839EARLY DIAGNOSIS OF AORTIC SYPHILIS

HAROLD WARD DUDLEY, F.R.S.

THE death on Oct. 3rd of Mr. H. W. Dudley, Ph.D.,F.R.S., at the early age of 47, removes one of theoutstanding research workers in biochemistry as

applied to medical problems. As a student at Leedshe came under the influence of J. B. Cohen, one ofthe first organic chemists in this country to see thepromising future that lay before biochemistry. Aresearch scholarship enabled him to spend two

years in Berlin working at the structure of purinesunder Wilhelm Traube in Emil Fischer’s laboratory ;from there he went to Herter’s laboratory in NewYork where he met H. D. Dakin, another of Cohen’sold students, and entered into a fruitful collaborationwith him. Most noteworthy perhaps was the dis-

covery of the enzyme glyoxalase, which rapidlyconverts methyl glyoxal at body temperature tolactic acid. During the late war he was attachedto the R.A.M. College in London, and was sent tothe United States in charge of an anti-gas mission.On his return to England he joined the staff of theMedical Research Council as chief biochemist, a postthat brought him into close contact with colleaguesworking in many different fields of medical research,to whom he gave freely of his deep knowledge ofchemistry and his skill in complex analysis.The first problem presented to him was that of

the chemical nature of the constituents of the pos-terior lobe of the pituitary body ; he was able toshow that the pressor constituent and the con-

stituent responsible for causing contraction of uterinemuscle were separable by chemical means. He thenturned his attention to the newly discovered insulin,and was the first to devise a method of preparation(still used in its manufacture) which gave a dry stableproduct having ten times the activity of the originalcrude material, and to suggest that the hormoneitself was a complex protein derivative-a conclusionamply confirmed later by other workers. Meanwhilein collaboration with 0. Rosenheim and W. W.

Starling he proved the constitution of spermine andspermidine, two bases now known to be generaltissue constituents for which no physiological functioncan yet be even suggested. The importance of cer-tain vasodilator constituents of the animal bodywith a histamine-like action for the normal function-

ing of the capillaries had long been emphasised bySir Henry Dale. Dudley, in collaboration withW. V. Thorpe,- was able to identify the substancehaving this action with histamine itself, which wasisolated from several organs under conditions whichprecluded putrefactive changes. Next came a bril-liant research with Dale which led to the isolationof acetylcholine from horse and ox spleen. HereDudley’s analytical skill was shown at its best; hismethod of separating this unstable substance fromcholine and other substances present by means oftheir chloroplatinates bears the stamp of genius.Dudley’s last research, which was fortunately

brought to a successful conclusion before his untimelydeath, dealt with the active principle of ergot. Ithad been assumed that the substances active towardsthe uterine muscle were the alkaloids ergotoxine andergotamine, but in 1932 Chassar Moir obtained directevidence that aqueous extracts of ergot free fromthese complex alkaloids were active when adminis-tered by the mouth. The active principle musttherefore be different from any of those knownhitherto and Dudley undertook a chemical investiga-tion of this unknown substance in association withthe direct clinical observations of Moir. The resultwas the isolation of a new water-soluble alkaloid,

ergometrine, which in minute doses has the charac-teristic activity of ergot. This discovery of ergo-metrine, which solves a long-standing problem ofthe pharmacology of ergot and its use in therapeutics,has aroused widespread interest, as is shown bythe fact that it has already been confirmed, ineffect, in three other laboratories where researchwas independently in progress. While his maininterests were definitely in the laboratory Dudleydid not neglect those other biochemical activitieswhich he was called upon to perform. From 1922-24he was secretary of the Biochemical Society, andfrom 1925-30 joint editor with Prof. Harden of theBiochemical Journal. He was also for many yearsan assistant editor of Chemical Abstractsandwasrespon-sible for the high level of the section of abstracts

dealing with biochemistry. His great attainmentswere recognised in his election to the fellowship ofthe Royal Society in 1930.

