1012
hydrocephalus is a misnomer, have raised resting pressure
since patients often with superimposed waves of raised pressure similar to LUNDBERG’S B waves, especially at night. 15 Of seven patients without such waves none improved after shunting whereas all five patients with B waves improved.16 Reduction of cerebral blood-flow and volume, with increase after removal of lumbar c.s.F., has also been reported as an indication for shunting.17 Computerised tomographic (c.T.) scanning has now been added to the investigations.18 This non-invasive technique will show dilated ventricles with normal or small cortical sulci in communicating hydrocephalus, separating it from obstructive
hydrocephalus or hydrocephalus associated with atrophy. Thus it provides a valuable screening test, though it will not indicate which patients will benefit from shunting. Reports on the effect of shunting are difficult to evaluate. Eight patients in one series did not improve19 but, though the investigators record "striking similarity" to the cases described by HAKIM and ADAMS, the case-histories do not bear this out since there is no mention of incontinence. In another series, of 28 patients, two-thirds were said to have improved after shunting, but the dementia was described as "symptoms resembling senility", 20 which is not the syndrome of HAKIM and ADAMS. Other reports have been concerned with hydrocephalus ex vacuo.21, 22 In three series matching more closely the original description, appreciable improvement has been achieved in 25%,23 70%,24 and 23%.8 An important point is that patients with a recognisable cause for their communicating hydrocephalushead injury, meningitis, or subarachnoid hæmorrhage-seem to do better than the idiopathic cases.8, 15 Otherwise no combination of tests has been found to predict reliably who will benefit from shunting.’ At present, the best way to identify patients who may benefit from shunting seems to be, firstly, to pay close attention to the clinical features as originally described and look especially for patients with predisposing factors; secondly, to use c.T. scanning as a screening test; and, finally, to monitor intracranial pressure either directly or via the lumbar route. Patients who show neither raised basic pressure nor pressure waves seem unlikely to benefit from shunting.
Drugs for Duodenal Ulcer IN the management of duodenal ulcer, medical has been a cynic’s delight. Under the eye of science, the "logical" treatments tend to be found wanting. Two symposia at the Royal College of Physicians, in London, and a spate of publications, have extolled the merits of cimetidine and carbenoxolone in duodenal ulcer. There is now ample evidence from good controlled trials that cimetidine will promote the healing of duodenal ulceration, and between two and three times as many ulcers can be expected to heal during a 4-8-week course of cimetidine as with dummy tablets.I-4 Virtually equivalent claims have now been treatment
made
support the use of carbenoxolone sodium in positioned-release capsules (though evigiven dence that the capsules themselves are essential is lacking), and two Australian trials discussed at the carbenoxolone symposium have confirmed results obtained in three others already published.5-9 Whereas we know cimetidine to be a potent antisecretory agent, the mode of action of carbenoxolone is uncertain; it does not seem to alter gastricacid output.10 Though carbenoxolone has some antipeptic activity it seems more likely to act by strengthening mucosal resistance. It reduces gastric-cell loss and promotes the synthesis of gastric mucosal glycoprotein,11,12 but direct evidence of the same action in the duodenum is lacking. One might expect a combination of carbenoxolone and cimetidine to be especially useful; this remains to be tested. Alternative possible treatments are few. Tripotassium dicitratobismuthate has been found in three studies to accelerate ulcer healing,13-15 the mechanism again being obscure. Deglycyrrhizinated liquorice has been tested as a possible sideeffect-free alternative to carbenoxolone, but it neither relieves symptoms 16 nor heals ulcers." Antacid treatment has lately been reassessed in the to
Blackwood, W. S., Maudgal, D. P., Pickard, R. G., Lawrence, D., Northfield, T. C. Lancet, 1976, ii, 174. 2. Bodemar, G., Walan, A. ibid. p. 161. 3. Gillespie, G., Gray, G. R., Smith, I. S., Mackenzie, I., Crean, G. P. in Proceedings of the Second International Symposium on Histamine H2 Receptor Antagonists, Amsterdam, 1977. 1.
4. Multicentre trial. ibid. 5. Davies, W. I., Reed, P. I. Gut, 1977, 18, 78. 6. Archambault, A., North American Symposium
on
Carbenoxolone. Amster-
dam, 1976. 15. Symon, L., Dorsch, N. W. C., Stephens, R. J. Lancet, 1972, ii, 1291. 16. Chawla, J. C., Hulme, A., Cooper, R. J. Neurosurg. 1974, 40, 376. 17. Mathew, N. T., Meyer, J. S., Hartmann, A., Ott, E. O. Archs Neurol. 18.
