消化性溃疡疾病和幽门螺杆菌发现年表

消化性溃疡疾病和幽门螺杆菌发现年表列出了消化性溃疡和幽门螺杆菌研究历史中的重大事件。巴里·马歇尔和罗宾·沃伦于2005年因为发现幽门螺杆菌是消化性溃疡的最初成因而获得诺贝尔生理医学奖，幽门螺杆菌是一种适合在胃部等酸性环境生长的细菌。此项研究发表前的过往30年，一般认为消化性溃疡是由过多胃酸造成的；因为他们的研究成果，现在和幽门螺杆菌有关的消化性溃疡已改用抗生素消除感染。以往采用的胃酸控制疗法也能获得部分成效，这是因为抑制胃液的酸度将使胃内不再适合幽门螺杆菌生长。

Thumb — 幽门螺杆菌（*Helicobacter pylori*）的电子显微镜图

1950年代以前，人们对胃内和胃酸中的细菌已有许多微生物学观察，为消化性溃疡的感染理论和胃酸过多理论奠定了基础^[1]。1954年，一项独立研究观察传统染色得为切片，但没有发现任何细菌，自此学界皆以胃酸理论为圭臬^[2]。这个准则一直到1980年代才透过巴里·马歇尔和罗宾·沃伦的一系列实验改变，他们依照柯霍氏法则成功证明幽门螺杆菌是造成消化性溃疡的主因，然而在当时，要说服医学界接受他们的研究成果需要更多的努力^[3]。现在，全球主要的肠胃医学会都已认同幽门螺杆菌是非药物导致之原发性消化性溃疡的成因，在胃和十二指肠溃疡的疗程中必须消灭此菌^[3]。此外，幽门螺杆菌也与胃淋巴癌（英语：gastric lymphoma）和胃腺癌有关，并被世界卫生组织列为致癌物^[4]。归功于20世纪末分子生物学技术的进步，现在幽门螺杆菌已完成全基因体定序，让科学家能从DNA层级进一步了解其菌落群聚的机制和造成感染的毒力因子（英语：virulence factor）^[5]。

16世纪以前: 希波克拉底首次描述了胃部的症状。^[1]; 伊本·西那注意到胃痛和用餐时间的关联。^[1]

1586: 曼切华的马塞卢斯·多纳图斯（Marcellus Donatus）在执行验尸时描述了胃溃疡的型态。^[6]

1688: 约翰内斯·冯·麦考利（Johannes von Murault）观察到十二指肠溃疡。^[6]

1728: 史达尔（Stahl）提出假说认为发烧和胃部感染与溃疡有关。^[1]

1761: 人们认为胃溃疡和疼痛有关。^[7]

1799: 马修·贝利（英语：Matthew Baillie）（Matthew Baillie）发表了描述溃疡的文句。^[6]

1812: 布鲁塞（英语：François-Joseph-Victor Broussais）（François-Joseph-Victor Broussais）发现急性胃炎若没有治疗会发展为慢性病。^[1]

1821: 内普弗（Nepveu）主张胃炎和胃癌有关联。^[1]

1822: 威廉·博蒙特（William Beaumont）展示了胃酸酸度和心情之间的关联。^[6]

1868: 阿道夫·库斯莫尔（英语：Adolph Kussmaul）（Adolph Kussmaul）建议使用铋化合物和抗生素来治疗消化性溃疡（次水杨酸铋从此时开始广泛作为治疗用药，其中包括用于治疗幽门螺杆菌的碱式水杨酸铋）。科学家在很久以后才了解铋的抗菌性质。^[1]

1875: 贝契尔（G. Bottcher）和烈脱尔（M. Letulle）提出假说认为溃疡是由细菌造成的。^[1]

1880: 孔海姆（英语：Julius Friedrich Cohnheim）（Julius Friedrich Cohnheim）认为溃疡可能由化学物质造成。^[1]

1881: 克雷白氏（英语：Edwin Klebs）（Edwin Klebs）注意到胃腺（英语：gastric gland）的管腔有类似细菌的生物。^[8]

1889: 加沃斯基（英语：Walery Jaworski）（Walery Jaworski）从人类肠胃道的沉积物中发现螺旋状生物体，他认为这些生物可能和胃疾有关。^[1]

1892: 比佐泽罗（英语：Giulio Bizzozero）（Giulio Bizzozero）在狗的胃内发现螺旋状生物体。^[9]^[10]

1896: 沙伦（Saloon）于猫和老鼠的胃内发现螺旋体。 ^[7]

1905: 李格尔（F. Reigel）认为溃疡可能是由过多酸液所造成。^[1]

1906: 克里尼茨（Krienitz）在胃癌病人的胃内发现细菌。^[6]; 图尔克（Turck）喂食犬只大肠杆菌后（当时称大肠杆菌为Bacillus coli）造成犬只罹患消化性溃疡。^[11]

1907: 莫伊尼汉（B. Moynihan）推测酸液是溃疡的成因。^[1]

1910: 史瓦兹（Schwartz）发表了溃疡的过酸理论，并创造了著名的标语：“没有酸，就没有溃疡。”^[6]; 吉贝利（Gibelli）宣称他无法重现图尔克喂食犬只细菌而导致其溃疡的实验。^[1]

1913: 罗塞诺推测链球菌（Strepococci）会造成溃疡。^[12]

