Timeline of peptic ulcer disease and Helicobacter pylori

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Electron micrograph of H. pylori

This is a timeline of the events relating to the discovery that peptic ulcer disease is caused by H. pylori. In 2005, Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their discovery that peptic ulcer disease (PUD) was primarily caused by Helicobacter pylori, a bacterium with affinity for acidic enivironments, such as the stomach. As a result, PUD that is associated with H. pylori is currently treated with antibiotics used to eradicate the infection. For 30 years prior to their discovery it was widely believed that PUD was caused by excess acid in the stomach. During this time, acid control was the primary method of treatment for PUD, to only partial success; among other effects, we now know that acid suppression alters the stomach milieu to make it less amenable to H. pylori infection.

Before the 1950s, there were many microbiological descriptions of bacteria in the stomach and in gastric acid secretions, lending credence to both the infective theory and the hyperacidity theory as being causes of peptic ulcer disease. A single study, conducted in 1954, did not find evidence of bacteria on biopsies of the stomach stained traditionally; this effectively established the acid theory as dogma. This paradigm was altered when Warren and Marshall effectively proved Koch's postulates for causation of PUD by H. pylori through a series of experiments in the 1980s; however, an extensive effort was required to convince the medical community of the relevance of their work. Now, all major gastrointestinal societies agree that H. pylori is the primary non-drug cause of PUD worldwide, and advocate its eradication as essential to treatment of gastric and duodenal ulcers. Additionally, H. pylori has been associated with lymphomas and adenocarcinomas of the stomach, and has been classified by the World Health Organization as a carcinogen. Advances in molecular biology in the late twentieth century led to the sequencing of the H. pylori genome, resulting in a better understanding of virulence factors responsible for its colonization and infection, on the DNA level.

Year	Events
Pre 16th century	Hippocrates first describes gastric symptoms.^[1] Avicenna notes the relationship between gastric pain and mealtimes.^[1]	Hippocrates
1586	Marceliun Pnatus of Mantua performs autopsies and describes gastric ulcers.^[2]	Gastric Ulcer
1688	Johannes von Murault observes duodenal ulcers.^[2]
1728	Stahl hypothesizes that some fevers are related to gastric inflammation and ulceration.^[1]
1761	Pain is associated with stomach ulcers.^[3]
1799	Matthew Baillie publishes a description of ulcers.^[2]
1812	Broussais discovers that if acute gastritis in untreated, it can become chronic.^[1]	François-Joseph-Victor Broussais
1821	Nepveu argues for a relationship between gastritis and gastric cancer.^[1]
1822	William Beaumont first demonstrates the acidity of the stomach and a relationship between acid levels and mood.^[2]
1868	Kussmaul suggests using bismuth compounds, an anti-bacterial agent, in order to treat peptic ulcers (bismuth subsalicylate has since been used in many commercial drugs, including Pepto Bismol as part of antibacterial H. pylori treatment) The antibacterial properties of bismuth were not known until much later.^[1]
1875	G. Bottcher and M. Letulle hypothesize that ulcers are caused by bacteria.^[1]
1880	J. Cohnheim suggests that ulcers may be caused by chemical factors.^[1]
1881	Klebs notes the presence of bacteria-like organisms in the lumen of the gastric glands.^[4]
1889	Walery Jaworski describes spiral organisms in sediment washings of humans. He suggests these organisms might be involved with gastric disease.^[1]
1892	Giulio Bizzozero observes spiral organisms in the stomach of dogs.^[5]^[6]
1896	Saloon finds spirochetes in the stomachs of cats and mice.^[3]	Spirochete bacteria
1905	F. Reigel suggests that ulcers are caused by excess acid.^[1]
1906	Krienitz finds bacteria in the stomach of people with gastric cancer.^[2] Turck feeds dogs Bacillus coli and produces ulcers.^[7]	Bacillus coli (E. coli)
1907	Berkley Moynihan suggests that acid is a cause of ulcers.^[1]
