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THE PRESENT POSITION OFCHEMOTHERAPY IN TUBERCULOSIS

BV JOHN C. ROBERTS, MA1.D., M.R.C.P.Consultant Physician, Harefield Hospital, Harefield, Middlesex

Considerable advances have been made in re-cent vears in the use of chemotherapy in tubercu-losis. WVhile alterations in technique are constantlyunder review the following summarises the presentposition.

Combinations of drugs and treatment schedulesthat combine maximum benefit with minimal drugtoxicity and bacterial resistance, have been theobject in much research all over the world.The drugs commonly in use are streptomycin,

para-amino-salicylic acid (PAS), isonicotinic acidhydrazide (INAH) and the thiosemicarbazones.

It is now generally agreed that combinations ofdrugs are more effective than one or other anti-biotic alone, and also such combinations delay theresistance of the tubercle bacillus to the individualdrugs.The toxic effects of the drugs used will first be

considered.

StreptomycinToxic effects are less common now that the

dosage is reduced to i g. per day rather than theoriginal dosage of 2 to 3 g. per day. A survey bythe Tuberculosis Association (1952) confirms this.Dihydrostreptomycin may cause deafness whereasstreptomycin sulphate appears to have an effect onthe v-estibular function, Bignall et al. discuss theseeffects. Both these complications are now lesscommon with lower dosage and improved purityof the drugs. Dihydrostreptomycin should, how-ever, be avoided intrathecally owing to the in-creased risk of deafness. The labyrinthinedisturbance tends to recover in time, but deafnesswN-hen it occurs is usually permanent. Heck et al.suggest that a mixture of equal quantities ofdihydrostreptomycin and streptomycin sulphatereduce the risk of neurotoxic effect. These dis-turbances are of importance and call for care inreturning a patient to an occupation where the dis-ability may be dangerous. Other toxic effects areskiin reactions-urticarial and ervthematous, lym-

phadenopathy, fever, nausea and vomiting. Sum-ner (I949) drew attention to the development of avitamin B deficiency and recommended prophy-lactic administration of vitamin B to patients hav-ing streptomycin. Local contact of the drug maysensitize the skin and has been recorded in nursesthrough giving injections without wearing glovesor taking precautions to avoid skin contact. Desen-sitization is usually possible and is carried out bvstarting with small injections, such as io mg.,and slowly working up to i g. Crofton (I952)gives a good account of this and in one case showedthat desensitization to dihydrostreptomycin doesnot desensitize against the sulphate. He took some35 days in one case and 23 weeks over the other todesensitize. He also used antihistamine prepara-tions. The writer can confirm these results.

Para-amino-salicylic AcidThe toxic effects of PAS are well summarized in

a Lancet annotation (I953). Nausea, vomiting anddiarrhoea are the commonest. Pyrexia, skin rashes,liver damage with associated defects and jaundiceoccur. Myxoedema, anuria, mental changes,glandular enlargement and splenomegaly are alsorecorded. The allergy may be more general andeffect sensitization to sulphonamides and strepto-mycin as well. Profound psychic disturbanceshave been described by Pugh et al. (1952), whoconsider that they are due to salicylate stimulationof the pituitary gland, resulting after a time inpituitary exhaustion and deficiency of cortin. Ingiving PAS it is wise to give it after a meal inliquid torm or, in some cases, enteric coatedgranules or cachets washed down with a drink ofmilk are preferred by the patient. Many prepara-tions are available which attempt to prevent orminimize the nausea. Adreno-corticotrophin(ACTH) has been successfullv used to overcomethe allergy to PAS (Houghton, 1952).As there is some evidence that ACTH and cor-

tisone when used alone have an adverse effect on

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tubercle, and also as these substances themselveshave their own unpleasant side effects, great careis necessary in their use. It is important whenusing ACTH or cortisone to make sure that thebacillus is sensitive to the antibiotic employedbefore either is used. It is probably safer wherethere is no urgency to desensitize, as described byCrofton.

