幽門螺旋菌是一種具螺旋形外觀且為革蘭氏陰性的細菌，最早是從人類的胃腸道分離出來而且被認為與胃腸道的疾病有關。特別重要的是此細菌被認為是導致胃腺癌的危險因子之一。在第一部分的研究中，我們首先探討幽門螺旋菌致病因子與臨床疾病的相關。幽門螺旋菌常因分離的地域不同而具有很高的基因變異性。某些幽門螺旋菌的基因型顯示與胃腸道疾病的嚴重程度有關。我們利用聚合酶連鎖反應分析101株從台中榮民總醫院所分離的幽門螺旋菌，其cagA與babA2的盛行率。cagA存在分離菌珠的盛行率為99%，而babA2則存在所有菌株中。結果顯示，在台灣cagA與babA2無法作為預測幽門螺旋菌高危險因子的標誌。
目前最常被建議來治療幽門螺旋菌的藥物包括質子幫浦抑制劑與抗生素。根除幽門螺旋菌會使潰瘍處癒合並且防止消化性潰瘍復發。利用這些方法，有些報告顯示治癒率高於90%。然而有些報告也發現失敗率從20%至40%不等。在本實驗的第二部分，我們將探討抗生素治療失敗的病人所分離的幽門螺旋菌菌株，是否跟抗生素的抗藥性有關。我們亦利用AGS細胞分析幽門螺旋菌侵入細胞的能力是否有任何變化。結果顯示從治療失敗病人所分離的細菌，其侵入細胞的能力明顯大於治療成功病人所分離的細菌(P < 0.01)。我們的結果指出細菌如果侵入細胞內可能可以保護幽門螺旋菌抵抗細胞外殺菌劑的作用，更進一步產生對細胞內抗生素的抗藥性。
在本論文的第三部分，我們將分析細胞脂質筏在幽門螺旋菌侵入上皮細胞所扮演的角色。我們確認幽門螺旋菌侵入上皮細胞與其脂質筏有關，但是與細菌的黏附能力無關。我們亦觀察到幽門螺旋菌侵入細胞之處有膽固醇的聚集。更進一步證明細菌的致病因子VacA、CagA與BabA2皆會與脂質筏作用，而且可能進一步提供脂質筏叢聚的功能。因此我們認為這個作用將為幽門螺旋菌侵入細胞的過程提供一個平台。

Helicobacter pylori is a spiral-shaped Gram negative bacteria which was first isolated in pure culture and was considered as a serious threat to gastrointestinal tracts of human. Of particular importance is its role as a risk factor for gastric adenocarcinomas. In the first investigation, we focus on the prevalence of H. pylori virulence factors and its association with clinical outcomes. H. pylori isolates possess unusually high genetic heterogeneity and diversify between geographic regions. Certain H. pylori genotypes are indicated to relate to severe gastrointestinal diseases. Two virulence markers, cagA and babA2, were characterized by PCR in 101 H. pylori isolates from a population who took medical treatment in Veterans General Hospital, Taichung. cagA was detected in 99% of the isolates, while babA2 was present in all of the isolates. The result showed that cagA and babA2 cannot be useful markers for predicting the high-risk patients of H. pylori infection in Taiwan.
The current recommended eradication therapies of H. pylori consist of a proton pump inhibitor and several antibiotics. Eradication of H. pylori results in ulcer healing and prevents the recurrence of gastric ulcer and duodenal ulcer. By use of these treatments, some reports suggest the cure rate is more than 90%. However, an eradication failure rate ranging from 20-40% is usually found. In the second part of the study, we investigate whether or not the clinical isolates of H. pylori from patients who failed in therapy were resistant to antibiotics. We also study the altered ability of the H. pylori strains invading into AGS cells by in vitro internalization assay. Bacterial invading activity of the H. pylori isolates from the failure group was significantly higher than those from the cure group (P < 0.01). Our results showed that bacterial epithelial internalization may protect H. pylori from extrcellular bactericidal effects and subsequently induce resistance to intracellular antibiotic.
In the third part, we determined and analyzed the role of host cell lipid rafts playing in the invasion of H. pylori into epithelial cells. We identified that internalization of H. pylori was associated with lipid rafts, while adherence was not. We also observed that accumulation of cholesterol at the sites of H. pylori attachment. Furthermore, we demonstrated that VacA, CagA, and BabA2 were able to associate with lipid rafts and have high efficiency for providing the clustering of the rafts. We suggested that this effect would generate platforms for the entry of H. pylori to AGS cells during the infection process.

Akopyanz, N., Bukanov, N.O., Westblom, T.U., Kresovich, S., and Berg, D.E. (1992) DNA diversity among clinical isolates of Helicobacter pylori detected by PCR-based RAPD fingerprinting. Nucleic Acids Res 20: 5137-5142.
Alm, R.A., Ling, L.S., Moir, D.T., King, B.L., Brown, E.D., Doig, P.C., Smith, D.R., Noonan, B., Guild, B.C., deJonge, B.L., Carmel, G., Tummino, P.J., Caruso, A., Uria-Nickelsen, M., Mills, D.M., Ives, C., Gibson, R., Merberg, D., Mills, S.D., Jiang, Q., Taylor, D.E., Vovis, G.F., and Trust, T.J. (1999) Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 397: 176-180.
Alm, R.A., and Trust, T.J. (1999) Analysis of the genetic diversity of Helicobacter pylori: the tale of two genomes. J Mol Med 77: 834-846.
Alm, R.A., Bina, J., Andrews, B.M., Doig, P., Hancock, R.E., and Trust, T.J. (2000) Comparative genomics of Helicobacter pylori: analysis of the outer membrane protein families. Infect Immun 68: 4155-4168.
Amieva, M.R., Salama, N.R., Tompkins, L.S., and Falkow, S. (2002) Helicobacter pylori enter and survive within multivesicular vacuoles of epithelial cells. Cell Microbiol 4: 677-690.
Amieva, M.R., Vogelmann, R., Covacci, A., Tompkins, L.S., Nelson, W.J., and Falkow, S. (2003) Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300: 1430-1434.
Andrutis, K.A., Fox, J.G., Schauer, D.B., Marini, R.P., Murphy, J.C., Yan, L., and Solnick, J.V. (1995) Inability of an isogenic urease-negative mutant stain of Helicobacter mustelae to colonize the ferret stomach. Infect Immun 63: 3722-3725.
Arents, N.L., van Zwet, A.A., Thijs, J.C., Kooistra-Smid, A.M., van Slochteren, K.R., Degener, J.E., Kleibeuker, J.H., and van Doorn, L.J. (2001) The importance of vacA, cagA, and iceA genotypes of Helicobacter pylori infection in peptic ulcer disease and gastroesophageal reflux disease. Am J Gastroenterol 96: 2603-2608.
Asahi, M., Tanaka, Y., Izumi, T., Ito, Y., Naiki, H., Kersulyte, D., Tsujikawa, K., Saito, M., Sada, K., Yanagi, S., Fujikawa, A., Noda, M., and Itokawa, Y. (2003) Helicobacter pylori CagA containing ITAM-like sequences localized to lipid rafts negatively regulates VacA-induced signaling in vivo. Helicobacter 8: 1-14.
Atherton, J.C., Cao, P., Peek, R.M., Jr., Tummuru, M.K., Blaser, M.J., and Cover, T.L. (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270: 17771-17777.
Atherton, J.C., Peek, R.M., Jr., Tham, K.T., Cover, T.L., and Blaser, M.J. (1997) Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 112: 92-99.