EARLY DIAGNOSIS OF AORTIC SYPHILIS

SYPHILIS of the aorta usually causes death withina few years of its clinical recognition. Affectingmost often the ascending portion of the vessel it isliable to damage the mouths of the coronary arteriesand the cusps of the aortic valves. If the inflam-matory process is confined to the transverse or

descending part of the arch, these vital structuresescape and the prognosis is much less grave.

There is reason to think that the aortic wall isinvaded early in the course of syphilitic infection,and that it is not until the destructive process hasbeen at work for many years that symptoms ariseand the diagnosis of aortic syphilis is made. Hencethe relatively poor results of treatment. In manydiseases subjective symptoms, indicating alteredfunction, precede any detectable alteration in struc-ture. In aortic syphilis, however, it has been sug-gested that a structural change may be recognisedlong before symptoms arise. E. P. Maynard andco-workers claim to diagnose such cases radio-graphically, and they have been able to investigate346 patients by working in cooperation with a syphilisclinic, and investigating the cardiovascular systemof every patient attending it, irrespective of the

stage of the disease and the symptoms complained of.All who have studied the X ray appearances of theaorta will appreciate, nevertheless, that the recog-nition of slight abnormality in the width of thisvessel is not easy. The width varies with age andwith the shape of the chest, and can be altered byother factors such as atheroma and high blood

pressure. The investigators use the method of

Vaquez and Bordet for measuring the vessel width,and after excluding cases with high diaphragm,scoliosis, a systolic pressure over 140 mm. Hg, orrheumatic aortic lesions, and patients with arterio-sclerosis or over fifty years of age, they accept anymeasurement over 7 cm. as pathological, and onebetween 6 and 7 cm. also, if the ascending aorta isprominent. Of 77 patients examined within nine

years of infection, 14 had aortic syphilis, but only4 of these had symptoms referable to the lesion.The proportion with aortitis gradually increasedwith the period since infection, and so did the pro-portion of these with symptoms ; out of 17 patientsexamined thirty years or more after infection 15were found to have cardiovascular syphilis. In the145 patients who showed evidence of aortic syphilisthe mean interval between infection and evidence of

1 Arch. Internal Med., 1935, lv., 873.

840 CHEMOTHERAPY IN STREPTOCOCCAL INFECTIONS

cardiovascular syphilis was twenty years ; yet in 25per cent. it was within ten years.On the other hand, H. Schlesinger 2 thinks that

certain clinical features are sufficient for an earlydiagnosis, even in the absence of X ray changes andof a positive Wassermann test. He attaches import-ance to certain signs usually considered too late inappearance to be of value, such as a distant first,and a ringing second aortic sound in conjunctionwith a low systolic pressure, aortic incompetence,and a systolic murmur at the aortic area. Symptomswhich he regards as of great diagnostic value includedyspnoea of sudden onset and without obvious cause,and aortalgia-i.e., retrosternal pain not related toeffort. Severe and long-lasting retrosternal pain,similar to that of atheromatous coronary occlusion,is also described, but it is stated that there is nosense of impending death, and that this is an impor-tant point in differential diagncsis. This symptom,however, is thought to-day to be neither constantlynor specifically related to coronary occlusion, andits absence cannot therefore be held to be of muchhelp in diagnosis. Many of these symptoms obviouslydepend on lesions involving the aortic cusps and

coronary orifices ; and it would seem that whenthese complications have developed the pathologicalprocess has gone too far for diagnosis to be of much

