541

believe that such " prophylaxis " is valueless and often

dangerous, and it is not practised in our patients. Our

prophylactic measures to prevent infection are: (1) Isola-tion in single rooms which are plenum-ventilated with airfiltered to remove particles down to 5 [L diameter; (2)reverse barrier-nursing procedures for patients with neutro-penia of less than 200 per ml.; (3) topical antiseptic agents;(4) sterile food; (5) nursing in plastic film isolators inselected cases; (6) sterilisation of the gut by orally ad-ministered non-absorbable antibiotics. The employmentand evaluation of these measures is the subject of a controlledclinical trial.Thus, we have no disagreement with Dr. Smith in his

condemnation of systemic antibiotic prophylaxis. Concern-ing the frequency with which blind antibiotic therapy (asagainst prophylaxis) is indicated, we may differ, but webelieve that both our own results and those of Schimpffand his colleagues 3 amply justify our readiness to embark atan early stage upon empirical antibiotic therapy in clinicallydiagnosed infections without awaiting bacteriologicalconfirmation.

A. S. D. SPIERSM. H. N. TATTERSALLJ. H. DARRELL.

Royal Postgraduate Medical SchoolLondon W.12.

GASTROINTESTINAL BLEEDING:A POSSIBLE ASSOCIATION WITH IBUPROFEN

D. J. HOLOSTOCK.

Ashford Hospital,Ashford,

Middlesex.

SIR,—Ibuprofen (’ Brufen ’) is said to be well toleratedby patients who experience gastric irritation with otheranti-inflammatory drugs.4 This may well lead to its beingwidely prescribed to patients with both peptic ulcerationand rheumatic conditions, and I therefore report a case offatal gastrointestinal bleeding after this drug had beengiven to a patient with duodenal ulcer.A 69-year-old man had had symptoms of duodenal ulcer for

25 years, but with no complications. In 1957 he had a myo-cardial infarct, followed by persistent angina, and for about 4years had had mild prostatic symptoms. The prostate was hardon rectal examination, but the serum-acid-phosphatase level wasnormal.

For several months he had complained of back pain; radio-

logical examination showed minor osteoarthritic changes and hewas treated with dihydrocodeine. Later ibuprofen (200 mg.three times daily) was also given; one week after this was startedhe passed a melasna stool and was admitted to hospital. Afteradmission meleana continued and the haemoglobin level fell inspite of transfusion, and emergency laparotomy was performedby Mr. R. T. Burkitt. A large posterior duodenal ulcer wasfound and a Polya partial gastrectomy performed.

Initially he did well after operation, but on the second post-operative day he collapsed with left ventricular failure and he diednext day. Necropsy (Dr. M. R. Crompton) showed the cause ofdeath to be rupture of an aneurysm of the splenic artery; therewas a carcinoma of the prostate with pulmonary metastases.The fatal outcome of the bleed from this patient’s duo-

denal ulcer is clearly due to multiple factors; however,the onset of this complication within a week of the startof treatment with ibuprofen, after many years during whichthere had been no complications from the ulcer, is striking.It seems that ibuprofen, like other anti-rheumatic drugs,should be avoided in patients with dyspeptic symptoms orknown ulcers, and paracetamol remains the analgesic ofchoice in such patients.

2. Preisler, H. D., Goldstein, I. M., Henderson, E. S. Cancer, 1970,26, 1076.

3. Schimpff, S., Satterlee, W., Young, V. M., Serpick, A. New Engl.J. Med. 1971, 284, 1061.

4. MIMS Annual Compendium, section 3, p. 86. London, 1971.

ACCOMMODATION FOR MEDICAL VISITORS

SiR,-Few would dispute that for a young doctor intraining a period of work overseas is of inestimable value,whether this is spent, depending upon his, specialty andintended career, in a research laboratory, in a clinical

department of a university hospital, in an under-doctoredarea of a developing country, or in general practice. Manyof us in Britain have been fortunate in having had suchopportunities and, in turn, we are also fortunate in beinginvited to act as hosts to increasing numbers of colleaguesfrom other countries, of various ages, qualifications, andexperience, who come to work for varying periods in ourclinics and departments. Some such individuals place aconsiderable strain on postgraduate teaching and researchfacilities, but they are nevertheless very welcome becauseof the contributions they make to the work of the hostdepartment; while most come to learn from us, some cometo teach, and there can be few from whom we do not learnsomething new, whether related to scientific medicine orresearch or to patterns of medical practice in the countriesfrom which they have come.

