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preoccupation towards the minutiae of diagnosis andterminology. Research on treatment is dominated byinnumerable trials of -new drugs in an ostensiblysaturated market, with each investigator straining toextract a tiny advantage of one compound over itscompetitors so that it can be seized upon by marketingmanagers for promotion. While variations in thissmall part of treatment outcome enjoy frenzied

activity, the remainder, from counselling to alternativemedicine, is left unexplored or inadequately studied.

Psychiatrists in the middle of this turbulence needto have some long-term aims and values if they are not

’ to pass from one group to another by randombrownian movement. The aims of the originalassociation 150 years ago are still desirable. Thereremains much room for improvement in the

management of institutions for the treatment of the

mentally ill and the need for "more extensive andmore correct knowledge" is unchanged. Lack ofprogress in the latter should not unduly hinder theformer. Far too often we learn about treatment fallingshort of accepted practice, staff who are demoralisedand lack direction, and psychiatrists who are betterknown for their absences than their leadership.

All is not gloomy. In the 150th anniversary issue ofthe British Journal of Psychiatry Birley4 reminds us ofthe proper concerns of psychiatrists and the reasonswhy our late Victorian forefathers were so effective-they were good communicators. Good psychiatry is ajoint enterprise, not only between doctors, but alsobetween other professionals and, increasingly, withpeople. Birley asks us "to raise the level of discourse tosomething more sophisticated than often passes atpresent" and to avoid the impression of occupying"either an omnipotent stance or an impotent one, withnothing much in between". Psychiatrists need towiden their horizons again and remind themselvesthat the likes of John Conolly and Samuel Tukeachieved so much through their generosity of spirit,humanity, and commitment. British psychiatry needsto work on both its internal and public relations if itsfirst 150 years are not to become its best.

1. Berrios GR, Freeman H, eds. 150 years of British psychiatry. London:Gaskell, 1991.

2. A sane patient. My experiences in a lunatic asylum. London: Chatto andWindus, 1879.

3. Wing JK. Vision and reality. In: Hall P, Brockington IF, eds. The closureof mental hospitals. London: Gaskell, 1991: 10-19.

4. Birley JLT. Psychiatrists and citizens. Br J Psychiatry 1991; 159: 1-7.

Thallium scintigraphy for diagnosisand risk assessment of coronary

artery disease

Exercise thallium-201 myocardial perfusionscintigraphy was introduced over ten years ago forinvestigating patients with suspected coronary arterydisease. A standardised exercise stress test withcontinuous electrocardiographic monitoring is used to

provoke myocardial ischaemia in susceptible subjects.Thallium-201 (2-3-5 mCi) is injected intravenously atpeak exercise and the heart is imaged with a gammacamera. The isotope, a potassium analogue,distributes homogeneously in normally perfusedmyocardium whereas ischaemic or infarcted areasappear as scintigraphic defects. Repeat imagingafter 2-4 h permits reassessment of the defects:those that disappear (reversible defects) indicateareas of exercise-induced ischaemia; those that

persist (fixed defects) indicate infarcted

myocardium.The capital and revenue costs of thallium perfusion

scintigraphy are considerably higher than those ofexercise electrocardiography, but the technique is safeand carries no additional risk apart from that attachedto administration of radioisotopes. Nevertheless, itsdiagnostic value has been widely debated and

publication of clinical guidelines by the AmericanCollege of Cardiologyl did nothing to resolve thecontroversy. Even the most enthusastic advocates ofthallium perfusion imaging were disappointed by thisreport which, despite a statement of intent to "impacton the cost of medical care without diminishing theeffectiveness of that care", identified a role forthallium perfusion scintigraphy in the diagnosis ofalmost every coronary syndrome from acute infarctionto silent ischaemia. Grounds for consensus havenow begun to emerge with publication last year ofthe American College of Physicians’ positionpaper,2 which was based on a review by Kotler andDiamond. 3

