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Fifty Years After

THE LANCETLONDON: SATURDAY, NOVEMBER 10, 1945

FIFTY years ago, at the age of fifty, RÖNTGEN dis-covered’X rays, and eight weeks later he made his firstcommunication on the subject. His results, as hehimself was the first to acknowledge, were not thoseof an individual but were a sequel to the laboriousinvestigations of other physicists. Ironically enough,nearly all of these pursued their peaceful studies inwhat we now know as Western Europe. But thoughthe latest results of the discovery are disquieting,we may yet note that, had it not been made, some ofus would not have survived to see its ominous possi-bilities. The days immediately following a vasthuman catastrophe are not the time for assessingdispassionately the rights or wrongs of applyingscientific knowledge to human destruction-theatomic bomb is, after all, only a symptom of a gravemalady. We shall do better for the moment to studythe effect of RONTGEN’S discovery on human happinessand to stimulate further research towards the sameobject.In 1895 clinical medicine was in the doldrums and

lagging far behind physiology and anatomy. Theliinitations of percussion, palpation, inspection, andauscultation were being realised, and the far-seeingknew that bacteriology could answer only a few of thequestions of medicine. Within a few weeks ofRoNTGEN’s report X rays were being used for thediagnosis of fractures, and within a year bone tumourswere being identified. The study of bone injuries,anomalies, and diseases progressed rapidly, and by1906 the subject had a considerable literature. Not

only had new light been thrown on such well-knownconditions as osteomyelitis, rickets, and scurvy, butnew diseases such as osteochondritis and osteitisfibrosa cystica had been recognised. Without radio-.graphy the vast modern knowledge of bone pathologycould never have been acquired. At first exposureswere reckoned in minutes, which meant that advanceswere limited to the study of objects which could bekept in a fixed position for some time. Progress in thestudy of abdominal and thoracic diseases was muchslower, and while exposure times remained long, fluor-oscopy was the method of choice-a method which

unfortunately cost the lives of many brilliant observers.Gall-stones and renal stones were differentiatedfrom calcified glands and gross enlargement of theheart and gross disease of the lung were carefullydescribed ; but it was not until 1910 that the firstbarium meal was given, and not until 1912 that themethod was considered useful in chest disease.The 1914-18 war abruptly terminated much clinical

radiological research, but this was perhaps compen-sated by the fact that many younger medical men

, gained their first knowledge of radiology in the fieldand were stimulated to study its peace-time applica-tions. The war clearly showed the urgent need forimproved apparatus, and by 1925 the erratic gas tubehad been superseded by the stable protected Coolidge-

type tube, and the unwieldy coil gave way to thereliable transformer. Exposure times were reducedto fractions of seconds and the closed book of gastro-enterology and chest pathology was quickly opened.Barium examinations became routine, and radio-

graphy of the chest was recognised as an indispensablepart of examination of the respiratory tract. Certainareas, such as the kidneys, the gall-bladder, the brain,and the vascular system-all of the same density-appeared to present an insoluble problem ; but radio-logical research gained such momentum that by 1930suitable and safe contrast agents were evolved for allof them. The years since then have seen steadyprogress both in better equipment and in increaseddiagnostic accuracy, and no limit to either is yet insight. Moreover progress has continued throughoutthe late war, and, with the advent of mass radio-graphy, radiology has entered the field of preventivemedicine.

Within a year of R6NTGEN’s discovery, a numberof people had developed X-ray burns of varyingseverity. Astute observers in different countriesat once saw the therapeutic possibilities of the newagent and began treating superficial tumours andchronic skin diseases. Their achievements were notso spectacular as in the diagnostic field ; and indeed,since the method was purely empirical, there weremore failures than successes. Gradually, however,reliable methods of dosage were worked out andradiation therapy became the recognised treatmentfor many benign and semi-malignant skin lesions.After the 1914-18 war these methods began to comeinto their own with the development of accuratemeans of estimating and delivering exactly a selecteddose of homogeneous rays to a lesion whose radio-sensitivity had been biologically estimated. Radio-therapy has thrown much light on the physiology ofthe cancer cell and has contributed immensely to therelief and in some cases the cure of malignant disease.At the same time, it is clear that the high hopes ofthe early enthusiasts have not been realised, and thatit is not yet the complete solution to the cancerproblem. As with radiodiagnosis, however, no

prediction is safe, and radioactive isotopes producedin the cyclotron may soon yield startling results.

