HÆMORRHAGE AND LOW-DOSE HEPARIN

1236 will fall into the commercial category. However, 2 303 000 commercial experiments in 1976 that

example, there

were

diagnostic, cancer research, or mandatory drug testing. Exactly what this enormous figure consists of we do not were not

yet know, but it will include the miserable deaths of hundreds of animals in the testing of new cosmetics, toiletries, non-nutritive food additives, and other inessential consumer products. Professor Shuster is also mistaken if he believes that the reformer’s creed "rests on no absolute moral standards". The idea that all sentients have rights is rapidly gaining ground in philosophical and theological circles and should make sense to scientists.. If we accept the darwinian idea of biological kinship then what is the logical reason why there should not be moral kinship? On what grounds, other than sentimentality, do we discriminate so unfairly against other species? Warneford

Hospital, Headington, Oxford OX3 7JX

RICHARD D. RYDER

relieved or cured with bone-marrow, syngeneic or H-2 compatible. Further experiences indicate that the degree of clearance of juvenile scaffolding bone is related to the cell dose given. Even clones of syngeneic cells may not expand sufficiently to produce ultimate cure and H-2 compatible but allogeneic cells are usually rejected in time. The radiographs of the case of Ballet et al., not ideally reproduced on Lancet paper, are reminiscent of pictures we see in mice4where, after initial resolution, relapse is occurring. The data given (594 mg/day calcium accretion, 594 mg/day positive calcium balance) also suggest that bone resorption must be low at this time. We, therefore, question the statement about the cells transplanted: "their persistence can be anticipated according to the observation made in the Op/Op rat", and it remains to be seen whether the rat or the mouse is the better model for man. Work on both should proceed. Charles Salt Research Centre, Robert Jones and Agnes Hunt

Orthopædic Hospital, Oswestry, Shropshire SY10 7AG M.R.C. Radiobiology Unit,

REFERRING URGENT PSYCHIATRIC PROBLEMS your caption Mental Health for the report by Dr Bowman and Dr Sturgeon upon urgent psychiatric cases (Nov. 19, p. 1067). Whose health? The report reveals much more than it states. Bowman and Sturgeon examine cases perceived as urgent by the referring agencies in one setting and assessed by themselves in another, and note disagreements. They conclude that referring agents "find assessment difficult" and that students in their clinic "will learn to cope better". The narrow sympathy astounds, excused I hope by as narrow experience. Long ago house-physicians understood that asthma often got better in the ambulance. House-surgeons know that some acute abdominal pain settles under observation. Referral is sometimes therapeutic. To be exposed as a specialist in one discipline to the problems of another is the experience of psychiatrists too; I wonder how Bowman and

SIR,-I

was

dismayed by

Sturgeon perform then. To be exposed without relief in the community to the extraordinary pressures of agitated, demanding, sometimes manipulative, disturbed people surrounded by neighbours, relatives, and even social services is hard indeed. There are psychiatrists willing to provide asylum as well as diagnose cases-an exclusive range of diagnoses too-without leaping to the conclusion that ignorance and inability to cope amount to

two-thirds of my troubles.

Medical Centre,

Shipston-on-Stour, Warwickshire CV36

GUY HARRIS

4BQ

BONE-MARROW TRANSPLANTATION IN OSTEOPETROSIS

SIR,-We welcome the report by Dr Ballet and his colleagues (Nov. 26, p. 1137) of the results of treatment of congenital osteopetrosis with bone-marrow of a sibling. The rationale was

based

op/op atrophy’

these workers’ experience with the osteopetrotic This genotype is said to be associated with thymic as well as osteopetrosis, and this may facilitate accepon

rat.

of a graft. Our preliminary experiencez.3 with osteopetrotic mt1mi mice (in which osteopetrosis is associated with microphthalmia and other phenotypic features) was that the osteopetrosis was tance

2.

Milhaud, G., Labat, M.-L., Parant, M., Damais, C., Chedid, L. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 339. Barnes, D. W. H., Loutit, J. F., Sansom, J. M. Proc. R. Soc. B. 1975, 188,

3.

Loutit, J. F., Sansom, J. M. Calcif. Tiss. Res. 1976, 20, 251.

1.

501.