Austin, J.W., Doig, P., Stewart, M., and Trust, T.J. (1991) Macromolecular structure and aggregation states of Helicobacter pylori urease. J Bacteriol 173: 5663-5667.
Backert, S., Ziska, E., Brinkmann, V., Zimny-Arndt, U., Fauconnier, A., Jungblut, P.R., Naumann, M., and Meyer, T.F. (2000) Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol 2: 155-164.
Bauerfeind, P., Garner, R., Dunn, B.E., and Mobley, H.L. (1997) Synthesis and activity of Helicobacter pylori urease and catalase at low pH. Gut 40: 25-30.
Bell, G.D., Powell, K., Burridge, S.M., Pallecaros, A., Jones, P.H., Gant, P.W., Harrison, G., and Trowell, J.E. (1992) Experience with 'triple' anti-Helicobacter pylori eradication therapy: side effects and the importance of testing the pre-treatment bacterial isolate for metronidazole resistance. Aliment Pharmacol Ther 6: 427-435.
Bjorkholm, B., Zhukhovitsky, V., Lofman, C., Hulten, K., Enroth, H., Block, M., Rigo, R., Falk, P., and Engstrand, L. (2000) Helicobacter pylori entry into human gastric epithelial cells: A potential determinant of virulence, persistence, and treatment failures. Helicobacter 5: 148-154.
Blaser, M.J. (1993) Helicobacter pylori: microbiology of a 'slow' bacterial infection. Trends Microbiol 1: 255-260.
Blaser, M.J., Perez-Perez, G.I., Kleanthous, H., Cover, T.L., Peek, R.M., Chyou, P.H., Stemmermann, G.N., and Nomura, A. (1995) Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55: 2111-2115.
Blaser, M.J. (1997) Heterogeneity of Helicobacter pylori. Eur J Gastroenterol Hepatol 9 Suppl 1: S3-6; discussion S6-7.
Blaser, M.J., and Berg, D.E. (2001) Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest 107: 767-773.
Bode, G., Malfertheiner, P., and Ditschuneit, H. (1988) Pathogenetic implications of ultrastructural findings in Campylobacter pylori related gastroduodenal disease. Scand J Gastroenterol Suppl 142: 25-39.
Boncristiano, M., Paccani, S.R., Barone, S., Ulivieri, C., Patrussi, L., Ilver, D., Amedei, A., D'Elios, M.M., Telford, J.L., and Baldari, C.T. (2003) The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 198: 1887-1897.
Boren, T., Falk, P., Roth, K.A., Larson, G., and Normark, S. (1993) Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 262: 1892-1895.
Brown, D.A., and Rose, J.K. (1992) Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68: 533-544.
Brown, D.A., and London, E. (1998) Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14: 111-136.
Cameron, E.A., Powell, K.U., Baldwin, L., Jones, P., Bell, G.D., and Williams, S.G. (2004) Helicobacter pylori: antibiotic resistance and eradication rates in Suffolk, UK, 1991-2001. J Med Microbiol 53: 535-538.
Cederbrant, G., Kahlmeter, G., and Ljungh, A. (1992) Proposed mechanism for metronidazole resistance in Helicobacter pylori. J Antimicrob Chemother 29: 115-120.
Censini, S., Lange, C., Xiang, Z., Crabtree, J.E., Ghiara, P., Borodovsky, M., Rappuoli, R., and Covacci, A. (1996) cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 93: 14648-14653.
Chen, L.K., Hwang, S.J., Wu, T.C., Chu, C.H., and Shaw, C.K. (2003) Helicobacter pylori and hepatitis A virus infection in school-aged children on two isolated neighborhood islands in Taiwan. Helicobacter 8: 168-172.
Ching, C.K., Leung, K.P., Yung, R.W., Lam, S.K., Wong, B.C., Lai, K.C., and Lai, C.L. (1996) Prevalence of metronidazole resistant Helicobacter pylori strains among Chinese peptic ulcer disease patients and normal controls in Hong Kong. Gut 38: 675-678.
Christie, P.J., and Vogel, J.P. (2000) Bacterial type IV secretion: conjugation systems adapted to deliver effector molecules to host cells. Trends Microbiol 8: 354-360.
Corthesy-Theulaz, I.E., Hopkins, S., Bachmann, D., Saldinger, P.F., Porta, N., Haas, R., Zheng-Xin, Y., Meyer, T., Bouzourene, H., Blum, A.L., and Kraehenbuhl, J.P. (1998) Mice are protected from Helicobacter pylori infection by nasal immunization with attenuated Salmonella typhimurium phoPc expressing urease A and B subunits. Infect Immun 66: 581-586.
Covacci, A., Censini, S., Bugnoli, M., Petracca, R., Burroni, D., Macchia, G., Massone, A., Papini, E., Xiang, Z., Figura, N., and 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: 5791-5795.
Covacci, A., and Rappuoli, R. (1998) Helicobacter pylori: molecular evolution of a bacterial quasi-species. Curr Opin Microbiol 1: 96-102.
Cover, T.L., Halter, S.A., and Blaser, M.J. (1992) Characterization of HeLa cell vacuoles induced by Helicobacter pylori broth culture supernatant. Hum Pathol 23: 1004-1010.
Cover, T.L., Glupczynski, Y., Lage, A.P., Burette, A., Tummuru, M.K., Perez-Perez, G.I., and Blaser, M.J. (1995) Serologic detection of infection with cagA+ Helicobacter pylori strains. J Clin Microbiol 33: 1496-1500.
Cover, T.L., Hanson, P.I., and Heuser, J.E. (1997) Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J Cell Biol 138: 759-769.
Crabtree, J.E., Taylor, J.D., Wyatt, J.I., Heatley, R.V., Shallcross, T.M., Tompkins, D.S., and Rathbone, B.J. (1991) Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet 338: 332-335.
Debets-Ossenkopp, Y.J., Sparrius, M., Kusters, J.G., Kolkman, J.J., and Vandenbroucke-Grauls, C.M. (1996) Mechanism of clarithromycin resistance in clinical isolates of Helicobacter pylori. FEMS Microbiol Lett 142: 37-42.
Del Giudice, G., Covacci, A., Telford, J.L., Montecucco, C., and Rappuoli, R. (2001) The design of vaccines against Helicobacter pylori and their development. Annu Rev Immunol 19: 523-563.
Dore, M.P., Osato, M.S., Realdi, G., Mura, I., Graham, D.Y., and Sepulveda, A.R. (1999) Amoxycillin tolerance in Helicobacter pylori. J Antimicrob Chemother 43: 47-54.
Dubois, A., Fiala, N., Heman-Ackah, L.M., Drazek, E.S., Tarnawski, A., Fishbein, W.N., Perez-Perez, G.I., and Blaser, M.J. (1994) Natural gastric infection with Helicobacter pylori in monkeys: a model for spiral bacteria infection in humans. Gastroenterology 106: 1405-1417.
Duncan, M.J., Li, G., Shin, J.S., Carson, J.L., and Abraham, S.N. (2004) Bacterial penetration of bladder epithelium through lipid rafts. J Biol Chem 279: 18944-18951.
Eaton, K.A., Brooks, C.L., Morgan, D.R., and Krakowka, S. (1991) Essential role of urease in pathogenesis of gastritis induced by Helicobacter pylori in gnotobiotic piglets. Infect Immun 59: 2470-2475.
Edwards, D.I. (1993a) Nitroimidazole drugs--action and resistance mechanisms. II. Mechanisms of resistance. J Antimicrob Chemother 31: 201-210.
Edwards, D.I. (1993b) Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action. J Antimicrob Chemother 31: 9-20.