32, 657. Crockard, H. A., Hanlon, K., Duda, surg Psychiat. 1977, 40, 736.
E.
E., Mullan, J. F., J. Neurol. Neuro-
19 Bannister, C. M. Acta neurochir., Wien. 1972, 27, 11. 20. Shenkin, H. A., Greenberg, J., Bouzarth, W. F., Gutterman, P., J. O. J. Am. med. Ass. 1973, 225, 1486. 21. 22. 23. 24.
1975,
Appenzeller, O., Salmon, J. H. J Neurosurg. 1967, 26, 478. Salmon, J. H., Armitage, J. L. Neurology, 1968, 18, 1223. Salmon, J. H. J. Neurosurg. 1972, 37, 423. Guidetti, B., Gagliardi, F. M. Acta neurochir., Wien. 1972, 27, 1.
Morales,
7. Multicentre trial. Gut. 1977, 8. Nagy, G. S. Unpublished. 9. Young, G. P., St. John, D. J. 10. Barron, J. H. Gut, 1977, 18,
18, 717. B., Coventry, D. A. Unpublished.
721.
11. Domschke, W., Domschke, J., Hagel, J., Demling, L., Croft, D. N. Gut, 1977, 18, 817. 12. Shillingford, J. S., Lindup, W. E., Parke, D. V. Biochem. Soc. Trans. 1974, 2, 1104. 13. Coughlin, G. P., Kupa, A., Alp, M. H. Med. J. Aust. 1977, i, 294. 14. Moshal, M. G. Postgrad. med. J. 1975, 51, suppl. 5, p. 36. 15. Shreeve, D. R. ibid. p. 33. 16. Feldman, H., Gilat, T. Gut, 1971, 12, 449. 17. Larkworthy, W., Holgate, P. F. L., McIllmurray, M. B., Langman, M. J. S. Br. med. J. 1977, ii, 1123.
1013
United States, and heroic doses—a small suitcase would be needed for a month’s treatment—seem to accelerate ulcer healing although, confusingly, symptomatic benefit seems to be lacking.18-20 Finally prostaglandin E2 analogues have been shown in one trial to reduce acid output and to accelerate ulcer healing,21 and a single endoscopically controlled trial suggests that the antidepressant trimipramine promotes ulcer healing.22 Desirable as short-term healing may be, the long-term outcome is what really matters. There is now ample evidence that, when initial treatment with histamine H2 antagonists stops, the ulcer symptoms return—perhaps in a more vicious manner than before.23,24 Maintenance treatment with cimetidine will reduce the relapse-rate during treatment,3 but we do not know whether such benefit is maintained when treatment ceases. Since carbenoxolone, chelated bismuth, and cimetidine may heal ulcers in different ways, relapse-rates may also differ and comparisons are clearly needed. The effectiveness of treatment has to be examined in the context of safety. Hypertension, salt and water retention, and hypokalæmia are wellknown adverse effects of carbenoxolone.25 They are frequent but usually mild. More severe problems arise in the elderly and in people with cardiorespiratory or renal disease—especially if treatment is injudiciously prolonged, with inadequate observation. The adverse effects of other drugs are less clear. Chelated bismuth seems so far to be side-effect free, and in particular no case of bismuth encephalopathy, as recorded with salts such as the subgallate and subnitrate, has yet been described.26,27 Prostaglandin analogues have scarcely been tested, but the 15S-15 and the 15R-15 methyl esters of prostaglandin E2 seem to cause diarrhœa and superficial gastritis.21 The nature and frequency of the adverse effects of cimetidine are more a matter of speculation than of knowledge. Short-term treatment has been found, on the whole, to be safe. Rises in serum creatinine and transaminase concentrations have been common but their meaning is obscure.28 The creatinine changes do not seem to be associated with any disorder of renal function, whilst the transaminase changes have not yet been
associated with severe hepatic necrosis, though two patients had minor abnormalities in liver biopsy specimens. Metiamide, the predecessor to cimetidine, was withdrawn because of bone-marrow toxicity, but so far, despite far greater use, there has been only one case of neutropenia, reversible, during cimetidine treatment. 29 Isolated reports of other possible adverse effects have included mental confusion, muscle twitching, cerebrovascular occlusion, gynaecomastia, and exacerbation of ileus in burned patients.30-34 The evidence that the abnormalities described were indeed due to cimetidine treatment is inadequate, chance associations being entirely possible. But H2 receptors are widely distributed in the body. A safety monitoring programme is clearly needed that identifies not only the bizarre effects which can confidently be ascribed to the drug but also the run-of-the-mill which demand a control population for comparison. It would be good to know that post-marketing surveillance is actually being practised and does not remain a theoretical plaything of clinical pharmacologists.
