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gestive failure may be preventable, especially in patientsin whom perforation occurs months after treatmenthas ended.5 Another interesting point which emergesfrom ROBINSON and RuEDY’s study is that the commonestinfecting organism has changed since the pre-antibioticera. As would be expected, infection by antibiotic-sensitive organisms such as the pnenumococcus andStr. viridans has become considerably less frequent,whereas staphylococcal infection has become commoner;but in 1950-60 the enterococcus was the most com-

monly isolated organism of all, and why this should beis difficult to understand. The cure-rate in enterococcalinfections is as high as in streptococcal infections; thatin staphylococcal endocarditis-39%-is the lowest ofthe three.

Penicillin remains, without question, the drug ofchoice in the treatment of bacterial endocarditis.

Occasionally, vancomycin, kanamycin, bacitracin,neomycin, polymyxin B, or erythyromycin may be

indicated, but with some of these toxicity is a seriousproblem. Even penicillin sensitivity need not be a

contraindication: hypersensitive patients have been

successfully managed by the concurrent administrationof prednisone 6 or, alternatively, by rapid desensitisation.Even if in-vitro tests show that the infecting organismis penicillin-resistant, this is no reason for withholdingthe drug. Where the invader is Str. viridans-an

organism highly sensitive to penicillin-some advocateshorter courses of therapy. GERACI 1 has pioneered aregimen of aqueous procaine penicillin 1 megaunit andstreptomycin 1 g. intramuscularly every twelve hours,with probenecid 0-5 g. orally every six hours, and hereports high cure-rates and low relapse-rates; others 7have confirmed that short-term treatment can be satis-

factory, although they report a higher relapse-rate 8than GERACI. TUMULTY,9 however, still prefers to givepenicillin G every six hours for four weeks, believingthat " sufficient time must be given to allow the healingprocess to become complete." Sufficient penicillinshould be given to achieve a blood level five to ten timesthe sensitivity of the organism; with resistant bacteriathis may necessitate the giving of penicillin by intra-venous drip, together with probenecid and streptomycin.Oral penicillin is recommended by neither GERACI norTUMULTY because it is not uniformly effective, althoughphenoxymethylpenicillin (penicillin V) has been suc-cessful in four-hourly doses of 0-6-1-2 g., either with 10or without 11 streptomycin. The newer semi-syntheticpenicillins are better absorbed from the gastro-intestinaltract; moreover, by virtue of their insensitivityto penicillinase, they may be active against some

resistant organisms. Phenethicillin given to 3 patientswith viridans or enterococcus infections produced bac-teriological cure in all,12 and methicillin 4-6 g. daily5. Morgan, W. L., Bland, E. F. Circulation, 1959, 19, 753.6. Theobald, T. J. ibid. 1961, 24, 1055.7. Hunter, T. H., Paterson, P. Y. in Disease a Month series. Chicago,

1956.8. Tompsett, R., Robbins, W. C., Bernstem, C. Amer. J. Med. 1958,

24, 57.9. Tumulty, P. A. Amer. Heart J. 1962, 64, 117.

10. Hamburger, H., Kaplan, S., Walker, W. F. J. Amer. med. Ass. 1961,175, 554.

11. Quinn, E. L., Colveille, J. M. New Engl. J. Med. 1961, 264, 835.12. Campeau, L., Lefebvre, M. Canad. med. Ass. J. 1961, 84, 535.

cured a patient infected by a penicillin-resistantStaphylococcus albus,13 The new isoxazolyl penicillin,cloxacillin (’Orbenin’)14, is as resistant to acid as penicil-lin V and more active than methicillin against penicillin-resistant staphylococci. It was given intramuscularlyto 2 patients with endocarditis, and the treatment

was successful in 1. The 2nd patient died. Post

mortem, staphylococci were isolated from abscesses inthe liver and kidneys, but a heart-valve vegetationyielded Str. faecalis. Although mixed infections are

rare 15 (17 reported cases up to 1961), they are an

additional reason for always giving streptomycin withthe penicillin.

