tion,7 which explains the association of albinismdue to maldistribution of the granules in melanocytes-the "constipated" engorged giant vacuoles, and defective killing of bacteria due to "ataxic" degranulation.
insulin, 12 and thyroid hormones,13 and in the release of lipoproteins from the liver14—it would be fascinating to know whether pancreatic secretion of insulin and of the digestive enzymes is delayed or incomplete in the Chediak-Higashi syndrome,
functions such as be the reladegranulation appear regulated by tive concentrations of the cyclic nucleotides A.M.P. (inhibitory) and G.M.P. (stimulatory).8These can be manipulated by cholinergic agonists and antagonists, and by the redox state of the cell, which is dependent upon the state of reduction of such compounds as ascorbic acid and glutathione.9 It was therefore exciting, and strong supportive evidence for defective microtubular function, when mediators such as dibutyryl cyclic G.M.P. (which can enter the cell), cholinergic agonists, and ascorbate, were seen to correct the in-vitro abnormalities observed in cells from patients with the Chediak-
and whether antidiabetic drugs that stimulate the secretion of insulin influence microtubular function. Kartagener’s syndromels comprises a number of seemingly unrelated conditions-why should dextrocardia be associated with sinusitis and bronchiectasis ? The answer came with the discovery of defective dynein arms on microtubules in the tails of spermatozoa from an infertile man with immotile spermatozoa and situs inversus. 16 The microtubular structure of cilia is similar to that of the sperm tail, and the function of cilia from the respiratory tract of patients with immotile but otherwise apparently normal spermatozoa was examined and found to be defective, and to be associated with abnormal dynein arms.17 Infection of the respiratory tract in this "immotile-cilia syndrome" is due to inadequate clearance of organisms because of mucociliary dysfunction. The situs inversus that may be associated could be due to failure of the normal control that cilia exert over the positioning of organs.18 In the absence of this control, the sidedness of the organs would become a random affair and situs inversus would be expected to occur in half the patients-the observed proportion. These examples illustrate the progress in the understanding and treatment of disease that can accrue from advances in molecular and cellular biology. The test-tube may soon displace the stethoscope from the physician’s pocket.
Higashi syndrome.7,10 Malakoplakia is a rare inflammatory granuloma characterised by the accumulation of macrophages which have large intracytoplasmic inclusions containing bacteria in various stages of digestion. patients are prone to chronic bacterial infecand tion, monocytes from one of them" demonstrated defective killing of ingested bacteria in association with large intracytoplasmic granules, and poor lysosomal enzyme release after phagocytosis. These factors pointed to defective function of the microtubule system, and it was therefore very gratifying for the investigators of this case when they detected low intracellular levels of cyclic-G.M.P. which, together with all the indicators of aberrant monocyte function, returned to normal after treatment of the patient with the cholinergic agonist bethanechol. 11 This suggests that the expression of the primary pathogenic lesion in malakoplakia is similar to, but less generalised than, that of the Chediak-Higashi syndrome, and results from a reversible dysfunction of the microtubular system. Now that it has been shown that dysfunction of microtubules can result in macrophage defects via poorly coordinated and incomplete degranulation of cytoplasmic granules into the phagocytic vacuole, the examination of this system and its regulation must be extended to other cells which These
have specialised cytoplasmic granules-notably, the endocrine and exocrine glands. The microtubule system may be important in the secretion of
8. Zurier, R. B., Weissmann, G., Hoffstein, S., Kammerman, S., Hsiung Tai, H. J. clin. Invest. 1974, 53, 297. 9. Mittal, C. K., Murad, F. Proc. natn. Acad. Sci., U.S.A. 1977, 74, 4360. 10. Boxer, L. A., Watanabe, A. M., Rister, M. Besch, H. R., Allen, J., Baehner,
R. L. New Engl. J. Med. 1976, 295, 1041. 11. Abdou, N. I., NaPombejara, C., Sagawa, A., Ragland, C., Stechschulte, D. J., Nilsson, U., Gourley, W., Watanabe, I., Lindsey, N. J., Allen, M. S. ibid. 1977, 297, 1413. 12. Lacy, P. E., Howell, S. L., Young, D. A., Fink, C. J. Nature, 1968, 219, 1177.
