrome and short­term PPI or H2RA therapy. This finding has had important implications for the design of effective strate gies of prevention and screening, since this study demo­nstrates that intra­oesophageal damage is a dynamic pro­cess, in which the metabolic syndrome is associated with accelerated progression to, or attenuated regression from, erosive states.

The authors conclude that the value of identifying risk factors and protecting the oesophageal mucosa from

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Ierardi E et al . Metabolic syndrome and gastro­esophageal reflux

Serious, frequent, or lasting(> 4 wk)

Symptoms

Episodic classic symptoms, lasting

> 4 wk

Medicalcheckup

4 wk lasting symptoms

Antacids and anti-H2 therapy, or

combinations

Controlled symptoms

PPI therapy with

standard dosage

Lack of serious or alarming

symptoms

Presence of serious

or alarming symptoms

Presence of symptoms

Controlled symptoms

High dosage of

PPI (bid)

Persisting symptoms

Specialistic checkup and/or

esophagas-troduodenoscopy

Maintenancetherapy

Figure 1 American Gastroenterology Association guidelines for gastro-esophageal reflux disease diagnostic approach with a particular regard to esophagastroduodenoscopy appropriateness[20].

Table 1 Waist circumference with ethnicity specific values

WHO (1998)

EGIR (1999)

NCEP (2001)

IDF (2005)

Waist circumference

BMI > 30 and/or

waist/hip comparison

Abdominal weight

Abdominal weight

Abdominal weight

> 0.90(men)

> 0.94 cm (men)

> 102 cm (men)

> 94 cm men

> 0.85 (women)

> 0.80 cm (women)

> 88 cm (women)

> 80 cm (women)

BMI: body mass index; WHO: World Health Organization;EGIR: The European Group for Study of Insulin Resistance; NCEP: National Cholesterol Education Program; IDF: International Diabetes Federation.

irreversible damage may be a key point, since spontaneous regression is possible in patients with mild erosive disease without pharmacological treatment. The evaluation of individual risk at this stage would therefore give patients the opportunity to modify their behaviour (weight re­duction, giving up smoking) and enable clinicians only to select patients most likely to develop irreversible changes for endoscopic screening, and to offer them early phar­macological treatment. A similar conclusion may be drawn from the experience of our group, which is described later.

Mechanical factors: The role of obesityIn the recent past, the occurrence of GERD has paralleled the increasing prevalence of obesity, with the incidence of GERD in the Western world found in more than 20% of the population[29]. The consensual increase in the frequency of obesity and GERD in Western countries[30] has suggested a possible pathogenetic link between these two diseases, and has generated great interest in explaining the mechanisms demonstrating this association.

Since there are probably multiple pathogenetic mecha­nisms of GERD, it is possible that not all of them are related to, or influenced by, the presence of obesity[31]. Obesity may be considered as an independent risk factor for GERD, and it seems that the risk of developing GE­RD increases with increasing weight. However, the exact pathophysiological mechanisms underlying the association have not been fully identified, even if some hypotheses have been suggested. It has long been hypothesized that visceral adiposity, expressed by an increased abdominal

waist circumference, could be associated with increased intra­abdominal pressure, which in turn promotes GERD by increasing intragastric pressure[32­35]. Furthermore, obe­sity might cause increased intra­abdominal pressure that results in extrinsic gastric compression by visceral fat, with a subsequent increase in intragastric pressure and the gastroesophageal pressure gradient[36], as well as an increased risk for developing a hiatal hernia[37­40]. In obese patients, other factors that play a role in the pathophy­siology of GERD are esophageal peristaltic abnormalities, such as malfunction of the lower esophageal sphincter, nu­tcracker esophagus and non­specific motility disorders[41].

Role of metabolic changesHowever, the most important reflux mechanism in obese subjects seems to be a transient lower esophageal sphi­ncter relaxation[10], generated by gastric distension, which leads to intense stimulation of both stretch and tension mechanoreceptors in the proximal stomach[42­43].

Recently, a European study investigated the prevalence of central adiposity, metabolic syndrome, and a proin­flammatory state in patients with Barrett’s esophagus, and found that the proinflammatory impact of adipocytokines associated with the metabolic syndrome of central adi­posity may play an important role in the pathogenesis of esophageal cancer[44­45]. In particular, it has been demon­strated that visceral fat is metabolically active[46] as well as being associated with low serum levels of protective cytokines, such as adiponectin. Therefore, high levels of

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Ierardi E et al . Metabolic syndrome and gastro­esophageal reflux

Triglyceride (intramuscular droplet)Prothrombotic state

FibrinogenPAI-1 Adiponectin

FFA

FFA CO2

Glycogen

Insulin

InsulinFFA

C-reactive protein

Interleukin 6

Sympathetic nervous system

Glucose

TNF-α interleukin 6

VLDL

↓ HDL cholesterol↑ Small dense LDL

Hypertension

C-ⅡC-ⅢB-100 and

Triglyceride

-

-

-

-

-

-

Figure 2 Role of insulin resistance in metabolic syndrome (from Eckel et al[25], Lancet 2005).

inflammatory cytokines, such as TNF­α, IL­1β and IL­6 all contribute to GERD development and symptoms.

DIETARY HABITS IN PATIENTS WITH GASTROESOPHAGEAL REFUX DISEASE: OUR EXPERIENCELifestyle factors (overweight/obesity, incorrect dietary habits, lack of regular physical activity and smoking) have frequently been suggested to be possible GERD risk factors. However, their exact pathogenetic role is still unclear, and the beneficial effect of specific recommended changes in lifestyle habits is controversial[10].

It is a common belief that some foods may induce or worsen GERD symptoms; in fact, in daily clinical practice, this leads to medical staff advising patients to avoid the suspected foods[47]. Furthermore, since GERD symptoms are most commonly reported postprandially, the role of diet components in inducing symptoms through a lower esophageal sphincter release or a delayed gastric emptying has been suggested. Nevertheless, different and conflicting results exist in the literature for identifying the most “refluxogenic” foods. Old experimental and clinical studies have shown a decrease in LES pressure and an increase in esophageal acid exposure in response to the ingestion of food rich in fats, chocolate and carminatives[48­49].

Our study examined the effects of dietary intake on GERD and, although performed on a small sample, re­presents the only study in which the diagnosis was based not only on the clinical symptoms, but also on the measu­rement of esophageal pH over a 24 h period.

The aim of this study was to evaluate the correlation between pH­metry results in GERD patients and their daily food intake, including the assessment of fibre consumption. We enrolled 60 patients, stratified for age and sex, divided into three groups of 20 patients each. The first group included subjects with pH­metry results showing a pathological acid reflux and with typical GERD symptoms; in the second group typical symptoms were present even if pH­metry was not irrefutably pathological (pH < 4 for a period < the 10% of record); the third group was composed by healthy volunteers[50]. For each patient, Body Mass Index was calculated, and a weekly dietary intake questionnaire, which allowed calculating

daily caloric and macronutrient intake with the use of a dedicated software (Winfood) had to be completed.

Our results are summarized in Table 2. Lipidic and glucidic intake was directly correlated to symptom pre­sence independently by pH­metry results by statistical uni­variated analysis. Nevertheless with statistical multivariated analysis, only lipid intake correlated with typical GERD symptom presence and pH­metry results. Finally, fibre intake seemed to play a protective role in the relief of GERD symptoms.

Whilst lipids are known for their ability to reduce lower esophageal sphincter pressure and delay gastric empting, a possible explanation for glucidic intake may be only speculative (i.e. their fermentation by intestinal bacterial flora may cause the production of gas enabling sphincter release and, consequently, GERD symptoms).

CONCLUSIONEpidemiologic evidence has consistently shown a growing association between metabolic syndrome and GERD in developed countries. Changes in gastroesophageal phy­siology may explain the link between these two conditions. Recent data suggest that central adiposity may be the most important factor for the development of reflux and complications such as Barrett’s esophagus and esophageal adenocarcinoma. Weight loss through caloric restriction (especially of lipids and glucids) appears to be beneficial in reducing GERD symptoms. These remarks as well as the recent experience of our group seem to support the relevance of eating habits and suggest a correction of lifestyle and diet as a primary therapeutic approach for GERD.

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Table 2 Body mass index and macronutrient intake in gastro-esophageal reflux disease patients1

Parameters Controls Symptoms P

BMI 26.4 ± 4.5 26.1 ± 2.7 < 0.88Kcal/die 2015 ± 384 1782 ± 420 < 0.05Lipids (%) 31.4 ± 3.2 33.9 ± 3.9 < 0.02Proteins (%) 16.8 ± 1.6 17.1 ± 2.5 < 0.70Glucids (%) 48.8 ± 5.1 52.1 ± 3.2 < 0.01Fibers (g/die) 43.8 ± 12.7 26.2 ± 7.6 < 0.04

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22 Alberti KG, Zimmet P, Shaw J. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366: 1059-1062

23 Gohil BC, Rosenblum LA, Coplan JD, Kral JG. Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity. CNS Spectr 2001; 6: 581-586, 589

24 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607

25 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndro-me. Lancet 2005; 365: 1415-1428

26 Tselepis C, Perry I, Dawson C, Hardy R, Darnton SJ, Mc-Conkey C, Stuart RC, Wright N, Harrison R, Jankowski JA. Tumour necrosis factor-alpha in Barrett’s oesophagus: a pote-ntial novel mechanism of action. Oncogene 2002; 21: 6071-6081

27 Liu Q, Bengmark S, Qu S. The role of hepatic fat accumu-lation in pathogenesis of non-alcoholic fatty liver disease (NA-FLD). Lipids Health Dis 2010; 9: 42

28 Lee YC, Yen AM, Tai JJ, Chang SH, Lin JT, Chiu HM, Wang HP, Wu MS, Chen TH. The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease. Gut 2009; 58: 174-181

29 Katzmarzyk PT, Leon AS, Wilmore JH, Skinner JS, Rao DC,

Rankinen T, Bouchard C. Targeting the metabolic syndrome with exercise: evidence from the HERITAGE Family Study. Med Sci Sports Exerc 2003; 35: 1703-1709

30 Nestle M. The ironic politics of obesity. Science 2003; 299: 78131 Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak

CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 2006; 295: 1549-1555

32 Falk GW. Obesity and gastroesophageal reflux disease: ano-ther piece of the puzzle. Gastroenterology 2008; 134: 1620-1622

33 Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK, Kahrilas PJ. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006; 130: 639-649

34 de Vries DR, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure. Am J Gastroenterol 2008; 103: 1349-1354

35 Lambert DM, Marceau S, Forse RA. Intra-abdominal pres-sure in the morbidly obese. Obes Surg 2005; 15: 1225-1232

36 El-Serag HB, Tran T, Richardson P, Ergun G. Anthropometric correlates of intragastric pressure. Scand J Gastroenterol 2006; 41: 887-891

37 Merrouche M, Sabaté JM, Jouet P, Harnois F, Scaringi S, Coffin B, Msika S. Gastro-esophageal reflux and esophageal motility disorders in morbidly obese patients before and after bariatric surgery. Obes Surg 2007; 17: 894-900