El-Omar, E.M., Rabkin, C.S., Gammon, M.D., Vaughan, T.L., Risch, H.A., Schoenberg, J.B., Stanford, J.L., Mayne, S.T., Goedert, J., Blot, W.J., Fraumeni, J.F., Jr., and Chow, W.H. (2003) Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124: 1193-1201.
Engstrand, L., Nguyen, A.M., Graham, D.Y., and el-Zaatari, F.A. (1992) Reverse transcription and polymerase chain reaction amplification of rRNA for detection of Helicobacter species. J Clin Microbiol 30: 2295-2301.
Engstrand, L., Graham, D., Scheynius, A., Genta, R.M., and El-Zaatari, F. (1997) Is the sanctuary where Helicobacter pylori avoids antibacterial treatment intracellular? Am J Clin Pathol 108: 504-509.
Evans, D.G., Evans, D.J., Jr., and Graham, D.Y. (1992) Adherence and internalization of Helicobacter pylori by HEp-2 cells. Gastroenterology 102: 1557-1567.
Evans, D.J., Jr., and Evans, D.G. (2000) Helicobacter pylori adhesins: review and perspectives. Helicobacter 5: 183-195.
Falk, P., Roth, K.A., Boren, T., Westblom, T.U., Gordon, J.I., and Normark, S. (1993) An in vitro adherence assay reveals that Helicobacter pylori exhibits cell lineage-specific tropism in the human gastric epithelium. Proc Natl Acad Sci U S A 90: 2035-2039.
Falk, P.G., Bry, L., Holgersson, J., and Gordon, J.I. (1995) Expression of a human alpha-1,3/4-fucosyltransferase in the pit cell lineage of FVB/N mouse stomach results in production of Leb-containing glycoconjugates: a potential transgenic mouse model for studying Helicobacter pylori infection. Proc Natl Acad Sci U S A 92: 1515-1519.
Fallone, C.A., Barkun, A.N., Gottke, M.U., Best, L.M., Loo, V.G., Veldhuyzen van Zanten, S., Nguyen, T., Lowe, A., Fainsilber, T., Kouri, K., and Beech, R. (2000) Association of Helicobacter pylori genotype with gastroesophageal reflux disease and other upper gastrointestinal diseases. Am J Gastroenterol 95: 659-669.
Figura, N., Guglielmetti, P., Rossolini, A., Barberi, A., Cusi, G., Musmanno, R.A., Russi, M., and Quaranta, S. (1989) Cytotoxin production by Campylobacter pylori strains isolated from patients with peptic ulcers and from patients with chronic gastritis only. J Clin Microbiol 27: 225-226.
Fox, J.G. (1995) Non-human reservoirs of Helicobacter pylori. Aliment Pharmacol Ther 9 Suppl 2: 93-103.
Frenck, R.W., Jr., and Clemens, J. (2003) Helicobacter in the developing world. Microbes Infect 5: 705-713.
Frevel, M., Daake, H., Janisch, H.D., Kellner, H.U., Krezdorn, H.G., Tanneberger, D., and Wack, R. (2000) Eradication of Helicobacter pylori with pantoprazole and two antibiotics: a comparison of two short-term regimens. Aliment Pharmacol Ther 14: 1151-1157.
Fujikawa, A., Shirasaka, D., Yamamoto, S., Ota, H., Yahiro, K., Fukada, M., Shintani, T., Wada, A., Aoyama, N., Hirayama, T., Fukamachi, H., and Noda, M. (2003) Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 33: 375-381.
Garner, J.A., and Cover, T.L. (1996) Binding and internalization of the Helicobacter pylori vacuolating cytotoxin by epithelial cells. Infect Immun 64: 4197-4203.
Gebert, B., Fischer, W., Weiss, E., Hoffmann, R., and Haas, R. (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301: 1099-1102.
Gerhard, M., Lehn, N., Neumayer, N., Boren, T., Rad, R., Schepp, W., Miehlke, S., Classen, M., and Prinz, C. (1999) Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci U S A 96: 12778-12783.
Ghiara, P., Rossi, M., Marchetti, M., Di Tommaso, A., Vindigni, C., Ciampolini, F., Covacci, A., Telford, J.L., De Magistris, M.T., Pizza, M., Rappuoli, R., and Del Giudice, G. (1997) Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection. Infect Immun 65: 4996-5002.
Gisbert, J.P., Gonzalez, L., Calvet, X., Garcia, N., Lopez, T., Roque, M., Gabriel, R., and Pajares, J.M. (2000) Proton pump inhibitor, clarithromycin and either amoxycillin or nitroimidazole: a meta-analysis of eradication of Helicobacter pylori. Aliment Pharmacol Ther 14: 1319-1328.
Goddard, A.F., and Logan, R.P. (1996) Antimicrobial resistance and Helicobacter pylori. J Antimicrob Chemother 37: 639-643.
Gomez-Duarte, O.G., Lucas, B., Yan, Z.X., Panthel, K., Haas, R., and Meyer, T.F. (1998) Protection of mice against gastric colonization by Helicobacter pylori by single oral dose immunization with attenuated Salmonella typhimurium producing urease subunits A and B. Vaccine 16: 460-471.
Goodman, K.J., and Correa, P. (2000) Transmission of Helicobacter pylori among siblings. Lancet 355: 358-362.
Graham, D.Y., Lew, G.M., Malaty, H.M., Evans, D.G., Evans, D.J., Jr., Klein, P.D., Alpert, L.C., and Genta, R.M. (1992) Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 102: 493-496.
Grassme, H., Jendrossek, V., Riehle, A., von Kurthy, G., Berger, J., Schwarz, H., Weller, M., Kolesnick, R., and Gulbins, E. (2003) Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med 9: 322-330.
Haas, C.E., Nix, D.E., and Schentag, J.J. (1990) In vitro selection of resistant Helicobacter pylori. Antimicrob Agents Chemother 34: 1637-1641.
Harris, A.W., Misiewicz, J.J., Bardhan, K.D., Levi, S., O'Morain, C., Cooper, B.T., Kerr, G.D., Dixon, M.F., Langworthy, H., and Piper, D. (1998) Incidence of duodenal ulcer healing after 1 week of proton pump inhibitor triple therapy for eradication of Helicobacter pylori. The Lansoprazole Helicobacter Study Group. Aliment Pharmacol Ther 12: 741-745.
Hentschel, E., Brandstatter, G., Dragosics, B., Hirschl, A.M., Nemec, H., Schutze, K., Taufer, M., and Wurzer, H. (1993) Effect of ranitidine and amoxicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. N Engl J Med 328: 308-312.
Higashi, H., Tsutsumi, R., Muto, S., Sugiyama, T., Azuma, T., Asaka, M., and Hatakeyama, M. (2002) SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295: 683-686.
Hooper, N.M. (1999) Detergent-insoluble glycosphingolipid/cholesterol-rich membrane domains, lipid rafts and caveolae (review). Mol Membr Biol 16: 145-156.
Houben, M.H., Hensen, E.F., Rauws, E.A., Hulst, R.W., Hoff, B.W., Ende, A.V., Kate, F.J., and Tytgat, G.N. (1999a) Randomized trial of omeprazole and clarithromycin combined with either metronidazole or amoxycillin in patients with metronidazole-resistant or -susceptible Helicobacter pylori strains. Aliment Pharmacol Ther 13: 883-889.
Houben, M.H., van de Beek, D., Hensen, E.F., Craen, A.J., Rauws, E.A., and Tytgat, G.N. (1999b) A systematic review of Helicobacter pylori eradication therapy--the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther 13: 1047-1055.
Howden, C.W., and Hunt, R.H. (1998) Guidelines for the management of Helicobacter pylori infection. Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol 93: 2330-2338.
