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A New Beginning

THE LANCETLl)1D0’’ : SATURDAY, JUNE .3. 1948

WHEN the representative meeting of the BritishMedical Association assembled last week it was

soon plain that its members’ mood had changedsince the previous gathering in March. All wereconscious that they no longer met as a united bodyfirm in opposition to an unacceptable health serviceand to an unrelenting Minister, and it was obviousthat very many of them deplored this change andsought a scapegoat on whom to place the blame.Rejecting the council’s opinion that the Aprilplebiscite was necessary in order to estimate theeffect of the Minister’s concessions on medical opinion,they argued that the holding of this plebiscite wasitself a factor in weakening the resistance of theprofession. Accordingly, as the first major actionof the day, they passed a resolution saying that theplebiscite was premature, that it indicated approvalof the new conditions offered, and that it therebyprejudiced the voting.The meeting then went on to consider what advice

it should give to the profession. The council thoughtthat doctors should now cooperate in the NationalHealth Service on the understanding that the Ministerwould continue negotiation ; but a great number ofdivisions had tabled amendments, ranging from totalrejection to minor verbal alterations of the council’sresolution. In the end the main debate took placeon one from Kingston-on-Thames which proposedthat cooperation should be deferred until all out-

standing matters had been finally and concretelysettled to the satisfaction of all sections of the pro-fession. In the discussion on this proposal muchinformation was given about the recent talks betweenrepresentatives of the B.M.A. council and the Ministryof Health. As will be seen from Sir WILLIAM DOUGLAS’Sletter, summarised on p. 880, it has been agreed thatthe amending legislation shall permit local executivecouncils to elect their own chairmen, shall allowchoice of the professional member of the tribunalfrom a panel of available members, and shall permitthe local medical committees to meet their expenses(if so wished) from a statutory levy from the prac-titioners’ remuneration. Other matters on whichthe Minister has consented to adapt his previousarrangements include a stipulation that doctors

opting for a basic salary of £ 3fl0 must submit theirclaim to the local executive council (which willconsult the local medical committee before makingits recommendation), and material modificationof the regulations for the maternity service. It isclear that the amending Bill cannot be made law byJuly 5. but wherever necessary it will be retro-

spective. Similarly it has been decided that a tem-porary contract shall be offered to consultants and

specialists and that this shall be revised retrospectivelyto July 5 when agreement has been reached on thereport of the Spens Committee, which is expectedthis week. As far as the remuneration of generalpractitioners is concerned, it seems that the newscheme will now have to start under the conditions

already suggested by the Minister, but the professionwill be able to make representations to the WhitleyCouncil on the shortcomings of the terms proposed.

Altogether the impression gained by the meetingwas that much constructive negotiation was alreadygoing on, and that much could be done by itscontinuance. Should the Government go back ontheir promises, the profession could and would uniteeven more solidly than in February, and resign.As it was, even without awaiting the advice of theB.M.A. representative body, considerable numbersof general practitioners had already joined the

service-26% of insurance practitioners in England,37% in Wales, and 36% in Scotland. Many otherswere delaying only because they had been askedto defer action until after the representative meeting.and it was unreasonable to ask them to withhold theirconsent until final legislation was completed,.perhapsseveral months hence. The profession should notconcentrate on the few points on which it had notgained the day but on the many on which it hadwon from a Minister, ordinarily so uncompromising.such notable concessions.-These points, hammeredhome by Dr. DAIN, the chairman of council, and byseveral of the best-known and most trusted membersof the representative body, eventually won the day.By a large majority the council’s original recom-mendation was accepted unaltered, except that a

rider was added to the effect that present cooperationdoes not preclude collective resignation later if the

promised legislation is not satisfactorily concluded.The representatives have gone back to their

divisions, where doubtless they will have much torecount, perhaps some disgruntlement to assuage.and some difficult questions to answer. They will.we hope, recall particularly some words of Dr. JANETAITKEN, when she said that the profession cannotnow prevent the new service coming into being onJuly 5 but may still prevent its efficient working.This, she believed, was a course it would never con-template ; if we are now to cooperate let us do sowholeheartedly.