Isonicotinic Acid HydrazideIn the dosage used, namely 200 to 400 mg.

daily, this seems to have little toxicity and is veryconvenient and easy to take. Damage to the liverand jaundice with haemopoetic depression hasbeen described in animal experiments (Rubin etal., 1952). Marked euphoria and convulsions arealso recorded. Some state, that a diminished sugartolerance occurs which is of importance in dia-betics (Luntz and Smith, I953). The writer hasnot experienced difficulty in using this drug indiabetics.

ThiosemicarbazonesThese are not used very frequently now. The

most effective and least toxic is said to be ethizone(TB.3). They have, however, toxic effects andmay cause liver damage and disturbance of thehaemopoetic tissues. An account of the use ofthis drug in genito-urinary tuberculosis is given byRoss-Cosbie et al. (I953) who gave up to 200 mg.daily for six months continuously, combined withalternating courses of PAS and dihydrostrepto-mycin.

ResistanceThe resistance of tubercle bacilli to the various

antibiotics used has been the subject of much dis-cussion. It is customary to assess the sensitivityby laboratory tests at the onset of treatment with-out necessarily waiting for the result, which takessome weeks, before starting treatment. A few re-sistant strains may be found in the sputum ofpatients who have had no previous chemotherapy.The organisms in the sputum may, during treat-ment, show increasing resistance in laboratory ex-aminations. Although laboratory investigationshave shown resistant strains in a particular case, thepatient may still continue to respond to the drugs.It must be appreciated that the specimen ex-amined is only a sample, and it cannot be presumedthat all the bacilli in the various lesions are equallysensitive or resistant. Resistance has, however,clinical significance in that some patients with re-sistant strains fail to respond to further chemo-therapy. Cavitated lesions are more liable to de-velop resistant strains than non-cavitated lesions.

In the early trials using streptomycin in dosageof 2 g. daily, resistant strains began to appear at

about the end of the second month of treatment,and after four months resistant strains were foundin 85 per cent. of those whose sputum remainedpositive. Attempts to reduce this incidence byreducing the dose and trying intermittent coursesof treatment met with some success. The additionof PAS or INAH not only proved more effectivein treatment but also in preventing or delaying theemergence of resistance to each of the drugs used.PAS used alone has a beneficial effect but not tothe same extent as streptomycin. Resistance de-velops but usually takes longer to do so than withstreptomycin. Turnbull et al. (I953) have shownwhen resistance to PAS has occurred it is uselessto use it with streptomycin in the hope of delayingthe development of streptomycin resistance.INAH has many advantages over PAS but re-

sistant strains develop quickly. After six weeks'treatment on a dosage of 200 mg. daily in thosepatients whose sputum still remains positive, 6oper cent. show bacilli resistant to INAH. It hasbeen shown experimentally by Barnett et al.(1953) that INAH resistant strains produced invitro and in mice reverted to sensitivity when con-tact with the drug was stopped after one sub-culture. They also showed that resistant strainsfrom human subjects tended to regain their sen-sitivity during three sub-cultures in the absence ofthe drug. Mice and guinea pigs inoculated withnon-resistant strains were completely protectedfrom developing tuberculosis by a dose of 20 mg.of INAH per kg. Even when the mice and guineapigs were inoculated with resistant strains a similardose of the drug increased the survival of theanimals considerably. Joiner et al. (I952) showedthat strains resistant to INAH from patientstended to revert to sensitivity after treatment wasstopped. This latter observation has not beenconfirmed in the recent Medical Research Counciltrials, where no alteration in resistance was foundafter three months following cessation of treatment.Treatment with INAH alone proved disappointingin that initial improvement was not maintained.The combination of streptomycin and INAH hasbeen shown to have as good if not better thera-peutic effect as streptomycin and PAS, and the re-sistance of organisms to both drugs is delayed.The usual dose of INAH for an adult is 200 to4oo mg. a day. Using INAH and streptomycin ina series of cases it was found that of those withpositive sputum cultures at the end of threemonths' treatment, only ii per cent. showed re-sistant strains, whereas using INAH alone thefigure rose to 64 per cent. Detailed investigationson these effects are continuing in the MedicalResearch Council trial (Lancet, 1953).

