PARA-AMINOSALICYLIC ACID IN TUBERCULOSIS

578 CONCENTRATION OF DIPHTHERIA ANTITOXIN IN CORD BLOOD SIR,-It seems that Dr. Wiener, who wrote last week, is not familiar with diphtheria-antitoxin titrations. May I suggest that he reads an article by Glenny and Llewellyn-Jones1 which describes the methods used at the laboratories where the cord-blood samples were tested f Very few tests are necessary to obtain an accuracy of 10%. The final tests on these blood samples were made at 10% differences (as was made clear in our paper) and not 100% differences as Dr. Wiener evidently thinks. All measurements of toxin and antitoxin in the titrations were made by a group of technicians with no knowledge of the nature of the samples they were handling. The readings of the reactions in the test animals were made by one of us who has had 20 years’ experience of such work, and these reactions were a very small proportion of a daily average of about 500 read at a single sitting, without any reference either to former or to

possibly expected results. Final results

were collected by a third person who formula to calculate the value of each applied rigid sample. Thus a sample for which a test mixture at 10 units gave no reaction on each occasion,’and a test mixture at 11 units always gave a reaction, was allotted a value of 10-5 units. If on one occasion the test for 11units was recorded as a reduced reaction, or a very slight reaction was produced in a test for 10 units, the calculated value would be slightly different, but still between 10 and 11 units. I have given an example of the simple procedure that we adopt in the interpretation of values, because some of your readers who do not know the extreme accuracy with which diphtheria antitoxin can be titrated might think that Dr. Wiener was writing with authority when he refers to a minimum error of 100%. MOLLIE BARR. Wellcome Research Laboratorie a

Beckenham, Kent. MALLEOLAR FRACTURES

SiR,-I cannot agree with Mr. Bonnin (Aug. 20) that should doubt the histories given by patients with

we

I am far more fractures of the external malleolus. and of the results of of Thorndike’s sceptical findings cadaveric experiments. Thorndikediagnosed 415 cases of sprain of the ankle in over a period of six years. He claims have located the sprain to a particular ligament in 317 cases. In 195 cases this was the anterior inferior tibiofibular ligament ; in 61 the lateral collateral ligament : in 38 the medial collateral ligament ; and in 23 the anterior tibioastragaloid ligament. He does not subdivide the lateral collateral ligament and makes no comment on the distinction between sprains of its anterior fasciculus and sprains of the anterior inferior tibiofibular ligament. Furthermore, while claiming that any sprains especially involving the anterior inferior tibiofibular ligament will give a permanently weakened and widened mortise to thejoint, he also claims that the

college sportsmen

to

average period of disability of all the ankle-sprains of the series was 81/2 days before return to full play in sports.

Mr. Bonnin refers to experimental work on the relation of the shape of the fracture-line to the mechanical stresses. But it does not follow that a particular fractureline is not produced by a particular force simply because this has not been observed experimentally. For instance, Honigschmied3 had 21 cases of dorsiflexion strains in his experiments on the cadaver, but, for fairly obvious reasons, in none of these was an anterior marginal fracture of the tibia produced ; yet such a fracture Glenny, A. T., Llewellyn-Jones, M. The Intracutaneous Method of J. Path. Bact. Testing Diphtheria Toxin and Antitoxin. 1931, 34, 143. 2. Thorndike, A. Athletic Injuries. London, 1942. 3. Honigschmied, J. H. Dtsch. Z. Chir. 1877, 8, 239.

reduce and fix in plantar flexion because we believe it to be produced by dorsiflexion. He had 17 cases of adduction strain, yet in none was there the so-called first-degree adduction fracture. Dupuytren had similar results. Thus it does not seem unreasonable to prefer " the unbiassed history of an " unbadgered patient. Mr. Bonnin classified my groups 2 and 3 as adduction" fractures, and my group 1 as external-rotation injuries. Yet, as I previously pointed out, I have seen fractures of the group 2 or 3 type associated with group-1 fractures and apparently due to the same recent injury. Lastly, Dupuytren did not contend that most fractures of the external malleolus consequent on indirect violence and unassociated with other bony or complete ligamentous injury in the region of the ankle, are due to inversion strain. He thought that isolated fractures of the fibula were a rarity, and he discourses on them as follow 4 : we

"

" It is at this spot therefore [21/2 in. above the lower of the fibula] that the least resistance is offered and that the causes capable of producing fracture act at most advantage, as for instance in forced eversion of the foot. Lastly, the fracture sometimes occurs below where the ligaments connect the tibia and fibula together but then it is rather a fracture of the malleolus and is consequent on inversion of the foot."

extremity

Dupuytren, incidentally, emphasised the importance of muscle-pull in producing displacement in fracturedislocations of the ankle, in contradistinction to the emphasis we now place on the causative violence. Perhaps we go too far in- allocating one type of fracture-line to one type of violence irrespective of the extent of associated lesions-

DAVID THOMAS.