1915: 首次有记载建议使用抗酸药治疗消化性溃疡。^[7]; 有些人认为细菌可能和消化性溃疡有关，但此时的假说认为这些细菌生存于口内。^[13]

1919: 葛西胜弥和小林六造从猫身上分离出螺旋菌并将之转移到兔子而造成后者溃疡。^[14]

1921: 卢格尔（Luger）在胃酸中发现螺旋菌，并认为此菌和胃癌有关。^[8]

1924: 勒克（Luck）和塞斯（Seth）于人类胃内发现脲酶，但他们认为这是胃内与生俱来的酵素。^[15]

1925: 霍夫曼（Hoffman）将从消化性溃疡病人取得的样本注射到麝香猪体内而造成后者溃疡，并分离出他认为造成溃疡的细菌。^[16]

1936: 俄语的《医学大百科》第一版认为感染是造成溃疡的可能成因。^[17]

1939: 弗里德贝格（A. Stone Freedberg）在贝斯以色列医院开始寻找人胃内的细菌，并找到了幽门螺杆菌（Helicobacter pylori）。谣传其他人无法复制这项结果，但事实上没有人发表反对此结果的研究。^[18]; 登格斯（James Doenges）在验尸时发现螺旋体。^[19]

1940: 弗里德贝格（Freedberg）和巴伦（Baron）在验尸时观察到螺旋体^[20] ；然而，弗里德贝格在老板的建议下，转换研究主题而放弃继续这项研究。2005年，马歇尔就猜测如果弗里德贝格当初继续这项研究，他应该能获得1951年的诺贝尔奖^[21]。

1948: 菲茨杰拉德（Fitzgerald）和墨菲（Murphy）提出假说认为消化性溃疡是由酸液侵蚀黏膜造成，同时也展示了尿素在治疗上的功效。^[22]

1951: 阿叶德（J. Allende）写了一本书，当中提到可以使用盘尼西林来治疗胃溃疡。^[6]

1953: 汀瑟斯（Dintzis）和海斯廷斯（Hastings）成功使用抗生素停止小鼠胃内产生脲酶，指出脲酶和细菌感染有关。^[23]

1954: 帕玛尔（Palmer）发表的研究声称没有在人类胃内找到任何细菌，因此下结论认为先前的研究均为样本污染。可惜的是，他没有选用银染色进行观察，之后沃伦和马歇尔正是使用银染色证实了幽门螺杆菌的存在。^[2]

1955: 塔诺波斯卡亚（Tarnopolskaya）观察到盘尼西林似乎能治愈一些消化性溃疡病患。^[17]; 穆捷（Moutier）和柯内特（Cornet）建议使用抗生素治疗胃炎。^[17]; 科恩伯格（Kornberg ）和戴维斯（Davies）观察到抗生素能减少猫胃内的脲酶。^[24]

1957: 查尔斯·利伯（Charles Lieber）和安德烈·勒费弗尔（Andre Lefèvre）发现抗生素能抑制胃内的尿素转换为氨。^[25]

1958: 戈登（Gordon）观察到盘尼西林能治愈一些消化性溃疡。^[17]; 莱库提斯（英语：John Lykoudis）（John Lykoudis）成功用抗生素治愈自己的肠胃炎。^[26]; 利伯和勒费弗尔将他们的研究成果发表在华盛顿世界肠胃学大会，然而此结果普遍不获接受，因为帕玛先前的研究，当时的人们认为细菌无法在人的胃内生存。^[27]

1959: 利伯和勒费弗尔发表了后续的追踪研究，显示抗生素能防止人胃内的尿素转变为氨。^[28]; 康威（Conway）等人质疑小鼠体内的脲酶有多少是由细菌产生的，并以此为论点反驳消化性溃疡的细菌理论。^[29]

1960: 维塔尔（Vital）和奥里戈（Orrego）在猫和狗的胃中观察到类似曲状杆菌（Campylobacter）的生物体。^[30]; 莱库提斯用抗生素治疗消化性溃疡的方法获得了希腊专利（#22,453）。^[26]

1962: 苏塞（Susser）和史坦恩（Stein）的研究发现英格兰地区的消化性溃疡有世代现象（英语：cohort effect），并认为这是压力导致消化性溃疡的证据。^[31]

1964: 莱库提斯在希腊的医学外科学大会中展示他使用抗生素治疗消化性溃疡的成果，但不为主流医学机构所接受。^[26]

1966: 莱库提斯的论文稿件遭《美国医学会杂志》拒绝。^[26]

1967: 伊东进（英语：Susumu Ito）观察到类似曲状杆菌的生物体黏附在胃的上皮。^[32]

1968: 莱库提斯因为用他的方法（包括使用抗生素）治疗消化性溃疡而遭罚4000德拉克马。^[26]

1971: 霍华德·斯特恩（Howard Steer）从溃疡病人的生物检体中观察到幽门螺杆菌。^[33]

1972: 中国的研究成功以富来顿（一种抗生素）治疗消化性溃疡。^[34]

1974: 莫洛索夫（Morozov）观察到幽门螺杆菌，但他没有将此发现与消化性溃疡做连结。^[17]; 派翠克（Patrick）等人发表了一份杰出的消化性溃疡研究，但内容完全没有提到细菌。^[33]^[35]