This flow of visitors, then, is one which few would wishto check, despite its apparent increase (which will surelycontinue when we are a part of the European community),because of the valuable cross-fertilisation which it engen-ders. But there is an important practical problem which isgiving increasing concern-namely, that of accommodation.Many of these visitors are married, with young families,and, at a time when our hospitals are generally incapable ofaccommodating their own married junior medical staff,they have as a rule no room to spare for foreign visitors,especially when they are coming to do research or onclinical attachment and are not holding salaried posts inthe hospital service. Those of us who have been fortunateenough to travel extensively have been impressed to notethe accommodation for visiting fellows and their families inmany American centres and the guest flats for short-term(and sometimes long-term) visitors in many Europeancentres (particularly Western Germany), in Australia, andeven in some centres in less highly developed countriessuch as India. It is a never-ending source of concern to usto note the difficulty experienced by many of our visitorsin the Provinces in finding suitable furnished accommoda-tion to rent, and then to note the often spartan conditionsin which they are compelled to live, so very different fromthose in the climatic and cultural setting from which theyhave come. My wife and I particularly recall spending asnowy New Year’s Eve 1970 with a distressed American

couple and their two young children, attempting to reassurethem that the unfamiliar coke-burning stove would even-tually heat the pleasant and clean (to an Englishman) butcold and forbidding (to an American) semi-detached housewhich they had rented. We could quote many more suchexamples, and one other visitor who came for a month leftafter four days after a series of minor catastrophes. Thetime and effort spent by medical, scientific, secretarial, andadministrative staff of our hospitals and departments intrying to find congenial living quarters for such individualscould be spent more profitably, and even the efforts of suchagencies as the British Council and the university accom-modation officer do not as a rule ease the burden of respon-sibility which we in the host departments feel towards ourguests.At present the Health Department will not allow hospital

boards or boards of governors to allocate funds for the

provision of residential accommodation which could beused by postgraduate students and overseas visitors andtheir families. Surely the new hospitals now being designedand built in major centres must have such facilities. If weare to continue in this country to attract some of thesepeople who contribute so much to our medical life and

542

thought, and if we are to continue to offer specialisedtraining to overseas doctors and medical scientists, then theHealth Department must be persuaded to change itsviews. And perhaps some of the charitable Trusts orFoundations which have already done much to provideaccommodation for single men and women in London,but not in other parts of the country, might be prepared totake a national look at this growing problem.

JOHN N. WALTON.General Hospital,

Newcastle upon Tyne.

DELAYED-TYPE HYPERSENSITIVITY AND

JUVENILE DIABETES MELLITUS

JAIME E. MEJÍA-LAGUNAENRIQUE PÉREZ-PASTÉNCLEMENTINA MAGOSEDUARDO ZORRILLA.

Departments of Endocrinology andImmunology,

Instituto Nacional de Cardiología,México.

SIR,-Several investigators have suggested that theonset of diabetes in children may be related to auto-

immunity. This contention is based mainly on the obser-vations of LeCompte and Gepts who demonstratedmononuclear-cell infiltration of the islets of Langerhansin a large proportion of patients with juvenile diabetesof short duration but not in patients with longstandingjuvenile diabetes. Renold et awl. found similar infiltratesin animals immunised with insulin, and Grodsky et awl. 4

gave the theory further support when they immunisedrabbits with bovine insulin in adjuvant and inducedinfiltration of the islets and diabetes. Immediate-typehypersensitivity is an unlikely explanation, since anti-insulin antibodies are absent in the circulation of untreateddiabetics 5 and these patients have normal levels of thesecond component of serum-complement.6 6 Since mono-nuclear-cell infiltration suggests hypersensitivity of the

delayed-type, we studied the incorporation of 3H-thymidineby cultures of peripheral leucocytes obtained from healthyand diabetic children, under the stimulus of phytohazm-agglutinin (P.H.A.) and in the presence of several con-centrations of crystalline bovine insulin. 3H-thymidineincorporation was used as an index of lymphocyte blastoidtransformation (an in-vitro correlate of delayed hyper-sensitivity).2 non-diabetic and 5 diabetic children were investigated.