38 Iovino P, Angrisani L, Galloro G, Consalvo D, Tremolaterra F, Pascariello A, Ciacci C. Proximal stomach function in obesity with normal or abnormal oesophageal acid exposure. Neurogastroenterol Motil 2006; 18: 425-432

39 Iovino P, Angrisani L, Tremolaterra F, Nirchio E, Ciannella M, Borrelli V, Sabbatini F, Mazzacca G, Ciacci C. Abnormal esophageal acid exposure is common in morbidly obese pa-tients and improves after a successful Lap-band system im-plantation. Surg Endosc 2002; 16: 1631-1635

40 Suter M, Dorta G, Giusti V, Calmes JM. Gastric banding interferes with esophageal motility and gastroesophageal reflux. Arch Surg 2005; 140: 639-643

41 Koppman JS, Poggi L, Szomstein S, Ukleja A, Botoman A, Rosenthal R. Esophageal motility disorders in the morbidly obese population. Surg Endosc 2007; 21: 761-764

42 Jaffin BW, Knoepflmacher P, Greenstein R. High prevalence of asymptomatic esophageal motility disorders among morbidly obese patients. Obes Surg 1999; 9: 390-395

43 Hong D, Khajanchee YS, Pereira N, Lockhart B, Patterson EJ, Swanstrom LL. Manometric abnormalities and gastroe-sophageal reflux disease in the morbidly obese. Obes Surg 2004; 14: 744-749

44 Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA Jr. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006; 354: 2340-2348

45 Nocon M, Labenz J, Willich SN. Lifestyle factors and sym-ptoms of gastro-oesophageal reflux -- a population-based study. Aliment Pharmacol Ther 2006; 23: 169-174

46 Ryan AM, Healy LA, Power DG, Byrne M, Murphy S, Byrne PJ, Kelleher D, Reynolds JV. Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflam-matory state. Ann Surg 2008; 247: 909-915

47 Nebel OT, Castell DO. Lower esophageal sphincter pressure changes after food ingestion. Gastroenterology 1972; 63: 778-783

48 Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate in-gestion. Am J Gastroenterol 1988; 83: 633-636

49 Nebel OT, Fornes MF, Castell DO. Symptomatic gastro-esophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21: 953-956

50 MF Minenna, A Palieri, MC Nacchiero, V De Francesco, N Della Valle, G Stoppino, A Tarollo, F Diterlizzi, G Verderosa, E Ierardi, C Panella. Macronutrient dietary intake and gastro-esophageal reflux disease: a clinic and pH-metric study. Dig­est Liver Dis 2007; 39: AS182

S- Editor Zhang HN L- Editor Herholdt A E- Editor Liu N

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REVIEW

Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome

Hirotada Akiho, Eikichi Ihara, Kazuhiko Nakamura

Hirotada Akiho, Eikichi Ihara, Kazuhiko Nakamura, De­partment of Medicine and Bioregulatory Science, Graduate Sch­ool of Medical Sciences, Kyushu University, Fukuoka 812­8582, JapanAuthor contributions: All authors contributed extensively in preparing this manuscript; Akiho H provided a significant edi­torial and literature contribution; Nakamura K performed the lite­rature review; and Ihara E provided literature related comments and review.Correspondence to: Hirotada Akiho, MD, PhD, Department of Medicine and Bioregulatory Science, Graduate School of Me­dical Sciences, Kyushu University, 3­1­1 Maidashi, Higashi­ku, Fukuoka 812­8582, Japan. akiho@intmed3.med.kyushu­u.ac.jpTelephone: +81­92­6425286 Fax: +81­92­6425287Received: June 12, 2010 Revised: July 26, 2010Accepted: August 2, 2010Published online: August 15, 2010

AbstractThe pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic stra-tegies for IBS.

© 2010 Baishideng. All rights reserved.

Key words: Irritable bowel syndrome; Serotonin; Enteri-tis; Gastrointestinal motility

Peer reviewers: Reiko Miyazawa, MD, PhD, Assistant Profe­sser, Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine, Showa­machi,

Maebashi 371­8511, Japan; Enzo Ierardi, Professor, Section of Gastroenterology, Departement of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, Foggia 71100, Italy

Akiho H, Ihara E, Nakamura K. Low­grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome. World J Gastrointest Pathophysiol 2010; 1(3): 97­105 Available from: URL: http://www.wjgnet.com/2150­5330/full/v1/i3/97.htm DOI: http://dx.doi.org/10.4291/wjgp.v1.i3.97

INTRODUCTIONIrritable bowel syndrome (IBS) is seen throughout the world with estimated prevalences ranging from 9%-23%[1], representing an important clinical problem. It is accom-panied by a poor quality of life[2]. Its symptoms include abdominal pain or discomfort associated with changes in bowel habits for which no obvious cause can be found on routine investigations[3] and its diagnosis is commonly dependent on the symptom-based Rome criteria (Table 1).

The pathogenesis is considered to be multifactorial and includes psychosocial factors, gastrointestinal (GI) dys-motility, enhanced perception of sensory stimuli conveyed from the gut wall to the central nervous system, stress, corticotrophin-releasing factor, infection, microbiota, ge-netics and gut wall immune activation[4]. It is now well rec-ognized that an episode of gastroenteritis can trigger IBS symptoms, known as post-infective IBS (PI-IBS). Low-grade inflammation and immune activation are evident in biopsies both from patients with IBS[5] and PI-IBS[6]. It is becoming clear that low grade inflammation in the mucosal compartment of the gut could alter function in the underlying neuromuscular tissues from animal studies. IBS represents a clinical entity largely diffused which may heavily affect the patient’s quality of life and a strong need of oriented therapeutic interventions could be avaible.

This review describes the evidence for low-grade in-flammation in patients with IBS, explores its mechanism

Online Submissions: http://www.wjgnet.com/2150-5330officewjgp@wjgnet.comdoi:10.4291/wjgp.v1.i3.97

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© 2010 Baishideng. All rights reserved.

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with particular focus on the inflammation-induced GI motility and highlights its implications for understanding the pathophysiology of IBS.

EVIDENCE OF INFLAMMATION IN IRRITABLE BOWEL SYNDROMECytokines and immune cellsSeveral reports have described increased numbers of T cells in various lymphoid compartments of the small or large intestine in IBS patients[5,7,8]. Proinflammatory cyto kines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α in peripheral blood mononuclear cells[9] and IL-6 and IL-8 in serum[10] were reported to be incre-ased in IBS patients. Thus, low-grade inflammation can be detected through biopsies from intestine and blood.

Subsequent studies in IBS patients revealed increased numbers of mast cells in the lamina propria of the termi-nal ileum[11] and mucosa of the colon[12,13]. It is becoming clear that mast cells may affect the sensorimotor func-tion and contribute to IBS symptoms[13,14]. Barbara et al[13] showed that activated mast cells released significant amounts of various mediators including tryptase and his-tamine. It has been reported that mast cell tryptase elicits neuronal hyperexcitability[15,16] while histamine activates visceral sensory nerves via histamine-1 and -2 receptors[17], indicating that tryptase and histamine are candidate me-diators for the gut sensorimotor dysfunction in IBS[18].

PI-IRRITABLE BOWEL SYNDROME Epidemiological studies have indicated that 6%-17% of patients with acute gastroenteritis develop IBS[19]. Low-grade inflammation and immune activation are evident in biopsies from patients with PI-IBS and there is also evidence of increased intestinal permeability[4].

NeurotransmittersSerotonin: Serotonin (5-hydroxytryptamine, 5-HT) is fou-nd in the GI tract and central nervous system and func-tions as a neurotransmitter[20]. 5-HT is the most studied neu rotransmitter in IBS. About 95% of the body’s 5-HT is localized in the GI tract and 5% is present in the brain. In the GI tract, 5-HT is synthesized in serotonergic neurons in the enteric nervous system as well as in enterochromaf-fin (EC) cells of the GI mucosa.

EC cells produce and secrete far more 5-HT than central or peripheral serotonergic neurons and it reaches the GI lumen and blood[21]. Overflowing 5-HT from EC cells, taken up and concentrated in platelets, is virtually the sole source of blood 5-HT. 5-HT exerts its actions by binding to its receptors (5-HT1-7) which are present on intrinsic and extrinsic primary afferent neurons. The large range of effects of 5-HT mainly results from the presence of the multiple receptor subtypes on enteric neurons, EC cells, gastrointestinal smooth muscle cells, enterocytes and immune tissues. Seven families and multiple subtypes of 5-HT receptors have now been identified[22]. The 5-HT1-4 and 5-HT7 receptors are known to affect gut motor fun-

ctions[23-26]. 5-HT is well known to increase in various GI disorders such as carcinoid syndrome, celiac disease, acute bacterial enteritis and inflammatory bowel disease (IBD)[27,28]. Several studies have shown that plasma 5-HT is increased in patients with IBS[29,30]. Furthermore, the effectiveness of 5-HT3 antagonists for IBS with diarrhea (IBS-D) has been demonstrated[31] and 5-HT3 antagonists are currently widely used for IBS-D in various countries. PI-IBS has been associated with increased numbers of EC cells[32]. Although IBS with constipation (IBS-C) patients showed decreased plasma 5-HT[29], colonic[29,33] and duodenal[34] mucosal 5-HT appeared to be increased. Opiate-induced constipation does not alter the 5-HT con-tent or mucosal serotonin transporter (SERT) level in hu-mans, suggesting that the changes in 5-HT metabolism in IBS-C are primary[27].

5-HT released in the mucosa is rapidly taken up by serotonin transporters in nerve terminals or mucosal en-terocytes and vascular endothelial cells[35]. The associations between SERT transcription levels, polymorphisms and IBS phenotypes have been investigated. The SERT gene-linked polymorphic region (SERT-LPR), an area 12 kb upstream of the SERT exon that has short (s) and long (l) alleles, is thought to influence the level of transcription[36].

Emerging biomarkersThe identification of reliable biomarkers represents a ma-jor step forward in the management of disease. The phy-siological changes accompanying IBS have been shown to be reflected in changes in the expression levels of biomar kers[37-39]. The reliable serum biomarker for IBS is expected to reduce an unnecessary colonoscopy caused by symp tom-based criteria.

Lembo et al[40] investigated blood-based diagnostic tests to differentiate IBS from non-IBS using the Smart Diagnostic Algorithm and complex patterns of the serum concentrations among 10 biomarkers, including IL-1β, growth-related oncogene-α, brain-derived neurotrophic factor, anti-Saccharomyces cerevisiae IgA antibodies, anti-CBir1 antibodies, anti-human tissue transglutaminase an-tibodies, TNF-like weak inducer of apoptosis (TWEAK), anti-neutrophil cytoplasmic antibodies, tissue inhibitor of metalloproteinase-1 and neutrophil gelatinase-associated lipocalin. They demonstrated that the positive predictive value was 81% and the negative predictive value was 64% at 50% IBS prevalence in the validation cohort[40]. There-fore, the pathophysiology of IBS is heterogeneous and the identification of multiple biomarkers is more reliable than detection of a single biomarker for IBS.

