GAMMA-GLOBULIN AND POLIOMYELITIS

552 mechanical models of nervous and muscular systems ; investigate the mechanisms of excitable tissues and the permeability of cell membranes ; and to study what starts, directs, and stops the migration of cells during the growth of the embryo, the process of healing, and the development of malignant growths. In the Commonwealth the Foundation are giving £12,000 towards the new unit which the Medical Research Council and the Uganda government are setting up at Mulago to study malnutrition in infants. The Foundation have also set aside £36,000 to nnance the team which has been investigating the function and design of hospitals. This work has for the past four years been sponsored by the Nuffield Provincial Hospitals Trust in association with the University of Bristol. The report of the team will not appear until the end of the year, but some of their papers on the design of hospitals have already been published in the architectural press and some of their recommendations, notably a proposal to reduce the floor area per bed, have been promptly put to the test of practice in experimental wards now being built in Scotland and Northern Ireland. We have also learned of some of the findings of the team on functionfor example, the work on cross-infection 12 in hospital wards. The results in hospitals suggest that these studies can be usefully extended to other buildings ; such an undertaking would be beyond the scope of the Trust, but not of the Foundation who are accordingly setting up a division to deal with research into the design of all kinds of buildings including hospitals. The Foundation have also undertaken during the next five years to provide £250,000 to help the pioneer work of the National Corporation for the Care of Old People. Their eighth report shows that the Foundation are as ready as ever to help in a big way or in a small way. They are equally anxious that no promising research shall founder in its early stages for lack of some relatively meagre sum, and that no important project shall fail because its vision outruns its finances. to

GAMMA-GLOBULIN AND POLIOMYELITIS and his colleagues1 showed that gamma-globulin to children gave temporary protection duringan epidemic of poliomyelitis, it was clear that there would soon be strong public demand for the use of gamma-globulin in this way. But

WHEN Ilamrmon administration of

there

are

many difnculties to be

overcome.

Gamma-

globulin is prepared from human plasma commercially by precipitation with alcohol at low temperature. A pint of blood, after processing, yields enough gammaglobulin to give partial protection against paralytic poliomyelitis to a child of 6 or 7 for a period of four or five weeks. But blood is already much in demand, and this need may increase. Gamma-globulin itself has been found to be effectivein the prophylaxis of measles and infective hepatitis in doses smaller than those used for poliomyelitis. Obviously there is a limit to the amount of blood and blood products which can be made available. It would need a committee of Solomons to decide how to distribute these limited resources among the many people with a claim on them. Such a committee met early this year in the United States, and its report is now published.2 It was soon agreed that the most fair and effective use of the million or so doses of gamma-globulin available for poliomyelitis this year would require controlled distribution and that should be allocated according to the reported incidence of the disease. The committee discussed four possible methods of using the gamma-globulin to the best advantage. In areas with exceptionally high incidence, community prophylaxis of those age-groups exposed to the greatest risk was considered. This proposal was based on the belief that the effectiveness of mass prophylaxis is proportional to the incidence of disease in the selected age-group during the few weeks following injection, but it presupposes accurate prediction of the course and duration of a poliomyelitis outbreak in a large

supplies

LUPUS ERYTHEMATOSUS TREATED WITH MEPACRINE

IN 1951 Page 13 reported promising results from the treatment of lupus erythematosus with mepacrine ; but he rightly emphasised the difficulty of assessing any remedy in this chronic relapsing disorder. Somerville et al.14 have since confirmed Page’s findings. Subjective, and later objective, improvement was noticed. They suggest that the more susceptible a patient is to pigmentation, the better is the result ; and they conclude that mepacrine is today the drug of choice in lupus erythematosus. Black 15 has treated 60 patients with mepacrine. He finds that women respond better than men and that skin staining is not significantly related to the response. He holds that, in the absence of a control series of patients or of an agreed spontaneous-cure rate, it cannot yet be confidently stated that this drug is effective. Page suggested that mepacrine might act by reducing light-sensitivity of the skin-a feature he had demonstrated in a few patients by estimating the minimum erythema dose before, during, and after the administration of the drug. Other possible explanations include an action similar to that of corticotrophin, or an antagonism to adinyl compounds. Black thinks that the effectiveness of mepacrine is partly due to a light barrier

action. In treating skin diseases, it is especially important to add up the risks of producing something worse, and to balance these against the severity of the malady itself. 12. Goodall, J. W. D. Ibid, 1952, i, 807. 13. Page, F. Ibid, 1951, ii, 755. 14. Somerville, J., Devine D. C., Logan, J. C. P. Brit. J. Derm. 64, 417. 15. Black, H. Ibid, 1953, 65, 195.