Otosclerosis OTOSCLEROSIS is’ one of the major unsolved problems of the pathology of the ear. This common cause of conductive deafness was known to VALSALVA;l and TOYNBEE,2 the father of British otology, found an ankylotic stapes in over 10% of the large series of human temporal bones he dissected. ENGSTROM3 and GUILD4 likewise found otosclerotic foci in about a tenth of the temporal bones they examined. In the past two decades research into the causes of this bony dystrophy has been revivified by microsurgical techniques which were devised primarily for treatment. Three main aetiological factors have been established5—genetic and constitutional ; local; and systemic (activating). The genetic disposition is generally recognised, and this concept is supported by cytochemical and electron microscopic observations.6-10 Of the local factors, some 29.
Peterson, W. L., Sturdevant, R. A. L., Frankl, H. D., Richardson, C. T., Isenberg, J. I., Elashoff, J. D., Sones, J. Q., Gross, R. A., McCallum, R. W., Fordtran, J. S. New Engl. J. Med. 1977, 297, 341. 19. Sturdevant, R. A. L., Isenberg, J. I., Secrist, D., Ansfield, J. Gastroentero-
18
logy, 1977, 72, 1. 20 Littman, A., Welch, R. W., Furin, R. C., Aronson, A. R. ibid. 1977, 73, 6. 21. Gibinski, K., Rybicka, J., Mikós, E., Nowak, A. Gut, 1977, 18, 636. 22 Wetterhus, S., Aubert, E., Berg, C. E., Bjerkeset, T., Halvorsen, L., Hovdenak, N., Myren, J., Roland, M., Sigstad, H., Guldahl, M. Scand. J. Gastroent.
1977, 12, suppl. 43, p. 33.
23. Saunders, J. H. B., Wormsley, K. G. Lancet, 1977, i, 765. 24. Wallace, W. A., Orr, C. M. E., Beam, A. R. Br. med. J. 1977, ii, 865. 25 Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Spencer, R., Avery, G. S. Drugs, 1976, 11, 245. 26. Loiseau, P., Henry, P., Jallon, P., Leroux, M. J. neurol. Sci. 1976, 27, 133. 27 Burns, R., Thomas, D. W., Baron, V. J. Br. med. J. 1974, i, 220. 28. Sharpe, P. C., Hawkins, B. W. in Proceedings of the Second International Symposium on Histamine H2 Receptor Antagonists. Amsterdam, 1977.
M. H., Brooks, C. M., Bosanac, P. R., Kintzel, J. E. Gastroenterology, 1977, 73, 635. 30. Grimson, T. A. Lancet, 1977, i, 858. 31. Delaney, J. C., Ravey, M. ibid. 1977, ii, 512. 32. Robinson, T. J., Mulligan, T. O. ibid. p. 719. 33. Watson, W. C., Kutty, P. K., Colcleugh, R. G. ibid. p. 720. 34. Hall, W. H. New Engl. J. Med. 1976, 295, 841 1. Valsalva, A. M. De Aure Humana Tractatus. 1704. 2. Toynbee, J. Med. Chir. Trans. 1841, 24, 190. 3. Engström, H. Über das Vorkommen der Otosklerose: Thesis Mercators
Ufberg,
Trykeri. Helsingfors, 1940. 4. Guild, S. Ann. Otol. Rhinol. Lar. 1944, 53, 246. 5. Schätzle, W., Haubrich, J. in Spezielle Path. Anatomie, vol. IX (edited by W. Doerr, G. Seifert, and E. Uehlinger). Berlin, 1975. 6. Chevance, L. G., et al. Acta otolar 1970, 272, 1 (suppl.). 7. Chevance, L. G., Causse, J., Jorgensen, M. B., Bretlau, P. Ann. Oto-Lar.,
Paris, 1972, 89, 5, 563. 8. Causse, J., et al. Clin. Otolar. 1977, 2, 23 9. Lim, D. J., Saunders, W. H. Acta otolar. 1975, 80, 255. 10. Lim, D. J., Saunders, W. H. Ann. Otol. Rhinol. Lar. 1977,
86, 525.