MicrobiotaThe intestinal microbiota influences a broad array of host

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Table 1 Rome Ⅲ criteria

Recurrent abdominal pain or discomfort for at least 3 d per month in the last 3 mo associated with two or more of the following Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool

organs including the gut and brain and is an important determinant of normal function in these systems. Dis-ruption of the delicate balance between the host and the intestinal microbiota (termed dysbiosis) results in changes in the mucosal immune system that range from overt inflammation, as seen in Crohn’s disease, to low-grade inflammation without tissue injury, as seen in a subset of IBS patients. The dysbiosis induced by infection, diet or antibiotics can produce the low-grade inflammation seen in IBS[41]. Malinen et al[42] showed that Lactobacillus species were decreased in IBS-D patients while Veionella species were increased in IBS-C patients.

Other groups have obtained evidence that the in-testinal microflora of patients with IBS differs from that of healthy subjects[43,44]. It has recently been suggested that IBS symptoms are partly caused by a process designated small intestinal bacterial overgrowth (SIBO)[45,46]. Fur-ther therapeutic manipulation of the gut flora with anti-biotics[47] or probiotics[48] improves the symptoms of IBS but is controversial. We consider SIBO as a subtype of IBS more than a distinct entity.

These lines of evidence provide proof of the con-cept that the intestinal microbiota can induce the persis-tent gut dysfunction seen in IBS.

GI MOTILITY AND SMOOTH MUSCLEGI motility is defined by the movements of the digestive system including two fundamental patterns of motility, propulsion and mixing. Several players including central nerves, enteric nerves, interstitial cells of Cajal (ICC) and smooth muscles contribute to a coordinated regulation of GI motility. Among them, smooth muscle probably plays the most important role in GI motility since the patterns of motility observed in gut are characteristic of smooth muscle which has different properties from skeletal muscle. The contractile properties of smooth muscle are mainly regulated by the phosphorylation of regulatory light chains of myosin Ⅱ (LC20)[49] which is driven by the balance between myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activities. MLCK depends on Ca2+-calmodulin. Intracellular Ca2+ [(Ca2+)i] is the primary determinant of smooth muscle contraction. However, MLCP functions independently of Ca2+-calmodulin and is regulated by G protein-coupled signaling pathways. Inhibition of MLCP leads to an increase in both MLC phosphorylation and contractile force development in smooth muscle without any changes in (Ca2+)i

[50]. This enhancement of the contractile response to Ca2+ is commonly referred to as 'calcium sensitization'[49]. In general, several protein kinases including Rho-associated kinase (ROK)[51], protein kinase C (PKC)[52], integrin-linked kinase (ILK)[53,54] and zipper-interacting protein kinase (ZIPK)[55] have been shown to contribute to regulation of MLCP and Ca2+ sensitization, mediated directly by phosphorylation of the myosin phosphatase targeting subunit of MLCP (MYPT1) and/or indirectly by phosphorylation of a PKC-potentiated

phosphatase inhibitor protein-17 kDa (CPI-17). In ad-dition, it has been shown that mitogen activated protein kinase pathways also contribute to intestinal smooth muscle contraction and Ca2+ sensitization possibly via regulation of MLCP[56].

GUT MOTOR FUNCTION IN INFLAMMATIONConditions ranging from infective acute enteritis or colitis to IBD and functional disorders such as IBS are accom-panied by altered GI motility[57] which can be a reflection of altered function of enteric nerves, ICC or smooth muscles. Alterations in GI motility with resultant changes in transit contribute to the abdominal pain, intestinal cramping and diarrhea. Colonic mast cell infiltration and mediator release in the proximity of mucosal innervations may contribute to abdominal pain perception in patients with IBS[13]. Patients with IBD in remission often generate IBS symptoms, termed IBD/IBS, and have pain and diar-rhea similar to those in IBS patients in association with minimal or no evident intestinal inflammation[58].

These findings suggest that low-grade inflammation contributes to the GI motor dysfunction and abdominal symptoms in patients with functional GI disorders and IBD in remission. Since we cannot use whole human intestinal tissue to investigate the pathophysiology of IBS, we have tried to establish bench-to-bedside animal models for the development of new therapies.

Which immune cells and mediators and how do they affect gastrointestinal motility?Macrophages: Macrophages perform a key role in innate defense against foreign invaders and produce a number of cytokines such as IL-1β, IL-6 and TNF-α. In animal experiments, macrophages infiltrate the gut wall including the neuromuscular layers during nematode infection in mice. It was reported that macrophages were not critical for the change in muscle contraction in Trichinella spiralis-infected mice[59] although another group reported that alternative activated macrophages affected the muscle hypercontractility in Nippostrongylus brasiliensis-infected mice[60].

T lymphocytes (Th1/Th2): T lymphocytes are crucial for many immune responses, including those associated with animal models such as dextran sulfate sodium coli-tis[61], 2,4,6-trinitrobenzenesulfonic acid colitis[62], nema-tode infection[57,63] and anti-CD3 antibody-induced en-teropathy[64]. Antigen-presenting cells present antigens to CD4+ T helper (Th) cells. Th cell-dependent immune re-sponses are generally divided into two major subsets, Th1 and Th2[65]. Th1 cells predominantly produce interferon (IFN) γ and IL-2 while Th2 cells produce IL-4, IL-5, IL-9 and IL-13. Th1 and Th2 cells cross-regulate one another. While few generalizations can be made, it appears that contractile dysfunction depends on the specific inflamma-tory environment. Recent accumulated data from animal

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models have shown that Th1 and Th2 immune response was associated with hypocontractility or hypercontractility of inflamed intestinal smooth muscle respectively.

Schwartz et al[66] showed that surgical manipulation suppressed jejunal contractions with upregulation of IL-6, TNF-α, cyclooxygenase-2 and inducible nitric oxide synthase. It has been shown that both TNF-α[67] and IL-1β[68] were associated with hypocontractility of inflamed intestinal smooth muscle. Furthermore, we have shown that incubation of IFNγ with intestinal smooth muscle decreased carbachol-induced smooth muscle cell contrac-tion[69]. It has also been shown how these Th1-related cytokines cause hypocontractility of inflamed intestinal smooth muscle. TNF-α and IL-1β inhibited carbachol-induced contraction via down-regulation of CPI-17[62] and L-type Ca2+ channels[70] respectively.

On the other hand, the Th2 cytokines IL-4 and IL-13 acting via Stat6 mediate the development of nematode in-fection-induced intestinal muscle hypercontractility which contributes to worm expulsion[71-73]. Other studies sup-ported our finding that Th2 responses mediated muscle contractility in nematode N. brasiliensis-infected mice[60,74]. Although it remains to be investigated how these Th2-related cytokines mediate hypercontractility of inflamed intestinal smooth muscle, Ihara et al[61] showed that mi-togen-activated protein kinase pathways played crucial roles in the Th2 cytokine-mediated Ca2+ sensitization and hypercontractility observed in inflamed colonic circular smooth muscle from dextran sulfate sodium-treated mice.

Th1/Th2 balance: To evaluate the role of Th1/Th2 in infection-induced alterations of enteric muscle function, Khan et al[75] investigated the effects of IL-12 overexpres-sion on intestinal muscle contractility and worm expulsion in T. spiralis-infected mice. IL-12 gene transfer via a single injection of a recombinant adenovirus vector expressing IL-12 (Ad5IL-12) in T. spiralis-infected mice effectively inhibited the development of infection-induced intestinal muscle hypercontractility and prolonged worm survival in the gut. A shift to a Th1 response after overexpression of IL-12 significantly altered the intestinal muscle hypercon-tractility in this Th2-based enteric infection.

Furthermore, we evaluated the association of 5-HT with Th1/Th2 responses. 5-HT influences intestinal ho-meostasis by altering the gut physiology and has been implicated in the pathophysiology of various GI dis-orders such as IBD, IBS and GI infection[35,36,76,77]. In a colonic parasitic infection with Trichuris muris, resistant strains (BALB/c, C57BL/6 and NIH Swiss) expelled the parasites through the generation of a Th2 response whe-reas susceptible strains (AKR and B10.BR) developed a chronic infection with activation of a Th1 response[78].

We used Trichuris muris-infected AKR (susceptible to infection with generation of a Th1 response), BALB/c (resistant to infection with generation of a Th2 response), Stat4-deficient (impaired in Th1 responses) and Stat6-deficient (impaired in Th2 responses) mice to explore the mechanism of the EC cell and 5-HT responses in Th1/Th2-dominant environments[79]. We found that the

EC cell and 5-HT responses to the same infectious agent were influenced by Th1 or Th2 cytokine predominance, suggesting that the immunological profile of the inflam-matory response is important in the regulation of EC cell biology in the gut. Furthermore, we evaluated the 5-HT response and intestinal motility in an IBD/IBS model using T cell-induced enteropathy in Th1/Th2-dominant environments[80]. In BALB/c mice, carbachol-induced intestinal smooth muscle cell contraction was significantly increased at d 7 after anti-CD3 antibody injection when the tissue damage returned to the normal histological appearance. We also observed that 5-HT protein in the intestine was significantly increased at d 7. On the other hand, in AKR mice, carbachol-induced muscle cell contraction was significantly decreased at d 7. 5-HT pro-tein in the intestine was also decreased at d 7. We showed that Th1 and Th2 cytokines had opposing effects on intestinal muscle contraction via 5-HT signaling in the post-inflammation phase in this model.

Th17: Previous concepts regarding the roles of Th cells in chronic inflammatory and autoimmune diseases have been challenged by the description of a novel T-cell sub-set characterized by the production of IL-17[81]. Several disorders originally considered to be Th1-mediated have been reclassified as Th17-mediated inflammation[82,83]. Th17 cells produce IL-17, IL-17F and IL-22, thereby in-ducing a massive tissue reaction owing to the broad distri-bution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the im-mune system. The differentiation factors (TGF-beta plus IL-6 or IL-21), the growth and stabilization factor (IL-23) and the transcription factors (STAT3, RORgammat and RORalpha) involved in the development of Th17 cells have just been identified[84]. IL-17 is a proinflammatory cytokine that activates T cells and other immune cells to produce a variety of cytokines, chemokines and cell adhe-sion molecules. This cytokine is augmented in the sera and/or tissues of patients with contact dermatitis, asthma

and rheumatoid arthritis[82]. Although the Th1/Th17 bal-ance in human IBD remains unclear, IBD seems to have a relationship with Th17 cells[85]. Low-grade inflammation in the mucosa is considered to be a factor involved in the pathophysiology of IBS and further investigations of Th17 cells in the intestinal mucosa of patients with IBS should therefore be carried out[86]. A recent study showed that Th17 cells were increased during acute infection with T. spiralis and that jejunal smooth muscle strips cultured with IL-17 showed enhanced contractions elicited by acetylcholine in a concentration-dependent manner[87]. We found that IL-17 protein in the small intestine was upregulated in mice injected with an anti-CD3 antibody[88] and that IL-17 incubation with smooth muscle cells en-hanced carbachol-induced smooth muscle cell contrac-tion (unpublished observation). Further investigations are required using IL-17-/- mouse and IL-17 antagonist to confirm the role of IL-17-induced muscle hypercontrac-tility (Table 2).