Hulten, K., Gibreel, A., Skold, O., and Engstrand, L. (1997) Macrolide resistance in Helicobacter pylori: mechanism and stability in strains from clarithromycin-treated patients. Antimicrob Agents Chemother 41: 2550-2553.
Hurenkamp, G.J., Van Der Ende, A., Grundmeijer, H.G., Tytgat, G.N., and Van Der Hulst, R.W. (2000) Equally high efficacy of 4, 7 and 10-day triple therapies to eradicate Helicobacter pylori infection in patients with ulcer disease. Aliment Pharmacol Ther 14: 1065-1070.
Ilver, D., Arnqvist, A., Ogren, J., Frick, I.M., Kersulyte, D., Incecik, E.T., Berg, D.E., Covacci, A., Engstrand, L., and Boren, T. (1998) Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science 279: 373-377.
Ilver, D., Barone, S., Mercati, D., Lupetti, P., and Telford, J.L. (2004) Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism. Cell Microbiol 6: 167-174.
Ito, Y., Azuma, T., Ito, S., Miyaji, H., Hirai, M., Yamazaki, Y., Sato, F., Kato, T., Kohli, Y., and Kuriyama, M. (1997) Analysis and typing of the vacA gene from cagA-positive strains of Helicobacter pylori isolated in Japan. J Clin Microbiol 35: 1710-1714.
Janes, P.W., Ley, S.C., Magee, A.I., and Kabouridis, P.S. (2000) The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin Immunol 12: 23-34.
Ji, X., Fernandez, T., Burroni, D., Pagliaccia, C., Atherton, J.C., Reyrat, J.M., Rappuoli, R., and Telford, J.L. (2000) Cell specificity of Helicobacter pylori cytotoxin is determined by a short region in the polymorphic midregion. Infect Immun 68: 3754-3757.
Kashimura, H., Suzuki, K., Hassan, M., Ikezawa, K., Sawahata, T., Watanabe, T., Nakahara, A., Mutoh, H., and Tanaka, N. (1999) Polaprezinc, a mucosal protective agent, in combination with lansoprazole, amoxycillin and clarithromycin increases the cure rate of Helicobacter pylori infection. Aliment Pharmacol Ther 13: 483-487.
Kazi, J.L., Sinniah, R., Zaman, V., Ng, M.L., Jafarey, N.A., Alam, S.M., Zuberi, S.J., and Kazi, A.M. (1990) Ultrastructural study of Helicobacter pylori-associated gastritis. J Pathol 161: 65-70.
Keenan, J., Day, T., Neal, S., Cook, B., Perez-Perez, G., Allardyce, R., and Bagshaw, P. (2000) A role for the bacterial outer membrane in the pathogenesis of Helicobacter pylori infection. FEMS Microbiol Lett 182: 259-264.
Ko, G.H., Kang, S.M., Kim, Y.K., Lee, J.H., Park, C.K., Youn, H.S., Baik, S.C., Cho, M.J., Lee, W.K., and Rhee, K.H. (1999) Invasiveness of Helicobacter pylori into human gastric mucosa. Helicobacter 4: 77-81.
Konturek, P.C., Brzozowski, T., Konturek, S.J., Kwiecien, S., Pajdo, R., Drozdowicz, D., Stachura, J., Karczewska, E., and Hahn, E.G. (2003) Functional and morphological aspects of Helicobacter pylori -induced gastric cancer in Mongolian gerbils. Eur J Gastroenterol Hepatol 15: 745-754.
Kuipers, E. (1999) Review article: exploring the link between Helicobacter pylori and gastric cancer. Aliment Pharmacol Ther 13: 3-11.
Kuo, C.H., Poon, S.K., Su, Y.C., Su, R., Chang, C.S., and Wang, W.C. (1999) Heterogeneous Helicobacter pylori isolates from H. pylori-infected couples in Taiwan. J Infect Dis 180: 2064-2068.
Kuo, C.H., and Wang, W.C. (2003) Binding and internalization of Helicobacter pylori VacA via cellular lipid rafts in epithelial cells. Biochem Biophys Res Commun 303: 640-644.
Kupiers, E.J. (1999.) Review article: exploring the linke between Helicobacter pylori and gastric cancer. Aliment. Pharmacol. Ther. 13: 3-11.
Kurzchalia, T.V., and Parton, R.G. (1999) Membrane microdomains and caveolae. Curr Opin Cell Biol 11: 424-431.
Kwok, T., Backert, S., Schwarz, H., Berger, J., and Meyer, T.F. (2002) Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism. Infect Immun 70: 2108-2120.
Labenz, J., Gyenes, E., Ruhl, G.H., and Borsch, G. (1992) Two weeks treatment with amoxicillin/omeprazole for eradication of Helicobacter pylori. Z Gastroenterol 30: 776-778.
Labigne, A., Cussac, V., and Courcoux, P. (1991) Shuttle cloning and nucleotide sequences of Helicobacter pylori genes responsible for urease activity. J Bacteriol 173: 1920-1931.
Lafont, F., Tran Van Nhieu, G., Hanada, K., Sansonetti, P., and van der Goot, F.G. (2002) Initial steps of Shigella infection depend on the cholesterol/sphingolipid raft-mediated CD44-IpaB interaction. Embo J 21: 4449-4457.
Laine, L., and Sugg, J. (2002) Effect of Helicobacter pylori eradication on development of erosive esophagitis and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double blind prospective studies. Am J Gastroenterol 97: 2992-2997.
Langlet, C., Bernard, A.M., Drevot, P., and He, H.T. (2000) Membrane rafts and signaling by the multichain immune recognition receptors. Curr Opin Immunol 12: 250-255.
Lee, I.H., Ni, Y.H., and Chang, M.H. (2004) Stable seroprevalence of Helicobacter pylori infection in children during 1989-1999 in Taipei, Taiwan. Pediatr Int 46: 311-314.
Leunk, R.D., Johnson, P.T., David, B.C., Kraft, W.G., and Morgan, D.R. (1988) Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol 26: 93-99.
Lin, J.T., Wang, J.T., Wang, T.H., Wu, M.S., Lee, T.K., and Chen, C.J. (1993) Helicobacter pylori infection in a randomly selected population, healthy volunteers, and patients with gastric ulcer and gastric adenocarcinoma. A seroprevalence study in Taiwan. Scand J Gastroenterol 28: 1067-1072.
Ling, T.K., Cheng, A.F., Sung, J.J., Yiu, P.Y., and Chung, S.S. (1996) An increase in Helicobacter pylori strains resistant to metronidazole: a five-year study. Helicobacter 1: 57-61.
Loffeld, R.J., Werdmuller, B.F., Kuster, J.G., Perez-Perez, G.I., Blaser, M.J., and Kuipers, E.J. (2000) Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett's esophagus. Digestion 62: 95-99.
Logan, R.P., Gummett, P.A., Misiewicz, J.J., Karim, Q.N., Walker, M.M., and Baron, J.H. (1991) One week eradication regimen for Helicobacter pylori. Lancet 338: 1249-1252.
Logan, R.P., Gummett, P.A., Schaufelberger, H.D., Greaves, R.R., Mendelson, G.M., Walker, M.M., Thomas, P.H., Baron, J.H., and Misiewicz, J.J. (1994) Eradication of Helicobacter pylori with clarithromycin and omeprazole. Gut 35: 323-326.
Lopez-Brea, M., Domingo, D., Sanchez, I., and Alarcon, T. (1997) Evolution of resistance to metronidazole and clarithromycin in Helicobacter pylori clinical isolates from Spain. J Antimicrob Chemother 40: 279-281.
