487

18. Labarre, J., Still, E. W. Am. J. Physiol. 1930, 91, 649.19. Berson, S. A., Yalow, R. S. Gastroenterology, 1972, 62, 1061.20. Frohman, L. A., Bernardis, L. L. Am. J. Physiol. 1971, 221,

1596.21. Idahl, L. A., Martin, J. M. J. Endocr. Metab. 1971, 51, 601.22. Kalk, W. J., Vinik, A. I., Keller, P., Jackson, W. P. U. Un-

published.23. Brown, J. C. Endocrinology 1973 (abstr.); p. 20. London, 1973.24. Dupre, J. Symposium on Gastrointestinal Hormones, Interna-

tional Diabetes Federation Meetings, Brussels, Belgium, July1973.

25. Nakajima, S. Gut, 1973, 14, 607.26. Krause, U., Puchinger, H., Wacker, A. Hormone Metab. Res.

1973, 5, 325.27. Maier, V., Pfeiffer, E. F. Hoppe-Seyler’s, Z. Physiol. Chem.

1972, 353, 1546.28. Goldsmith, S. J., Yalow, R. S., Berson, S. A. Diabetes, 1969,

18, 834.29. Hellman, B., Lernmark, A., Sehlin, J., Täljedal, I. B. Metabo-

lism. 1972, 21, 60.

30. Joffe, B. I., Bank, S., Jackson, W. P. U., Keller, P., O’Reilly,I. G., Vinik, A. I. Lancet, 1968, ii, 890.

31. Harvey, R. F., Dowsett, L., Hartog, M., Read, A. E. ibid. 1973,ii, 826.

32. Bastenie, P. A. Eighth Congress International Diabetes Feder-ation, Brussels, Belgium, July, 1973.

33. Ballinger, W. F., Lacy, T. E. Surgery, 1972, 72, 175.34. Kemp, K. B., Knight, M. J., Scharp, D. W., Lacy, T. E.,

Ballinger, W. F. Nature, 1973, 244, 447.35. Mainz, D. L., Black, O., Webster, P. D. J. clin. Invest. 1973,

52, 2300.36. Unger, R. H. Diabetes, 1971, 20, 834.37. Muller, W. A., Faloona, C. R., Aguilar-Parada, E., Unger,

R. H. New Engl. J. Med. 1970, 283, 109.38. Day, S. L., Anderson, J. Clin. Endocr. 1973, 2, 211.39. Kalk, W. J., Vinik, A. I., Bank, S., Keller, P., Jackson,

W. P. U. Diabetes (in the press).40. Orci, L. Eighth International Diabetes Federation, Brussels,

Belgium, July, 1973.

Reviews of Books

Sir James Mackenzie, M.D.General Practitioner 1853 to 1925. ALEX MAIR, profes-sor of social and occupational medicine, University ofDundee. Edinburgh: Churchill Livingstone. 1973. Pp.366. f4.

THOSE doctors who have heard of Sir James Mackenziewill probably remember him as the man who invented thepolygraph. This instrument recorded on a revolvingsmoked drum a tracing of the jugular venous pulse andthe radial arterial pulse simultaneously. The instrumentmade Mackenzie famous and enabled him to throw lighton various cardiac irregularities. He subsequently becameworld famous as a cardiologist while working as a gen-eral practitioner in Burnley, where he stayed for 28 years.In 1907 he moved to London and got a footing in theWest End Hospital for Nervous Diseases. He was ap-pointed lecturer in cardiac research to the London Hos-pital in 1911 but there was great resistance to making hima consultant in charge of beds, and this was not doneuntil 1913. Two years later he became F.R.s. and wasknighted for his contribution to medical science.He does not seem to have been very happy during his

period as a consultant to the London Hospital, and in1918 at the age of 65 and already suffering from anginahe retired to St Andrews. Soon after he began perhapsthe most extraordinary, though unsuccesful, phase of hislife’s work. He persuaded the local general practitionersto enter upon a long-term research programme with himon the early symptoms of disease and their interpretation.The Institute of Clinical Research was created in a largethree-storey house in St Andrews 18 months after he hadretired there. The underlying idea seems to have been toidentify the earliest stages of illness in order to get asnear to the cause as possible with a view to prevention.The conditions under which the patient lived would alsobe studied and patients would be followed up to observethe outcome of their complaint. Looking back we can seethat Mackenzie had the right idea but failed to appreciatethe difficulties of carrying out the task which he set him-self or to realise that the techniques of investigation hadnot been developed.

