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of a further 27 lives-if one accepted the speculative argu-ment of Dr Webb (March 30, p. 559). Naturally, as ex-plained in my last letter (June 8, p. 1169), I do not acceptthis argument.Dr Adgey states that the Belfast unit’s response-time to a

099 call is similar to that of the Brighton unit. This is

quite correct. However, it is by virtue of accepting farmore calls direct from the public (involving a large numberof cases for which the Belfast scheme has nothing to offer)that the Brighton service is enabled to reach its patientsearlier overall.Dr Adgey’s remarks about " bundling patients into

ambulances and rushing them to hospital " are very unkindto highly skilled ambulancemen who have undergone sixmonths’ intensive training. Furthermore, I firmly believethat the level of paramedical care can be raised still furtherby allowing ambulancemen to administer drugs to relievepain and stabilise heart rhythm, as has been done, withsome success, in the United States. 1

Dr Adgey concluded that I may still insist that ambulancepersonnel are as effective as physicians in all these spheres.I should like to point out that I have never claimed thatambulancemen are as effective in relieving pain or stabilisingheart rhythm: we do not have any data on which to makesuch a comparison. I still claim, however, as I did originally,that on the evidence of the data I reviewed in my firstletter (Feb. 16, p. 263) the ambulance-staffed unit inBrighton provides a quicker, cheaper service for a far

greater population than the medically staffed Belfast unit,with no overall loss of benefit to the community. Thereason that the Brighton and Belfast communities havederived the same degree of benefit from their respectivemobile units, despite the necessarily more limited facilitiesoffered by the former, is probably that the Brighton serviceis able to deal with more patients, and to reach themquicker.The very limited N.H.S. resources might, therefore, be

better spent on the training of ambulancemen in coronarycare, rather than in increasing the number of physician-staffed units, which apart from being more expensivemight draw doctors away from other, understaffed partsof the N.H.S.

University Hospital of Wales,Heath Park,

Cardiff CF4 4XW. T. J. ORCHARD.

SOCIETY OVERMEDICATED ?

SIR,-Your editorial of June 29 (p. 1325) discussed aconference held in Bethesda, Maryland, concerningwhether society is overmedicated or not in regard to

psychotropic drugs. The article ends with a statement that"... the consumers were misrepresented in opinion ...".Some of us who were at that meeting have pondered overthis statement, neither understanding what was meantnor what the basis for it might be. Could one ask forclarification ?

School of Medicine and Dentistry,University of Rochester,260 Crittenden Boulevard,

Rochester, New York 14642, U.S.A. LOUIS LASAGNA.

*, Our remark referred to patients’ opinions aboutpsychotropic drugs. The conference, we feel, may havemisrepresented their views. Firstly, there was a beliefopenly stated by internists at the meeting that a majorreason for prescribing psychotropic drugs was the patient’sdemand for them-a reason which we question. Secondly,in partial support of this assumption, data about attitudes to

1. Rose, L. B., Press, E. J. Am. med. Ass. 1972, 219, 63.

psychotropic drugs were, we believe, presented in an over-simplified manner which conveyed the impression that mostpeople in the U.S.A. are satisfied with the way in whichthese drugs are at present used.-ED. L.

BEHAVIOUR OF TUMOURS IN CONDITIONS OFEXPERIMENTAL MAGNESIUM DEFICIENCY

SIR, The description by Parsons et aLl of strikingregression of advanced tumours in conditions of artificialmagnesium and potassium deficiency, makes it advisable tostudy the phenomenon further in animals. In the followingexperiments, the Walker carcinosarcoma 256 was used. Thistransplantable tumour of rats has been in use since 1928 inthe assessment of chemotherapeutic agents because it growsvery rapidly in a regular, constant, and predictable fashion,killing the host in 12-16 days when the tumour measuresabout 8 x 5 x 5 cm. and weighs 60 g.2 Young, fast-growingrats weighing 40-60 g. showed typical symptoms of mag-nesium deficiency in 5-7 days when fed on a diet deficientonly in magnesium, and containing only 2-8 parts permillion of magnesium or 2-8 mg. per kg. At this stage, theplasma-magnesium had fallen by more than half to 0-405mM (0-98 mg. per 100 ml.), and magnesium in the erythro-cytes was reduced to 2-36 mM (normal 3-65 mM).