hydrocephalus is a misnomer, have raised resting pressure
since patients often with superimposed waves of raised pressure similar to LUNDBERG’S B waves, especially at night. 15 Of seven patients without such waves none improved after shunting whereas all five patients with B waves improved.16 Reduction of cerebral blood-flow and volume, with increase after removal of lumbar c.s.F., has also been reported as an indication for shunting.17 Computerised tomographic (c.T.) scanning has now been added to the investigations.18 This non-invasive technique will show dilated ventricles with normal or small cortical sulci in communicating hydrocephalus, separating it from obstructive
hydrocephalus or hydrocephalus associated with atrophy. Thus it provides a valuable screening test, though it will not indicate which patients will benefit from shunting. Reports on the effect of shunting are difficult to evaluate. Eight patients in one series did not improve19 but, though the investigators record "striking similarity" to the cases described by HAKIM and ADAMS, the case-histories do not bear this out since there is no mention of incontinence. In another series, of 28 patients, two-thirds were said to have improved after shunting, but the dementia was described as "symptoms resembling senility", 20 which is not the syndrome of HAKIM and ADAMS. Other reports have been concerned with hydrocephalus ex vacuo.21, 22 In three series matching more closely the original description, appreciable improvement has been achieved in 25%,23 70%,24 and 23%.8 An important point is that patients with a recognisable cause for their communicating hydrocephalushead injury, meningitis, or subarachnoid hæmorrhage-seem to do better than the idiopathic cases.8, 15 Otherwise no combination of tests has been found to predict reliably who will benefit from shunting.’ At present, the best way to identify patients who may benefit from shunting seems to be, firstly, to pay close attention to the clinical features as originally described and look especially for patients with predisposing factors; secondly, to use c.T. scanning as a screening test; and, finally, to monitor intracranial pressure either directly or via the lumbar route. Patients who show neither raised basic pressure nor pressure waves seem unlikely to benefit from shunting.
Drugs for Duodenal Ulcer IN the management of duodenal ulcer, medical has been a cynic’s delight. Under the eye of science, the "logical" treatments tend to be found wanting. Two symposia at the Royal College of Physicians, in London, and a spate of publications, have extolled the merits of cimetidine and carbenoxolone in duodenal ulcer. There is now ample evidence from good controlled trials that cimetidine will promote the healing of duodenal ulceration, and between two and three times as many ulcers can be expected to heal during a 4-8-week course of cimetidine as with dummy tablets.I-4 Virtually equivalent claims have now been treatment
made
support the use of carbenoxolone sodium in positioned-release capsules (though evigiven dence that the capsules themselves are essential is lacking), and two Australian trials discussed at the carbenoxolone symposium have confirmed results obtained in three others already published.5-9 Whereas we know cimetidine to be a potent antisecretory agent, the mode of action of carbenoxolone is uncertain; it does not seem to alter gastricacid output.10 Though carbenoxolone has some antipeptic activity it seems more likely to act by strengthening mucosal resistance. It reduces gastric-cell loss and promotes the synthesis of gastric mucosal glycoprotein,11,12 but direct evidence of the same action in the duodenum is lacking. One might expect a combination of carbenoxolone and cimetidine to be especially useful; this remains to be tested. Alternative possible treatments are few. Tripotassium dicitratobismuthate has been found in three studies to accelerate ulcer healing,13-15 the mechanism again being obscure. Deglycyrrhizinated liquorice has been tested as a possible sideeffect-free alternative to carbenoxolone, but it neither relieves symptoms 16 nor heals ulcers." Antacid treatment has lately been reassessed in the to
Blackwood, W. S., Maudgal, D. P., Pickard, R. G., Lawrence, D., Northfield, T. C. Lancet, 1976, ii, 174. 2. Bodemar, G., Walan, A. ibid. p. 161. 3. Gillespie, G., Gray, G. R., Smith, I. S., Mackenzie, I., Crean, G. P. in Proceedings of the Second International Symposium on Histamine H2 Receptor Antagonists, Amsterdam, 1977. 1.
4. Multicentre trial. ibid. 5. Davies, W. I., Reed, P. I. Gut, 1977, 18, 78. 6. Archambault, A., North American Symposium
on
Carbenoxolone. Amster-
dam, 1976. 15. Symon, L., Dorsch, N. W. C., Stephens, R. J. Lancet, 1972, ii, 1291. 16. Chawla, J. C., Hulme, A., Cooper, R. J. Neurosurg. 1974, 40, 376. 17. Mathew, N. T., Meyer, J. S., Hartmann, A., Ott, E. O. Archs Neurol. 18.
