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M O D E R N T H E R A P E U T I C S IN P A E D I A T R I C S ~

By JOHN MOWBRAY, M.I).

Childre~'s Hospila.1, Temple St., Dublin.

S O headlong is the speed of advance o1' at least of change in

t therapeutics that it is almost impossible to give a report which will not be out of date before it appears in print . This is the fate of

pract ical ly every textbook of medicine in its post-war editions, with the exception of one such as Brenneman ' s which solves the problem by sub- s t i tut ing each year fresh mater ia l in its loose-leaf volumes. Even then it often fails. This preamble will serve as an apology in advance for any old-hat in this collection offered to specialists in a branch which not alone takes pa r t in pract ical ly all the advances of general medicine, but which telescopes into a few years of this scientific era more new paediatr ic t rea tments than its elder sisters have seen in half a century. I t is manifes t ly impossible within the confines of a President ial Address to do more than touch on some of ~he more impor tan t or fascinat ing of the new approaches; as the selection has to be a personal choice, t reatments which may seem to others to demand pr ior i ty may be crowded out of this restr icted canvas.

The good paedia t r ic ian recognises tha t life commences at the moment of conception and that if he commences prophylaxis at bir th many valuable months will have been lost. Two instances will suffice: con- genital defects and erythroblastosis foetalis. The association between materna l rubella in the first three months of pregnancy and congenital cataract, microphthalmos, deaf tourism and congenital heart defects noted by Gregg in 1941 has been ful ly corroborated, but perhaps the fact that the infectivi"~y o~ rubella commences f rom one to four days before the appearance of the rash has not made us realise that such a mother, and cer ta inly one who has not had a previous attack, should be pro- tected f rom contac't with any sick child for the first two days of an illness unless a diagnosis excluding rubella can be made. As the rash is usually the first obvious sign, this is hardly pract icable and we must seriously ask ourselves is the prevent ion of rubella in childhood any longer desirable.

We are still losing f a r too m a n y babies f rom erythroblastosis foetalis, and one hopes tha t in the very near fu ture every p regnan t woman will be protected by ABO and Rh blood grouping. The routine is p re t ty well universal ly established. I f the mother is Rh-negative, her serum must be tested for presence of antibodies. The fa ther might be Rh- negative, but the mother as a girl may have had a t ransfusion or injec- t ion of Rh-positive blood. A rising t i t re of ant ibody means that arrange- ments for exchange t ransfusion must be made before birth. No excuse can be found fo r such a confinement taking place fa r f rom proper facilities. The indications for exchange t ransfusion are no longer a ma t t e r for individual opinion; a cord bil irubin of 2.8 rag/100 ml. and a cord haemoglobin below 15 g /100 ml. in normal infants, or below 17"5 g. in immatures, wa r ran t an exchange which may have to be repeated if

* :President's Address delivered to the Section of Paediatrlcs, May 4th, 1956.

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the serum bil irubin rises again towards 20 mg/100 ml. About 150 cases a year will require transfusion, and proficiency in dealing with them can only be acquired if they are sent to a few specialists in a few centres. Time is so precious tha t it should not have to be wasted on a postnatal diagnosis. The Hea l th Act actual ly makes this service avail- able to Section 14 and 15 classes, but the service should also be available to the higher income group for a reasonable composite fee.