These fifty years have seen the whole science ofmedicine revolutionised, and every branch of it hasbenefited by the impact of radiology. Given another

fifty years of peaceful development the applicationsof RÖNTGEN’S discovery will improve the health andoutlook of mankind to an extent no-one can foresee.

Improving Penicillin ActivityOF the many suggestions for improvement in the

clinical use of penicillin not all have the same purpose.Some are designed to improve the performance of asingle intramuscular dose by prolonging its action,while others have the more fundamental purpose ofincreasing antibacterial range or efficiency, whetherby maintaining a higher blood-level, by synergicaction, or by altering the properties of penicillin itself.Any reduction in the number of doses required will

reduce the tedium of treatment for both the patientand his attendants ; and in the treatment of gonorrhoeain the Services a single dose has obvious administra-tive advantages over a series of doses given every 2 or3 hours for, say, 12 hours. Among vehicles which

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have been tried on a small experimental scale to pro- (

long penicillin action are 20% gelatin, with and without 1

a vasoconstrictor,l saline with various proportions of !’

adrenaline,2 oil or a water-in-oilemulsion,4 and a mixed i

bag of bases of various physical and chemical types.5 1The use of esters of penicillin 678 and combinations of 1

penicillin with proteins 9 has also been suggested in ]the hope that the active substance will be slowlyreleased in the body, and success with the esters hasbeen claimed in mouse-protection tests, the effectivedose of the benzyl ester being said to be smaller than ithat of sodium penicillin.8 The method advocated byROMANSKY and RITTMAN 10 has received a considerableclinical trial. By one injection of 100,000 units ofcalcium penicillin in 1 c.cm. of 4% (by volume) bees- .wax in peanut oil, 93 out of 100 men with gonorrhoealurethritis were cured," and by one injection of 150,000units all of 75. The patients were treated in hospitaland the follow-up period was only two weeks. Theseresults should not be taken too optimistically till theyhave been confirmed by other workers under otherconditions, since elsewhere it has been difficult tomake satisfactory preparations and to repeat thesuccesses. Further, the object of the method is partlyto avoid admission to hospital, and it remains to beseen what irregularities of absorption and eliminationare produced by the ambulant conditions of outpatienttreatment. Even under the most uniform conditionsthe difference between individuals is wide. ThusATCHESON and EDMEADES 11 found that in 23 patientswho received 200,000 units in peanut oil and beeswaxpenicillin was detectable in the blood for periods whichvaried from 4 to 8 hours and in the urine from 14 to 48hours. Similarly the total excreted varied from15,691 to 164,639 units. Taking the average for allthe patients the concentration in the blood would haveinhibited a sensitive staphylococcus in vitro for about8 hours. The injection would therefore have to berepeated at least 12-hourly in, say, acute osteomyelitis,and the consumption of penicillin would be three tofour times that by infusion or 3-hourly injection. The

advantages of this method, therefore, even if it provessatisfactory for diseases other than gonorrhoea, mustbe weighed against its extravagance-though this per-haps is only a temporary consideration.

