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longer-term treatment with calcium and vitamin D are beginning to appear. While one investigation suggests a barely significant benefit26 another shows none. 10

Oestrogen deficiency has long been implicated in postmenopausal osteoporosis,13 and two long-term studies of oestrogen therapy have somewhat strengthened the indications for its use. In one follow-up of postmenopausal women, absorption densitometry, and measurements of cortical thickness in the radius revealed a significantly slower rate of bone mineral loss in those who for various reasons had been treated with restrogens.27 Nevertheless, in untreated women who had sustained "osteoporotic fractures", bone loss had been no more rapid than in non-osteoporotic subjects. In another study, metacarpal cortex thinned more slowly in restrogen-treated women, although overlap with controls was considerable.26 Raised urine calcium and total hydroxyproline excretion may fall during longterm oestrogen treatment to within the control range.28 Bone-resorbing surfaces within the iliac crest may decrease during oestrogen therapy, but this effect becomes less obvious with time.29 While oestrogen therapy has long been known to decrease urine calcium excretion, its effect on the negative calcium balance of acute osteoporosis is not consistent.15 Some postmenopausal women lose bone negligibly with age, yet all ultimately lose ovarian function. Relative oestrogen deficiency, of either ovarian or adrenal origin, or perhaps some form of "increased requirement", may thus be contributary causes. In the absence of methods for determining oestrogen requirement, cyclical oestrogen therapy for osteoporosis in females past the menopause can be justified-at least in those with no history of carcinoma-unless subsequent side-effects give distress. At present there is no evidence of its value at other ages or in males. The role of parathyroid hormone in osteoporosis is controversial. Huge increases in circulating levels of immunoreactive parathyroid hormone have been reported among the very elderly, 30 without clinical evidence of hyperparathyroidism. Multiple correlation - coefficients with other data relating to diminished renal function were cited in support of a causal role of secondary hyperparathyroidism in "senile" osteoporosis. These data conflict with studies in a less elderly population showing either no increase or a decrease in parathyroid hormone (depending on the antiserum used in the assay) nor 26. Nordin, B. E. C., Horsman, A., Gallagher, J. C. in Calcium Metabolism, Bone and Metabolic Bone Diseases (edited by F. Kuhlencordt and H-P. Kruse); p. 233. Berlin, 1975. 27. Meema, S., Bunker, M. L., Meema, H. E. Archs intern. Med. 1975, 135, 1436. 28. Gallagher, J. C., Aaron, J., Horsman, A., Marshall, D. H., Wilkinson, R., Nordin, B. E. C. Clins Endocr. Metab. 1973, 2, 293. 29. Riggs, B. L., Jowsey, J., Goldsmith, R. S., Kelly, P. J., Hoffman, D. L., Arnaud, C. D. J. clin. Invest. 1972, 51, 1659. 30. Berlyne, G. M., Ben-Ari, J., Kushelevsky, A., Idelman, A., Galinsky, D., Hirrsch, M., Shainkin, R., Yagil, R., Ziotnik, M. Q. Jl Med. 1975, 44, 505.

any correlation between hormone levels and histological criteria of bone resorption.31Interestingly, a significant correlation between parathyroid hormone and bone resorption may arise during calcitonin therapy,32 presumably owing to secondary hyperparathyroidism. Even more conflicting is recent

evidence that

treatment

of osteoporosis with

human 1-34 parathyroid hormone in low dosage may actuallly increase net bone formation.33 The dose-dependency of this effect was emphasised. These findings are consistent with the osteosclerosis

which can be produced experimentally by treatment with parathyroid hormone in low dosage .34 35 Parathyroid-hormone secretion in osteoporosis may thus affect both bone resorption and bone formation, and the possible modification of either effect by oestrogen deficiency with ageing needs clarification. Despite these uncertainties the clinician has clear guidelines in management; after diagnosis based on bone histology, we can reassure the patient that spontaneous recovery is likely: early careful remobilisation is then started, with spinal exercises to strengthen muscle (and perhaps bone) and encouragement to take suitable exercise. lmmobilisation by spinal braces should be avoided if possible. An "optimal" calcium and vitamin D intake is sensible, with supplementation if dietary measures are unsuccessful. Osteoporosis will arise after a daily loss of 50 mg calcium from the skeleton over 20 years, a negative balance too small for measurement by present techniques. Further understanding of the disease should come from prospective epidemiological studies and clinical investigation of its acute phase at all ages.