Endocarditis after shunt operations in the tetralogyof Fallot has been recognised for years,16 and now openheart surgery is being complicated by infection, particularlywhen a plastic prosthesis has been inserted." The useof artificial heart-valves is increasingly common andendocarditis is likely to be an important complicationof their introduction. Brucellosis is a rare cause

of endocarditis, but it is interesting because of the

suggestion of PEERY 18 that this infection itself producesvalvular lesions. He points out that in practically everycase of brucella endocarditis there is isolated calcificaortic stenosis, and he presents evidence from a few tosuggest that the infection preceded the cardiac murmur.Certainly, if any infection can produce a valve lesion,then brucellosis is well qualified to do so because of itschronicity-the product of spontaneous recovery andrecurrent reinfection. But in bacterial endocarditis of all

types, prophylaxis is still of prime importance, and anti-biotics should be given to all patients with congenitalheart-disease or acquired valve lesions before any formof surgery which may provoke bacterxmia. Penicillin (1megaunit) should be given intramuscularly an hour beforeany dental extraction, and the antibiotic should be startedearlier and continued longer if gross sepsis is present.This is still not sufficiently appreciated. Still less

appreciated is the need to give prophylaxis before instru-mentation or operation on the urogenital tract; in thisinstance, since penicillin-resistant organisms are likelyto be present, both penicillin and streptomycin shouldbe administered.

Copper, Kidneys, and CalciumSKELETAL abnormalities may be found in patients with

Wilson’s disease, and a patient with spontaneous frac-tures was described by VON ECONOMO 19 as long ago as1918. By and large, however, this aspect of the disorderhas attracted little attention from those working on thedisturbance of copper metabolism which is thought tobe fundamental to Wilson’s disease; the bony abnor-malities have presumably been seen as secondaryfeatures not directly related to the primary geneticallydetermined metabolic fault. Indeed, CUMINGS 20 says13. Dickinson, J. M., Pride, N. B. Brit. med. J. 1962, i, 432.14. Report from Six Hospitals, Lancet, Sept. 29, 1962, p. 634.15. Dale, A. J. D., Geraci, J. E. Proc. Mayo Clin. 1961, 36, 288.16. Vogler, W. R., Dorney, E. R. Amer. Heart J. 1962, 64, 198.17. Lord, J. W., Imparato, A. M., Hackel, A., Doyle, E. F. Circulation,

1961, 23, 489.18. Peery, T. M., Evans, J. M. Ann. intern. Med. 1958, 49, 568.19. von Economo, C. Z. ges. Neurol. Psychiat. 1918, 43, 173.20. Cumings, J. N. Heavy Metals and the Brain; p. 29. Oxford, 1959.

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simply: " fractures have been found in a few patients "

and he gives no further details about the nature of theskeletal defects or their pathogenesis. Even at the inter-national meeting, held in London in 1959,21 this topicwas only touched upon-although BOUDIN and PEPIN 22did give a full account of a remarkable patient in whomthere was generalised demineralisation of the skeleton,multiple microcysts at the regions of tendinous and liga-mentary insertion, and a curious hazy appearance of thearticular regions on X-ray. They had found no veryobvious disturbance of calcium or phosphorus metabol-ism, nor any clear association between the bone lesionson the one hand and urinary aminoacid loss or disturbedcopper metabolism on the other. Isolated accounts of

single cases with bone disorder may give a misleadingpicture of its frequency. BEARN and FINBY 23 surveyedthe bones of 20 patients with Wilson’s diseases and foundX-ray changes in 14; ROSENOER 24 made similar findingsin " 80% of 12 cases ". The lesions they reportedincluded generalised demineralisation of the skeleton(probably the commonest), osteochondritis of the spineand knees, periarticular fragmentation of bone, osteo-arthritis out of proportion to the age- of the patient,spontaneous fractures, pseudofractures, osteomalacia, andfrank rickets; this last finding would appear to be rare andso far there are only three well-documented cases. 23 25 2 6Associated biochemical findings have included hyper-calcuria,27 hyperphosphaturia with hypophosphataemia,2 11and aminoaciduria with normal blood-aminoacids 2930;other evidence of renal-tubular abnormality hasalso been reported-glycosuria,29 uricosuria,31 andrenal-tubular proteinuria. 32 Thus the picture has beenbuilt up of bone disease associated with renal tubularleak of calcium, phosphorus, aminoacids, glucose, andurates. The similarity to the findings in the Fanconisyndrome has already been noted 29 33 and has ledBEARN 34 to comment : " The renal lesion in Wilson’sdisease bears a striking resemblance to that seen in theFanconi syndrome but is not confined to disturbanceof tubular function. The glomerular filtration rate is

