603 the high.peak had been reached, however, the rate of decline was similar to that in control experiments and a demonstrable blood-level of penicillin was not main- tained for longer than 3 or 4 hours. To maintain levels substantially above those which would have been reached by the penicillin alone it was necessary to inject the penicillin every 2-3 hours, and to give benzoic acid every 4 hours, as well as restricting the diet. This method seems more unpleasant for the patient, and less effective in maintaining a high level of penicillin in the blood, than BEYER’S. To enhance the action of penicillin the possibility of synergism has been considered-especially with the sulphonamides. When dry preparations of penicillin for 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 absorbed from a wound without producing irritation, its anti- bacterial action in the presence of pus being negligible compared with that of the penicillin. Again, it was largely because it could be given by mouth to check the infection before penicillin therapy could be begun that CAtrTS 19 recommended using sulphadiazine or sulphamezathine as well as penicillin for preventing or treating meningitis. There is, however, some evi- dence of synergism between the sulphonamides and penicillin against the gram-positive cocci, the increase in the titre of the penicillin in vitro being usually about 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 Animal therapeutic experiments have had varied results.22 24 In mice infected with streptococci Soo-Hoo and SCHNITZER 24 obtained some evidence that if penicillin and a sulphonamide were both given in subtherapeutic doses survival was better than from the same dose of each alone. They tried other substances but only p-nitrobenzoic acid had an effect similar to the sulphonamide. In clinical reports on the elimination of penicillin-sensitive organisms there is no convincing evidence of synergic action,23 25 and in any event little would be gained by it where the organisms are very sensitive to penicillin. Where an organism is fairly sensitive to the sulphonamides and relatively resistant to penicillin a synergic effect might with advantage’ be sought. Much more desirable would be a synergic effect which would bring gram-negative bacilli and other very resistant organisms into therapeutic range. SHW ARTZMAN, 26 who has investigated the resistance of Bact. coli to penicillin has recently shown that if a large 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, the activity of penicillin against gram-negative organisms is enhanced, usually from two to four times. Much more 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 it effective in infections by such organisms. With the lifting of war-time restrictions we may hope soon to see in print much of what is known about the chemi- stry of penicillin and the possibilities of modification. Immunisation against Protozoal Diseases SOME immunity to protozoal infection must develop in nature, for without it the native cattle and big game in the trypanosomiasis areas of Africa, and the human inhabitants of the endemic malaria areas of the world, could not survive. But what this immunity really is has been difficult to establish. The mainten- ance at a high level of the host’s immunity to sleeping sickness and malaria probably depends on the continu- ance of a low-grade infection to which he has become tolerant and with which he lives in comparative amity so long as his general resistance is not debased by extraneous factors. This state of continued infection has been called " premunisation." Allied with some hereditary tolerance, the result of long-continued infection of the host’s forebears, it enables, for example, the big game of Africa without seeming detriment to harbour species of trypanosomes which prove 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 infancy he becomes progressively less troubled by his constant chronic and periodically renewed malarial infection until, after puberty, he can disregard it. Indeed it would be harmful to free him of this infection, keep him free from reinfection for some years, and then return him to the endemic area, for he would suffer nearly as much from his reinfection as the completely non-immune European. Examples of this are seen among West Africans who revisit their homes after spending 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 with stock, in an effort to introduce better breeds of cattle into the pastoral zones of tropical Africa ; but here again dubious success has attended the experiments. Lately, however, FREUND and his colleagues in New York have reported favourable results from their efforts to immunise ducks against the avian malaria parasite Plasmodium lophurae,1 and rhesus monkeys against the simian malaria parasite P. knowlesi.2 An antigen was prepared from intra corpuscular parasites killed in formalin, and adjuvants were added to the inoculum in the form of liquid paraffin, a lanolin-like proprietary substance, ’Falba,’ and sometimes killed tubercle bacilli. The vaccines were given into subcutaneous tissue or muscle on two or three occa- sions, with intervals of at least a month between the injections. The ducks or monkeys were subsequently infected with the appropriate living parasites and the course of the infections were studied with adequate controls. In the ducks the infection was considerably milder in the vaccine-treated birds than in the controls, and only one of the eight birds so protected died, compared with four deaths among the eight controls. 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.
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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.
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similarly prevented, while the controls had heavyinfections which would probably have proved fatal inthirteen of the fourteen infected if they had not beenkilled for experimental purposes.
This investigation is still in its preliminary stages,and the findings require confirmation, but it never-theless suggests that prophylactic inoculation againstthe protozoal infections of mammals may eventuallybecome a practicable proposition.
Annotations
SCIENCE IN THE USSR
THE war made impossible the free flow of publicationsas well as personal visiting between our country and theSoviet Union. In a recent article Prof. Arnold Sorsbyregrets this the more because we have been so inade-quately informed of Russian progress in medicine andscience. During his visit there, early this year, with agroup of scientists, he was impressed by the " assuredplace research has in the organisation of society."Distances are so great in that vast territory that themedical services as a whole, and research in particular,are decentralised. The medical services are, indeed,conceived on a central plan, but each of the republics inthe Union controls its own services, which supplementthose of the Union as a whole. In addition, cities,industries, collective farms, and other labour organisa-tions have their own services, supplementing the others.He sees Soviet medicine as a national medical service inits widest sense rather than as a State medical service.
