32

for cases in which atelectasis persists or developssecondarily. A Drinker-type apparatus did not provewholly satisfactory for this purpose, owing to itsrelative functional inflexibility. Even in healthypremature babies respiration may be very irregular,4 6so that one of the dangers of artificial respiration ishyper ventilation with consequent alkalosis. Further-more, newborn infants vary widely in their rate ofrespiration.4 5 These difficulties have been avoided

by developing a machine that amplifies spontaneousrespiratory efforts only. A photo-electric mechanismactuated by a light mirror attached to the flap ofthe inspiratory valves, is sensitive to the first0-1-02 ml. of attempted respiration ; it is effectivewith breaths too feeble to be measured by spirometer.Either negative or positive pressure, or both, can beapplied to the body. With respirators of the plethys-mographic type it has proved difficult to find anefficient method of sealing the neck or face from thebody-chamber. Neck seals hitherto tried may cause"

pistoning " of the whole child or, particularly if it

cries or struggles, engorgement of the blood-vesselsof the head and neck. DONALD and LORD use arapid-setting alginate which can be injected aroundthe neck, or around the entire head and neck leavingonly the face free. The mask is embedded in the

alginate. They prefer to leave only the face free as"

pistoning " is thus avoided, and should spirometry

be needed readings are more likely to be accurate.The alginate can be easily broken and removed bythe fingers. This method might be thought to restrictthe sick and restless infant, but it appears to givesatisfactory results. The alginate remains competentat pressures rather lower than - 15-30 em. water.With regard to safe pressures, DONALD and LORDhave seen no harm follow the use of - 40 cm. water ;and once they used - 65 em. with no evidence ofpulmonary damage. This agrees with the finding ofSMITH and CHISHOLM 7 that mature, and even somepremature, babies could exert negative pressures of40-50 cm. water. It would seem undesirable to use

pressure of this degree for more than a short time ;and DONALD and LoRD have found that - 15-30 cm.water is sufficient.

These workers follow the usual routine after theinfant’s birth, and they consider using the respiratoronly if atelectasis persists. Endotracheal intubationis avoided, especially in premature infants, andgastric oxygen is given instead if the baby needsassistance before it can be put in the respirator.Fortunately the newborn, and especially the premature,infant, seems to withstand pronounced oxygen lack ;moreover, the tissues are thin so that a fair amountof oxygen passes into the blood from the stomach,and the haemoglobin has a greater affinity for oxygenthan that of the older baby or adult. This respiratorovercomes the serious disability of weak musculature.In the feeble anoxic infant struggling for breath thediaphragm- exerts a powerful downwards pull. If the

cohering or blocked alveoli do not expand, the intra-thoracic subatmospheric pressure is transmitted tothe chest wall. This force may be considerable.

8

The soft -ribs and weak intercostal muscles are suckedin, with resulting sternal - retraction. This makes

6. Cross, K. W., Oppé, T. E. Ibid, 1952, 116, 168.7. Smith, C. A., Chisholm, T. C. J. Pediat. 1938, 20, 338.

8. Hermann, L. Arch. ges. Physiol. 1879, 20, 365.

matters worse, since the pressure on the lungs stillfurther obstructs the entry of air. When negativepressure is applied outside the chest, as in the

respirator, sternal retraction is prevented and thesubatmospheric intrathoracic pressure is applied whereit is most needed-namely, to the lungs. DONALDand LORD give a mixture of 50% oxygen and 50%nitrogen. The anoxic infant needs oxygen but notcarbon dioxide, which is probably already at a highconcentration in its blood. On the other hand, toohigh a concentration of oxygen is toxic and damagesthe pulmonary epithelium. CROSS and WARNER 9

found in -infants, as did DRIpPS and COMROE 10 in.adults, that 50-60% oxygen after a short initialdepression of respiration stimulated ventilation. Oneobstacle to assured success is the formation of hyalinemembrane. Little is known of the causes of thiscondition, which may supervene after a period of

apparently normal breathing. At necropsy the

appearance sometimes suggests that resorption offluid has caused the deposition of granular materialin an increasingly thick layer, which has blocked thealveolar ducts and obstructed the alveoli.! POTTER 1

has the impression that the incidence of hyalinemembrane has been reduced in the Chicago Lying-inHospital since infants with signs of respiratory distresshave been given oxygen in which the humidity ismaintained at 90-95%.

