418

Though the number of subjects whom we investigatedis small, the difference shown between the incidence ofstress in the coronary-disease group and that in the con-trols confirms the impression (common among doctorsand nurses who deal with large numbers of these patients)that they, and especially the younger ones, are people towhom life has given something of a battering, whether ornot it is of their own seeking. We would thereforewelcome corroboration by further work on a larger seriesof patients.There are two main difficulties in this work. The first

is the dependence on the patient himself as the solewitness of his own stresses, which puts much of the

responsibility for the accuracy of the work on the judg-ment of the interviewer. The other is the perennialdifficulty of establishing a standard of comparison, byfinding the normal subject (or " non-case ") who can beinvestigated in exactly the same way as the patient. Thedevice used to overcome this difficulty in our study hasobvious limitations for more general application.

It might well be profitable to approach the problemfrom the point of view of health instead of disease, usingas the basis a group of

" non-cases " who are presumedfree from coronary-artery disease, and matching them forcomparison with those who have been unsuccessful inavoiding this trouble.

SummaryThe incidence of emotional stress was found by inter-

view to be significantly greater in a group of patients withcoronary-artery disease than it was among their matched

controls, the main differences appearing in the fields ofwork, leisure, and rush-hour travel. The pathogenic roleof stress is discussed with reference to some causes of the

present confusion of opinion.This work was undertaken by means of a grant from the North

West Metropolitan Regional Hospital Board, with material help fromthe Archway Group Hospital Management Committee. We wish tothank both these bodies, and also our colleagues, Dr. T. St. M.Norris and Mr. S. L. Strange, for providing controls from theirpatients.The secretarial side of the investigation, including the assembly

and matching of the subjects, has been in the charge of Mrs.Geoffrey Cook, and it is a pleasure to record our indebtedness to her.

REFERENCES

Arnott, W. M. (1954) Brit. med. J. ii, 891.Bogdanoff, M. D., Estes E. H., Wiessler, A. M. (1960) Sth. med. J. 53, 680.Cady, L. D., Gertler, M. M., Woodbury, M. A. (1961) Geriatrics, 16, 69.Cartwright, A. (1957) Appl. Statist. 6, 1.Dock, W. (1960) Canad. med. Ass. J. 83, 1403.Dreyfuss, F. (1959) Amer. J. Cardiol. 3, 590.Enos, W. F., Holmes, R. H., Beyer, J. C. (1962) ibid. 9, 343.Friedman, M., Rosenman, R. H., Carroll, V. (1958) Circulation, 17, 852.

— St. George, S., Sanford, O. B., Rosenman, R. H. (1960) J. clin. Invest.39, 758.

Hickman, J. B., Cargill, R. H., Golden, A. (1948) ibid. 27, 290.Jouve, A., Dongier, M., Delaage, M., Barrabino, J. (1960) Arch. Mal. Cœur,

2, 154.Lancet (1959) ii, 276.Master, A. M. (1960) J. Amer. med. Ass. 174, 942.Morris, J. N. (1959) in Pathogenesis and Treatment of Occlusive Arterial

Disease (report of Royal College of Physicians’ conference, edited byE. Lawson McDonald); p. 115. London.

— (1961) Yale J. Biol. Med. 34, 359.Miles, H. H. W., Waldfogel, S., Barrabee, E. L., Cobb, S. (1954) Psychosom.

Med. 16, 455.Myasnikov, A. L. (1958) Circulation, 17, 99.Oster, W. F. (1960) Bull. Md Sch. Med. 44, 23.Pomato, A. T., Corsini, I. J. (1961) Rev. Asoc. méd. argent. 75, 559.Reid, D. D. (1958) Practitioner, 180, 184.Russek, H. I. (1958) Amer. J. Cardiol. 2, 129.

— (1959) J. Amer. med. Ass. 171, 503.— (1961) Angiology, 12, 239.

Selye, H. (1950) Stress. Montreal.— (1956) The Stress of Life. New York.

Skeat, W. W. (1958) A Concise Etymological Dictionary of the EnglishLanguage. Oxford.