Before discussing the chemotherapeutic usagein individual fields, certain general principles

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ROBERTS: Present Position of Chemotherapy in Tuberculosis

should be observed. A careful assessment of thecase is essential, as chemotherapy is only one factorin the treatment, and its use should fit in with thegeneral plan. Full bacterial examination withsensitivity tests should be carried out, the materialbeing obtained before treatment with the drugs isinitiated, although in most cases it is not practic-able to await the results before commencing treat-ment. In the present state of our knowledge, asingle antibiotic should never be used alone.Streptomycin should always be combined witheither PAS or INAH or both. There is someevidence that PAS and INAH will prove anefficient combination, but there is as yet insufficientinformation on this point. There is also someevidence that streptomycin used on alternate daysin 2 g. dosage together with INAH, I50 mg. daily,has produced good results and also inhibited thedevelopment of the resistant strains.

Clinical Applicationsi. Pulmonary Tuberculosis

(a) Primary tuberculosis.- Some authorities ad-vise chemotherapy as a routine in children underthe age of two in view of the greater seriousness ofthe condition at this age. Lorber (1950) hasshown that streptomycin has little effect on simpleprimary lesions. The writer agrees with this viewand reserves antibiotic treatment for complicatedlesions, such as progressive primary lesions withcavitation. The drugs also should be used to coversurgical procedures such as tonsillectomy orbronchoscopic examinations or resections inpatients with primary tuberculosis. The dosage ofstreptomycin in infants depends on the weight-ausual guide is .02 g. of streptomycin per lb. bodyweight. The drug should always be combinedwith PAS or INAH. The latter is more easilytolerated by infants and children. Suggested dos-age is ioo mg. daily in infants under two, I50 mg.between the ages of two and ten and zoo mg. atthe age of ten or over.

(b) Miliary tuberculosis. It is necessary here fortreatment to be prolonged. In adults a gramme ofstreptomycin a day is now considered adequate.This is combined with PAS, 20 g. a day in divideddosage, and INAH, 200 to 400 mg. daily. Wherethe PAS is not well tolerated the dose may have tobe reduced or the drug omitted altogether andINAH used alone with the streptomycin. Eventhough clearing of the lesions occurs in threemonths it is wise to continue treatment for at leastsix months and preferably nine months to a year.The streptomycin can be given less frequentlyafter three months if progress is good. PAS andINAH may be used alternatively with the strepto-mycin. Some prefer to use the three drugs to-gether. There is no rigid rule but it is wise to

insist on prolonged treatment to prevent relapse.Routine lumbar punctures should be performedand if the fluid becomes abnormal the case shouldbe treated as one of tuberculous meningitis.

(c) Bronchogenic tuberculosis. The best resultsare undoubtedly obtained in recent active disease.Chronic disease is often benefited but relapse iscommon. Resistance of the organism to the anti-biotic and failure of the patient to respond is morelikely to develop in those with chronic thick-walledcavitated disease.

It cannot be too strongly stressed that generalmeasures are very important in all forms oftuberculous disease.

In early active disease a frequent course con-sists of three months of streptomycin combinedwith INAH or PAS or a combination of the three.Some use daily streptomycin for the first six weeksand then alternate days for the next six weeks. Asingle injection daily of a gramme is consideredadequate. The oral antibiotics are given daily;20 g. of PAS is usually given in 24 hours in 5-g.doses, if this is not well tolerated the dose may bereduced to i6 or even to I0 g.; 200 to 400 mg. ofINAH is given daily, divided into two or threedoses. After three months some give no furtherdrugs if improvement has occurred, but resumechemotherapy if the improvement is not main-tained or there is any evidence of a relapse. InAmerica there is a greater tendency to use con-tinuous chemotherapy for tuberculosis, even whensurgical treatment is envisaged. One year or morecontinuous treatment with antibiotics is notuncommon.

In chronic ambulant cases courses of anti-biotics may improve the patient clinically and alsosterilize the sputum for some time. The risk ofdissemination of resistant strains does not appearto have been as great as was expected and it doesnot seem justifiable to withhold treatment in thesecases for this reason. Again some use inter-mittent courses of three months, some reservetreatment for the times when the disease showssigns of activity and others favour more prolongedtreatment. Little is known of the end results inthis group.

