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normal people have been reported by many observers,and variations of 20-30 per cent. have been recordedin a given subject during the same day. The methods

employed have not been so precise as those nowavailable. Colorimetric methods do not allow forthe effect of variations in substances other thanhaemoglobin, such as lipids, which may affect thelight absorption of the samples. Oxygen-capacityvalues can be significantly lowered by the amount ofcarbon monoxide in the blood of modern man. In

eighteen young men haemoglobin determination byVan Slyke and Hiller’s manometric CO capacitymethod were performed at intervals of two to threehours from 9 A.M. to I P.M. on one or more days.The range between highest and lowest values in anindividual through a day averaged 1-3 volumes percent., the greatest range seen in any of the twenty-three observed days being 2-3 volumes per cent.,equivalent to 11 per cent. of the mean hsemoglobincontent for the day. Usually the haemoglobin contentwas lower in the evening than in the morning ; buta subject showing this change on one day reversedit on another. The accuracy of this method is shownby the fact that the mean difference between dupli-cate analyses was only 0-06 volume per cent. Dr.MacCarthy attributed the much greater ranges ofdiurnal haemoglobin variation reported in the pastliterature to the less accurate methods of analysis.He thought the time variations were possibly due to thedischarge of some reservoir such as the spleen. Themain point of the present investigation was to findout what margin of error it was necessary to allowfor in assessing the significance of changes in

haemoglobin readings from day to day.

ROYAL SOCIETY OF TROPICAL MEDICINEAND HYGIENE

AT a meeting of this society on June 15, withSir RIGg 1RD CHRISTOPHERS, the president, in thechair, a discussion on

The Sulphonamides in Tropical Medicinewas opened by Dr. G. A. H. BUTTLE. He traced the

stages in the development of sulphonamide therapyfrom the discovery by G. Domagk in 1935 that Pron-tosil Rubrum is therapeutically active against strep-tococcal infections in mice. Later in 1935 J. Trefouel,F. Nitti and D. Bovet observed that the simplercompound sulphanilamide is equally effective, andsince then the activity of various sulphanilamidederivatives has been investigated. These derivativescan be divided into two classes according to whetherthe substituents are introduced into the amino groupor the amide group of sulphanilamide: examplesof the former are prontosil rubrum, Prontosil Soluble,Rubiazol, Proseptasine and Soluseptasine, and of thelatter Uleron, Albucid and M. & B. 693. Substancesin the first group probably break down into sulphanil-amide, whereas those in the second group are probablythemselves the active agents.The first group is on the whole less toxic but also

less effective than sulphanilamide-in mice thera-peutic doses of proseptasine, which is poorly absorbed,produce a sulphanilamide concentration in the bloodof only 4 mg. per 100 c.cm., this being less than aquarter of that obtainable with sulphanilamide.Proseptasine is therefore not suitable for severe

or resistant infections. Rubiazol, which is like

prontosil rubrum with an added carboxyl group,and which seems to break down in the body moreslowly than prontosil, is milder in action and

relatively non-toxic. Soluseptasine and prontosilsoluble, given parenterally, are rapidly excreted,so that injections should be given at short intervals.Since 5 c.cm. of either compound is equivalent onlyto about half of a 0-5 g. sulphanilamide tablet,enormous quantities (about 120 c.cm. daily) are

necessary if no preparation is given orally-that is,assuming that sulphanilamide is the active principle.Of the second group of derivatives M. & B. 693 has,Dr. Buttle said, a range of activity definitely greaterthan that of sulphanilamide : it has given good resultsin pneumonia and meningococcal meningitis, and toa less extent in pneumococcal meningitis and instaphylococcal infections. Uleron is used mainlyin gonorrhoea ; except for its effect on the nervoussystem it is less toxic than sulphanilamide, and thepossibility of peripheral neuritis developing may becombated by giving short courses. Albucid hasgiven good results in gonorrhoea and no toxicsymptoms have been noted with this drug. Themode of action of sulphonamide drugs is as yet anopen question : the essential part of the sulphanil-amide molecule for in-vitro activity appears to besulphanilic acid, but it seems that the amide is

