929

18 were uncircumcised; and they suggested that thismight explain the association of cervical carcinoma inany regular partners of such men. Only RAwLs et al.produced a control series, and the numbers in all thesereports are small. But the suggested association,though far from established, points the way to furtherinvestigations.

Chronic Heart-block

PERMANENT artificial pacing for patients with chronicheart-block is now an established treatment. 1 The

development of pacing techniques and the complexitiesof their maintenance,2 has led to the establishment ofspecial centres where many patients have been assessedfor pacing and their progress closely followed. One suchcentre is the cardiac department at St. George’s Hos-pital, London, where LEATHAM and his colleagues havea vast experience in the management of heart-block.Two new papers 3 4 from that team highlight someimportant clinicopathological lessons. Necropsy findingsare recorded for 65 patients with chronic heart-block,61 of whom had been paced.3 The post-mortem examina-tion included serial sectioning of conducting tissue andcoronary arteriography, the sections to include the arteryto the atrioventricular (A.v.) node. The commonestcardiac lesion, bilateral bundle-branch fibrosis unasso-ciated with arterial disease, was present in 26 patients.Cardiomyopathy affecting the conducting system wasfound in 11 patients and coronary-artery disease in only10 others, including 1 patient with selective infarctionof the main bundle and A.v. node. Active myocarditis(2 rheumatic and 2

"

non-specific ") was identified in 4patients, and massive calcification of the mitral or aorticvalve rings, destroying the main and/or left bundles, in4 others. Destruction of the A.v. node by massivedeposits of iron (transfusion siderosis) or amyloid wasseen in 4 cases, and in 3 others the conduction tissuewas infiltrated by fibrous strands and chronic inflam-matory cells, thought to be part of a generalised connec-tive-tissue disease. Other rarities included a case eachwith congenital heart-block, an aneurysm of the inter-ventricular septum, and a syphilitic gumma.DAVIES and HARRIS4 turned their attention to a detailed

morphological study of the patients with bilateral bundle-branch fibrosis. In the usual anatomical arrangement5 ofthe cardiac conduction system, the right bundle is asingle discrete structure (and thus susceptible to even asmall confined lesion), in contrast to the left bundle,which consists of a series of radiating fine structures,directly branching from the main bundle. In their age-matched control series of 40 patients, DAVIES andHARRIS noted an age-related progressive loss of conduc-tion fibres in the origin of the left branches, though thisloss rarely reached significant levels. In the patients with1. Harris, A., Bluestone, R., Busby, E., Davies, G., Leatham, A., Siddons,

H., Sowton, E. Br. Heart J. 1965, 27, 469.2. Bluestone, R., Harris, A., Davies, G. Br. med. J. 1965, i, 1589.3. Harris, A., Davies, M., Redwood, D., Leatham, A., Siddons, H. ibid.

1969, 31, 206.4. Davies, M., Harris, A. ibid. p. 219.5. Hudson, R. E. B. Cardiovascular Pathology; vol. I, p. 111. London,

1965.

heart-block, however, the process of fibrosis was markedby a progressive loss of fibres in the distal conductionsystem and a diffuse myocardial scarring, remote fromthe conduction system, but not associated with obvious

coronary-artery disease. These histological findingsclearly reflect the end-stage of a chronic process, thecause of which is so far unknown. A preceding acuteinflammation and then focal scarring, or an exaggeratednormal age-change within the cardiac fibrous skeleton, 6or a combination of both processes, are possibilities.

For the clinician the underlying pathological changesin a patient with chronic heart-block may defyrecognition. HARRIS and his colleagues point to thelimited range of symptoms in complete heart-block,regardless of cause, and to the difficulties in detectingcoronary-artery obstruction, active myocarditis, or valvu-lar disease in their patients. Certainly a history of cardiacpain is little help in diagnosis, although heart-blocksecondary to acute myocardial infarction is, in any event,usually a transient arrhythmia. There are, however,some useful clues for the clinician. Patients with heart-block and diffuse myocardial disease are more prone toepisodes of ventricular tachyarrhythmia and heart-failure. This finding is probably reflected in anotherobservation-that patients with isolated disease of theconduction tissue usually have a longer symptomatichistory, suggesting a better prognosis.

