193
pathogenesis
REFERENCES
and nomenclature of
benign
breast disorders. Lancet
1987; ii: 1316-19. 1. Preece PE, Hughes LE, Mansel RE, Baum M, Bolton PM, Gravelle IH.
of mastalgia. Lancet 1976; ii: 670-73. 2. Wisbey JR, Kumar S, Mansel RE, Preece PE, Pye JK, Hughes LE. Natural history of breast pain. Lancet 1983; ii: 672-74. 3. Kumar S, Mansel RE, Hughes LE, Edwards CA, Scanlon MR. Prediction of response to endocrine therapy in pronounced cyclical mastalgia using dynamic tests for prolactin release. Clinical Endocrinol Clinical syndromes
1985; 23: 699-704. 4. Dogliotti L, Orlandi F, Torta M. Bromocriptine treatment of fibrocystic breast disease. A survey. In: Dogliotti L, Mansel RE. Fibrocystic breast disease. Aulendorf: Editio
Cantor, 1986: 46-53.
5. Mansel RE, Preece PE, Hughes LE. A double blind trial of the prolactin inhibitor bromocriptine in painful benign breast disease. Br J Surg 1978; 65: 724-27.
KD, Del Pozo E, Lose KH, Kunzig HJ, Geiger W. Successful of mastodynia with the prolactin inhibitor bromocriptine (CB-154). Arch Gynak 1975; 220: 83-87. 7. Martin-Comin J, Pujol-Amat P, Cararach V, Davi E, Robyn C. Treatment of fibrocystic disease of the breast with a prolactin inhibitor: 2 Br. Alpha. Ergocryptine (CB154). Obstet Gynecol 1976; 48: 703-06. 8. Hughes LE, Mansel RE, Webster DJT. Aberrations of normal development and involution (ANDI): a new perspective on 6. Schulz
treatment
Durning P, Sellwood RA. Bromocriptine in severe cyclical breast pain. Br J Surg 1982; 69: 248-49. 10. Parlati E, Polinari U, Salvi G, et al. Bromocriptine for treatment of benign disease: a double-blind clinical trial versus placebo. Acta Obstet Gynecol Scand 1987; 66: 483-88. 11. Blichert-Toft M, Anderson AN, Henriksen OB, Mygind T. Treatment of mastalgia with bromocriptine. A double blind crossover study. Br 9.
Med J 1979; 1: 237. 12. Mansel
RE, Wisbey JR, Hughes LE. Controlled trial antigonadotropin danazol in painful nodular benign breast
Lancet 1982; i: 928-31. 13. Hinton CP, Williams MR, Roebuck EJ, Blarney RW. A controlled trial of danazol in the treatment of multiple recurrent breast cysts. Br J Clin Pract 1986; 40: 368-70. 14. Sandrucci S, Massa A, Festa V, Borre A, Grosso M, Dogliotti L. Comparison of tamoxifen and bromocriptine in management of fibrocystic disease: a randomised blind study. In: Angeli A, Bradlow HL, Dogliotti L. Endocrinology of the breast. Ann NY Acad Sci 1986; 464: 626-28. 15. Pye JK, Mansel RE, Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet 1985; ii: 373-77. 16. Groom GV, Hughes LE, Mansel RE, Pashby NL, Wisbey JR. The effect of withdrawal of bromocriptine on serum prolactin in patients with benign breast disease. J Physiol 1980; 306: 39P.
Hypothesis: Helicobacter pylori, urease, gastric ulcer
Ammonia, released in the gastric
mucosa
by the
action of Helicobacter pylori urease on transuded plasma urea, curtails the biosynthesis of mucus and/or causes the mucus to be disassembled at the mucosal surface. These changes facilitate colonisation by H pylori and may promote gastric ulcer formation.
Introduction Helicobacter (previously Campylobacter) pylori is found in the antral mucosa of at least 70% of patients with gastric ulcer. The organism is adapted to a mucus habitat and selectively colonises mucus secreted by gastric-type epithelium, especially antral mucus in patients with type B (non-autoimmune) gastritis.l,2 H pylori produces copious amounts of extracellular urease, which liberates ammonia and carbon dioxide from transuded plasma urea. Thus H pylori might modify the structure of "normal" antral mucus (facilitating colonisation and increasing susceptibility to gastric ulcer) and the extracellular urease might initiate this change.