32, 657. Crockard, H. A., Hanlon, K., Duda, surg Psychiat. 1977, 40, 736.
E.
E., Mullan, J. F., J. Neurol. Neuro-
19 Bannister, C. M. Acta neurochir., Wien. 1972, 27, 11. 20. Shenkin, H. A., Greenberg, J., Bouzarth, W. F., Gutterman, P., J. O. J. Am. med. Ass. 1973, 225, 1486. 21. 22. 23. 24.
1975,
Appenzeller, O., Salmon, J. H. J Neurosurg. 1967, 26, 478. Salmon, J. H., Armitage, J. L. Neurology, 1968, 18, 1223. Salmon, J. H. J. Neurosurg. 1972, 37, 423. Guidetti, B., Gagliardi, F. M. Acta neurochir., Wien. 1972, 27, 1.
Morales,
7. Multicentre trial. Gut. 1977, 8. Nagy, G. S. Unpublished. 9. Young, G. P., St. John, D. J. 10. Barron, J. H. Gut, 1977, 18,
18, 717. B., Coventry, D. A. Unpublished.
721.
11. Domschke, W., Domschke, J., Hagel, J., Demling, L., Croft, D. N. Gut, 1977, 18, 817. 12. Shillingford, J. S., Lindup, W. E., Parke, D. V. Biochem. Soc. Trans. 1974, 2, 1104. 13. Coughlin, G. P., Kupa, A., Alp, M. H. Med. J. Aust. 1977, i, 294. 14. Moshal, M. G. Postgrad. med. J. 1975, 51, suppl. 5, p. 36. 15. Shreeve, D. R. ibid. p. 33. 16. Feldman, H., Gilat, T. Gut, 1971, 12, 449. 17. Larkworthy, W., Holgate, P. F. L., McIllmurray, M. B., Langman, M. J. S. Br. med. J. 1977, ii, 1123.
1013
United States, and heroic doses—a small suitcase would be needed for a month’s treatment—seem to accelerate ulcer healing although, confusingly, symptomatic benefit seems to be lacking.18-20 Finally prostaglandin E2 analogues have been shown in one trial to reduce acid output and to accelerate ulcer healing,21 and a single endoscopically controlled trial suggests that the antidepressant trimipramine promotes ulcer healing.22 Desirable as short-term healing may be, the long-term outcome is what really matters. There is now ample evidence that, when initial treatment with histamine H2 antagonists stops, the ulcer symptoms return—perhaps in a more vicious manner than before.23,24 Maintenance treatment with cimetidine will reduce the relapse-rate during treatment,3 but we do not know whether such benefit is maintained when treatment ceases. Since carbenoxolone, chelated bismuth, and cimetidine may heal ulcers in different ways, relapse-rates may also differ and comparisons are clearly needed. The effectiveness of treatment has to be examined in the context of safety. Hypertension, salt and water retention, and hypokalæmia are wellknown adverse effects of carbenoxolone.25 They are frequent but usually mild. More severe problems arise in the elderly and in people with cardiorespiratory or renal disease—especially if treatment is injudiciously prolonged, with inadequate observation. The adverse effects of other drugs are less clear. Chelated bismuth seems so far to be side-effect free, and in particular no case of bismuth encephalopathy, as recorded with salts such as the subgallate and subnitrate, has yet been described.26,27 Prostaglandin analogues have scarcely been tested, but the 15S-15 and the 15R-15 methyl esters of prostaglandin E2 seem to cause diarrhœa and superficial gastritis.21 The nature and frequency of the adverse effects of cimetidine are more a matter of speculation than of knowledge. Short-term treatment has been found, on the whole, to be safe. Rises in serum creatinine and transaminase concentrations have been common but their meaning is obscure.28 The creatinine changes do not seem to be associated with any disorder of renal function, whilst the transaminase changes have not yet been
associated with severe hepatic necrosis, though two patients had minor abnormalities in liver biopsy specimens. Metiamide, the predecessor to cimetidine, was withdrawn because of bone-marrow toxicity, but so far, despite far greater use, there has been only one case of neutropenia, reversible, during cimetidine treatment. 29 Isolated reports of other possible adverse effects have included mental confusion, muscle twitching, cerebrovascular occlusion, gynaecomastia, and exacerbation of ileus in burned patients.30-34 The evidence that the abnormalities described were indeed due to cimetidine treatment is inadequate, chance associations being entirely possible. But H2 receptors are widely distributed in the body. A safety monitoring programme is clearly needed that identifies not only the bizarre effects which can confidently be ascribed to the drug but also the run-of-the-mill which demand a control population for comparison. It would be good to know that post-marketing surveillance is actually being practised and does not remain a theoretical plaything of clinical pharmacologists.