necessary in vivo.Filarial elephantiasis appears to have been cured

(H. Floch 1936, P. Berny and E. Gippet 1937,M. Advier 1937, M. Chabeuf 1938) by small dosesof prontosil rubrum or proseptasine-namely, 1-5 g.daily for six days. The effect is due to the actionof the drugs on the secondary infection, and not on thefilaria itself. ’

In malaria L. T. Coggeshall (1938) has shown that0-5 g. sulphanilamide, given to monkeys on the first,third and fifth days after infection with Plasmodiumk-,nou7lesi, prevents the appearance of the parasitesin the blood altogether, whereas they appear incontrol animals on the fourth day and death occursin from nine to twelve days: if sulphanilamide isstarted on the fourth day after infection the parasitessometimes disappear within two days. Given beforeinfection it appears to have a prophylactic effect.On the other hand with P. relictum or P. cathemeriumin canaries, and with P. lophuriae in chicks the drugcauses no delay in the appearance of the parasites-the sodium salt of M. & B. 693 produces a delay ofone day only. R. N. Chopra (1939) reports thatM. & B. 693 is more effective than Atebrin in monkeymalaria. In 5 cases of G.P.I. bitten by mosquitoesinfected with P. falciparum, J. A. Sinton and others(1939) showed that proseptasine (9 g. daily beforeinfection and continued until eight hours afterinfection) prevents the appearance of parasites (inthe one failure the incubation period was twenty-two days compared with eleven days in the controlcases) but experiments made by W. Kikuth on canariessimilarly infected with sporozoites of P. relictumgave negative results. In the treatment of tertianand quartan malaria beneficial effects are reportedby some authors (D. de Leon 1937, Y. van der Wielen1937, R. A. Hill and M. H. Goodwin 1937, and R.Pakenham-Walsh and A. Rennie 1938) whereas others(W. E. B. Hall 1938, G. H. Faget et al. 1938, andA. N. Kingsbury 1938) met with failure, perhapsbecause of differences in the susceptibility of differentstrains of plasmodia. Dr. Buttle pointed out thatthe drugs do not seem to be nearly as effective in thehuman disease as in monkeys, so that they are notlikely to prove useful in the treatment of establishedcases in man.Turning to bacterial infections, Dr. Buttle referred

to the large number of favourable reports on

M. & B. 693 in pneumonia, and to the value of

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M. & B. 693 and sulphanilamide in meningococcalmeningitis-e.g., R. B. Usher Somers 1939, J. Bryantand H. D. Fairman 1939, and G. Muraz et al. 1938.Experimental plague infections of rats and micehave been cured with M. & B. 693 (H. Schiitze 1939),and P. Durand (1939) found that M. & B. 693 (2 mg.per gramme body-weight a day) will protect miceagainst 10,000 m.l.d. of Bacillus pestis. Clinically,J. A. Carman (1937) cured 3 out of 6 cases with

prontosil, and R. S. Vine (1938) reported 3 recoverieswith prontosil soluble in doses of 5-10 c.cm. Sulphanil-amide will protect mice infected with 100 m.l.d.of B. typhosus culture so that it might be usefulin the first week of typhoid fever. K. V. Subbarao(1938) reported benefit in one typhoid case on thefourth day, and E. H. R. Harries and his colleagues(1939) showed that in the established disease theblood-culture becomes negative although in some casesthis takes ten days. Clearly more evidence must beawaited before passing judgment. In guineapigslarge doses of sulphanilamide render the spleen sterilein Brucella abortus fever but infection persists incontrol cases (R. F. Montgomerie 1938 and B. D.Chinn 1938). The guineapig’s spleen is also sterilised inBr. melitensis infections and good experimental resultsare reported by E. E. Menefee and M. A. Poston (1939),although clinically C. Z. Neumann (1938) reportedfailure in this infection, but his dosage was inadequate.Success has been reported in Br. abortus cases butprobably many failures are not made public.The only virus infections on which sulphanilamide