In the surgical treatment of pulmonary tubercu-losis, particularly in those patients subjected toresection, all agree on the desirability of coveringthe procedure with antibiotics. Most patientshave had some months or years of conservativetreatment first and the majority have had one ormore courses of antibiotic treatment. The opera-tive cover is usually started one or two weeks priorto surgery and continued for four to six weeksafterwards, daily streptomycin (i g.) with PAS orINAH by mouth being given in addition. Somethen reduce the frequency of the streptomycin and

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continue the antibiotic treatment for a further sixweeks or so. Much depends on the individualcase and the nature of the surgery. The sensitivityof the bacilli to antibiotics in influencing a surgicaldecision is a matter of opinion. Some surgeonshesitate to undertake pulmonary resection unlessthe bacillus is known to be sensitive to at least oneof the antibiotics.

Tuberculosis of the lary-nx and of the bronchishow good response to chemotherapy. There isa tendencv for fibrosis to occur with streptomycin,and bronchial stricture may develop. This com-plication is of much importance when it occurs ina main bronchus or one of the major divisions,since infected secretions may be held up beyondthe stricture and produce progressive lung des-truction. It is therefore of importance to re-member this possibility in treating tracheobronchialtuberculosis with streptomycin.

Laryngeal tuberculosis if treated early shows adramatic response. Symptoms may disappear in24 hours and the writer has observed completeresolution occur in as short a period as a week.

(d) Pleural effusion. There is no convincingevidence that antibiotics influence the course ofpleural effusion or prevent sequelae. But somephysicians give a course during the acute phase.In tuberculous empyema good results have beenreported using streptomvcin and PAS both locallvand systemicallv. In earlv empvemas the responseis very good.

2. Tuberculolus M1eningitisIt is in this disease that the most spectacular

advances have been achieved. The general ten-dency has been to prolong treatment. McCarthvand Mann (1950) recommend three months intra-muscular streptomycin combined with threemonths intrathecal streptomycin. The intra-muscular dose depends on the weight of the child;the intrathecal dose varies between .os and .i g.On this regime recoveries up to about 5o per cent.have been reported. It is usual to combine PASdaily Nith streptomycin or, more recently, INAH.The latter is much easier to administer.

Anderson et al. (1953) describe a few cases inwhich INAH was the main treatment. Intra-muscular and intrathecal streptomycin was givenfor one week onlv in a few cases, and for onemonth in ts-o cases. INAH w-as continued orallyfor i6 wNeeks. One case which had relapsed fromprevious treatment was treated entirely bv INAHorally for i6 weeks. All cases were said to showremarkable response. Ritchie et al. (I953) sug-gested that INAH is more diffusible than strepto-mycin, having a more rapid action on the bacilliand promoting increased vascularity and resolutionof the lesions in miliary disease and meningitis.

Juan Torres-Gost (1953) reports on ioo cases withsix deaths only. He uses intramuscular strepto-mycin in dosage of .3 g. daily in infants under two,increasing the dose to .5 g. in severe cases. Be-tween the ages of two and ten i g. daily in twodoses for ten days followed by .5 g. daily until thefever subsides. In adults i g. daily is given intwo doses until the pyrexia subsides, combiningthis treatment with oral and intrathecal INAH. Inchildren under two he gives I50 mg. of INAHdaily, the dose increasing with age until the adultdose of 400 mg. is reached. He also gives io mg.of intrathecal INAH daily to infants under two,increasing the dose to a maximum of 50 mg.intrathecally daily for adults. A total dosage of30 to 45 g. of streptomycin over three months,25 to 30 g. of INAH orally and 55 intrathecal in-jections is the suggested course. In the first monththe intrathecal injections are daily, in the secondmonth on alternate days and in the third monthevery third day. Torres-Gost suggests that if thecell count in the cerebrospinal fluid is higher than20 after four months' completion of treatment, asecond course of streptomycin combined with oraland intravenous INAH should be given.