Gastric
mucus
barrier
Normal mucus The healthy gastric mucosa is protected by a barrier of surface epithelial cells and a continuous layer of bicarbonatebuffered mucus. Gastric mucus is a gel formed from mucus glycoproteins. These macromolecules are bound into
complex structures: mucus glycoproteins (molecular weight 5 x 105) are cross-linked through proteins to form mucus glycoprotein complexes (structure II) of molecular weight
of the disease.
mucus,
and
106,3 which are incorporated with lipids into very large micelles (structure I).4-ó The micelles interact to form the continuous mucus layer and endow this
2
x
spherical/ellipsoidal
layer with the properties of elasticity, resistance to proteolysis.
hydrophobicity,
and
Mucus from patients with gastric ulcer The proportion of mucus glycoprotein incorporated into is significantly reduced in adherent antral mucus from patients with gastric ulcer compared with individuals without peptic ulcer.7 We have found that structure I is similarly decreased and structure II increased in mucus aspirated from patients with gastritis associated with gastric ulcer compared with healthy volunteers.8 The proportion of mucus glycoprotein incorporated into structure I was not significantly correlated with acid, pepsin, or reflux. We concluded that the decrease of structure I in mucus from patients with gastric ulcer is a result of defective biosynthesis or breakdown at the mucosal surface, and that because De-Nol’ partly reverses this change H pylori infection is the likely cause.9 The change might be brought about by the following mechanisms, either alone or combined. structure I
Mechanism 1. The synthesis of structure I is impaired because of increased turnover in epithelial cells in the presence of H pylori and hence less time for biosynthesis of mucus. Epithelial cell turnover in gastric mucosa is driven by apical expulsion of mucus and cell exfoliation. A feedback mechanism involving breakdown of the mucus barrier and acid diffusion into the mucosa may normally control the process. In type-B gastritis the rate of cell turnover is
ADDRESS: Royal Postgraduate Medical School, Hammersmith Hospital, London W120NN, UK (R L Sidebotham, PhD, J. H. Baron, DM) Correspondence to Dr J H. Baron
194
increased We postulate that this increase is a result of the liberation of ammonia at the mucosal surface by the action of H pylori urease on transuded plasma urea, which promotes the apical expulsion of mucus" and supplants the normal feedback mechanism. Structural defects in the mucus will be limited since cell turnover will be constrained initially by the level of H pylori infection and later by the availability of urea substrate.lz The friability of structure I might be increased by this mechanism because of inadequate incorporation of lipids into the mucus.13,14
Mechanism 2. Structure I is disassembled by formation at the mucosal surface of a NaHC03/ammonium carbonate buffer (about 25-50 mmol/1, pH 8-7) from the action of H pylori urease on transuded plasma urea.2 Structure I is broken down to structure II when incubated in vitro in this buffer or with urea in the presence of H pylori urease.15 Such breakdown might occur by the breaking of pH sensitive protein/lipid interactions that normally stabilise structure 1.16
Pathological implications structure I is greatly decreased should be less stable mechanically7,17 and appears inherently less capable of maintaining a protective pH gradient against luminal acid at the mucosal surface. 17 118 According to current thinking, this change would promote gastric ulcer formation, and indeed mucus so transformed is associated with increased susceptibility to aspirin-induced ulceration in rats.19 However, there are no indications that the mucosal barrier is functionally impaired by loss of structure Iexcept at the ulcer site. In patients with gastric ulcer the mucus layer has greater depth,2° is no more susceptible to peptic erosion,8 and does not seem to break down at a greater rate2l than that in normal subjects. Despite increased diffusion through the mucus17,18 acidification of the mucosa should be prevented by the buffering action of ammonia generated at the mucosal surface.22 Conceivably the ulcerogenic potential of the structural change found in mucus from patients with gastric ulcer is realised only when other factors intervene at the "ulcer" site (fig 1).