Dr. DONALD and Dr. LORD describe their account ofthe new respirator as an interim one ; but alreadythey can claim three cases, and perhaps a fourth, assuccessful results as far as saving life is concerned.

They are, with some success, doing their best to treatresults ; but we greatly need more information aboutcauses, so that fewer newborn infants will have to

struggle against anoxia.

9. Cross, K. W., Warner, P. J. Physiol. 1951, 114, 283.10. Dripps, R. D., Comroe, J. H. Amer. J. Physiol. 1947, 149, 277.11. Lancet, 1951, ii, 300 ; Ibid, 1952, ii, 73.12. Bonser, G. M., Clayson, D. B., Jull, J. W. Ibid, 1951, ii, 286.13. Jull, J. W. Brit. J. Cancer, 1951, 5, 328.

Carcinogenic Aromatic AminesWE have lately commented 11 on the research

which is being undertaken into the subject of bladderpapilloma and carcinoma as an industrial hazardin the chemical industry. Although this danger hasbeen recognised for nearly sixty years, and muchhas been done to reduce the contact of the workerswith noxious chemicals, the progress towards an

explanation of the fundamental causes has beenslow. The dog was the only species known to besusceptible to these tumours, so that an individualexperiment required up to ten years for its comple-tion ; for a long time attempts to find a reason forthe unusual localisation of the tumours in the bladder

epithelium, while all other organs remained apparentlynormal, failed. It was, therefore, an importantstep when BONSER, CLAYSON, and JULL 12 found thatthe urine of dogs treated with &bgr;-naphthylaminecontained a carcinogenic metabolite derived fromthis substance. This metabolite was a water-soluble

orthohydroxyamine, 2-amino-l-naphthol, and its

tumour-inducing properties were demonstrated bya new technique of implanting a pellet of the chemicalsuspended in wax into the mouse bladder-.13 A seriesof experiments has now confirmed that the meta-bolite is carcinogenic, whereas the parent amine

33

is not.14 Moreover, an insight was gained into themetabolism of this substance in different species .12- another important landmark in the chemical

investigation of the disease. -Naphthylamine is

only one of a group of some twenty aromatic amineswhich have been tested for carcinogenic activity inrecent years. Although there is no uniformity in thelocation of the tumours or in species susceptibility,these chemicals all tend to induce distant carcinomasat sites along the routes of excretion. The additionof new carcinogenic members to this group and thecollection of more information about their mode ofaction may lead to the discovery of a common

metabolic plan for a diverse, though related, series ofcompounds, some of which are used in industry.

SCOTT 15 has produced good evidence to show thatthe manufacture and handling of benzidine, anotheraromatic amine, involve a risk of carcinoma tothe workmen. His extensive investigation confirmsthe findings of BILLIARD-DuCHESNE 16 and DESOILLEet al.,17 and seems to put the carcinogenic action ofbenzidine beyond doubt. On the experimental side,SPITZ et al.18 had already shown that this chemicalinduced hepatic, intestinal, and acoustic-gland tumoursin rats and (more doubtfully) bladder tumours in

dogs. A chemical closely related in structure tobenzidine is 4-aminodiphenyl, which has been shownby WALPOLE et al.19 to be carcinogenic in the rat.It seems possible that this compound may have beenpresent in distillation residues from aniline in dyefactories, though it is probably not so today. In this

experiment the commonest tumour was in the largebowel ; of 14 rats which survived five hundred

days, 7 had epithelial tumours of the large bowel,the exact nature of the growth being uncertain. It

may be accepted, however, that the tumours variedin their degree of "

progression," 20 and that themost advanced of them had probably reached earlymalignancy. Methylation is a well-known method ofincreasing carcinogenicity, and when methyl groupswere substituted in both the benzene rings of 4-amino-diphenyl, giving 3 : 2’-dimethyl-4-aminodiphenyl, its

carcinogenic power was much greater. Intestinaltumours were commoner and they developed earlierin both large and small intestines. MILLER et al. 21also found that another methylated diphenyl (N : N-dimethyl-4-aminodiphenyl) induced tumours in variousorgans (but not in the bowel) earlier and more oftenthan 4-aminodiphenyl did in the later experimentsof WALPOLE and his colleagues. The latter con-

cluded that the effective carcinogen in all thesecases was a metabolite of the particular amine beingtested, and that in the rat these metabolites wereexcreted in the bile. They suggested that, by analogywith the work of BONSER et al.12 and others, theeffective metabolite is an orthohydroxyamine, andthat when o-methyl or N : N-dimethyl substitutiontakes place, metabolic hydroxylation is " steered "