In the first experiment, Walker tumour, implantedsubcutaneously into a group of magnesium-deprived rats,grew much more slowly than in normal controls. After6 days, tumours in the test group could be detected onlywith difficulty, whereas they were quite advanced (greaterthan 1 cm. maximum diameter) in the control group. Onthe basis of measurement in various stages in several

groups, the tumour-growth rate was assessed at about

5% of normal. This figure coincides with that of a similarstudy 3 in which a much more slowly growing carcinomawas used.One group of magnesium-deficient rats, in which the

tumours were barely identifiable after 5 days, was placedon a normal diet containing adequate magnesium. A

remarkable, almost explosive, increase in tumour growthrecurred. After 3 days, the tumours measured approxi-mately 5 x 4 x 4 cm. All the young animals were verysick and died on that day or shortly afterwards.The spurt of growth produced by the change to normal

diet led to the thought that most of the magnesium andother nutrients available to the animals were utilised inincreased tumour growth alone, and that the use of radio-active magnesium might have a destructive effect on thetumour in this phase. The main radioactive isotope ismagnesium-28, which is a P- emitter, with some y activity,and a half-life of 21 -3 hours. It is available in small amountsof very low specific activity (approximately 150 mCi

per g. magnesium), which means that the greater proportionof magnesium is in the normal inactive form. Theoretically,magnesium-28 could be produced in the carrier-free statein a much higher specific activity, but the method hasnever been developed due to the absence of demand andthe high cost. A group of magnesium-deficient rats ofaverage weight 55 g., with very small transplanted tumours5 days old, were each given 70 (lCi magnesium-28 in0-4 mg. magnesium. This is equivalent to 100 mCi in0-6 g. magnesium in a 70 kg. man.A flare of growth occurred and the animals were very

sick within 3 days. No therapeutic effect was seen at all.In retrospect, it is possible to see that the animals weregrossly overloaded with magnesium and that most of the

1. Parsons, F. M., Edwards, G. F., Anderson, C. K., Ahmad, S.,Clark, P. B., Hetherington, C., Young, G. A. Lancet, 1974, i, 243.

2. Rosenoer, V. M., Mitchley, B. C. V., Roe, F. J. C., Connors, T. A.Cancer Res. 1966, 26, suppl. part 2, p. 937.

3. Suigiura, K., Benedict, S. R. Am. J. Cancer, 1935, 23, 300.

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active magnesium-28 was excreted. Concentrations ofmagnesium-28 of specific activity 12-20 times greater(i.e., 2-3 Ci per g.) would be needed to prevent this.However, the whole subject of the use of magnesium-28seems to have been neglected, especially in the magnesium-deficient state. It is possible that certain other radioactiveelements, such as phosphorus-32, may have some effecton certain cancers during recovery from magnesiumdeficiency or other artificially produced deficiency states.A single dose of chlorambucil 2 mg. per kg. in sus-

pension in arachis oil was given intraperitoneally to a groupof magnesium-deprived rats bearing the Walker tumour.This is slightly less than the average minimum effectivedose 2which reduces the growth to 10% of normal. Theserats were then fed on a diet containing adequate magnesium.The tumour-growth rate remained very slow and the usualgreatly increased growth-rate was inhibited. After 3 daysit was difficult to detect the tumours, which all weighedless than 0-5 g. after 8 days. This is considerably belowthe predicted weight of tumours in normal animals giventhe M.E.D. dose 2; and although it is an observation res-tricted to one dosage level only, it raises the possibilitythat cytotoxic drugs may be useful in combination withmagnesium deficiency in the treatment of tumours in man.

Royal College of Surgeons,Lincoln’s Inn Fields,

London WC2. FRANK H. MILLS.*

* Present address: 4 Penrhyn Street, Redhill, A.C.T. 2603, Australia

DANGERS OF CORTICOTROPHIN IN

PHÆOCHROMOCYTOMA

SIR,-Patients with phxochromocytoma or other cate-cholamine-secreting tumours occasionally show signs of

Cushing’s syndrome. 4 This could result either from therelease of pituitary corticotrophin by the catecholaminesor from the production of a corticotrophin-like substanceby the tumour itself. The association of the two diseaseshas led to some patients with phaeochromocytoma beingsubjected to tests of pituitary-adrenocortical function.

