World Journal of Gastroenterology

Volume 18 Number 35September 21, 2012

ISSN 1007-9327 CN 14-1219/R Local Post Offices Code No. 82-261

Published by Baishideng Publishing Group Co., LimitedRoom 1701, 17/F, Henan Building,

No. 90 Jaffe Road, Wanchai, Hong Kong, ChinaFax: +852-31158812

Telephone: +852-58042046E-mail: bpg@baishideng.com

http://www.wjgnet.com

World Journal of GastroenterologyWorld J Gastroenterol 2012 September 21; 18(35): 4801-4972

ISSN 1007-9327 (print)ISSN 2219-2840 (online)

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The World Journal of Gastroenterology Editorial Board consists of 1352 members, representing a team of worldwide experts in gastroenterology and hepatology. They are from 64 countries, including Albania (1), Argentina (8), Australia (33), Austria (15), Belgium (14), Brazil (13), Brunei Darussalam (1), Bulgaria (2), Canada (21), Chile (3), China (82), Colombia (1), Croatia (2), Cuba (1), Czech (6), Denmark (9), Ecuador (1), Egypt (4), Estonia (2), Finland (8), France (29), Germany (87), Greece (22), Hungary (11), India (32), Indonesia (2), Iran (10), Ireland (6), Israel (13), Italy (124), Japan (140), Jordan (2), Kuwait (1), Lebanon (4), Lithuania (2), Malaysia (1), Mexico (11), Morocco (1), Moldova (1), Netherlands (32), New Zealand (2), Norway (13), Pakistan (2), Poland (11), Portugal (6), Romania (4), Russia (1), Saudi Arabia (3), Serbia (3), Singapore (11), Slovenia (1), South Africa (3), South Korea (46), Spain (43), Sri Lanka (1), Sweden (17), Switzerland (12), Thailand (1), Trinidad and Tobago (1), Turkey (30), United Arab Emirates (2), United Kingdom (95), United States (285), and Uruguay (1).

Editorial Board2010-2013

HONORARY EDITORS-IN-CHIEFJames L Boyer, New HavenKe-Ji Chen, BeijingMartin H Floch, New HavenBo-Rong Pan, Xi'anEamonn M Quigley, CorkRafiq A Sheikh, SacramentoNicholas J Talley, Rochester

EDITOR-IN-CHIEFFerruccio Bonino, PisaMyung-Hwan Kim, SeoulKjell Öberg, UppsalaMatt Rutter, Stockton-on-TeesAndrzej S Tarnawski, Long Beach

STRATEGY ASSOCIATE EDITORS-IN-CHIEFYou-Yong Lu, BeijingPeter Draganov, FloridaHugh J Freeman, VancouverMaria Concepción Gutiérrez-Ruiz, MéxicoKazuhiro Hanazaki, KochiAkio Inui, KagoshimaKalpesh Jani, BarodaJavier San Martin, Punta del EsteNatalia A Osna, OmahaWei Tang, TokyoAlan BR Thomson, EdmontonHarry Hua-Xiang Xia, LivingstonJohn M Luk, Hong KongHiroshi Shimada, Yokohama

GUEST EDITORIAL BOARD MEMBERSJiunn-Jong Wu, Tainan

Cheng-Shyong Wu, Chia-YiTa-Sen Yeh, TaoyuanTsung-Hui Hu, KaohsiungChuah Seng-Kee, KaohsiungI-Rue Lai, TaipeiJin-Town Wang, TaipeiMing-Shiang Wu, TaipeiTeng-Yu Lee, TaichungYang-Yuan Chen, ChanghuaPo-Shiuan Hsieh, TaipeiChao-Hung Hung, KaohsiungHon-Yi Shi, KaohsiungHui-kang Liu, TaipeiJen-Hwey Chiu, TaipeiChih-Chi Wang, KaohsiungWan-Long Chuang, KaohsiungWen-Hsin Huang, TaichungHsu-Heng Yen, ChanghuaChing Chung Lin, TaipeiChien-Jen Chen, TaipeiJaw-Ching Wu, TaipeiMing-Chih Hou, TaipeiKevin Cheng-Wen Hsiao, TaipeiChiun Hsu, TaipeiYu-Jen Chen, TaipeiChen Hsiu-Hsi Chen, TaipeiLiang-Shun Wang, Taipeihun-Fa Yang, TaichungMin-Hsiung Pan, KaohsiungChun- Hung Lin, TaipeiMing-Whei Yu, TaipeiChuen Hsueh, TaoyuanHsiu-Po Wang, TaipeiLein-Ray Mo, TainanMing-Lung Yu, Kaohsiung

MEMBERS OF THE EDITORIAL BOARD

Albania

Bashkim Resuli, Tirana

Argentina

Julio H Carri, CórdobaBernabe Matias Quesada, Buenos AiresBernardo Frider, Buenos AiresMaria Ines Vaccaro, Buenos AiresEduardo de Santibañes, Buenos AiresAdriana M Torres, RosarioCarlos J Pirola, Buenos AiresSilvia Sookoian, Buenos Aires

Australia

Finlay A Macrae, VictoriaDavid Ian Watson, Bedford ParkJacob George, SydneyLeon Anton Adams, NedlandsMinoti V Apte, LiverpoolAndrew V Biankin, SydneyFilip Braet, SydneyGuy D Eslick, SydneyMichael A Fink, MelbourneMark D Gorrell, SydneyMichael Horowitz, AdelaideJohn E Kellow, SydneyDaniel Markovich, Brisbane

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Phillip S Oates, PerthRoss C Smith, SydneyKevin J Spring, BrisbanePhilip G Dinning, KoagarahChristopher Christophi, MelbourneCuong D Tran, North AdelaideShan Rajendra, TasmaniaRajvinder Singh, AdelaideWilliam Kemp, MelbournePhil Sutton, MelbourneRichard Anderson, VictoriaVance Matthews, MelbourneAlexander G Heriot, MelbourneDebbie Trinder, FremantleIan C Lawrance, PerthAdrian G Cummins, AdelaideJohn K Olynyk, FremantleAlex Boussioutas, MelbourneEmilia Prakoso, SydneyRobert JL Fraser, Daw Park

Austria

Wolfgang Mikulits, ViennaAlfred Gangl, ViennaDietmar Öfner, SalzburgGeorg Roth, ViennaHerwig R Cerwenka, GrazAshraf Dahaba, GrazMarkus Raderer, ViennaAlexander M Hirschl, WienThomas Wild, KapellerfeldPeter Ferenci, ViennaValentin Fuhrmann, ViennaKurt Lenz, LinzMarkus Peck-Radosavljevic, ViennaMichael Trauner, ViennaStefan Riss, Vienna

Belgium

Rudi Beyaert, GentInge I Depoortere, LeuvenOlivier Detry, LiègeBenedicte Y De Winter, AntwerpEtienne M Sokal, BrusselsMarc Peeters, De PintelaanEddie Wisse, KeerbergenJean-Yves L Reginster, LiègeMark De Ridder, BrusselFreddy Penninckx, LeuvenKristin Verbeke, LeuvenLukas Van Oudenhove, LeuvenLeo van Grunsven, BrusselsPhilip Meuleman, Ghent

Brazil

Heitor Rosa, GoianiaRoberto J Carvalho-Filho, Sao PauloDamiao Carlos Moraes Santos, Rio de JaneiroMarcelo Lima Ribeiro, Braganca PaulistaEduardo Garcia Vilela, Belo Horizonte Jaime Natan Eisig, São PauloAndre Castro Lyra, SalvadorJosé Liberato Ferreira Caboclo, BrazilYukie Sato-Kuwabara, São PauloRaquel Rocha, Salvador

Paolo R Salvalaggio, Sao PauloAna Cristina Simões e Silva, Belo HorizonteJoao Batista Teixeira Rocha, Santa Maria

Brunei Darussalam

Vui Heng Chong, Bandar Seri Begawan

Bulgaria

Zahariy Krastev, SofiaMihaela Petrova, Sofia

Canada

Eldon Shaffer, CalgaryNathalie Perreault, SherbrookePhilip H Gordon, MontrealRam Prakash Galwa, OttawaBaljinder Singh Salh, VancouverClaudia Zwingmann, MontrealAlain Bitton, MontrealPingchang Yang, HamiltonMichael F Byrne,VancouverAndrew L Mason, AlbertaJohn K Marshall, Hamilton OntarioKostas Pantopoulos, MontrealWaliul Khan, OntarioEric M Yoshida, VancouverGeoffrey C Nguyen, TorontoDevendra K Amre, MontrealTedros Bezabeh, WinnipegWangxue Chen, OttawaQiang Liu, Saskatoon

Chile

De Aretxabala Xabier, SantiagoMarcelo A Beltran, La SerenaSilvana Zanlungo, Santiago

China

Chi-Hin Cho, Hong KongChun-Qing Zhang, JinanRen Xiang Tan, NanjingFei Li, BeijingHui-Jie Bian, Xi'anXiao-Peng Zhang, BeijingXing-Hua Lu, BeijingFu-Sheng Wang, BeijingAn-Gang Yang, Xi’anXiao-Ping Chen, WuhanZong-Jie Cui, BeijingMing-Liang He, Hong KongYuk-Tong Lee, Hong KongQin Su, BeijingJian-Zhong Zhang, BeijingPaul Kwong-Hang Tam, Hong KongWen-Rong Xu, ZhenjiangChun-Yi Hao, BeijingSan-Jun Cai, ShanghaiSimon Law, Hong KongYuk Him Tam, Hong KongDe-Liang Fu, ShanghaiEric WC Tse, Hong Kong

Justin CY Wu, Hong KongNathalie Wong, Hong KongJing Yuan Fang, ShanghaiYi-Min Mao, ShanghaiWei-Cheng You, BeijingXiang-Dong Wang, ShanghaiXuan Zhang, BeijingZhao-Shen Li, Shanghai Guang-Wen Cao, ShanghaiEn-min Li, ShantouYu-Yuan Li, Guangzhou Fook Hong Ng, Hong KongHsiang-Fu Kung, Hong KongWai Lun Law, Hong KongEric CH Lai, Hong KongJun Yu, Hong KongZe-Guang Han, ShanghaiBian zhao-xiang, Hong KongWei-Dong Tong, Chongqing

Colombia

Germán Campuzano-Maya, Medellín

Croatia

Tamara Cacev, ZagrebMarko Duvnjak, Zagreb

Cuba

Damian C Rodriguez, Havana

Czech

Milan Jirsa, PrahaPavel Trunečka, PragueJan Bures, Hradec KraloveMarcela Kopacova, Hradec KraloveOndrej Slaby, BrnoRadan Bruha, Prague

Denmark

Asbjørn M Drewes, AalborgLeif Percival Andersen, CopenhagenJan Mollenhauer, Odense CMorten Frisch, Copenhagen SJorgen Rask-Madsen, SkodsborgMorten Hylander Møller, HolteSøren Rafaelsen, VejleVibeke Andersen, AabenraaOle Haagen Nielsen, Herlev

Ecuador

Fernando E Sempértegui, Quito

Egypt

Zeinab Nabil Ahmed Said, CairoHussein M Atta, El-MiniaAsmaa Gaber Abdou, Shebein Elkom

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Maha Maher Shehata, Mansoura

Estonia

Riina Salupere, TartuTamara Vorobjova, Tartu

Finland

Saila Kauhanen, TurkuPauli Antero Puolakkainen, TurkuMinna Nyström, HelsinkiJuhani Sand, TampereJukka-Pekka Mecklin, JyvaskylaLea Veijola, HelsinkiKaija-Leena Kolho, HelsinkiThomas Kietzmann, Oulu

France

Boris Guiu, DijonBaumert F Thomas, StrasbourgAlain L Servin, Châtenay-MalabryPatrick Marcellin, ParisJean-Jacques Tuech, RouenFrancoise L Fabiani, AngersJean-Luc Faucheron, GrenoblePhilippe Lehours, BordeauxStephane Supiot, NantesLionel Bueno, ToulouseFlavio Maina, MarseillePaul Hofman, NiceAbdel-Majid Khatib, ParisAnnie Schmid-Alliana, Nice cedex 3Frank Zerbib, Bordeaux CedexRene Gerolami Santandera, MarseilleSabine Colnot, ParisCatherine Daniel, Lille CedexThabut Dominique, ParisLaurent Huwart, ParisAlain Braillon, AmiensBruno Bonaz, GrenobleEvelyne Schvoerer, StrasbourgM Coeffier, RouenMathias Chamaillard, LilleHang Nguyen, Clermont-FerrandVeronique Vitton, MarseilleAlexis Desmoulière, LimogesJuan Iovanna, Marseille