Fewer and fewer cases are being relegated to the waste paper basket of marasmus which is becoming rap id ly the last refuge of the diagnosti- cally destitute. The latest to be saved f rom it are those now given the pigeon-holes marked renal acidosis and hypercalcaemia. Vomiting, i r r i tabi l i ty and fai lure to thr ive are no longer blamed indefinitely on the wrong food, but are diagnosed as renal acidosis if there is an alkaline urine and a low alkali reserve, in other words a discrepancy between a low p H in the blood and a high p H in the urine. By contrast, those with a normal or perhaps very occasionally alkaline urine, but with a high serum calcium and a normal alkali reserve, are labelled hypercal- caemia. The recognition of renal acidosis by Lightwood in 1955 took some t ime to make an impact on paediatr ic ians, but it has already led t o a great saving of life as the condition is fa i r ly common and if the child is t rea ted dur ing its first two years of l ife with an alkaline mixture such as Sulkovi tch 's 1 in divided doses controlled by fa i r ly frequent esti- mations of p lasma COz combining power, the outlook is excellent as the condition is self-l imiting and t rea tment can be then omitted. Many of these cases have escaped the diagnosis of marasmus only to be mistaken for chronic pyelitis, as leucocytes in excess of normal are found in the ur ine which on culture is found to be sterile.

Within the past three years Payne and Lightwood 17 have drawn our a t tent ion to idiopathic hypercalcaemia. A l imen ta ry over-absorption of calcium is the probable cause whether this be due to excessive intake or abnormal sensit ivity to v i tamin D. Al though the prognosis is good a raised blood urea is produced by the hyperca lcaemia and hypercalcur ia with perhaps a nephroculcinosis as in renal acidosis and if the condition were kep t in mind in cases of anorexia , dehydra t ion and fa i lure to thr ive the spontaneous recovery could be ant ic ipated by a low calcium diet and the omission of v i tamin D. H I t is pract ical ly certain that m a n y cases could be prevented by the realisation tha t the pendulum has swung too f a r as regards v i tamin D and overdosage is an ever-present tempta- tion. The addit ion of v i tamin D to a diet of milk already fortified by it is a common error. We should teach our students to confine them- selves to one or two prepara t ions with the dosage of which they have made themselves famil iar . We should also impress on them (a) that in spite of advert is ing teaching to the con t ra ry 800 i.u. of v i tamin D are sufficient for prophylaxis dur ing the first year, 2 (b) that they should at least recognise the facies of hypercalcaemia likened to an apathet ic Peke when seen in advanced cases.

Dr. Harbison, who recently re t i red f rom his position as M.O.H. for

1 Citric acid, 60 g., sodium citrate, 100 g., apuae ad 1,000 ml. Dosage, 50-]20 m]. per diem.

2 And, the dose for children between 2 and 10 years should be halved, not doubled. (B.M.A. Nutr i t ion Committee, 1950.)

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Dublin City wi~h the satisfaction of having seen the infantile mortality reduced from 125 to 35 per 1,000 in the last twelve years, would be the first to admit that much remains to be done as regards neonatal mor- tality. Incubators complete with facilities for oxygen administration are having their effect in materni ty and children's hospitals, but the family doctor is still not proper ly equipped to deal with asphyxia neonatorum. Endotracheal intubation and intermit tent insuffiation are out of the question and seem to be no more effective than the relatively simple administra'tion of intra-gastric oxygen 2~ except in the severely asphyxiated, and even in these it has proved successful. An outle't catheter is passed, preferably af te r a prel iminary wash-out of the stomach, and its external end placed under an inch or two of water. Too much water would prevent the escape of the oxygen, which is led in through another polythene catheter at one litre per minute, a pressure which does not cause undue distension of the abdomen. This pressure could not lead to retrolental fibroplasia, and this t reatment is a tremendous advance on misguided attempts to make an anoxic baby breathe by assault and battery. Not alone will it save life, but it will prevent the permanent cerebral damage which may follow prolonged or severe anoxia.

In this connection signs of kernicterus not associated with Rhesus or any o~her incompatibili ty 3 are being noted in some prematures f rom the 4th to the 6th day - - a few days later than the kernicterus of erythro- blastosis--and, in a high proport ion of cases, varying from very severe to a transient attack lasting an hour or ~wo. Anoxia is probably a factor in combination with a high serum bilirubin due to hepatic imma- tu r i ty availing of the delayed closing of the blood-brain barr ier to work havoc on the delicate cerebral tissue. The researches into this condi- tion led to the discovery that vitamin K is a haemolytic agent, especially in prematures, and that there is a universal tendency to overdosage. The dose required to counteract hypoprothrombinaemia and consequent haemorrhagic disease of the newborn is only 1 rag., not the ampoule of 10 mg. which is often not merely given, but repeated several times. I t would be safer and maybe bet ter to give it orally to the mother during the last weeks of pregnancy or intramuscularly shortly before delivery.