Sprague, H. B. (1958) Circulation, 17, 1.Texon, M. (1957) Arch. intern. Med. 99, 418.Trulson, M. F., Stare, F J. (1961) Postgrad. Med. 30, 67.Weiss, E. W., Dlin, B. M., Rollin, H. R., Fischer, H .K., Bepler, C. R. (1957)

Arch. intern. Med. 99, 628.Wolf, S. (1960) Mod. Conc. cardiov. Dis. 29, 599.Wright, I. S. (1960) J. Amer. geriat. Soc. 8, 237.

MEASLES VACCINATION OF ADULTS

IN ICELAND

F. L. BLACKPh.D. California

YALE UNIVERSITY SCHOOL OF MEDICINE, NEW HAVEN, CONNECTICUT

MARGRÉT GUDNADOTTIRCand. Med. Reykjavik

INSTITUTE FOR EXPERIMENTAL PATHOLOGY, REYKJAVIK, ICELAND

MEASLES, though not ordinarily a serious disease, maycause death when it attacks very young children, when itis superimposed on malnutrition or other disease, or whenit gains access to populations which have had little or noprevious exposure to the infection. In the first twosituations, the live attenuated measles vaccine has proveduseful (Stokes et al. 1960, Katz et al. 1961). In children itprovokes a pronounced reaction but has not been asso-ciated with any serious complications or sequels. Wehave been investigating the effect of this vaccine in olderpersons and trying to determine its efficacy in protectingpopulations that have been isolated from measles.

In the only previous report of vaccination to includesignificant numbers of adults (Hoekenga et al. 1960)susceptibility was not confirmed serologically; moreover,no adults over 30 years of age were studied. Thepresent trial was organised in conjunction with otherssponsored by the World Health Organisation in severalparts of the world. More detailed analyses and results oflaboratory tests will be published later with reports ofthese other trials of measles vaccine.

In recent times, cases of measles have occurred in themore densely populated parts of Iceland almost everyyear; but most of the country is sparsely populated and theoutbreaks have usually been limited to a few areas. WhileIceland is not, therefore, virgin territory for the measlesvirus, there are many susceptible adults in the ruralareas and mortality-rates have been higher than in otherWestern countries.

The vaccine trials were carried out from June to

September, 1962. A few of the subjects lived in institu-tions near Reykjavik, but most of the vaccinations weredone in the rural areas of Borgarfjardarsysla and Thingey-jarsysla on the west and north coasts respectively.

The Trial

The vaccine and y-globulin used were from lots set aside forthe World Health Organisation by Dr. M. Hilleman of MerckSharp & Dohme Ltd. 0’25 ml. vaccine, containing about8000 infectious units of live attenuated virus, was injected intothe arm of each subject. Half the subjects were also given a doseof y-globulin in the other arm, amounting to 0-02 ml. (or80 units) per kg. body-weight. A third and comparable groupreceived no vaccine at the time of the initial vaccination butwere observed during the period of vaccine reaction in thesame way as the vaccinees; the members of this control groupwere offered vaccine with y-globulin at the end of the controlledtrial, thus swelling the total number vaccinated in this manner.During the period of reaction, subjects were examined by aphysician either daily or, in later trials, every second day.Temperatures were taken rectally at least once a day and moreoften if there was fever.

Specimens of venous blood were obtained from bothvaccinated and control subjects at the time of vaccination and2 to 5 weeks later. Measles haemagglutination-inhibition testswere performed on these specimens by the technique of

Rosen (1961). Only subjects whose prevaccination sera gavenegative reactions have been included in the table of vaccinereactions.

419

FREQUENCY OF FEVER * AND RASH IN VACCINATED AND CONTROL SUBJECTS

* Rectal temperature over 37’5°C

Results

The frequency of fever and rash in the different age-groups is shown in the table, and the mean peak andduration of fever is plotted for each age-group in fig. 1.The frequency, height, and duration of fever were all

slightly lower in the young adults than in the children. Inolder adults who received no y-globulin, these three

parameters of the febrile response increased again to

levels near those seen in childhood. The frequency ofrash showed no clear trend with age : in general, it wasslightly higher than in other studies, possibly because therashes were more easily recognisable in this fair-skinnedpopulation.