Germany

Hans L Tillmann, LeipzigStefan Kubicka, HannoverElke Cario, EssenHans Scherubl, BerlinHarald F Teutsch, Ulm Peter Konturek, ErlangenThilo Hackert, HeidelbergJurgen M Stein, Frankfurt Andrej Khandoga, MunichKarsten Schulmann, BochumJutta Elisabeth Lüttges, RiegelsbergWolfgang Hagmann, HeidelbergHubert Blum, Freiburg Thomas Bock, Berlin

Christa Buechler, RegensburgChristoph F Dietrich, Bad Mergentheim Ulrich R Fölsch, Kiel Nikolaus Gassler, AachenMarkus Gerhard, MunichDieter Glebe, GiessenKlaus R Herrlinger, StuttgartEberhard Hildt, BerlinJoerg C Hoffmann, LudwigshafenJoachim Labenz, SiegenPeter Malfertheiner, MagdeburgSabine Mihm, GöttingenMarkus Reiser, BochumSteffen Rickes, MagdeburgAndreas G Schreyer, RegensburgHenning Schulze-Bergkamen, HeidelbergUlrike S Stein, BerlinWolfgang R Stremmel, Heidelberg Fritz von Weizsäcker, BerlinStefan Wirth, WuppertalDean Bogoevski, HamburgBruno Christ, Halle/SaalePeter N Meier, HannoverStephan Johannes Ott, KielArndt Vogel, HannoverDirk Haller, FreisingJens Standop, BonnJonas Mudter, ErlangenJürgen Büning, LübeckMatthias Ocker, ErlangenJoerg Trojan, FrankfurtChristian Trautwein, AachenJorg Kleeff, MunichChristian Rust, MunichClaus Hellerbrand, RegensburgElke Roeb, GiessenErwin Biecker, SiegburgIngmar Königsrainer, TübingenJürgen Borlak, HannoverAxel M Gressner, AachenOliver Mann, HamburgMarty Zdichavsky, TübingenChristoph Reichel, Bad BrückenauNils Habbe, MarburgThomas Wex, MagdeburgFrank Ulrich Weiss, GreifswaldManfred V Singer, MannheimMartin K Schilling, HomburgPhilip D Hard, GiessenMichael Linnebacher, RostockRalph Graeser, FreiburgRene Schmidt, FreiburgRobert Obermaier, FreiburgSebastian Mueller, HeidelbergAndrea Hille, GoettingenKlaus Mönkemüller, BottropElfriede Bollschweiler, KölnSiegfried Wagner, DeggendorfDieter Schilling, MannheimJoerg F Schlaak, EssenMichael Keese, FrankfurtRobert Grützmann, DresdenAli Canbay, EssenDirk Domagk, MuensterJens Hoeppner, FreiburgFrank Tacke, AachenPatrick Michl, MarburgAlfred A Königsrainer, TübingenKilian Weigand, HeidelbergMohamed Hassan, DuesseldorfGustav Paumgartner, Munich

Philipe N Khalil, MunichMartin Storr, Munich

Greece

Andreas Larentzakis, AthensTsianos Epameinondas, IoanninaElias A Kouroumalis, Heraklion Helen Christopoulou-Aletra, ThessalonikiGeorge Papatheodoridis, AthensIoannis Kanellos, ThessalonikiMichael Koutsilieris, AthensT Choli-Papadopoulou, ThessalonikiEmanuel K Manesis, AthensEvangelos Tsiambas, Ag Paraskevi AttikiKonstantinos Mimidis, AlexandroupolisSpilios Manolakopoulos, AthensSpiros Sgouros, AthensIoannis E Koutroubakis, HeraklionStefanos Karagiannis, AthensSpiros Ladas, AthensElena Vezali, AthensDina G Tiniakos, AthensEkaterini Chatzaki, AlexandroupolisDimitrios Roukos, IoanninaGeorge Sgourakis, AthensMaroulio Talieri, Athens

Hungary

Peter L Lakatos, BudapestYvette Mándi, SzegedFerenc Sipos, BudapestGyörgy M Buzás, BudapestLászló Czakó, SzegedPeter Hegyi, SzegedZoltan Rakonczay, SzegedGyula Farkas, SzegedZsuzsa Szondy, DebrecenGabor Veres, BudapestZsuzsa Schaff, Budapest

India

Philip Abraham, MumbaiSri P Misra, Allahabad Ramesh Roop Rai, JaipurNageshwar D Reddy, HyderabadRakesh Kumar Tandon, New DelhiJai Dev Wig, ChandigarhUday C Ghoshal, LucknowPramod Kumar Garg, New DelhiBarjesh Chander Sharma, New DelhiGopal Nath, VaranasiBhupendra Kumar Jain, DelhiDevinder Kumar Dhawan, ChandigarhAshok Kumar, LucknowBenjamin Perakath, Tamil NaduDebidas Ghosh, MidnporePankaj Garg, PanchkulaSamiran Nundy, New DelhiVirendra Singh, ChandigarhBikash Medhi, ChandigarhRadha K Dhiman, Chandigarh Vandana Panda, MumbaiVineet Ahuja, New DelhiSV Rana, Chandigarh

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Deepak N Amarapurkar, MumbaiAbhijit Chowdhury, KolkataJasbir Singh, KurukshetraB Mittal, LucknowSundeep Singh Saluja, New DelhiPradyumna Kumar Mishra, MumbaiRunu Chakravarty, KolkataNagarajan Perumal, New Delhi

Indonesia

David handojo Muljono, JakartaAndi Utama, Tangerang

Iran

Seyed-Moayed Alavian, TehranReza Malekzadeh, TehranPeyman Adibi, IsfahanAlireza Mani, TehranSeyed Mohsen Dehghani, ShirazMohammad Abdollahi, TehranMajid Assadi, BushehrArezoo Aghakhani, TehranMarjan Mohammadi, TehranFariborz Mansour-Ghanaei, Rasht

Ireland

Ross McManus, DublinBilly Bourke, DublinCatherine Greene, DublinTed Dinan, CorkMarion Rowland, Dublin

Israel

Abraham R Eliakim, Haifa Simon Bar-Meir, Tel HashomerAmi D Sperber, Beer-Sheva Boris Kirshtein, Beer ShevaMark Pines, Bet DaganMenachem Moshkowitz, Tel-AvivRon Shaoul, HaifaShmuel Odes, Beer ShevaSigal Fishman, Tel AvivAlexander Becker, AfulaAssy Nimer, SafedEli Magen, AshdodAmir Shlomai, Tel-Aviv

Italy

Mauro Bortolotti, BolognaGianlorenzo Dionigi, VareseFiorucci Stefano, PerugiaRoberto Berni Canani, NaplesBallarin Roberto, ModenaBruno Annibale, RomaVincenzo Stanghellini, BolognaGiovanni B Gaeta, NapoliClaudio Bassi, VeronaMauro Bernardi, BolognaGiuseppe Chiarioni, ValeggioMichele Cicala, Rome

Dario Conte, Milano Francesco Costa, PisaGiovanni D De Palma, NaplesGiammarco Fava, AnconaFrancesco Feo, SassariEdoardo G Giannini, Genoa Fabio Grizzi, MilanSalvatore Gruttadauria, PalermoPietro Invernizzi, MilanEzio Laconi, CagliariGiuseppe Montalto, Palermo Giovanni Musso, TorinoGerardo Nardone, NapoliValerio Nobili, RomeRaffaele Pezzilli, Bologna Alberto Piperno, MonzaAnna C Piscaglia, RomaPiero Portincasa, Bari Giovanni Tarantino, NaplesCesare Tosetti, Porretta TermeAlessandra Ferlini, FerraraAlessandro Ferrero, TorinoDonato F Altomare, BariGiovanni Milito, RomeGiuseppe Sica, RomeGuglielmo Borgia, NaplesGiovanni Latella, L'AquilaSalvatore Auricchio, NaplesAlberto Biondi, RomeAlberto Tommasini, TriesteAntonio Basoli, RomaGiuliana Decorti, TriesteMarco Silano, RomaMichele Reni, MilanPierpaolo Sileri, RomeAchille Iolascon, NaplesAlessandro Granito, BolognaAngelo A Izzo, NaplesGiuseppe Currò, MessinaPier Mannuccio Mannucci, MilanoMarco Vivarelli, BolognaMassimo Levrero, RomeMassimo Rugge, PadovaPaolo Angeli, PadovaSilvio Danese, MilanoAntonello Trecca, RomeAntonio Gasbarrini, RomeCesare Ruffolo, TrevisoMassimo Falconi, VeronaFausto Catena, BolognaFrancesco Manguso, NapoliGiancarlo Mansueto, VeronaLuca Morelli, TrentoMarco Scarpa, PadovaMario M D'Elios, FlorenceFrancesco Luzza, CatanzaroFranco Roviello, SienaGuido Torzilli, Rozzano MilanoLuca Frulloni, VeronaLucia Malaguarnera, CataniaLucia Ricci Vitiani, RomeMara Massimi, L'AquilaMario Pescatori, RomeMario Rizzetto, TorinoMirko D’Onofrio, VeronaNadia Peparini, RomePaola De Nardi, MilanPaolo Aurello, RomePiero Amodio, PadovaRiccardo Nascimbeni, Brescia

Vincenzo Villanacci, BresciaVittorio Ricci, PaviaSilvia Fargion, MilanLuigi Bonavina, Milano Oliviero Riggio, RomeFabio Pace, MilanoGabrio Bassotti, Perugia Giulio Marchesini, Bologna Roberto de Franchis, MilanoGiovanni Monteleone, RomeC armelo Scarpignato, ParmaLuca VC Valenti, MilanUrgesi Riccardo, RomeMarcello Persico, NaplesAntonio Moschetta, BariLuigi Muratori, BolognaAngelo Zullo, RomaVito Annese, FlorenceSimone Lanini, RomeAlessandro Grasso, SavonaGiovanni Targher, VeronaDomenico Girelli, VeronaAlessandro Cucchetti, BolognaFabio Marra, FlorenceMichele Milella, RomeFrancesco Franceschi, RomeGiuseppina De Petro, BresciaSalvatore Leonardi, CataniaCristiano Simone, Santa Maria ImbaroBernardino Rampone, SalernoFrancesco Crea, PisaWalter Fries, MessinaAntonio Craxì, PalermoGerardo Rosati, PotenzaMario Guslandi, Milano Gianluigi Giannelli, BariPaola Loria, ModenaPaolo Sorrentino, AvellinoArmando Santoro, RozzanoGabriele Grassi, TriesteAntonio Orlacchio, Rome

Japan

Tsuneo Kitamura, Chiba Katsutoshi Yoshizato, HigashihiroshimaMasahiro Arai, Tokyo Shinji Tanaka, Hiroshima Keiji Hirata, KitakyushuYoshio Shirai, Niigata Susumu Ohmada, Maebashi Kenichi Ikejima, TokyoMasatoshi Kudo, OsakaYoshiaki Murakami, HiroshimaMasahiro Tajika, NagoyaKentaro Yoshika, ToyoakeKyoichi Adachi, Izumo Yasushi Adachi, SapporoTakafumi Ando, Nagoya Akira Andoh, Otsu Hitoshi Asakura, Tokyo Mitsuhiro Fujishiro, TokyoToru Hiyama, HigashihiroshimaYutaka Inagaki, KanagawaHiromi Ishibashi, Nagasaki Shunji Ishihara, Izumo Toru Ishikawa, Niigata Yoshiaki Iwasaki, OkayamaTerumi Kamisawa, Tokyo