Fletcher (I953) has shown that adequate levelsin the spinal fluid of INAH are obtained intuberculous meningitis on an oral dosage of 200mg. per day. It is therefore difficult to see whyintrathecal INAH should be necessary. Intra-thecal streptomycin enhances the prospect of deaf-ness particularlv if dihydrostreptomycin sulphateis used, and for this reason alone any satisfactorytreatment which avoids the use of intrathecalstreptomycin is desirable.

Frequent lumbar punctures even when carriedout expertly in a sedated child or adult, tend toimpose considerable strain on the patient after atime and it is to be hoped that the early results withINAH orally combined with streptomycin intra-muscularly will prove an adequate treatment inthis condition. It would seem reasonable to com-mence on these lines and only to add intrathecalstreptomycin if progress does not appear satis-factory.One of the problems in tuberculous meningitis

is the occurrence of spinal block. Cathie (1950)used intrathecal streptokinase in an attempt toliquifv the exudate at the base of the brain toprevent the development of obstruction. Un-fortunately reactions to this treatment occur andthe writer had to abandon its use in one case onaccount of severe hypersensitivity changes.

Tuberculin intrathecally has been usedbv Smith et al. (I950). The initial dose is.0000035 mg., which is increased every day. Thedosage and rate of increase wxill depend on the re-action produced. These reactions consist of an

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intensification of the meningeal signs which aresometimes very severe, with hyperpyrexia andcoma due to a great rise in intracranial pressure.The treatment is reserved for cases not improvingon routine lines and should only be carried out inspecial units. Some of their results werespectacular.Some authorities make burr holes as a routine

measure so that if spinal block occurs and thecerebralspinal fluid pressure becomes high thiscan be relieved by tapping the lateral ventricles bycatheters and introducing antibiotics through thisroute. Most authorities regard a spinal fluid thatis not normal or showing progessive return tonormal after one of the courses of treatment out-lined above as an indication for further activetreatment. Luminal should be given to all casesof meningitis for a period of two years to minimizethe chance of epileptic fits occurring. Relapse isnot likely if the spinal fluid has become completelynormal.

3. Bone and Joint TuberculosisIt is the experience of most workers that the

cases associated with toxaemia and sinuses respondbest. The closed spinal lesion without fever ortoxaemia shows little response. Our Americancolleagues, Evans et al. (1952), favour long coursesof antibiotic treatment with active surgical inter-vention under streptomycin cover. Evans con-siders that streptomycin should only be used forcritical episodes in the patient's illness. They allreport improvement in tubercular synovitis. InEngland chemotherapy is most commonly used inbone and joint tuberculosis where there is toxaemiawith progressive destruction of bones or joints,where there are sinuses, or to cover surgical inter-vention. The drug should always be combinedwith INAH or PAS. There is no uniform agree-ment as to the length of the treatment.

4. Genito- Urinary TuberculosisRoss et al. report on the treatment of renal

tuberculosis by using a combination of ethizone,200 mg. daily for six months, combined with PASalternating with dihydrostreptomycin. The PASis given daily for 25 days and is followed by thedihydrostreptomycin for 30 days. They also makethe urine alkaline with a citrate mixture. Thetreatment is combined with surgical removal whereindicated. Dick (I953) reports on the good effectof INAH and on histological evidence states thedrug increases vascularity in the lesions favouringabsorption. One of the disadvantages of strepto-mycin therapy in tuberculous cystitis is thatfibrosis of the bladder occurs which is associatedwith a reduction in size and sometimes some degreeof ureteric obstruction by fibrosis in the region of

the ureteric orifices. Most surgical authorities usechemotherapy as an adjuvant to surgery. Chemo-therapy used as the sole method of treatment hasproved disappointing. Some attempts are beingmade, however, to perform segmental renal re-sections under antibiotic cover to preserve as muchrenal tissue as possible.

Genital Tuberculosis in the Female. This isbeing diagnosed more frequently since investiga-tions in sterility clinics show an appreciablenumber of women complaining of sterility havetuberculous infection of the tubes, ovaries, andsometimes the uterus. Surgical treatment is ofnecessity rather radical and there is a tendency togive antibiotic treatment a more lengthy trial.Burns et al. (I953), treating 43 cases with INAHfollowed by streptomycin and PAS for a totalperiod of four months, report that 40 out of 43cases showed no evidence of infection at the endof treatment. One patient became pregnant.