1975: 史提尔（Steer）和柯林-琼斯（Colin-Jones）发表了他们研究幽门螺杆菌与消化性溃疡间关系的成果，认为之前发现的细菌其实是假单胞菌（Pseudomonas）污染，且此菌和消化性溃疡没有关系。^[36]

1978: 美国肠胃学协会在拉斯维加斯的一场会议上，数份研究指出使用H₂受体阻抗剂控制胃酸对消化性溃疡的治疗效果很差。^[37]

1979: 拉姆塞（Ramsey）发表的研究显示铋能帮助治愈消化性溃疡，铋是一种抗菌物质，虽然拉姆塞并没有认可这种说法。^[38]; 华伦（J. Robin Warren）首先在胃检体的切片中发现了幽门螺杆菌。^[39]; 冯（Fung）、帕帕季米特里乌（Papadimitriou）和马兹（Matz）观察到幽门螺杆菌。^[40]

1981: 施尧在胃内观察到弯曲的细菌，但认为它们只是通过胃部的过客，而没有进行培养。^[34]; 7月：巴里·马歇尔进入皇家佩思医院（英语：Royal Perth Hospital）肠胃学科，遇到了罗宾·沃伦。^[3]; 10月：马歇尔和沃伦成功用抗生素治愈了他们的第一个消化性溃疡病患。^[3]

1983: 1月：两份分别由沃伦和马歇尔署名的研究快讯送至学术期刊《刺胳针》，当中描述了他们的研究成果。^[3]; 2月：澳洲肠胃学会拒绝马歇尔在年度会议上发表研究，并将他送来的论文摘要评为所有投稿中最差的10%。但同样的稿件为布鲁塞尔曲状杆菌工作坊所接受，并准予他在论坛中发表成果。^[3]; 4月：马歇尔和伊恩·希斯洛普（Ian Hislop）开始比较铋和西咪替丁（Cimetidine）对消化性溃疡的疗效，但最后因为无法得到有效的结论，他们放弃了这项研究。^[3]; 6月：沃伦和马歇尔的研究快讯出现在《刺胳针》上。^[41]; 9月：澳洲以外的消化性溃疡病人身上也观察到了幽门螺杆菌。^[3]; 沃伦和马歇尔的研究快讯出现在《刺胳针》后，全世界的研究团队都开始分离幽门螺杆菌。^[3]

1984: 马歇尔和沃伦的研究报告获得澳洲肠胃学会接受并准予发表。^[3]; 马歇尔和古德温（Goodwin）尝试用幽门螺杆菌感染猪，但没有造成猪的消化性溃疡，以失败收场。^[3]; 5月：马歇尔和沃伦的研究报告获《刺胳针》接受，并于隔月刊出，但遭来许多批评。^[3]; 麦纳提（McNulty）和华生（Watson）成功重现马歇尔和沃伦的结果。^[42]; 6月12日：马歇尔有意地吃下幽门螺杆菌并造成自己生病，他随后服用抗生素，并成功解除症状。^[3]; 澳洲国家健康暨医药研究委员会（英语：National Health and Medical Research Council）全额资助马歇尔研究幽门螺杆菌。^[3]; 中国刊出一篇研究，讲述抗菌物质能有效治疗消化性溃疡。^[34]; 7月31日：《纽约时报》的医学专栏作家阿特曼医师（Dr. Lawrence K. Altman）发表一篇文章，说明幽门螺杆菌和消化性溃疡之间可能的关联性。^[43] 他在2002年说道：“我从来没看过医学社群对一个故事的发展采取如此防卫且挑剔的态度”，而他从1969年加入新闻业以来已经30多年。^[44]

1985: 马歇尔发表了他刻意感染自己的研究成果。^[3]

1987: 德拉姆（Drumm）与其同事将针对儿童的研究报告发表在《新英格兰医学杂志》上，指出幽门螺杆菌只和原发性胃炎、无法解释的胃炎、及原发性十二指肠溃疡有关，其它如克隆氏症或重大疾病所造成的次级胃炎则和细菌无关。由于儿童的胃炎和十二指肠溃疡很少见，因此这份研究有足够的说服力说明幽门螺杆菌是胃炎的致病原，而非仅是在发炎或溃疡的黏膜上伺机繁殖，这也就证明沃伦和马歇尔是正确的。这是全球首屈一指的学术期刊《新英格兰医学杂志》第一次刊登和幽门螺杆菌相关的研究。^[45]; 莫利斯（Morris）刻意服下幽门螺杆菌后生病了，但和马歇尔不同的是，抗生素无法完全治愈他的疾病，感染持续了三年之久。^[46]; 都柏林的一项大规模研究指出消除幽门螺杆菌能大幅降低溃疡复发的几率。^[47]

1990: 罗斯（Rauws）和提特盖特（Tytgat）以铋和两种抗生素组成的三联疗法消除幽门螺杆菌，成功治愈十二指肠溃疡。^[48] 现代的三联疗法则改用氢离子泵阻断剂和两种抗生素，并很快成为了治疗首选；使用氢离子泵阻断剂的用意在于抑制胃液的酸度，使胃内不再适合幽门螺杆菌生长。^[49]。; 世界肠胃学会议建议消除幽门螺杆菌以治疗十二指肠溃疡。^[50]; 首次有报告指出幽门螺杆菌对甲硝唑产生抗药性^[51]。此次发现的抗药性导致未来发展出各式使用抗生素和氢离子泵阻断剂的疗法^[49]。