14. Bonser, G. M., Clayson, D. B., July J. W., Pyrah, L. N. Ibid(in the press).

15. Scott, T. S. Brit. J. industr. Med. 1952, 9, 127.16. Billiard-Duchesne, J. L. Arch. Mal. prof. 1948, 9, 109.17. Désoille, H., Hochfield, M., Aboulker, P. Ibid, p. 149.18. Spitz, S., Maguigan, W. H., Dobriner, K. Cancer, N.Y. 1950, 3,

789.19. Walpole, A. L., Williams, M. H. C., Roberts, D. C. Brit.

J. industr. Med. 1952, 9, 255.20. Foulds, L. J. R. mier. Soc. 1950, 70, 173.21. Miller, E. C., Miller, J. A., Sandin, R. B., Brown, R. K. Cancer

Res. 1949, 9, 504.

into the ortho position relative to the amino group,and carcinogenicity is increased ; but these interestingsuggestions as yet lack experimental proof.An American group, 22 led by the MILLERS, have

investigated some aromatic amines and azo com-

pounds in another way. They have done muchwork on fluorine substitution in various positionsin the benzene-ring systems of these compounds.The effect of this substitution is to form a tightbond so that particular positions can be blocked,as it were, against metabolic activity. They con-cluded that the amino-azo dyes are carcinogenicto the extent that they are methylated in vivo andbound to the liver protein.The metabolism of the aromatic amines in the

widest sense lends itself well to organic chemical

analysis ; and it would be valuable at this excitingstage of the inquiry into their carcinogenic propertiesto try to forecast which compounds should mostprofitably be tested. Each amine requires monthsof careful study in at least two species (the dogand the rat or rabbit) before the final investigationof the carcinogenic power of its metabolites can bemade. Nevertheless, remarkable progress has beenmade in a few years, and it is reasonable to hopethat the problem will be solved before long. The

knowledge thus gained may point the way to fruitfulinvestigation of the metabolism of other types ofcompound. Doctors who see many patients withmalignant disease every day are sometimes irritatedby the reports of work on this carcinogen or that- work which seems to them to be far away fromhuman disease. But research of this kind is essentialto an understanding of the way in which the bodyis likely to react to carcinogens, and it thereforehas an important place in the complete picture ofmalignant disease.

22. Miller, E. C., Miller, J. A. Ibid, 1952, 12, 283. Miller, J. A.,Miller, E. C., Sandin, R. B., Rusch, H. P. Ibid.

23. Disabilities. London : The Lancet Ltd. 1952, Pp. 243.10s. 6d. (postage 6d.).

Annotations

" DISABILITIES"

OuR series of articles, written by people disabled bydisease or injury, have been widely read ; and we maysay-without taking credit to ourselves-no wonder.These writers, setting out to show how they have got thebetter of their handicaps, in great ways or small,unconsciously display so much courage, cunning, andhumour that the collected pieces are a testimony to thehuman spirit. They have now appeared as a book,23which should, we think, appeal to laymen as well asdoctors.

A CHALLENGE MET

LAST summer Denmark was struck by an -epidemic ofpoliomyelitis which was far more severe than anyprevious one in that country. Professor Lassen, whoseaccount of his experience in Copenhagen during thepast six months appears on a later page, is probablyright in supposing that " nothing comparable has everbeen seen in Europe." Between July 24 and Dec. 3,866 cases with paralysis were admitted to BlegdamHospital, Copenhagen ; and 316 of these required specialmeasures-such as tracheotomy, artificial respiration,postural drainage, or a combination of these. In fourmonths the hospital dealt with three times as manycases with respiratory insufficiency, paralysis of the