Treatment of Acute Cholecystitis IN patients fit enough for operation, early planned biliary surgery, including operative chowithin the first week of hospital admission is probably the best management of acute cholecystitis. 16-4Advantages over the traditional conservative management, with elective cholecystectomy 6-12 weeks later, are early diagnosis and treatment of the inflamed gallbladders which may otherwise perforate,41-43 definitive diagnosis

langiography,

31.

Riggs, B. L., Arnaud, C. D., Jowsey, J., Goldsmith, R. S., Kelly, P. J. J. clin Invest. 1973, 52, 181. 32. Jowsey, J., Riggs, B. L., Goldsmith, R. S., Kelly, P. J., Arnaud, C. D. J. clin Endocr. Metab. 1971, 33, 752. 33. Reeve, J., Parsons, J. A., Tregear, G. W., Darby, A. J., Hesp, R., Hulme, P., Klenerman, L., Williams, D., Potts, J. T. Clin. Sci. mol. Med. (in the press). 34. Kalu, D. N., Pennock, J., Doyle, F. H., Foster, G. V. Lancet, 1970, i, 1363 35. Walker, D. G. Endocrinology, 1971, 89, 1389. 36. Payne, R. A. Br. J. Surg. 1969, 56, 200. 37. Wenckert, A., Hallgren, T. Acta chir. scand. 1969, 135, 701. 38. van der Linden, W., Sunzel, H. Am. J. Surg. 1970, 120, 7. 39. Ferris, D. O., Sterling, W. A. Surg. Clins N. Am. 1967, 47, 861. 40. Raine, P. A. M., Gunn, A. A. Br. J. Surg. 1975, 62, 697. 41. Gagic, N., Frey, C. F., Gaines, R. Surgery Gynec. Obstet. 1975, 140, 868.

183

and therapy in a single hospital admission, and less time in hospital with earlier return to full activity. The few controlled investigations which have been done indicate that the two approaches to management carry much the same mortality and morbidity. 38 44 Several recommendations stand out in re-

ports advocating early surgical intervention:38-41 44 emergency middle-of-the-night procedures are rarely necessary, indeed they are deprecated because extended observation and biliary radiological investigation over a number of days reduce the chance of a wrong diagnosis;"’ 19 the procedure should be done by an experienced surgeon, after fluid replacement and cardiorespiratory and renal assessment;38-40 operative cholangiography should be a routine; and operation in the first week of illness is less difficult than later (though GAGic and his colleagues4° reported no particular difficulty between five and twelve days after onset of symptoms). In the patient who is desperately ill cholecystostomy has an important place, though this technique may not effectively decompress the common bileduct and may thus allow hazardous cholangitis to continue.40 Acute pancreatitis in association with suspected or known biliary disease is usually a contraindication to early cholecystectomy; but the combination of cholangitis and pancreatitis (a common one in South-East Asia, where worm infestation, and not stone, is often the aetiology4s) may do best with early operation. Though antibiotics are advised before early surgery40 41 44 4’7 48 postoperative infection still causes much morbidity and mortality.38 40 41Two-thirds of CHETLIN and ELLIOTT’Spatients had a positive bile culture;46 and wound infection,38 subphrenic abscess,36 40 bacteraemic shock, and biliary peritonitis seem to be more common than in elective biliary surgery.40 The choice of antibiotic is not easy. Prophylactic cephaloridine4’ and gentamicin 48 have been assessed in double-blind trials. Both reduced septic complications but in neither trial did a large number of patients have early cholecystectomy for acute cholecystitis. The Liverpool doubleblind trial44 is only at a preliminary stage: ampicillin is being used-surprisingly since few organisms isolated from the biliary system are now susceptible to this antibiotic (or to tetracycline). 47 48 No single antibiotic will provide complete prophylaxis. Bacteroids, Streptococcus fæcalis, and Clostridium welchii are occasionally found in bile cultures and even cephaloridine/gentamicin would not counter all these.47 48 Doubts over the value of antibiotic may justify a double-blind trial. It would be necessary to exclude patients with cholangitis-by 42 Du Plessis, D. J., Jersky, J. Surg. Clins. N. Am. 1973, 53, 1071. 43 Strohl, E. L., et al. Int. Abst. Surg. 1962, 114, 1. 44 McArthur, P., et al. Br. J. Surg. 1975, 62, 850. 45 Ong, G B., Adiseshiah, M., Leong, C. H. ibid. 1971, 58, 891. 46 Chetlin, S. H., Elliott, D. W. Archs. Surg. 1971, 102, 303. 47 Chetlin, S. H., Elliott, D. W. ibid. 1973, 107, 319. 48 Keighley, M. R. B., et al. Br. J. Surg. 1975, 62, 275. 49 Maddocks, A. C., et al. Ann. R. Coll. Surg. 1973, 52, 316.