The marasma has also lifted from under-feeding and subacute enteritis due to some strains of E coli, and parents no longer have ~o comfort themselves for the loss of their babies from this condition with the knowledge that a succession of highly abstruse feeding formulae had been tried. The antibiotics have cleared up this unusual infection, together with thousands of parenteral , infections in a few days where a short time ago we used to spend weeks and months in an unavailing at tempt ~o find the right formula.

There are no figures for the incidence of acute nephrit is in Dublin, but it is likely that this condition is becoming less frequent, as in New York City, following the increased use of sulphonamides and anti- biotics for infections of streptococcal origin. A similar efficacy of the antibiotics is unfor tunate ly not evident in the treatment of acute glomerulonephritis, which still is mainly dietetic; nor is there even complete unanimity as regards the amount of fluid and protein which should be allowed, but experience of renal insufficiency during the last

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war has shown that increased water does not increase the ur inary ou tpu t , it simply causes water retention. The fatalit ies produced by intra- venous saline in post- t raumatic renal insufficiency were due to increased blood volume, oedema, hypertension and heart failure. Certainly in cases of nephri t is with oedema, often a macroscopic haematuria and hypei~tension, the danger in the initial stages is less f rom uraemia than from left ventr icular failure with pu lmonary oedema or hypertensive encephalopathy with cerebral oedema. The generally accepted opinion is that one must supply fluid (a) to correct water loss due to vomiting, anorexia and pyrexia and (b) to supply about 25 oz. of fluid to com- pensate for extra renal loss plus the amount of urine excreted during the previous 24 hours. The sodium intake should not exceed 0.2 gramme dai ly : the use of Edosol, a salt-poor milk powder, makes this a simple matter. The protein need not be restr icted below 10 grammes. This can be supplied by �89 pint of milk or Edosol (1~ oz. Edosol to �89 pint of water), and there is strong experimental evidence to show that if any- thing less than 20 grammes is given the body protein will be broken up to a greater amount than this. Glucose is still the great stand-by in sparing protein and lessening the product ion of urea; it also lessens the danger of hyperkalaemia and is anti-ketogenic. Even in vomiting patients, it can be given by mouth with the help of chlorpromazine. When gross haematuria, hypertension and uraemia have disappeared (remembering that the normal blood urea in childhood rarely exceeds 20 mg./100 ml.), great laxi ty is permit ted as regards prote in; the tendency in fact is towards a normal diet from the time the pat ient is willing to take it. ~

In this condition, as in many others, so much emphasis has been placed on the criminali ty of allowing a child to go on to chronic nephrit is that bed-rest has been unduly prolonged in many cases. The urine may show a t race of albumin, and a few red cells may persist for months and even the E.S.R. which has been a guide may fluctuate in the " teens ", as in rheumatic fever when the condition is cured. The new C-reactive protein determination in the serum will probably serve, as it certainly does in rheumatic fever, as a much more certain criterion. There is no necessity for penicillin prophylaxis once the attack is over: a second attack of acute glomerulonephrit is is practical ly unkonwn.

Nephrosis still appears f requent ly in our wards and, although an infection with measles has p r o d u c e d a remission so often that in some centres it is deliberately used as a therapeutic agent, the administration of corticosteroids is more ethical. Luckily, deltacortone is just as effec- tive as its predecessors and causes no sodium retention in the usual dosage of 30 to 50 mg. daily for 10 days. The dramatic diuresis which follows in 70 per cent. of cases was often only the prelude, in spite of a proper protein diet of 2.5 g. per kilo body weight and sodium restriction, to a disappointing relapse. This is now being prevented by giving a maintenance dose of deltacortone three times weekly. I t is always per- missible to hope for a complete spontaneous remission, and the child's expectation of this is great ly increased by ei ther antibiotic t reatment of infections as they arise or by prophylaxis, as is practised in the case of rheumatic fever.