With mepacrinc, lichenoid dermatitis may arise; and affections of the central nervous system, hæmopoietic system, and eyes have occasionally been reported. All patients receiving mepacrine should be interviewed at intervals of not more than a, fortuight, and inquiry made as to itching or rashes, before continuing the treatment, Dosage usually has to be greater than the maintenance dose for the prevention of malaria. If there is satisfactory improvement, it is usually with a dosage of 02-03 g. a day ; and Somerville et a1. found that in some cases maintenance dosage with perhaps 0-1 g. daily may have to be continued indefinitely.

1952,

The method also imposes heavy strains on the administrative machinery of the inoculation service. A second method is to immunise household contacts of cases diagnosed clinically. But the fact that infection is often widespread in families when the first case is recognised may diminish greatly the effectiveness of the gamma-globulin ; furthermore, failures of gammaglobulin in this type of situation would be conspicuous and rapidly bring the method into disrepute. Close contacts outside the family of clinical cases form a third group which is rather difficult to define accurately; and injection of a fourth group, household contacts of suspected cases, is advocated in sparsely populated areas where sporadic cases may lead to a very high incidence of disease. Hannnon s favours this method where high rates are recorded, since he believes it gives a epidemic more selective method of immunisation than mass

community.

prophylaxis. It was proposed2 to allocate the bulk of the gammaglobulin to State and territorial departments on the basis 1. Hammon, W. McD., Corriell, L. L., Stokes, J. jun. J. Amer. med. Ass. 1952, 150, 739. 2. National Research Council. Publ. Hlth Rep., Wash. 1953, 68, 659. 3. Hammon, W. McD. Amer. J. med. Sci. 1953, 226, 125.

553

of their past and current experience with poliomyelitis and to keep additional supplies centrally im reserve for emergency use. It would then ho the responsibility of

the local health officer to decide which method of prophy-

laxis would be most effective irt

n,

pnrt,icsnl:r,r

Ioca.1 situa-

this nation-wide

tion. Fascinating though experiment may be, the prevention of one ct,,4e of paralytic 1)()Iiomyelitis would, under moderately fa.voura,hle conditions, require about 1000 prophylactic injeetiolli4. The outstanding question is whether or not this iH the best use for 1000 pints of blood.

toxins and antitoxins, but nmch acadernic research and many theoretical conclusions have heen based on the reasonable assumption titat the precipitate produced when toxin and antitoxin preparation)-) were mixed consisted essentially of pure toxin and antitoxin. It will hc strange iruleed if it should prove that toxin and antitoxin are present in floccules merely as impurities contaminating other antigen-antibody complexes. M ufo h speculation and many conclusions in immunochemistry will need revision in the light of this recent experimental work. Apart from the theoretical implications, however, the fact remains that the flocculation reaction has been a boon to antitoxin manufacturers and a stimulus to immunological research. Antisera prepared by injection of maeerated tissues such as lung. liver, spleen, or kidney contain mixtures of antibodies, Some separation of these antibodies has now been obtained 9 by absorption with various tissue extracts. The distribution of the antibodies in the body tissues after injection can be followed by preliminary After treatment of the sera with radioactive iodine. absorption with suitable tissue extracts, antibody preparations havebeen obtained which tend to become localised in the homologous organ used for the original