Williams, J. A., Wolff, J. Proc. natn. Acad. Sci., U.S.A. 1970, 67, 1901.
Peace at the Last? IT is more than forty years since Lord HORDEE observed that dying in pain and being killed do not exhaust the possibilities available to the dying patient. Yet these two options often seem the only two open to many patients dying of cancer. PARKES compared hospital-centred and home-centred terminal care by means of post-bereavement visits to the surviving spouse, and found that about 20% of the hospital patients died with their severe and mostly continuous pain unrelieved.2 A similar percentage experienced pain of comparable intensity
14. Stein, O., Sanger, L., Stein, Y. J. cell. Biol. 1974, 62, 90. 15. Kartagener, M. Beitr. Klin. Tuberk. 1933, 83, 489. 16. Pedersen, H., Rebbe, H. Biol. Reprod. 1975, 12, 541. 17. Eliasson, R., Mossberg, B., Camner, P., Afzelius, B. A. New
1977, 297, 1. 18. Afzelius, B. A. Science, 1976, 193, 317. 1. Horder, Lord. Speech in the House of Lords, December, 2. Parkes, C. M. JlR. Coll. gen. Practnrs, 1978, 28, 19.
Engl. J. Med.
before admission, which suggests that admission to hospital did not lead to improved relief. Of those who died at home, 10% had severe pain preterminally, but terminally the proportion rose to almost half. In contrast, after admission to St. Christopher’s Hospice-a unit specialising in symptom control in far-advanced cancer-the percentage of patients with severe pain fell from 36 to 8. In the home-based patients, the main reason for poor pain control seemed to be failure of the general practitioner to ensure that regular doses of an appropriate analgesic, were given in sufficient quantity to alleviate the pain. One man of 54 became totally demoralised and for several months spent much of the time crying. He was so frightened that he clung to his wife and became "hysterical" whenever she left the room. He received an injection each week and was not able to go into hospital as there was no bed available. Similar accounts given by other respondents suggested that neurotic exaggeration was not the explanation. Several patients put up with their pain without on the supposition that nothing could be done to relieve it or that their chances of recovery would be enhanced if they abstained from powerful
light of his suffering. A patient can be in pain without looking obviously distressed. Analgesics should be given regularly, usually
has made severe
every four hours.3 The aim is to titrate the dose of the analgesic against the patient’s pain, gradually increasing the dose until the patient is pain-free. The next dose is given before the effect of the previous one has fully worn off-and therefore before the patient may think it necessary. In this way it is possible to erase the memory and fear of pain. If a drug ceases to be effective the patient should be given a stronger one. "Maximum" or "recom-
mended" doses, derived
postoperative parenteral single-dose studies, are not applicable to the treatment of cancer pain. The effective dose of oral morphine ranges from as little as 5 mg to more than 100 mg every four hours.4Pain unrelieved by less potent analgesics, not short life expectancy, is the primary criterion for the use of morphine or diamorphine. Tolerance is not a practical problem when these drugs are correctly used as part of a comprehensive programme of patient care.s Moreover, unrelieved pain, by disturbing rest and upsetting nutrition, will tend to worsen the patient’s condition and lead to an earlier death. There is more to analgesia than analgesics; many patients derive greatest benefit from a combination of treat-
Radiotherapy gives partial or even complete relief in 90% of patients with bone pain, and generally may be administered in a single, non-fractionated dose.6 TwYCROSS has lately re-emphasised the importance of aspirin in the relief of bone pain.4Many osseous metastases produce or induce the production of a prostaglandin, probably E2, which causes osteolysis’ and also lowers the "peripheral pain threshold" by sensitising free nerveendings.8 Aspirin and related drugs inhibit the synthesis of prostaglandins and by so doing alleviate pain. An intrathecal phenol nerve-block may be necessary when pain is caused by invasion of the brachial plexus or sciatic nerve. Headache due to ments.