1910	Schwartz publishes the excess acid theory of the ulcer, coining the famous phrase "no acid, no ulcer." ^[2] Gibelli claims to be unable to reproduce Turck's study where he artificially created ulcers by feeding dogs bacteria.^[1]
1913	Rosenow suggests that Streptococci produce ulcers.^[8]	Strepococci
1915	Antacids are first recommended for the treatment of PUD.^[3] Bacteria are associated with PUD, but it is assumed that the bacteria reside in the mouth.^[9]
1919	Kasai and Kobayashi isolate spirochetes in cats and transmit them to rabbits, producing ulcers.^[10]
1921	Luger discovers spirochetes in the gastric juice, and associates their presence with gastric cancer. ^[4]
1924	Luck and Seth discover urease in the human stomach, which they believe is naturally occurring.^[11] It is now known that one of the virulence factors of H. pylori is the urease enzyme, which splits urea into ammonia	Urease
1925	Hoffman injects a small sample from a human with PUD into a guinea pig, producing ulcers, and isolates a bacteria which he believes caused the ulcers.^[12]
1936	First edition of the Russian Large Medical Encyclopedia suggests infection is one of the causes of PUD.^[13]
1939	A. Stone Freedberg begins a study to look for bacteria in the human stomach at Beth Israel Hospital. He finds H. pylori. It is rumored that others cannot reproduce the results, although no negative results are published.^[14] James Doenges describes spirochetes in autopsies.^[15]
1940	Freedberg and Baron observe spirochetes in autopsies.^[16]
1948	Fitzgerald and Murphy hypothesize that PUD is caused by acid eating away mucosa, and demonstrate the effectiveness of urea as a treatment for PUD.^[17]	Chemical structure of Urea
1951	J. Allende publishes a book describing the treatment of gastric ulcers with penicillin.^[2]	Penicillin core
1953	Dintzis and Hastings are able to stop urease production in mice with antibiotics, suggesting a relationship between urease and a bacterial infection.^[18]
1954	Palmer publishes a study which finds no bacteria in the human stomach. He concludes earlier discoveries were a result of contamination. Unfortunately, he chooses not to use a silver staining method, which will be later used to reveal H. pylori by Warren and Marshall. ^[19]	Stained tissue
1955	Tarnopolskaya observes that penicillin cures some peptic ulcers.^[13] Moutier and Cornet suggest treating gastritis with antibiotics.^[13] Kornberg and Davies observe that antibiotics reduce urease in cats.^[20]
1957	Charles Lieber and Andre Lefèvre discover that antibiotics reduce gastric urea to ammonia conversion.^[21]	Ammonia
1958	Gordon observes that penicillin cures some peptic ulcers.^[13] John Lykoudis successfully treats his own gastroenteritis with antibiotics.^[22] Lieber and Lefèvre present their results at the World Congress of Gastroenterology in Washington. It is not well received because of the widespread belief that bacteria cannot survive in the human stomach, due to Palmer.^[23]
1959	Lieber and Lefèvre publish a follow-up study demonstrating that antibiotics prevent the conversion of urea to ammonia in the human stomach.^[24] Conway et al. call into question the extent of urease produced by bacteria in mice, as an argument against the bacterial theory of PUD.^[25]
1960	Vital and Orrego observe campylobacter-like organisms in the stomachs of cats and dogs.^[26] November 16 - Lykoudis is awarded a Greek patent (#22,453) for his antibiotic treatment of PUD.^[22]	Campylobacter fetus
1962	Susser and Stein publish a paper identifying a birth cohort phenomenon of PUD in England. This is taken as evidence for stress causing PUD.^[27]
1964	May 4 - Lykoudis presents his antibiotic treatment for PUD at a meeting of the Medico-Surgical Society in Greece. He is largely shunned by the medical establishment.^[22]
1966	September 1 - Lykoudis' manuscript is rejected by the Journal of the American Medical Association.^[22]
1967	Susumu Ito describes campylobacter-like organisms attached to a gastric epithelial cell.^[28]
1968	November 6 - Lykoudis is fined 4,000 drachmas for treating PUD patients with his treatment, which includes antibiotics.^[22]