Mucus in which
Fig 2-Restructuring of gastric mucus in presence of H pylori. Spherical micelle (structure I) is changed to less stable form by mechanism 1 and/or 2 and readily converts to lamellar micelle when stressed (in a manner analogous to that proposed for Vibrio cholerae’5 and spermatozoa) along axis of chemotactic gradient (CG) by the "corkscrewing" action’ of H pylori.. and elongated black triangles= hydrophobic structure, and short, thin lines=mucus glycoproteins. HC---> hydrophilic channels. Long axis of H pylori will be about 2-4 times greater than diameter of spherical micelle. =
The
particular importance of the structural change probably lies in the fact that it facilitates colonisation by H pylori and potentiates other (ulcerogenic) effects of the organism, such as somatostatin inhibition, vagal stimulation, and endotoxin release.24 Effective colonisation of
gastric mucosa will depend on the ease with which H pylori penetrates the mucus layer. The motility of H pylori is affected by the viscosity of the containing medium.l Thus the reduction in mucus viscosity that occurs in patients with gastric ulcer17 due to loss of structure I ought to promote colonisation by enabling the organism to traverse the mucus layer rapidly. H pylori may be drawn towards the epithelium by chemotactic stimuli,l with the bacteria tracking in parallel streams along (hydrophilic) channels within the mucus. A restructuring of the mucus, that aligns hydrophilic channels with a chemotactic gradient, may therefore be a prerequisite for optimal colonisation of the mucosal surface (fig 2). Compared with normal gastric mucus, mucus depleted of structure I has reduced hydrophobicity13,14 and fewer hydrophobic (lipid) binding domains.13 This may favour H pylori motility and colonisation of the mucosa, because the movement of H pylori might normally be restricted by non-specific bonding27 between the bacterium, which has high surface hydrophobicity,28 and hydrophobic structures14,16 in the mucus layer. We thank Dr R. P. H. Logan, Dr J. J. Misiewicz, Prof L. A. Turnberg, and Prof N. A. Wright for their helpful criticisms.
REFERENCES 1. Hazell
Fig 1-Model of gastric ulcer (after Capper). Erosion is initiated by duodenogastric reflux through morphologically abnormal pylorus, which produces localised acceleration in breakdown of mucus barrier. At "ulcer" site: H pylori will be eliminated;z’ ulcerogenic cycle (m consequence) will be driven by increasing acid diffusion into mucosa; and cell turnover will be unconstrained, with loss of mucus production, mucosal regression, and peptic ulcer. *=ulcerogenic changes that should be promoted by decrease of structure I in
mucus.
SL, Lee A, Brady L, Hennessy W. Campylobactor pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonisation of the gastric epithelium. J Infect Dis 1986; 153: 658-63. 2. Bode G, Malfertheiner P, Ditschuneit H. Pathogenic implications of ultrastructural findings in Campylobacter pylori related gastroduodenal disease. Scand J Gastroenterol 1988; 23 (suppl 142): 25-39. 3. Pearson JP, Allen A, Parry S. A 70 000 molecular weight protein isolated from purified pig gastric mucus glycoprotein by reduction of disulphide bridges and its implications in the polymeric structure. Biochem J 1981; 197: 155-62.
195
MC, Voter WA, Brown CF, Kaufman B. Structural features of human tracheobronchial mucus glycoprotein. Biochem J 1984; 222: 371-77. 5. Slayter HS, Lamblin G, Le Treut A, Galabert C, Houdret N. Complex structure of human bronchial mucus glycoprotein. Eur J Biochem 1984; 142: 209-18. 6. Lawrence AI, Forsman WC. Conformation of canine tracheal mucin as determined by small-angle neutron diffraction. In: Chantler E, ed. Mucus and related topics. Symposium, Society for Experimental Biology, University of Manchester, July, 1988: 7 (abstr). 7. Younan F, Pearson JP, Allen A, Venables C. Changes in the structure of the mucous gel on the mucosal surface of the stomach in association with peptic ulcer disease. Gastroenterology 1982; 82: 827-31. 8. Batten JJ, Sidebotham RL, Spencer J, Baron JH. Changes to mucus glycoprotein structures in patients with gastritis associated with gastric ulcer. Clin Sci 1989; 77 (suppl 21): 8P. 9. Batten JJ, Li K, Sidebotham RL, Spencer J, Baron JH. Effects of De-Nol on pepsin proteolysis and the gastric mucus barrier in patients with peptic ulcer. In: Chantler E, ed. Mucus and related topics. Symposium, Society for Experimental Biology, University of Manchester, July, 1988: 20 (abstr). 10. Lipkin M. Proliferation and differentiation of gastrointestinal cells in normal and diseased states. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven Press, 1987: 255-84. 11. Richardson PS, Phipps RJ, Balfre K, Hall R. The roles of mediators, irritants and allergens in causing mucin secretion from the trachea. In: Porter R, Rivers J, O’Connor M, eds. Respiratory tract mucus. CIBA symposium. Amsterdam: Elsevier, 1978: 111-31. 12. Snook J. Urea/creatinine ratio and gastrointestinal haemorrhage. Lancet 1986; ii: 400. 13. Sarosiek J, Piotrowski J, Gabryelewicz A, Slomiany A, Slomiany BL. Alterations in mucin hydrophobicity and molecular form distribution with peptic ulcer. Gastroenterology 1989; 96 (suppl): A441. 14. Murty VLN, Sarosiek J, Slomiany A, Slomiany BL. Effects of lipids and proteins on the viscosity of gastric mucus glycoprotein. Biochem Biophys Res Commun 1984; 121: 521-29. 15. Sidebotham RL, Batten JJ, Karim QN, Baron JH. Changes in the gastric mucus barrier associated with C pylori infection. Clin Sci 1989; 77 (suppl 21): 8P. 4. Rose
Slomiany BL, Nishikawa H, Slomiany A. Gastric mucin hydrophobicity: effects of proteolysis, reduction and lipid removal. Gastroenterology 1989; 96 (suppl): A478. 17. Sarosiek J, Slomiany A, Gabryelewicz A, Slomiany BL. Changes in the macromolecular organisation and physical properties of gastric mucus with peptic ulcer. Gastroenterology 1987; 92: 1615. 18. Tasman-Jones C, Maher C, Thomsen L, Lee SP, Vanderwee M. Mucosal defenses and gastroduodenal disease. Digestion 1987; 37 (suppl 2): 1-7. 19. Bagshaw PF, Munster DJ, Wilson JG. Molecular weight of gastric mucus glycoprotein is a determinant of the degree of subsequent aspirin-induced chronic gastric ulceration in the rat. Gut 1987; 28: 16.
287-93. 20. Allen A, Ward R, Cunliffe WJ, Hutton DA, Pearson JP, Venables CW. Changes in adherent mucus gel and pepsinolysis in peptic ulcer patients. Dig Dis Sci 1985; 30: 365. 21. Batten JJ, Li K, Sidebotham RL, Spencer J, Baron JH. Effects of acid, pepsin, volume of secretion and mucus composition on the breakdown of the gastric mucus barrier. Clin Sci 1988; 74 (suppl 18): 53P. 22. Thompson L, Tasman-Jones C, Morris A, Wiggins P, Lee S, Forlong C. Ammonia produced by Campylobacter pylori neutralises H+ moving through gastric mucus. Scand J Gastroenterol 1989; 24: 761-68. 23. Tompkins DS, West AP. Campylobacter pylori, acid and bile. J Clin Pathol 1987; 40: 1387. 24. Mattsby-Baltzer I, Goodwin CS. Lipid A in C pylori. In: Kaijser B, Falsen E, eds. Campylobacter IV. Goterna, Sweden: University of Goteborg, 1988: 141-42. 25. Jones GW, Abrams GD, Freter R. Adhesive properties of Vibrio cholerae: adhesion to isolated rabbit brush border membranes and haemagglutinating activity. Infect Immun 1976; 14: 232-39. 26. Lee WI, Verdugo P, Blandau RJ, Gaddum-Rosse P. Molecular arrangement of cervical mucus: a reevaluation based on laser light scattering spectroscopy. Gynaecol Invest 1977; 8: 254-66. 27. Beachey EH. Bacterial adherence: adhesin-receptor interactions mediating the attachment of bacteria to mucosal surfaces. J Infect Dis 1981; 143: 325-45. 28. Pruul H, Lewis G, Lee PC, McDonald PJ. Interactions of Campylobacter pylori with immune defense mechanisms. In: Kaijser B, Falsen E, eds. Campylobacter IV. Goterna, Sweden: University of Goteborg, 1988: pp 404-06.
BOOKSHELF into the
The Practice of Behavioural Medicine Edited
by Shirley Pearce and Jane Wardle. Oxford: Oxford University Press. 1989. Pp 313. 35.00. ISBN 0-192616919. Doctors usually assume that patients want to get better and will make an effort to do so. Only sometimes is this assumption correct. Behavioural psychologists take nothing for granted and act as if patients do not know how they are ill, how to get better, or even how to want to get better. The results of this latter approach are a revelation, and the treatment
strategies generated are fascinating and inspiring,
not
alternatives
as
to
orthodox
medicine
but
as
complements. What is behavioural medicine? Loosely speaking, it is the application of behavioural psychology to the assessment and treatment of physical illness. For a fuller explanation, read the excellent introduction to this book. There are sixteen authors, two of whom edited the book, spread over 11 chapters, each of which tackles a specific medical topic. Some of the topics are as expected-hypertension, cardiac rehabilitation, pain, obesity. Others are less so-childhood diabetes, asthma, and menstrual troubles. Every chapter offers insights and answers to problems which must baffle and frustrate most clinicians. The authors hope to expand their discipline out of the hut behind the psychiatry unit and
powerful
general
medical wards and clinics.