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VISCERAL HYPERSENSITIVITYAbdominal pain is an essential symptom of IBS and vis-ceral hypersensitivity is the most widely accepted mecha-nism[89]. Visceral sensitivity is regulated at the level of the peripheral (mucosa/submucosa), spinal cord and central nervous system. Non-inflammatory mediators such as stress, glycerol and glutamate, as well as inflammatory mediators have the potential to trigger visceral pain[89].

Inflammatory mediators such as prostaglandin E2 from inflammatory cells, or chemical mediators such as ATP, bradykinin, 5-HT, substance P and calcitonin gene-related peptide, directly activate nerve endings and trigger the release of algesic mediators, histamine, 5-HT, nerve growth factor and prostanoids from other cells and afferent nerves, resulting in an increasing response of pain[89]. Nerve fibers expressing the capsaicin receptor, transient receptor potential vanilloid type-1, were incre-ased in colonic mucosa from IBS patients and may con-tribute to the visceral hypersensitivity and pain in IBS[90]. Recent animal studies showed that 5-HT2B receptor an tagonists[91,92], melatonin[93], corticotrophin-releasing hor-mone receptor 1 antagonists[94] and protease-activated re-ceptor-4[95] inhibited visceral hypersensitivity. These mole-cules are candidates for novel therapies against the visceral hypersensitivity in IBS.

SECRETOMOTOR DYSREGULATIONSecretomotor neuronsDisordered defecation in IBS is directly related to the physiology of the enteric secretomotor neurons. Secre-tomotor neurons are excitatory motor neurons in the submucosal plexus of the enteric nervous system which innervate and stimulate secretion from the intestinal crypts of Lieberkuhn, Brunner’s glands and goblet cells.

Secretomotor neurons have receptors that receive excitatory and inhibitory synaptic inputs from other neurons in the integrative circuitry of the enteric nervous system and from sympathetic postganglionic neurons. They are also influenced by paracrine chemical messages from non-neural cell types in the mucosa and submucosa such as EC cells and immune/inflammatory cells[17,90].

Activation of the excitatory receptors on secretomotor neurons stimulates the neurons to fire and release their transmitters at neuroepithelial junctions in the crypts. Secretomotor neurons express excitatory receptors for acetylcholine, 5-HT and histamine. The overall result of the activation of the excitatory receptors and associated increase in secretomotor neuronal firing is stimulation of the secretion of H2O, electrolytes and mucus from the crypts into the intestinal lumen[90].

Knowledge of the cellular neurobiology of submucosal secretomotor neurons is key to understanding the patho-physiology of secretory diarrhea and constipation. Sup-pression of secretomotor firing by antidiarrheal agents such as opiates is manifested as harder-drier stools. On the contrary, stimulation by chemical mediators such as acetylcholine, 5-HT and histamine is manifested as more

liquid stools[90]. The proinflammatory cytokines IL-1β and TNF-α increased epithelial tight junction permeability in vitro in Caco-2 cells in a dose- and time-dependent man-ner[96,97]. This effect was mediated by an increase in myosin L chain kinase expression and activity. IFNγ is well known to increase tight junction permeability in the T84 cell line accompanied by activation of the PI3-kinase pathway[98]. Green tea[99] and probiotics[100] are candidates for reducing the mucosal hyperpermeability seen in IBS.

EFFECTIVE TREATMENTSSeveral emerging clinical trials for IBS are ongoing that target visceral hypersensitivity, motility, neurotransmitters, microbiota and immune systems acting peripherally and/or centrally. Thus far, 5-HT agents have been the most effective for IBS[101,102]. A systematic review showed that the 5-HT3 antagonist alosetron and 5-HT4 agonist tegaserod were more effective than placebos and that serious adverse events were rare, although the Food and Drug Administration announced discontinued marketing of tegaserod due to a potential risk of adverse events, cerebrovascular and cardiovascular ischemic events in 2007[101,102].

One of the excitatory receptors on secretomotor neu rons belongs to the 5-HT3 serotonergic receptor subty-pe[20,103,104]. The observed efficacy of blockade of 5-HT3 receptors by a 5-HT3 antagonist in the treatment of dia rrhea in diarrhea-predominant IBS suggests that over-stimulation of secretomotor neurons by 5-HT is a signifi cant pathophysiological factor in this form of IBS[105,106]. On the contrary, 5-HT4 agonists stimulate GI motility and intestinal secretion and have demonstrated efficacy in improving bowel habits for constipation-predominant IBS[107].

Three 5-HT4 agonists, prucalopride, ATI-7505 and TD-5108, in development are reported to have greater selectivity for 5-HT4 over other receptors and have advan-ced to human trial. 5-HT3 receptor antagonist, ramose-

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Table 2 Immune cells and mediators affecting gastrointestinal motility

Immune cells/mediators Muscle contractility Ref.

Macrophage ↑→ [59,60]

T cell ↑↓ [57,61-64,72]

Proinflammatory cytokines; IL-1β, IL-6, TNFα

↓ [62,66-68,70]

Th1 cytokines; IFNγ, IL-12 ↓ [69,75]

Th2 cytokines; IL-4, IL-9, IL-13 ↑ [60,71-74]

Th17 cytokines; IL-17 ↑ [87,88]

Th1/Th2 balance; Th1 > Th2 ↓ [79,80]

Th1 < Th2 ↑ [61,79,80]

5-HT ↑ [17,20,27,28,80]

MAP kinase ↑ [56,61]

CPI-17 ↓ [62]

L type Ca2+ channel ↓ [70]

TNF: tumor necrosis factor; IFN: interferon; IL: interleukin; 5-HT: serotonin; MAP: mitogen activated protein; CPI-17: protein kinase C-potentiated phosphatase inhibitor protein-17 kDa; Ref: references.

tron, was effective and well tolerated in the treatment of abdominal pain, discomfort and bowel habits in IBS-D patients[108].

IMPLICATIONSIt is becoming increasingly clear that inflammation of the intestinal mucosa and nerves causes the altered GI dysfunction seen in IBS. Several studies have been per-formed to detect robust and reliable biomarkers for IBS[40,109,110]. However, IBS contains many different con-ditions with different underlying causes and different responses to therapy and different mechanisms, biomar-kers and therapies therefore need to be identified in each IBS subgroup. Understanding the underlying immu-nological basis of the altered GI motor dysfunction in IBS by considering the role of the Th1/Th2 balance or Th17 cytokines may ultimately lead to new therapeutic strategies for IBS.

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82 Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. IL-17 plays an important role in the development of experimental autoimmune ence-phalomyelitis. J Immunol 2006; 177: 566-573

83 Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-defi-cient mice. J Immunol 2003; 171: 6173-6177

84 Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485-517

85 Kobayashi T, Okamoto S, Hisamatsu T, Kamada N, Chinen H, Saito R, Kitazume MT, Nakazawa A, Sugita A, Koganei K, Isobe K, Hibi T. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 2008; 57: 1682-1689

86 Andoh A, Ogawa A, Bamba S, Fujiyama Y. Interaction be-

tween interleukin-17-producing CD4+ T cells and colonic subepithelial myofibroblasts: what are they doing in mucosal inflammation? J Gastroenterol 2007; 42 Suppl 17: 29-33

87 Fu Y, Wang W, Tong J, Pan Q, Long Y, Qian W, Hou X. Th17: a new participant in gut dysfunction in mice infected with Trichinella spiralis. Mediators Inflamm 2009; 2009: 517052

88 Tokita Y, Sato K, Nishiyama M, Ikemura R, Akiho H, Naka-mura K, Murao H, Ogino H, Kanayama K, Aso A, Iboshi Y, Itaba S, Takayanagi R, Yamamoto M. Modulation of smooth muscle cell contractility by Th1/Th2 cytokines in gut hyper-contractility in a murine model of T cell-mediated persistent gut motor dysfunction. (Abstract) W1928 DDW2010

89 Bueno L, Fioramonti J. Visceral perception: inflammatory and non-inflammatory mediators. Gut 2002; 51 Suppl 1: i19-i23

90 Wood JD. Neuropathophysiology of functional gastroin-testinal disorders. World J Gastroenterol 2007; 13: 1313-1332

91 O’Mahony SM, Bulmer DC, Coelho AM, Fitzgerald P, Bongiovanni C, Lee K, Winchester W, Dinan TG, Cryan JF. 5-HT(2B) receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction. Neurogastroenterol Motil 2010; 22: 573-578, e124

92 Ohashi-Doi K, Himaki D, Nagao K, Kawai M, Gale JD, Furness JB, Kurebayashi Y. A selective, high affinity 5-HT2B receptor antagonist inhibits visceral hypersensitivity in rats. Neurogastoenterol Motil 2009; 22: e69-e76

93 Mickle A, Sood M, Zhang Z, Shahmohammadi G, Sengupta JN, Miranda A. Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process. Pain 2010; 149: 555-564

94 Saito-Nakaya K, Hasegawa R, Nagura Y, Ito H, Fukudo S. Corticotropin-releasing hormone receptor 1 antagonist blocks colonic hypersensitivity induced by a combination of inflammation and repetitive colorectal distension. Neuro­gastroenterol Motil 2008; 20: 1147-1156

95 Augé C, Balz-Hara D, Steinhoff M, Vergnolle N, Cenac N. Protease-activated receptor-4 (PAR 4): a role as inhibitor of visceral pain and hypersensitivity. Neurogastroenterol Motil 2009; 21: 1189-e107

96 Ma TY, Boivin MA, Ye D, Pedram A, Said HM. Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol Gastrointest Liver Physiol 2005; 288: G422-G430

97 Al-Sadi RM, Ma TY. IL-1beta causes an increase in intes-tinal epithelial tight junction permeability. J Immunol 2007; 178: 4641-4649

98 Al-Sadi R, Boivin M, Ma T. Mechanism of cytokine modu-lation of epithelial tight junction barrier. Front Biosci 2009; 14: 2765-2778

99 Watson JL, Ansari S, Cameron H, Wang A, Akhtar M, McKay DM. Green tea polyphenol (-)-epigallocatechin gallate blocks epithelial barrier dysfunction provoked by IFN-gamma but not by IL-4. Am J Physiol Gastrointest Liver Physiol 2004; 287: G954-G961

100 Ramakrishna BS. Probiotic-induced changes in the intestinal epithelium: implications in gastrointestinal disease. Trop Gas­troenterol 2009; 30: 76-85

101 Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Scho-enfeld PS, Spiegel BM, Talley NJ, Quigley EM. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104 Suppl 1: S1-S35

102 Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009; 104: 1831-1843; quiz 1844