CHEMOTHERAPY IN STREPTOCOCCAL

INFECTIONS

THE limitations of chemotherapeusis in controllinginfective diseases are as remarkable as its successes.In a lecture delivered to the section of tropicaldiseases and parasitology of the Royal Society ofMedicine on Oct. 3rd Prof. H. Horlein, of Diisseldorf,elaborated the thesis that the possibility of com-

bating infective diseases with chemotherapeuticallyactive substances depends to a large extent on thestructure of the pathogenic organism. The more

highly developed the pathogenic organism, the morepoints for attack it appears to offer to the action ofchemotherapeutic substances. Many infections withdifferent kinds of protozoa and spirochaetes haveyielded to appropriate synthetic remedies, butbacterial infections generally have hitherto proveddisappointingly resistant to such agents ; and apartfrom the cure of contagious pleuro-pneumonia in horseswith neoarsphenamine, we have, as yet, no chemo-therapeutic substance which is active in virus diseases.Not only spirochsetal diseases such as syphilis,relapsing fever, framboesia, and protozoal diseasessuch as trypanosomiasis, malaria, amcebic dysentery,and leishmaniasis, but epizootics resembling humandiseases are also relatively easy to deal with by syn-thetic drugs. Diseases of animals which, though attri-butable to protozoa, are not closely related to thetropical diseases of man are not amenable to suchtreatment. The most important of these epizooticsare the piroplasmoses, which are caused by babesiseand theilerise and are found notonly in tropical andsubtropical regions but also in temperate zones.

Piroplasmosis is a condition marked by chronic

irregular fever, enlargement of the spleen, bronchitis,cedema, of the feet, subcutaneous h2emorrhage, anddiarrhoea. It affects dogs, horses, sheep, and oxen.Trypan-blue, originally recommended by G. H. F.Nuttall for this condition has been used againstthe disease with some measure of success. Prof.Horlein claims that a new compound Acaprinprepared in his laboratories is three times as

2 Arch. f. Inn. Med., 1935, xxvi., 341.

active as is trypan-blue for piroplasmosis. Evenmore interesting, however, are his claims for twoother new compounds Prontosil and Prontosil S.,which are said to be potent against infections causedby hsemolytic streptococci. The results of the

administration of either of these two compounds,which can be given by mouth or by subcutaneousinjection, to mice experimentally infected with thisorganism by the intraperitoneal route have beenso encouraging as to lead to their trial in humanpatients. 1500 case records are now available inGermany of acute infections caused by the Streptb-coccus haemolyticus and treated by prontosil or

prontosil S. These infections included many casesof puerperal sepsis. The results as a whole weredescribed by Prof. Horlein as being strikingly suc-cessful, though exact figures are still to come. Inthe course of the discussion Dr. G. A. H. Buttle, work-ing at the Wellcome Research Laboratories, describedhis own experience with the drug in infected mice.Whereas in Prof. Horlein’s series all the affiictedmice recovered, Dr. Buttle, using different strainsof streptococci, was not successful in doing more thandelaying death. But it emerged that certain dif-ferences in technique might have accounted for thediscrepancy, and Dr. Buttle left no doubt in theminds of the audience that the new compound is

therapeutically active ; the point at issue is onlyone of degree.. Dr. P. Manson-Bahr, who presidedover the meeting and translated Prof. Horlein’s

replies, which were made in German, with con-

siderable skill, voiced the impression of all presentthat a contribution to chemotherapeutics had beenmade by Prof. Horlein and his co-workers whichmight indeed prove to be monumental.

NEXT Friday, Oct. 18th, Sir Henry Dale, F.R.S., willdeliver the Harveian oration of the Royal College ofPhysicians of London. His title is Some Epochs inMedical Research.

THE Metropolitan Hospital last week announcedits incorporation as a company limited by guarantee.The management committee will thereby avoidpersonal responsibility for the discharge of the

hospital’s liabilities, should the assets at any time beinsufficient for the purpose. Such a responsibility,however remote, might, it was felt, deter personswhose services would be valuable to the hospitalfrom joining the committee. When the Queen’sHospital for Children recently took a similar stepwe pointed out the convenience to a hospital of

becoming an independent legal entity with an

existence separate from the existence of the totalof its members. The system of incorporated com-panies dispenses with the system of trustees.