Structure of the EpidermisMOST histologists probably no longer regard the

cellular composition of the epidermis as a live prob-lem, however worried they may still be about thecellular anatomy of the nervous system and of someendocrine glands. The generally accepted view isthat all the cells of the epidermis are derivatives byfission of parent cells of one uniform type-thegerminative cells of the basal layer of the epidermis.These cells divide on the one hand to produce moregerminative cells, and on the other hand to producecells which, by their progressive degeneration accom-panied by movement towards the skin surface, giverise to the stratification characteristic of the epidermis.It is not generally believed that cells of diiTerent.

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origin, structure, function, and lineage coexist withthem in the epidermis, for otherwise they would revealtheir presence in the ordinary transverse microtomesections on which the histologist has come, perhapstoo exclusively; to rely.Two papers by MASSON ’ and BILLINGHAM 2 make

it clear that this orthodox view of epidermal structureis no longer acceptable. As long ago as 1868,LANGERHANS 3 showed that acid gold impregnationrevealed cells of a new type in the epidermis-repeatedly branching cells, quite distinct from theother ingredients of the epidermis, and evenly distri-buted in such density that the territory covered bythe branches of one such cell immediately adjoinedthe territory -covered by the branches of its neigh-bours. Gold-impregnation methods are notoriouslyuncertain in their results ; they are applied to tissuesquashes or teasings and not to sections. For thesereasons, histologists have hesitated to acknowledgethe cellular status of the cells LANGERHANS described.COWDRY,4 in his standard textbook, does not believethem to be individual cells and doubts whether theyhave nuclei. But dermatologists 5 have in the mainaccepted LANGERHANS’S findings, and have given hiscells a royal christening : Langerhans cells, stellatecells, dendritic cells, cellule8 amboceptrices, " clearcells," melanoblasts, melanophores, and chromato-phores are among the names that have been given tothem, each one reflecting some aspect of the cells’real or supposed structure or function. BILLINGHAMand MASSON have now re-investigated the problemindependently, using quite different techniques.BILLINGHAM uses living material, supravital stainingwith methylene-blue, and gold impregnation, and hehas worked mostly with whole mounts and squashesrather than with sections. MASSON has relied onorthodox histological methods using alkaline silver

impregnation. Their accounts agree in the followingparticulars. Dendritic cells occur in the basal layerof the epidermis, at the dermo-epidermal interface ;their cell bodies are slightly larger than those of theordinary ’’ malpighian

" cells round them, and havea more generous allowance of cytoplasm. Thebranches that arise from them weave with repeateddichotomisation between the cells about them, andeach branch ends in a little end-button closely appliedto the surface of a malpighian cell. Their cell bodiesand the proximal ends of their branches can beidentified in transverse sections stained by routinemethods as the so-called clear cells already well knownto histologists.The dendritic cell is the only seat of pigmentary

function in the epidermis. Malpighian cells containpigment granules but do not manufacture them:BiLLiNGHAM’s vital studies now finally make it clearthat formed melanin granules are somehow passedfrom the branches of the dendritic cells into thecells on which the branches end. The malpighiancell therefore gets its melanin at second hand.MASSON comes to the same conclusion, and points outthat when cells of different origin are given access todendritic cells (as with gut epithelial cells in tumourmetastases) they too may acquire pigment. Alone of

1. Masson, P. Spec. Publ. N.Y. Acad. Sci. 1948, 4, 15.2. Billingham, R. E. J. Anat., Lond. 1948, 82, 93.3. Langerhans, P. Virchows Arch. 1868, 44, 325.4. Cowdry, E. V. Textbook of Histology. Philadelphia, 1938.5. Cf. Becker, S. W. Arch. Derm. Syph. N.Y. 1927, 16, 259.