Several lines of research have been followed inthe attempt to keep up a higher level of penicillin inthe blood in face of the ever-present difficulty of"

filling the bath with the plug out." At present thesurest way to maintain a high blood-level is by thecontinuous infusion of much greater amounts of

penicillin than are customary or necessary for curinginfections by sensitive bacteria. RANTZ, KIRBY, andRANDALL 12 showed that continuous intravenousinfusion of 400,000 units in 24 hours would maintain1. Parkins, W. M., Wiley, M., Chandy, J., Zintel, H. A. Science,

1945, 101, 203.2. Fisk, R. T., Foord, A. G., Alles, G. Ibid, p. 124.3. Raiziss, G. W. Ibid, 1944, 100, 412.4. Cohn, A., Kornblith, B. A., Grunstein, I., Thomson, K. J.,

Freund, J. Proc. Soc. exp. Biol., N.Y. 1945, 59, 145.5. Armstrong, C. D., Halpern, R. M., Cutting, W.C. Ibid, 1945, 58, 74.6. Meyer, K., Hobby, G. L., Dawson, M. H. Ibid, 1943, 53, 100.7. Hickey, R. J. Science, 1945, 101, 462.8. Cavallito, C. J., Kirchner, F. K., Miller, L. C., Bailey, J. H.,

Klimek, J. W., Warner, W. F., Suter, C. M., Tainter, M. L.Ibid, 1945, 102, 150.

9. Chow, B. F., McKee, C. M. Ibid, 1945, 101, 67. Perlstein, D.Liebmann, A. J. Ibid, 1945, 102, 174, 197.

10. Romansky, M. J., Murphy, R. J., Rittman, G. F. J. Amer. med.Ass. 1945, 128, 404.

11. Atcheson, D. W., Edmeades, D. T. Science, 1945, 102, 199.12. Rantz, L. A., Kirby, W. M. M., Randall, E. J. clin. Invest.

1944, 23, 789.

0-42 units per c.cm. in the blood (average of 4 subjects),with proportionately lower levels from smaller doses.SMITH and HARFORD 13 got closely similar figures withintramuscular infusions, though there was variationbetween different subjects. They found that 800,000units in 24 hours maintained a level of 0-6-0-8 units

per c.cm., while with 100,000 units hourly the levelwas 1-5 units per c.cm. at 3 hours, and 3-0 units at 9and 12 hours. A high proportion of their subjects-young patients with early syphilis-had a local orgeneral reaction. Without indicating the relationof the incidence of reactions to the size of the doseor to the batch of penicillin used, these workersconclude that with the preparations of penicillinnow obtainable intramuscular infusion should notbe used as a routine. Seeing that this method hasbeen much used in this country and elsewhere withoutunfavourable reports, this conclusion cannot beaccepted. It seems likely, as SMITH and HARFORDsuggest, that if penicillin were plentiful infectionsby some relatively insensitive bacteria could be con.trolled in this way. RAMMELKAMP and BRADLEY 14were the first to relate the rapid clearance of penicillinfrom the serum to excretion by the tubule epitheliumof the kidneys, seeing a parallel to other rapidlyeliminated substances known to be excreted throughthe tubules. They tested the idea by giving diodone(’Diodrast ’) simultaneously with penicillin andobserved the same slowing of excretion which occurswhenever two substances excreted by the tubules aregiven together. BEYER and his collaborators 15 areattempting to establish an experimental basis for-

applying this principle in therapeutics. The sub-stance chosen to compete with penicillin in the tubulesis para-aminohippu ric acid, and from experiments inman and animals it is clear that the simultaneousadministration of this substance will under appro-priate conditions raise the level of penicillin in theserum from 2t to 4 times. Infusion of the two sub-stances together into a vein gave the best results,and the rise in the level of penicillin in the serum andits fall in the urine began and ended quite sharply asthe p-aminohippuric acid was begun and stopped. No toxic effects could be detected, but there wassome oedema from the large amount of fluid infused(3 c.cm. a minute to a dog). A few similar experi-ments on man by LOEWE and others 16 support thesefindings.