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Norihiro Kokudo, TokyoShin Maeda, Tokyo Yasushi Matsuzaki, Ibaraki Kenji Miki, TokyoHiroto Miwa, HyogoYoshiharu Motoo, Kanazawa Kunihiko Murase, TusimaAtsushi Nakajima, YokohamaYuji Naito, Hisato Nakajima, TokyoHiroki Nakamura, Yamaguchi Shotaro Nakamura, FukuokaMikio Nishioka, Niihama Hirohide Ohnishi, AkitaKazuichi Okazaki, OsakaMorikazu Onji, EhimeSatoshi Osawa, Hamamatsu Hidetsugu Saito, TokyoYutaka Saito, TokyoYasushi Sano, KobeTomohiko Shimatani, KureYukihiro Shimizu, ToyamaShinji Shimoda, FukuokaMasayuki Sho, NaraHidekazu Suzuki, TokyoShinji Togo, YokohamaSatoshi Yamagiwa, NiigataTakayuki Yamamoto, Yokkaichi Hiroshi Yoshida, Tokyo Norimasa Yoshida, Kyoto Akihito Nagahara, TokyoHiroaki Takeuchi, KochiKeiji Ogura, TokyoKotaro Miyake, TokushimaMitsunori Yamakawa, YamagataNaoaki Sakata, SendaiNaoya Kato, TokyoSatoshi Mamori, HyogoShogo Kikuchi, AichiShoichiro Sumi, KyotoSusumu Ikehara, OsakaTaketo Yamaguchi, ChibaTokihiko Sawada, TochigiTomoharu Yoshizumi, FukuokaToshiyuki Ishiwata, Tokyo Yasuhiro Fujino, AkashiYasuhiro Koga, Isehara cityYoshihisa Takahashi, TokyoYoshitaka Takuma, OkayamaYutaka Yata, Maebashi-cityItaru Endo, YokohamaKazuo Chijiiwa, MiyazakiKouhei Fukushima, SendaiMasahiro Iizuka, Akita Mitsuyoshi Urashima, TokyoMunechika Enjoji, FukuokaTakashi Kojima, SapporoTakumi Kawaguchi, KurumeYoshiyuki Ueno, SendaiYuichiro Eguchi, SagaAkihiro Tamori, OsakaAtsushi Masamune, SendaiAtsushi Tanaka, TokyoHitoshi Tsuda, TokyoTakashi Kobayashi, TokyoAkimasa Nakao, NagogyaHiroyuki Uehara, OsakaMasahito Uemura, KashiharaSatoshi Tanno, SapporoToshinari Takamura, KanazawaYohei Kida, Kainan

Masanori Hatakeyama, TokyoSatoru Kakizaki, GunmaShuhei Nishiguchi, HyogoYuichi Yoshida, OsakaManabu Morimoto, JapanMototsugu Kato, Sapporo Naoki Ishii, TokyoNoriko Nakajima, TokyoNobuhiro Ohkohchi, TsukubaTakanori Kanai, TokyoKenichi Goda, TokyoMitsugi Shimoda, MibuZenichi Morise, NagoyaHitoshi Yoshiji, KashiharaTakahiro Nakazawa, NagoyaUtaroh Motosugi, YamanashiNobuyuki Matsuhashi, TokyoYasuhiro Kodera, NagoyaTakayoshi Ito, TokyoYasuhito Tanaka, NagoyaHaruhiko Sugimura, HamamatsuHiroki Yamaue, WakayamaMasao Ichinose, WakayamaTakaaki Arigami, KagoshimaNobuhiro Zaima, NaraNaoki Tanaka, MatsumotoSatoru Motoyama, AkitaTomoyuki Shibata, ToyoakeTatsuya Ide, KurumeTsutomu Fujii, NagoyaOsamu Kanauchi, TokyAtsushi Irisawa, AizuwakamatsuHikaru Nagahara, TokyoKeiji Hanada, OnomichiKeiichi Mitsuyama, FukuokaShin Maeda, YokohamaTakuya Watanabe, NiigataToshihiro Mitaka, SapporoYoshiki Murakami, KyotoTadashi Shimoyama, Hirosaki

Jordan

Ismail Matalka, IrbidKhaled Jadallah, Irbid

Kuwait

Islam Khan, Safat

Lebanon

Bassam N Abboud, BeirutRami Moucari, BeirutAla I Sharara, BeirutRita Slim, Beirut

Lithuania

Giedrius Barauskas, KaunasLimas Kupcinskas, Kaunas

Malaysia

Andrew Seng Boon Chua, Ipoh

Mexico

Saúl Villa-Trevio, MéxicoOmar Vergara-Fernandez, MexicoDiego Garcia-Compean, MonterreyArturo Panduro, JaliscoMiguel Angel Mercado, Distrito FederalRichard A Awad, MexicoAldo Torre Delgadillo, MéxicoPaulino Martínez Hernández Magro, CelayaCarlos A Aguilar-Salinas, MexicoJesus K Yamamoto-Furusho, Mexico

Morocco

Samir Ahboucha, Khouribga

Moldova

Igor Mishin, Kishinev

Netherlands

Ulrich Beuers, AmsterdamAlbert Frederik Pull ter Gunne, TilburgJantine van Baal, HeidelberglaanWendy Wilhelmina Johanna de Leng, UtrechtGerrit A Meijer, AmsterdamLee Bouwman, LeidenJ Bart A Crusius, AmsterdamFrank Hoentjen, HaarlemServaas Morré, AmsterdamChris JJ Mulder, Amsterdam Paul E Sijens, GroningenKarel van Erpecum, Utrecht BW Marcel Spanier, ArnhemMisha Luyer, SittardPieter JF de Jonge, RotterdamRobert Christiaan Verdonk, GroningenJohn Plukker, Groningen Maarten Tushuizen, AmsterdamWouter de Herder, RotterdamErwin G Zoetendal, WageningenRobert J de Knegt, RotterdamAlbert J Bredenoord, NieuwegeinAnnemarie de Vries, RotterdamAstrid van der Velde, EdeLodewijk AA Brosens, UtrechtJames CH Hardwick, LeidenLoes van Keimpema, NijmegenWJ de Jonge, AmsterdamZuzana Zelinkova, RotterdamLN van Steenbergen, EindhovenFrank G Schaap, AmsterdamJeroen Maljaars, Leiden

New Zealand

Andrew S Day, ChristchurchMax S Petrov, Auckland

Norway

Espen Melum, Oslo

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Trine Olsen, TromsøEyvind J Paulssen, TromsøRasmus Goll, TromsøAsle W Medhus, OsloJon Arne Søreide, StavangerKjetil Soreide, StavangerReidar Fossmark, TrondheimTrond Peder Flaten, TrondheimOlav Dalgard, OsloOle Høie, ArendalMagdy El-Salhy, BergenJørgen Valeur, Oslo

Pakistan

Shahab Abid, KarachiSyed MW Jafri, Karachi

Poland

Beata Jolanta Jablońska, KatowiceHalina Cichoż-Lach, LublinTomasz Brzozowski, Cracow Hanna Gregorek, WarsawMarek Hartleb, KatowiceStanislaw J Konturek, KrakowAndrzej Dabrowski, BialystokJan Kulig, KrakówJulian Swierczynski, GdanskMarek Bebenek, WroclawDariusz M Lebensztejn, Bialystok

Portugal

Ricardo Marcos, PortoGuida Portela-Gomes, EstorilAna Isabel Lopes, Lisboa CodexRaquel Almeida, PortoRui Tato Marinho, LisbonCeu Figueiredo, Porto

Romania

Dan L Dumitrascu, ClujAdrian Saftoiu, CraiovaAndrada Seicean, Cluj-NapocaAnca Trifan, Iasi

Russia

Vasiliy I Reshetnyak, Moscow

Saudi Arabia

Ibrahim A Al Mofleh, RiyadhAbdul-Wahed Meshikhes, QatifFaisal Sanai, Riyadh

Serbia

Tamara M Alempijevic, BelgradeDusan M Jovanovic, Sremska KamenicaZoran Krivokapic, Belgrade

Singapore

Brian Kim Poh Goh, SingaporeKhek-Yu Ho, SingaporeFock Kwong Ming, SingaporeFrancis Seow-Choen, Singapore Kok Sun Ho, SingaporeKong Weng Eu, SingaporeMadhav Bhatia, SingaporeLondon Lucien Ooi, SingaporeWei Ning Chen, SingaporeRichie Soong, SingaporeKok Ann Gwee, Singapore

Slovenia

Matjaz Homan, Ljubljana

South Africa

Rosemary Joyce Burnett, PretoriaMichael Kew, Cape TownRoland Ndip, Alice

South Korea

Byung Chul Yoo, SeoulJae J Kim, SeoulJin-Hong Kim, SuwonMarie Yeo, Suwon Jeong Min Lee, SeoulEun-Yi Moon, SeoulJoong-Won Park, GoyangHoon Jai Chun, SeoulMyung-Gyu Choi, SeoulSang Kil Lee, SeoulSang Yeoup Lee, Gyeongsangnam-doWon Ho Kim, SeoulDae-Yeul Yu, DaejeonDonghee Kim, SeoulSang Geon Kim, SeoulSun Pyo Hong, Geonggi-doSung-Gil Chi, SeoulYeun-Jun Chung, SeoulKi-Baik Hahm, IncheonJi Kon Ryu, SeoulKyu Taek Lee, Seoul Yong Chan Lee, SeoulSeong Gyu Hwang, SeongnamSeung Woon Paik, SeoulSung Kim, SeoulHong Joo Kim, SeoulHyoung-Chul Oh, SeoulNayoung Kim, Seongnam-siSang Hoon Ahn, SeoulSeon Hahn Kim, SeoulSi Young Song, SeoulYoung-Hwa Chung, SeoulHyo-Cheol Kim, SeoulKwang Jae Lee, SwonSang Min Park, SeoulYoung Chul Kim, SeoulDo Hyun Park, SeoulDae Won Jun, SeoulDong Wan Seo, SeoulSoon-Sun Hong, Incheon

Hoguen Kim, SeoulHo-Young Song, SeoulJoo-Ho Lee, SeoulJung Eun Lee, SeoulJong H Moon, Bucheon

Spain

Eva Vaquero, BarcelonaAndres Cardenas, BarcelonaLaureano Fernández-Cruz, BarcelonaAntoni Farré, SpainMaria-Angeles Aller, MadridRaul J Andrade, MálagaFernando Azpiroz, Barcelona Josep M Bordas, Barcelona Antoni Castells, Barcelona Vicente Felipo, ValenciaIsabel Fabregat, BarcelonaAngel Lanas, Zaragoza Juan-Ramón Larrubia, GuadalajaraMaría IT López, JaénJesús M Prieto, Pamplona Mireia Miquel, SabadellRamon Bataller, BarcelonaFernando J Corrales, PamplonaJulio Mayol, MadridMatias A Avila, PamplonaJuan Macías, SevilleJuan Carlos Laguna Egea, BarcelonaJuli Busquets, BarcelonaBelén Beltrán, ValenciaJosé Manuel Martin-Villa, MadridLisardo Boscá, MadridLuis Grande, BarcelonaPedro Lorenzo Majano Rodriguez, MadridAdolfo Benages, ValenciaDomínguez-Muñoz JE, Santiago de CompostelaGloria González Aseguinolaza, NavarraJavier Martin, GranadaLuis Bujanda, San SebastiánMatilde Bustos, PamplonaLuis Aparisi, ValenciaJosé Julián calvo Andrés, SalamancaBenito Velayos, ValladolidJavier Gonzalez-Gallego, LeónRuben Ciria, CórdobaFrancisco Rodriguez-Frias, BarcelonaManuel Romero-Gómez, SevillaAlbert Parés, BarcelonaJoan Roselló-Catafau, Barcelona

Sri Lanka

Arjuna De Silva, Kelaniya

Sweden

Stefan G Pierzynowski, LundHanns-Ulrich Marschall, StockholmLars A Pahlman, UppsalaHelena Nordenstedt, StockholmBobby Tingstedt, LundEvangelos Kalaitzakis, GothenburgLars Erik Agréus, HuddingeAnnika Lindblom, Stockholm

January 7, 2012VIWJG|www.wjgnet.com

Roland Andersson, LundZongli Zheng, StockholmMauro D'Amato, HuddingeGreger Lindberg, Stockholm Pär Erik Myrelid, LinköpingSara Lindén, GöteborgSara Regnér, MalmöÅke Nilsson, Lund