1971	August 26 - Howard Steer observes H. pylori from biopsies of a patient with ulcers.^[29]
1972	The first report of successfully using ferazolidone (an anti-bacterial agent) to treat PUD in China.^[30]
1974	Morozov observes H. pylori; he does not connect this discovery to PUD.^[13] A well regarded study of PUD is published which does not mention bacteria.^[29]^[31]
1975	Steer and Colin-Jones publish their results regarding H. pylori and its relation to PUD. They decide that it was Pseudomonas, a contaminant, and not related to PUD.^[32]	Pseudomonas aeruginosa
1978	At a meeting of the American Gastroenterology Association in Las Vegas, several papers are presented which suggest that acid control via H₂ blockers is ineffective at curing PUD.^[33]
1979	Ramsey publishes a study demonstrating that bismuth can help eradicate PUD. Bismuth is an antibacterial agent, although this is not recognized by Ramsey.^[34] June 11 - J. Robin Warren first observes H. pylori in a gastric biopsy.^[35] Fung, Papadimitriou, and Matz observe H. pylori.^[36]	H. pylori
1981	Yao Shi observes bacteria in the stomach, but he believes they are bacteria that are passing through the stomach and not colonizing it.^[30] July - Barry Marshall joins gastroenterology division of Royal Perth Hospital and meets Robin Warren ^[37] October - Marshall and Warren successfully treat their first PUD patient with antibiotics.^[37]
1982	Satoha et al. find evidence for an infectious cause of ulcers in rats.^[38] Marshall and Warren begin their first study to determine the relationship between H. pylori and PUD.^[37] April 8 - First successful culturing of H. pylori performed; it occurs almost by accident.^[37] October - Marshall discovers the bacteria he is investigating are not campylobacters, by looking at electron micrographs.^[37] October 2 - Marshall presents his and Warren's results at a local College of Physicians meeting. He meets with criticism, which Marshall later admits was well-founded (at least in part).^[37]
1983	January - Two letters authored by Warren and Marshall respectively are sent to The Lancet describing their results.^[37] February - Gastroenterological Society of Australia rejects Marshall's abstract to present his research at their yearly conference. They deem it in the bottom 10% of papers submitted. The same abstract is accepted for presentation at a Campylobacter workshop in Brussels.^[37] April - Marshall and Ian Hislop begin a study to compare bismuth treatment with cimetidine. The study is abandoned because it is inconclusive.^[37] June - Warren and Marshall's letter appears in The Lancet.^[39] September - H. pylori is observed in patients outside of Australia.^[37] After the appearance of the letters in The Lancet, groups around the world begin isolating H. pylori.^[37]	Cimetidine
1984	A paper describing Marshall and Warren's results is accepted by the Gastroenterological Society of Australia for presentation.^[37] Marshall and Goodwin attempt to infect pigs with H. pylori in an attempt to demonstrate that it causes PUD. The experiment fails.^[37] Marshall and Warren's paper is accepted by The Lancet in May and published in June. Many reviewers dislike the paper.^[37] McNulty and Watson are able to reproduce Marshall and Warren's results.^[40] June 12 - Marshall intentionally consumes H. pylori and becomes ill. He takes antibiotics and is relieved of his symptoms.^[37] The National Health and Medical Research Council of Australia fully funds Marshall's research into H. pylori.^[37] Study published in China about the effectiveness of treating PUD with an antibacterial agent. ^[30]
1985	Marshall publishes the results of self-induced infection.^[37]
1987	Morris intentionally consumes H. pylori. Like Marshall, he become ill, but unlike Marshall, he is not completely cured by antibiotics. The infection will remain with him for three years.^[41] An extensive study in Dublin demonstrates that eradicating H. pylori substantially reduces recurrence of ulcers.^[42]