,

Another attempt to apply this principle has beenmade by BRONFENBRENNER and FAVOUR 17 by givingbenzoic acid, which is changed in the normal liverwith the formation of hippuric acid. Several subjectsreceived 2-5 g. of benzoic acid 4-hourly by mouth and20,000 units of penicillin intramuscularly 20-30minutes after eacli dose of benzoic acid. On anunrestricted diet the penicillin level in the serum in thefirst hour after injection was usually about doublewhat it would have been without benzoic acid, but ifthe fluid intake was limited to 1-1-1 litres and the saltintake to 3 g. the level was raised 4-8 times. Once13. Smith, R. O., Harford, C. G. J. Lab. clin. Med. 1945, 30, 502.14. Rammelkamp, C. H., Bradley, S. E. Proc. Soc. exp. Biol., N.Y.

1943, 53, 30.15. Beyer, K. H., Flippin, H., Verwey, W. F., Woodward, R.

J. Amer. med. Ass. 1944, 126, 1007. Beyer, K. H., Verwey,W. F., Woodward, R., Peters, L., Mattis, P. A. Amer. J. med.Sci. 1945, 209, 608. Mattis, P. A., Beyer, K. H., McKinney,S. E., Patch, E. A. J. Pharmacol. 1945, 84, 147.

16. Loewe, L., Rosenblatt, P., Alture-Werber, E., Kozak, M. Proc.Soc. exp. Biol., N.Y. 1945, 58, 298.

17. Bronfenbrenner, J., Favour, C. B. Science, 1945, 101, 673.

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the high.peak had been reached, however, the rate ofdecline was similar to that in control experiments anda demonstrable blood-level of penicillin was not main-tained for longer than 3 or 4 hours. To maintainlevels substantially above those which would havebeen reached by the penicillin alone it was necessaryto inject the penicillin every 2-3 hours, and to givebenzoic acid every 4 hours, as well as restricting thediet. This method seems more unpleasant for thepatient, and less effective in maintaining a high levelof penicillin in the blood, than BEYER’S.To enhance the action of penicillin the possibility

of synergism has been considered-especially with thesulphonamides. When dry preparations of penicillinfor local application were first required on a large scale

. sulphanilamide powder was chosen to dilute the peni-cillin,18 for no reason except that it would be absorbedfrom a wound without producing irritation, its anti-bacterial action in the presence of pus being negligiblecompared with that of the penicillin. Again, it waslargely because it could be given by mouth to checkthe infection before penicillin therapy could be begunthat CAtrTS 19 recommended using sulphadiazine orsulphamezathine as well as penicillin for preventingor treating meningitis. There is, however, some evi-dence of synergism between the sulphonamides andpenicillin against the gram-positive cocci, the increasein the titre of the penicillin in vitro being usuallyabout two-fold,2O though some have failed to demon-strate any synergism 21 22 and it could not be demon-strated against strains of actinomyces.23 Animaltherapeutic experiments have had varied results.22 24In mice infected with streptococci Soo-Hoo andSCHNITZER 24 obtained some evidence that if penicillinand a sulphonamide were both given in subtherapeuticdoses survival was better than from the same doseof each alone. They tried other substances but

only p-nitrobenzoic acid had an effect similar to thesulphonamide. In clinical reports on the eliminationof penicillin-sensitive organisms there is no convincingevidence of synergic action,23 25 and in any event littlewould be gained by it where the organisms are verysensitive to penicillin. Where an organism is fairlysensitive to the sulphonamides and relatively resistantto penicillin a synergic effect might with advantage’be sought.Much more desirable would be a synergic effect

which would bring gram-negative bacilli and othervery resistant organisms into therapeutic range.SHW ARTZMAN, 26 who has investigated the resistance ofBact. coli to penicillin has recently shown that if alarge amount (e.g. 3-125 mg. per c.cm.) of the amino-acid methionine sulphoxide is added to the medium,and if methionine and threonine are also present, theactivity of penicillin against gram-negative organismsis enhanced, usually from two to four times. Muchmore exploration of this and kindred subjects is needed,but it seems doubtful whether anything less than a

18. Florey, H. W., Cairns, H. Report to War Office and MRC,October, 1943.

19. Cairns, H. Brit. J. Surg. 1944, 32, 199.20. Ungar, J. Nat., Lond. 1943, 152, 245. Bigger. J. W. Lancet,

1944, ii, 142. Chain, E., Duthie, E. S., Callow. D. Ibid, 1945, i, 652.21. Kirby, W. M. M., Proc. Soc. exp. Biol., N.Y. 1944, 57, 149.