These pathological findings confirm the impressionthat many patients with chronic heart-block have a

limited, but crucially located lesion; and the resultsjustify the great amount of time and effort devotedto the improvement of present pacing techniques and tothe selection of patients for this treatment. 8

Annotations

HAVE WE HAD HONG KONG FLU BEFORE?

THE influenza virus is always surprising us. Wethought it was getting near the time for a new epidemicsubtype of influenza A, though no-one knew exactly whenit would appear or what it would be like. But the HongKong strain or its effects are familiar to most of us by now,for, since 1968, when it was detected, it has swept acrossthe globe. Now, however, it is behaving rather curiouslyin Britain. Here large numbers of strains are beingisolated from patients by the Public Health LaboratoryService, but in spite of fierce local outbreaks the nationalmortality figures have given little sign of the disease.

Epidemiologists might look more discerningly into thefuture if they understood more of the past history ofepidemics, but the influenza viruses were first cultivatedonly in the 1930s and that is only a few major epidemicsago. It is possible, however, to deduce something aboutthe viruses which were current before then by studyingantibodies in human sera. These deductions depend onthe well-established immunological principle that oncethe antibody-forming mechanism has been " primed "6. Lev, M. Am. J. Med. 1964, 37, 742.7. Portal, R. W., Davies, J. G., Leatham, A. Lancet, 1962, ii, 1369.8. Hollingsworth, J. H., Muller, W. H., Beckwith, J. R., McGuire, L. B.

Ann. intern. Med. 1969, 70, 263.

930

with a certain antigen it produces antibody against thatantigen and goes on doing so even when stimulated byother antigens which are only distantly related to it. Thephenomenon in relation to influenza has been called" original antigenic sin ".A group of workers associated with the late Prof. J.

Mulder of Leiden have made a number of interestingcontributions to this kind of retrospective serologicalepidemiology, and we publish further findings by one ofthem, Dr. Masurel, on p. 907. The earlier experimentsshowed that sera from people who were children in 1890had antibodies against the Asian A2 strain and that

slightly younger subjects had antibody against a virusrecently epidemic in horses-A/Equi 2. When this wasconfirmed by other workers, the conclusion was that theepidemic of 1890 was probably caused by a virus relatedto A2 strains and that there followed a period of pre-valence of a virus related to the horse virus.The new observations support and extend this view.

They are based on tests on over 3000 sera collected in 1957and just before the present epidemic; they show that theantibodies against A/Equi 2 in the sera of old subjectshave apparently been boosted by A2 virus infections inthe past ten years. More impressive, however, is thefact that when the sera collected in 1957 were tested withA2 Hong Kong virus the sera in subjects over 60 provedto have a high incidence of antibody against this strain.Masurel has shown that A/Equi 2 and A2 Hong Kongare antigenically related, so it is not surprising that thesesera also contain some antibodies against A/Equi 2.No-one is sure how to interpret changes in antigenic

type, and virologists will note that these results supportthe view that there are a limited number of human sero-

types which replace each other.It now looks as though the history of influenza virus has

repeated itself: the sequence of epidemic serotypes whichhas affected us in the past decade probably occurred at theturn of the century. Maybe the epidemiological patternof influenza will not always remain mysterious.