Febrile reactions in the children who received y-globulinwere in the range reported by Weibel et al. (1962) in trialsin the United States-if allowance is made for thedifference between rectal and oral temperatures. Adults

given y-globulin had fewer high fevers than the children

Fig. I-Mean peak temperature and number of days with fever over37-5’C in each age-group.

in Weibel’s series, and the frequency and duration ofhigh fevers did not increase with age as they did in thosewho received no y-globulin.

In determining the value of a vaccination programme,the most severe individual reactions may be more

important than average reactions. Details of the mostsevere single reactions to vaccination with and without’(-globulin are shown in figs. 2 and 3. In neither of thesetwo subjects was there evidence of any disease other thanthe vaccine reaction. The 69-year-old woman whoreceived vaccine alone (fig. 2) had a history of asthma andof hyperreaction to minor infections. She remained inbed during the febrile period which followed the vaccina-tion and complained of weakness for a week afterwards.Fairly severe reactions of this kind occurred in a few othersubjects over 50 years of age who received no y-globulin.

Fig. 3 shows a severe reaction in a man of 26 whoreceived y-globulin: he ran a fever of 40 °C, but once histemperature had returned to normal he was able to

resume his work with no persistent feeling of weakness.In five of the most severe postvaccinal disturbances

reaction to the vaccine seemed to be exacerbated bybacterial infection of the throat. In these persons,ulcerative lesions of the pharynx and high fluctuatingtemperatures persisted for up to a week. There were nofacilities for bacterial culture; but penicillin was given,and in each case recovery followed without further

complication. Since no such throat injection was seen inthe control group, there was possibly a synergistic orcausal relation between the infection and the vaccine.

Like children, adults were not as ill after measles

Fig. 2-Course of reaction to vaccine alone in a woman of 69.

vaccination as the height of the reactive fever would

suggest. Not uncommonly a vaccinee would continue todo a full day’s work while running a temperature ofover 38°C; with very few exceptions, those who didrestrict their activities during the febrile period reportedno continuing weakness once temperatures had returnedto normal. Of the people who at first served as controls,none declined vaccination when it was offered at the endof the controlled period.A good immunological response was obtained in almost

every subject vaccinated. In two there was no clearevidence of the development of antibodies inhibitinghxmagglutination; but, in any immune population, it isusual for a small proportion of sera to give negative resultsin the routine test. Possibly, more sensitive procedureswould reveal some degree of immunity in these two

subjects.Conclusions

In adults, reactions to the measles attenuated-virusvaccine were moderately severe. But they were no moresevere than those in children; nor were they severe

enough to outweight the usefulness of the preparation inpreventing natural measles. In our series we encountered

Fig. 3- Course of reaction to vaccine plus y-globulin in a man of 26.

420

no serious complications’ or sequelx. If the most severereactions are to be eliminated, older adults, at least,should be given y-globulin with the vaccine. Treatmentfor intercurrent infections may be needed.We wish to thank Miss Kristin Gisladottir, Dr. R. Ingibergsdottir,

Dr. T. Oddsson, Dr. D. Danielsson, and Dr. T. Jonasson for theirhelp in conducting the field trials. The project was aided by a grantfrom the Institute of Allergy and Infectious Diseases, NationalInstitutes of Health, Bethesda, Maryland.

REFERENCES

Goldenberg, M. I., Gudnadottir, M. (1959) Conn. Med. 23, 693.Hoekenga, M. T., Schwarz, A. J. F., Palma, H. C., Boyer, P. A. (1960)

J. Amer. med. Ass. 173, 868.Katz, S. L., Morley, D. C., Krugman, S. (1961) Amer. J. Dis. Child. 103, 402.Rosen, L. (1961) Virology, 13, 139.Stokes, J., Reilly, D. M., Hilleman, M. R., Buynak, E. B. (1960) New

Engl. J. Med. 263, 230.Weibel, R., Halenda, R., Stokes, J., Hilleman, M. R., Buynak, E. B. (1962)