usually lower than normal, as is the effective renal plasmaflow."The relationship of the bone disease to the renal

lesion is less clear than it might seem at first, and eventhat of the renal lesion to the primary metabolic abnor-mality is a matter of debate. UZMAN and DENNYBROWN 35 believe that genetically determined amino-aciduria is associated with an error of protein and peptide21 Wilson’s Disease: Some Current Concepts (edited by J. M. Walshe

and J. N. Cumings). Oxford, 1962.22. Boudin, G., Pepin, B. ibid. p. 233.23. Finby, N., Bearn, A. G Amer. J. Roentgenol. 1958, 79, 603.24. Rosenoer, V. in Wilson’s Disease: Some Current Concepts (edited by

J. M. Walshe and J. N. Cumings); p. 245. Oxford, 1962.25 Andre, M. J. Rev. beige Sci. méd. 1946, 17, 185.26. Morgan, H. G., Stewart, W. K., Lowe, K. G., Stowers, J. M.,

Johnstone, J. H. Quart. J. Med. 1962, 31, 361.27. Goldstein, N. P., Randall, R. V., Gross, J. B., Rosevear, J. W.,

McGuckin, W. F. Neurology, 1962, 12, 231.28. Bearn, A. G., Yu, T. F., Gutman, A. B. J. clin. Invest. 1957, 36, 1107.29. Cooper, A. M., Eckhardt, R. D., Faloon, W. W., Davidson, C. S. ibid.

1950, 29, 265.30. Stein, W. H., Bearn, A. G., Moore, S. ibid. 1954, 33, 410.31 Bishop, C., Zimdahl, W. T., Talbott, J. H. Proc. Sac. exp. Biol., N.Y.

1954, 86, 440.32 Butler, E. A., Flynn, F. V., Harris, H., Robson, E. R. Clin. Chim. Acta,

1962, 7, 34.33 Dent, C. E., Harris, H. Ann. Eugenics, 1951, 16, 60.34. Bearn, A. G. Amer. J. Med. 1957, 22, 747.35 Uzman, L., Denny Brown, D. Amer. J. med. Sci. 1948, 215, 599.

metabolism and that aminoaciduria can be detected inother healthy members of the family; SOOTHILL et al. 36have since taken up this view. But most people havetended to regard the renal-tubular defect as secondary tocopper deposition in the tubules: the severity of therenal lesions appears to be related to the duration of thedisease rather than to the age of the patient or theseverity of the illness,3’ and in many ways the renalimpairment resembles that due to intoxication with otherheavy metals. Moreover, a few well-authenticated earlycases have been reported in which the aminoacid patternin the urine was normal.30 311 Probably, more than onemechanism contributes to the production of the bonelesions: in general, decalcification of the skeleton andspontaneous fractures are associated with hypercalcuria,whereas rickets or osteomalacia and pseudofractures arefound with the renal-tubular lesion characteristic of theFanconi syndrome; the exact type of lesion depends uponthe age of the patient at the onset of the disorder.Disturbed copper metabolism may itself be the primarycause of the periarticular fragmentation and jointchanges which are rather commonly found in Wilson’sdisease, but the exact effect of copper in this respect isquite obscure. In copper-deficient animals, for instance,there is known to be defective osteoblastic activity 39 withskeletal changes similar to those found in scurvy; butthat the bony changes of Wilson’s disease are due toexcessive copper deposition in the tissues would seemmore likely-despite the low plasma-copper levelscharacteristic of the disease. Bone analyses will be