Coeliac disease has lost much of its ter rors since the discovery that a

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protein, gluten, was the cause of intestinal malabsorption, but it is not yet sufficiently realised that the dehydrat ion crises are due more to in- fections than to dietetic indiscretions, although these are much less f requent on the gluten-free diet. Many in this condition could be saved from admission 'to hospital by prompt t reatment with either oral or intramuscular tetracycline. In passing, it should be noted that over- dosage with antibiotics (in infants part icularly) is far too common; this must not be blamed on the manufacturers , who keep their doses usually at 12-5 to 20 mgm. per kilo body weight. A dangerously slow resump- tion of feeding has given place to the early at ta inment of a high calorific diet of 70 cals. per lb. body weight. Probana, with its 50 per cent. pro- tein milk, 10 per cent. casein hydrolysate, 20 per cent. banana powder and 20 per cent. dextrose, is a very suitable food. In its ordinary dilu- tion of one packed level measure to 2 oz. of water it provides a mixture containing protein 3"9 per cent., calories 7"3 per cent. and fat 2 per cent. to give 20 calories to the ounce. Af te r a few days on 50 cals. per lb. body weight one can, by using 1�89 measures to 2 oz. of water, produce a diet of 70 cals. to the lb. body weight. The gluten-free diet is then resumed and usually requires a for tnight to show improved absorption. Incidentally, the parenteral administration of the fat- soluble vitamins is no longer necessary, because they are better absorbed than heretofore and in any case are now obtainable in water-soluble pre- parations. The B Complex and B 12 are still useful adjuncts either orally or by injection. The gluten-free diet now includes bread, cakes and biscuits, which make it easier to maintain for many years. I t is cus- tomary to continue the diet up to the age of 12 years, when the condi- tion generally clears up ; but recent work has shown that it may persist through adult life as a chronic relapsing illness. TM

Probana in concentrated form is also useful in mucoviscidosis, the new and more appropr ia te name for the condition misnamed pancreatic fibrosis. Even mucoviscidosis no longer covers this affection of secreting glands, because Schwachman e t al . 2~ have shown that the sweat glands are also involved. There is excessive secretion of sodium chloride by these and the parot id gland, and for reasons of speed and simplicity its estimation in both these secretions may oust the t rypsin test for duodenal juice. The chloride content is : for the saliva 30-60 mg/100 ml ; for sweat, 0.12-0.33 per cent. Continuous prophylaxis with antibiotics has great ly improved the prognosis and the bugbear of local (and worse still, systemic) moniliasis has been eliminated by the recent discovery of a fungicidal antibiotic, Mycostatin, which can be given in combination with tetracycline.

Controversy still rages about the efficacy of corticosteroids in the t reatment of the cardiac complications of rheumatic fever. The con- clusions of the combined investigation ~ of the Rheumatic Fever Working Pa r ty of the M.R.C. of Great Bri ta in and the Council on Rheumatic Fever and Congenital Hear t Disease of the American Hear t Association that there is no evidence to suggest that rheumatic fever in children can be uniformly arrested by any of the three agents A.C.T.H., cortisone and aspirin, and that there was no significant difference between them in their effect on the cardiac status of the pat ient at the end of one year, have denigrated cortisone to an unjustified extent. The most extra-

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ord inary thing about it was the agreement to limit the t rea tments to a period of six weeks, al though it has been recognised since the t ime of Poynton that the average durat ion of a rheumatic episode was three months ; some have lasted in cyclic fashion for 2�89 years. Buried in the voluminous and wonderful ly tabulated repor t are the following signifi- cant findings: the hormones, compared with aspirin, showed: (1) more rap id disappearance of soft apical systolic and mid-diastolic murmurs ; (2) more rapid fall of the E.S.R. ; (3) more rap id initial decrease in the P.R. interval when prolonged; (4) no effect on the appearance or dis- appearance of loud systolic murmurs .