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5-HT3 antagonist alosetron on basal and cholera toxin-in-duced secretion in the human jejunum: a segmental perfusion study. Aliment Pharmacol Ther 1997; 11: 1109-1114

105 Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, Mangel AM. A randomized con-trolled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bo-wel syndrome. Arch Intern Med 2001; 161: 1733-1740

106 Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomized, placebo-controlled trial. Lancet 2000; 355: 1035-1040

107 Gale JD. The use of novel promotility and prosecretory ag-

ents for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Adv Ther 2009; 26: 519-530

108 Camilleri M. Review article: new receptor targets for medical therapy in irritable bowel syndrome. Aliment Pharmacol Ther 2010; 31: 35-46

109 Clarke G, Quigley EM, Cryan JF, Dinan TG. Irritable bowel syndrome: towards biomarker identification. Trends Mol Med 2009; 15: 478-489

110 Macsharry J, O'Mahony L, Fanning A, Bairead E, Sherlock G, Tiesman J, Fulmer A, Kiely B, Dinan TG, Shanahan F, Quigley EM. Mucosal cytokine imbalance in irritable bowel syndrome. Scand J Gastroenterol 2008; 43: 1467-1476

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CASE REPORT

Colo-renal fistula: An unusual cause of hematochezia

John D Wysocki, Virendra Joshi, John W Eiser, Naveed Gil

John D Wysocki, Virendra Joshi, Naveed Gil, Tulane Uni­versity School of Medicine, LA 70112 , United StatesJohn W Eiser, Lake Erie College of Osteopathic Medicine, Erie, PA 16509, United StatesAuthor contributions: Wysocki J drafted the paper; Joshi V reviewed, edited and approved the final paper; Eiser J collected radiology images, drafted radiology captions, and reviewed the paper; and Gil N provided histology images and captions.Correspondence to: John D Wysocki, MD, Tulane University School of Medicine, 1430 Tulane Ave, LA 70112, United States. jwysocki@tulane.eduTelephone: +1­814­6174294223 Received: April 8, 2010 Revised: June 3, 2010Accepted: June 10, 2010Published online: August 15, 2010

AbstractA 76 year old woman with bloody stools and symp­tomatic anemia presented to the Emergency Depart­ment approximately 2 wk after computed tomography (CT)­guided cryoablation to a 4.5 cm renal cell car­cinoma on her left posterior kidney. The patient was initially prepped for a colonoscopy to view possible causes of lower gastrointestinal bleeding. However, the patient had a CT with PO contrast that revealed a variation of a renoalimentary fistula. The patient was subsequently brought to the operating room, and it was discovered that a colo­renal fistula had formed, with transmural perforation of the posterior descending colon. A left nephrectomy, left colectomy with colostomy and Hartmann’s pouch was performed.

© 2010 Baishideng. All rights reserved.

Key words: Colo-renal fistula; Renocolic fistula; Hema-tochezia; Cryoablation; Alimentary fistula

Peer reviewers: Qing Zhu, MD, PhD, NIH/NIAID, Bethesda, MD 20814, United States; Elke Cario, MD, Professor, Uni­versity Hospital of Essen, Division of Gastroenterology and Hepatology, Institutsgruppe I, Virchowstr. 171, Essen 45147, Germany

Wysocki JD, Joshi V, Eiser JW, Gil N. Colo-renal fistula: An un-usual cause of hematochezia. World J Gastrointest Pathophysiol 2010; 1(3): 106-108 Available from: URL: http://www.wjg­net.com/2150-5330/full/v1/i3/106.htm DOI: http://dx.doi.org/10.4291/wjgp.v1.i3.106

INTRODUCTIONLower gastrointestinal bleeding in an elderly patient has a variety of etiologies. The most common causes of bleeding typically include diverticulosis, ischemic colitis, cancer, and angiodysplasia. Invasive procedures, such as percutaneous ablation, have introduced a new mechanism for the discovery of renalimentary fistula (RFA), of which only a few cases have been described in the literature. In 2006, Arruda et al described a case of renoduodenal fistula after RFA. In 2007, Vanderbrink et al described the first known case of colo-renal fistula after percutaneous cryoablation of renal cell carcinoma. The patient in their case was treated successfully with an internal ureteral stent and the fistula resolved. We present a patient with a colo-renal fistula who required an open surgical procedure as a result of the severity of her clinical presentation. A literature review of colo-renal fistulae is also presented.

CASE REPORTA 76 year-old African American woman presented with a one day history of hematochezia and syncope. She also noted lower abdominal pain, but denied nausea or vomit-ing. Prior to these recent bowel movements, she had been constipated for the past 10 d. She had had a negative colonoscopy 20 years ago. She has type 2 diabetes, hyper-tension, and renal cell carcinoma. Two wk ago, she had computed tomography (CT)-guided percutaneous pal-liative cryoablation to a 4.5 cm tumor on her left kidney. Since the surgery, she had had a poor appetite and had been eating less.

She was afebrile, with a blood pressure of 142/65

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mmHg; her other vital signs were stable. Her left lower abdomen was tender to deep palpation. She had hyperac-tive bowel sounds and, on rectal examination, bright red blood was noted.

Upon admission, her hemoglobin was 9.1 g/dL. Six h later, it had dropped to 7.3 g/dL. Her white blood cell count was 10 300/µL, platelet count 481 000/mL, crea-tinine 1.7 mg/dL, prothrombin time/International Nor-malized Ratio - 10.0 s/0.9. Her urinalysis had glucose > 1000 mg/dL, 26 white blood cells/high power field and trace mucous. There was no fecaluria. A CT scan revealed a 6.8 cm × 7.2 cm × 7.5 cm area within the left kidney, representing prior cryoablation of renal cell carcinoma. Inflammatory changes, oral contrast, and foci of air (Fig-ure 1) were also noted. Small and large bowel were both in close association with this area and possibly denoted a bowel fistula. Extensive atherosclerosis of the abdominal aorta was also noted. The patient was taken to surgery and a left nephrectomy, left colectomy and Hartman’s Pouch was completed.

The left kidney and left colon were surgically resected and reviewed histopathologically (Figures 2 and 3). The kidney had a completely infarcted 6 cm left lower pole

tumor, with nephro-colonic fistula of the left colon. The colon demonstrated focal acute colitis with perforation and fistulous tract to the kidney.

DISCUSSIONHematochezia in an elderly patient has a variety of etiolo-gies, including diverticulosis, ischemic colitis, cancer, and angiodysplasia. Recently, percutaneous cryoablation has introduced a new mechanism for the discovery of lower gastrointestinal (GI) bleeding. While the colon is typically hydrodissected during cryoablation to reduce the risk of injury to the descending colon, it is possible to inadver-tently puncture the bowel with an applicator or extension of the ablation zone. Perforation may be followed by fis-tula and abscess formation[1]. Fistulography is valuable in diagnosing some types of fistulae, but Parvey et al[2] found that CT was the single most useful diagnostic modality for colo-renal fistula. While colonoscopy is usually indicated in lower GI bleeding, there is no body of evidence to support this procedure for the management of colo-renal fistulae.

Conservative management should be considered in stable patients with normal kidney function and previous success with ureteral stenting to close fistulas[3]. When conservative management is not an option, or the fistula is complex, surgery is the primary method of treatment. Symptoms indicating that surgery is required include in-testinal obstruction, bleeding, sepsis, or renal failure[4] and the surgery then should be nephrectomy and partial bowel resection. Due to this patient’s co-morbidities, surgical ex-ploration was performed to treat her lower GI bleeding.

Only a few case reports describe colo-renal fistula after ablative techniques: Uribe et al[5] and Weizer et al[6] des-cribed them after laparoscopic and percutaneous RFA, re-spectively. Silverman[7] and Vanderbrink[3] described colo-renal fistulae after percutaneous cryoablation of renal cell carcinoma. Although rare, physicians should be aware of the risks of these ablative techniques. Patients may appear to have a classic presentation of hematochezia, but, in rea-lity, require timely imaging, and close coordination with

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Figure 3 The histopathology represented is a tissue sample from the intestinal fistula. Note the inflammation on the serosal layer with an accu­mulation of neutrophils (arrow).

Figure 1 This image illustrates the reflux of the oral contrast into the left kidney via the colo-renal fistula, as well as free air in the renal parenchyma and perinephric space (arrow). Also noted is thickened small bowel wall adjacent to the left kidney (arrow tip).

Figure 2 This is a gross specimen of the descending colon that fistulized with the kidney. There are granular and smoothing changes of the large bowel encompassing the fistula, indicating that there was adhesion and phlegmon prior to fistulization (arrow).

the surgical team. In this case, a carefully taken history of recent intra-abdominal interventions prevented unneces-sary endoscopic evaluation.

REFERENCES1 Uppot RN, Silverman SG, Zagoria RJ, Tuncali K, Childs

DD, Gervais DA. Imaging-guided percutaneous ablation of renal cell carcinoma: a primer of how we do it. AJR 2009; 192: 1558-1570

2 Parvey HR, Cochran ST, Payan J, Goldman S, Sandler CM. Renocolic fistulas: complementary roles of computed to-mography and direct pyelography. Abdom Imaging 1997; 22: 96-99

3 Vanderbrink BA, Rastinehad A, Caplin D, Ost MC, Lobko

I, Lee BR. Successful conservative management of colorenal fistula after percutaneous cryoablation of renal-cell carcino-ma. J Endourol 2007; 21: 726-729

4 Feldman M, Friedman S, Brandt LJ. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 8th edition. Philadelphia, 2006: 534-538

5 Uribe PS, Costabile RA, Peterson AC. Progression of renal tumors after laparoscopic radiofrequency ablation. Urology 2006; 68: 968-671

6 Weizer AZ, Raj GV, O’Connell M, Robertson CN, Nelson RC, Polascik TJ. Complications after percutaneous radiofrequency ablation of renal tumors. Urology 2005; 66: 1176-1180

7 Silverman SG, Tuncali K, vanSonnenberg E, Morrison PR, Shankar S, Ramaiya N, Richie JP. Renal tumors: MR imaging-guided percutaneous cryotherapy--initial experience in 23 patients. Radiology 2005; 236: 716-724

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CASE REPORT

Isolated splenic tuberculosis: A case report

Feng Zhan, Chang-Jun Wang, Ju-Ze Lin, Pei-Jin Zhong, Wei-Zhong Qiu, Hua-Huan Lin, Yan-Hui Liu, Zhen-Jun Zhao

Feng Zhan, Chang-Jun Wang, Ju-Ze Lin, Pei-Jin Zhong, Wei-Zhong Qiu, Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangzhou 510080, Guangdong Province, ChinaHua-Huan Lin, Department of Pathology, Guangdong General Hospital, Guangzhou 510080, Guangdong Province, ChinaZhen-Jun Zhao, Yan-Hui Liu, Department of Radiology, Gu­angdong General Hospital, Guangzhou 510080, Guangdong Province, ChinaAuthor contributions: Zhan F, Wang CJ and Lin JZ performed the literature review and wrote the paper; Zhong PJ and Qiu WZ were involved in the clinical care; Zhao ZJ performed CT­guid­ed splenic puncture; and Lin HH and Liu YH performed patho­logical examination.Correspondence to: Feng Zhan, MD, Physician, Department of Traditional Chinese Medicine, Guangdong General Hospital, Guangzhou 510080, Guangdong Province, China. zhanfeng425@yahoo.com.cn Telephone: +86­20­83827812­70512Received: April 23, 2010 Revised: August 2, 2010Accepted: August 9, 2010Published online: August 15, 2010

AbstractWe present a rare case of a 36 year old man who pre-sented with recurrent fever but no other symptoms. Laboratory data provided no specific information for diagnosis. Abdominal ultrasonography revealed sple-nomegaly with multiple small hypoechoic lesions within the spleen. Computed tomography of abdomen showed a hypodense diffuse lesion. A diagnosis of isolated sple-nic tuberculosis was confirmed after a splenic puncture and histopathological examination.