Switzerland

Jean L Frossard, GenevaAndreas Geier, ZürichBruno Stieger, Zürich Pascal Gervaz, GenevaPaul M Schneider, ZurichFelix Stickel, BerneFabrizio Montecucco, GenevaInti Zlobec, BaselMichelangelo Foti, GenevaPascal Bucher, GenevaAndrea De Gottardi, BerneChristian Toso, Geneva

Thailand

Weekitt Kittisupamongkol, Bangkok

Trinidad and Tobago

Shivananda Nayak, Mount Hope

Turkey

Tarkan Karakan, AnkaraYusuf Bayraktar, Ankara Ahmet Tekin, MersinAydin Karabacakoglu, KonyaOsman C Ozdogan, IstanbulÖzlem Yilmaz, IzmirBülent Salman, AnkaraCan GONEN, KutahyaCuneyt Kayaalp, MalatyaEkmel Tezel, AnkaraEren Ersoy, AnkaraHayrullah Derici, BalıkesirMehmet Refik Mas, Etlik-AnkaraSinan Akay, TekirdagA Mithat Bozdayi, AnkaraMetin Basaranoglu, IstanbulMesut Tez, AnkaraOrhan Sezgin, MersinMukaddes Esrefoglu, MalatyaIlker Tasci, AnkaraKemal Kismet, Ankara Selin Kapan, IstanbulSeyfettin Köklü, AnkaraMurat Sayan, KocaeliSabahattin Kaymakoglu, IstanbulYucel Ustundag, ZonguldakCan Gonen, IstanbulYusuf Yilmaz, IstanbulMüge Tecder-Ünal, Ankaraİlhami Yüksel, Ankara

United Arab Emirates

Fikri M Abu-Zidan, Al-AinSherif M Karam, Al-Ain

United Kingdom

Anastasios Koulaouzidis, EdinburghSylvia LF Pender, SouthamptonHong-Xiang Liu, Cambridge William Dickey, LondonderrySimon D Taylor-Robinson, London James Neuberger, Birmingham Frank I Tovey, LondonKevin Robertson, GlasgowChew Thean Soon, ManchesterGeoffrey Burnstock, LondonVamsi R Velchuru, United KingdomSimon Afford, BirminghamNavneet K Ahluwalia, StockportLesley A Anderson, BelfastAnthony TR Axon, Leeds Jim D Bell, London Alastair D Burt, NewcastleTatjana Crnogorac-Jurcevic, LondonDaniel R Gaya, EdinburghWilliam Greenhalf, Liverpool Indra N Guha, SouthamptonStefan G Hübscher, BirminghamRobin Hughes, LondonPali Hungin, StocktonJanusz AZ Jankowski, Oxford Peter Karayiannis, LondonPatricia F Lalor, BirminghamGiorgina Mieli-Vergani, London D Mark Pritchard, LiverpoolMarco Senzolo, PadovaRoger Williams, LondonM H Ahmed, SouthamptonChristos Paraskeva, BristolEmad M El-Omar, AberdeenA M El-Tawil, BirminghamAnne McCune, BristolCharles B Ferguson, BelfastChin Wee Ang, LiverpoolClement W Imrie, GlasgowDileep N Lobo, NottinghamGraham MacKay, GlasgowGuy Fairbairn Nash, PooleIan Lindsey, OxfordJason CB Goh, BirminghamJeremy FL Cobbold, LondonJulian RF Walters, LondonJamie Murphy, LondonJohn Beynon, SwanseaJohn B Schofield, KentAnil George, LondonAravind Suppiah, East YorkshireBasil Ammori, SalfordCatherine Walter, CheltenhamChris Briggs, SheffieldJeff Butterworth, ShrewsburyNawfal Hussein, NottinghamPatrick O'Dwyer, GlasgowRob Glynne-Jones, NorthwoodSharad Karandikar, Venkatesh Shanmugam, Derby

Yeng S Ang, WiganAlberto Quaglia, LondonAndrew Fowell, SouthamptonGianpiero Gravante, LeicesterPiers Gatenby, LondonKondragunta Rajendra Prasad, LeedsSunil Dolwani, Cardiff Andrew McCulloch Veitch, WolverhamptonBrian Green, BelfastNoriko Suzuki, MiddlesexRichard Parker, North StaffordshireShahid A Khan, LondonAkhilesh B Reddy, CambridgeJean E Crabtree, LeedsJohn S Leeds, SheffieldPaul Sharp, LondonSumita Verma, BrightonThamara Perera, BirminghamDonald Campbell McMillan, GlasgowKathleen B Bamford, LondonHelen Coleman, BelfastEyad Elkord, ManchesterMohammad Ilyas, NottinghamSimon R Carding, NorwichIan Chau, SuttonClaudio Nicoletti, NorwichHendrik-Tobias Arkenau, LondonMuhammad Imran Aslam, LeicesterGiuseppe Orlando, OxfordJohn S Leeds, AberdeenS Madhusudan, NottinghamAmin Ibrahim Amin, DunfermlineDavid C Hay,EdinburghAlan Burns, London

United States

Tauseef Ali, Oklahoma CityGeorge Y Wu, Farmington Josef E Fischer, BostonThomas Clancy, BostonJohn Morton, StanfordLuca Stocchi, ClevelandKevin Michael Reavis, OrangeShiu-Ming Kuo, Buffalo Gary R Lichtenstein, Philadelphia Natalie J Torok, SacramentoScott A Waldman, PhiladelphiaGeorgios Papachristou, PittsburghCarla W Brady, DurhamRobert CG Martin, LouisvilleEugene P Ceppa, DurhamShashi Bala, WorcesterImran Hassan, SpringfieldKlaus Thaler, ColumbiaAndreas M Kaiser, Los AngelesShawn D Safford, NorfolkMassimo Raimondo, JacksonvilleKazuaki Takabe, Richmond VAStephen M Kavic, BaltimoreT Clark Gamblin, Pittsburgh BS Anand, HoustonAnanthanarayanan M, New YorkAnthony J Bauer, PittsburghEdmund J Bini, New YorkXian-Ming Chen, Omaha Ramsey Chi-man Cheung, Palo AltoParimal Chowdhury, ArkansasMark J Czaja, New York

January 7, 2012VIIWJG|www.wjgnet.com

Conor P Delaney, ClevelandSharon DeMorrow, TempleBijan Eghtesad, ClevelandAlessandro Fichera, ChicagoGlenn T Furuta, AuroraJean-Francois Geschwind, BaltimoreShannon S Glaser, TempleAjay Goel, DallasJames H Grendell, New YorkAnna S Gukovskaya, Los AngelesJamal A Ibdah, ColumbiaAtif Iqbal, Omaha Hajime Isomoto, Rochester Hartmut Jaeschke, KansasLeonard R Johnson, MemphisRashmi Kaul, TulsaAli Keshavarzian, ChicagoMiran Kim, ProvidenceBurton I Korelitz, New York Richard A Kozarek, Seattle Alyssa M Krasinskas, PittsburghMing Li, New Orleans Zhiping Li, BaltimoreChen Liu, GainesvilleMichael R Lucey, MadisonJames D Luketich, Pittsburgh Patrick M Lynch, HoustonWillis C Maddrey, DallasMercedes Susan Mandell, AuroraWendy M Mars, PittsburghLaura E Matarese, PittsburghLynne V McFarland, WashingtonStephan Menne, New YorkDidier Merlin, AtlantaGeorge Michalopoulos, PittsburghJames M Millis, ChicagoPramod K Mistry, New HavenEmiko Mizoguchi, BostonPeter L Moses, BurlingtonMasaki Nagaya, BostonRobert D Odze, BostonStephen JD O’Keefe, PittsburghZhiheng Pei, New YorkRaymund R Razonable, MinnesotaBasil Rigas, New YorkRichard A Rippe, Chapel HillPhilip Rosenthal, San FranciscoStuart Sherman, Indianapolis Christina Surawicz, SeattleWing-Kin Syn, DurhamYvette Taché, Los AngelesK-M Tchou-Wong, New YorkGeorge Triadafilopoulos, StanfordChung-Jyi Tsai, LexingtonAndrew Ukleja, FloridaArnold Wald, WisconsinIrving Waxman, ChicagoSteven D Wexner, Weston Jackie Wood, OhioJian Wu, SacramentoZobair M Younossi, VirginiaLiqing Yu, Winston-SalemRuben Zamora, Pittsburgh Michael E Zenilman, New YorkMichael A Zimmerman, ColoradoBeat Schnüriger, CaliforniaClifford S Cho, Madison

R Mark Ghobrial, TexasAnthony T Yeung, PhiladelphiaChang Kim, West LafayetteBalamurugan N Appakalai, MinneapolisAejaz Nasir, TampaAshkan Farhadi, Irvine Kevin E Behrns, GainesvilleJoseph J Cullen, Iowa CityDavid J McGee, ShreveportAnthony J Demetris, PittsburghDimitrios V Avgerinos, New YorkDong-Hui Li, HoustonEric S Hungness, ChicagoGiuseppe Orlando, Winston SalemHai-Yong Han, PhoenixHuanbiao Mo, DentonJong Park, TampaJustin MM Cates, NashvilleCharles P Heise, MadisonCraig D Logsdon, HoustonEce A Mutlu, ChicagoJessica A Davila, HoustonRabih M Salloum, RochesterAmir Maqbul Khan, MarshallBruce E Sands, BostonChakshu Gupta, Saint JosephRicardo Alberto Cruciani, New YorkMariana D Dabeva, BronxEdward L Bradley III, SarasotaMartín E Fernández-Zapico, RochesterHenry J Binder, New HavenJohn R Grider, RichmondRonnie Fass, TucsonDinesh Vyas, WashingtonWael El-Rifai, NashvilleCraig J McClain, LouisvilleChristopher Mantyh, DurhamDaniel S Straus, RiversideDavid A Brenner, San DiegoEileen F Grady, San FranciscoEkihiro Seki, La JollaFang Yan, NashvilleFritz Francois, New YorkGiamila Fantuzzi, ChicagoGuang-Yin Xu, GalvestonJianyuan Chai, Long BeachJingXuan Kang, CharlestownLe Shen, ChicagoLin Zhang, PittsburghMitchell L Shiffman, RichmondDouglas K Rex, IndianapolisBo Shen, ClevelandEdward J Ciaccio, New YorkJean S Wang, Saint LouisBao-Ting Zhu, KansasTamir Miloh, PhoenixEric R Kallwitz, ChicagoYujin Hoshida, CambridgeC Chris Yun, AtlantaAlan C Moss, BostonOliver Grundmann, GainesvilleLinda A Feagins, DallasChanjuan Shi, NashvilleXiaonan Han, CincinnatiWilliam R Brugge, BostonRichard W McCallum, El PasoLisa Ganley-Leal, BostonLin-Feng Chen, Urbana

Elaine Y Lin, New YorkJulian Abrams, New YorkArun Swaminath, New YorkHuiping Zhou, RichmondKorkut Uygun, BostonAnupam Bishayee, Signal HillC Bart Rountree, HersheyAvinash Kambadakone, BostonCourtney W Houchen, OklahomaJoshua R Friedman, PhiladelphiaJustin H Nguyen, JackonvilleSophoclis Alexopoulos, Los AngelesSuryakanth R Gurudu, ScottsdaleWei Jia, KannapolisYoon-Young Jang, BaltimoreOurania M Andrisani, West LafayetteRoderick M Quiros, BethlehemTimothy R Koch, WashingtonAdam S Cheifetz, BostonLifang Hou, ChicagoThiru vengadam Muniraj, PittsburghDhiraj Yadav, PittsburghYing Gao, RockvilleJohn F Gibbs, BuffaloAaron Vinik, NorfolkCharles Thomas, OregonRobert Jensen, BethesdaJohn W Wiley, Ann ArborJonathan Strosberg, TampaRandeep Singh Kashyap, New YorkKaye M Reid Lombardo, RochesterLygia Stewart, San FranciscoMartin D Zielinski, RochesterMatthew James Schuchert, PittsburghMichelle Lai, BostonMillion Mulugeta, Los AngelesPatricia Sylla, BostonPete Muscarella, ColumbusRaul J Rosenthal, WestonRobert V Rege, DallasRoberto Bergamaschi, New York Ronald S Chamberlain, LivingstonAlexander S Rosemurgy, TampaRun Yu, Los AngelesSamuel B Ho, San DiegoSami R Achem, FloridaSandeep Mukherjee, OmahaSanthi Swaroop Vege, RochesterScott Steele, Fort LewisSteven Hochwald, GainesvilleUdayakumar Navaneethan, CincinnatiRadha Krishna Yellapu, New YorkRupjyoti Talukdar, RochesterShi-Ying Cai, New HavenThérèse Tuohy, Salt Lake CityTor C Savidge, GalvestonWilliam R Parker, DurhamXiaofa Qin, NewarkZhang-Xu Liu, Los AngelesAdeel A Butt, Pittsburgh Dean Y Kim, DetroitDenesh Chitkara, East BrunswickMohamad A Eloubeidi, AlabamaJiPing Wang, BostonOscar Joe Hines, Los AngelesJon C Gould, MadisonKirk Ludwig, WisconsinMansour A Parsi, Cleveland