The fact that a loud systolic m u r m u r did not d isappear has a signifi- cance as regards the day of the disease on which t rea tment commences and the dosage. The dosage in this exper iment was obviously inadequate ; i t could possibly have stemmed f rom a subconscious memory on the pa r t of the Bri t ish section of their scanty rat ion while. America and I re land ( thanks to Ker r igan of Merck's and the late Professor H e n r y Moore) were enjoying almost unl imited quantities. The inadequacy of both dosage and length of t rea tment was realised by Roy and others 1~ of the House of the Good Samar i t an in Boston who dealt with a parallel group of init ial at tacks at the same t ime as Roy was working in ~he combined inves- tigation. Ins tead of t rea t ing them for six weeks with a total of 4-1 gm. cortisone, he gave them a total of between 13-15 gm. in a period of 16 weeks, still a relat ively moderate t ime and dosage. The heart damage in Roy's pr iva te group was only 38 per cent. as compared with 70 per cent. in the combined group, m urm ur s d isappeared in 40 per cent. of cases as compared with only 20 per cent. The incidence in both series was definitely re la ted to the dura t ion of illness. In the combined group children coming under t rea tment in the first week of illness had almost twice as good a chance of avoiding hear t damage and of losing a signifi- cant m u r m u r as those commencing t rea tment dur ing the second week, and thine times tha t of the th i rd to six weeks. I n the pr iva te group, with higher dosage, the advantage in the ear ly t rea tment was not so marked, but still was of a high order. This work showed clearly the necessity of p rompt t rea tment within the first week of the rheumatic episode if possible, with relat ively large doses given over a relatively long period. Kroop 9 and Done 1 in their published results, and Massell TM in a review of the impor tan t Amer ican l i terature, are also in conflict with the M.R.C. findings. Their emphasis is also on early t reatment , permanent heart damage occurr ing in only 6-5 per cent. of cases where adequate hormone t rea tment had been given dur ing the first week of illness, rising to 49 per cent. when there had been delay beyond this time.

The most remarkable discrepancy of all concerns the effects of the hormones on congestive fai lure alone or on per icardi t is which presumably had an element of failure. The combined group found that these were unaffected, but Massell 's figures show a relief of pericardi t is in 84 per cent. of cases within one week. Roy 's (Boston), when replying to his pape r a't the Amer ican Rheumat ism Association's Annual Meeting stated tha t all the evidence was to the effect that before the introduction of hormone the rapy young children admit ted with acute congestive fai lure used ~o die like flies. At the same meeting Fe ldman laid stress on the importance not of high dosage or low dosage but of adequate dosage.

M O D E R N T H E R A P E U T I C S IN P A E D I A T R I C S 307

Schlesinger 2~ takes the via media of support ing the Anglo-American t r ia l dosage, but thinks that the course should be prolonged and in some cases the dosage increased.

My own experience, which would have been the subject of this address, had not the advent of Deltaeortone introduced a new factor which it will take another year to evMuate, has led me to aim at a normal E.S.R. within 7 days of commencing t reatment , the dosage being roughly 1"7 gin. of cortisone as compared with the 1.3 given in tha t t ime by the combined group, and the amount over six weeks being 5"2 gin. as compared with the 4.19, t rea tment being continued until the episode is over. The twin factors of virulence of a t tack and the chi ld 's resistance must not be ignored by the fixation of an a rb i t r a ry standard. Although doses of cortisone up to 400 rag. or 500 rag. daily for 2 or 3 weeks (Kroop 9) or 300 rag. daily for 6 to 8 weeks (MeEwen '3) are dangerously high when one considers their probable effect in suppressing adrenal function, and perhaps destroying the zona faseieulata of the cortex altogether, we are glad to have the new synthetic hormone Prednisone (known also as Metacor tandracin or Deltacortone) to relieve us of such high dosage, with the added advantage of being able to allow the pat ient a diet of normal salt content without the occurrence of sodium retention.