Otosclerosis OTOSCLEROSIS is’ one of the major unsolved problems of the pathology of the ear. This common cause of conductive deafness was known to VALSALVA;l and TOYNBEE,2 the father of British otology, found an ankylotic stapes in over 10% of the large series of human temporal bones he dissected. ENGSTROM3 and GUILD4 likewise found otosclerotic foci in about a tenth of the temporal bones they examined. In the past two decades research into the causes of this bony dystrophy has been revivified by microsurgical techniques which were devised primarily for treatment. Three main aetiological factors have been established5—genetic and constitutional ; local; and systemic (activating). The genetic disposition is generally recognised, and this concept is supported by cytochemical and electron microscopic observations.6-10 Of the local factors, some 29.
Peterson, W. L., Sturdevant, R. A. L., Frankl, H. D., Richardson, C. T., Isenberg, J. I., Elashoff, J. D., Sones, J. Q., Gross, R. A., McCallum, R. W., Fordtran, J. S. New Engl. J. Med. 1977, 297, 341. 19. Sturdevant, R. A. L., Isenberg, J. I., Secrist, D., Ansfield, J. Gastroentero-
18
logy, 1977, 72, 1. 20 Littman, A., Welch, R. W., Furin, R. C., Aronson, A. R. ibid. 1977, 73, 6. 21. Gibinski, K., Rybicka, J., Mikós, E., Nowak, A. Gut, 1977, 18, 636. 22 Wetterhus, S., Aubert, E., Berg, C. E., Bjerkeset, T., Halvorsen, L., Hovdenak, N., Myren, J., Roland, M., Sigstad, H., Guldahl, M. Scand. J. Gastroent.
1977, 12, suppl. 43, p. 33.
23. Saunders, J. H. B., Wormsley, K. G. Lancet, 1977, i, 765. 24. Wallace, W. A., Orr, C. M. E., Beam, A. R. Br. med. J. 1977, ii, 865. 25 Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Spencer, R., Avery, G. S. Drugs, 1976, 11, 245. 26. Loiseau, P., Henry, P., Jallon, P., Leroux, M. J. neurol. Sci. 1976, 27, 133. 27 Burns, R., Thomas, D. W., Baron, V. J. Br. med. J. 1974, i, 220. 28. Sharpe, P. C., Hawkins, B. W. in Proceedings of the Second International Symposium on Histamine H2 Receptor Antagonists. Amsterdam, 1977.
M. H., Brooks, C. M., Bosanac, P. R., Kintzel, J. E. Gastroenterology, 1977, 73, 635. 30. Grimson, T. A. Lancet, 1977, i, 858. 31. Delaney, J. C., Ravey, M. ibid. 1977, ii, 512. 32. Robinson, T. J., Mulligan, T. O. ibid. p. 719. 33. Watson, W. C., Kutty, P. K., Colcleugh, R. G. ibid. p. 720. 34. Hall, W. H. New Engl. J. Med. 1976, 295, 841 1. Valsalva, A. M. De Aure Humana Tractatus. 1704. 2. Toynbee, J. Med. Chir. Trans. 1841, 24, 190. 3. Engström, H. Über das Vorkommen der Otosklerose: Thesis Mercators
Ufberg,
Trykeri. Helsingfors, 1940. 4. Guild, S. Ann. Otol. Rhinol. Lar. 1944, 53, 246. 5. Schätzle, W., Haubrich, J. in Spezielle Path. Anatomie, vol. IX (edited by W. Doerr, G. Seifert, and E. Uehlinger). Berlin, 1975. 6. Chevance, L. G., et al. Acta otolar 1970, 272, 1 (suppl.). 7. Chevance, L. G., Causse, J., Jorgensen, M. B., Bretlau, P. Ann. Oto-Lar.,
Paris, 1972, 89, 5, 563. 8. Causse, J., et al. Clin. Otolar. 1977, 2, 23 9. Lim, D. J., Saunders, W. H. Acta otolar. 1975, 80, 255. 10. Lim, D. J., Saunders, W. H. Ann. Otol. Rhinol. Lar. 1977,
86, 525.