Harwell, Didcot, Oxon OX 11 0RD

N. W. NISBET J. MENAGE

J. F. LOUTIT

HÆMORRHAGE AND LOW-DOSE HEPARIN

SIR,-Icannot understand the concern expressed by Mr Britton and his colleagues (Sept. 17, p. 604) about the safety of low-dose heparin prophylaxis in the prevention of postoperative fatal pulmonary embolism. 3 (0.3%) out of their 1000 patients receiving heparin had life-threatening postoperative bleeding. This has nothing to do with the administration of heparin because it represents the expected frequency of this complication after elective and emergency major abdominal surgery. In the multicentre trial’ 5 out of 2076 controls died from postoperative haemorrhage. Dr Sharnoffs comments (Nov. 19, p. 1087) are equally disappointing. He maintains that 5000 units of heparin administered 2 h before surgery is likely to produce "hypocoagulation" and serious haemorrhage because heparin is given too close to the time of surgery; when 10 000 units of heparin has been administered 8-10 h preoperatively no serious haemorrhage has occurred during surgery. However, no significant difference in plasma-heparin concentraton has been observed when the samples were withdrawn 8 h after administration of 10 000 units of heparin compared with the samples obtained 2 h after injection of 5000 units.2 Furthermore, no evidence has ever been presented in randomised prospective studies that monitoring the dose of heparin to be administered during the postoperative period will reduce the frequency of bleeding complications. Yet Sharnoff considers this to be the most crucial part of low-dose heparin prophylaxis. The evidence that low-dose heparin prophylaxis prevents death from pulmonary embolism is convincing. In the international multicentre trial,’ 2 out of 2045 heparin-treated patients died from massive pulmonary embolism compared with 16 out of 2076 controls. These findings are further supported by the data presented by Britton et at, since only 1 out of 1000 patients receiving heparin prophylaxis died from massive pulmonary embolism. The most persuasive evidence for the efficacy of low-dose heparin is presented in the review by Matt and Gruber;3 42 (0-8%) out of 3943 control patients had fatal postoperative pulmonarv tnbolism compared with 8 (0.2%) out of 3919 heparin-treated patients (P<0001). There is a slight risk of postoperative bleeding when lowdose heparin prophylaxis is used. In the multicentre trial the difference between the frequency of wound hxmatoma was higher in the heparin group than in the control group 4. Nisbet, N. W.

Menage, J., Loutit, J. F. Nature, (in the press).

1. International Multicentre Trial, Lancet, 1975, ii, 45. 2. Pitney, W. R., Dean, S. Aust. N.Z. Jl Med. 1976, 6, 454. 3. Matt, von E. M., Gruber, U. F. Fortschr. Dev. Med. 1977, 95,

669.

1237

(r<001). The main question is whether the benefit/risk ratio favours low-dose heparin. Published evidence and clinical experience clearly show that the risk is worth while. I hope that the Oxford group will reconsider their position and will continue to allow their patients to have the benefit of a wellproven method of prophylaxis, the value of which is confirmed hv their own data. Thrombosis Research Unit, King’s College Hospital Medical School, London SE5 8RX. V. V. KAKKAR JEJUNAL BIOPSY IN COW’S MILK PROTEIN INTOLERANCE

J. A. WALKER-SMITH

CHRONIC CONSTIPATION IN CHILDHOOD

SIR,-Your editorial (Nov. 19, p. 1064) was a clear and concise review of the problem of constipation. However, the reference to the histochemical diagnosis of Hirschsprung’s disease needs qualification. We agree that an increase in acetylcholinesterase-positive nerves is seen in most rectal-biopsy specimens from aganglionic bowel, but this is not always the case. For example, in 19 cases of Hirschsprung’s disease we found 3 with normal or less than normal acetylcholinesterase-positive nerves in the distal rectal wall,’ and Martinez et al. have reported similar observations in 5 out of 60 cases. Indeed, studies at King’s College Hospital have revealed a wide variation in both acetylcholinesterase activity and catecholamine fluorescence (adrenergic nerves) in these patients. The physiological control of the hind-gut is very complex. Animal experiments have shown the presence of motor pathways involving both adrenergic and cholinergic mechanisms and of inhibitory pathways involving both adrenergic and nonadrenergic non-cholinergic types.3,4 It is probable, therefore, that functional abnormalities in the hind-gut may result from a variety of subtle neurophysiological disorders, even when ganglia are present. King’s College Hospital, London SE5

E. R. HOWARD J. R. GARRETT

E.C.G. ABNORMALITIES IN STEROID-TREATED RHEUMATOID PATIENTS

SIR,-Dr Ichikawa and colleagues (Oct. 15, p. 828) reported an increased frequency of electrocardiographic (E.c.c.) abnormalities in steroid-treated rheumatoid patients. We have examined the routine preoperative E.c.G.s on 64 patients with seropositive rheumatoid arthritis admitted for orthopxdic surgery. We excluded patients with cutaneous vasculitis, rheumatoid lung disease, or clinical or serological features suggesting overlap with systemic lupus. Thirty-one patients were receiving steroids with a mean daily maintenance dose of prednisolone 7 mg (range 3—12-3) and mean Westergren erythrocyte-sedimentation rate (E.S.R.) of 44 mm in lst h (range 11-135) and were clinically comparable with the 33patients in the non-steroid-treated group with a mean E.s.R. of 50 mm in lst h (range 7-130). The E.c.G. abnormalities found were:

1. Garrett, J. R., Howard, E. R., Nixon, H. H. Archs Dis. Childh. 1969, 44, 406. 2 Martinez-Almoyna, C., Claver, M., Monereo, J., Contreras, F. Ann. Chir.