The medical profession has far to go before it. can confidently assure patients that severe pain in advanced cancer can be controlled. Reasons for inadequate relief are many; a more fundamental one than incorrect use or under-use of analgesics is doctors’ tendency to lose their systematic approach and their objectivity when confronted with a dying patient. Instead of carefully analysing the cause(s) of the patient’s pain(s), they dispense a standard prescription of some favourite preparation; or they may under-rate the intensity of a patient’s discomfort and do nothing. A diagnosis of cancer does not mean that the malignant process is necessarily the cause of the pain. As in other areas of medicine,
Bedsores, precede diagnosis ought constipation, peptic ulcer, cystitis, or musculoskeleto
tal disorders may prove to be the
cause and are all conditions that benefit from specific treatment. When the cancer is responsible, the underlying mechanism(s) must be given thought; descriptions of pain as "like raving toothache" and "stabbing, especially when I move" would point to nerve compression and influence the course of treatment should analgesics alone fail to relieve. Intensity of pain is assessed not only by the patient’s description but also by discovering which drugs have failed to relieve, whether sleep is disturbed, and in what way activity is limited ("How long is it since you went out?", "What are you doing around the house?"). In addition, the patient’s spouse should be interviewed; usually one finds that the patient
raised intracranial pressure is best treated with a glucocorticosteroid as well as an analgesic. Attention must also be paid to factors that modulate pain threshold such as anxiety and depression. Most patients fear the process of dying-"Will it hurt?", "Will I suffocate?"-and many fear death itself. These fears tend to remain unspoken unless the patient is given an opportunity to express them. The doctor needs to give time and opportunity for the patient to talk about his pro-
3. Vere, D. W. in Topics in Therapeutics 4 (edited by D. W. Vere). Tunbridge Wells (in the press) 4. Twycross, R. G. ibid. 5. Twycross, R. G., Wald, S. J. in Advances in Pain Research and Therapy I (edited by J. J. Bonica and D. Albe-Fessard); p. 653. New York, 1976. 6. Penn, C. R. H. Clin. Radiol. 1976, 27, 405. 7. Lancet, 1976, ii, 1063. 8. Ferreira, S. H. Nature New Biol. 1972, 240, 200.
700 or lack of it. The doctor must be determined succeed and be prepared to spend much time assessing and reassessing the patient’s pain and other distressing symptoms. Indecision breeds inaction-as exemplified by the case of a man of 90, admitted to a London teaching hospital with bone pain, who died still in pain three months later.9 With cancer one is dealing with a progressive pathological process. This means that new pains may develop or old pains re-emerge. A fresh complaint of pain does not merely call for an increase in a previously satisfactory analgesic regimen; it demands reassessment, explanation to the patient, and, only then, modification of drug therapy or other intervention.
ŒSOPHAGEAL TROUBLES AFTER REPAIRS IN INFANCY
primary results of surgery for oesophageal atreimprove, long-term problems become increasingly important. Among the most troublesome are dysphagia, choking, and cyanotic attacks during swallowing, and recurrent chest infection. Probably the commonest cause of dysphagia is narrowing of the anastomosis: in 30-50% of these babies strictures develop which are severe enough to need dilatation. 10,11 When, after an apparently successful repair, a baby has attacks of choking and cyanosis associated with feeds, recurrent chest infection, and persistent abdominal distension, a second tracheo-oesophageal fistula or recurrence of the original As the
fistula must be considered. The fistula recurs in 5-15% of cases; and a second fistula is present in between 1% and 8%.12 Severe cyanotic and apnœic attacks are seen, often during feeding, due to compression of the trachea with tracheomalacia or due to pressure either from a dilated upper oesophagus above a stricture or from an aberrant subclavian artery of a vascular ring.13,14 Rarer causes are congenital or acquired abnormalities of the larynx- e.g., laryngeal clefts or subglottic stenosis. The dramatic nature of these troubles and the generally good progress of babies after corrective surgery have tended to divert attention from the abnormalities of These include incoordination between the upper and lower oesophageal segments, spasm in the oesophagus just distal to the anastomosis, and relative inertia of the lower
cesophageal peristalsis nearly always present.15-20
9. Hunt, J. M., Stollar, T. D., Littlejohns, D. W., Twycross, R. G., Vere, D. W. J. med. Ethics. 1977, 3, 61. 10. Daum, R. Progr. pediat. Surg. 1970, 1, 209. 11 Holder, T. M., Cloud, D. T., Lewis, J. E., Pilling, G. P. Pediatrics, 1964,
34, 542. 12. 13. 14. 15.