Lozniewski, A., Haristoy, X., Rasko, D.A., Hatier, R., Plenat, F., Taylor, D.E., and Angioi-Duprez, K. (2003) Influence of Lewis antigen expression by Helicobacter pylori on bacterial internalization by gastric epithelial cells. Infect Immun 71: 2902-2906.
Lupetti, P., Heuser, J.E., Manetti, R., Massari, P., Lanzavecchia, S., Bellon, P.L., Dallai, R., Rappuoli, R., and Telford, J.L. (1996) Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J Cell Biol 133: 801-807.
Maconi, G., Russo, A., Imbesi, V., Cucino, C., and Bianchi Porro, G. (2000) Prolonging proton pump inhibitor-based anti-Helicobacter pylori treatment from one to two weeks in duodenal ulcer: is it worthwhile? Dig Liver Dis 32: 275-280.
Maeda, S., Ogura, K., Yoshida, H., Kanai, F., Ikenoue, T., Kato, N., Shiratori, Y., and Omata, M. (1998) Major virulence factors, VacA and CagA, are commonly positive in Helicobacter pylori isolates in Japan. Gut 42: 338-343.
Mahdavi, J., Sonden, B., Hurtig, M., Olfat, F.O., Forsberg, L., Roche, N., Angstrom, J., Larsson, T., Teneberg, S., Karlsson, K.A., Altraja, S., Wadstrom, T., Kersulyte, D., Berg, D.E., Dubois, A., Petersson, C., Magnusson, K.E., Norberg, T., Lindh, F., Lundskog, B.B., Arnqvist, A., Hammarstrom, L., and Boren, T. (2002) Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 297: 573-578.
Mai, U.E., Perez-Perez, G.I., Allen, J.B., Wahl, S.M., Blaser, M.J., and Smith, P.D. (1992) Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa. J Exp Med 175: 517-525.
Malfertheiner, P., O'Connor, H.J., Genta, R.M., Unge, P., and Axon, A.T. (2002) Symposium: Helicobacter pylori and clinical risks--focus on gastro-oesophageal reflux disease. Aliment Pharmacol Ther 16 Suppl 3: 1-10.
Malfertheiner, P., Megraud F, O'Morain C, Hungin AP, Jones R, Axon A, Graham DY, Tytgat G; European Helicobacter Pylori Study Group (EHPSG). (2002) Current concepts in the management of Helicobacter pylori infection--the Maastricht 2-2000 Consensus Report. Aliment Pharmacol Ther 16: 167-180.
Manes, S., del Real, G., Lacalle, R.A., Lucas, P., Gomez-Mouton, C., Sanchez-Palomino, S., Delgado, R., Alcami, J., Mira, E., and Martinez, A.C. (2000) Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection. EMBO Rep 1: 190-196.
Manes, S., del Real, G., and Martinez, A.C. (2003) Pathogens: raft hijackers. Nat Rev Immunol 3: 557-568.
Marchetti, M., Arico, B., Burroni, D., Figura, N., Rappuoli, R., and Ghiara, P. (1995) Development of a mouse model of Helicobacter pylori infection that mimics human disease. Science 267: 1655-1658.
Marshall, B.J., and Warren, J.R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1: 1311-1315.
Marshall, B.J., McGechie, D.B., Rogers, P.A., and Glancy, R.J. (1985) Pyloric Campylobacter infection and gastroduodenal disease. Med J Aust 142: 439-444.
Marshall, B.J., Barrett, L.J., Prakash, C., McCallum, R.W., and Guerrant, R.L. (1990) Urea protects Helicobacter (Campylobacter) pylori from the bactericidal effect of acid. Gastroenterology 99: 697-702.
Matysiak-Budnik, T., Heyman, M., Candalh, C., Lethuaire, D., and Megraud, F. (2002) In vitro transfer of clarithromycin and amoxicillin across the epithelial barrier: effect of Helicobacter pylori. J Antimicrob Chemother 50: 865-872.
McGuigan, J.E. (1996) Helicobacter pylori: the versatile pathogen. Dig Dis 14: 289-303.
Megraud, F. (1998) Epidemiology and mechanism of antibiotic resistance in Helicobacter pylori. Gastroenterology 115: 1278-1282.
Megraud, F., and Lamouliatte, H. (2003) Review article: the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 17: 1333-1343.
Melkonian, K.A., Ostermeyer, A.G., Chen, J.Z., Roth, M.G., and Brown, D.A. (1999) Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated. J Biol Chem 274: 3910-3917.
Mendonca, S., Ecclissato, C., Sartori, M.S., Godoy, A.P., Guerzoni, R.A., Degger, M., and Pedrazzoli, J., Jr. (2000) Prevalence of Helicobacter pylori resistance to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone in Brazil. Helicobacter 5: 79-83.
Midolo, P.D., Lambert, J.R., and Turnidge, J. (1996) Metronidazole resistance: a predictor of failure of Helicobacter pylori eradication by triple therapy. J Gastroenterol Hepatol 11: 290-292.
Midolo, P.D., and Sievert, W. (2000) Amoxycillin resistance in an isolate of Helicobacter pylori from Melbourne. Med J Aust 173: 555.
Mimuro, H., Suzuki, T., Tanaka, J., Asahi, M., Haas, R., and Sasakawa, C. (2002) Grb2 is a key mediator of helicobacter pylori CagA protein activities. Mol Cell 10: 745-755.
Mitchell, H.M., Hazell, S.L., Li, Y.Y., and Hu, P.J. (1996) Serological response to specific Helicobacter pylori antigens: antibody against CagA antigen is not predictive of gastric cancer in a developing country. Am J Gastroenterol 91: 1785-1788.
Miyaji, H., Azuma, T., Ito, S., Abe, Y., Gejyo, F., Hashimoto, N., Sugimoto, H., Suto, H., Ito, Y., Yamazaki, Y., Kohli, Y., and Kuriyama, M. (2000) Helicobacter pylori infection occurs via close contact with infected individuals in early childhood. J Gastroenterol Hepatol 15: 257-262.
Mizushima, T., Sugiyama, T., Komatsu, Y., Ishizuka, J., Kato, M., and Asaka, M. (2001) Clinical relevance of the babA2 genotype of Helicobacter pylori in Japanese clinical isolates. J Clin Microbiol 39: 2463-2465.
Molinari, M., Salio, M., Galli, C., Norais, N., Rappuoli, R., Lanzavecchia, A., and Montecucco, C. (1998) Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med 187: 135-140.
Monack, D.M., Mueller, A., and Falkow, S. (2004) Persistent bacterial infections: the interface of the pathogen and the host immune system. Nat Rev Microbiol 2: 747-765.
Muller, M. (1983) Mode of action of metronidazole on anaerobic bacteria and protozoa. Surgery 93: 165-171.
Muller, M., and Gorrell, T.E. (1983) Metabolism and metronidazole uptake in Trichomonas vaginalis isolates with different metronidazole susceptibilities. Antimicrob Agents Chemother 24: 667-673.
Mulvey, M.A., Schilling, J.D., and Hultgren, S.J. (2001) Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection. Infect Immun 69: 4572-4579.
Neri, M., Susi, D., Bovani, I., Laterza, F., Porreca, E., and Cuccurullo, F. (1996) Gastric mucosal infiltration by Helicobacter pylori favours bacterial survival after treatment. Aliment Pharmacol Ther 10: 181-185.
Nilsson, C., Sillen, A., Eriksson, L., Strand, M.L., Enroth, H., Normark, S., Falk, P., and Engstrand, L. (2003) Correlation between cag pathogenicity island composition and Helicobacter pylori-associated gastroduodenal disease. Infect Immun 71: 6573-6581.