Kotler and Diamond found that average values for

diagnostic sensitivity (84%, range 68-96%) andspecificity (78%, range 65-100%) were higher thanfor exercise electrocardiography, but pointed out that,because thallium scintigraphy is always done in

conjunction with exercise testing, it is more

appropriate to analyse the results of both techniquescollectively. The published data have exaggerated thediagnostic value of thallium scintigraphy because ofselection bias: (a) sensitivity may be inflated byrestricting analysis to subgroups chosen for

catheterisation; or (b) both sensitivity and specificitymay be inflated by including an excess of patients witha very high probability of disease.4 In manystudies diagnostic sensitivity has been further

exaggerated by exclusion of patients with lowexercise heart rates who are often false-negativeresponders. These considerations are likewisepertinent to studies of thallium-201 single photonemission computed tomography, which seems tooffer little advantage over conventional planarimaging. 6The figures cited by Kotler and Diamond for

inter-observer (3-16%) and intra-observer (4-11%)variability of visual assessment, which have bedevilledinterpretation of thallium scintigrams, are higher thanthose reported for the analysis of ST segment change.(This difficulty is only partly resolved by quantitative

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computer algorithms.) Thus, in clinical practice, thediagnostic value of thallium scintigraphy is almost

certainly lower than the usually reported figures and iscritically dependent on the prevalence of disease in thepopulation tested.’ If prevalence is very low

(symptom-free individuals, young women with

atypical symptoms) or very high (patients aged over 50with typical angina), thallium scintigraphy is of littleor no diagnostic value; between these extremes it cansignificantly increase or reduce diagnostic probability.The technique is especially helpful when

repolarisation abnormalities, caused by left bundlebranch block, pacing, or digitalis therapy, prohibit STsegment analysis and contraindicate diagnosticexercise electrocardiography. It also has a role whenpatients are unable to complete an adequate stresstest-pharmacological coronary vasodilatation withdipyridamole provides an effective alternative to

exercise before administration of thallium-201.8 Inother patients with an intermediate prevalence ofcoronary disease, the choice of initial diagnostic test ismore finely balanced.Thallium scintigraphy has also been used for

prognostic assessment in patients with coronary arterydisease; several studies have shown that, in patientswith angina, the amount of myocardial hypoperfusionis a useful predictor of coronary events.9-11

Nevertheless, as Kotler and Diamond3 point out, fewof these studies evaluated the "incremental"

prognostic information provided by the test over andabove that given by the history, examination,electrocardiogram, and chest radiograph (data that arereadily available).3 Thus, Ladenheim et al12 found

that, in patients with a normal restingelectrocardiogram, thallium scintigraphy providedonly incremental prognostic information when diseaseprobability (based on clinical criteria) was eitherintermediate with a positive exercise

electrocardiogram or high with a negative exerciseelectrocardiogram. In patients with an abnormalresting electrocardiogram the incremental prognosticyield was higher, all patients benefiting fromcombined exercise electrocardiography and thalliumscintigraphy. In patients with recent uncomplicatedmyocardial infarction, the sensitivity and predictiveaccuracy of thallium scintigraphy for detecting thoseat risk of recurrent cardiac events (as determined bydocumenting multivessel disease) is generally betterthan that of exercise electrocardiography. 13--16 Inclinical practice it remains uncertain to whatextent (and at what financial cost) thallium

scintigraphy adds to the prognostic informationprovided by clinical evaluation and exercise

electrocardiography. Moreover, how relevant is suchtesting in 1991, when most patients will have receivedthrombolytic agents? Nowadays, recurrent events arecommonly the result of reocclusion of the infarct-related artery, and may be unrelated to the extent ofcoronary diseasey,18What about dipyridamole thallium scintigraphy for

preoperative screening to identify patients undergoingvascular surgery who are at risk of adverse cardiacoutcomes? The encouraging findings of unblindedstudies’920 were not borne out in the report of

Mangano et al;21 when the treating physicians wereblinded to the results of the preoperative scintigram,the predictive accuracy of redistribution defects foradverse outcomes proved to be very low.On the evidence of the review by Kotler and

Diamond, the American College of Physicians wereable to recommend diagnostic thallium scintigraphyfor patients with an intermediate prevalence of

coronary artery disease but judged it clearly preferableto exercise electrocardiography only in those withrepolarisation abnormalities that impair interpretationof the electrocardiogram. They were more guarded inrecommending this technique to evaluate outcomeafter myocardial infarction-it was seen as clearlypreferable to exercise electrocardiography only whenresting repolarisation abnormalities were present.2The relative merits of exercise electrocardiographyalone or in combination with thallium scintigraphycould not be defmed by the American College becausethere have been no good comparisons of the cost-effectiveness of these testing strategies. There is nocontroversy, however, about the relative costs of thesetests (in terms of time, staff, and materials) andit is clear, therefore, that in the current climateof financial restraint any case for extending theavailability of thallium scintigraphy for the

investigation of coronary artery disease, at the

expense of exercise electrocardiography, cannot

yet be sustained.

