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in those with oesophageal motor than in those without,21 that patients with dysfunction "oesophageal" chest pain have a lower threshold to pain than healthy controls,22 and that antidepressants can relieve the chest pain while leaving unchanged the dysmotility patterns.23 Thus the abnormal motility may be a consequence or epiphenomenon of the chest pain rather than its cause. Is there benefit in further investigation of patients with recurrent chest pain once ischaemic heart disease and oesophagitis have been excluded? When reflux and acid sensitivity are proven by pH recording or acid perfusion, symptoms may be relieved by gastricacid suppressants. A therapeutic trial is a pragmatic alternative, being quicker, cheaper, and more comfortable, if less scientific. Even if investigations are are

commoner

done and

dysmotility is discovered, this finding will the help patient very much because smoothmuscle relaxants provide little or no relief of symptoms.24 A positive diagnosis may make patient management easier, 25 but one must take care to avoid not

improving diagnostic accuracy by devising categories of "non-disease". 26 What of prognosis? Many studies have shown that recurrent non-cardiac chest pain is associated with normal life-expectancy, although the symptom tends to remain. 27 There is less information about outcome when oesophageal dysmotility was believed to be the cause of chest pain, but again the prognosis seems to be good.1O Perhaps chest pain is attributed to oesophageal sensitivity more often than is fully warranted. Cannon,28 a proponent of microvascular angina, points out that studies on the aetiology of obscure chest pain tend to show abnormalities in the organ system that is the special interest of the researchers. It may be more honest, if less tidy, to keep an open mind in the knowledge that the outlook is good and that reassurance is a safe and effective remedy.18 1. Marchandise B, Bourassa MG, Chaitman BR, Lesperance J. Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 1978; 41: 216-20. 2. Cannon RO, Bonow RO, Bacharach SL, et al. Left ventricular dysfunction in patients with angina pectoris, normal epicardial coronary arteries and abnormal vasodilator reserve. Circulation 1985; 71: 218-26. 3. de Caestecker JS, Blackwell JN, Brown J, Heading RC. The oesophagus as a cause of recurrent chest pain. Which patients should be investigated and which tests should be used? Lancet 1985; ii: 1143-46. 4. Benjamin SE, Gerhardt DC, Castell DO. High amplitude peristaltic esophageal contractions associated with chest pain and or dysphagia.

Gastroenterology 1979; 77: 478-83. 5. Richter JE, Castell DO. Diffuse esophageal spasm: a reappraisal. Ann Intern Med 1984; 100: 242-45. 6. Code CF, Schlegel JF, Kelley ML, et al. Hypertensive gastro-esophageal sphincter. Mayo Clin Proc 1986; 35: 391-99. 7. Katz PO, Dalton CB, Richter JE, Wu WC, Castell DO. Esophageal testing in patients with non cardiac chest pain or dysphagia: results of three years’ experience with 1161 patients. Ann Intern Med 1987; 106: 593-97. 8. Richter JE, Wu WC, Johns DN, et al. Esophageal manometry in 95 healthy adult volunteers: variability of pressure with age and frequency of abnormal contractions. Digestive Dis Sci 1987; 32: 583-92. 9. Peters L, Mass L, Petty D, et al. Spontaneous non cardiac chest pam: evaluation by 24 hour ambulatory esophageal motility and pH monitoring. Gastroenterology 1988; 94: 878-86.

10. Swift GL, Alban Davies H, McKirdy H, Lownes R, Lewis D, Rhodes J. A long-term clinical review of patients with oesophageal pain. Q J Med 1991; 81: 937-44. 11. Vantrappen G, Janssens J, Ghillebert G. The irritable oesophagus—a frequent cause of angina-like pain. Lancet 1987; i: 1232-34. 12. Ghillebert G, Janssens J, Vantrappen G, Nevens F, Piessens J. Ambulatory 24 hour intraoesophageal pH and pressure recordings v provocation tests in the diagnosis of chest pain of oesophageal ongin. Gut 1990; 31: 738-44. 13. Hick DG, Morrison JFB, Casey JF, Al-Ashhab W, Williams GJ, Davies GA. Oesophageal motility, luminal pH, and electrocardiographic-ST segment analysis during spontaneous episodes of angina like chest pain. Gut 1992; 33: 79-86. 14. Richter JE, Peters LJ, Dalton CB, Castell DO. Ambulatory oesophageal motility and pH monitoring: analysis techniques alter results. Dig Dis Sci 1978; 32: 924 (abstr). 15. Janssens J, Vantrappen G. Oesophageal chest pain. Curr Opin Gastroenterol 1989; 5: 525-28. 16. Richter JE, Bradley LA, Castell DO. Esophageal chest pain: current controversies in pathogenesis, diagnosis and therapy. Ann Intern Med 1989; 110: 66-78. 17. Valori RM. Nutcracker, neurosis, or sampling bias? Gut 1990; 31: 736-37. 18. Cohen S. Esophageal motility disorders and their response to calcium channel antagonists: the sphinx revisited. Gastroenterology 1987; 93: 201-03. 19. Tytgat GMJ. Oesophagus—editorial overview. Curr Opin Gastroenterol 1990; 6: 569-71. 20. Young LD, Richter JE, Anderson KO, et al. The effects of psychological