© 2010 Baishideng. All rights reserved.

Key words: Splenic tuberculosis

Peer reviewer: Chao Qin, MD, Department of Physiology, College of Medicine, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, United States

Zhan F, Wang CJ, Lin JZ, Zhong PJ, Qiu WZ, Lin HH, Liu YH, Zhao ZJ. Isolated splenic tuberculosis: A case report. World J Gastrointest Pathophysiol 2010; 1(3): 109­111 Available from: URL: http://www.wjgnet.com/2150­5330/full/v1/i3/109.htm DOI: http://dx.doi.org/10.4291/wjgp.v1.i3.109

INTRODUCTIONSplenic tuberculosis (splenic TB) is extremely rare and has no characteristic symptoms or abnormal imaging findings. Therefore, it is likely to be misdiagnosed as carcinoma of spleen, splenic abscess, lymphoma, rheumatic fever or others. Isolated splenic tuberculosis is rare although secondary involvement in miliary TB is common. The misdiagnosis rate is high if there is no tuberculosis history in other organs. In this case report, we present the pre­sentation, diagnosis, treatment and a literature review.

CASE REPORT A 36 year old Chinese man presented with a history of frequent fevers for 2 mo. The fever often occurred at night with body temperature ranging from 38.5℃ to 40℃. He had chills before fevers and occasional shivers accompanying the fever. There was no history of throat pain, cough, sputum, chest or abdominal pain, night sweats, weight loss or anorexia. His urinary and bowel movements were normal. His medical history did not include any TB and HIV infection. He denied any history of recent foreign travel or a family history of TB and AIDS. On admission, when physically examined, his body temperature was 37.8℃ and he had mild splenomegaly. Laboratory data showed that his red blood cell count was within normal limits, erythrocytic sedimentation rate (ESR) was 64 mm/h, Wildal’s reaction, tuberculous antibody test and HIV antibody reaction were all negative and C­protein level was 69.1 mg/L. Chest radiography revealed no abnormalities. Cardiac ultrasound showed no

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abnormality in morphology and function. An abdominal ultrasound scan showed that the thickness of the spleen was about 5.6 cm, indicating an enlarged spleen with multiple hypoechoic lesions representing solid foci, one of which was 1.0 cm × 0.8 cm with a clear boundary (Figure 1).

Bone marrow puncture and biopsy showed a phenom­enon of animated myelosis including increased activity of granulocytic series and megakaryocytic series; pathologi­cal hematopoiesis can be seen. Computed tomography (CT) of abdomen revealed many hypodense cysts with an unclear boundary which became clear after an enhanced scanning. Fungus infection had not been ruled out be­cause of the diffuse hypodense lesions in the spleen (Figure 2); splenic biopsy was suggested.

A CT­guided splenic puncture and biopsy were taken. The histopathological report showed that a granuloma nodule can be seen with large areas of caseation in the center surrounded by a variable number of Langhan’s giant cells and epithelioid cells accompanying inflamma­tory cells infiltration (Figure 3). Acid­fast staining found no acid­fast bacilli.

Therefore, a final diagnosis of isolated tuberculosis of the spleen was made as there was no other focus of tuberculosis detected in the lung, gastrointestinal tract or lymph nodes. Thus, the patient was started on quadruple anti­TB therapy (rimifon, streptomycin, rifapin, pyrazina­mide and ethambutol). Three days later his fever and chills improved. A repeated abdominal ultrasound showed

notable improvement of the lesion 6 mo later. No recur­rence has been found in the last 3 years.

DISCUSSIONTuberculosis is a multi­system disease, 90% of which locates primarily in lung, whereas isolated splenic tuber­culosis, as we present here, is a rare form of extrapulmo­nary TB. The number of reports of the disease is less than 100 in China according to some expert’s estimates[1]. Patients with AIDS or who are otherwise immunocom­petent have been reported to be at a high risk for splenic TB. Although Winternitz (1912) categorized splenic TB as a primary or secondary form, some scholars insist that all patients with splenic TB are secondary to the previous infection of tubercle bacillus in other organs[2]. In our case, the patient denied a history of TB and there was no indication of any other involvement in other sites or organs at the time of admission. There are no specific symptoms for establishing the diagnosis of splenic TB[3]. Fever was the only symptom in our case and is one of UFO (fever and pyrexia of unknown origin) as defined by Petersdorf and Beeson in 1961[4]. Helpful laboratory data includes anemia, elevated ESR, increased CPR and a positive OT test.

Ultrasound examination is simple, non­invasive and useful. There are 5 types of pathomorphological clas­sifications for splenic TB including miliary TB, nodular TB, tuberculous spleen abscess, calcific TB and mixed type TB.

CT scan is also helpful in the diagnosis, especially for splenic abscess. However, it has its limitations. On one hand, there are many situations that may have presen­tations of multiple, hypodense splenic lesions on CT such as malignant lymphoma, metastatic cancer, echinococcal cysts, hemangioma or even infectious diseases due to frequent fever. Our patient may have been diagnosed with a fungus infection. Fungal splenic abscesses are being increasingly recognized, especially in immunosuppressed patients and Candida is the most involved fungus[5]. How­

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Figure 1 Ultrasound showing splenomegaly with multiple hypoechoic lesions in the spleen.

Figure 2 Abdominal computed tomography demonstrated multiple hypodense diffuse le­sions in the spleen.

Figure 3 A section of the biopsy specimen showing a granuloma nodule with central areas of caseation surrounded by Langerhan’s giant cells and epithelioid cells (Hematoxylin and eosin stained technique, middle­multiplications).

ever, CT can not be suggestive of the nature of lesions in spleen. On the other hand, typical nodules on the splenic capsule are usually too small to be detected easily by CT scan[2].

Needle biopsy of the spleen is an important method of diagnosis. This can proceed by splenic aspiration punc­ture under image guidance. The typical manifestation is caseation along with granuloma of epitheloid cells and Langhan’s cells. Biopsys specimens from cervical lymph node, lymphonodi coeliac, hydroabdomen and pyocelia are also pathological evidence for diagnosis. In other si­tuations, small nodules may be missed on needle biopsy and occasionally laparotomy or even splenectomy may be required. So far, histopathological examination is still an ideal method to confirm the diagnosis. However, many patients are reluctant to accept it due to its invasive nature. Therefore, it is common that patients with the disease are misdiagnosed or diagnosis is delayed.

Laparoscopy has been used in the diagnosis of splenic TB and has proved to be a minimally invasive approach avoiding unnecessary splenectomy. It is recommended for any form of splenic biopsy[6].

In a new case report of solitary splenic TB, micro­biological and molecular examinations have been carried out which are helpful in etiological diagnosis[7].

Like the treatment of pulmonary tuberculosis, treat­ment of splenic TB must be carried out in accordance

with the following principles ­ timely treatment in combi­nation, regularly and properly through the whole course whether or not an operation is performed. Treatment for tuberculosis should last for more than 6 mo. Standard anti­tuberculosis medication should be taken preoperatively and postoperatively if an operation is carried out.

REFERENCES1 Chen XZ, Peng B. Clinical diagnosis and treatment for sple-

nic tuberculosis. Huaxi Medicine 2008; 23: 1142 Singh B, Ramdial PK, Royeppen E, Moodley J, Chetty R.

Isolated splenic tuberculosis. Trop Doct 2005; 35: 48-493 Ozgüroğlu M, Celik AF, Demir G, Aki H, Demirelli F, Man-

del N, Büyükünal E, Serdengeçti S, Berkarda B. Primary splenic tuberculosis in a patient with nasal angiocentric lym-phoma: mimicking metastatic tumor on abdominal CT. J Clin Gastroenterol 1999; 29: 96-98

4 Ho PL, Chim CS, Yuen KY. Isolated splenic tuberculosis presenting with pyrexia of unknown origin. Scand J Infect Dis 2000; 32: 700-701

5 Llenas-García J, Fernánde-Ruiz M, Caurcel L, Enguita-Valls A, Vila-Santos J, Guerra-Vales JM. Splenic abscess: A review of 22 cases in a single institution. Eur J Intern Med 2009; 20: 537-539

6 Meshikhes AWN, Al-Momen SAM. Laparoscopic diagnosis of splenic tuberculosis. Surg Laparosc Endosc Tech 2006; 16: 355-356

7 Fooladi AAI, Hosseini MJ, Azizi T. Splenic tuberculosis: a case report. Int J Infect Dis 2009; 13: e273-e275

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CASE REPORT

Syphilitic proctitis mimicking rectal cancer: A case report

Wen-Tao Zhao, Jing Liu, Yu-Ying Li

Wen-Tao Zhao, Yu-Ying Li, Department of colorectal surgery, the First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, ChinaJing Liu, Department of Dermatology, the First Affiliated Hos­pital, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, ChinaAuthor contributions: Zhao WT wrote and revised the article; Liu J collected and analyzed data; and Li YY supervised the patient management.Correspondence to: Wen-Tao Zhao, Attending Doctor, De­partment of Colorectal Surgery, the First Affiliated Hospital, Gu­angzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China. zhao_wen_tao@tom.comTelephone: +86­20­36588719Received: April 23, 2010 Revised: July 25, 2010Accepted: August 1, 2010Published online: August 15, 2010

AbstractSyphilitic proctitis is a rare disease. It usually presents as proctitis, ulcer and neoplasm but lacks pathognomonic clinical symptoms. It is, therefore, difficult to diagnose and is occasionally treated inappropriately. We report the case of a 51-year-old man who had a hard, ulce-rated mass, which occupied the circumference of the rectal wall and which mimicked a rectal tumor. Fortu nately, positive finding from routine toluidine red un heated serum test and treponema pallidum particle ag glutination tests made us reevaluate the patient and led us to suspect syphilitic proctitis. This diagnosis was finally confirmed after successful penicillin G benzathine therapy which made surgery unnecessary.

© 2010 Baishideng. All rights reserved.