January 7, 2012VIIIWJG|www.wjgnet.com

Perry Shen, Winston-SalemPiero Marco Fisichella, Maywood Marco Giuseppe Patti, ChicagoMichael Leitman, New YorkParviz M Pour, Omaha Florencia Georgina Que, RochesterRichard Hu, Los AngelesRobert E Schoen, PittsburghValentina Medici, SacramentoWojciech Blonski, PhiladelphiaYuan-Ping Han, Los AngelesGrigoriy E Gurvits, New YorkRobert C Moesinger, OgdenMark Bloomston, Columbus

Bronislaw L Slomiany, NewarkLaurie DeLeve, Los AngelesMichel M Murr, TampaJohn Marshall, ColumbiaWilfred M Weinstein, Los AngelesJonathan D Kaunitz, Los AngelesJosh Korzenik, BostonKareem M Abu-Elmagd, PittsburghMichael L Schilsky, New HavenJohn David Christein, BirminghamMark A Zern, SacramentoAna J Coito, Los AngelesGolo Ahlenstiel, BethesdaSmruti R Mohanty, Chicago

Victor E Reyes, Galveston CS Pitchumoni, New BrunswickYoshio Yamaoka, HoustonSukru H Emre, New HavenBranko Stefanovic, TallahasseeJack R Wands, ProvidenceWen Xie, PittsburghRobert Todd Striker, MadisonShivendra Shukla, ColumbiaLaura E Nagy, ClevelandFei Chen, MorgantownKusum K Kharbanda, OmahaPal Pacher, RockvillePietro Valdastri, Nashville

January 7, 2012IXWJG|www.wjgnet.com

S

4801 Biliarycysts:Etiology,diagnosisandmanagement

Jabłońska B

4811 Qualityofulcerhealingingastrointestinaltract:Itspathophysiologyand

clinicalrelevance

Arakawa T, Watanabe T, Tanigawa T, Tominaga K, Fujiwara Y, Morimoto K

4823 Useofthetumornecrosisfactor-blockersforCrohn'sdisease

Thomson ABR, Gupta M, Freeman HJ

4855 Roleformycobacterialinfectioninpathogenesisofprimarybiliarycirrhosis?

Smyk D, Rigopoulou EI, Zen Y, Abeles RD, Billinis C, Pares A, Bogdanos DP

4866 Indomethacinbutnotaselectivecyclooxygenase-2inhibitorinhibits

esophagealadenocarcinogenesisinrats

Esquivias P, Morandeira A, Escartín A, Cebrián C, Santander S, Esteva F,

García-González MA, Ortego J, Lanas A, Piazuelo E

4875 EffectofTangweianJianjionuppergastrointestinalremodelingin

streptozotocin-induceddiabeticrats

Liu GF, Zhao JB, Zhen Z, Sha H, Chen PM, Li M, Zhang JC, Yuan MZ, Gao W,

Gregersen H, Tong XL

4885 Clinicalusefulnessofadherencetogastro-esophagealrefluxdiseaseguideline

bySpanishgastroenterologists

Mearin F, Ponce J, Ponce M, Balboa A, González MA, Zapardiel J

4892 IL28BpolymorphismasapredictorofantiviralresponseinchronichepatitisC

Cieśla A, Bociąga-Jasik M, Sobczyk-Krupiarz I, Głowacki MK, Owczarek D, Cibor D,

Sanak M, Mach T

4898 Analysisofcolonoscopicperforationsatalocalclinicandatertiaryhospital

Sagawa T, Kakizaki S, Iizuka H, Onozato Y, Sohara N, Okamura S, Mori M

Contents

EDITORIAL

Weekly Volume 18 Number 35 September 21, 2012

� September 21, 2012|Volume 18|�ssue 35|WJG|www.wjgnet.com

FRONTIER

GUIDELINES FOR

CLINICAL PRACTICE

REVIEW

ORIGINAL ARTICLE

BRIEF ARTICLE

ContentsWorld Journal of Gastroenterology

Volume 18 Number 35 September 21, 2012

4905 High-riskesophagealvaricesinpatientstreatedwithlocoregionaltherapyfor

hepatocellularcarcinoma:Assessmentwithlivercomputedtomography

Kim H, Choi D, Lee JH, Lee SJ, Jo H, Gwak GY, Koh KC, Choi MS, Kim S

4912 Pentoxifyllineinhepatopulmonarysyndrome

Kianifar HR, Khalesi M, Mahmoodi E, Afzal Aghaei M

4917 InduciblenitricoxidesynthetasegenotypeandHelicobacterpylori infection

affectgastriccancerrisk

Rafiei A, Hosseini V, Janbabai G, Fazli B, Ajami A, Hosseini-khah Z, Gilbreath J, Merrell DS

4925 Endothelialprecursorcellspromoteangiogenesisinhepatocellularcarcinoma

Sun XT, Yuan XW, Zhu HT, Deng ZM, Yu DC, Zhou X, Ding YT

4934 Coexistenceofhyperlipidemiaandacutecerebralischemia/reperfusion

inducessevereliverdamageinaratmodel

Gong WH, Zheng WX, Wang J, Chen SH, Pang B, Hu XM, Cao XL

4944 Doesgemcitabine-basedcombinationtherapyimprovetheprognosisof

unresectablepancreaticcancer?

Sun C, Ansari D, Andersson R, Wu DQ

4959 Cameronulcers:Anatypicalsourceforamassiveuppergastrointestinalbleed

Kapadia S, Jagroop S, Kumar A

4962 Metastasesofesophagealcarcinomatoskeletalmuscle:Singlecenter

experience

Cincibuch J, Mysliveček M, Melichar B, Neoral Č, Metelková I, Zezulová M,

Procházková-Študentová H, Flodr P, Zlevorová M, Aujeský R, Cwiertka K

4967 Hepaticschwannoma:ImagingfindingsonCT,MRIandcontrast-enhanced

ultrasonography

Ota Y, Aso K, Watanabe K, Einama T, Imai K, Karasaki H, Sudo R, Tamaki Y, Okada M,

Tokusashi Y, Kono T, Miyokawa N, Haneda M, Taniguchi M, Furukawa H

�� September 21, 2012|Volume 18|�ssue 35|WJG|www.wjgnet.com

CASE REPORT

NAMEOFJOURNALWorld Journal of Gastroenterology

ISSNANDEISSNISSN 1007-9327 (print)ISSN 2219-2840 (online)

LAUNCHDATEOctober 1, 1995

FREQUENCYWeekly

RESPONSIBLEINSTITUTIONDepartment of Science and Technology of Shanxi Province

SPONSORTaiyuan Research and Treatment Center for Digestive Diseases, 77 Shuangta Xijie, Taiyuan 030001, Shanxi Province, China

EDITINGEditorial Board of World Journal of Gastroenterology Room 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: +86-10-59080039Fax: +86-10-85381893E-mail: wjg@wjgnet.comhttp://www.wjgnet.com

EDITOR-IN-CHIEFFerruccio Bonino, MD, PhD, Professor of Gastro-enterology, Director of Liver and Digestive Disease Division, Department of Internal Medicine, Uni-

versity of Pisa, Director of General Medicine 2 Unit University Hospital of Pisa, Via Roma 67, 56124 Pisa, Italy

Myung-Hwan Kim, MD, PhD, Professor, Head, Department of Gastroenterology, Director, Center for Biliary Diseases, University of Ulsan College of Medi-cine, Asan Medical Center, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, South Korea

Kjell Öberg, MD, PhD, Professor, Department of Endocrine Oncology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden

Matt D Rutter, MBBS, MD, FRCP, Consultant Gas-troenterologist, Senior Lecturer, Director, Tees Bowel Cancer Screening Centre, University Hospital of North Tees, Durham University, Stockton-on-Tees, Cleveland TS19 8PE, United Kingdom

Andrzej S Tarnawski, MD, PhD, DSc (Med), Pro-fessor of Medicine, Chief Gastroenterology, VA Long Beach Health Care System, University of Cali-fornia, Irvine, CA, 5901 E. Seventh Str., Long Beach, CA 90822, United States

EDITORIALOFFICEJian-Xia Cheng, DirectorWorld Journal of GastroenterologyRoom 903, Building D, Ocean International Center, No. 62 Dongsihuan Zhonglu, Chaoyang District, Beijing 100025, ChinaTelephone: +86-10-59080039Fax: +86-10-85381893E-mail: wjg@wjgnet.comhttp://www.wjgnet.com

Contents

APPENDIX

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Yuan Zhou Responsible Science Editor: Xiu-Xia SongResponsible Electronic Editor: Dan-Ni Zhang Proofing Editorial Office Director: Jian-Xia ChengProofing Editor-in-Chief: Lian-Sheng Ma

ABOUT COVER

ACKNOWLEDGMENTS

��� September 21, 2012|Volume 18|�ssue 35|WJG|www.wjgnet.com

PUBLISHERBaishideng Publishing Group Co., LimitedRoom 1701, 17/F, Henan Building, No.90 Jaffe Road, Wanchai, Hong Kong, ChinaFax: +852-31158812Telephone: +852-58042046E-mail: bpg@baishideng.comhttp://www.wjgnet.com

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COPYRIGHT© 2012 Baishideng. Articles published by this Open-Access journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and repro-duction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

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World Journal of GastroenterologyVolume 18 Number 35 September 21, 2012

I AcknowledgmentstoreviewersofWorldJournalofGastroenterology

I Meetings

I-VI Instructionstoauthors

TetsuoArakawa,MD,PhD,DeanandChairmanandProfessor,Departmentof

Gastroenterology,OsakaCityUniversityGraduateSchoolofMedicine,

1-4-3Asahi-machi,Abeno-ku,Osaka545-8585,Japan

World Journal of Gastroenterology (World J Gastroenterol, WJG, print ISSN 1007-9327, DOI: 10.3748) is a weekly, open-access, peer-reviewed journal supported by an editorial board of 1352 experts in gastroenterology and hepatology from 64 countries.

The major task of WJG is to report rapidly the most recent results in basic and clinical research on esophageal, gastrointestinal, liver, pancreas and biliary tract diseases, Helicobacter pylori, endoscopy and gastrointestinal surgery, including: gastroesophageal reflux disease, gastrointestinal bleeding, infection and tumors; gastric and duodenal disorders; intestinal inflammation, microflora and immunity; celiac disease, dyspepsia and nutrition; viral hepatitis, portal hypertension, liver fibrosis, liver cirrhosis, liver transplantation, and metabolic liver disease; molecular and cell biology; geriatric and pediatric gastroenterology; diagnosis and screening, imaging and advanced technology.