and environmental stressors on peristaltic oesophageal contractions in healthy volunteers. Psychophysiology 1987; 24: 132-41. 21. Richter JE, Obrecht WF, Bradley LA, Young LD, Anderson DO. Psychological comparison of patients with nutcracker esophagus and irritable bowel syndrome. Dig Dis Sci 1986; 31: 131-38. 22. Richter JE, Barish CF, Castell DO. Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 1986; 91: 845-52. 23. Clouse RE, Lustman PJ, Eckert TC, Ferney DM, Griffith LS. Low dose trazodone for symptomatic patients with esophageal contraction abnormalities: a double blind placebo controlled trial. Gastroenterology 1987; 92: 1027-36. 24. Richter J, Dalton C, Bradley L, Castell D. Oral nifedipine in the treatment of non cardiac chest pain in patients with the nutcracker oesophagus. Gastroenterology 1987; 93: 21-28. 25. Blackwell JN, Castell DO. Oesophageal chest pain—a point of view. Gut

1984; 25: 1-6. AJ. Diagnostic accuracy would be improved by developing more categories of "non-disease". Med Hypoth 1977; 3: 135-37. 27. Wielgosz AT, Fletcher RH, McCants CB, McKinnes RA, Hanes TL, 26. Scott

Williams RB. Unimproved chest pain in patients with minimal or no coronary disease: a behavioral phenomenon. Am Heart J 1984; 108: 67-72. 28. Cannon RO. Causes of chest pain in patients with normal coronary angiograms: the eye of the beholder. Am J Cardiol 1988; 62: 306-08.

Pop goes the asthma Asthma is a disease that manifests itself as reversible airflow obstruction, caused in most cases by a special type of inflammation in which mast cells and eosinophils participate.In the presence of specific allergens these cells become activated by cross-linkage of cell-bound IgE, which results in the non-cytotoxic release of preformed and newly generated mediators of inflammation.Asthma has long been associated with atopy3,4-ie, the ability of the immune system to

IgE response against common aeroallergens-but only recently has it been possible mount

an

to understand how this association relates to the mucosal inflammatory response. In genetically

susceptible individuals, exposure to specific aeroallergens results in recruitment into the airway of a specific CD4 T-lymphocyte subtype designed TH2 which, when stimulated, has the capacity to elaborate cytokines that are specifically involved in the allergic

585

inflammatory response.5 These include interleukins (IL) 3, 4, and 5 and granulocyte-macrophage colony stimulating factor (GM-CSF) which, in various combinations, switch B cells to IgE synthesis (IL-4)6 and serve as growth and priming factors for mast cells and basophils (IL-3)7 and eosinophils (IL-3, IL-4, and GM-CSF).8 Some of these cytokines have been localised to basophils and mast cells,9 thereby providing an additional source of these growth factors.

Why some proteins but not others initiate the allergic tissue response is not known. By far the most important allergens associated with perennial asthma are those from the house dust mite Dermatophagoides pteronyssinus.lO The allergens Der PI-Der P3 are found in their highest concentration in the mite’s faecal particles" and are now known to be hydrolytic enzymes secreted by the mite’s gastrointestinal tractDer PI (cysteine protease), Der P2 (lysozyme), Der P3 (serine protease), and Der P4 (amylase). 12 The next important class of allergens are those derived from animal proteins, especially the domestic cat." The major allergen Fel dI, originating from the salivary and sebaceous glands, has kallikrein-like activity. It is possible that the enzymic activities of allergens partly account for their ability to penetrate the mucosal barrier to initiate sensitisation and subsequently evoke the inflammatory response. Asthma is also found in association with pollen exposure. Charles Blackley, 14 in his classic treatise on the nature of catarrhus aestivus, was the first to make the link between seasonal respiratory tract symptoms and the presence of aeroallergens in the form of pollen grains. As with other allergens, modem biochemical and molecular biological techniques have led to the identification of specific proteins in grass pollen that are especially allergenic. Of the grass allergens, those from rye grass (Lolium perenne) and timothy grass