They
make
a
case.
But if the content is impressive the style is a disappointment. The text is stuffed with a surfeit of tests, scales, symptom questionnaires, and assessment schedules, and of course nobody seems to use the same tests twice running. This is perhaps inevitable in a new discipline, and to be fair each chapter is a detailed critique and synthesis of the relevant work. Worse still, the reader will stumble over hideous phrases such as "face-valid tools" and "nonregulatory eating" and we are advised at one point "to post-test counsel an individual". These quibbles are not simply a reviewer’s easy sarcasm, for here is a typical sentence: "Furthermore, the group itself acts as a powerful reinforcer once norms affirming task completion are
established". The style itself prompts a question. Do the authors think in the way that they write? I hope not. With careful reading, however, nothing is completely obscure, and this is no mean achievement within the confines of the cramped and spiritless language of behavioural science. It is not easy to recommend a book that is so hard to read, but the content merits the widest possible readership. Middleton Lodge, New Ollerton NG22 9SZ, UK
MICHAEL F. LOUDON
pathogenesis
REFERENCES
and nomenclature of
benign
breast disorders. Lancet
1987; ii: 1316-19. 1. Preece PE, Hughes LE, Mansel RE, Baum M, Bolton PM, Gravelle IH.
of mastalgia. Lancet 1976; ii: 670-73. 2. Wisbey JR, Kumar S, Mansel RE, Preece PE, Pye JK, Hughes LE. Natural history of breast pain. Lancet 1983; ii: 672-74. 3. Kumar S, Mansel RE, Hughes LE, Edwards CA, Scanlon MR. Prediction of response to endocrine therapy in pronounced cyclical mastalgia using dynamic tests for prolactin release. Clinical Endocrinol Clinical syndromes
1985; 23: 699-704. 4. Dogliotti L, Orlandi F, Torta M. Bromocriptine treatment of fibrocystic breast disease. A survey. In: Dogliotti L, Mansel RE. Fibrocystic breast disease. Aulendorf: Editio
Cantor, 1986: 46-53.
5. Mansel RE, Preece PE, Hughes LE. A double blind trial of the prolactin inhibitor bromocriptine in painful benign breast disease. Br J Surg 1978; 65: 724-27.
KD, Del Pozo E, Lose KH, Kunzig HJ, Geiger W. Successful of mastodynia with the prolactin inhibitor bromocriptine (CB-154). Arch Gynak 1975; 220: 83-87. 7. Martin-Comin J, Pujol-Amat P, Cararach V, Davi E, Robyn C. Treatment of fibrocystic disease of the breast with a prolactin inhibitor: 2 Br. Alpha. Ergocryptine (CB154). Obstet Gynecol 1976; 48: 703-06. 8. Hughes LE, Mansel RE, Webster DJT. Aberrations of normal development and involution (ANDI): a new perspective on 6. Schulz
treatment
Durning P, Sellwood RA. Bromocriptine in severe cyclical breast pain. Br J Surg 1982; 69: 248-49. 10. Parlati E, Polinari U, Salvi G, et al. Bromocriptine for treatment of benign disease: a double-blind clinical trial versus placebo. Acta Obstet Gynecol Scand 1987; 66: 483-88. 11. Blichert-Toft M, Anderson AN, Henriksen OB, Mygind T. Treatment of mastalgia with bromocriptine. A double blind crossover study. Br 9.
Med J 1979; 1: 237. 12. Mansel
RE, Wisbey JR, Hughes LE. Controlled trial antigonadotropin danazol in painful nodular benign breast
Lancet 1982; i: 928-31. 13. Hinton CP, Williams MR, Roebuck EJ, Blarney RW. A controlled trial of danazol in the treatment of multiple recurrent breast cysts. Br J Clin Pract 1986; 40: 368-70. 14. Sandrucci S, Massa A, Festa V, Borre A, Grosso M, Dogliotti L. Comparison of tamoxifen and bromocriptine in management of fibrocystic disease: a randomised blind study. In: Angeli A, Bradlow HL, Dogliotti L. Endocrinology of the breast. Ann NY Acad Sci 1986; 464: 626-28. 15. Pye JK, Mansel RE, Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet 1985; ii: 373-77. 16. Groom GV, Hughes LE, Mansel RE, Pashby NL, Wisbey JR. The effect of withdrawal of bromocriptine on serum prolactin in patients with benign breast disease. J Physiol 1980; 306: 39P.