1992: 福田善弘等人证明恒河猴食入幽门螺杆菌后会造成胃炎。^[8]; 科瓦奇（Covacci）成功定序出CagA基因，该基因编码的细胞毒素和幽门螺杆菌造成的十二指肠溃疡有密切关系。这是科学家第一次以分子生物学技术确认幽门螺杆菌的致病因子（英语：virulence factor）。^[52]

1994: 藤冈利生等人得到和福田善弘相似的结果。^[8]; 抗酸药专利过期，相关利益人士失去了拒绝使用抗生素治疗幽门螺杆菌的财务动机。^[3]; 美国国立卫生研究院举办的会议显示美国科学家已普遍接受幽门螺杆菌是造成消化性溃疡的原因。^[3]; 世界卫生组织国际癌症研究机构公告幽门螺杆菌为第一类致癌物。^[4]; 帕尔森内特（Parsonnet）等人阐述了幽门螺杆菌和肠胃道淋巴癌之间的关联，这些恶性（英语：MALT lymphoma）溃疡也能以消灭幽门螺杆菌的方式治疗。^[53]

1997: 汤姆（Tomb）等人完成幽门螺杆菌全基因体定序，共含1,667,867对碱基。定序结果有助于科学家从分子层次辨识新的致病因子。^[5]^[54]

2001: 陈家亮等人透过随机对照试验证实消除胃幽门螺杆菌甚至能预防阿司匹林和非类固醇消炎止痛药造成的溃疡出血。^[55]

2002: 欧洲幽门螺杆菌研究小组正式出版2000年第二次马斯垂特共识会议报告（the Maastricht 2-2000 Consensus Report），建议对没有非典型症状的年轻病患采用“先筛检后治疗”的策略，该策略提倡非侵略性的幽门螺杆菌筛检，若结果呈阳性，无论内视镜检查有没有溃疡症状，都直接给予治疗。^[49]

2005: 沃伦和马歇尔因为他们在幽门螺杆菌和消化性溃疡研究上的贡献获颁诺贝尔生理学及医学奖。^[56]