(Phleumpratense) have been studied in most detail.ls.l6 However, considerable IgE cross-reactivity occurs with groups of allergens across the various grass species. 15,17 The major allergen of rye is Z.o/1, which is recognised by 80-95% of rye-allergic individuals and consists of an acidic 27 kDa glycoprotein localised to the outer wall and cytoplasm of the pollen grain. At least ten other allergen types have lent themselves to detailed study. Group IX allergens are found in small cytoplasmic vesicles within the pollen grains while group X allergens are identical to cytochrome C. To initiate an attack of asthma an allergen has first to penetrate the effective filtering system of the respiratory tract. Pollen grains themselves, measuring > 35 nm across, are too large to penetrate to lower airways.18 How, therefore, do allergens reach this critical site to precipitate pollen-related asthma? In this issue (p 569) Suphioglu and colleagues show that each pollen grain contains up to 700 starch grains 06-2-5 J..ll11 in diameter, which are released by osmotic lysis when the grain is exposed to water. Since these particles contain LolpIX and are coated with Lolpl they are the most likely source of the low micronic

fraction of pollen-related allergens19 and are an ideal size to enter the lower airways. The researchers have clearly shown that inhalation of a granule suspension of a lysed pollen grain extract can precipitate IgEdependent bronchoconstriction in asthma, so these studies might provide an explanation for the wellknown observation of attacks of asthma being especially prevalent after heavy rainstonns.2o A similar mechanism could account for the indoor submicronic airborne allergens associated with perennial asthma. Thus, warm humid conditions in the home, in addition to encouraging mite replication and growth.,21 may contribute to the mechanisms releasing potent allergens from faecal pellets. Djukanović R, Wilson JW, Britten KM, et al. Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry. Am Rev Respir Dis 1990; 142: 863-71. 2. Holgate ST. Mediator and cellular mechanisms in asthma. J R Coll Physicians Lond 1990; 24: 304-12. 3. Burrows B, Lebowitz MD, Barbee RA. Respiratory disorders and allergy 1.

skin test reactions. Ann Intern Med 1976; 84: 134-39. 4. Britton WJ, Woolcock AJ, Peat JK, Sedgwick CJ, Lloyd DM, Leeder SR. Prevalence of bronchial hyperresponsiveness in children: the relationship between asthma and skin test reactivity to allergens in two communities. Int J Epidemiol 1986; 15: 202-09. 5. Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like broncholaveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326: 298-304. 6. Del Prete G, Maggie E, Parronchi P. IL-4 is an essential co-factor for the IgE synthesis induced in vitro by human T-cell clones and their supernatants. J Immunol 1985; 140: 4193-98. 7. Kirshenbaum AS, Goff JP, Kessler SW, Micab JM, Zsebo K, Metcalfe DD. The effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34- pluripotent, progenitor cells. J Immunol 1992: 148: 772-77. 8.Clutterbuck EJ, Hirst EMA, Sanderson CJ. Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, GM-CSF. Blood 1989; 73: 1504-12. 9. Piccini MP, Machia D, Paronchi P, et al. Human bone marrow non-B non-T-cells produce interleukin 4 in response to cross-linkage of Fc epsilon and Fc gamma receptors. Proc Natl Acad Sci 1991; 88: 8656-68. 10. Platts-Mills TAE, Thomas WR, Aalberse RC, Vervloet D, Chapman MD, eds. Dust mite allergens and asthma. 2nd international workshop, Minstell Lovell, Oxon, 1990. Brussels: UCB Institute of Allergy, 1991. 11. Tovey ER, Chapman MD, Platts-Mills TAE. Mite faeces are the major source of house dust mite allergens. Nature 1981; 289: 592-93. 12. Stewart GA, Thompson PJ, Simpson RJ. Protease antigens from house dust. Lancet 1989; ii: 154-55. 13. Ohman JL, Lowell FC, Block J. Allergens of mammalian origin: characterization of allergen extracts from cat pelts. J Allergy Clin Immunol 1973 52: 231-34. 14. Blackley CH. Catarrhus aestivus (hay fever or lung asthma). London: Ballière Tindall & Cox, 1873. 15. Standring R, Spackman V, Porter SJ. Distribution of a major allergen of rye grass (Lolium perenne) pollen between other grass species. Int Arch Allergy Appl Immunol 1987; 83: 96-103. 16. Lowenstein H. Isolation and partial characterization of allergens from timothy grass pollen. Allergy 1978; 33: 30-41. 17. Lowenstein H. Immunological partial identity and in vitro inhibitory effect of two major pollen allergens to whole pollen extract of four grasses. Int Arch Allergy Appl Immunol 1978; 57: 379-83. 18. Wilson AF, Novey HS, Berke RA, Surpenant EL. Reposition of inhaled pollen and pollen extract in human airways. N Engl J Med 1973; 288: 1056-60. 19. Stewart GA, Holt PG. Submicronic airborne allergens. Med J Aust 1985; 143: 426-27. 20. Packe GE, Ayres JG. Asthma outbreak during a thunderstorm. Lancet 1987; ii: 199-203. 21. Collolf MJ. Effects of temperature and relative humidity on development times and mortality of eggs from laboratory and wild populations of the European house dust mite Dermatophagoides pteronyssinus (Acari pyroglyphidae). Exp Appl Acarol 1987; 3: 279-89.

Pop goes the asthma.

584 in those with oesophageal motor than in those without,21 that patients with dysfunction "oesophageal" chest pain have a lower threshold to pain t...
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