Hobby, G. L., Dawson. M. H. Ibid, 1944, 56, 184.22. von Sallmann, L. Arch. Ophthal. 1944, 32, 190.23. Dobson, L., Cutting, W. C. J. Amer. med. Ass. 1945, 128, 856.24. Soo-Hoo, G., Schnitzer, R. J. Arch. Biochem. 1944, 5, 99.25. Oard, H. C., Jordan, E. V., Nimaroff, M., Phelan, W. J. J. Amer.

med. Ass. 1944, 125, 323. Appelbaum, E., Nelson, J. Ibid,1945, 128, 778.

26. Shwartzman, G. Science, 1945, 102, 48.

modification of the penicillin molecule could make iteffective in infections by such organisms. With thelifting of war-time restrictions we may hope soon tosee in print much of what is known about the chemi-stry of penicillin and the possibilities of modification.

Immunisation against Protozoal DiseasesSOME immunity to protozoal infection must

develop in nature, for without it the native cattle andbig game in the trypanosomiasis areas of Africa, andthe human inhabitants of the endemic malaria areas ofthe world, could not survive. But what this immunityreally is has been difficult to establish. The mainten-ance at a high level of the host’s immunity to sleepingsickness and malaria probably depends on the continu-ance of a low-grade infection to which he has becometolerant and with which he lives in comparative amityso long as his general resistance is not debased byextraneous factors. This state of continued infectionhas been called " premunisation." Allied with some

hereditary tolerance, the result of long-continuedinfection of the host’s forebears, it enables, for

example, the big game of Africa without seemingdetriment to harbour species of trypanosomes whichprove rapidly lethal to non-immune stock from non-endemic areas. The same applies to the African

native ; after the heavy initial morbidity and mortal-ity associated with malaria acquired in earliest infancyhe becomes progressively less troubled by his constantchronic and periodically renewed malarial infectionuntil, after puberty, he can disregard it. Indeed itwould be harmful to free him of this infection, keephim free from reinfection for some years, and thenreturn him to the endemic area, for he would suffernearly as much from his reinfection as the completelynon-immune European. Examples of this are seenamong West Africans who revisit their homes afterspending some years in Europe.The artificial immunisation of humans against any

of the protozoal infections has not so far been success-ful. Much has been attempted in this direction withstock, in an effort to introduce better breeds of cattleinto the pastoral zones of tropical Africa ; but hereagain dubious success has attended the experiments.Lately, however, FREUND and his colleagues in NewYork have reported favourable results from theirefforts to immunise ducks against the avian malariaparasite Plasmodium lophurae,1 and rhesus monkeysagainst the simian malaria parasite P. knowlesi.2 An

antigen was prepared from intra corpuscular parasiteskilled in formalin, and adjuvants were added to theinoculum in the form of liquid paraffin, a lanolin-likeproprietary substance, ’Falba,’ and sometimes killedtubercle bacilli. The vaccines were given intosubcutaneous tissue or muscle on two or three occa-sions, with intervals of at least a month between theinjections. The ducks or monkeys were subsequentlyinfected with the appropriate living parasites and thecourse of the infections were studied with adequatecontrols. In the ducks the infection was considerablymilder in the vaccine-treated birds than in thecontrols, and only one of the eight birds so protecteddied, compared with four deaths among the eightcontrols. In the monkeys a fatal infection was

1. Freund, J., Sommer, H. E., Walter, A. W. Science, 1945, 102,200.

2. Freund, J., Thomson, K. J., Sommer, H. E., Walter, A. W.,Schenkein, E. L. Ibid, p. 202.