has a direct effect, continued Dr. Buttle, are those oftrachoma and lymphogranuloma inguinale. In experi-mental mouse infections with lymphogranulom(l virusinjected intracerebrally sulphanilamide gives someprotection (F. Bar 1938) and F. 0. MacCallum andG. M. Findlay (1938), reported still better results withthe glucose compound of 4’ : 4-diaminodiphenyl-sulphone. Clinically, G. R. Hamilton (1938) reportsthat sulphanilamide, 6 g. daily gradually reducedto 3 g. daily for eight days, cured 13 out of 15 cases ;2 relapsed and it may be that the drug is only effectiveduring the stage of’ glandular involvement. Intrachoma the corneal improvement with sulphanil-amide is more marked than that of the conjunctiva(B. Lian 1938, F. Loe 1938, and R. Kirk et al. 1938),and E. Burnet and his associates (1939) report similardisparity but greater improvement by a 7 per cent.solution of a derivative of 4’: 4-diaminodiphenyl-sulphone. W. 0. McCammon (1939) reported that in4 cases of smallpox treated with sulphanilamide,0-65 g. three- or four-hourly, the pustular stage didnot develop, whereas 3 other cases in the sameepidemic all had typical pustules and did not recoverso rapidly as the treated cases. In another case(C. King and K. A. de Rozario 1938) the secondaryrise of temperature at the beginning of the pustularstage was prevented by treatment with prontosil,2-5 g. daily. It seems to prevent the secondarystreptococcal infection of the skin with which thepustular eruption is associated and thereby rendersthe disease relatively mild.

Lieut.-Colonel J. A. SINTON held that in malariathe new drugs are not as effective as the old ones.In malignant tertian infection the condition relapsesafter reducing the dose of proseptasine, and againstP. vivax he had observed practically no effect. Inone case with both P. ovale and quartan infectionproseptasine, 6 g. daily for six days, was withouteffect but quinine was satisfactory. In’ this case

proseptasine was continued for eighteen days on

account of the patient’s septic condition and afteran eight days’ interval another course was given but

still with no effect. However he believed that atrue causal prophylactic action was demonstratedwith proseptasine in the 4 malignant tertian casesto which Buttle had referred, and he thought thatthe problem of tropical rural malaria might be solvedby a drug having this action if it was generally applic-able to the tropics and if one or two doses wouldsuffice for two or three months. He suggested thatbetter results might be obtained from a sulphon-amide which is excreted more slowly.

Dr. PHILIP MANSON-BAHR referred to a case ofrecurrent staphylococcal ulceration of the hands oftwo and a half years’ standing, for which a dis-

tinguished surgeon had contemplated removing bothhands. The patient was treated with uleron, andapart from some limitation of movement the conditionhas cleared up completely. In pneumonia, he said,M. & B. 693 is a miracle-the dullness disappearsand the breath sounds become normal within threedays. He had treated 5 cases of Br. abortus infection(all with a positive blood-culture) with M. & B. 693,3 g. daily, reinforced with intramuscular sulphonamide,and in all the temperature fell to normal and the sizeof the spleen diminished; later there was a relapsebut he thinks that this final flare-up may be normal.In one case of Br. melitensis, proved by blood-culture,the patient was better after the same dosage ofM. & B. 693, but he had painful nodules at the site ofinjection. Dr. Manson-Bahr does not favour thistreatment in lymphogranuloma inguinale and climaticbubo in the purulent stage-it is probably necessaryto give sulphanilamide at an early stage-andin a case of ulcerative granuloma due to an

anaerobic non-h2emolytic streptococcus sulphonamidewas without effect. He had seen 2 cases diagnosedclinically as ulcerative endocarditis, and both appar-ently dying, recover after treatment with prontosil,30 c.cm. daily intravenously, together with sulphon-amide by mouth.