Hypothesis: Helicobacter pylori, urease, gastric ulcer
Ammonia, released in the gastric
mucosa
by the
action of Helicobacter pylori urease on transuded plasma urea, curtails the biosynthesis of mucus and/or causes the mucus to be disassembled at the mucosal surface. These changes facilitate colonisation by H pylori and may promote gastric ulcer formation.
Introduction Helicobacter (previously Campylobacter) pylori is found in the antral mucosa of at least 70% of patients with gastric ulcer. The organism is adapted to a mucus habitat and selectively colonises mucus secreted by gastric-type epithelium, especially antral mucus in patients with type B (non-autoimmune) gastritis.l,2 H pylori produces copious amounts of extracellular urease, which liberates ammonia and carbon dioxide from transuded plasma urea. Thus H pylori might modify the structure of "normal" antral mucus (facilitating colonisation and increasing susceptibility to gastric ulcer) and the extracellular urease might initiate this change.
Gastric
mucus
barrier
Normal mucus The healthy gastric mucosa is protected by a barrier of surface epithelial cells and a continuous layer of bicarbonatebuffered mucus. Gastric mucus is a gel formed from mucus glycoproteins. These macromolecules are bound into
complex structures: mucus glycoproteins (molecular weight 5 x 105) are cross-linked through proteins to form mucus glycoprotein complexes (structure II) of molecular weight
of the disease.
mucus,
and
106,3 which are incorporated with lipids into very large micelles (structure I).4-ó The micelles interact to form the continuous mucus layer and endow this
2
x
spherical/ellipsoidal
layer with the properties of elasticity, resistance to proteolysis.
hydrophobicity,
and
Mucus from patients with gastric ulcer The proportion of mucus glycoprotein incorporated into is significantly reduced in adherent antral mucus from patients with gastric ulcer compared with individuals without peptic ulcer.7 We have found that structure I is similarly decreased and structure II increased in mucus aspirated from patients with gastritis associated with gastric ulcer compared with healthy volunteers.8 The proportion of mucus glycoprotein incorporated into structure I was not significantly correlated with acid, pepsin, or reflux. We concluded that the decrease of structure I in mucus from patients with gastric ulcer is a result of defective biosynthesis or breakdown at the mucosal surface, and that because De-Nol’ partly reverses this change H pylori infection is the likely cause.9 The change might be brought about by the following mechanisms, either alone or combined. structure I
Mechanism 1. The synthesis of structure I is impaired because of increased turnover in epithelial cells in the presence of H pylori and hence less time for biosynthesis of mucus. Epithelial cell turnover in gastric mucosa is driven by apical expulsion of mucus and cell exfoliation. A feedback mechanism involving breakdown of the mucus barrier and acid diffusion into the mucosa may normally control the process. In type-B gastritis the rate of cell turnover is
ADDRESS: Royal Postgraduate Medical School, Hammersmith Hospital, London W120NN, UK (R L Sidebotham, PhD, J. H. Baron, DM) Correspondence to Dr J H. Baron
194
increased We postulate that this increase is a result of the liberation of ammonia at the mucosal surface by the action of H pylori urease on transuded plasma urea, which promotes the apical expulsion of mucus" and supplants the normal feedback mechanism. Structural defects in the mucus will be limited since cell turnover will be constrained initially by the level of H pylori infection and later by the availability of urea substrate.lz The friability of structure I might be increased by this mechanism because of inadequate incorporation of lipids into the mucus.13,14
Mechanism 2. Structure I is disassembled by formation at the mucosal surface of a NaHC03/ammonium carbonate buffer (about 25-50 mmol/1, pH 8-7) from the action of H pylori urease on transuded plasma urea.2 Structure I is broken down to structure II when incubated in vitro in this buffer or with urea in the presence of H pylori urease.15 Such breakdown might occur by the breaking of pH sensitive protein/lipid interactions that normally stabilise structure 1.16
Pathological implications structure I is greatly decreased should be less stable mechanically7,17 and appears inherently less capable of maintaining a protective pH gradient against luminal acid at the mucosal surface. 17 118 According to current thinking, this change would promote gastric ulcer formation, and indeed mucus so transformed is associated with increased susceptibility to aspirin-induced ulceration in rats.19 However, there are no indications that the mucosal barrier is functionally impaired by loss of structure Iexcept at the ulcer site. In patients with gastric ulcer the mucus layer has greater depth,2° is no more susceptible to peptic erosion,8 and does not seem to break down at a greater rate2l than that in normal subjects. Despite increased diffusion through the mucus17,18 acidification of the mucosa should be prevented by the buffering action of ammonia generated at the mucosal surface.22 Conceivably the ulcerogenic potential of the structural change found in mucus from patients with gastric ulcer is realised only when other factors intervene at the "ulcer" site (fig 1).