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[3]
Marshall, Barry. The discovery that Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 165–202. ISBN 0-86793-035-7.
[4]
WHO International Agency for Research on Cancer. List of Agents Classified by the IARC Monographs (PDF). [2016-09-05]. （原始内容 (PDF)存档于2016-09-05）.
[5]
Tomb J, White O, Kerlavage A, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 1997, 388 (6642): 539–47. PMID 9252185. doi:10.1038/41483.
[6]
Unge, Peter. Helicobacter pylori treatment in the past and in the 21st century. Barry Marshall (编). Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia. 2002: 203–213. ISBN 0-86793-035-7.
[7]
Buckley, Martin J.M; Colm A. O'Morain. Helicobacter biology – discovery. British Medical Bulletin. 1998, 54 (1): 7–16. PMID 9604426. doi:10.1093/oxfordjournals.bmb.a011681.
[8]
Fukuda, Yoshihiro et al., "Kasai, Kobayashi and Koch's postulates in the history of Helicobacter pylori", in Helicobacter Pioneers, pp. 15–24.
[9]
Bizzozero, Giulio. Ueber die schlauchförmigen Drüsen des Magendarmkanals und die Beziehungen ihres Epitheles zu dem Oberflächenepithel der Schleimhaut. Archiv für mikroskopische Anatomie. 1893, 42: 82–152. doi:10.1007/BF02975307.
[10]
Figura, Natale & Laura Bianciardi, "Helicobacters were discovered in Italy in 1892: An episode in the scientific life of an eclectic pathologist, Giulio Bizzozero", in Helicobacter Pioneers, pp. 1–13.
[11]
Turck, F.B. J.M. Ulcer of the stomach: Pathogenesis and pathology: Experiments in producing artificial gastric ulcer and genuine induced peptic ulcer. Journal of the American Medical Association. 1906, 46: 872. doi:10.1001/jama.1906.62510500017003a.
[12]
Rosenow, E.C. J.M. The production of ulcer of the stomach by injection of streptococci. Journal of the American Medical Association. 1913, 61: 1947. doi:10.1001/jama.1913.04350230001001.
[13]
Rosenow, E.C.; A.H. Sanford. The Bacteriology of Ulcer of the Stomach and Duodenum in Man. Journal of Infectious Diseases. 1915, 17: 219–226. doi:10.1093/infdis/17.1.219.
[14]
Kasai, K.; R. Kobayashi. The stomach Spirochete Occurring in Mammals. Journal of Parasitology. 1919, 6: 1–11. doi:10.2307/3271009.
[15]
Luck; Seth. Gastric Urease. Biochemical Journal. 1924, 37: 1227–1231.
[16]
Hoffman, A. Experimental gastric duodenal inflammation and ulcer, produced with a specific organism fulfilling Koch's postulates. American Journal of the Medical Sciences. 1925, 170: 212.
[17]
Mozorov, Igor A., "Helicobacter pylori was discovered in Russia in 1974", in Helicobacter Pioneers, pp. 105–118.
[18]
Freedberg, A. Stone, "An Early Study of Human Stomach Bacteria", in Helicobacter Pioneers, pp. 25–28.
[19]
Doenges, James. Spirochaetes in the gastric glands of the Macaus Rhesus and Human without definite history of related disease. Archives of Pathology. 1939, 27: 469–477.
[20]
Freedberg, A.S.; L.E. Baron. The presence of spirochaetes in human gastric mucosa. American Journal of Digestive Diseases. 1940, 7 (10): 443–445. doi:10.1007/BF02997393.
[21]
Altman, Lawrence K. A Scientist, Gazing Toward Stockholm, Ponders 'What If?'. The New York Times. 2005-12-06 [March 12, 2011].
[22]
O'Connor, Humphrey J. and Colm A. O'Morain, "Gastric urease in ulcer patients in the 1940s: The Irish connection", in Helicobacter Pioneers, pp. 29–38.
[23]
Dintzis RZ, Hastings AB. The Effect of Antibiotics on Urea Breakdown in Mice. Proc. Natl. Acad. Sci. U.S.A. July 1953, 39 (7): 571–8. PMC 1063826 . PMID 16589306. doi:10.1073/pnas.39.7.57.
[24]
Kornberg, H.L.; R.E. Davies. Gastric Urease. Physiology Review. 1955, 35 (1): 169–177. PMID 14356931.
[25]
Lieber, C.S.; A. Lefèvre. Effect of oxytetracycline on acidity, ammonia, and urea in gastric juice in normal and uremic subjects. Comptes Rendus des Séances et Mémoires de la Société de Biologie. 1957, 151 (5): 1038–1042. PMID 13500735.
[26]
Rigas, Basil and Efstathios D. Papavassiliou, "John Lykoudis: The general practitioner in Greece who in 1958 discovered etiology of, and a treatment for, peptic ulcer disease", in Helicobacter Pioneers, pp. 75–84.
[27]
Lieber, Charles S. J., "How it was discovered in Belgium and the USA (1955–1976) that Gastric Urease was Caused by a Bacterial Infectio", in Helicobacter Pioneers, pp. 39–52.
[28]
Lieber CS, Lefèvre A. AMMONIA AS A SOURCE OF GASTRIC HYPOACIDITY IN PATIENTS WITH UREMIA. J. Clin. Invest. August 1959, 38 (8): 1271–7. PMC 442081 . PMID 13673083. doi:10.1172/JCI103902.
[29]
Conway, E.J.; O. Fitzgerald; K. McGeeney; F. Geoghegan. The location and origin of gastric urease. Gastroenterology. 1959, 37: 449–56. PMID 13811656.
[30]
Vital, J.D.; H. Orrego. Electron Microscope Observations on the Fine Structure of Parietal Cells. Journal of Biophysical and Biochemical Cytology. 1960, 7 (2): 367–72 [2016-08-30]. PMC 2224815 . PMID 13842039. doi:10.1083/jcb.7.2.367. （原始内容存档于2008-12-02）.
[31]
Susser, M.; Z. Stein. Civilization and peptic ulcer. Lancet. 1962, 1 (7221): 115–9. PMID 13918500. doi:10.1016/s0140-6736(62)91127-3.. Reprinted as Susser M, Stein Z. Civilization and peptic ulcer. 1962. International Journal of Epidemiology. 2002, 31 (1): 13–7 [2016-08-30]. PMID 11914283. doi:10.1093/ije/31.1.13. （原始内容存档于2008-07-23）.
[32]
Ito, Susumu. Anatomic structure of the gastric mucosa. Heidel, US; Code, CF (编). Handbook of Physiology Section 6 Volume 2. American Physiological Society. 1967: 705–741.
[33]
Steer, Howard W. The discovery of Helicobacter pylori in England in the 1970s. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 119–29. ISBN 0-86793-035-7.
[34]
Xiao, Shu Dong. How we discovered in China in 1972 that antibiotics cure peptic ulcer. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 165–202. ISBN 0-86793-035-7.
[35]
Patrick, W.J.A.; D. Denham; A.P.M. Forrest. Mucous change in the human duodenum: A light and electron microscopic study and correlation with disease and gastric acid secretion. Gut. 1974, 15 (10): 767–76. PMC 1412991 . PMID 4434919. doi:10.1136/gut.15.10.767.
[36]
Steer, H.W.; D.G. Colin-Jones. Mucosal changes in gastric ulceration and their response to carbenoxolone sodium. Gut. 1975, 16 (8): 590–7. PMC 1411007 . PMID 810394. doi:10.1136/gut.16.8.590.
[37]
Peterson, Walter L. The Dallas experience with acute Helicobacter pylori infection. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 143–50. ISBN 0-86793-035-7.
[38]
Ramsey EJ, K.V. Carey, et al. Epidemic gastritis with hypochlorhydria. Gastroenterology. 1979, 76 (6): 1449–57. PMID 437444.
[39]
Warren, J. Robin. The discovery of Helicobacter pylori in Perth, Western Australia. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 151–64. ISBN 0-86793-035-7.
[40]
Fung, W.P.; J.M Papadimitriou; L.R. Matz. Endoscopic, histological and ultrastructural correlations in chronic gastritis. American Journal of Gastroenterology. 1979, 71 (3): 269–79. PMID 443229.
[41]
Warren, J.R.; Barry Marshall. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983, 1 (8336): 1273–5. PMID 6134060. doi:10.1016/S0140-6736(83)92719-8.
[42]
McNulty, C.A.; D.M. Watson. Spiral bacteria of the gastric antrum. The Lancet. 1984, 1 (8385): 1068–9. PMID 6143990. doi:10.1016/S0140-6736(84)91469-7.
[43]
Altman, Lawrence K. NEW BACTERIUM LINKED TO PAINFUL STOMACH ILLS. The New York Times. 1984-07-31 [March 12, 2011]. （原始内容存档于2016-03-03）.
[44]
Humphrey, Nancy. Award-winning journalist informs doctors, world. The Reporter, Vanderbilt University Medical Center's Weekly Newspaper. 2002-09-27 [March 12, 2011]. （原始内容存档于2018-12-30）.
[45]
Drumm B; et al. Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children. New England Journal of Medicine. 1987, 316: 1557–1661. doi:10.1056/nejm198706183162501.
[46]
Morris, A.; G. Nicholson. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. American Journal of Gastroenterology. 1987, 82 (3): 192–9. PMID 3826027.
[47]
Coghlan JG, H. Humphrise, et al. Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up study. The Lancet. 1987, 2 (8568): 109–11. PMID 2890019. doi:10.1016/S0140-6736(02)93231-9.
[48]
Rauws E, Tytgat G. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet. 1990, 335 (8700): 1233–5. PMID 1971318. doi:10.1016/0140-6736(90)91301-P.
[49]
Malfertheiner P, Mégraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection—the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther. 2002, 16 (2): 167–80. PMID 11860399. doi:10.1046/j.1365-2036.2002.01169.x.
[50]
Rauws, E.A.J.; G.N.J. Tytgat. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. The Lancet. 1990, 335 (8700): 1233–5. PMID 1971318. doi:10.1016/0140-6736(90)91301-P.
[51]
Becx M, Janssen A, et al. Metronidazole-resistant Helicobacter pylori. Lancet. 1990, 335 (8688): 539–40. PMID 1968548. doi:10.1016/0140-6736(90)90772-W.
[52]
Covacci A, Censini S, Bugnoli M, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA. 1993, 90 (12): 5791–5. PMC 46808 . PMID 8516329. doi:10.1073/pnas.90.12.5791.
[53]
Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine. 1994, 330 (18): 1267–71. PMID 8145781. doi:10.1056/NEJM199405053301803.
[54]
Aspholm-Hurtig M, Dailide G, Lahmann M, et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science. 2004, 305 (5683): 519–22. PMID 15273394. doi:10.1126/science.1098801.
[55]
Chan F, Chung S, Suen B, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001, 344 (13): 967–73. PMID 11274623. doi:10.1056/NEJM200103293441304.
[56]
Nobel Prize in Medicine 2005. Nobel Foundation. [October 3, 2006]. （原始内容存档于2016-09-10）.