Key words: Syphilis; Rectum; Proctitis; Rectal cancer; Treponema pallidum

Peer reviewer: Shouji Shimoyama, MD, Department of Gas­trointestinal Surgery, University of Tokyo, Bunkyo­ku, Tokyo 113­8655, Japan

Zhao WT, Liu J, Li YY. Syphilitic proctitis mimicking rectal ca ncer: A case report. World J Gastrointest Pathophysiol 2010; 1(3): 112­114 Available from: URL: http://www.wjgnet.com/2150­5330/full/v1/i3/112.htm DOI: http://dx.doi.org/10.4291/wjgp.v1.i3.112

INTRODUCTIONSyphilitic proctitis is a rare disease. It usually presents as proctitis, ulcer and neoplasm but lacks pathognomonic clinical symptoms[1-4]. It is, therefore, difficult to diagnose and is occasionally treated inappropriately[5]. Here, we report a case of syphilitic proctitis which was initially con-sidered to be a rectal cancer.

CASE REPORTA 51-year-old man was referred to our hospital with a 2 wk history of anorectal discomfort. He complained of anorectal discomfort, tenesmus, mucous discharge, increase in the number of stools by 3-4 per day, and intermittent presence of blood in stool. He experienced a weight loss of about 2-kilogram over the previous two weeks. His past history was negative for any anorectal disease, surgery, genetically transmitted problems, or infective illness. He denied improper sexual and same-sex sexual behavior. Rectal examination revealed a hard, ulcerated mass, occupying the circumference of the rectal wall, at 3 cm to 7 cm from the anal verge. Laboratory studies revealed normal results on complete blood cell, urinalysis and serum chemistry testing. Faecal occult blood test was positive. Serum tumor markers were ne-gative. Toluidine red unheated serum test (TRUST) was positive at a dilution of 1: 16 and treponema pallidum particle agglutination (TPPA) test was positive. A human immunodeficiency virus antibody test was negative. Hepatitis B surface antigen, hepatitis B core antibody and hepatitis e antibody were positive. The electrocardiogram and chest radiograph showed no abnormalities. The

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computed tomography of the abdomen demonstrated local inhomogeneous and confounded thickening of the rectal wall, about 3 cm from the anal verge which was believed to represent an infiltrating tumor (Figure 1). The colonoscopy showed an irregular ulcerated mass, 3 cm from the anal verge, with hyperemia and erosion encircling the wall of the rectum (Figure 2A and B). A biopsy specimen was obtained for confirmation of the rectal mass. Histological findings of the biopsy showed extensive infiltration of a large number of lymphocytes, plasma cells and neutrophil granulocytes with formation of lymphoid follicles and ulcer but no heterotypic cells or lymph epithelial lesions (Figure 3). The patient was treated with intramuscular penicillin G benzathine, 2.4 million units per week for 3 wk[2]. Three wk later, the patient was

asymptomatic and a repeat colonoscopy showed the rectal mass completely cleared (Figure 2C).

DISCUSSIONSyphilitic proctitis is observed exceedingly infrequently both because of its low clinical incidence and because of the lack of specific signs and symptoms. It is usually diagnosed as other anorectal disease such as a neoplasm[2]. For examples, in this case, symptoms and signs sugg-ested rectal cancer. The findings from the computed tomography, the colonoscopy and colonoscopic biopsy specimen could not confirm the diagnosis. Fortunately, the positive findings from the routine TRUST and TPPA tests made us reevaluate the patient and led us

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Zhao WT et al . Syphilitic proctitis mimicking rectal cancer

Figure 1 Computed tomography of the ab­domen shows a locally, inhomogenously and confoundedly thicken rectal wall (computed tomography value of 35 Hu). A: Sagittal recon­struction; B: Coronal reco­nstruction.

A B

A B C

Figure 2 Colonoscopic findings. A, B: Colonoscopic findings indicate a rectal mass encircling the wall of the rectum; C: Follow-up colonoscopy after 3 wk reveals complete regression of the rectal mass.

A BFigure 3 Histological findings from colonoscopic biopsy specimen show diffuse extensive infiltration of a large number of lymphocytes, plasma cells and neutrophil granu­locytes (HE staining). A: × 40; B: × 400.

to suspect syphilitic proctitis. This diagnosis was finally confirmed after the penicillin G benzathine therapy in-duced a rapid and completely regression of the rectal mass and the disappearance of symptoms. In summary, a high index of suspicion is important for this disease. The clinical, endoscopic and radiological appearance of syphilitic proctitis may easily be confused with rectal neoplasm. The most common symptoms of syphilitic proctitis are hematochezia, tenesmus, mucous discharge, and changes in bowel habit. The endoscopic appearance may vary from diffuse edema, erythematic, friable or multiple erosions, to ulceration[3]. Moreover, endoscopic rectal mucosal biopsies often show nonspecific chronic inflammation. Radiological appearance is also nonspecific. Serological testing for syphilis is very important for the diagnosis of the disease. We believe that this should be routinely performed on all patients admitted to hospital. If syphilis is considered and positive findings of the test

are obtained, a diagnosis can be confirmed. The patient may then be treated appropriately, and spared unnecessary surgery.

REFERENCES1 Faris MR, Perry JJ, Westermeier TG, Redmond J 3rd. Rectal

syphilis mimicking histiocytic lymphoma. Am J Clin Pathol 1983; 80: 719-721

2 Song SH, Jang I, Kim BS, Kim ET, Woo SH, Park MJ, Kim CN. A case of primary syphilis in the rectum. J Korean Med Sci 2005; 20: 886-887

3 Bassi O, Cosa G, Colavolpe A, Argentieri R. Primary syphilis of the rectum--endoscopic and clinical features. Report of a case. Dis Colon Rectum 1991; 34: 1024-1026

4 Akdamar K, Martin RJ, Ichinose H. Syphilitic proctitis. Am J Dig Dis 1977; 22: 701-704

5 Quinn TC, Lukehart SA, Goodell S, Mkrtichian E, Schuffler MD, Holmes KK. Rectal mass caused by Treponema palli-dum: confirmation by immunofluorescent staining. Gastroen­terology 1982; 82: 135-1398

S- Editor Zhang HN L- Editor Hughes D E- Editor Liu N

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Zhao WT et al . Syphilitic proctitis mimicking rectal cancer

ACKNOWLEDGMENTS

Acknowledgments to reviewers of World Journal of Gastrointestinal Pathophysiology

Many reviewers have contributed their expertise and time to the peer review, a critical process to ensure the quality of World Journal of Gastrointestinal Pathophysiology. The editors and authors of the articles submitted to the journal are grateful to the following reviewers for evaluating the articles (including those published in this issue and those rejected for this issue) during the last editing time period.

Elke Cario, MD, Professor, University Hospital of Essen, Divi­sion of Gastroenterology and Hepatology, Institutsgruppe I, Vir­chowstr. 171, Essen 45147, Germany

Walter Fries, MD, Dip di Medicina Interna e Terapia Medica, (Deptartment of Internal Medicine and Medical Therapy Uni­versità di Messina (University of Messina), 98125 Messina, Via C. Valeria 1, Italy

Ilse Hoffman, Professor, Division of Pediatrics, University Hos­pitals Leuven, Leuven 3000, Belgium

Enzo Ierardi, Professor, Section of Gastroenterology, Depar­tement of Medical Sciences, University of Foggia, AOU Ospedali Riuniti, Viale Pinto, Foggia 71100, Italy

Reiko Miyazawa, MD, PhD, Assistant Professer, Department of Pediatrics and Developmental Medicine, Gunma University Graduate School of Medicine, Showa­machi, Maebashi 371­8511, Japan

Chao Qin, MD, Department of Physiology, College of Medicine, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, United States

Shouji Shimoyama, MD, Department of Gastrointestinal Sur­gery, University of Tokyo, Bunkyo­ku, Tokyo 113­8655, Japan

Jing-Bo Zhao, Associate Professor, Department of Abdominal Surgery, Aalborg Hospital, Aalborg, DK 9000, Denmark

Qing Zhu, MD, PhD, NIH/NIAID, Bethesda, MD 20814, Uni­ted States

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Meetings

Events Calendar 2010January 25-26Tamilnadu, India International Conference on Medical Negligence and Litigation in Medical Practice

January 25-29Waikoloa, HI, United States Selected Topics in Internal Medicine

January 26-27Dubai, United Arab Emirates 2nd Middle East Gastroenterology Conference

January 28-30Hong Kong, China The 1st International Congress on Abdominal Obesity

February 11-13Fort Lauderdale, FL, United States21th Annual International Colorectal Disease Symposium

February 26-28Carolina, United StatesFirst Symposium of GI Oncology at The Caribbean

March 04-06Bethesda, MD, United States8th International Symposium on Targeted Anticancer Therapies

March 05-07Peshawar, Pakistan26th Pakistan Society of Gastroenterology & Endoscopy Meeting

March 09-12Brussels, Belgium 30th International Symposium on Intensive Care and Emergency Medicine

March 12-14Bhubaneswar, India18th Annual Meeting of Indian National Association for Study of the Liver

March 23-26Cairo, Egypt 14th Pan Arab Conference on Diabetes PACD14

March 25-28Beijing, ChinaThe 20th Conference of the Asian

Pacific Association for the Study of the Liver

March 27-28San Diego, California, United States25th Annual New Treatments in Chronic Liver Disease

April 07-09Dubai, United Arab EmiratesThe 6th Emirates Gastroenterology and Hepatology Conference, EGHC 2010

April 14-17Landover, Maryland, United States12th World Congress of Endoscopic Surgery

April 14-18Vienna, AustriaThe International Liver Congress™ 2010

April 28-May 01Dubrovnik, Croatia3rd Central European Congress of surgery and the 5th Croatian Congress of Surgery

May 01-05New Orleans, LA, United StatesDigestive Disease Week Annual Meeting

May 06-08Munich, GermanyThe Power of Programming: International Conference on Developmental Origins of Health and Disease

May 15-19Minneapolis, MN, United StatesAmerican Society of Colon and Rectal Surgeons Annual Meeting

June 04-06Chicago, IL, United StatesAmerican Society of Clinical Oncologists Annual Meeting

June 09-12Singapore, Singapore 13th International Conference on Emergency Medicine

June 14Kosice, Slovakia Gastro-intestinal Models in the Research of Probiotics and Prebiotics-Scientific Symposium

June 16-19Hong Kong, ChinaILTS: International Liver Transplantation Society ILTS Annual

International Congress

June 20-23Mannheim, Germany16th World Congress for Bronchoesophagology-WCBE

June 25-29Orlando, FL, United States70th ADA Diabetes Scientific Sessions

August 28-31Boston, Massachusetts, United States10th OESO World Congress on Diseases of the Oesophagus 2010

September 10-12Montreal, CanadaInternational Liver Association's Fourth Annual Conference

September 11-12La Jolla, CA, United StatesNew Advances in Inflammatory Bowel Disease

September 12-15Boston, MA, United StatesICAAC: Interscience Conference on Antimicrobial Agents and Chemotherapy Annual Meeting

September 16-18Prague, Czech RepublicPrague Hepatology Meeting 2010

September 23-26Prague, Czech RepublicThe 1st World Congress on Controversies in Gastroenterology & Liver Diseases

October 07-09Belgrade, SerbiaThe 7th Biannual International Symposium of Society of Coloproctology

October 15-20San Antonio, TX, United StatesACG 2010: American College of Gastroenterology Annual Scienitfic Meeting

October 23-27Barcelona, Spain18th United European Gastroenterology Week

October 29-November 02Boston, Massachusetts, United StatesThe Liver Meeting® 2010--AASLD's 61st Annual Meeting

November 13-14San Francisco, CA, United States

Case-Based Approach to the Management of Inflammatory Bowel Disease

December 02-04San Francisco, CA, United States The Medical Management of HIV/AIDS

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GENERAL INFORMATIONWorld Journal of Gastrointestinal Pathophysiology (World J Gastrointest Pathophysiol, WJGP, online ISSN 2150-5330, DOI: 10.4291), is a bimonthly, open-access (OA), peer-reviewed journal supported by an editorial board of 154 experts in gastrointestinal patho-physiology from 27 countries.