Research is organised in the same liberal way. Someinstitutes are controlled by the USSR commissariat ofhealth, others by the Academy of Medicine, or the govern-ments of the various republics. The medical schools anduniversities take a large share in research. Differentresearch departments work well together in spite of greatspecialisation. Thus in Moscow the institutes dealingwith neurology, neurosurgery, occupational diseases, andophthalmology all take the form of large clinical unitswith well-equipped clinical and research laboratories.
They are staffed partly by whole-time laboratoryworkers, partly by others who have both clinical andlaboratory duties. These different workers approach anagreed problem, each from his special angle, and thisplan ensures that the laboratory workers are clear aboutthe clinical needs, and the clinicians are aware of thepossibilities and limitations of the laboratory. Allclinical institutes are broadly planned with many specialdepartments ; so that work on ophthalmology, for
example, is proceeding in the institutes of neurology,neurosurgery, and occupational therapy as well as inthe institute of ophthalmology. The interlocking ofresearch enables workers in the Soviet laboratories to learnmore of unpublished work than is customary elsewhere,so that publication has not the same importance as inGreat Britain. Professor Sorsby feels that this is onemore reason for regretting our lack of personal contactwith Soviet scientists.The training of doctors has been adapted to needs over
‘ the past years : when a large increase was wanted,standards were not too exacting. In 1913 there were fewerthan 20,000 doctors in the Czarist Empire ; under theSoviet Union today there are 150,000-still too few. Asnumbers rose the standard of training was improved, andits duration is now fixed at six years in Moscow ; trainingof this length is to be made universal within the next fouryears. Specialisation in the last year of training is nolonger necessary. The Union, however, is continuing totrain " feldschers," who are something like our oldbarber-surgeons. They undertake routine work undersupervision. The persistence of this grade, Professor
1. Nature, Aug. 25, p. 226.
Sorsby suggests, is the price paid for the intensive train-ing of physicians : it will disappear in time. Studentsare paid during training, and their salary is raised eachyear. On qualifying they are required to do three years’service wherever in the USSR the need is greatest.Postgraduate study is the rule.
Prof. E. D. Adrian, FRS, who was also among thosevisiting the Soviet Union, notes that there have beenfew outstanding advances in physiology in recent yearseither in the USSR or elsewhere ; but a general raising ofRussian standards in training and equipment has shownits effects in the quality of the work published. The seniorphysiologists are,of high repute, many of them pupils ofPavlov ; and they are training juniors of like calibre.The central nervous system is keenly studied, and newfields are being approached with new techniques. Theoutput to be expected of this great body of physiologists,in years to come, will presumably exceed that of anycountry in Europe ; and it is significant, he feels, that thefirst international meeting of scientific workers since thewar has been held in the USSR.
ETHER AS IRRITANT
DESPITE the cessation of open hostilities in otherspheres, controversy continues unabated between theanaesthetists who claim to give ether without ill effectsand those to whom its use is " criminal." On the fencebetween sit those who, while deprecating its " toxicity,"confess to using it in
" minimal " quantities. One of thebones of contention now well-gnawed by both sides is theeffect of ether on the respiratory system. The " antis "
have it that ether is responsible for most postoperativerespiratory complications. The " pros " maintain thatthe site of operation is the big determining factor andthat the choice of anaesthetic agent plays an insignificantpart. On the one side we find Beecher and Adams 3
describing ether as a desirable anaesthetic for intra-thoracic operations, while writers in the opposite campstill stress the irritant effect of ice-cold ether on thetracheobronchial tree. It has long been known that theheat capacity of a gas is so low that a very little heat willwarm up a considerable volume. Thus, Epstein andPask demonstrated that anaesthetic gases passingthrough a standard corrugated breathing-tube reach thepatient at room temperature, irrespective of the tempera-ture at which the gases enter the tube. Traina 5 hasrecorded the temperature in the pharynx during nasalinspiration at various atmospheric temperatures. Whenthe atmosphere is at 0° C the temperature in the pharynxis 36° C. Lately Moritz and Weisiger 6 have measuredwith thermocouples the temperature at the bifurcationof the trachea in dogs made to breathe cold air for periodsof 20-133 minutes. When air was delivered into the
larynx at temperatures ranging from - 28° to - 50° Cthe readings in the trachea never fell below 18°. Laryn-geal temperatures of - 30° produced a localised sub-laryngeal tracheitis with an increased secretion of mucusand sometimes local destruction of epithelium, but therewas no evidence of injury to the lower portion of thetrachea, the bronchi, or the lungs. The localisation of thedamage is again explained by the -fact that the heatrequired to raise the temperature of cold air manydegrees can be produced by the cooling of a small amountof tissue through a few degrees. Moritz and Weisigerconclude that even if cold air is inhaled rapidly through awidely opened mouth it will be warmed to well abovefreezing-point by the time it reaches the bronchi. Weresuch an efficient mechanism for heating the inspired airabsent, consumptives would hardly be sent to recoveramidst the Alpine snows. Arkels has recently deter-
2. Nature, Aug. 25, p. 222.3. Beecher, H. K., Adams, R.J. Amer. med. Ass. 1942, 118, 1204.4. Epstein, H. G., Pask, E. A. Lancet, 1941, ii, 66.5. Traina, S. Arch. Fisiol. 1931, 29, 385.6. Moritz, A. R., Weisiger, J. R. Arch. intern. Med. 1945, 75, 233.7. Arkels, C. S. Afr. med. J. 1945, 19, 223.