1990	Rauws and Tytgat describe cure of duodenal ulcer by eradication of H. pylori using a triple-therapy regimen, consisting of bismuth and two antibiotics.^[43] Triple-therapy, modernized to a proton pump inhibitor and two antibiotics soon becomes first line therapy for eradication. World Congress of Gastroenterology recommends eradicating H. pylori in order to cure duodenal ulcers.^[44] First report of resistance of H. pylori to the antibiotic metronidazole.^[45] Resistance of H. pylori to treatment will lead to the development of many different antibiotic and proton-pump inhibitor regimens for eradication.^[46]
1992	Fukuda et al. prove ingestion of H. pylori causes gastritis in rhesus monkeys.^[4] Covacci et al. sequence the CagA gene, which encodes for a cytotoxin-associated surface protein, which correlated strongly with strains of H. pylori that caused duodenal ulcers. This was the first description of a virulence factor for H. pylori infection determined by molecular techniques.^[47]
1994	Fujioka et al. prove similar results as those from Fukuda et al.^[4] Patents for acid reducing drugs expire, removing financial incentive to resist antibiotics as treatment of PUD.^[37] Conference held by National Institute of Health (USA) demonstrating the general acceptance of H. pylori as cause of PUD in the US.^[37] The World Health Organization's International Agency for Research on Cancer declares H. pylori a Group 1 carcinogen.^[48] Parsonnet et al. describe an association between H. pylori and lymphomas of the gastrointestinal tract. These malignant ulcers can also be treated by eradicating Helicobacter.^[49]	Gastric cancer
1997	Tomb et al. complete sequencing of the entire 1,667,867 base pair H. pylori genome. This assists in identifying new virulence factors for the infectivity of H. pylori on the molecular level.^[50] ^[51]
2001	Chan et al. show in a randomized control trial that eradication of H. pylori even prevents bleeding from ulcers that are caused by aspirin and non-steroidal antiinflammatory drugs^[52]
2002	The European Helicobacter Pylori Study Group published the Maastricht 2-2000 Consensus Report, suggesting a test-and-treat strategy for H. pylori in young patients without atypical symptoms. This strategy advocates the use of non-invasive testing to evaluate for H. pylori and simply treating if found, even in the absence of ulcer disease documented on endoscopy.^[46]
2005	Warren and Marshall are awarded the Nobel Prize in Physiology or Medicine for their work on H. pylori and PUD.^[53]

[edit] References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Kidd, Mark; Irvin M. Modlin (1998). "A century of Helicobacter pylori". Digestion 59: 1-15. PMID 9468093.
^ ^a ^b ^c ^d ^e ^f ^g Unge, Peter (2002). "Helicobacter pylori treatment in the past and in the 21st century", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 203-213. ISBN 0-86793-035-7.
^ ^a ^b ^c Buckley, Martin J.M; Colm A. O'Morain (1998). "Helicobacter biology - discovery". British Medical Bulletin 54 (1): 7-16. PMID 9604426.
^ ^a ^b ^c ^d Fukuda, Yoshihiro; Tadashi Shimoyama, Takashi Shimoyama, and Barry J. Marshall (2002). "Kasai, Kobayashi and Koch's postulates in the history of Helicobacter pylori", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 1-13. ISBN 0-86793-035-7.
^ Bizzozero, Giulio (1893). "Ueber die schlauchförmigen Drüsen des Magendarmkanals und die Beziehungen ihres Epitheles zu dem Oberflächenepithel der Schleimhaut". Archiv für mikroskopische Anatomie 42: 82–152.
^ Figura, Natale; Laura Bianciardi (2002). "Helicobacters were discovered in Italy in 1892: An episode in the scientific life of an eclectic pathologist, Giulio Bizzozero.", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 1-13. ISBN 0-86793-035-7.
^ Turck, F.B. J.M (1906). "Ulcer of the stomach: Pathogenesis and pathology: Experiments in producing artificial gastric ulcer and genuine induced peptic ulcer". Journal of the American Medical Association 46: 872.
^ Rosenow, E.C. J.M (1913). "The production of ulcer of the stomach by injection of streptococci". Journal of the American Medical Association 61: 1947.
^ Rosenow, E.C.; A.H. Sanford (1915). "The Bacteriology of Ulcer of the Stomach and Duodenum in Man". Journal of Infectious Diseases 15: 219-226.
^ Kasai, K.; R. Kobayashi (1919). "The stomach Spirochete Occurring in Mammals". Journal of Parasitology (6): 1-11.
^ Luck; Seth (1924). "Gastric Urease". Biochemical Journal 37: 1227-1231.