I-IX EditorialBoard

AIM AND SCOPE

FLYLEAF

Tetsuo Arakawa, Toshio Watanabe, Tetsuya Tanigawa, Kazunari Tominaga, Yasuhiro Fujiwara, Ken’ichi Morimoto

Quality of ulcer healing in gastrointestinal tract: Its pathophysiology and clinical relevance

Tetsuo Arakawa, Toshio Watanabe, Tetsuya Tanigawa, Kazunari Tominaga, Yasuhiro Fujiwara, Ken’ichi Morimoto, Department of Gastroenterology, Osaka City University Gradu-ate School of Medicine, Osaka 545-8585, JapanAuthor contributions: Arakawa T performed all the manage-ments and decision making to conduct animal experiments and clinical studies, and prepared this manuscript; Watanabe T and Tanigawa T performed most of the animal experiments; Tomi-naga K and Fujiwara Y performed most of the human study of peptic ulcer disease; Morimoto K performed the human study of Crohn’s disease.Correspondence to: Tetsuo Arakawa, MD, PhD, Professor, Dean and Chairman, Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. arakawat@med.osaka-cu.ac.jpTelephone: +81-6-66453810 Fax: +81-6-66463413Received: July 20, 2012 Revised: August 2, 2012Accepted: August 26, 2012Published online: September 21, 2012

AbstractIn this paper, we review the concept of quality of ulcer healing (QOUH) in the gastrointestinal tract and its role in the ulcer recurrence. In the past, peptic ulcer disease (PUD) has been a chronic disease with a cycle of repeated healing/remission and recurrence. The main etiological factor of PUD is Helicobacter pylori (H. pylori ), which is also the cause of ulcer recur-rence. However, H. pylori -negative ulcers are pres-ent in 12%-20% of patients; they also recur and are on occasion intractable. QOUH focuses on the fact that mucosal and submucosal structures within ulcer scars are incompletely regenerated. Within the scars of healed ulcers, regenerated tissue is immature and with distorted architecture, suggesting poor QOUH. The abnormalities in mucosal regeneration can be the basis for ulcer recurrence. Our studies have shown that persistence of macrophages in the regenerated area plays a key role in ulcer recurrence. Our studies

in a rat model of ulcer recurrence have indicated that proinflammatory cytokines trigger activation of macro-phages, which in turn produce increased amounts of cytokines and chemokines, which attract neutrophils to the regenerated area. Neutrophils release proteolytic enzymes that destroy the tissue, resulting in ulcer re-currence. Another important factor in poor QOUH can be deficiency of endogenous prostaglandins and a defi-ciency and/or an imbalance of endogenous growth fac-tors. Topically active mucosal protective and antiulcer drugs promote high QOUH and reduce inflammatory cell infiltration in the ulcer scar. In addition to PUD, the concept of QOUH is likely applicable to inflammatory bowel diseases including Crohn’s disease and ulcer-ative colitis.

© 2012 Baishideng. All rights reserved.

Key words: Quality of ulcer healing; Peptic ulcer dis-ease; Recurrence; Prostaglandin; Cytokines; Growth factors

Peer reviewers: Dr. Selin Kapan, Associate Professor of Gen-eral Surgery, Dr. Sadi Konuk Training and Research Hospital, Department of General Surgery, Kucukcekmece, Istanbul 34150, Turkey; Frank I Tovey, OBE, ChM, FRCS, Honorary Research Felllow, Department of Surgery and Interventional. Science, Uni-versity College London, London W1W 7EJ, United Kingdom

Arakawa T, Watanabe T, Tanigawa T, Tominaga K, Fujiwara Y, Morimoto K. Quality of ulcer healing in gastrointestinal tract: Its pathophysiology and clinical relevance. World J Gastroenterol 2012; 18(35): 4811-4822 Available from: URL: http://www.wjg-net.com/1007-9327/full/v18/i35/4811.htm DOI: http://dx.doi.org/10.3748/wjg.v18.i35.4811

BIOGRAPHY Professor Tetsuo Arakawa (Figure 1) received his MD

FRONTIER

Online Submissions: http://www.wjgnet.com/esps/wjg@wjgnet.comdoi:10.3748/wjg.v18.i35.4811

4811 September 21, 2012|Volume 18|Issue 35|WJG|www.wjgnet.com

World J Gastroenterol 2012 September 21; 18(35): 4811-4822 ISSN 1007-9327 (print) ISSN 2219-2840 (online)

© 2012 Baishideng. All rights reserved.

and PhD degrees from Osaka City University Gradu-ate Medical School, Japan. He was Visiting Research Scholar and Professor at the University of California, Irvine (1990) and the University of Arizona, Tucson, AZ, United States (2000). He is currently Dean and Chairman, Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan. His Curriculum Vitae lists 404 original articles, 421 review articles, 275 book chapters, 24 edited books, prestigious academic awards and honors, and numerous presentations at national and international meetings, including American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), Pasteur Institute and others (over 300 presentations). He has been President/Governor: Japanese Gastroen-terological Association, Japanese Society of Gastroin-testinal Endoscopy, Japanese Society of Ulcer Research, International Conference on Ulcer Research, Japanese Society of Neurogastroenterology, Japanese Society of Gastroenterological Immunology, and Japanese Society of Capsule Endoscopy chaired numerous sessions dur-ing American Gastroenterological Association Meetings and is member of 10 national/international societies, including Fellow of AGA and Fellow of ACG. His re-search interests cover numerous areas of gastroenterol-ogy, endoscopy and pathophysiology; he significantly contributed to the concept of cytoprotection, molecular mechanisms of gastric ulcer healing, mechanisms of anti-ulcer drugs action and translation of basic research to clinical application.

INTRODUCTIONPrior to the introduction of Helicobacter pylori (H. pylori) eradication treatment, peptic ulcer disease (PUD) had been a chronic disease affecting 5%-10% of the popula-tion with a cycle of repeated healing/remission and re-currence. The treatment aimed at eradication of H. pylori has changed the life cycle of this disease and the preva-lence rate has dramatically decreased. However, the dictum “no H. pylori, no ulcer” is over-rated[1]. H. pylori- negative PUD exists, similar to PUD in nonusers of nonsteroidal anti-inflammatory drugs (NSAIDs). This PUD is referred to as non-H. pylori, non-NSAIDs ulcer or idiopathic PUD (IPUD)[2]. A prevalence rate of IPUD has been reported as 12%-20%, suggesting that IPUD is not rare[2]. A recent report has shown the increase in the prevalence of IPUD[3], however this remains controver-sial[4].

The recurrence rate of IPUD is higher than H. pylori and/or NSAID-associated PUD[5] and their management is more difficult and more costly compared to other ulcers[5]. The recurrence rate of ulcer may be related to quality of ulcer healing (QOUH). The pathogenesis of poor QOUH may be the underlying cause of the refrac-toriness and ulcer recurrence. In addition to PUD, the concept of QOUH may be applicable to inflammatory

bowel disease (IBD), which is also a chronic and recur-rent ulcer disease. It is likely that in order to obtain a permanent ulcer healing and remission, the high QOUH is necessary for any type of ulcer disease.

MYSTERY OF ULCER RECURRENCE: PAST HISTORY OF PATHOPHYSIOLOGYUlcer recurrence has long been thought to be an un-avoidable feature of PUD, and therefore, maintenance treatment has been necessary to prevent recurrence. H. pylori is a major cause of both PUD and its recur-rence. The bacteria are, however, not the only cause of ulcer recurrence, and still there are a certain number of patients with PUD not related to H. pylori and NSAIDs, referred to as IPUD[2,4]. To prevent recurrence of IPUD, the investigations examining the pathophysiology of ul-cer recurrence are important.

Oi et al[6] have proposed the double-regulation theory to explain why PUD favors the gastric angle. They exam-ined many stomachs with ulcers that had been operated upon, and found that the ulcer site was usually at the interphase of the distal side of the glandular borderline (mucosal rule) and line of distortion of movement (mus-cular rule). This may be the point of combination of the mechanical tension and exposure to high concentrations of acid in the pyloric gland area. The latter mucosa has a weaker resistance to acid compared to the fundic gland area. This theory may also explain why the ulcer often recurs at the same or neighboring site of a previous ul-cer. This theory, however, does not fit with duodenal or gastric ulcer at other sites. Therefore, it is important to determine how the ulcer recurs.

Pan et al[7] have reported that the recurrence of healed duodenal ulcer depends on the histological maturity of regenerated mucosa. They have indicated that the cause of ulcer recurrence may be related to the abnormalities of the scar of healed ulcer, leading to the concept of QOUH[7]. Takagi et al[8] have developed a chronic gastric ulcer model in rats by topical application of acetic acid from the serosal side of the gastric glandular borderline. This model closely mimics human PUD both in histol-

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Arakawa T et al . Quality of ulcer healing

Figure 1 Tetsuo Arakawa, MD, PhD, Dean, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.

ogy and life cycle of ulcer recurrence. Tarnawski et al[9]

have demonstrated in this rat model that the subepithe-lial mucosa of macroscopically healed gastric ulcer dis-plays disorganized restoration of glandular and vascular structures and remains histologically and ultrastructurally abnormal. They have concluded that these abnormalities may interfere with oxygenation, nutrient supply, and with mucosal resistance and defense, and therefore could be the basis for ulcer recurrence. They proposed the con-cept of QOUH based on an experimental ulcer model in 1990[9-11]. In a previous clinical study by our group, we proposed the concept and definition of QOUH in human gastric ulcer in a Japanese journal, which was published in an English journal 18 mo later[12] (Table 1). A flat or non-flat ulcer scar pattern has been defined with chromoendoscopy using indigo carmine, which was not demonstrated with conventional endoscopy (Fig-ure 2). These patterns are compatible with histological maturity of regenerated mucosa of healed gastric ulcer; the flat pattern represents a good QOUH and non-flat represents poor QOUH[13] (Figure 2). The incidence of ulcer recurrence is much higher in a non-flat scar than in a flat scar pattern[13,14] (Figure 3), suggesting that the en-doscopically assessed QOUH may detect scars that are predisposed to future ulcer recurrence.

ULCER HEALING AND PROSTAGLANDINS Prostaglandins (PGs) and the discovery of the phenom-enon of cytoprotection by Robert et al[15] sparked an enormous interest in the critical role of PGs in mucosal defense and ulcer healing. In humans, “artificial” ulcers in the gastrointestinal tract produced by endoscopic mucosal resection for neoplasm heal rapidly and do not recur. We have shown that the surrounding mucosa of such artificial ulcers synthesizes increased amount of prostaglandin E2 (PGE2) and prostacyclin[16], which may have a crucial role in producing high QOUH. This

observation has led to our contention that PUD may be a PG-deficiency disease[17] and that PG deficiency may cause poor QOUH. We have demonstrated that low-dose indomethacin causing PG-insufficiency forms an experimental chronic gastric ulcer with poor QOUH, and that exogenous PGE2 reverses poor QOUH as assessed by recurrence rate after healing, and reduces inflammatory cell infiltration of the ulcer scar[18] (Figure 4). Therefore, PG derivatives and/or PG-inducing drugs such as mucosal protective compounds may promote high QOUH[19,20].

Another important factor in poor QOUH could be a deficiency and/or an imbalance of endogenous growth factors. Jones et al[21] have demonstrated that local gene therapy with vascular endothelial growth factor (VEGF) and angiopoietin 1 (Ang1), with limited duration of target gene expression, significantly accelerates experi-mental gastric ulcer healing in rats. Co-injection of both plasmids encoding rhVEGF 165 and rhAng1 resulted in formation of more mature vessels and more complete restoration of gastric glandular structures within the ulcer scar, reflecting better QOUH. Inhibition of ac-celerated healing by a neutralizing anti-VEGF antibody indicates an essential role for VEGF and enhanced an-giogenesis in ulcer healing.

PATHOPHYSIOLOGY OF QOUHHistological evaluation of scars of healed gastric ulcers shows increased infiltration of regenerated tissue with numerous neutrophils and macrophages in a non-flat scar compared to a flat scar (Figure 5). The persistence of chronic inflammation may be reflected by the finding of a hypoechoic area beneath the ulcer scar with a non-flat pattern, assessed by endoscopic ultrasonography (Figure 6). The number of macrophages infiltrating scar tissue is five times higher than neutrophils in a non-flat scar, suggesting that these macrophages may play a key role in pathophysiology of QOUH, and hence future ulcer recurrence. These macrophages produce increased amounts of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1 (Figure 7). The proinflammatory cytokines, IL-1β and TNF-α further activate and stimulate macrophages, thus constituting a self-perpetuating circuit. The increased stimulation of production of these cytokines induced by NSAIDs, stress, or H. pylori may cause these macrophages to increase cytokine production and/or release, leading in turn to attraction and accumulation of neutrophils. Neu-trophils by releasing proteases and active oxygen species damage the scar tissue and induce ulcer recurrence.