It was an extraordinary career, and we are indebted toProfessor Mair for assembling so much informationabout Mackenzie. Much of this is in the form of lettersto or from Mackenzie, and the book would have beenmore readable if the volume of correspondence had beenreduced and the narrative had been increased and had

been made more coherent. However, it is a fascinatingbiography, not least because those of us who had de-

pended entirely upon McNair Wilson’s The Beloved

Physician for our knowledge of Mackenzie find that ourhero had some human imperfections. He was not freefrom vanity, though perhaps one should not deduce toomuch from letters to his brother in which he said "theposition I took in the discussions forced me to the fore-

front, and I think I can say without vanity that all myremarks were distinctly original and presented new factsin a light that surprised the most intelligent of the au-dience" and "having determined to leave Burnley I amnot quite sure Edinburgh is big enough to contain me".His judgments of some of his colleagues were sometimessurprising and in writing to his nephew he referred toSir Thomas Lewis thus: "he always takes himself veryseriously, and wears an air of solemnity which seems tocover a great mass of profound wisdom, whereas it is buta lid over an empty pot!" Professor Mair tells us, how-ever, that this was the only derogatory remark which hefound in masses of private correspondence. Apart from alove of old English and Scots ballads Mackenzie seemsto have had no interest in the arts, and golf.was almostthe only relaxation he allowed himself.This biography reminds us yet again of the important

medical discoveries that can be made in the field of gen-eral practice and in particular how the general practi-tioner is in a uniquely advantageous position to study theearly signs of disease in its early stages. Perhaps the timeis ripe for the creation of a second institute of clinicalresearch staffed by general practitioners, equipped withmodern apparatus for data handling and analysis, and ledby a modern James Mackenzie.Leukemia in Childhood

ANDRE D. LASCARI, M.D., professor of pediatrics, South-ern Illinois School of Medicine. Springfield, Illinois:Charles C Thomas. 1973. Pp. 486.$16.75.

DOCTORS who consider that leukaemia research and thecare of patients with leukaemia transcend the boundariesof age-groups may object to the title of this book. Theyare, however, likely to be well-pleased with the text it-

self, for this is a very thorough account of the leukaemiaswhich combines scholarship with a practical approach toclinical problems. Important changes in the managementand prognosis of childhood leukaemia, especially the

lymphoblastic variety, have created the need for an up-to-date book such as this. Separate chapters consider theclinical manifestations and morphological diagnosis of theleukaemias, and there are useful chapters on differentialdiagnosis and rare diseases resembling leukaemia. DrLascari discusses the common and the rare leukaemias of

488

children, and there is much useful material on uncommonproblems such as myeloma and chronic lymphocytic leu-kaemia in childhood: even the most experienced haema-tologist will be grateful that this often hard-to-find in-formation is now readily accessible in a single book. The1600 references provide a valuable literature key, thoughthere is a preponderance of American references andsome European papers are omitted. The chapter on

chronic granulocytic leukaemia distinguishes clearly be-tween true C.G.L. and the completely different so-called"chronic granulocytic leukaemia of childhood". There isa good coverage of the chromosomal findings in C.G.L.

but in places this is uncritical, especially in the discussionof Ph’ chromosome in patients with features other thanthose of classical C.G.L.: all these features have also beenfrequently noted in patients who at some other time hadclassical manifestations of C.G.L. The author adheres tothe outmoded term "blast crisis" which imperfectly de-scribes the broad spectrum of manifestations in theterminal stages of C.G.L. The chapter on treatment of theleukaemias deals very well with a difficult task. As wellas surveying published results, the author makes usefulpositive recommendations based on his own experience,and these are valuable to the clinician who may be meet-ing an unfamiliar problem. Practical details of manage-ment and consideration of unusual but important compli-cations are especially well-covered, although the treatmentof acute promyelocytic leukaemia is not entirely up-to-date. There is an important chapter on the emotionalaspects of childhood leukaemia and a useful one on thepharmacology of antileukaemic drugs. The presentation issatisfactory on the whole, but there are several spellingerrors, some black-and-white illustrations are poor, andthe single colour plate adds nothing to the book. Thesefaults are outweighed by the virtues of the text, and thisvolume can be recommended to haematologists and to

paediatricians.

Antimicrobial Agents in MedicineBRIAN M. BARKER, Bristol Myers International, andFREDERICK PRESCOTT, Wellcome Foundation. Oxford:Blackwell. 1973. Pp. 296..64.50.

ANTIBIOTIC therapy advances so rapidly that any refer-ence work has to be both accurate and up to date. Un-

fortunately, this work is neither. Many clinicians and bac-teriologists will disagree with the authors’ choice of anti-biotics for given infections-e.g., to treat a Bacteroides

infection, tetracycline is advocated while clindamycin isnot mentioned, and the section on salmonellosis (whichwould seem to be synonymous with typhoid fever) mightbe considered by many to be misleading. It is regrettablethat a book of this price should not contain informationon antibiotics currently under clinical trial which maywell soon be on the market. Inevitably, the book will havea limited useful life.