Scunthorpe.

PARA-AMINOSALICYLIC ACID IN TUBERCULOSIS

SIR,-Dr. Swanson’s letter in your issue of July 23 draws attention to the hypoprothrombinaemic effect of p-aminosalicylic acid (P.A.S.) therapy in 5 out of 6 patients with rheumatoid arthritis-an effect which he points out is well known to occur during the exhibition of other salicylates. This dicoumarol-like effect of other salicylates can be prevented by simultaneous treatment with vitamin K or but when salicylate one of its synthetic analogues ; vitamin-K therapy place haemorrhage has already taken is unlikely to be effective.55 It seems reasonable to assume that in these respects P.A.s. resembles other

salicylates. Meanwhile,

some

patients

with tuberculosis

are

being

treated with both P.A.s. and streptomycin. In these patients the possibility of hypoprothrombinaemia appears to be increased because of the bacteriostatic effect of streptomycin on Bact. coli in the gut and the consequent decrease in the supply of vitamin K from this bacterial source.

The

of the mode of therapeutic action of still unsolved, though Lehman6 attributes its bacteriostatic action to its role as a competitive inhibitor of metabolites of the tubercle bacillus, these metabolites possibly resembling salicylic and benzoic acids. At this stage, when trials of combined P.A.s. and streptomycin are no doubt in progress, it may be worth drawing attention to three considerations, not necessarily incompatible with Lehman’s view. The first is that the vitamin K first used therapeutically in man was obtained from the pigment of the tubercle bacillus,7 and it may therefore be assumed to play a part in the metabolism of the bacillus. The second is that the dicoumarol-like hypoprothrombinaemic action of salicylates on the liver is possibly an anti-vitamin-K effect. The third, which

problems

P.A.s. are

1.

4. Dupuytren, G. Diseases and Injuries of Bones. 5. See annotation, Lancet, 1943, ii, 419. 6. Lehman, J. Ibid, 1946, i, 15. 7. See leading article, Brit. med. J. 1939, ii, 1232.

London, 1847.

579

suggests that prevention of the anticoagulant effect of a -chemotherapeutic drug is not necessarily desirable, is8 oontained in a statement by Prof. A. St. G. Huggett to the Biochemical Society, that the anticoagulation anti-enzyme action of some trypanocidal dyes may have an analogy to their mechanism as trypanocidal agents. Thus in therapeutic trials with combined P.A.S. and streptomycin it appears worth considering that any Jiypoprothombinsemic effect observed may represent a greater hazard to the tubercle bacillus than to its host. It would then be possible to make a comparison between patients risking hypoprothrombinaemia but safeguarded by serial prothrombin estimations, and those given a .supplement of vitamin K. Rostrevor,

co.

Down.

two-thirds of the insured men reaching minimum pensionable age and nearly one-half of the insured women do not claim their retirement pensions, because they are continuing in regular work until later. F. D. BICKERTON Ministry of National Insurance,

J. A. FISHER.

EMPLOYMENT OF ELDERLY PERSONS

SiR,-The explanation of the conditions on which National Insurance retirement pensions are paid, ’contained in your leading article of Sept. 10, is correct only in respect of persons who reached minimum pensionable .age before July 5, 1948, and accordingly qualified for their pensions under the old Contributory Pension Acts. The effect of the new National Insurance arrangements - on the willingness of elderly people to continue at work is obviously a matter of considerable national importance, and I hope, therefore, that you will allow me to explain the very different arrangements which apply to those Teaching pensionable age after July 5, 1948. Assuming that the contribution conditions are fully satisfied, a man may claim a retirement pension of 26s. from the age of 65 provided he has retired from regular employment, inconsiderable occupations being ignored (for women the qualifying age is 60). A man who does not retire until after age 65 now goes on paying National Insurance contributions in exactly the same way as he did before and remains’ entitled to sickness or unemployment benefit at the same rate as pension, so that any temporary interruption of earnings after minimum pension age provides no temptation to claim the retirement pension. For every 25 contributions paid in employment after his 65th birthday the rate of pension payable from retirement is increased by Is. a week. If the man’s wife has already reached 60 her notional pension-rate (including that payable to her as a widow if her husband dies before her) is also increased by Is. for every 25 contributions he pays. It is possible, therefore, for a man who goes on working until he is 70 to acquire the right to a pension of 36s. a week for himself, and one of 26s. a week for his wife during his lifetime and 36s. thereafter. The increased rates of pension payable in, this way are, taking one case with another, actuarially broadly equivalent in value to the sum of the pension forgone by postponing retirement and the contributions paid after minimum pension age. The arrangements therefore achieve the objective of the suggestion referred to in your, leading article. From age 70 (65 for women) the increased rate of pension earned by postponed retirement is payable unconditionally whether work continues or not. As a reinforcement of the retirement condition, where pension is claimed on retirement before age 70 (or 65, as the case may be), its payment up to that age is regulated by an earnings rule the effect of which is to reduce the pension paid for any week by Is. for every Is. of net earnings over 1:1in that week. The general objective of the provisions of the new National Insurance Act is, of course, to encourage all those who can to continue in regular work wherever possible up to age 70 or even beyond. It may interest your readers to know that at the present time about 8. See