Dr. DYCE SHARP said that in one group of 750cases of tetanus in West Africa the mortality-ratewas about 50 per cent., but with sulphonamide treat-ment he had had 5 consecutive recoveries. If themouth was not open (in 3 of his cases lockjawnecessitated rectal feeding) he gave the drug inwater and gum intramuscularly every four hours.Serum was not given since in his view it is useless.

Dr. RAYMOND LEWTHWAITE described experi-ments in which a group of guineapigs were inoculatedwith the rickettsia of typhus (tsutsugamushi) andtreated during the incubation period with variouscombinations of prontosil rubrum, prontosil soluble,soluseptasine, uleron, sulphonamide-P or M. & B. 693.Out of a total of 27 guineapigs 25 had the usual severefebrile reaction and in 2 it was mild. There was nosuccess in the treatment of the established disease.

Dr. N. HAMILTON FAIRLEY said that B. coliinfections in tropical sprue stand treatment withprontosil or proseptasine well and clear up. He

thought M. &. B. 693 particularly useful in thefulminating pneumonia associated with chronicmalarial cachexia. Clinicians in the East, he said,are particularly apt to give drugs by injection whenthey might be given by mouth; this practice isoften responsible for an inadequate dosage of thedrug and for septic infections at the site of injection.

Mr. A. FELix, D.Sc., remarked that from privatecommunications the evidence was against employingsulphonamides in typhoid fever.

Dr. BuTTLE, in reply, posed several questions relat-ing to malaria. What is the effect of the drugs onP. knowlesi infection of G.P.I. cases ? Are thesporozoites of P. vivax influenced by proseptasine ?

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He would like to see work on the sporozoite stage invitro. In tetanus R. L. Meyer (1939), who saystetanus toxin is destroyed in vitro by aerobic incuba-tion with sulphanilamide, has recently reported curein 80 per cent. of mice infected with tetanus spores,but experimental results are not uniform, perhapsbecause of differences in strain. Dr. Buttle suggested

that in brucella infection sulphonamide drugs givenwith Brucellin might be more effective. He wonderedwhether tropical sunlight affects the action of sulphanil-amide adversely (cf. A. J. Nedzel and L. Pincussen1939) and whether the incidence of haematuria afterM. & B. 693 is greater in the East because of theformation of urinary calculi.

REVIEWS AND NOTICES OF BOOKS

Clinical Studies in PsychopathologyBy HENRY V. DICKS, M.D. Camb., M.R.C.P., assis-tant medical director, Tavistock Clinic. London:Edward Arnold and Co. 1939. Pp. 248. 12s. 6d.By putting together his systematic lectures Dr.

Dicks has bridged the gap between the classicalwritings of Freud, Jung and Adler and the loose andoccasional writings which have made psychopathologyaccessible but not necessarily intelligible to thestudent. The task of " getting over " psycho-pathology to the student and practitioner is by nomeans easy. Hitherto the data of mental medicinehave been confined to the more clinical picture oftypes of disturbance, and only clinical psychiatryhas presented the pathology and setiology of psychosissystematically. Even in the writings of the greatpioneers the theory has tended to outrun the clinicalaspects of individual cases, so much so that only the

. analyst has been able to get a really clear grasp ofJung and Freud. Dr. Dicks has here brought theoryand practice together in a volume largely devotedto case-material, clearly expounded in the light ofcurrent theories. To purists of particular schoolshis sober eclecticism will be an irritant, but to thestudent eager to know and to understand the natureof psychogenesis, his method of approach will provea stimulus. The chapters deal in an orderly mannerwith outstanding clinical forms, and the cases givea very fair insight into the mental mechanismsinvolved. Though the expert will join issue withhim on many points of theory and interpretation,no student and practitioner, or prospective psycho-therapist, can afford to ignore this useful study.