TOWARDS PURE ANTITOXIN OVER thirty years ago Ramon1 observed that when diphtheria toxin and antitoxin were mixed in various proportions a flocculent precipitate appeared and that the mixture containing equivalent amounts of toxin and antitoxin flocculated first. This provided a convenient method for titrating toxins and antitoxins in vitro without the use of animals. Discrepancies between the results of flocculation tests and animal experiments were reported,2-4 so that confirmatory animal tests were still necessary for material to be used therapeutically, but for routine control purposes the flocculationreaction antibody production. became standard laboratory practice. The original diphtheria antitoxin for treatment was in CLINICAL ELECTROPHYSIOLOGY OF THE BRAIN the form of crude horse-serum, and there were about 5000 units of antitoxin per gramme of protein adminisSINCE Berger described the electro-encephalogram tered. Fractionation of serum by saltillg-out methods over twenty years ago, our knowledge of the electrical yielded antitoxic globulin solutions, and commercial activity of the cortex has grown considerably, though preparations became available which contained about we are still far from knowing exactly what its primary constituents are. Animal experiments have shown that 10,000 units per gramme of protein. A further step in thalamic stimulation can modify cortical activity. In antitoxin refining was taken by treating antitoxin with 10 11 break down and his have the the antitoxic Williams had man, pepsin. Proteolytic enzymes colleagues globulin molecule and inert protein can be removed, opportunity of studying electrical recordings from the leaving the antitoxin in a higher state of purity. Modern region of the thalamus in patients with petit mal. Their evidence suggests that, here also, the " wavecommercial diphtheria antitoxins contain at least 20,000 units of antitoxin per gramme of protein, but the and-spike " rhythm of petit mal, though recorded no means and from the cortex, is a reflection of what is primarily are by pure, crystalline preparations thalamic activity. antitoxin containing 130,000 units per gramme of protein It seems, however, that such has been described.6 Pursuing the search for the origins of cortical activity, a deal of contain non-antitoxic still Bickford 12 and his colleagues at the Mayo Clinic have great preparations material. The diphtheria-culture filtrates used for the lately examined recordings from the subcortical white matter in psychotic patients who were to undergo immunisation of horses contain other antigens besides have been found to frontal antitoxin and toxin, preparations leucotomy. Fine wire electrodes, considerably smaller than the brain needles used by Williams and contain at least 24 distinct antibodies.7 By absorption therefore less likely to produce traumatic artefacts, of crude antitoxin with toxin-free diphtheria-culture filtrates, it is possible to remove some of the other anti- were introduced into the frontal white matter and left in situ, so that both recording and stimulation were bodies and preparations containing 210,000 antitoxin units per gramme of protein are obtained, but these are possible. These depth recordings showed rhythms As antitoxin similar to those obtained from the surface. Thus, both still not immunologically homogeneous. amount of the obtained the alpha and beta frequencies of the electro-encephalopurification proceeds, precipitate when crude diphtheria toxin is added decreases until, graph were found, and the cortical changes associated in the purest preparation yet obtained, there is no with sleep appeared also in the deep electrodes, sleep flocculation at all when equivalent amounts of toxin and spindles sometimes occurring first in subcortical leads. antitoxin are present.8 In one case, with a cortical epileptic discharge, the It is suggested, therefore, that pure diphtheria antidischarge also appeared first in the depth electrodes. toxin and toxin do not form a precipitate, but that the Records from the white matter of the orbital surface flocculation obtained with crude preparations is due to showed many slow rhythms in the 1/2-4 cycles-perthe interaction of other antigens in diphtheria-culture second range. A constant finding in their schizophrenic filtrates with their corresponding antibodies. The patients was an area of relative inactivity in the depth of the frontal lobes. They suggest tentatively that if this presence of diphtheria toxin and antitoxin in the floccules is attributed to entrainmellt of the toxin-antitoxin indicates an abnormal focus-at present an assumption, complex in the precipitate formed by other antigen-in the absence of normal controls-then the position of the silent area in relation to the leucotomy cut may antibody systems. Not only has the in-vitro flocculation test been of be important. Stimulation of the subcortex gave clinical responses great value for many years for evaluating commercial in many ways similar to those noted by Penfield and 1. Ramon, G. C.R. Soc. Biol., Paris, 1922, 86, 611. others during cortical stimulation. Responses some2. Maloney, P. J., Weld, C. It. J. Path. Bact. 1925, 28, 655. times persisted after the electrical stimulus had stopped, 3. Sordelli, A., Serpa, R. C.R. Soc. Biol., Paris, 1925, 92, 824. 4.

Glenny, A. T., Wallace, U. J. Path. Bact. 1925, 28, 333. Parfentjev, I. A. U.S. Patent nos. 2065196, 2123198. Northrop, J. H. J. gen. Physiol. 1912, 25, 465. Pope, C. G., Stevens, M. F., Caspary, E. A., Fenton, E. L. Brit. J. exp. Path. 1952, 32, 246. 8. Pope, C. G., Stevens, M. F. Ibid, 1953, 34, 241. 5.

6. 7.

9. Korngold, L., Pressman, D. J. Immunol. 1953, 71, 1. 10. Williams, D. G., Parsons-Smith, G. Brain, 1949, 72, 450. 11. Williams, D. G. Ibid, 1953, 76, 50. 12. Bickford, It. G. Proc. Mayo Clin. 1953, 28, 135.