MECHANISMS UNDERLYING ULCER RECURRENCEAs mentioned previously, Okabe’s rat model of chronic ulcer mimics human peptic ulcer not only morphologi-

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Table 1 Definition and criteria of quality of ulcer healing

Definition: QOUH represents histological maturity of healed peptic ulcer; Evaluation of QOUH should be done to assess functional and endoscopic maturity additionally to histological maturity; For a clinical use an endoscopic evaluation of maturity should be the main methodCriteria: 1: Endoscopic evaluation of maturity Dye-contrast method, magnified endoscopy, endoscopic ultrasonography2: Histological maturity Regenerated mucosa: thickness, width, morphological abnormalities of glands, inflammatory cell infiltration Granulation tissue: angiogenesis, fibroblasts and fibrosis, regeneration of muscularis mucosae, inflammatory cell infiltration3: Functional evaluation of maturity Microcirculation, production of mucin, prostanoids, growth factors, cell proliferation, receptor expression, adhesion molecules

Arakawa et al[12]. QOUH: Quality of ulcer healing.

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ulcer recurrence that we reported in 1997, we found in-creased expression of adhesion molecules, intercellular adhesion molecule (ICAM)-1 in endothelial cells and leukocytic β2 integrins, lymphocyte function-associated antigen (LFA-1; CD11a/CD18) and Mac-1 (CD11b/CD18) in leukocytes, and also of cytokines, IL1β and TNF-α[22], and chemokine, MCP-1[23]. This increase oc-curred in the regenerated tissue of the healed ulcer site (scar) 12 h after injection of an inflammatory cytokine, and was followed by massive infiltration of macrophages and neutrophils, ultimately resulting in ulcer recurrence. Antineutrophil antiserum prevents ulcer recurrence in this model, suggesting that neutrophils (producing nox-ious protease and active oxygen species) are the final mediator of tissue injury[22]. This hypothesis is further supported by the demonstration that antibodies against adhesion molecules (ICAM-1 and LFA-1) also inhibit ulcer recurrence[22]. These molecules regulate migration of neutrophils from arterioles into the interstitial space. Antibody against MCP-1 prevents gastric ulcer recur-rence in this model[23], suggesting that the overexpres-sion of MCP-1 in resident macrophages accumulated in the interstitial space of the ulcer scar is a first step in the mechanism of ulcer recurrence, because neutrophils and macrophages infiltrate the interstitial space of the ulcer scar only after overexpression of MCP-1[24]. Proton-pump inhibitors (PPIs) prevent gastric ulcer recurrence caused by injection of IL1β[24] and administration of

cally and histologically but also with regard to the life cycle of spontaneous recurrence. Numerous neutrophils and macrophages persist in and beneath the regener-ated epithelium even after ulcer healing. This persistent chronic inflammation may have a key role in causing future ulcer recurrence. Watanabe et al[22] have demon-strated that inflammatory cytokines, IL-1β and TNF-α, administered systemically in rats with macroscopically healed gastric ulcer, cause ulcer recurrence at the site of the previous ulcer (Figure 8). In this model of gastric

Conventional endoscopy Chromoendoscopy Histology

B

A

Endoscopic pattern n Regenerated gland index P-value

Flat 10 48.0 ± 2.8Non-flat 5 40.2 ± 2.6 < 0.05

Figure 2 Assessment of endoscopic quality of ulcer healing. Flat pattern (A) and non-flat pattern (B) are identified by chromoendoscopy, but not by conventional endoscopy. Flat pattern reflects good quality of healing compared to nodular pattern as assessed by histological maturity (Arakawa et al[12] ).

100

50

0

Rem

issi

on r

ate

(%)

Flat (n = 24)

Non-flat (n = 25)

P < 0.001

0 6 12 18 Months after therapy ended

Figure 3 Cumulative remission rates of healed gastric ulcers with flat and non-flat pattern. The incidence of ulcer recurrence is much higher in the ulcer scar with a non-flat than flat pattern (Nebiki et al[14]).

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exogenous acid reverses the protective action of PPIs on ulcer recurrence, suggesting that presence of acid is necessary to induce ulcer recurrence[24]. Based on these studies, we propose a working hypothesis of gastric ulcer recurrence presented in Figure 9[25].

EFFECT OF ANTIULCER DRUGS ON QOUHThe histological maturity of regenerated mucosa is poor after treatment with H2-receptor antagonists[26]. This

Indomethacin +16, 16-dimethyl PGE2

100

90

80

70

60

50

40

30

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10

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% r

emis

sion

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P < 0.02

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25

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trop

hils

(ce

lls/fi

eld)

ControlIndomethacinIndomethacin +16, 16-dimethyl PGE2

Indomethacin 1 mg/kg per day

10 30 60 90 Days after production of ulcer

B

a

a

7 67 7 6 6 7 7 7 7 7 7

Figure 4 Effect of low-dose indomethacin given during initial period of healing process of gastric ulcer induced by application of acetic acid in rats on cumulative remission rate after healing and on neutrophil infiltration of the interstitial space of the ulcer scar. Indomethacin treatment enhances neutrophil infiltration and this phenomenon persists even after cessation of this drug. Concomitant administration of 16, 16-dimethyl prostaglandin E2 (PGE2) with indomethacin reverses these effects by indomethacin. A: Cumulative remission rate after healing; B: Infiltration with polymorphonuclear cells during and after healing. Control; indo-methacin; indomethacin + 16, 16-dimethyl prostaglandin E2 (Arakawa et al[18]). aP < 0.05 vs control group.

100

80

60

40

20

0Flat Non-flat

Neutrophil Neutrophil

Cells

/fiel

d

500

400

300

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100

0Flat Non-flat

Macrophage

Cells

/fiel

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Macrophage

b

b

Figure 5 Number of inflammatory cells infiltrating interstitial space of ulcer scar with flat or non-flat pattern assessed by chromoendoscopy in patients with macroscopically healed gastric ulcer. The number of neutrophils and macrophages is much higher in non-flat than in flat pattern. The number of macrophages is increased five times vs neutrophils in non-flat scar. n = 6, bP < 0.01 vs flat group.

Arakawa T et al . Quality of ulcer healing

Indomethacin

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may be related to their action to decrease mucosal PG levels[27]. Rebamipide, a mucosal-protective drug that stimulates synthesis of PGs, accelerates ulcer healing and reduces relapse of acetic-acid-induced gastric ulcer in rats. In contrast, ulcer relapse is not prevented by ci-metidine[26]. Similar results regarding improving QOUH by rebamipide have been reported by Qi et al[28]. In a clinical setting rebamipide has been shown to improve QOUH of human gastric ulcers, as assessed by chro-moendoscopy. Moreover, the ulcer recurrence rate after healing with rebamipide was similar to that found in gastric ulcer patients after H. pylori eradication with dual therapy[29]. Rebamipide has been shown to exert anti-in-flammatory action, accelerate gastric ulcer healing, and promote high QOUH in both experimental and clinical studies[30,31].

Regarding the action of other drugs related to QO-UH, antacid hydrotalcite provides better restoration of glandular structures in the gastric ulcer scar in rats

compared to omeprazole[32]. In clinical studies, initial treatment with sucralfate is superior to cimetidine in de-creasing recurrence rate of healed duodenal ulcer during maintenance therapy with cimetidine[33]. Direct evidence of promoting better QOUH, as assessed by chromoen-doscopy, has been reported with lafutidine in a placebo-controlled trial, and ranitidine compared to famotidine in patients with gastric ulcer[34,35]. Lafutidine is a novel H2-receptor antagonist developed in Japan. It has the unique property of stimulating capsaicin-sensitive nerves, pro-ducing NO, a cytoprotective mediator.

RECENT ADVANCES IN EVALUATION OF QOUHRecent preliminary findings with magnifying endoscopy and narrow band imaging (NBI) may be useful for a more precise evaluation of QOUH. Magnifying endos-copy shows a fine regular glandular pattern in flat scar

BA

Flat Non-flat P-value

Internal hypoechoic area (+/-) 3/21 16/9 0.0003

Figure 6 Assessment of interstitial space beneath gastric ulcer scar with endoscopic ultrasonography. Hypoechoic area (circle of black line) is clearly seen in non-flat scar (B), but not in flat scar (A). Arrow shows a point of ulcer scar (Nebiki et al[14]).

150

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/fiel

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TNF-α IL-1β MCP-1

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/fiel

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/fiel

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Figure 7 Number of tumor necrosis factor-α-, interleukin-1β-, and monocyte chemotactic protein-1-producing cells in interstitial space of ulcer scar site in patients with gastric ulcer whose ulcer healed with flat vs non-flat pattern assessed by chromoendoscopy. n = 6, bP < 0.01 vs flat group. TNF-α: Tumor necrosis factor α; IL-1β: Interleukin-1β; MCP-1: Monocyte chemotactic protein-1.

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BA

IL-1βTNF-α

Anti-neutrophil antiserumAntibodies against adhesion

moleculesAntibody against MCP-1Proton-pump inhibitors

Figure 8 Original rat model of gastric ulcer recurrence. A: Ulcer scar of acetic-acid-induced gastric ulcer healed spontaneously (big arrow) with fold convergence (small arrows); B: Recurrence of ulcer with white coat at the same site as previous ulcer (big arrow). Interleukin-1β (IL-1β) or tumor necrosis factor α (TNF-α) administered systemically causes recurrence of ulcer macroscopically and histologically. Antineutrophil antiserum, antibodies against adhesion molecules, antibody against monocyte chemotactic protein-1 (MCP-1), or proton-pump inhibitors prevent recurrence. MCP-1 is overexpressed in macrophages in the interstitial space of the ulcer scar site at 12 h after administration of IL-1β or TNF-α. Adhesion molecules are overexpressed only at the ulcer scar site (Watanabe et al[22-24]). ICAM: Intercellular adhesion molecule.

Figure 9 Proposed mechanisms of ulcer recurrence. Ulcerogenic factors such as nonsteroidal anti-inflammatory drugs, stress, and Helicobacter pylori stimulate the production of inflammatory cytokines, which activate macrophages under acidic conditions. The activated macrophages produce monocyte chemotactic protein-1 (MCP-1), which accumulates other macrophages. These macrophages all produce a large amount of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), which activate the cytokine network, resulting in activation of adhesion molecules and neutrophils. Activated neutrophils migrate from arterioles to the interstitial space and injure the tissue with noxious substances such as reactive oxygen species and elastase produced by themselves together with gastric acid (Arakawa et al[25]).

Nonsteroidal anti-inflammatory drugs, stress, Helicobacter pylori

Inflammatory cytokines

Activate

Activate

Gastric acid

Macrophage

Cell injury

Recurrence

Active oxygen species

Elastase TNF-α IL-1β

MCP-1

Cytokine network

ActivateNeutrophil

Disturbance of microcirculation Adhesion molecules

12 h 24 h 48 h

MCP-1 Macrophages ICAM-1

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and coarse, irregular, and hyperemic glandular pattern in non-flat scar (Figure 10), suggesting that a more precise assessment is possible in the near future. In addition to this procedure, NBI may be the most promising tool to assess QOUH combined with magnification because NBI shows pattern of vessels that may reflect QOUH (Figure 11).

MUCOSAL HEALING IN CROHN’S DISEASEBiological drugs aimed at TNF-α, such as infliximab (and other related antibodies) as well as thalidomide[36], promote ulcer healing in Crohn’s disease resistant to cor-

ticosteroids. This action is completely different from the mucosal healing obtained with a PPI for gastric and/or duodenal ulcers, because a PPI inhibits only acid secre-tion, but may not suppress inflammation. Therefore, PPIs promote rapid healing of acid-related ulcers, but do not improve QOUH, especially in the presence of H. py-lori. The biological drugs directly suppress inflammation, and thus they may improve QOUH. However, as long as the factor responsible for inflammation is unknown, the efficacy of such drugs may be limited.

Granulomas beneath the regenerated tissue may have an important role in cell-to-cell contact of macrophages with T lymphocytes in Crohn’s disease and cause chronic inflammation, and on this background poor QOUH[37,38].

B

A

Figure 10 Magnifying chromoendoscopy shows different findings in flat scar as a fine regular pattern (A) and non-flat scar as coarse irregular pattern (B) compatible with histological findings.