of an immediate gram film and subsequent culture of the common-bileduct bile-since in cholangitis antibiotics are indicated 41 46 47 48 means

INTRAUTERINE MOULDING

of the relationship between mechanical factors in the intrauterine environment and congenital postural deformities such as talipes, scoliosis, and hip dislocation has been debated since Hippocrates. Despite the persistent advocacy of Browne,’ Chapple,2 Torpin,3 and others who have espoused the mechanical hypothesis, the concept received little solid support from medical scientists. Streeter,4 the leader of the opposition, held firmly to the opinion that a localised failure in germ plasm and not the presence of amniotic bands was responsible for ring constrictions, missing digits, and amputated extremities--other malformations included by the proposers of the mechanical hypothesis in their catalogue of anomalies induced by factors affecting the intrauterine environment. But application of scientific analytical methods to the classification of neonatal defects has now turned the scales again, with substantial evidence that mechanical factors arising from variations in the size and shape of the gravid uterus can mould the rapidly growing fetus into distinct patterns of deformation. Dunn,’ in an epidemiological perinatal study involving a large series of infants, has displayed a highly significant association between the main groups of postural deformaties, and further support for a mechanical cause comes with the demonstration that about a third of affected infants had two or more deforuties. A high proportion of the deformed neonates in this Birmingham Maternity Hospital study were small-for-dates babies; 14% had fetal distress during labour and 12% showed signs of malnourishment and wasting at birth. These observations suggest that there was in operation, over a considerable period of fetal life, some mechanism affecting utero-placental circulation or placental functionconditions which in turn may have produced the oligohydramnios that was commonly observed at the birth of these deformed neonates. Since many of the conditions which produce placental insufficiency have been associated with oligohydramnios, it would not be surprising, in pregnancies complicated by maternal hypertension or pre-eclampsia, to find at THE

nature

degree of oligohydramnios together with signs of prenatal deprivation. (Oligohydramnios may, in such circumstances, be self-perpetuating, for infants of low birth-weight pass less urine than normal infants6 and

term a

the volume of amniotic fluid could remain too low to permit normal fetal movements.) In animals oligohydramnios induced by amnion puncture at critical stages of fetal development consistently causes postural moulding defects of the palate, jaws, and limbs.7 The close similarities between such induced deformities and those associated with oligohydramnios in man provides 1. Browne, D. Ad. Teratol. 1967, 2, 1. 2. Chapple, C. C. Birth Def. orig. Art. Ser. 1972, 8, 6. 3. Torpin, R. Am. J. Obstet. Gynec. 1965, 91, 65. 4. Streeter, G. L. Contrib. Embryol. 1930, 22, 1. 5. Dunn, P. M. Br. med. Bull. 1976, 23, 71. This latest British Medical Bulletin (published by the Medical Department, The British Council, 65 Davies Street, London W1Y 2AA) is devoted to Human Malformations. Price in U.K. £3; elsewhere £3·50. 6. Wladimiroff, J. W., Campbell, S. Lancet, 1974, i, 151. 7. Poswillo, D. Ann. R. Coll. Surg. Engl. 1968, 43, 61.

Editorial: Treatment of acute cholecystitis.

182 longer-term treatment with calcium and vitamin D are beginning to appear. While one investigation suggests a barely significant benefit26 another...
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