[KM-1] [1]
Kidd, Mark; Irvin M. Modlin. A century of Helicobacter pylori. Digestion. 1998, 59 (1): 1–15. PMID 9468093. doi:10.1159/000007461.

[:0-2] [2]
Palmer, E.D. Investigation of the gastric mucosa spirochetes of the human. Gastroenterology. 1954, 27 (2): 218–220. PMID 13183283.

[BM-hp-3] [3]
Marshall, Barry. The discovery that Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 165–202. ISBN 0-86793-035-7.

[:2-4] [4]
WHO International Agency for Research on Cancer. List of Agents Classified by the IARC Monographs (PDF). [2016-09-05]. （原始内容 (PDF)存档于2016-09-05）.

[:3-5] [5]
Tomb J, White O, Kerlavage A, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 1997, 388 (6642): 539–47. PMID 9252185. doi:10.1038/41483.

[PU-hp-6] [6]
Unge, Peter. Helicobacter pylori treatment in the past and in the 21st century. Barry Marshall (编). Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia. 2002: 203–213. ISBN 0-86793-035-7.

[BOM-7] [7]
Buckley, Martin J.M; Colm A. O'Morain. Helicobacter biology – discovery. British Medical Bulletin. 1998, 54 (1): 7–16. PMID 9604426. doi:10.1093/oxfordjournals.bmb.a011681.

[FSSM-hp-8] [8]
Fukuda, Yoshihiro et al., "Kasai, Kobayashi and Koch's postulates in the history of Helicobacter pylori", in Helicobacter Pioneers, pp. 15–24.

[9] [9]
Bizzozero, Giulio. Ueber die schlauchförmigen Drüsen des Magendarmkanals und die Beziehungen ihres Epitheles zu dem Oberflächenepithel der Schleimhaut. Archiv für mikroskopische Anatomie. 1893, 42: 82–152. doi:10.1007/BF02975307.

[FB-hp-10] [10]
Figura, Natale & Laura Bianciardi, "Helicobacters were discovered in Italy in 1892: An episode in the scientific life of an eclectic pathologist, Giulio Bizzozero", in Helicobacter Pioneers, pp. 1–13.

[11] [11]
Turck, F.B. J.M. Ulcer of the stomach: Pathogenesis and pathology: Experiments in producing artificial gastric ulcer and genuine induced peptic ulcer. Journal of the American Medical Association. 1906, 46: 872. doi:10.1001/jama.1906.62510500017003a.