Mucus in which
Fig 2-Restructuring of gastric mucus in presence of H pylori. Spherical micelle (structure I) is changed to less stable form by mechanism 1 and/or 2 and readily converts to lamellar micelle when stressed (in a manner analogous to that proposed for Vibrio cholerae’5 and spermatozoa) along axis of chemotactic gradient (CG) by the "corkscrewing" action’ of H pylori.. and elongated black triangles= hydrophobic structure, and short, thin lines=mucus glycoproteins. HC---> hydrophilic channels. Long axis of H pylori will be about 2-4 times greater than diameter of spherical micelle. =
The
particular importance of the structural change probably lies in the fact that it facilitates colonisation by H pylori and potentiates other (ulcerogenic) effects of the organism, such as somatostatin inhibition, vagal stimulation, and endotoxin release.24 Effective colonisation of
gastric mucosa will depend on the ease with which H pylori penetrates the mucus layer. The motility of H pylori is affected by the viscosity of the containing medium.l Thus the reduction in mucus viscosity that occurs in patients with gastric ulcer17 due to loss of structure I ought to promote colonisation by enabling the organism to traverse the mucus layer rapidly. H pylori may be drawn towards the epithelium by chemotactic stimuli,l with the bacteria tracking in parallel streams along (hydrophilic) channels within the mucus. A restructuring of the mucus, that aligns hydrophilic channels with a chemotactic gradient, may therefore be a prerequisite for optimal colonisation of the mucosal surface (fig 2). Compared with normal gastric mucus, mucus depleted of structure I has reduced hydrophobicity13,14 and fewer hydrophobic (lipid) binding domains.13 This may favour H pylori motility and colonisation of the mucosa, because the movement of H pylori might normally be restricted by non-specific bonding27 between the bacterium, which has high surface hydrophobicity,28 and hydrophobic structures14,16 in the mucus layer. We thank Dr R. P. H. Logan, Dr J. J. Misiewicz, Prof L. A. Turnberg, and Prof N. A. Wright for their helpful criticisms.
REFERENCES 1. Hazell
Fig 1-Model of gastric ulcer (after Capper). Erosion is initiated by duodenogastric reflux through morphologically abnormal pylorus, which produces localised acceleration in breakdown of mucus barrier. At "ulcer" site: H pylori will be eliminated;z’ ulcerogenic cycle (m consequence) will be driven by increasing acid diffusion into mucosa; and cell turnover will be unconstrained, with loss of mucus production, mucosal regression, and peptic ulcer. *=ulcerogenic changes that should be promoted by decrease of structure I in
mucus.
SL, Lee A, Brady L, Hennessy W. Campylobactor pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonisation of the gastric epithelium. J Infect Dis 1986; 153: 658-63. 2. Bode G, Malfertheiner P, Ditschuneit H. Pathogenic implications of ultrastructural findings in Campylobacter pylori related gastroduodenal disease. Scand J Gastroenterol 1988; 23 (suppl 142): 25-39. 3. Pearson JP, Allen A, Parry S. A 70 000 molecular weight protein isolated from purified pig gastric mucus glycoprotein by reduction of disulphide bridges and its implications in the polymeric structure. Biochem J 1981; 197: 155-62.