CBA

Figure 11 Narrow band imaging with magnification by endoscopy in patients with gastric ulcer shows fine vascular patterns, which may reflect precise quality of ulcer healing. A: Conventional endoscopy; B: Magnifying endoscopy; C: Magnification + narrow band imaging.

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The inflammation in Crohn’s disease in based on Th1 and Th17 reaction[39-41] that is similar to H. pylori-associated gastritis[42,43]. Therefore, the inflammation in Crohn’s disease may have similar immunopathophysiology to

H. pylori-associated inflammation, which causes poor QOUH and underlies the ulcer recurrence. The similar-ity of immunological abnormality in Crohn’s disease and H. pylori-associated gastritis may also be related to distur-

D

CBA

E

IHG

F

J

Figure 12 Morphological characteristics of active ulcer in patients with Crohn’s disease. Shape of ulcer edge, flat (A) or non-flat (B); fold convergence, nega-tive or positive (C); shape of ulcer base, flat (D) or non-flat (E); stenosis, negative or positive (F); neighboring ulcer, negative (G) or positive (H); width of ulcer, narrow (I) or wide (J).

Arakawa T et al . Quality of ulcer healing

Table 2 Morphological characteristics of active ulcers in patients with Crohn’s disease reflecting possible future mucosal healing after treatment with infliximab

Morphological finding Mucosal healing

Good (n = 10) Poor (n = 11) P value1

Shape of ulcer edge Flat 8 3Non-flat 2 8 0.03

Fold convergence Negative 7 3Positive 3 8 0.08

Shape of ulcer base Flat 4 3Non-flat 6 8 0.65

Stenosis Negative 8 9Positive 2 2 0.99

Neighboring ulcer Negative 9 4Positive 1 7 0.02

Width of ulcer Narrow 9 4Wide 1 7 0.02

1Fisher’s exact test. P value indicates the statistical difference in morpho-logical findings between good and poor mucosal healing.

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bance of the ghrelin system[44,45].In our preliminary study of 21 patients with Crohn’s

disease treated with infliximab, morphological charac-teristics of active ulcer were defined, namely shape of ulcer edge, flat or non-flat; fold convergence, negative or positive; shape of ulcer base, flat or non-flat; stenosis, negative or positive; neighboring ulcer, negative or posi-tive; width of ulcer, narrow or wide (Figure 12). The incidence of mucosal healing of active ulcer with a flat edge, absence of neighboring ulcer, or a narrow width of ulcer is significantly higher. A negative mucosal fold convergence tends to be more frequent than non-flat ulcer edge, positive fold convergence, positive neigh-boring ulcer, or wide ulcer (Table 2). The latter type of ulcer may require stronger anti-inflammatory treatment to obtain mucosal healing. These ulcers may need an endoscopic follow-up observation with assessment of mucosal healing after remission. If the ulcer does not recur, the mucosal healing may be high QOUH. Mucosal fold convergence (Figure 12C) may be one of the fac-tors reflecting poor QOUH. Therefore, prevention of the convergence may improve QOUH of Crohn’s dis-ease. Stimulation of the local angiotensin Ⅱ system may have a key role in fibrosis, resulting in fold convergence and stricture[46], suggesting that inhibitors on this system such as angiotensin Ⅱ receptor blockers may promote high QOUH in Crohn’s disease. However, to identify a causative factor of inflammation in Crohn’s disease is the most essential. The responsible antigen needs to be elucidated from candidates such as yeast-like antigen[47], and others. Elimination of the possible antigen may be a powerful tool to obtain high QOUH and permanent remission.

The concept and the paradigm of QOUH may also apply to ulcerative colitis. Tarnawski and coworkers us-ing confocal endomicroscopy and molecular imaging have demonstrated in colonic mucosa of patients with

ulcerative colitis in remission impaired crypt regenera-tion, persistent inflammation, pathological angiogenesis and increased microvascular permeability; all reflecting impaired QOUH. They have found that the underlying mechanisms include dysregulation of survivin, aberrant activation of VEGF gene, and persistent inflammatory cell infiltration[48].

ACKNOWLEDGMENTSI would like to thank Professor Andrzej S Tarnawski for giving me a valuable advice and correction on this review article and Emilitus Professor Kenzo Kobayashi for his guidance on the concept of QOUH.

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22 Watanabe T, Arakawa T, Fukuda T, Higuchi K, Kobayashi K. Role of neutrophils in a rat model of gastric ulcer recur-rence caused by interleukin-1 beta. Am J Pathol 1997; 150: 971-979

23 Watanabe T, Higuchi K, Hamaguchi M, Shiba M, Tominaga K, Fujiwara Y, Matsumoto T, Arakawa T. Monocyte che-motactic protein-1 regulates leukocyte recruitment during gastric ulcer recurrence induced by tumor necrosis factor-alpha. Am J Physiol Gastrointest Liver Physiol 2004; 287: G919-G928

24 Watanabe T, Higuchi K, Tominaga K, Fujiwara Y, Arakawa T. Acid regulates inflammatory response in a rat model of induction of gastric ulcer recurrence by interleukin 1beta. Gut 2001; 48: 774-781

25 Arakawa T, Watanabe T, Fukuda T, Higuchi K, Fujiwara Y, Kobayashi K, Tarnawski A. Ulcer recurrence: cytokines and inflammatory response-dependent process. Dig Dis Sci 1998; 43: 61S-66S

26 Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K. Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gas-tric ulcer. Comparison with cimetidine. Dig Dis Sci 1995; 40: 2469-2472

27 Arakawa T, Satoh H, Fukuda T, Sakuma H, Nakamura H, Kobayashi K. Gastric mucosal resistance and prostanoid levels after cimetidine treatment in rats. Digestion 1988; 41: 1-8

28 Qi Z, Jie L, Haixia C, Xiaoying Z. Effect of rebamipide on quality of peptic ulcer healing in rat. Dig Dis Sci 2009; 54: 1876-1883

29 Higuchi K, Arakawa T, Nebiki H, Uchida T, Fujiwara Y, Ando K, Yamasaki K, Takaishi O, Fukuda T, Kobayashi K, Kuroki T. Rebamipide prevents recurrence of gastric ulcers

without affecting Helicobacter pylori status. Dig Dis Sci 1998; 43: 99S-106S

30 Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A. Re-bamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci 1998; 43: 5S-13S

31 Arakawa T, Higuchi K, Fujiwara Y, Watanabe T, Tominaga K, Sasaki E, Oshitani N, Yoshikawa T, Tarnawski AS. 15th anniversary of rebamipide: looking ahead to the new mech-anisms and new applications. Dig Dis Sci 2005; 50 Suppl 1: S3-S11

32 Schmassmann A, Tarnawski A, Gerber HA, Flogerzi B, Sanner M, Varga L, Halter F. Antacid provides better resto-ration of glandular structures within the gastric ulcer scar than omeprazole. Gut 1994; 35: 896-904

33 Tovey FI, Husband EM, Yiu YC, Baker L, McPhail G, Jayaraj AP, Lewin MR, Clark CG. Differences in mucosal appear-ances and in relapse rates in duodenal ulceration treated with sucralfate or cimetidine. Am J Med 1989; 86: 141-144

34 Higuchi K, Watanabe T, Tominaga K, Shiba M, Nakagawa K, Uno H, Kitada K, Satoh H, Chono S, Oshitani N, Fuji-wara Y, Arakawa T. Lafutidine can improve the quality of gastric ulcer healing in humans: a randomized, controlled, multicenter trial. Inflammopharmacology 2006; 14: 226-230

35 Higuchi K, Watanabe T, Tominaga K, Shiba M, Nakagawa K, Uno H, Kitada K, Satoh H, Chono S, Uchida T, Fujiwara Y, Arakawa T. Effects of ranitidine on quality of gastric ulcer healing compared with famotidine: a randomized, con-trolled, multicenter trial. Int J Clin Pharmacol Res 2005; 25: 187-194

36 Leite MR, Santos SS, Lyra AC, Mota J, Santana GO. Tha-lidomide induces mucosal healing in Crohn’s disease: case report. World J Gastroenterol 2011; 17: 5028-5031

37 Hara J, Ohtani H, Matsumoto T, Nakamura S, Kitano A, Arakawa T, Nagura H, Kobayashi K. Expression of co-stimulatory molecules B7-1 and B7-2 in macrophages and granulomas of Crohn’s disease: demonstration of cell-to-cell contact with T lymphocytes. Lab Invest 1997; 77: 175-184

38 Kakazu T, Hara J, Matsumoto T, Nakamura S, Oshitani N, Arakawa T, Kitano A, Nakatani K, Kinjo F, Kuroki T. Type 1 T-helper cell predominance in granulomas of Crohn’s dis-ease. Am J Gastroenterol 1999; 94: 2149-2155

39 Morimoto K, Hosomi S, Yamagami H, Watanabe K, Ka-mata N, Sogawa M, Machida H, Okazaki H, Tanigawa T, Nagahara H, Noda E, Tominaga K, Watanabe T, Fujiwara Y, Maeda K, Hirakawa K, Arakawa T. Dysregulated upregula-tion of T-cell immunoglobulin and mucin domain-3 on mu-cosal T helper 1 cells in patients with Crohn’s disease. Scand J Gastroenterol 2011; 46: 701-709

40 Kawashima D, Oshitani N, Jinno Y, Watanabe K, Nakamura S, Higuchi K, Arakawa T. Augmented expression of second-ary lymphoid tissue chemokine and EBI1 ligand chemokine in Crohn’s disease. J Clin Pathol 2005; 58: 1057-1063

41 Monteleone I, Sarra M, Pallone F, Monteleone G. Th17-related cytokines in inflammatory bowel diseases: friends or foes? Curr Mol Med 2012; 12: 592-597

42 Hitzler I, Kohler E, Engler DB, Yazgan AS, Müller A. The role of Th cell subsets in the control of Helicobacter infec-tions and in T cell-driven gastric immunopathology. Front Immunol 2012; 3: 142

43 Otani K, Watanabe T, Tanigawa T, Okazaki H, Yamagami H, Watanabe K, Tominaga K, Fujiwara Y, Oshitani N, Arakawa T. Anti-inflammatory effects of IL-17A on Helicobacter pylori-induced gastritis. Biochem Biophys Res Commun 2009; 382: 252-258

44 Hosomi S, Oshitani N, Kamata N, Sogawa M, Yamagami H, Watanabe K, Tominaga K, Watanabe T, Fujiwara Y, Maeda K, Hirakawa K, Arakawa T. Phenotypical and functional

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study of ghrelin and its receptor in the pathogenesis of Crohn’s disease. Inflamm Bowel Dis 2008; 14: 1205-1213

45 Ochi M, Tominaga K, Tanaka F, Tanigawa T, Shiba M, Watanabe T, Fujiwara Y, Oshitani N, Higuchi K, Arakawa T. Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats. Life Sci 2008; 82: 862-868

46 Suekane T, Ikura Y, Watanabe K, Arimoto J, Iwasa Y, Su-gama Y, Kayo S, Sugioka K, Naruko T, Maeda K, Hirakawa K, Arakawa T, Ueda M. Phenotypic change and accumula-tion of smooth muscle cells in strictures in Crohn’s disease: relevance to local angiotensin II system. J Gastroenterol 2010; 45: 821-830

47 Oshitani N, Hato F, Suzuki K, Sawa Y, Matsumoto T, Mae-da K, Higuchi K, Kitagawa S, Arakawa T. Cross-reactivity of yeast antigens in human colon and peripheral leukocytes. J Pathol 2003; 199: 361-367

48 Tarnawski AS, Coron E, Sandor Z, Mosnier JF, Ahluwalia A, Rhun ML, Galmiche JP, Matysiak-Budnik T. Confocal endo-microscopy and molecular imaging demonstrates in colonic mucosa of patients with IBD in remission impaired crypt regeneration, persistent inflammation and pathological an-giogenesis. Underlying mechanisms include dysregulation of survivin and aberrant activation of VEGF gene. Gastroen-terology 2010; 138 Suppl 1: S-75

S- Editor Huang XZ L- Editor Kerr C E- Editor Zhang DN

Arakawa T et al . Quality of ulcer healing