5. Pericardial EffusionThis has been treated with systemic strepto-

mycin and PAS and in some cases intrapericardialstreptomycin has been used. Pericardial resectionhas been successfully carried out under strepto-mycin cover in quiescent cases.

6. Lupus VulgarisThis is said to be influenced favourably by

INAH.With increasing research there is little doubt

that more and more anti-tuberculous preparationswill be evolved and further light will be thrown onthe most effective combinations. It must not beforgotten that at all times there will be of necessityindividual variations both in the reaction of thepatient and in the views of the physicians andsurgeons on treatment. It is of the greatest im-portance that indiscriminate use of anti-tuberculousdrugs should be avoided. Treatment should onlybe carried out after careful assessment of theproblem as a whole; wherever possible completebacteriological examination should be carried outbefore treatment starts and sensitivity tests ar-ranged. It is obviously not practicable to waitfor the results before commencing treatment.There are still many problems with regard to theeffect of the drugs and particularly with regard tothe development of, and the significance of, re-sistant strains which have yet to be cleared up. Itmay be said that in general there is a tendency touse more prolonged antibiotic treatment and thatin the surgical treatment of tuberculosis thenecessity for careful pre- and post-operativesanatorium regimes for longer periods is beingaccepted.Continued on page 293.

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June 1954 MACPHERSON: Problem of Tuberculosis in Childhood

Streptomycin, para-amino salicylic acid andisoniazide

In the acute forms of tuberculosis antibiotics areof great value. It is doubtful whether they haveany definite use in the treatment of large caseatingglands or chronic caseating pneumonia. Neitherthe size of the caseating lesions nor the rate ofhealing is dramatically influenced. There is notat present sufficient evidence to assess their valuein those cases where ulceration of a bronchus ispresent.

Since it is probable that haematogenous infec-tion to a greater or less degree arises in manyprimary lesions, especially in infants, antibioticsare given by some physicians to young childrenwho have evidence of recent infection with definiteprimary lesions, hoping in this way to reduce thepossibility of miliary lesions both evident andoccult.

Bronchoscopy and Surgical TreatmentTreatment when a bronchus has become

involved in the primary lesion presents manyproblems. It may be necessary, though rarely, as anemergency measure to clear the lumen of a bronchusof tuberculous material when stridor is marked andendangering a child's life. Bronchoscopic removalof the material may be attempted or, alternatively,thoracotomy and removal of the mass of glandsinvading the bronchial wall. Bronchoscopy maybe indicated for removal by suction of pus frombronchi, beyond the partial obstruction, whichhave become secondarily infected. RichardsandBlair6 recommend routine bronchoscopy in orderto reduce the possibility of bronchiectasis de-veloping in the collapsed lobe.How to treat the collapsed lobe is still a debatable

point. That bronchiectasis may result from suchcollapse is an established fact. As yet the numberof cases with collapse which develop bronchiectasiswith symptoms in later life is not known. Preven-tion and treatment of secondary infection in the

collapsed segment is no doubt of importance.The problem of the collapsed lobe is at presentbeing dealt with usually in one of three ways.Expectant treatment is advocated by some on theassumption that the majority heal sufficiently to-allow complete or partial re-expansion of thecollapsed lobe and, in only a few cases, willbronchiectasis develop later; others recommendresection of the collapsed lobe, or segment,either at an early stage or after a period of a year ormore if there has not been complete recovery, sopreventing future trouble in an unexpanded orpartially re-expanded segment. The third formof treatment is thoracotomy and removal of themass of caseating glands in order to preventpossible irreversible collapse and development ofbronchiectasis.The treatment of chronic caseating lesions

occupying large areas of the lung is also varied.With our present knowledge of this type of lesionit is not possible to say how many of them healcompletely, although apparently there are somewhich do so. It is clear that many of them remainin a chronic state for a year or more. It has beensuggested that parts of these lesions may remainunhealed and, in later life, give rise to clinicalpulmonary tuberculosis. On this assumption, itis suggested that removal of such caseating lunglesions is preferable to a ' wait and see ' policy.7On the one hand there is the risk of the operationand the possible disadvantage to a child of the lossof a lobe or even a complete lung and, on theother, the disadvantage of a long period oftreatment probably away from home and thepossible relationship of these lesions to clinicaltuberculosis in later life.