necessary to settle the point, although, hitherto, figuresfor the copper content of bone have been strikinglyabsent from reports of Wilson’s disease. The relation ofthe Fanconi syndrome to Wilson’s disease has beenstudied by MORGAN et al.26 who report their findings in aremarkable patient-a lad presented at the age ofseventeen with rickets and osteochondritis, associatedwith defective reabsorption of glucose, inorganic phos-phate, and aminoacids by the renal tubules. MORGANet al. considered that this association " warranted the

diagnosis of the Fanconi syndrome." Only later did theappearance of hepatic and neurological symptoms showthat the patient in fact had Wilson’s disease. Micro-dissection of the renal tubule revealed no structural

abnormality, thus confirming an earlier report to thiseffect.40 If the tubular defect were simply due to

copper deposition it should, like other symptoms, im-prove with chelation therapy. This, however, does notappear to be so: in 2 patients, renal function has beenstudied in detail before and after treatment with penicil-lamine 26 41; little or no improvement was noted, althoughin other respects the clinical response was good. Thisobservation could be construed as support for the

hypothesis that the primary metabolic defect is one of36. Soothill, J. F., Blainey, J. D., Hall, G. S., Neale, F. C., Fischer Williams,

M., Melnick, S. C. in Wilson’s Disease: Some Current Concepts (editedby J. M. Walshe and J. N. Cumings); p. 124. Oxford, 1962.

37. Bearn, A. G., Kunkel, H. G. Ergebn. inn. Med. Kinderheilk. 1956, 7, 147.38. Cartwright, G. E., Hodges, R. E., Gubler, C. J., Mahoney, J. P., Daum,

K., Wintrobe, M. M., Bean, W. B. J. clin. Invest. 1954, 33, 1487.39. Follis, R. H., Bush, J. A., Cartwright, G. E., Wintrobe, M. M. Johns

Hopk. Hosp. Bull. 1955, 97, 405.40. Clay, R. D., Darmady, E. M., Hawkins, M. J. Path. Bact. 1953, 65, 551.41. Shaldon, S. in Wilson’s Disease: Some Current Concepts (edited by

J. M. Walshe and J. N. Cumings); p. 245. Oxford, 1962.

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aminoacid and protein metabolism. In 1 of these

patients, calcium absorption from the gut was increased;but the patient was so unusual in other respects that thisfinding may well not be universally applicable to Wilson’sdisease. Unfortunately, the relation of the renal lesionto copper metabolism was not investigated in this patient:histochemical examination of the renal tubules for thedistribution of copper might have thrown light on thisfundamental point.How frequently is Wilson’s disease associated with the

Fanconi syndrome ? Is the combination one of thoserarities which provide such valuable clues to the under-standing of obscure metabolic pathways, or is it one weshould constantly bear in mind? MORGAN et al. 26

suggest that other published examples of the Fanconisyndrome may equally well have been cases of Wilson’sdisease, a possibility which also seems to have beenenvisaged by BEARN and KUNKEL 37 who advocated astudy of trace-metal metabolism in patients with theFanconi syndrome. Retrospective diagnosis is seldom

easy: but re-examination of tissue sections from cases ofthe Fanconi syndrome for changes characteristic ofWilson’s disease 42 and for copper deposits, might proveinteresting.

Annotations

NOBEL PRIZE FOR MEDICINE

FOR the third time since 1957, a Nobel prize has beengiven for work on nucleic acids-a proper reflection of theimportance of this subject and of the rate at which

developments have occurred. In 1957 Lord Todd wasawarded the prize for structural elucidations and synthesesof the subunits (nucleotides) of nucleic acids.43 In 1959Ochoa and Kornberg’s work on the enzymatic synthesesof nucleic acids from the nucleotide subunits was similarlyrecognised.44 And now Dr. Maurice Wilkins, Dr. JamesWatson, and Dr. Francis Crick have received the prize inmedicine for relating the physical and chemical structureof nucleic acids to genetics in general.