Lancet, 1941, ii, 761.

Chief Press Officer.

London, S.W.1.

VITAMIN E

SIR,-With regard to the letter from Professor Boyd and others (July 16), may I quote experimental data’? R. L. ,Holman1 observed that, in dogs, vitamin E (3 mg. per kg. body-weight) had a significant protective action against hyperlipidic arteritis ; while Tusini2 administered to rats altogether 5 mg. of ergotamine tartrate and found that the ensuing arterial spasm in the tail was, in over 90% of the animals, almost completely- inhibited by giving 20 mg. of vitamin E daily. A synergistic action between vitamin E and vasodilators was also demonstrated, with very interesting therapeutic results. Perhaps these results may lead to clearer judgment of the " etra va.fya.Tit claims Milan.

"

from the S1mt.e Fc)ijtid2tioi-t. V. FERRERO.

WHOOPING-COUGH TREATED WITH CHLOROMYCETIN

SiR,-Your leading article of Sept. 10 prompts

me to what may well be the first case of whooping-cough treated in this country by chloramphenicol (’ Chloro-

report

mycetin ’). My daughter, then aged 51/2 months, developed whoopingcough about the beginning of May this year and was in the early paroxysmal stage towards the middle of the month. Her older brother and sister had contracted the disease at the beginning of April and were by then well advanced in the paroxysmal stage. The infant was fully breast-fed and had been kept away from her brother and sister as much as possible, but of course some contact was inevitable. Although her general condition was good, the attack was becoming fairly severe ; paroxysms became frequent, especially at nights, and during the two nights before treatment was started they occurred about every thirty minutes and often ended in vomiting. As good results with chloromycetin in whooping-cough had been reported from the U.S.A., and as the toxicity of the drug was supposed to be very low, I decided to try its effect while the baby was still in good condition and free from complications. The drug had only come on the market during the previous week, and the dosage recommended was approximately that for typhoid fever-i.e., initially 50 mg. per kg. body-weight, followed by smaller amounts three-hourly. Chloromycetin being made up in 250 mg. capsules, I decided to give one capsule four-hourly as the baby was on four-hourly feeds. Her weight was then about 6-7 kg. Administration proved very difficult, since of course an infant cannot swallow these capsules. We tried to give the powder first in orange juice and then in expressed breast-milk. Both methods proved impossible because of the extreme bitterness of the drug ; the smallest taste of it made the baby retch and cry. We therefore decided to use an oesophageal catheter and found it easiest to introduce this through the mouth ; a good hearty The first time cry assured us that it was in the right place. we attempted this immediately after a feed, and the whole feed was brought up ; after that we gave it half an hour before each feed, when the stomach was presumably empty. This was successful and from that time on the baby retained the full amount of drug given and continued to feed normally. Because of these difficulties we continued to give 250 mg. four-hourly, up to a total of seven doses. Already after twelve hours the effect was noticeable, and the following night paroxysms were down to one every two or three hours. The drug was stopped as it was causing some colic and diarrhcea ; this subsided in twenty-four hours. The effect on the whooping-cough was dramatic. After thirty-six hours the paroxysms stopped completely and the baby was obviously improving. The cough remained, and for many weeks the baby had occasional attacks of coughing, which, however, never gave rise to the slightest anxiety; 1. Proc. Soc. exp. Biol. N.Y. 1947, 66, 307. 2. Atti Soc. Lomb. Sci. Med. Biol.: Meeting of March 11, 1949.