epidermal elements, the dendritic cell is " dopa-positive "—i.e., it gives the histochemical reactionthought to reveal the oxidases that transformdihydroxyphenylalanine into melanin. In negro skin,then, the dendritic cells can appropriately be called" melanoblasts." They are also melanoblasts in whitehuman skin, barring the special case of albinos,;indeed, MASSON’S technique for showing them upturns on the fact that silver is deposited on and so"

develops " pre-existing melanin granules. But the

pigmentary function of white human skin is feebleand normally suppressed. Its dopa-reaction is corre-spondingly weak. Dendritic cells which completelylack pigmentary function, contain no trace of melanin,and fail to give the dopa-reaction are found in thewhite skin of spotted guineapigs. Ultraviolet lightwill soon bring colour to the " white " skin of humanbeings, but neither ultraviolet light nor any otherphysical or chemical stimulus will cause the non-

pigmentary dendritic cells of spotted guineapigs tomanufacture pigment. Their negative reaction to

dopa suggests that the appropriate enzymic equipmentis simply lacking.BILLINGHAM figures successive division stages in

living dendritic cells of guineapig’s skin, and MASSONshows us a clear cell in the act of dividing. Dendriticcells therefore have a lineage or pedigree of theirown : the old view that they are physiological variantsof the malpighian cell can no longer be taken seriously.Not much can be said of their wider affinities. Simi-larity of structure, cell interrelationships, stainingproperties, and embryological origin suggest thatdendritic cells are near cousins to some of the elementsof neuroglia. For the entire tissue system of epidermaldendritic cells a new name is obviously required.The term " epidermal glial system " 6 is innocentenough etymologically, since " glial " carries the

implication of glue and cohesion and not of associationwith the nervous system.MASSON introduces one novel concept. He believes

the dendritic cell to be squamous, in the sense thatsome of its division products pass up through theepidermal strata to be flaked off at the skin surface.In his opinion the cells revealed by LANGERHANS’Sacid gold impregnation do not belong to the basallayer, but are dendritic cells in process of beingcast off.From the pathologist’s point of view, one

property of dendritic cells is likely to prove out-

standing. Dendritic cells may make the same sortof physiological contact with each other as each doesindividually with the malpighian cells within reachof its branches. Sometimes their processes are con-fluent, and sometimes an end-button from the branchof one dendritic cell applies itself to the cell body ofanother. What happens if a melanin-forming den-dritic cell makes contact with a non-pigmentarydendritic cell, as happens at the margin of black andwhite areas in a spotted guineapig ? It has beenknown for more than 50 years that in spotted guinea-pigs pigmentation does in fact slowly spread fromblack skin areas into white. BILLINGHAM andMEDAWAR 6 believe that this is due to the conversion

6. Billingham, R. E., Medawar, P. B. Heredity, 1948, 2 (in thepress).

7. Billingham. R. E., Medawar, P. B. Nature, Lond. 1947, 159,115; Ibid, 160, 61.

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of non-pigmentary dendritic cells into melanin-forming cells by contact with their melanin-formingneighbours. The transformation is permanent, and issuch that a non-pigmentary cell, once converted topigmentary function, can in its turn transform its non-pigmentary neighbours. The process is thus formallyakin to a virus-induced cell transformation. Dis-

regarding the relevance of this phenomenon to theproblem of cell heredity, it is clear that it has animmediate bearing on the manner of spread of virusinfections in the skin and on the type of concertedreaction by skin cells revealed by some forms of

sensitivity. The greater part of skin histopathologyhas been worked out in ignorance or neglect of theexistence of an epidermal glial system, and must nowbe revised accordingly. The urgent need at themoment is the development of simple and reliabletechniques for showing up dendritic cells by ordinarystraightforward histological methods.

Sequels of Epidemic JaundiceTHE epidemics of jaundice during the late war were

studied vigorously and taught us a great deal. It isnow agreed that epidemic jaundice is a virus diseasewith an incubation period of 25-35 days, usuallytransmitted by fæcal contamination of ingested foodor water; and that there is a closely similar diseasewith a 3-month incubation period which is trans-mitted by an agent present in the serum of manypeople who themselves do not suffer from jaundice.Clinically the two are identical, but there is no

cross-immunity between them. Biopsy methods haveclarified the histology of the non-fatal forms, andit has been surprising to see how severe the liver

damage can be in cases which subsequently recover,the liver returning completely to normal on furtherhistological examination.l SHERLOCK 2 has also madecareful assessment of the value of liver-function testsin diagnosis and prognosis, with biopsy controls. ’