However, deaths due to severe hypertensive crisis havefollowed the administration of corticotrophin to phaso-chromocytoma patients.5 5

In the dog, we have shown that corticotrophin causes aprolonged release of catecholamines from the adrenalmedulla. This appears to be mediated by the high con-centrations of steroids which reach the medulla throughthe portal system from the adrenal cortex. Furthermore,in isolated perfused adrenal glands of dogs and sheep wehave shown that cortisol in concentrations similar to thosefound in adrenal venous blood after stress increasescatecholamine output.We also find that deoxycorticosterone, in the order of

concentration one would expect after metyrapone, is a

potent releaser of adrenal catecholamines: metyrapone is

commonly used to test pituitary-adrenal competence.This may account for the release of adrenal catecholaminesfound after metyrapone administration. 7

Our observations on the role of the pituitary-adreno-cortical axis in the release of catecholamines from theadrenal medulla would explain the deaths mentioned above,especially when one remembers that steroids have beenshown to potentiate the peripheral actions of catechol-amines. 8

Our findings highlight the dangers of administering

4. Williams, G. A., Crockett, C. L., Butler, W. W. S., Crispell, K. R.J. clin. Endocr. Metab. 1960, 20, 622.

5. Moorhead, E. L., Caldwell, J. R., Kelly, A. R., Morales, A. R.J. Am. med. Ass. 1966, 196, 1107.

6. Critchley, J. A. J. H., Ungar, A. J. Physiol., Lond. 1974, 239, 16 P.7. Chart, J. J., Sheppard, H. J. med. pharm. Chem. 1959, 1, 407.8. Ramey, E. R., Goldstein, M. S. Physiol. Rev. 1957, 37, 155.

corticotrophin or metyrapone when investigating possiblecases of phxochromocytoma.

University Department ofPharmacology,

1 George Square,Edinburgh EH8 9JZ.

JULIAN A. J. H. CRITCHLEYCHRISTINE P. WEST

JONATHAN WAITE.

ALLERGY, TOLERANCE, AND IMMUNO-GLOBULIN A

SIR,-I should like to offer some conclusions from myown experimental data in relation to the article by Stokesand others (Aug. 31, p. 485), who emphasised that over-stimulation of the IgE system in atopy may result from adefective IgA response. My results in rats and miceconcern the study of the reciprocal influence of digestiveand parenteral immunisation by alimentary antigens.When intragastric immunisation was performed earlyafter parenteral injection of the same antigen, the classicalimmunological response following a primary digestivecontact with this antigen is not modified. In contrast,unresponsiveness or a marked hyporeactivity is observedwhen the parenteral stimulation is given after oral immuni-sation. Normal reactivity was not restored until 3-6months later. Unresponsiveness to parenteral immunisa-tion is also induced by the intraperitoneal injection ofserum collected from orally immunised animals. Thesesera contained quite small amounts of specific antibodiesof the IgA class. Thus I suggest that immunoglobulin Acould produce in vivo antibody-mediated tolerance, a

situation already well established in vitro. Such a mech-anism could inhibit the production of antibodies directedagainst harmless dietary antigens and bacteria usuallypresent in the digestive lumen. Breakdown of this toleranceby impaired immunoglobulin-A function should result inantigenic stimulation. Digestive allergy or atopy will

appear if this antigenic stimulation involves plasmocytesof the IgE class.

Unité de Recherches de Physiopathologie,Digestive, INSERM U 45,Hôpital Edouard-Herriot,

69374 Lyon, France. CLAUDE ANDRE.

INFECTION IN THE SINK

SIR,-Having been responsible for the design andintroduction of the heated sink waste-trap unit I wasvery interested in the paper by Dr Ayliffe and his col-

leagues (Sept. 7, p. 578). I was glad to see that our resultsregarding the heated waste trap were confirmed to a largeextent and that we have similar views regarding design andconstruction of sink and wash basins.3 3

I agree that possible transmission of Pseudomonasaeruginosa from a sink trap to a patient is a relatively un-common event, but it certainly does happen from time totime 4 and this may constitute a serious risk, particularlyin units with a highly susceptible population-e.g., patientson intensive cytotoxic therapy, or on immunosuppressivedrugs for transplantation. Under these circumstances the

sterilising trap may be of more value than in a burns unit,for instance. It is just one more hole, admittedly small, inthe leaking umbrella of cross-infection control. Our

experiments quite clearly demonstrated back-splashcontamination on the hands when washing under the tapover a sink-seeded with marker organisms. This may be agreater hazard than a direct splash. Another knotty prob-lem in the assessment and role of pathogenic strains is thenumber of strains isolated, typed, and identified. It is not

1. Feldmann, M., Nossal, G. J. V. Transplant. Rev. 1972, 13, 3.2. Lancet, 1970, ii, 550.3. Br. med. J. 1967, iv, 548.4. Lancet, 1973, ii, 415.