The diabetic children had never been treated with insulin;3 had a positive family history and an abnormal glucose-tolerance test (chemical diabetes), and the remaining 2had overt symptomatic juvenile diabetes of 2 and 12 weeks’duration. The leucocytes from the diabetic childrenincorporated 3H-thymidine normally under the non-

specific stimulus of P.H.A., but addition of several concen-trations of insulin to the cultures did not cause significantincorporation.These results suggest that patients with untreated juvenile

diabetes do not have delayed-type hypersensitivity to

insulin. This agrees with the observations of Nerup et al.,7who used the leucocyte-migration test as another correlateof delayed hypersensitivity. They found that the in-vitromigration of leucocytes from diabetics is inhibited by anextract of pig pancreas containing subcellular organelles,but not by insulin.

1. LeCompte, P. M. Archs Path. 1958, 66, 450.2. Gepts, W. Diabetes, 1965, 14, 619.3. Renold, A. E., Gonet, A., Crofford, O. B., et al. Fedn Proc. 1966,

25, 827.4. Grodsky, G. M., Feldman, R., Toreson, W. E., Lee, J. Diabetes,

1966, 15, 579.5. Grodsky, G. M., Forsham, P. H. Fedn Proc. 1958, 17, 234.6. Zorrilla, E., Ohrenberg, C., Soeldner, S. J., Sheffer, A. L. Lahey

Clin. Fdn Bull. 1969, 18, 55.7. Nerup, J., Andersen, O. O., Bendixen, G., Egeberg, J., Poulsen,

J. E. Diabetes, 1971, 20, 424.

ASCORBIC ACID, CELL PROLIFERATION,AND CANCER

EWAN CAMERON.

Vale of Leven Hospital,Alexandria, Dunbartonshire G83 0UA,

Scotland.

DOUGLAS ROTMAN.

156 Dauntless Lane,Hartford, Connecticut 06105,

U.S.A.

SiR,-We suggest that an important physiological func-tion of ascorbic acid is to act as an inhibitor of hyaluronidase.It seems probable to us that the " serum physiologicalhyaluronidase inhibitor " (P.H.I.) is a protein-glycosamino-glycan complex in which some or all of the glucuronic-acidunits are replaced by ascorbic acid. We visualise the

glycosaminoglycan component of this complex to be a

long-chain polymer with the general configuration:

In dietary deficiency of ascorbic acid the serum-P.H.I. levelwould gradually fall. This would allow progressive enzy-matic depolymerisation of intercellular material to continueunchecked, leading eventually to the widespread patho-logical changes of tissue disruption and disintegration thatwe recognise as scurvy.

If this is true, and if it is also accepted that many varietiesof cellular proliferation, including some forms of neoplasticproliferation, depend upon the release of hyaluronidase/ 1then it follows that ascorbic acid might be a valuable remedyin the suppression of many cell-proliferative disorders,including cancer.

This hypothesis is under clinical trial. The preliminaryimpressions are encouraging.

DIAZEPAM AND BREAST-FEEDING

SiR,—We wish to report a case in which diazepam(‘ Valium ’) is shown to have been transferred from motherto baby in breast milk.A male baby was delivered by csesarean section on Nov. 1,

1971. Birth-weight 4-13 kg. at 40 weeks’ gestation. Breast feed-ing was started. The mother became depressed and was givendiazepam, orally, 10 mg. three times a day from Nov. 6. Breast-feeding was discontinued for 24 hours from Nov. 7 to Nov. 8.On the following day the baby was lethargic and had lost 170 g.during the previous 24 hours. The mother by this time hadreceived a total of 90 mg. of diazepam. Breast-feeding was dis-continued, but the mother continued to receive diazepam 5 mg.three times a day.On Nov. 9 a urine specimen was collected from the baby and

an encephalogram carried out. Urine was again collected 30hours after breast-feeding was discontinued, and a specimen ofbreast milk was collected at the same time. The baby’s activitywas normal by this time and the weight increasing.A chloroform extract of urine was run on a silica gel thin-

layer plate, using methanol-ammonia (100/1-5) solvent system.Diazepam and oxazepam standards were also run. The extractof the first sample produced a single spot, with Rf, colourreactions, and fluorescence characteristics on spraying withcinnemaldehyde and F.P.N. reagents identical to those from theoxazepam standards. The second urine sample was also positivefor oxazepam, although at the limits of detection.The protein-free supernatant prepared from the breast milk

showed neither diazepam nor oxazepam. The limit cf detectionof oxazepam extracted from urine by the above technique is2 ILg., in our hands. Similar levels added to cow’s milkcould be detected. The thin-layer chromatogram of the breast-milk extract did, however, show a spot with fluorescence charac-teristics similar to oxazepam but with a different Rf.

1. Cameron, E. Hyaluronidase and Cancer. Oxford and New York,1966.