Noach, L.A., Rolf, T.M., and Tytgat, G.N. (1994) Electron microscopic study of association between Helicobacter pylori and gastric and duodenal mucosa. J Clin Pathol 47: 699-704.
Nomura, A., Stemmermann, G.N., Chyou, P.H., Kato, I., Perez-Perez, G.I., and Blaser, M.J. (1991) Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med 325: 1132-1136.
Nozaki, K., Shimizu, N., Ikehara, Y., Inoue, M., Tsukamoto, T., Inada, K., Tanaka, H., Kumagai, T., Kaminishi, M., and Tatematsu, M. (2003) Effect of early eradication on Helicobacter pylori-related gastric carcinogenesis in Mongolian gerbils. Cancer Sci 94: 235-239.
Nusrat, A., Parkos, C.A., Verkade, P., Foley, C.S., Liang, T.W., Innis-Whitehouse, W., Eastburn, K.K., and Madara, J.L. (2000) Tight junctions are membrane microdomains. J Cell Sci 113 ( Pt 10): 1771-1781.
Occhialini, A., Urdaci, M., Doucet-Populaire, F., Bebear, C.M., Lamouliatte, H., and Megraud, F. (1997) Macrolide resistance in Helicobacter pylori: rapid detection of point mutations and assays of macrolide binding to ribosomes. Antimicrob Agents Chemother 41: 2724-2728.
Odenbreit, S., Puls, J., Sedlmaier, B., Gerland, E., Fischer, W., and Haas, R. (2000) Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287: 1497-1500.
Ogura, K., Maeda, S., Nakao, M., Watanabe, T., Tada, M., Kyutoku, T., Yoshida, H., Shiratori, Y., and Omata, M. (2000) Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J Exp Med 192: 1601-1610.
Pagliaccia, C., de Bernard, M., Lupetti, P., Ji, X., Burroni, D., Cover, T.L., Papini, E., Rappuoli, R., Telford, J.L., and Reyrat, J.M. (1998) The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc Natl Acad Sci U S A 95: 10212-10217.
Pan, Z.J., Berg, D.E., van der Hulst, R.W., Su, W.W., Raudonikiene, A., Xiao, S.D., Dankert, J., Tytgat, G.N., and van der Ende, A. (1998) Prevalence of vacuolating cytotoxin production and distribution of distinct vacA alleles in Helicobacter pylori from China. J Infect Dis 178: 220-226.
Parsonnet, J., Friedman, G.D., Vandersteen, D.P., Chang, Y., Vogelman, J.H., Orentreich, N., and Sibley, R.K. (1991) Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325: 1127-1131.
Parsonnet, J., Replogle, M., Yang, S., and Hiatt, R. (1997) Seroprevalence of CagA-positive strains among Helicobacter pylori-infected, healthy young adults. J Infect Dis 175: 1240-1242.
Parton, R.G. (1994) Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem 42: 155-166.
Parton, R.G., Joggerst, B., and Simons, K. (1994) Regulated internalization of caveolae. J Cell Biol 127: 1199-1215.
Patel, H.K., Willhite, D.C., Patel, R.M., Ye, D., Williams, C.L., Torres, E.M., Marty, K.B., MacDonald, R.A., and Blanke, S.R. (2002) Plasma membrane cholesterol modulates cellular vacuolation induced by the Helicobacter pylori vacuolating cytotoxin. Infect Immun 70: 4112-4123.
Paul, R., Postius, S., Melchers, K., and Schafer, K.P. (2001) Mutations of the Helicobacter pylori genes rdxA and pbp1 cause resistance against metronidazole and amoxicillin. Antimicrob Agents Chemother 45: 962-965.
Pelkmans, L., and Helenius, A. (2002) Endocytosis via caveolae. Traffic 3: 311-320.
Perez-Perez, G.I., Rothenbacher, D., and Brenner, H. (2004) Epidemiology of Helicobacter pylori infection. Helicobacter 9 Suppl 1: 1-6.
Petersen, A.M., Blom, J., Andersen, L.P., and Krogfelt, K.A. (2000) Role of strain type, AGS cells and fetal calf serum in Helicobacter pylori adhesion and invasion assays. FEMS Immunol Med Microbiol 29: 59-67.
Petersen, A.M., Sorensen, K., Blom, J., and Krogfelt, K.A. (2001) Reduced intracellular survival of Helicobacter pylori vacA mutants in comparison with their wild-types indicates the role of VacA in pathogenesis. FEMS Immunol Med Microbiol 30: 103-108.
Petersen, A.M., and Krogfelt, K.A. (2003) Helicobacter pylori: an invading microorganism? A review. FEMS Immunol Med Microbiol 36: 117-126.
Piccolomini, R., Di Bonaventura, G., Picciani, C., Laterza, F., Vecchiet, J., and Neri, M. (2001) In vitro activity of clarithromycin against intracellular Helicobacter pylori. Antimicrob Agents Chemother 45: 1568-1571.
Poon, S.K., Chang, C.S., Su, J., Lai, C.H., Yang, C.C., Chen, G.H., and Wang, W.C. (2002) Primary resistance to antibiotics and its clinical impact on the efficacy of Helicobacter pylori lansoprazole-based triple therapies. Aliment Pharmacol Ther 16: 291-296.
Pride, D.T., Meinersmann, R.J., and Blaser, M.J. (2001) Allelic Variation within Helicobacter pylori babA and babB. Infect Immun 69: 1160-1171.
Raghunath, A.S., Hungin, A.P., Wooff, D., and Childs, S. (2004) Systematic review: the effect of Helicobacter pylori and its eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis. Aliment Pharmacol Ther 20: 733-744.
Rautelin, H., Seppala, K., Renkonen, O.V., Vainio, U., and Kosunen, T.U. (1992) Role of metronidazole resistance in therapy of Helicobacter pylori infections. Antimicrob Agents Chemother 36: 163-166.
Rauws, E.A., and Tytgat, G.N. (1990) Cure of duodenal ulcer associated with eradication of Helicobacter pylori. Lancet 335: 1233-1235.
Ricci, V., Sommi, P., Fiocca, R., Romano, M., Solcia, E., and Ventura, U. (1997) Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J Pathol 183: 453-459.
Ricci, V., Galmiche, A., Doye, A., Necchi, V., Solcia, E., and Boquet, P. (2000) High cell sensitivity to Helicobacter pylori VacA toxin depends on a GPI-anchored protein and is not blocked by inhibition of the clathrin-mediated pathway of endocytosis. Mol Biol Cell 11: 3897-3909.
Rodgers, W., Crise, B., and Rose, J.K. (1994) Signals determining protein tyrosine kinase and glycosyl-phosphatidylinositol-anchored protein targeting to a glycolipid-enriched membrane fraction. Mol Cell Biol 14: 5384-5391.
Rohde, M., Puls, J., Buhrdorf, R., Fischer, W., and Haas, R. (2003) A novel sheathed surface organelle of the Helicobacter pylori cag type IV secretion system. Mol Microbiol 49: 219-234.
Rossi, G., Rossi, M., Vitali, C.G., Fortuna, D., Burroni, D., Pancotto, L., Capecchi, S., Sozzi, S., Renzoni, G., Braca, G., Del Giudice, G., Rappuoli, R., Ghiara, P., and Taccini, E. (1999) A conventional beagle dog model for acute and chronic infection with Helicobacter pylori. Infect Immun 67: 3112-3120.