195
MC, Voter WA, Brown CF, Kaufman B. Structural features of human tracheobronchial mucus glycoprotein. Biochem J 1984; 222: 371-77. 5. Slayter HS, Lamblin G, Le Treut A, Galabert C, Houdret N. Complex structure of human bronchial mucus glycoprotein. Eur J Biochem 1984; 142: 209-18. 6. Lawrence AI, Forsman WC. Conformation of canine tracheal mucin as determined by small-angle neutron diffraction. In: Chantler E, ed. Mucus and related topics. Symposium, Society for Experimental Biology, University of Manchester, July, 1988: 7 (abstr). 7. Younan F, Pearson JP, Allen A, Venables C. Changes in the structure of the mucous gel on the mucosal surface of the stomach in association with peptic ulcer disease. Gastroenterology 1982; 82: 827-31. 8. Batten JJ, Sidebotham RL, Spencer J, Baron JH. Changes to mucus glycoprotein structures in patients with gastritis associated with gastric ulcer. Clin Sci 1989; 77 (suppl 21): 8P. 9. Batten JJ, Li K, Sidebotham RL, Spencer J, Baron JH. Effects of De-Nol on pepsin proteolysis and the gastric mucus barrier in patients with peptic ulcer. In: Chantler E, ed. Mucus and related topics. Symposium, Society for Experimental Biology, University of Manchester, July, 1988: 20 (abstr). 10. Lipkin M. Proliferation and differentiation of gastrointestinal cells in normal and diseased states. In: Johnson LR, Christensen J, Grossman MI, Jacobson ED, Schultz SG, eds. Physiology of the gastrointestinal tract. New York: Raven Press, 1987: 255-84. 11. Richardson PS, Phipps RJ, Balfre K, Hall R. The roles of mediators, irritants and allergens in causing mucin secretion from the trachea. In: Porter R, Rivers J, O’Connor M, eds. Respiratory tract mucus. CIBA symposium. Amsterdam: Elsevier, 1978: 111-31. 12. Snook J. Urea/creatinine ratio and gastrointestinal haemorrhage. Lancet 1986; ii: 400. 13. Sarosiek J, Piotrowski J, Gabryelewicz A, Slomiany A, Slomiany BL. Alterations in mucin hydrophobicity and molecular form distribution with peptic ulcer. Gastroenterology 1989; 96 (suppl): A441. 14. Murty VLN, Sarosiek J, Slomiany A, Slomiany BL. Effects of lipids and proteins on the viscosity of gastric mucus glycoprotein. Biochem Biophys Res Commun 1984; 121: 521-29. 15. Sidebotham RL, Batten JJ, Karim QN, Baron JH. Changes in the gastric mucus barrier associated with C pylori infection. Clin Sci 1989; 77 (suppl 21): 8P. 4. Rose
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BOOKSHELF into the
The Practice of Behavioural Medicine Edited
by Shirley Pearce and Jane Wardle. Oxford: Oxford University Press. 1989. Pp 313. 35.00. ISBN 0-192616919. Doctors usually assume that patients want to get better and will make an effort to do so. Only sometimes is this assumption correct. Behavioural psychologists take nothing for granted and act as if patients do not know how they are ill, how to get better, or even how to want to get better. The results of this latter approach are a revelation, and the treatment
strategies generated are fascinating and inspiring,
not
alternatives
as
to
orthodox
medicine
but
as
complements. What is behavioural medicine? Loosely speaking, it is the application of behavioural psychology to the assessment and treatment of physical illness. For a fuller explanation, read the excellent introduction to this book. There are sixteen authors, two of whom edited the book, spread over 11 chapters, each of which tackles a specific medical topic. Some of the topics are as expected-hypertension, cardiac rehabilitation, pain, obesity. Others are less so-childhood diabetes, asthma, and menstrual troubles. Every chapter offers insights and answers to problems which must baffle and frustrate most clinicians. The authors hope to expand their discipline out of the hut behind the psychiatry unit and
powerful
general
medical wards and clinics.
They
make
a
case.
But if the content is impressive the style is a disappointment. The text is stuffed with a surfeit of tests, scales, symptom questionnaires, and assessment schedules, and of course nobody seems to use the same tests twice running. This is perhaps inevitable in a new discipline, and to be fair each chapter is a detailed critique and synthesis of the relevant work. Worse still, the reader will stumble over hideous phrases such as "face-valid tools" and "nonregulatory eating" and we are advised at one point "to post-test counsel an individual". These quibbles are not simply a reviewer’s easy sarcasm, for here is a typical sentence: "Furthermore, the group itself acts as a powerful reinforcer once norms affirming task completion are
established". The style itself prompts a question. Do the authors think in the way that they write? I hope not. With careful reading, however, nothing is completely obscure, and this is no mean achievement within the confines of the cramped and spiritless language of behavioural science. It is not easy to recommend a book that is so hard to read, but the content merits the widest possible readership. Middleton Lodge, New Ollerton NG22 9SZ, UK
MICHAEL F. LOUDON