[12] [12]
Rosenow, E.C. J.M. The production of ulcer of the stomach by injection of streptococci. Journal of the American Medical Association. 1913, 61: 1947. doi:10.1001/jama.1913.04350230001001.

[13] [13]
Rosenow, E.C.; A.H. Sanford. The Bacteriology of Ulcer of the Stomach and Duodenum in Man. Journal of Infectious Diseases. 1915, 17: 219–226. doi:10.1093/infdis/17.1.219.

[14] [14]
Kasai, K.; R. Kobayashi. The stomach Spirochete Occurring in Mammals. Journal of Parasitology. 1919, 6: 1–11. doi:10.2307/3271009.

[15] [15]
Luck; Seth. Gastric Urease. Biochemical Journal. 1924, 37: 1227–1231.

[16] [16]
Hoffman, A. Experimental gastric duodenal inflammation and ulcer, produced with a specific organism fulfilling Koch's postulates. American Journal of the Medical Sciences. 1925, 170: 212.

[IM-hp-17] [17]
Mozorov, Igor A., "Helicobacter pylori was discovered in Russia in 1974", in Helicobacter Pioneers, pp. 105–118.

[ASF-hp-18] [18]
Freedberg, A. Stone, "An Early Study of Human Stomach Bacteria", in Helicobacter Pioneers, pp. 25–28.

[19] [19]
Doenges, James. Spirochaetes in the gastric glands of the Macaus Rhesus and Human without definite history of related disease. Archives of Pathology. 1939, 27: 469–477.

[20] [20]
Freedberg, A.S.; L.E. Baron. The presence of spirochaetes in human gastric mucosa. American Journal of Digestive Diseases. 1940, 7 (10): 443–445. doi:10.1007/BF02997393.

[altman20051206-21] [21]
Altman, Lawrence K. A Scientist, Gazing Toward Stockholm, Ponders 'What If?'. The New York Times. 2005-12-06 [March 12, 2011].

[OO-hp-22] [22]
O'Connor, Humphrey J. and Colm A. O'Morain, "Gastric urease in ulcer patients in the 1940s: The Irish connection", in Helicobacter Pioneers, pp. 29–38.

[23] [23]
Dintzis RZ, Hastings AB. The Effect of Antibiotics on Urea Breakdown in Mice. Proc. Natl. Acad. Sci. U.S.A. July 1953, 39 (7): 571–8. PMC 1063826 . PMID 16589306. doi:10.1073/pnas.39.7.57.

[24] [24]
Kornberg, H.L.; R.E. Davies. Gastric Urease. Physiology Review. 1955, 35 (1): 169–177. PMID 14356931.

[25] [25]
Lieber, C.S.; A. Lefèvre. Effect of oxytetracycline on acidity, ammonia, and urea in gastric juice in normal and uremic subjects. Comptes Rendus des Séances et Mémoires de la Société de Biologie. 1957, 151 (5): 1038–1042. PMID 13500735.

[RP-hp-26] [26]
Rigas, Basil and Efstathios D. Papavassiliou, "John Lykoudis: The general practitioner in Greece who in 1958 discovered etiology of, and a treatment for, peptic ulcer disease", in Helicobacter Pioneers, pp. 75–84.

[CSL-hp-27] [27]
Lieber, Charles S. J., "How it was discovered in Belgium and the USA (1955–1976) that Gastric Urease was Caused by a Bacterial Infectio", in Helicobacter Pioneers, pp. 39–52.

[28] [28]
Lieber CS, Lefèvre A. AMMONIA AS A SOURCE OF GASTRIC HYPOACIDITY IN PATIENTS WITH UREMIA. J. Clin. Invest. August 1959, 38 (8): 1271–7. PMC 442081 . PMID 13673083. doi:10.1172/JCI103902.

[29] [29]
Conway, E.J.; O. Fitzgerald; K. McGeeney; F. Geoghegan. The location and origin of gastric urease. Gastroenterology. 1959, 37: 449–56. PMID 13811656.

[30] [30]
Vital, J.D.; H. Orrego. Electron Microscope Observations on the Fine Structure of Parietal Cells. Journal of Biophysical and Biochemical Cytology. 1960, 7 (2): 367–72 [2016-08-30]. PMC 2224815 . PMID 13842039. doi:10.1083/jcb.7.2.367. （原始内容存档于2008-12-02）.

[31] [31]
Susser, M.; Z. Stein. Civilization and peptic ulcer. Lancet. 1962, 1 (7221): 115–9. PMID 13918500. doi:10.1016/s0140-6736(62)91127-3.. Reprinted as Susser M, Stein Z. Civilization and peptic ulcer. 1962. International Journal of Epidemiology. 2002, 31 (1): 13–7 [2016-08-30]. PMID 11914283. doi:10.1093/ije/31.1.13. （原始内容存档于2008-07-23）.

[32] [32]
Ito, Susumu. Anatomic structure of the gastric mucosa. Heidel, US; Code, CF (编). Handbook of Physiology Section 6 Volume 2. American Physiological Society. 1967: 705–741.

[HWS-hp-33] [33]
Steer, Howard W. The discovery of Helicobacter pylori in England in the 1970s. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 119–29. ISBN 0-86793-035-7.