REFERENCESI.MEDICAL RESEARCH COUNCIL, National Tuberculin

Survey (1952), Lancet, i, 775.2. HYGE, T. V. (I945), Ugesk. f. Iacger, 105, 779.3. CAMMOCK, R. M., and MILLER, F. J. W. (I953), Lancet,

i, is8.4. BEAVEN, P. W. (igso), Dis. of Chest, 17, 28o.5. THOMPSON, B. C. (1952), Proc. Roy. Soc. Med., 45, 74I.6. BLAIR, L. G., and ROBBERTS, S. C. (I950), Lancet, i, 386.7. THOMAS, D. (I952), Proc. Roy. Soc. Med., 45, 743.

Continuation of Biblio-rabhv-Yohn C. Roberts, M.D., M.R.C.P., from page 287.BIBLIOGRAPHY

-MAHER-LOUGHNAN, G. P. (1952), Tubercle, 33, 342.BIGNALL, J. R., CROFTON, J. W., and THOMAS, J. A. B.

(i95i), Brit. med J7 i, 554.NHECK, W., and CORk IN HINSHAW H., i2th U.S. Dept. Vet.Admin. Cont. on Chemotherapy of Tuberculosis.

SUMNER, J. (i949), Tubercle, 3, 62.CROFTON, J. (1952), Brit. med. J., ii, IOI4.ANNOTATION (I9S3), Lancet, i, 23I.PUGH, D. L., EDWARDS, G. F., McLAREN, R. G., and

JONES, E. R. (1952), Tubercle, 33, 369.HOUGHTON, L. E. (1952), Ibid., 33, 381.RUBIN, B. HASSETT, G. L.Jun.,THOMAS, B. G. H., and

BURKE, J. C. (1952), Amer. Ret. Tthberc., 65, 392.LUNTZ, G. R. W. N., and SMITH, S. G. (1953), Brit. med. J7.,

i, 296.ROSS-COSBIE, J., GOW, J. G., and ST. HILL, C. A. (I953),

Ibid i, 901TURIBJULL, F. W. A., WALLACE, A. T., STEWART,SHEILA, and CROFTON, J. W. (I953), Ibid., i, 1244.

MIcCARTHY, D., and MANN, T. P. (I950), Ibid., i, 341.

BARNETT, MARGARET, BUSHBY, S. R. M., and MIT-CHESON, D. A. (I953), Lancet, i, 314.

JOINER, C. L., MACLEAN, K. S., PRITCHARD, E. K., ANDER-SON, K., COLLARD, P., KING, M. B., and KNOX, R.(1952), Ibd., ii, 843.

MEDICAL RESEARCH COUNCIL REPORT No. 4 (1953),Ibid., ii, 217.

LORBER, J. (i950), Ibid., i, 389.ANDERSON, T., KERR, MIARY, and LANDSMAN, JOAN

(1953), Ibid., ii, 69i.RITCtilE, M., TAYLOR, R. M., and DICK, J. C. (1953), Ibid.,

ii, 4I9.TORRES-GOST,-J. (I953), Ibid., ii, 693.FLETCHER, A. P. (I953), Ibid., ii, 694.CATHIE, L. A. P. (i950), Ibid., i, 44I.SMITH, HONOR V., and VOLLUM, R. L. (I950), Ibid., ii, 275.EVANS, E. T. (1952), J. Bone and yoint Surg., 2, 267.DEROY, M. S., and FISHIER, H. (1952), Ibid., 2, 299.DICK, J. C. (I953), Lancet, i, 8o8.BURNS, T., SMITH, H. G. M., and SNAITH, L. M. (I953),

Ibid., i, 8I7.

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