The biggest advantage of the OA model is that it provides free, full-text articles in PDF and other formats for experts and the public without registration, which eliminates the obstacle that traditional journals possess and usually delays the speed of the propagation and communication of scientific research results.

The role of academic journals is to exhibit the scientific levels of a country, a university, a center, a department, and even a scientist, and build an important bridge for commu-nication between scientists and the public. As we all know, the significance of the publication of scientific articles lies not only in disseminating and communicating innovative scientific achievements and academic views, as well as promoting the application of scientific achievements, but also in formally recognizing the “priority” and “copyright” of innovative achievements published, as well as evaluating research per-formance and academic levels. So, to realize these desired attributes of WJGP and create a well-recognized journal, the following four types of personal benefits should be maximized. The maximization of personal benefits refers to the pursuit of the maximum personal benefits in a well-considered optimal manner without violation of the laws, ethical rules and the benefits of others. (1) Maximization of the benefits of editorial board members: The primary task of editorial board members is to give a peer review of an unpublished scientific article via online office system to evaluate its innovativeness, scientific and practical values and determine whether it should be published or not. During peer review, editorial board members can also obtain cutting-edge information in that field at first hand. As leaders in their field, they have priority to be invited to write articles and publish commentary articles. We will put peer reviewers’ names and affiliations along with the article they reviewed in the journal to acknowledge their contribution; (2) Maximization of the benefits of authors: Since WJGP is an open-access journal, readers around the world can immediately download and read, free of charge, high-quality, peer-reviewed articles from WJGP official website, thereby realizing the goals and significance of the communication between authors and peers as well as public reading; (3) Maximization of the benefits of readers: Readers can read or use, free of charge, high-quality peer-reviewed articles without any limits, and cite the arguments, viewpoints, concepts, theories, methods, results, conclusion or facts and data of pertinent literature so as to validate the innovativeness, scientific and practical values of their own research achievements, thus ensuring that their articles have novel arguments or viewpoints, solid evidence and correct conclusion; and (4) Maximization of the benefits of employees: It is an iron law that a first-class journal is unable to

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Author contributions: The format of this section should be: Author contributions: Wang CL and Liang L contributed equally to this work; Wang CL, Liang L, Fu JF, Zou CC, Hong F and Wu XM designed the research; Wang CL, Zou CC, Hong F and Wu XM performed the research; Xue JZ and Lu JR contributed new reagents/analytic tools; Wang CL, Liang L and Fu JF analyzed the data; and Wang CL, Liang L and Fu JF wrote the paper.

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Peer reviewers: All articles received are subject to peer re-view. Normally, three experts are invited for each article. Decision for acceptance is made only when at least two ex-perts recommend an article for publication. Reviewers for accepted manuscripts are acknowledged in each manuscript, and reviewers of articles which were not accepted will be acknowledged at the end of each issue. To ensure the quality of the articles published in WJGP, reviewers of accepted manuscripts will be announced by publishing the name, title/position and institution of the reviewer in the footnote accompanying the printed article. For example, reviewers: Professor Jing-Yuan Fang, Shanghai Institute of Digestive Disease, Shanghai, Affiliated Renji Hospital, Medical Faculty, Shanghai Jiaotong University, Shanghai, China; Professor Xin-Wei Han, Department of Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Province, China; and Professor Anren Kuang, Department of Nuclear Medicine, Huaxi Hospital, Sichuan University, Chengdu, Sichuan Province, China.

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and structured abstracts (no more than 480). The specific requirements for structured abstracts are as follows:

An informative, structured abstracts of no more than 480 words should accompany each manuscript. Abstracts for original contributions should be structured into the following sections. AIM (no more than 20 words): Only the purpose should be included. Please write the aim as the form of “To investigate/study/…; MATERIALS AND METHODS (no more than 140 words); RESULTS (no more than 294 words): You should present P values where appropriate and must provide relevant data to illustrate how they were obtained, e.g. 6.92 ± 3.86 vs 3.61 ± 1.67, P < 0.001; CONCLUSION (no more than 26 words).

Key wordsPlease list 5-10 key words, selected mainly from Index Medicus, which reflect the content of the study.

TextFor articles of these sections, original articles, rapid commu-nication and case reports, the main text should be structured into the following sections: INTRODUCTION, MATERIALS AND METHODS, RESULTS and DISCUSSION, and should include appropriate Figures and Tables. Data should be presented in the main text or in Figures and Tables, but not in both. The main text format of these sections, editorial, topic highlight, case report, letters to the editors, can be found at: http://www.wjgnet.com/2150-5330/g_info_20100316080000.htm.

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REFERENCESCoding systemThe author should number the references in Arabic numerals ac-cording to the citation order in the text. Put reference numbers in square brackets in superscript at the end of citation content or after the cited author’s name. For citation content which is part of the narration, the coding number and square brackets should be typeset normally. For example, “Crohn’s disease (CD) is associated with increased intestinal permeability[1,2]”. If references are cited directly in the text, they should be put together within the text, for example, “From references[19,22-24], we know that...”

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Style for journal referencesAuthors: the name of the first author should be typed in bold-faced letters. The family name of all authors should be typed with the initial letter capitalized, followed by their abbreviated first and middle initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong Pan as Pan BR). The title of the cited article and italicized journal title (journal title should be in its abbreviated form as shown in PubMed), publication date, volume number (in black), start page, and end page [PMID: 11819634 DOI: 10.3748/wjg.13.5396].

Style for book referencesAuthors: the name of the first author should be typed in bold-faced letters. The surname of all authors should be typed with the initial letter capitalized, followed by their abbreviated middle and first initials. (For example, Lian-Sheng Ma is abbreviated as Ma LS, Bo-Rong Pan as Pan BR) Book title. Publication number. Publication place: Publication press, Year: start page and end page.

FormatJournals English journal article (list all authors and include the PMID where

applicable)1 Jung EM, Clevert DA, Schreyer AG, Schmitt S, Rennert J,

Instructions to authors

August 15, 2010|Volume 1|Issue 3|WJGP|www.wjgnet.com III

Kubale R, Feuerbach S, Jung F. Evaluation of quantitative contrast harmonic imaging to assess malignancy of liver tumors: A prospective controlled two-center study. World J Gastroenterol 2007; 13: 6356-6364 [PMID: 18081224 DOI: 10.3748/wjg.13.6356]

Chinese journal article (list all authors and include the PMID where applicable)

2 Lin GZ, Wang XZ, Wang P, Lin J, Yang FD. Immunologic effect of Jianpi Yishen decoction in treatment of Pixu-diarrhoea. Shijie Huaren Xiaohua Zazhi 1999; 7: 285-287

In press3 Tian D, Araki H, Stahl E, Bergelson J, Kreitman M.

Signature of balancing selection in Arabidopsis. Proc Natl Acad Sci USA 2006; In press

Organization as author4 Diabetes Prevention Program Research Group. Hy-

pertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension 2002; 40: 679-686 [PMID: 12411462 PMCID:2516377 DOI:10.1161/01.HYP.0000035706.28494.09]

Both personal authors and an organization as author 5 Vallancien G, Emberton M, Harving N, van Moorselaar

RJ; Alf-One Study Group. Sexual dysfunction in 1, 274 European men suffering from lower urinary tract symptoms. J Urol 2003; 169: 2257-2261 [PMID: 12771764 DOI:10.1097/01.ju.0000067940.76090.73]

No author given6 21st century heart solution may have a sting in the tail.

BMJ 2002; 325: 184 [PMID: 12142303 DOI:10.1136/bmj.325.7357.184]

Volume with supplement7 Geraud G, Spierings EL, Keywood C. Tolerability and

safety of frovatriptan with short- and long-term use for treatment of migraine and in comparison with sumatriptan. Headache 2002; 42 Suppl 2: S93-99 [PMID: 12028325 DOI:10.1046/j.1526-4610.42.s2.7.x]

Issue with no volume8 Banit DM, Kaufer H, Hartford JM. Intraoperative frozen

section analysis in revision total joint arthroplasty. Clin Orthop Relat Res 2002; (401): 230-238 [PMID: 12151900 DOI:10.1097/00003086-200208000-00026]

No volume or issue9 Outreach: Bringing HIV-positive individuals into care.

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Conference proceedings13 Harnden P, Joffe JK, Jones WG, editors. Germ cell

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Statistical dataWrite as mean ± SD or mean ± SE.

Statistical expressionExpress t test as t (in italics), F test as F (in italics), chi square test as χ2 (in Greek), related coefficient as r (in italics), degree of freedom as υ (in Greek), sample number as n (in italics), and probability as P (in italics).

UnitsUse SI units. For example: body mass, m (B) = 78 kg; blood pressure, p (B) = 16.2/12.3 kPa; incubation time, t (incubation) = 96 h, blood glucose concentration, c (glucose) 6.4 ± 2.1 mmol/L; blood CEA mass concentration, p (CEA) = 8.6 24.5 mg/L; CO2 volume fraction, 50 mL/L CO2, not 5% CO2; likewise for 40 g/L formaldehyde, not 10% formalin; and mass fraction, 8 ng/g, etc. Arabic numerals such as 23, 243, 641 should be read 23 243 641.

The format for how to accurately write common units and quantums can be found at: http://www.wjgnet.com/2150-5330/g_info_20100107160355.htm.

AbbreviationsStandard abbreviations should be defined in the abstract and on first mention in the text. In general, terms should not be abbreviated unless they are used repeatedly and the abbreviation is helpful to the reader. Permissible abbreviations are listed in Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Ed. Baron DN, 1988) published by The Royal Society of Medicine, London. Certain commonly used abbreviations, such as DNA, RNA, HIV, LD50, PCR, HBV, ECG, WBC, RBC, CT, ESR, CSF, IgG, ELISA, PBS, ATP, EDTA, mAb, can be used directly without further explanation.

ItalicsQuantities: t time or temperature, c concentration, A area, l length, m mass, V volume.Genotypes: gyrA, arg 1, c myc, c fos, etc.Restriction enzymes: EcoRI, HindI, BamHI, Kbo I, Kpn I, etc.Biology: H. pylori, E coli, etc.

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