1. American College of Cardiology/American Heart Association Task Forceon Assessment of Cardiovascular Procedures (Subcommittee onNuclear Imaging). Guidelines for clinical use of cardiac radionuclideimaging, December 1986. JACC 1986; 8: 1471-83.

2. American College of Physicians. Position paper: efficacy of exercisethallium-201 scintigraphy in the diagnosis and prognosis of coronaryartery disease. Ann Intern Med 1990; 113: 703-304.

3. Kotler TS, Diamond GA. Exercise thallium-201 scintigraphy in thediagnosis and prognosis of coronary artery disease. Ann Intern Med1990; 113: 684-702.

4. Diamond GA. Reverend Bayes’ silent majority: an alternative factoraffecting sensitivity and specificity of exercise electrocardiography. AmJ Cardiol 1986; 57: 1175-80.

5. Iskandrian AS, Heo J, Kong B, Lyons E. Effect of exercise level on theability of thallium-201 tomographic imaging in detecting coronaryartery disease: analysis of 461 patients. JACC 1989; 14: 1477-86.

6. Diamond GA. How accurate is SPECT thallium scintigraphy? JACC1990; 16: 1017-21.

7. Timmis AD. Probability analysis in the diagnosis of coronary arterydisease. Br Med J 1985; 291: 1443-44.

8. Leppo J, Boucher CA, Okada RD, Newell JB, Strauss HW, Pohost GM.Serial thallium-201 myocardial imaging after dipyridamole infusion:diagnostic utility in detecting coronary stenoses and relationship toregional wall motion. Circulation 1982; 66: 649-57.

9. Brown KA, Boucher CA, Okada RD, et al. Prognostic value of exercisethallium-201 imaging in patients presenting for evaluation of chestpain. JACC 1983; 1: 994-1001.

10. Iskandrian AS, Hakki AH, Kane-Marsch S. Prognostic implications ofexercise thallium-201 scintigraphy in patients with suspected or knowncoronary artery disease. Am Heart J 1985; 110: 135-43.

11. Ladenheim ML, Pollock BH, Rozanski A, et al. Extent and severity ofmyocardial hypoperfusion as predictors of prognosis in patients withsuspected coronary artery disease. JACC 1986; 7: 464-71.

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12. Ladenheim ML, Kotler TS, Pollock BH, Berman DS, Diamond GA.Incremental prognostic power of clinical history, exercise

electrocardiography and myocardial perfusion scintigraphy in

suspected coronary artery disease. Am J Cardiol 1987; 59:270-77.

13. Dunn RF, Freedman B, Bailey IK, Uren R, Kelly DT. Noninvasiveprediction of multivessel disease after myocardial infarction.Circulation 1980; 62: 726-36.

14. Gibson RS, Taylor GJ, Watson DD, et al. Predicting the extent andlocation of coronary artery disease during the early postinfarctionperiod by quantitative thallium-201 scintigraphy. Am J Cardiol 1981;47: 1010-19.

15. Legrand V, Albert A, Rigo P, Kulbertus HE. Complementary role ofthallium-201 scintigraphy to predischarge exercise electrocardiographyfor patients stratification after a first myocardial infarction. Eur Heart J1986; 7: 644-53.

16. Abraham RD, Freedman B, Dunn RF, et al. Prediction of multivesselcoronary artery disease and prognosis early after acute myocardialinfarction by exercise electrocardiography and thallium-201

myocardial perfusion scanning. Am J Cardiol 1986; 58: 423-27.17. Gruppo Italiano per lo Studio Streptochinasi nell’infarto Miocardico

(GISSI). Long-term effects of intravenous thrombolysis in acutemyocardial infarction: final report of the GISSI Study. Lancet 1987; ii;871-74.

18. Schroder R, Nehaus K, Linderer T, Leizorovicz A, Wegscheider K,Tebbe U. Risk of death from recurrent ischemic events afterintravenous streptokinase in acute myocardial infarction: results fromthe Intravenous Streptokinase in Myocardial Infarction (ISAM)Study. Circulation 1987; 76 (suppl II); 44-51.

19. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW,Pohost GM. Determination of cardiac risk by dipyridamole-thalliumimaging before peripheral vascular surgery. N Engl J Med 1985; 312:389-94.

20. Leppo J, Plaja J, Gionet M, Tumolo J, Paraskos JA, Cutler BS.Noninvasive evaluation of cardiac risk before elective vascular surgery.JACC 1987; 9: 269-76.

21. Mangano DT, London MJ, Tubau JF, et al. Dipyridamole thallium-201scintigraphy as a preoperative screening test: a reexamination of itspredictive potential. Circulation 1991; 84: 493-502.

The thymus at thirtyThe familiar comment that "half the scientists who

have ever lived are alive today" almost certainlyunderstates the case with respect to immunologists-for this particular breed the proportion extant must becloser to 90%. Although clinical immunology cantrace its origins back some two hundred years toEdward Jenner, and the formal scientific study ofimmune phenomena began a century ago with

Metchnikoff, it is only very recently that the subjecthas gained the status of a major discipline, spawninginstitutes, university departments, international

associations, and numerous publications. Most

immunologists now working must have been bornbefore any function had been assigned to the

lymphocyte1-the equivalent, in bacteriologicalterms, of being Pasteur’s contemporary-yet it evokesno surprise to hear the topic of circulating CD4 cellsdiscussed knowledgeably on popular radio

programmes about AIDS or to find that manymembers of the public are tolerably well informedabout immunosuppression in the context of organtransplants and even about monoclonal antibodies aspossible therapeutic agents. The clearing of

immunological mists can be attributed to a series ofcritical discoveries allied to some remarkable insightsthat have placed the experimental observations in a

coherent context. An outstanding example is our

understanding of the role of the thymus which, thirtyyears ago, was highlighted in The Lancet by a

preliminary communication from J. F. A. P. Miller.2 2Before 1960 the thymus evoked little interest. It was

known to undergo progressive involution in adult life;in children with respiratory distress, demonstration ofa large thymic shadow radiographically often led to theunnecessary removal or irradiation of the "enlarged"gland. Working for his PhD at the Chester BeattyInstitute in London, Miller was initially interested inthe cellular origins of a virally induced mouse

lymphatic leukaemia and undertook thymectomy inyoung animals with subsequent reimplantation ofsyngeneic thymus in some.2,3 He was able to show thatthe neonatal thymus was the site of leukaemogenicvirus/cell interaction, but he became more fascinatedby the pathological consequences he observed whenthymectomy was carried out immediately after birth.Sheer technical difficulties had prevented anyprevious experiments of this type and, althoughseveral forms of congenital thymic aplasia withassociated defects of immune function are now well

recognised in man,4 they had not been described atthat time. Miller recognised that his neonatallythymectomised mice were unusually susceptible toinfections and surmised that they were

immunologically impaired. When he took special careto protect them from pathogens so that they remainedapparently healthy, he found that they were tolerant ofskin grafts from mice of unrelated strains and evenfrom rats. Removal of the thymus from slightly olderanimals had no such dramatic effects, suggesting thatin early life the thymus was a site of education of cellspassing through it. Careful necropsy of his animalsshowed that neonatal thymectomy led to a deficiencyof lymphocytes in the blood and peripheral lymphoidtissues.z 2

This work established that the thymus was animportant organ in the development of a functioningimmune system. Furthermore, the timing of thesediscoveries was propitious-not only did they followclose on the heels of Gowans’ observation that thesmall lymphocyte is capable of mediating immuneresponses,s but also they came just as the division oflymphoid cells into anatomically and functionallydistinct subsets was being recognised in birds.6Subsequent experiments in mice by several groups,who manipulated thymic, thoracic duct, and marrow-derived lymphocyte populations, confirmed that thesesubdivisions apply also in mammals and led ultimatelyto our current understanding of the intricate cellularinteractions that underlie virtually all immunereactions.7,8At least three main lines of immunological inquiry

may be said to stem, directly or indirectly, from thediscovery that thymus-derived lymphocytes havedistinctive properties: (a) identification of cell-surfaceantigens that denote direction and stage of lymphocytedifferentiation; (b) study of molecular events