Although the manufac tu re r s were against a dosage higher than 30 mgm. daily, in many centres up to 50 mgm. daily have been given in the initial stages. This is reasonable when one remembers that even tha t dose only corresponds to 250 mgm. of cortisone. In a recent case of mine on a dose of 310 mgm. in the first week there was hepatomegaly to the level of the umbilicus with no other side-effect. This most dangerous and insidious side-effect, mentioned in a previous communication, ~'~ deserves more at tent ion : it has been shown that i f high dosage is continued the end result will be a non-reversible f a t ty degeneration of the liver, whereas a p rompt reduction when the liver begins to enlarge is reflected in immediate rev.ersal of the process. Deltacortone remains nevertheless a great advance in dealing with the rheumatic episode. We know now tha t the Asehoff node represents an a t tempt at muscle regenerat ion and is a late phase in the rheumat ic process. H a r m o n and Osbourne '~ have shown the importance of the mitochondria or interst i t ial granules of Koelliker in the hear~ muscle, and that i t is the mitochrondial oxidative phosphorylat ion which sustains both form and contracti le function. The effect of an ant igen-ant ibody flare-up on this complicated and sensitive mechanism is intense f rom the outset; if, in addition, the monocyte is given t ime to become a macrophage with the subsequent development of sear tissue it is unnecessary to repeat that t reatment . To be effective it must be p romp t and adequate.

A problem which faces us all is the determinat ion of the end-point of the rheumatic episode. An E.S.R. above the figure of 30 ram. in one hour or 30 ram. at 37 ~ F. in half an hour is a sensitive and reliable test of rheumatic activity. But its fall below this figure, if slavishly accepted as abnormal until it reaches 10 or 12 ram., may result in keeping many children unnecessari ly in bed. The C.-reaetive protein test bids fa i r to take over at this impor tan t point and indeed may soon ous~ the E.S.R. at all stages of the episode? '~ In Dublin we have had to wait a long time for a tr ial of this reaction although the American workers have

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been using it for a couple of yeal~s. They, in turn, were slow in taking it up considering that the C-reactive protein was first reported by Tillett and Francis in 1930. They found that the sera f rom patients during the acute phase of pneunococcal pneumonia formed a precipitate upon the addition of the somatic C. polysaccharide of the pneumococcus. During convalescence this reaction disappeared. I t was then noted that this protein was found in many other conditions, and by injecting the purified product into rabbits a specific antiserum was produced which has no effect on normal serum, but with those of patients suffering from a var ie ty of inflammatory conditions causes a precipitation. The test is done in a capil lary tube and when negative proves that the disease pro- cess is no longer active, although the E.S.R. may still be raised. When positive, the amount of precipitation is a fa i r ly sensitive measure of the degree of the inflammatory process.~2 As patients va ry in the amount of precipitation, the best course is to keep the patient 's serum from week to week and test an early specimen against a late. Its main benefit will be to permit patients with rheumatic fever to be freed from the bed- restr ict ing power of the E.S.R. The corticosteroids have no effect on the test, another reason for its supplant ing the E.S.R., which is under a cloud of unwarranted suspicion that it is non-specifically reduced by them. The fact that in subacute bacterial endo- carditis when cortisone and antibiotics are used in conjunction the E.S.R. may be brought to normal when the streptococcus viridans can still be isolated from the blood stream is not a valid argument. As against that, i t must be stated that in two cases of a series of 23 that the C.R.P. react ion became negative al though obvious rheumatic act ivi ty was evidenced by a raised E.S.R., taehycardia and electrocardiographic changes. 1~