^ Hoffman, A (1925). "Experimental gastric duodenal inflammation and ulcer, produced with a specific organism fulfilling Koch's postulates". American Journal of Medical Science 170: 212.
^ ^a ^b ^c ^d ^e Morozov, Igor A.. "Helicobacter pylori was discovered in Russia in 1974", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 105-118. ISBN 0-86793-035-7.
^ Freedberg, A. Stone. "=An Early Study of Human Stomach Bacteria", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 25-28. ISBN 0-86793-035-7.
^ Doenges, James (1939). "Spirochaetes in the gastric glands of the Macaus Rhesus and Human without definite history of related disease". Archives of Pathology 27: 469-477.
^ Freedberg, A.S.; L.E. Baron (1940). "The presence of spirochaetes in human gastric mucosa". American Journal of Digestive Diseases 7: 443-445.
^ O'Connor, Humphrey J.; Colm A. O'Morain. "Gastric urease in ulcer patients in the 1940s: The Irish connection", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 25-28. ISBN 0-86793-035-7.
^ Dintzis, R.Z.; A.B. Hastings (1953). "The effect of Antibiotics on Urea Breakdown in Mice.". Proceedings of the National Academy of Sciences of the USA 39: 571–8. PMID 16589306.
^ Palmer, E.D. (1954). "Investigation of the gastric mucosa spirochetes of the human". Gastroenterology 27 (2): 218-220. PMID 13183283.
^ Kornberg, H.L.; R.E. Davies (1955). "Gastric Urease". Physiology Review 35 (1): 169-177. PMID 14356931.
^ Lieber, C.S.; A. Lefèvre (1957). "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 151 (5): 1038-1042. PMID 13500735.
^ ^a ^b ^c ^d ^e Rigas, Basil; Efstathios D. Papavassiliou. "John Lykoudis: The general practitioner in Greece who in 1958 discovered etiology of, and a treatment for, peptic ulcer disease", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 375-84. ISBN 0-86793-035-7.
^ Lieber, Charles S. J.. "How it was discovered in Belgium and the USA (1955-1976) that Gastric Urease was Caused by a Bacterial Infection", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 39-52. ISBN 0-86793-035-7.
^ Lieber, C.S.; A. Lefèvre (1959). "Ammonia as a source of gastric hypoacidity in patients with uremia". Journal of Clinical Investigation 38: 1271-7. PMID 13673083.
^ Conway, E.J.; O. Fitzgerald, K. McGeeney, and F. Geoghegan (1959). "The location and origin of gastric urease". Gastroenterology 37: 449-56. PMID 13811656.
^ Vital, J.D.; H. Orrego (1960). "Electron microscope observations on the fine structure of parietal cells". Journal of Biophysical and Biochemical Cytology 7: 367-72. PMID 13842039.
^ Susser, M.; Z. Stein (1962). "Civilization and peptic ulcer". Lancet 1: 115-9. PMID 13918500. . Reprinted as Susser M, Stein Z (2002). "Civilization and peptic ulcer. 1962.". International Journal of Epidemiology 31 (1): 13-7. PMID 11914283.
^ Ito, Susumu (1967). "Anatomic structure of the gastric mucosa", in Heidel, US and Code, CF: Handbook of Physiology Section 6 Volume 2. American Physiological Society, 705-741.
^ ^a ^b Steer, Howard W. (2002). "The discover of Helicobacter pylori in England in the 1970s", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 119-129. ISBN 0-86793-035-7.
^ ^a ^b ^c Xiao, Shu-Dong; Yao Shi, and Wen-Zong-Liu (2002). "How we discovered in China in 1972 that antibiotics cure peptic ulcer", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 165-202. ISBN 0-86793-035-7.
^ Patrick, W.J.A.; D. Denham, and A.P.M. Forrest (1974). "Mucous change in the human duodenum: a light and electron microscopic study and correlation with disease and gastric acid secretion". Gut 15 (10): 767-76. PMID 4434919.
^ Steer, H.W.; D.G. Colin-Jones (1975). "Mucosal changes in gastric ulceration and their response to carbenoxolone sodium". Gut 16 (8): 590-7. PMID 810394.