Wilkins and his colleagues 45 studied the scattering ofa beam of X rays by specially prepared threads of

undegraded desoxyribose nucleic acid (D.N.A.)-the con-stituent of the cell nucleus believed to be the carrier of the

hereditary message from one generation of cells to thenext. They reported that the D.N.A. was a highly crystallinesubstance, and calculations from the angle of scatteringsuggested that the D.N.A. molecule was arranged as a coiledtwo-stranded helix. On the basis of this structure,Watson and Crick 46 suggested a plausible mechanism forthe accurate reduplication of the molecule which is

necessary if the hereditary message is to be correctlytransmitted to daughter cells. The structural units of theD.N.A. molecule were known to be of four different types-nucleotides of adenine, guanine, cytosine, and thymine.Watson and Crick postulated that the units of one chainfitted those of the other by a system of hydrogen bondingsuch that, wherever adenine appeared in one chain, the42. Anderson, P. J., Popper, H. Amer. J. Path. 1960, 36, 483.43. Lancet, 1957, ii, 934.44. ibid. 1959, ii, 655.45. Wilkins, M. F. H., Stokes, A. R., Wilson, H. R. Nature, Lond. 1953,

171, 738.46. Watson, J. D., Crick, F. H. C. ibid. p. 737.

other contained thymine, and wherever guanine appeared,the complementary chain contained cytosine. A sectionof a typical D.N.A. double-strand might therefore appearas:

During cell division the two chains would separate, andan exact replica of the original could then be built up oneach since only the right sequence of newly synthesisedunits would fit.

This suggestion has been followed up vigorouslythroughout the scientific world, and later work has

suggested how the arrangement of the subunits can beused as a code to build up a specific order of aminoacidsin a protein. Information is stored in a triplet code-that is, a specific arrangement of three nucleotides refersto a particular aminoacid. A sequence of groups of threenucleotides can therefore dictate the synthesis of a specificprotein, the code being transmitted by way of specialribonucleic-acid units.47 48

With the award to Dr. Crick, two floors of the three-storey laboratory run by the Medical Research Councilin Cambridge house Nobel-prize winners-reflection ofa remarkable record of achievement.

AMBULANT TREATMENT OFSPINAL TUBERCULOSIS

THE era of long-term rest in the conservative treatmentof tuberculosis of the spine came to an abrupt end withthe advent of chemotherapy. Even before this, however,Wilkinson 49 had already shown the value of a directsurgical attack upon the lesion. The combination of

chemotherapy and anterior spinal fusion has been exten-sively explored by Hodgson and Stock,5O and the excellenceof their results, with the high rate of bony fusion, leaveslittle doubt that this method reduces both the length ofstay in hospital and the risk of deformity; but this treat-ment demands a high standard of surgical and nursingcare which can seldom be attained in those countrieswhere the disease is most common.

Ambulant treatment for pulmonary tuberculosis is nowwell established and will inevitably be applied one dayto tuberculosis of bones and joints. From Nigeria,Konstam and Blesovsky 61 have reported their experienceof 207 patients with spinal tuberculosis whom they treatedin this way. 56 presented with paraplegia of varyingextent and 144 with paraspinal abscesses. Basically,treatment consisted in oral antituberculous drugs(isoniazid and p-aminosalicylic acid) and simple evacuationof abscesses; it was continued for a year or more. Para-

plegics unable to walk and patients requiring drainage ofan abscess were admitted to hospital for short periods, butall the others were treated as outpatients. Plaster castsand spinal supports were not used, and deformity wasaccepted as a necessary part of the process of healing. Ofthe 207 patients so treated, 178 were eventually regardedas healed and 5 as unhealed; 3 died. A further 21 patients,whose lesions were thought to be progressing satisfactorily,absconded from further treatment.47. Brenner, S., Jacob, F., Meselson, M. ibid. 1961, 190, 576.48. Gros, F., Hiatt, H., Gilbert, W., Kurland, C. G., Risebrough, R. W.,

Watson, J. D. ibid. p. 581.49. Wilkinson, M. C. Proc. R. Soc. Med. 1950, 43, 114.50. Hodgson, A. R., Stock, F. E. J. Bone Jt Surg. 1960, 42A, 295.51. Konstam, P. G., Blesovsky, A. ibid. 1962, 50, 26.