Dental Manifestations of Systemic DiseaseDAVID H. TRAPNELL and J. E. BOWERMAN. London:Butterworths. 1973. Pp. 186. 4.95.

THis book forms part of a series on Radiology in Clin-ical Diagnosis aimed to give clinicians an up-to-date sur-vey of different aspects of radiology and to provide ahandbook for radiologists in training. This volume dealswith the changes found in the teeth and, more especially,the soft tissues and bone surrounding them, in a widevariety of systemic diseases. The book begins with chap-ters on the anatomy and the radiology of the jaws, skele-tal and connective-tissue disorders, and chromosomal ab-normalities. Later chapters cover diseases of the endocrinesystem, neoplastic disease, the haemoglobinopathies, and

disorders of metabolism. The extent of dental involve-ment in these diseases is very variable. In some cases afew lines suffice, whereas others, such as fibrous dys-plasia, take several pages. Although systemic diseasesare rarely diagnosed as a result of dental examination,the authors do give some interesting examples where thishas happened. A patient with osteomyelitis of the jawafter dental extraction was subsequently found to haveAlbers-Schonberg disease not previously recognised: pa-tients with this condition are especially prone to osteo-myelitis as a complication of dental extraction. Eachsection in the book begins with a brief description of adisease, and this is followed by an account of the radio-graphic findings in other parts of the body and by a

description of the X-ray changes seen in the teeth andjaws. Numerous high-quality illustrations-mainly re-

productions of radiographs-are included, and a usefullist of the more important references is given at the endof each chapter. This book brings together much usefulinformation not easily found in a single volume. It shouldhelp oral surgeons and radiologists working in dentalhospitals. Trainee radiologists will find the succinct de-scription of the general radiological findings in manydiseases especially useful. The price seems high for a

small paperback.

The Variation and Adaptive Expression of AntibodiesG. P. SMITH, postdoctoral fellow, department of medi-cal genetics, University of Wisconsin, Madison, U.S.A.Cambridge, Massachusetts: Harvard University Press.London: Oxford University Press. 1973. Pp. 219.

$12 ; 6.

THE origin of antibody diversity has fascinated im-munologists and molecular biologists for more than thirtyyears, but interest has been most intense in the past fiveyears. The advances in our understanding of antibodystructure made in the 1960s, and the introduction of theautomatic aminoacid sequencer has resulted in a plethoraof primary aminoacid sequences, especially from humanand mouse myeloma proteins. Since the aminoacid se-

quence reflects the original genetic "message" it providesa possible entrée to the controlling mechanisms. Severaltheories to explain diversity have been proposed, and thecontroversy is raging fiercely. This book examines eachof the major theories and puts the case for and against.The presentation is fair and balanced, but in the endDr Smith does come off the fence and expresses a

preference for a germline theory in which each anti-body variant is coded by a separate inherited structuralgene. This is a book for the advanced student or research-worker, and is not recommended for someone desiring abasic guide. It is well referenced up to 1971 and includesa few papers from 1972. An especially valuable featureis the collection of most of the relevant primary data intoan appendix. There are a few typographical errors andseveral highly complex figures and tables, but the presen-tation is otherwise attractive.

Biographical Memoirs of Fellows of the Royal Society:vol. XIX (London: Royal Society. 1973. Pp. 694. i8).-"As one now has to look at the Australopithecine story,it was fortunate perhaps for Le Gros that death camewhen it did." Comments in some of these memoirs aremore restrained than this, but the summaries of the con-tributions of twenty-five men to science during a periodspanning two-thirds of a century are always fascinatingThose remembered here include, besides Le Gros Clark,C. H. Browning, J. N. Davidson, P. G. Fildes, and L. S.Penrose. Outside medicine Bertrand Russell lies, uncom-fortably one suspects, next to the 5th Marquess of Salis-

bury.