J. Amer. med. Ass. 180, 1086.

Preliminary Communications

PREVENTION OF ARRHYTHMIAS

DUE TO CARDIAC GLYCOSIDES

BY BLOCK OF SYMPATHETIC &bgr; RECEPTORS

THE sympathetic system has long been implicated inthe production of ventricular fibrillation. Intravenousadrenaline or isoprenaline may alone induce arrhythmias,and fatal ventricular fibrillation may result, especially ifthe cardiac muscle has been sensitised by chloroform,cyclopropane, or a number of other substances. 1 2 Morerecently it has been shown 3 that cardiac glycosides wereantagonists of the chronotropic action of adrenaline; andthe interesting observation was made that, after sym-pathectomy and adrenalectomy, overdoses of glycosidesno longer produced ventricular fibrillation. The chrono-tropic action of sympathomimetics on the heart is classi-fied as a actionŅi.e., it is produced by adrenaline andisoprenaline and it is not blocked by phentolamine andsimilar noradrenaline antagonists. Modification of thecatechol ring of isoprenaline has yielded antagonists ofthe sympathetic actions,4 5 and these drugs have madepossible an investigation into the importance of normalphysiological sympathetic activity in the production ofcardiac arrhythmias.

METHOD

Female guineapigs of about 500 g. were anaesthetised withurethane 1.6 g. per kg. body-weight intraperitoneally, andthey were artificially respired. Ouabain 80 !Jog. per ml. in salinewas run into a vein using a motor-driven syringe, 4 !Jog. beinginfused during 30 seconds in every 11/2 minutes. The minuteinterval between infusions allowed each step in the dose toproduce its effect and sharpened the end-point of the assay.Note was made of the dose required (1) to lengthen the PRinterval, (2) to produce unequal intervals between beats, (3) to

1. Dawes, G. S. Pharmacol. Rev. 1952, 2, 43.2. Moore, J. I., Swain, H. H. J. Pharmacol. 1960, 128, 243.3. Méndez, C., Aceves, J., Méndez, R. ibid. 1961, 131, 191.4. Powell, C. E., Slater, I. H. ibid. 1958, 122, 480.5. Black, J. W., Stephenson, J. S. Lancet, 1962, ii, 311.

induce extrasystoles, (4) to cause a purely ventricular rhythm,(5) to induce fibrillation, and (6) to stop the heart. The

experiments were then repeated after intravenous nethalide5 mg. per kg. and 15 mg. per kg.5 The results are summarisedin the table.

DISCUSSION

Cardiac glycosides cause a fall in heart-rate which is

only in part attributable to vagal action, because the ratestill falls after atropine. The rate subsequently rises againwhen ventricular excitability is increased and extrasystolesand a purely ventricular rhythm are established. At thestart of the experiments the mean heart-rates in thecontrol series andthe two nethalideseries were 278,273, and 253 perminute. Nethalide5 mg. per kg.caused a fall inrate from 273 to

168 per minute,and 15 mg. perkg. from 253 to

135 per minute.When the ouabainwas infused afternethalide therewas no furtherfall in rate, and

only the increasedue to increasedventricular excit-

ability was seen.

This absence of afall in rate afterouabain in thepresence of netha-lide is probably attributable to the rate having already beengreatly reduced by the removal of the normal sympatheticbackground. Nethalide prolonged the PR interval slightlyin four and not at all in seven experiments. Further,though there was some increase in the dose of ouabainrequired to produce vagal effects (columns 1 and 2 in thetable) it was not statistically significant, and it seems

probable that nethalide does not antagonise the usual

" vagal sensitisation " by ouabain. The most strikingeffects of nethalide were a highly significant increase in thedose of ouabain required to produce a ventricular rhythm,the complete absence of fibrillation, and a significantincrease in the lethal dose.The question naturally arose whether nethalide would

reverse fibrillation that was already established:In column 6 of the table there were only ten instead of

thirteen control results. In these ten the mean additionalamount of ouabain required to produce cardiac arrest afterfibrillation was already established was 47::1: 11.4 jig. per kg.

Top: control electrocardiogram. Centre:ventricular fibrillation induced byouabain 207 ug. per kg. Bottom: effectof nethalide 3 mg. per kg.

AMOUNTS OF OUABAIN ([lug. per kg.), WITH STANDARD ERRORS, REQUIRED TO PRODUCE EFFECTS DESCRIBED IN TEXT

Nethalide significantly increased the amount required to produce ventricular effects, but had no significant effect on " vagal sensitisation (columns 1 and2). Figures in parentheses indicate the number of results in each group.