^ Peterson, Walter L.; William Harford, and Barry J. Marshall (2002). "The Dallas experience with acute Helicobacter pylori infection", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 143-150. ISBN 0-86793-035-7.
^ Ramsey, E.J.; K.V. Carey, W.L. Peterson, et al. (1979). "Epidemic gastritis with hypochlorhydria". Gastroenterology 76 (6): 1449-57. PMID 437444.
^ Warren, J. Robin (2002). "The discovery of Helicobacter pylori in Perth, Western Australia", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 165-202. ISBN 0-86793-035-7.
^ Fung, W.P.; J.M Papadimitriou and L.R. Matz (1979). "Endoscopic, histological and ultrastructural correlations in chronic gastritis". American Journal of Gastroenterology 71 (3): 269-79. PMID 443229.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s Marshall, Barry (2002). "The discovery that Helicobacter pylori, a spiral bacterium, caused peptic ulcer disease.", in Barry Marshall: Helicobacter Pioneers: Firsthand Accounts from the Scientists Who Discovered Helicobacters. Victoria, Australia: Blackwell Science Asia, 165-202. ISBN 0-86793-035-7.
^ Satoh, H.; P.H. Guth, and M.I. Grossman (1983). "Role of bacteria in gastric ulceration produced by indomethacin in the rat: cytoprotective action of antibiotics". Gastroenterology 84 (3): 483-9. PMID 6822322.
^ Warren, J.R.; Barry Marshall (1983). "Unidentified curved bacilli on gastric epithelium in active chronic gastritis". Lancet 1 (8336): 1273-5. PMID 6134060.
^ McNulty, C.A.; D.M. Watson (1984). "Spiral bacteria of the gastric antrum". The Lancet 1 (8385): 1068-9. PMID 6143990.
^ Morris, A.; G. Nicholson (1987). "Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH". American Journal of Gastroenterology 82 (3): 192-9. PMID 3826027.
^ Coghlan, J.G.; H. Humphrise, C. Dooley, et al. (1987). "Campylobacter pylori and recurrence of duodenal ulcers—a 12-month follow-up study". The Lancet 2 (8568): 109-11. PMID 2890019.
^ Rauws E, Tytgat G (1990). "Cure of duodenal ulcer associated with eradication of Helicobacter pylori". Lancet 335 (8700): 1233-5. PMID 1971318.
^ Rauws, E.A.J.; G.N.J. Tytgat (1990). "Cure of duodenal ulcer associated with eradication of Helicobacter pylori". The Lancet 335 (8700): 1233-5. PMID 1971318.
^ Becx M, Janssen A, et al. (1990). "Metronidazole-resistant Helicobacter pylori". Lancet 335 (8688): 539-40. PMID 1968548.
^ ^a ^b Malfertheiner P, Mégraud F, O'Morain C, et al. (2002). "Current concepts in the management of Helicobacter pylori infection--the Maastricht 2-2000 Consensus Report". Aliment Pharmacol Ther 16 (2): 167-80. PMID 11860399.
^ Covacci A, Censini S, Bugnoli M, et al. (1993). "Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer". Proc Natl Acad Sci U S A 90 (12): 5791-5. PMID 8516329.
^ (1994) "IARC Monograph on the Evaluation of Carcinogenic Risks to Humans". Lyon: World Health Organization: 177-240.
^ Parsonnet J, Hansen S, Rodriguez L, et al (1994). "Helicobacter pylori infection and gastric lymphoma". New England Journal of Medicine 330 (18): 1267-71. PMID 8145781.
^ Tomb J, White O, Kerlavage A, et al. (1997). "The complete genome sequence of the gastric pathogen Helicobacter pylori". Nature 388 (6642): 539-47. PMID 9252185.
^ Aspholm-Hurtig M, Dailide G, Lahmann M, et al. (2004). "Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin". Science 305 (5683): 519-22. PMID 15273394.
^ Chan F, Chung S, Suen B, et al. (2001). "Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen". N Engl J Med 344 (13): 967-73. PMID 11274623.
^ Nobel Prize in Medicine 2005. Nobel Foundation. Retrieved on October 3, 2006.