489

THE LANCET

More Light Through the OphthalmoscopeALMOST a hundred years ago, shortly after the

introduction of the ophthalmoscope, GOWERS madesome of the earliest observations on the fundus oculiin patients with raised blood-pressure.1,2 He was

quick to realise the importance of the retinal vesselsas an illustration of a general vascular reaction inhypertension-an importance which a century hasdone nothing to diminish. A reduction in calibreof retinal arteries was one of his first findings,but it was only recently that some constricted seg-ments were shown to be capable of dilatation whenhypertension was relieved, indicating a reversiblestate of hypertonus.3 This observation is consistentwith the view that retinal arteries, like those in thebrain, have intrinsic regulatory properties capable ofadjusting resistance to perfusion pressure and of

maintaining a constant blood-flow. However, thisstate of long-term regulation evidently takes its tollsince occlusive and haemorrhagic vascular disease inbrain and retina is far commoner in hypertensionthan in normotension. A correlation between the

ophthalmoscopic appearance of hypertensive retino-pathy and its pathological counterpart was attemptedby LEISHMAN,4 who showed the importance ofsclerosis in modifying the effect of raised pressure.Now for the first time a detailed study has appearedwhich relates not one but serial retinal appearanceswith pathology.HARNISH and PEARCE 5 have examined eight

patients with severe hypertension who showed a

wide variety of vascular lesions in the retina, includingreversible narrowing, sheathing, arterial occlusion,and collateral vessels. The retina was photographedmany times during life and the same areas werelater examined histologically. This painstakingstudy, which involved multiple sections in manydifferent planes to reconstruct an arterial map of thewhole retina, represents pathological detective workof a high order. There was good correlation betweenclinical and post-mortem vessel calibre; surprisingly,even regions of labile vasoconstriction were foundto be still narrowed after death and to have thickerwalls with numerous overlapping muscle-cells. Somesegments, however, showed unexpected vasodilata-tion, and in these regions muscle-cells were found tobe replaced by fibrous tissue. Silvery sheathed

narrowing of retinal arteries was shown to correspond1. Gowers, W. R. Br. med. J. 1876, ii, 743.2. Gowers, W. R. A Manual and Atlas of Medical Ophthalmoscopy.

Philadelphia, 1882.3. Hill, D. W., Dollery, C. T. Trans. Ophthal. Soc. U.K. 1963, 83,

61.4. Leishman, R. Br. J. Ophthal. 1957, 41, 641.5. Harnish, A., Pearce, M. L. Medicine, Baltimore, 1973, 52, 483.

to intimal thickening with normal or atrophic media.Occlusion of narrowed arteries was recognisedclinically by a white string-like appearance and bythe development of focal capillary ischasmia withcollateral capillary channels. Histologically, occludedsegments were found to have disorganised wallsinfiltrated with P.A.s.-positive material and with norecognisable muscle-cells.HARNISH and PEARCE do not speculate on the

cause of arteriolar occlusion in hypertension, buttheir findings should be viewed in the light ofBYROM’S work 6,7 and of GARNER and ASHTON’Saccount 8 of experimental hypertension in the

monkey. The latter workers confirmed the relationbetween arteriolar occlusion and focal capillaryischaemia. Furthermore, in some occluded arteriolesthey identified plasma, fibrin, red cells, and plateletswithin the wall, although they were unable to showbreaks in the endothelium; such plasmotic vasculosiswas usually associated with necrosis of the muscleand with disorganisation of artery wall. - Bothfibrinoid and hyaline changes in the arterioles (whichmay be a different stage in the same process) arenow shown to be due to a substance which has thehistochemical, ultramiscroscopic, and immunologicalproperties of fibrin within the vessel wall.9

Arteriolar occlusion with leakage of plasma intothe wall thus seems to be a feature of both experi-mental and human retinal arteries in hypertension,but what is the primary event ? BYROM at first

suggested focal vasospasm,6 but later preferred toregard overdistension of segments of artery as theprobable source.10 In the presence of hypertension,both on the surface of the rat brain and in the humanretina, there are regions of dilatation as well as

constriction. Dilatation may be a mechanical resultof increased wall tension which causes the weaker-resistance vessels or weaker zones of individualvessels to give way before rising pressure; byincreasing in radius such a vessel becomes pro-gressively vulnerable to further stretch while strongerareas are still able to contract. In BYROM’S view theresult is widespread irregularity in calibre with fixedpatterns of contraction and dilatation. Thoughreversible in the early stages, severe overdistensionis associated with focal oedema, segmental dis-

organisation, and aneurysm formation probably dueto overstretching or tearing of some, fibres, withconsequent leakage. The findings of HARNISH andPEARCE support this concept of vascular damage bydistension. In only one of the many arterial occlusionsstudied was there evidence of previous constric-

tions ; in the majority the artery was dilated.There remains the difficulty of intensely contracted

6. Byrom, F. B. Lancet, 1954, ii, 201.7. Byrom, F. B. ibid. 1963, i, 516.8. Garner, A., Ashton, N. Excerpta med. int. Congr. Ser. 1970, no.

222.9. Adams, C. W. M. Vascular Histochemistry. London, 1967.

10. Byrom, F. B. The Hypertensive Vascular Crisis. London, 1969.