Hays, D. M., Wooley, M. M., Snyder, W. H. J. pediat. Surg. 1966, 1, 240. Filler, R. M., Rossello, P. J., Lebowitz, R. L. ibid. 1976, 11, 739. Benjamin, B., Cohen, D., Glasson, M. Surgery, 1976, 79, 504. Desjardins, J. G., Stephens, C. A., Moes, C. A. F. Ann. Surg. 1964, 160,
16 17. 18.
Chrispin, A. R., et al. Thorax, 1966, 26, 104. Shepard, R., Fenn, S., Sieber, W. K. Surgery, 1966, 59, 608. Lind, J. F., Blanchard, R. J., Guyda, H. Surgery Gynec. Obstet. 1966, 123,
Burgess, J. N., Carlson, H. C., Ellis, F. H. J. thorac. 56, 667. Moroz, S. P., et al. Gastroenterology, 1976, 71, 236.
oesophagus. Of the oesophageal sphincters, the upper is usually normal but the lower may show anything from increased tone with cardiospasm, through normality, to laxity with free gastro-oesophageal reflux. Many babies also have reflux due to hiatus hernia, because the intraabdominal oesophagus was shortened during aesophageal repair,. The reflux then tends to cause œsophagitis— with stricture formation. Two manometric studies have produced useful information on these matters. Duranceau et al. 21 studied the motility of the oesophagus in ten patients 10-27 years after the repair, and Whittington et al.22 (reviewing the aetiology of recurrent pneumonia) studied oesophageal pressures in eight patients 11 weeks to 20 years after the primary operation. Both groups confirm that severe abnormalities of function may persist in an endoscopically adequate oesophagus, causing inability to swallow solids or lumps. The explanation for these dysfunctions is obscure. Abnormalities are seen even in children who have simple division of a fistula without atresia, which suggests that there must be an inherent defect of neuromuscular coordination. A picture very similar to the relative atony of the oesophagus distal to the fistula can be produced by local division of vagal fibres.23,24 This suggests that surgical damage to the vagus and its oesophageal branches is an important factor, but there must be an additional underlying defect because similar abnormalities are seen after the Duhamel operation, in which the lower oesophagus is hardly disturbed at all. Management of disordered motility is not satisfactory. The diet has to be kept fluid or soft without lumps. Oesophageal emptying improves and gastro-oesophageal reflux is reduced when the child is erect, so infants often have to be nursed in a hiatus-hernia box. Drugs are of limited value but Duranceau12 successfully increased lower-sphincter tone and corrected reflux with bethanecol. Metoclopromide may help by promoting gastric emptying. Fortunately, despite persistence of the manometric abnormality, most children learn to swallow adequately and become symptom-free.
INDICATIONS FOR ADENOTONSILLECTOMY
ADENOTONSILLECTOMY is one of the commonest operations done in the United Kingdom, and one of the most controversial. The main method of deciding whether the operation is necessary is to take a history from the mother. For tonsillectomy the usual indication is a story of four or more episodes of sore throat and pyrexia each year which are thought typical of tonsillitis. But as Paradise and others’ point out, this practice depends on two untested assumptions-that such a history will accurately predict the frequency and severity of throat infections in the future, and that when the history of throat infection seems excessive the efficacy of tonsillectomy outweighs the cost and risks. They saw 65 children
21. Duranceau, A., et al. Surgery, 1977, 82, 116. 22. Whittington, P. F., et al. J. Pediat. 1977, 91, 550. 23. Carveth, S. W., et al. Surgery, Gynec. Obstet. 1962, 114, 31. 24. Haller, J. A., et al. Ann. thorac. Surg. 1966, 2, 180. 1. Paradise, J. L., et al. New Engl. J. Med. 1978, 298, 409. 2. Hibbert, J. Clin. Otolar. 1977, 2, 239. 3. Hibbert, J., Tweedie, M. C. K. ibid. p. 297.