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gross secondary changes in the pulmonary circu-lation, it should be kept in mind that progression isoften very slow and that the operation itself may bemuch improved technically in the years to come." We do not yet know whether the operations ...will be of permant value or ... only set the clock backfor these patients by a few years." 11 We cannot yettell how commonly re-stenosis will take place in

patients who have undergone valvotomy. Hithertothis has been only rarely recorded; but WooD 4

mentions that it followed 3 of the first 20 valvotomies.

Only persistent and accurate follow-up will establishthe extent of this risk.

Isoniazid and Clinical TrialsISONIAZID is a highly effective drug, and its side-effects are few and unimportant. The attention stillaccorded its isopropyl derivative-iproniazid-is there-fore a little surprising ; for there are many reportsthat, in man, iproniazid is much the more toxic of thetwo. Thus CHEIFETZ et al.12 said that its administrationhad to be discontinued in 25 out of 52 cases treated.LICHENSTEIN and MrzENBERG 13 found that toxic

symptoms were " common and troublesome," andCoATES et al.14 thought it too toxic for general use.MITCHELL 15 attributed to it a death from toxic

encephalitis. Its use in preference to isoniazid wouldbe justified if its therapeutic effect were so much

greater that its higher toxicity was outweighed ; butthere is no convincing evidence of this. OGILVIE 16has now reported on the course of the disease in 24patients treated with isoniazid and 30 treated withiproniazid, both groups also receiving 1 g. streptomycinthree times a week. After two months’ treatment itwas found that more than three-quarters of thosewho received iproniazid had had some toxic symptoms,compared with a third of those who received isoniazid(and this seems an unusually high proportion). Themean gain in weight was twice as great in the ipro-niazid as in the isoniazid group ; but this was the onlyconvincing difference. OGILVIE says that " prognosis,as judged by temperature response, the closure of largecavities and the incidence of bacterial resistance, wasmore favourable in the iproniazid group " ; and it istrue that only 3 out of 6 patients treated with isoniazidbecame afebrile within two weeks, compared withall the 5 treated with iproniazid. Furthermore, largecavities closed in 2 out of 11 treated with isoniazid,compared with 6 out of 12 treated with iproniazid,and sensitive bacilli were isolated in 4 out of 8, com-pared with 8 out of 8. But these differences are reallyquite small, and in the much more important factorsof radiographic clearing and sputum " conversion "the differences were even smaller. They give nosubstantial support to the use of the more toxic

product.Some of the problems concerning isoniazid still

resist solution despite large trials. Fox and SUTHER-LAND 17 working for the Medical Research Council, havesought to determine the clinical significance of iso-11. Graham, G. K., Taylor, J. A., Ellis, L. B., Grunberg, D. J.,

Robbins, S. L. Arch. intern. Med. 1951, 88, 532.12. Cheifetz, I., Paulin, C., Tuatay, H., Rubin, E. H. Dis. Chest,

1954, 25, 390.13. Lichenstein, M. R., Mizenberg, E. Ibid, p. 573.14. Coates, E. O., Brickman, G. L., Meade, G.M. Arch. intern. Med.

1954, 93, 541.15. Mitchell, R. S. Ann. intern. Med. 1954, 42, 417.16. Ogilvie, C. M. Quart. J. Med. 1955, 24, 175.17. Fox, W., Sutherland, I. Thorax, 1955, 10, 85.

niazid resistance by an investigation of 234 patientsfrom which they conclude that " the study of possibleclinical disadvantages due directly to the developmentof isoniazid resistance is inconclusive. Nevertheless,because isoniazid resistance tends to occur in diseasewhich is pursuing a relatively unfavourable course,its development is an adverse prognostic sign." Howmuch value there will be in this sign is perhaps amatter of opinion, since the unfavourable course willgenerally have been apparent at the bedside longbefore the arrival of the laboratory report. Clearlyit is very important to find out whether isoniazid can,as has been suggested,18 safely be used alone; but

retrospective analysis of a group of patients, howeverlarge, treated for only two or three months in a trialnot specially designed for the purpose is unlikely togive the definite answer one could wish. As Dr.SCADDING said in the Lettsomian lectures,19 suchproblems " can only be solved by carefully plannedand controlled investigations," and " until unequivocalresults are available from such investigations the wisephysician will continue to treat his patients on thesupposition that isoniazid-resistance is unfavourable,and to plan antibacterial treatment in such a way as tominimise the risk of the emergence of resistant bacilli."

There are other pressing problems. For instance, itseems probable that only a controlled clinical trial-will satisfactorily answer the question whether it is

necessary to remove tuberculous nodules remainingafter protracted antibacterial treatment. But wecannot, unfortunately, hope that this answer willcome out of the survey now being made jointly by theBritish Tuberculosis Association and the Society ofThoracic Surgeons, even though here as many as 8500cases are available for analysis. 20 This type ofinvestiga-tion shows broadly what is happening, throughout thecountry, to patients treated surgically, and for thatit is valuable. But unless the fate of similar patientsnot surgically treated is known, the chest physiciancan make no reasoned judgment. Perhaps some ofthe questions concerning thoracic surgery in pulmon-ary tuberculosis could be answered by relatively smallclinical trials. These would require no more workthan do national unselective surveys ; but they wouldrequire much more cooperation. Such cooperationwas obtained when the Medical Research Councilconducted their clinical trials-now unfortunatelydiscontinued-and the results amply justified theunselfishness of the clinicians.

Reserpine and the MindIN a recent issue we published three articles on the

clinical applications of reserpine. Professor SMIRKand Dr. McQuEEN in New Zealand 21 and Dr. WALLACEin Australia 22 have used reserpine in the treatment ofhypertension, both alone and in combination withpentolinium. The results were good, except that

disturbing mental symptoms appeared in some of thepatients who received reserpine. SMIRK and McQuEENfound further that the alkaloid rescinnamine, alsoobtained from Rauwolfia serpentina and chemicallyrelated to reserpine, is also liable to produce mental-symptoms in hypertensives. In the same issue Dr.

18. See Lancet, 1954, ii, 691. 19. Scadding, J. G. Ibid, July 9, 1955, p. 49 ; Ibid, July 16, 1955,

p. 99 ; Ibid, July 23, 1955. p. 154.20. See Ibid, July 9, 1955, p. 83.21. Smirk; F. H., McQueen, E. G. Ibid, July 16, 1955, p. 115.22. Wallace, D. C. Ibid, p. 116.