Rossi, G., Ruggiero, P., Peppoloni, S., Pancotto, L., Fortuna, D., Lauretti, L., Volpini, G., Mancianti, S., Corazza, M., Taccini, E., Di Pisa, F., Rappuoli, R., and Del Giudice, G. (2004) Therapeutic vaccination against Helicobacter pylori in the beagle dog experimental model: safety, immunogenicity, and efficacy. Infect Immun 72: 3252-3259.
Rothenbacher, D., Bode, G., Berg, G., Knayer, U., Gonser, T., Adler, G., and Brenner, H. (1999) Helicobacter pylori among preschool children and their parents: evidence of parent-child transmission. J Infect Dis 179: 398-402.
Rothenbacher, D., and Brenner, H. (2003) Burden of Helicobacter pylori and H. pylori-related diseases in developed countries: recent developments and future implications. Microbes Infect 5: 693-703.
Salama, N.R., Otto, G., Tompkins, L., and Falkow, S. (2001) Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69: 730-736.
Schilling, J.D., Lorenz, R.G., and Hultgren, S.J. (2002) Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli. Infect Immun 70: 7042-7049.
Schraw, W., Li, Y., McClain, M.S., van der Goot, F.G., and Cover, T.L. (2002) Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J Biol Chem 277: 34642-34650.
Segal, E.D., Falkow, S., and Tompkins, L.S. (1996) Helicobacter pylori attachment to gastric cells induces cytoskeletal rearrangements and tyrosine phosphorylation of host cell proteins. Proc Natl Acad Sci U S A 93: 1259-1264.
Segal, E.D., Cha, J., Lo, J., Falkow, S., and Tompkins, L.S. (1999) Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci U S A 96: 14559-14564.
Selbach, M., Moese, S., Hurwitz, R., Hauck, C.R., Meyer, T.F., and Backert, S. (2003) The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. Embo J 22: 515-528.
Sheets, E.D., Holowka, D., and Baird, B. (1999) Membrane organization in immunoglobulin E receptor signaling. Curr Opin Chem Biol 3: 95-99.
Shimoyama, T., Fukuda, S., Tanaka, M., Mikami, T., Saito, Y., and Munakata, A. (1997) High prevalence of the CagA-positive Helicobacter pylori strains in Japanese asymptomatic patients and gastric cancer patients. Scand J Gastroenterol 32: 465-468.
Shin, J.S., Gao, Z., and Abraham, S.N. (2000) Involvement of cellular caveolae in bacterial entry into mast cells. Science 289: 785-788.
Shyu, R.Y., Jiang, S.Y., Lai, C.H., Hsu, C.T., Young, T.H., and Yeh, M.Y. (1998) High frequency of cytotoxin-associated gene A in Helicobacter pylori isolated from asymptomatic subjects and peptic ulcer patients in Taiwan. J Clin Gastroenterol 27: 54-59.
Simons, K., and Ikonen, E. (1997) Functional rafts in cell membranes. Nature 387: 569-572.
Simons, K., and Toomre, D. (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1: 31-39.
Simons, K., and Ehehalt, R. (2002) Cholesterol, lipid rafts, and disease. J Clin Invest 110: 597-603.
Sinha, S.K., Martin, B., Gold, B.D., Song, Q., Sargent, M., and Bernstein, C.N. (2004) The incidence of Helicobacter pylori acquisition in children of a Canadian First Nations community and the potential for parent-to-child transmission. Helicobacter 9: 59-68.
Smart, E.J., Graf, G.A., McNiven, M.A., Sessa, W.C., Engelman, J.A., Scherer, P.E., Okamoto, T., and Lisanti, M.P. (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol 19: 7289-7304.
Smith, M.A., and Edwards, D.I. (1995) The influence of microaerophilia and anaerobiosis on metronidazole uptake in Helicobacter pylori. J Antimicrob Chemother 36: 453-461.
Smith, S.I., Oyedeji, K.S., Arigbabu, A.O., Atimomo, C., and Coker, A.O. (2001) High amoxycillin resistance in Helicobacter pylori isolated from gastritis and peptic ulcer patients in western Nigeria. J Gastroenterol 36: 67-68.
Stein, M., Rappuoli, R., and Covacci, A. (2000) Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci U S A 97: 1263-1268.
Stone, G.G., Shortridge, D., Flamm, R.K., Versalovic, J., Beyer, J., Idler, K., Zulawinski, L., and Tanaka, S.K. (1996) Identification of a 23S rRNA gene mutation in clarithromycin-resistant Helicobacter pylori. Helicobacter 1: 227-228.
Stone, G.G., Shortridge, D., Versalovic, J., Beyer, J., Flamm, R.K., Graham, D.Y., Ghoneim, A.T., and Tanaka, S.K. (1997) A PCR-oligonucleotide ligation assay to determine the prevalence of 23S rRNA gene mutations in clarithromycin-resistant Helicobacter pylori. Antimicrob Agents Chemother 41: 712-714.
Su, B., Johansson, S., Fallman, M., Patarroyo, M., Granstrom, M., and Normark, S. (1999) Signal transduction-mediated adherence and entry of Helicobacter pylori into cultured cells. Gastroenterology 117: 595-604.
Szabo, I., Brutsche, S., Tombola, F., Moschioni, M., Satin, B., Telford, J.L., Rappuoli, R., Montecucco, C., Papini, E., and Zoratti, M. (1999) Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. Embo J 18: 5517-5527.
Tanaka, J., Suzuki, T., Mimuro, H., and Sasakawa, C. (2003) Structural definition on the surface of Helicobacter pylori type IV secretion apparatus. Cell Microbiol 5: 395-404.
Taylor, D.E., Ge, Z., Purych, D., Lo, T., and Hiratsuka, K. (1997) Cloning and sequence analysis of two copies of a 23S rRNA gene from Helicobacter pylori and association of clarithromycin resistance with 23S rRNA mutations. Antimicrob Agents Chemother 41: 2621-2628.
Telford, J.L., Ghiara, P., Dell'Orco, M., Comanducci, M., Burroni, D., Bugnoli, M., Tecce, M.F., Censini, S., Covacci, A., Xiang, Z., and et al. (1994) Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med 179: 1653-1658.
Tomb, J.F., White, O., Kerlavage, A.R., Clayton, R.A., Sutton, G.G., Fleischmann, R.D., Ketchum, K.A., Klenk, H.P., Gill, S., Dougherty, B.A., Nelson, K., Quackenbush, J., Zhou, L., Kirkness, E.F., Peterson, S., Loftus, B., Richardson, D., Dodson, R., Khalak, H.G., Glodek, A., McKenney, K., Fitzegerald, L.M., Lee, N., Adams, M.D., Hickey, E.K., Berg, D.E., Gocayne, J.D., Utterback, T.R., Peterson, J.D., Kelley, J.M., Cotton, M.D., Weidman, J.M., Fujii, C., Bowman, C., Watthey, L., Wallin, E., Hayes, W.S., Borodovsky, M., Karp, P.D., Smith, H.O., Fraser, C.M., and Venter, J.C. (1997) The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388: 539-547.
Troost, E., Hold, G.L., Smith, M.G., Chow, W.H., Rabkin, C.S., McColl, K.E., and El-Omar, E.M. (2003) The role of interleukin-1beta and other potential genetic markers as indicators of gastric cancer risk. Can J Gastroenterol 17 Suppl B: 8B-12B.
Tsujii, M., Kawano, S., Tsuji, S., Fusamoto, H., Kamada, T., and Sato, N. (1992) Mechanism of gastric mucosal damage induced by ammonia. Gastroenterology 102: 1881-1888.
Tummuru, M.K., Cover, T.L., and Blaser, M.J. (1993) Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect Immun 61: 1799-1809.