Shmerling, D. H. Acta pœdiat. scand. 1968, 58, 311.

Meeuwisse, G. W. ibid. 1970, 59, 461. 3. Walker-Smith, J. A. Archs Dis. Childh. 1975, 50, 347. 4. Goldman, A. A., Anderson, D. W., Sellars, W. A., W. T., Halpern, S. R. Pediatrics, 1963, 32, 425.

of Child Health, St Bartholomew’s Hospital, London EC1

Department

SIR,-Dr Sumithran and Dr Iyngkaran (Nov. 26, p. 1122) have made an interesting and important study of cow’s milk protein intolerance (c.M.p.l.) in infancy, but their conclusion that small-intestinal biopsy is not really necessary in making the diagnosis is very questionable. They have clearly established, by serial biopsy, the presence of a cow’s milk sensitive enteropathy in 30 of 39 infants clinically challenged with milk. Yet because 8 subsequently, despite this, had no clinical relapse they conclude that biopsy is not necessary. As they point out, the extent of mucosal damage probably determines whether or not symptoms develop. In the gluten-sensitive enteropathy of coeliac disease children who have been on a gluten-free diet often do not have a return of symptoms after a gluten challenge despite histological relapse on biopsy.’ Nevertheless there is general agreement that such histological relapse permits a firm diagnosis of coetiac disease and that it anticipates eventual, sometimes delayed, clinical relapse.2 Unlike coeliac disease c.M.p.L is a temporary enteropathy and disappears by the age of two years. Not surprisingly, therefore, some cases, despite histological relapse, do not relapse clinically but just get better. I agree that routine post-challenge biopsy in the absence of symptoms is unnecessary. I do a post-challenge biopsy only if symptoms appear.3 Sumithran and Iyngkaran found that those who reacted strongly and within 48 h had severe mucosal damage. They seem then to recommend that c.M.p.l. be diagnosed on the basis of a single clinical challenge. They are incorrect when they assert that those who react vigorously meet Goldman’s criteria.4 He demanded three positive milk challenges with similar onset, duration, and clinical features. Sumithran and Iyngkaran’s data do not meet Goldman’s criteria, but their children certainly had C.M.P.I. Until serial small-intestinal biopsy was introduced into the diagnosis of C.M.P.I. there were many who were sceptical of the very existence of the syndrome. We have found that an apparent clinical relapse after a milk challenge is a less than sufficient reason to diagnose c.M.p.l. A child may have such symptoms from intercurrent illness (e.g., infection), and in these circumstances the demonstration of a normal mucosa on biopsy has enabled us to advise with confidence continuation of a milk-containing diet, thus avoiding unecessary dietary restriction. By virtue of the syndrome’s transience biopsy may not be necessary in every child suspected of having C.M.P.I. Nevertheless when a child is already on a milk-free diet a single milk challenge combined with serial small-intestinal biopsy as indicated is a rapid and accurate way in which to make a diagnosis. The accurate diagnosis of C.M.P.I. is more difficult, in view of the patchy and variable severity of the enteropathy, than that of coeliac disease where the enteropathy is usually uniform and severe. It is not yet even certain whether a cow’s milk sensitive enteropathy is present in all who have the syndrome 1. 2.

of C.M.P.I. in its non-gastroenterological forms. Biopsy has not long been used in the diagnosis of C.M.P.I. yet it has already helped to establish C.M.P.I. as a real syndrome and helped us to understand the pathogenesis. It would be unfortunate if clinicians were to abandon biopsy in C.M.P.I. on the basis of Sumithran and Iyngkaran’s study. In time some indicator other than small-intestinal mucosal appearance may emerge for serial observation in relation to milk withdrawal and challenge, but that day is not yet here. It must not be forgotten that a child who presents with apparent milk intolerance and is having gluten may also have coeliac disease, and biopsy is then essential.

infant. 1976, 17, 309.

Saperstein, S., Kniker,

3 Garrett, J. 4. Garrett, J.

R., Howard, E. R., Jones, W. J. Physiol. 1974, 243, 153. R., Howard, E. R. ibid. 1975, 247, 25P.