CONTROL OF CHEMOTHERAPY

As the pattern of infectious disease changes and anti-biotic-resistant gram-negative organisms tend to displacethe gram-positive ones, 1 antibiotics with a different

spectrum are needed. Better diagnostic methods havebrought the detection of potentially dangerous and fatalinfections to an early enough stage to permit lifesavingtreatment; but new problems are created when anti-microbial agents have to be used in high doses whichaccentuate their toxic properties. The danger of toxicityis even greater when body metabolism and normal excre-tory processes are deranged. The role of the micro-

biologist and the physician in infectious diseases is alsochanging, and control of treatment demands knowledge ofthe pharmacodynamics of antibiotics and the variationsrequired in their use when complications such as renalfailure supervene. Techniques for rapid determination oflevels in body-fluids, estimation of inhibitory and cidalconcentrations of an antibiotic, and measurement of

synergy or antagonism between antibiotics are only a fewof the demands on the clinical laboratory. At a recentmeeting at the Wright-Fleming Institute, St. Mary’s1. Finland, M., Jones, W. F., Jr., Barnes, W. M. J. Am. med. Ass. 1959,

170, 2188.2. Watt, P. J., Okubadejo, O. A. Br. med. J. 1967, i, 210.

Hospital, London, workers of various disciplines, witha common interest in the control of chemotherapy,discussed some of these matters.The tube dilution technique has long been used to

measure the minimum inhibitory concentration of anti-biotic for a particular organism. More recently the testhas been refined by making allowance for protein bindingof serum, by standardising and varying the bacterial

inoculum, and by adjusting the electrolyte concentration.Nevertheless, the technique is based on doubling dilutionsof the antibiotics and, despite improvements, this basicinaccuracy remains. For many purposes the error is

acceptable, but for antibiotics where the therapeutic andtoxic levels are close the method is unsuitable.Another difficulty arises when combined chemotherapy

is necessary and assay of the individual substances isneeded. Assay of individual compounds can be simplifiedif the two substances have different pH optima for activity.Thus, assay of an antibiotic in the presence of an amino-glycoside should be carried out in acid pH to reduce theactivity of the aminoglycoside. Even more elegant tech-niques exist and electrophoresis of a pre-seeded agar blockallows separation from protein followed by demonstrationof different mobility of two antibiotics. If the agar hasbeen seeded with bacteria, incubation causes their growthand quantitative estimation of the antibiotics is possibleby studying the zone of inhibition. The logistics of apply-ing this technique to the clinical laboratory deserve investi-gation. Delay in determination of antibiotic sensitivitiesand assay is still a problem and no suitable rapid methodwas reported.In some European countries strains of staphylococci

resistant to the penicillinase-stable penicillins and cepha-losporins are an important cause of hospital infection.This observation has not been widely confirmed in thiscountry, although it was reported from Newcastle that5-25% of multiply resistant hospital staphylococci werealso methicillin-resistant. Several reasons for failure todetect these resistant strains were suggested and the needto use methicillin-impregnated discs (rather than oxacillinor cloxacillin) was emphasised. It is also important to use5% salt agar rather than conventional medium for the

sensitivity test, but it is dangerous to use 5% salt mediumfor testing other antibiotics. For example, on suchmedium fucidic-acid-resistant staphylococci might appearsensitive, while kanamycin-sensitive strains can appearresistant.A possible solution to the dilemma of choosing the right

electrolyte concentration for testing the sensitivity ofstaphylococci to methicillin emerged from the observationthat at 30°C methicillin-resistant strains express theirresistance on standard media.3 This method is at presentbeing more widely evaluated.The difficulties in routine testing of the activity of anti-

tuberculous drugs led to the suggestion that such testingshould be abandoned and response to therapy taken as aguide to the value of the drugs. The microscopic examina-tion of sputum smears together with culture would be usedto monitor therapy: only when results were positive wouldsensitivity testing be carried out in order to decide howto modify the drug regimen.

Clinico-laboratory studies of chemotherapy are obvi-ously important. In such an investigation it was foundthat the serum half-life of antibiotics rapidly decreasedduring the first two weeks of neonatal life. Thus therapy

3. Annear, D. I. Med. J. Aust. 1968, i, 444.