This problem of the raised E.S.R. is bound up with the rebound phenomenon, which may and does occur in spite of the most careful staircase descent in corticosteroids dosage. As was common experience, and specifically shown by Canadian workers, the E.S.R., although slower and more gradual in its descent under salicylate treatment, did not usually rise again when the drug was omitted. This has led some Ital ian workers 4 recently to combine this drug with corticosteroids; although the initial dose of cortisone was only 50 mgm. (much too low by any standards), and the dose of salicylate at 60 to 90 gr. daily was relatively high, no patient in the series relapsed af te r a course of about three months. A prel iminary report 7 f rom the University of Sheffield, although only on a series of 20 children, confirmed the Italian observa- tions : it showed that the E.S.R. fell more rapidly and that the durat ion of the episode was shorter on cortisone and salicylates than when sali- cylates were given in high or low dosage alone. The dose of cortisone was 200 mg. daily at first, the dose being reduced in steps to 50 mg. daily in five weeks. Salicylate was given in the Coburn dosage, sufficient to give a serum salicylate level of 30 to 40 rag/100 ml.

Since adopting this type of combined therapy, giving Deltacortone at a dose of not less than 30 mg. daily until the E.S.R. becomes normal, and then descending to a plateau of 20 rag. daily for a month, followed by a gradual descent to zero, with Ekammon, which combines aspirin with vitamin K and the still little investigated vitamin C, in doses not

MODERN THERAPEUTICS IN PAEDIATRICS 309

exceeding 60 gr. daily, I have found the rebound phenomenon definitely less troublesome. The high Coburn dosage has invariably resulted in salicylism within a week, a sequence of events noted also by HolP with his combined therapy.

I am afraid that ~his paper, which purported to give a broad survey of paediatric therapeutics, has degenerated into undue emphasis on the treatment of rheumatic carditis. It only goes to prove tha~ it is not the doctor who has the speciality, but the speciality which has the doctor. One may confidently hope, however, that the discussion to follow will supplement the paper sufficiently to permit it to justify its title.

References.

1. Done, Ely et al. (1955). Paediatrlcs, 15, 522. 2. Fishberg, A. M. (1955). Practitioner, 175, 1048, 41. 3. Forrester and Miller (1955). Arch. Dis . Childh., 30, 224. 4. Gelli, G. (1954). Minerva paediatr. (Torino), 6,951. 5. t t a r m e n and Osbourne (1953). J . E x p . Med. , 98, 181. 6. :Holt, E . S. (1954). Lancet, ii, 1197. 7. Holt , Jelingworth et al. Ibid. ii, 1144. 8. Il ingworth et al. Arch. Dis . Childh., 29, 551. 9. Kroop, I. G. (1954). N e w York St . J . Med. , 54, 2699.

10. Lindsay et al. (1956). Bri t . Med. J . , i, 14. 11. Lowe et al. (1954). Lancet, ii, 110. 12. Lucherino et al. (1955). Reumat i smo, 7, 214. 13. McEwen, C. (1954). A m . J . Med . , 17, 794. 14. Massell, B. F. (1954). N e w Eng. J . Med. , 251, 183 ; 263, 221. 15. Mowbray, J. (1953). J . Ir ish Med. Assn . , xxxii, 192, 178. 16. Med. Research Council and American Hear t Assn. (1955). Brit . Med. J . , i, 155. 17. Payne and Lightwood (1952). Arch. Dis . Childh., 27, 302. 18. Roy ann Masse1 (1955). Ann . Rheum. Dis . . xvi 4, 427. 19. Shackman et al. (1954). Amer . Heart J . , 48, 599. 20. Schlesinger, B. (1955). Practitioner, 175, 1049, 563. 21. Schwachman et al. (1955). Report of the Combined Meeting of the American, British

and Canadian Paediatric Associations. 22. Waller and Morris (1953). Lancet, ii, 951.