[XSL-hp-34] [34]
Xiao, Shu Dong. How we discovered in China in 1972 that antibiotics cure peptic ulcer. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 165–202. ISBN 0-86793-035-7.

[35] [35]
Patrick, W.J.A.; D. Denham; A.P.M. Forrest. Mucous change in the human duodenum: A light and electron microscopic study and correlation with disease and gastric acid secretion. Gut. 1974, 15 (10): 767–76. PMC 1412991 . PMID 4434919. doi:10.1136/gut.15.10.767.

[36] [36]
Steer, H.W.; D.G. Colin-Jones. Mucosal changes in gastric ulceration and their response to carbenoxolone sodium. Gut. 1975, 16 (8): 590–7. PMC 1411007 . PMID 810394. doi:10.1136/gut.16.8.590.

[PHM-hp-37] [37]
Peterson, Walter L. The Dallas experience with acute Helicobacter pylori infection. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 143–50. ISBN 0-86793-035-7.

[38] [38]
Ramsey EJ, K.V. Carey, et al. Epidemic gastritis with hypochlorhydria. Gastroenterology. 1979, 76 (6): 1449–57. PMID 437444.

[JRW-hp-39] [39]
Warren, J. Robin. The discovery of Helicobacter pylori in Perth, Western Australia. Barry J. Marshall (编). Helicobacter pioneers: firsthand accounts from the scientists who discovered helicobacters, 1892–1982. Oxford: Blackwell. 2002: 151–64. ISBN 0-86793-035-7.

[40] [40]
Fung, W.P.; J.M Papadimitriou; L.R. Matz. Endoscopic, histological and ultrastructural correlations in chronic gastritis. American Journal of Gastroenterology. 1979, 71 (3): 269–79. PMID 443229.

[WM-l-41] [41]
Warren, J.R.; Barry Marshall. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983, 1 (8336): 1273–5. PMID 6134060. doi:10.1016/S0140-6736(83)92719-8.

[42] [42]
McNulty, C.A.; D.M. Watson. Spiral bacteria of the gastric antrum. The Lancet. 1984, 1 (8385): 1068–9. PMID 6143990. doi:10.1016/S0140-6736(84)91469-7.

[altman19840731-43] [43]
Altman, Lawrence K. NEW BACTERIUM LINKED TO PAINFUL STOMACH ILLS. The New York Times. 1984-07-31 [March 12, 2011]. （原始内容存档于2016-03-03）.

[humphrey20020927-44] [44]
Humphrey, Nancy. Award-winning journalist informs doctors, world. The Reporter, Vanderbilt University Medical Center's Weekly Newspaper. 2002-09-27 [March 12, 2011]. （原始内容存档于2018-12-30）.

[45] [45]
Drumm B; et al. Association of Campylobacter pylori on the gastric mucosa with antral gastritis in children. New England Journal of Medicine. 1987, 316: 1557–1661. doi:10.1056/nejm198706183162501.

[46] [46]
Morris, A.; G. Nicholson. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. American Journal of Gastroenterology. 1987, 82 (3): 192–9. PMID 3826027.

[47] [47]
Coghlan JG, H. Humphrise, et al. Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up study. The Lancet. 1987, 2 (8568): 109–11. PMID 2890019. doi:10.1016/S0140-6736(02)93231-9.

[48] [48]
Rauws E, Tytgat G. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet. 1990, 335 (8700): 1233–5. PMID 1971318. doi:10.1016/0140-6736(90)91301-P.

[Maas-49] [49]
Malfertheiner P, Mégraud F, O'Morain C, et al. Current concepts in the management of Helicobacter pylori infection—the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther. 2002, 16 (2): 167–80. PMID 11860399. doi:10.1046/j.1365-2036.2002.01169.x.

[:1-50] [50]
Rauws, E.A.J.; G.N.J. Tytgat. Cure of duodenal ulcer associated with eradication of Helicobacter pylori. The Lancet. 1990, 335 (8700): 1233–5. PMID 1971318. doi:10.1016/0140-6736(90)91301-P.

[51] [51]
Becx M, Janssen A, et al. Metronidazole-resistant Helicobacter pylori. Lancet. 1990, 335 (8688): 539–40. PMID 1968548. doi:10.1016/0140-6736(90)90772-W.

[52] [52]
Covacci A, Censini S, Bugnoli M, et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA. 1993, 90 (12): 5791–5. PMC 46808 . PMID 8516329. doi:10.1073/pnas.90.12.5791.

[53] [53]
Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine. 1994, 330 (18): 1267–71. PMID 8145781. doi:10.1056/NEJM199405053301803.

[:4-54] [54]
Aspholm-Hurtig M, Dailide G, Lahmann M, et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science. 2004, 305 (5683): 519–22. PMID 15273394. doi:10.1126/science.1098801.

[55] [55]
Chan F, Chung S, Suen B, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001, 344 (13): 967–73. PMID 11274623. doi:10.1056/NEJM200103293441304.

[56] [56]
Nobel Prize in Medicine 2005. Nobel Foundation. [October 3, 2006]. （原始内容存档于2016-09-10）.

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[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

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消化性溃疡疾病和幽门螺杆菌发现年表

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发现背景

20世纪以前

1900－1950

1950－1970

1970－至今

参考文献