Craniocerebral InjuriesBy DONALD MUNRO, M.D., F.A.C.S., surgeon inchief for neurological surgery, Boston City Hos-pital ; assistant professor of neurological surgery,medical school, Harvard University. London:Humphrey Milford, Oxford University Press.1938. Pp. 412. 21s.MuCH more attention is now being paid to the

treatment of head injuries, owing to their increasingfrequency and the general realisation that end-resultsare often unsatisfactory. Provided there has beenno gross operable lesion, treatment has hithertocommonly been relegated entirely to the residentand the sister. The time-honoured formula of atleast three weeks flat in bed has been followed, andthe cases have been considered to be devoid of clinicalinterest. There are now too many head injuries forthe neurosurgeon to accept exclusive responsibility forthem, and it is up to the general surgeon to undertakea fuller study of the problems involved. It is thegeneral surgeon that Dr. Munro here sets out to guide.

In order to rationalise his treatment Dr. Munrodiscusses first the physiology of the intracranialcirculation and of the hydrodynamics of intracranialpressure, and then the changes that may arise as aresult of an injury. Although autopsy findings arebeyond dispute, their significance and their bearing

on the relevant clinical states are at present ill under-stood. The intracranial pressure is not invariablyraised in cases of brain injury, indeed at times it isabnormally low, and it is probably unwise to regardthis single feature of the condition as the criterion ofcomplex disturbances of the intracranial contents.In an endeavour to simplify treatment Dr. Munromakes some dogmatic but rather contradictory state-ments and reaches some doubtful conclusions con-cerning oedema of the brain and congestion of cerebralvessels. Our knowledge of these things is still meagre,and such dogmatism tends to strangle any incentiveto further research. The clinical aspects of thesubject are dealt with exhaustively ; every detail ofdiagnosis and of treatment is discussed, and this sectionshould prove of the greatest value. The especialimportance of nursing care and of feeding is carefullybrought out. In the list of alternative methods of

feeding an unconscious patient the oesophageal tubemight justifiably have been given pride of place, forits use in such cases has probably saved more livesthan any other single method of treatment. Dr.Munro puts great faith in the various methods ofdehydration in the non-operable group of cases, andrecommends that treatment should be controlled byperiodic estimations of the cerebrospinal fluid pressure.Provided this is done, the repeated employment ofmagnesium sulphate per rectum, of intravenous injec-tions of hypertonic solutions, and of drainage of

cerebrospinal fluid by lumbar puncture is rational.Whether the value of these procedures dependsentirely on their effect on the intracranial pressureor whether they also exert a more direct effect on thepathological changes is not yet clear ; this field ofclinical research awaits thorough exploitation.

In this country convalescence is graduated in stages,each advance being dependent on freedom fromsymptoms. Dr. Munro scorns the value of symptoms,and his first period of convalescence begins " whenthe intracranial pressure has been re-established andfixed at norma!," and the patient is then kept fortwo weeks flat in bed, a period that may be far tooshort in severe injuries to the brain. The need forthe patient’s cooperation during his return to a

normal life is well recognised, and the author is

particularly thorough in his management of thiscritical period. His attitude towards the post-contusion syndrome is equally critical, and hisremarks on exploratory trephination deserve carefulattention. In cases needing operation Dr. Munrofollows orthodox lines, except in the treatment oflacerations and compound fractures. " A compoundfracture of the skull," he says, "is a problem in

sepsis and nothing else " but " provided the woundis not manipulated ... significant radial spread ofbacteria does not take place for 48 hours ... withthe exception of hsemolytic streptococci and pneumo-cocci." He recommends that a dry sterile dressingshould be applied to the wound, and the patientshould not be operated on for at least 24 hours afterthe receipt of the injury "whether or not he is inshock during the period." Debridement is performed