Tummuru, M.K., Cover, T.L., and Blaser, M.J. (1994) Mutation of the cytotoxin-associated cagA gene does not affect the vacuolating cytotoxin activity of Helicobacter pylori. Infect Immun 62: 2609-2613.
Vaira, D., Holton, J., Ricci, C., Menegatti, M., Gatta, L., Berardi, S., Tampieri, A., and Miglioli, M. (2001) Review article: the transmission of Helicobacter pylori from stomach to stomach. Aliment Pharmacol Ther 15 Suppl 1: 33-42.
Vakil, N., Hahn, B., and McSorley, D. (2000) Recurrent symptoms and gastro-oesophageal reflux disease in patients with duodenal ulcer treated for Helicobacter pylori infection. Aliment Pharmacol Ther 14: 45-51.
Van Der Wouden, E.J., Thijs, J.C., Van Zwet, A.A., and Kleibeuker, J.H. (2000) Review article: nitroimidazole resistance in Helicobacter pylori. Aliment Pharmacol Ther 14: 7-14.
Van Doorn, L.J., Figueiredo, C., Megraud, F., Pena, S., Midolo, P., Queiroz, D.M., Carneiro, F., Vanderborght, B., Pegado, M.D., Sanna, R., De Boer, W., Schneeberger, P.M., Correa, P., Ng, E.K., Atherton, J., Blaser, M.J., and Quint, W.G. (1999) Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 116: 823-830.
van Zwet, A.A., Vandenbroucke-Grauls, C.M., Thijs, J.C., van der Wouden, E.J., Gerrits, M.M., and Kusters, J.G. (1998) Stable amoxicillin resistance in Helicobacter pylori. Lancet 352: 1595.
Veldhuyzen van Zanten, S.J., Sherman, P.M., and Hunt, R.H. (1997) Helicobacter pylori: new developments and treatments. Cmaj 156: 1565-1574.
Versalovic, J., Osato, M.S., Spakovsky, K., Dore, M.P., Reddy, R., Stone, G.G., Shortridge, D., Flamm, R.K., Tanaka, S.K., and Graham, D.Y. (1997) Point mutations in the 23S rRNA gene of Helicobacter pylori associated with different levels of clarithromycin resistance. J Antimicrob Chemother 40: 283-286.
Wang, H.J., Kuo, C.H., Yeh, A.A., Chang, P.C., and Wang, W.C. (1998) Vacuolating toxin production in clinical isolates of Helicobacter pylori with different vacA genotypes. J Infect Dis 178: 207-212.
Wang, W.C., Wang, H.J., and Kuo, C.H. (2001) Two distinctive cell binding patterns by vacuolating toxin fused with glutathione S-transferase: one high-affinity m1-specific binding and the other lower-affinity binding for variant m forms. Biochemistry 40: 11887-11896.
Wang, Y., and Taylor, D.E. (1990) Chloramphenicol resistance in Campylobacter coli: nucleotide sequence, expression, and cloning vector construction. Gene 94: 23-28.
Wang, Y., Roos, K.P., and Taylor, D.E. (1993) Transformation of Helicobacter pylori by chromosomal metronidazole resistance and by a plasmid with a selectable chloramphenicol resistance marker. J Gen Microbiol 139: 2485-2493.
Watanabe, K., Tanaka, A., Imase, K., Tokunaga, K., Sugano, H., Kai, A., Ishida, H., Itoh, T., and Takahashi, S. (2005) Amoxicillin resistance in Helicobacter pylori: studies from Tokyo, Japan from 1985 to 2003. Helicobacter 10: 4-11.
Weel, J.F., van der Hulst, R.W., Gerrits, Y., Roorda, P., Feller, M., Dankert, J., Tytgat, G.N., and van der Ende, A. (1996) The interrelationship between cytotoxin-associated gene A, vacuolating cytotoxin, and Helicobacter pylori-related diseases. J Infect Dis 173: 1171-1175.
WHO (1994) IARC monographs on the evaluation of carcinogenic risks to humans. In: Schistosomes, liver flukes and Helicobacter pylori. In International Agency for Research on Cancer. WHO (ed.) Lyon, France: WHO.
Wilkinson, S.M., Uhl, J.R., Kline, B.C., and Cockerill, F.R., 3rd (1998) Assessment of invasion frequencies of cultured HEp-2 cells by clinical isolates of Helicobacter pylori using an acridine orange assay. J Clin Pathol 51: 127-133.
Wong, B.C., Chang, F.Y., Abid, S., Abbas, Z., Lin, B.R., Van Rensburg, C., Chen, P.C., Schneider, H., Simjee, A.E., Hamid, S.S., Seebaran, A., Zhang, J., Destefano, M., and Lam, S.K. (2000) Triple therapy with clarithromycin, omeprazole, and amoxicillin for eradication of Helicobacter pylori in duodenal ulcer patients in Asia and Africa. Aliment Pharmacol Ther 14: 1529-1535.
Wooldridge, K.G., Williams, P.H., and Ketley, J.M. (1996) Host signal transduction and endocytosis of Campylobacter jejuni. Microb Pathog 21: 299-305.
Wu, J.C., Sung, J.J., Chan, F.K., Ching, J.Y., Ng, A.C., Go, M.Y., Wong, S.K., Ng, E.K., and Chung, S.C. (2000) Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther 14: 427-432.
Wu, M.S., Wu, C.Y., Chen, C.J., Lin, M.T., Shun, C.T., and Lin, J.T. (2003) Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int J Cancer 104: 617-623.
Xiang, Z., Censini, S., Bayeli, P.F., Telford, J.L., Figura, N., Rappuoli, R., and Covacci, A. (1995) Analysis of expression of CagA and VacA virulence factors in 43 strains of Helicobacter pylori reveals that clinical isolates can be divided into two major types and that CagA is not necessary for expression of the vacuolating cytotoxin. Infect Immun 63: 94-98.
Xiao, S.D., Liu, W.Z., Hu, P.J., Ouyang, Q., Wang, J.L., Zhou, L.Y., and Cheng, N.N. (2001) A multicentre study on eradication of Helicobacter pylori using four 1-week triple therapies in China. Aliment Pharmacol Ther 15: 81-86.
Yahiro, K., Wada, A., Nakayama, M., Kimura, T., Ogushi, K., Niidome, T., Aoyagi, H., Yoshino, K., Yonezawa, K., Moss, J., and Hirayama, T. (2003) Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. J Biol Chem 278: 19183-19189.
Yang, J.C., Wang, T.H., Wang, H.J., Kuo, C.H., Wang, J.T., and Wang, W.C. (1997) Genetic analysis of the cytotoxin-associated gene and the vacuolating toxin gene in Helicobacter pylori strains isolated from Taiwanese patients. Am J Gastroenterol 92: 1316-1321.
Ye, D., Willhite, D.C., and Blanke, S.R. (1999) Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J Biol Chem 274: 9277-9282.
Zeng, Z.R., Hu, P.J., Hu, S., Pang, R.P., Chen, M.H., Ng, M., and Sung, J.J. (2003) Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut 52: 1684-1689.
Zentilin, P., Iiritano, E., Vignale, C., Bilardi, C., Mele, M.R., Spaggiari, P., Gambaro, C., Dulbecco, P., Tessieri, L., Reglioni, S., Mansi, C., Mastracci, L., Vigneri, S., Fiocca, R., and Savarino, V. (2003) Helicobacter pylori infection is not involved in the pathogenesis of either erosive or non-erosive gastro-oesophageal reflux disease. Aliment Pharmacol Ther 17: 1057-1064.
Zheng, P.Y., and Jones, N.L. (2003) Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol 5: 25-40.