It has been realised, especially in Scandinavia, thanksto the work of BERGSTRAND 3 in 1930, that there isa rising incidence of deaths from subacute necrosisand cirrhosis following an epidemic of hepatitis. Lastweek (p. 817) Dr. SHERLOCK reported on nine patientswith such sequelae, six following epidemic jaundice andthree the " serum " variety. Two showed evidenceof hepatic failure, from which one died, while foursuffered from the effects of portal hypertension, twoof them ending fatally with gastro-intestinal haemor-rhage. In the other three, however, the course hasbeen less severe and the disease seems to have becomechronic or even arrested ; one patient recoveredafter having severe ascites which required tappingfour times. Among the most ominous signs ina case of hepatitis is a persistent reversal of the

albumin-globulin ratio, a point which the Oxfordworkers 4 emphasised some years ago. In this issueDr. KING and his colleagues from Melbourne reportthe case of a young man who died of subacute hepatitis,1. Dible, J. H., McMichael, J., Sherlock, S. P. V. Lancet, 1943,

ii, 402.2. Sherlock, S. P. V. J. Path. Bact. 1946, 58, 523.3. Bergstrand, H. Ueber die akute und chronische gelbe Lebera-

trophie. Leipzig, 1930.4. Higgins, G., O’Brien, J. R. P., Stewart, A., Witts, L. J. Brit.

med. J. 1944, i, 211.

with biopsy studies as well as autopsy details. Theyemphasise one of the curious problems of this group-why should a virus infection turn into a chronic

progressive disease ? No other known virus infectionruns such a course. In their case the patient’smother died of " alcoholic " cirrhosis and the histo-

logy of her liver was very similar to that of her son’s.They suggest that the patient may have inheritedsome deficiency of the liver cells. Another explana-tion at which they hint is the possibility of an abnormalauto-antibody formation in these subjects. Somesuch mechanism may operate in the subjects of

streptococcal infection who develop acute nephritis.In BERGSTRAND’S original report a considerable

number of cases developed the coarsely nodular

type of lesion which may be called healed subacutenecrosis. It is to be noted that SHERLOCK’S casesshowed a finely granular cirrhosis or a histological-picture practically indistinguishable from Laennec’scirrhosis. This seems to support the view of WATSONand HOFFBAUER 5 that epidemic hepatitis mavbe an important precursor of chronic cirrhosis. Theapparently mild insidious, almost subclinical, hepa-titis may be as important in the later productionof cirrhosis as the clear-cut frank obvious attack ofjaundice. The persistence of definite organic signsafter an attack of acute hepatitis is a cause for anxietyand calls for a guarded prognosis, but symptomsalone, such as dyspepsia and vague upper abdominaldiscomfort, are not pathognomonic of persisting liverdamage. SHERLOCK and WALSHE 6 have shown thatsome patients with " liverish" symptoms after

hepatitis probably have a ‘‘

hepatic neurosis,’’ some-what analogous to the " effort syndrome " seen. in

patients who have had attention called to possibledamage to their hearts.Another facet of the same problem is illustrated

by Dr. BJØRNEBOE and his colleagues on page 867.During 1944-45 Copenhagen had an epidemic of

hepatitis with a particularly heavy incidence amongpeople over 50. At this age men and women were

equally affected, but whereas the men tended torecover in an ordinary manner the women often ..

went on to a chronic form of the disease with a case-mortality of 37% in hospital, possibly reaching muchhigher figures under longer periods of observation.Whether this is the result of a heightened virulenceof the virus affecting a part of the population whohave outlived their immunity it is difficult to say.The high fatality-rate among women past the meno-pause seems to be a new observation, in whichendocrine factors obviously may be involved. What-ever the explanation, we must recognise the unpredict-able character of epidemic hepatitis. Fortunatelyin most epidemics the case-mortality is low-of theorder of 1 in 500. But outbreaks of a more malignanttype must be recognised as possibilities.

These papers are all useful reminders of the gravityof epidemic hepatitis. It is a condition which shouldnever be taken lightly. Early rest in bed with adiet adequate in protein should be given, and a

careful watch should be kept on all cases until the .

jaundice has completely subsided.5. Watson, C. J., Hoffbauer, F. W. Ann. intern. Med. 1946.

25, 195.6. Sherlock, S., Walshe, V. Lancet, 1946, ii, 482.