28 ANNOTATIONS

anhydrase or butyryl coenzyme A dehydrogenase.2Likewise, it is fairly certain that molybdenum will turnout to be an important part of the xanthine oxidasesystem in man, as it has proved to be of that in rats.3 4At the Vatican City meeting, Prof. R. A. McCance,

F.R.S., considered several elements of medical interest.

Discussing the association of Kinnier Wilson’s diseasewith disordered copper metabolism,5 he said that thisdisease, as we see it today, may be described as follows :

There is a deficiency of coeruloplasmin (a specific proteinto which over 90% of the copper in the serum is normallybound firmly), which may be the hereditary lesion ; and owingto it, or for some reason connected with it, excessive amountsof copper are absorbed. This has been checked by the useof radioactive copper. 7 The metal does not remain in the

plasma. Much of it is excreted in the urine, and the rest seemsto pass into the cerebrospinal fluid and tissues where it is

deposited in progressive and ultimately destructive amounts.The brain and liver are the first to suffer ; whereas the heart,lungs, erythrocytes, and skeletal muscle remain relativelyclear. The separation of the metal in the eye tissue is thecause of the Kayser-Fleischer rings. The deposition of copperin the kidney may interfere with the reabsorptive mechanismfor amino-acids, or possibly the amino-acids pass through theglomerulus combined with copper in a chelated form, andthese compounds are not susceptible to reabsorption. Copperis also excreted in combination with peptides.8The administration of amino-acids by mouth increasesthe excretion of copper in patients with Kinnier Wilson’sdisease, but not it seems in normal people-or at leastnot to any great extent.9 s There are many puzzling_features about the metabolism and excretion of amino-acids by these patients. Their pattern and concentrationin the plasma seem to be normal, whereas the excretionis high and very variable. Histidine, serine, tyrosine,and threonine may predominate, but proline and citrullinehave been emphasised by other investigators. Theamounts excreted seem to depend on the dietary proteinsand the state of the disease rather than on the liverlesion.10 It is difficult, as Professor McCance remarked,to understand the observation by Cooper et al.ll thatunlimited protein food and even the infusion of amino-acids did not increase the loss.

Turning to mercury, Professor McCance remarked thatpink disease (acrodynia) has been ascribed to poisoningwith this element,l2 but that in treatment dimercaprolhas not fulfilled its earlier promise.13 It now seems thatsome of the symptoms and signs may be, due to mercury,but that they are essentially manifestations of grossoveractivity of the sympathetic system, and yieldsatisfactorily to administration of tolazoline.14 15

" Where then does the mercury come in ? ... If, for example,the symptoms and signs are due to sympathetic overactivityand relieved by drugs which are lytic for this system andstimulate the parasympathetic side, why do the patients stopsweating after the administration of the drug ? If mercuryis implicated, why was the disease not more common whenmercury was much more of a therapeutic standby than it istoday? ... Have the patients who get pink disease absorbedmore mercury than others who have been treated in a similarway, or deposited it in some abnormal site ? Are they sufferingfrom something analogous to Wilson’s disease ? It has been1. Berfenstam, R. Acta pœdiat., Stockh. 1952, 41, 32.2. Mahler, H. R. J. biol. Chem. 1954, 206, 13.3. Mahler, H. R., Mackler, B., Green, D. E., Bock, R. M. Ibid,

1954, 210, 465.4. Mackler, B., Mahler, H. R., Green, D. E. Ibid, p. 149.5. See Lancet, 1951, i, 1404 ; Ibid, 1952, i, 199 ; Ibid, 1952, ii, 325.6. Earl, C. J., Moulton, M. J., Selverstone, B. Amer. J. Med.

1954, 17, 205.7. Matthews, W. B. J. Neurol. Psychiat. 1954, 17, 242.8. Uzman, L. L. Amer. J. med. Sci. 1953, 226, 645.9. Matthews, W. B., Milne, M. D., Bell, M. Quart. J. Med. 1952,

21, 425.10. Cartwright, G. E., Hodges, R. E., Gubler, C. J., Mahoney, J. P.,

Daum, K., Wintrobe, M. M., Bean, W. B. J. clin. Invest.1954, 33, 1487.

11. Cooper, A. M., Eckhardt, R. A., Falcoon, W. W., Davidson, C. S.Ibid, 1950, 29, 265.

12. See Lancet, 1951, i, 1216.13. Southby, R. Med. J. Aust. 1953, ii, 420.14. Peterson, J. C., Laughmiller, R. Acta pœdiat., Stockh. 1954,

43, 517.15. See Pediatrics, 1955, 15, 202.

suggested that these patients have been ’ sensitised ’ - bythe mercury or were peculiarly sensitive ’ to mercury 16; butthese phrases have no exact meaning, and patch tests withcalomel or mercury have not proved a help.l7

"

CONTROL OF POLIOMYELITIS VACCINE

IN the detailed report on the Salk poliomyelitis vaccinewhich we recently summarised,18 the Surgeon-General ofthe United States Public Health Service described someof the procedures which are to be adopted for the bio-logical control of the vaccine. The manufacture of thevaccine on a large scale has shown that the process ofinactivating virus by formaldehyde does not alwaysfollow the original concept laid down by Dr. Salk.19 Theoriginal safety tests were designed " primarily to demon-strate mass contamination resulting from accidents inmanufacture, and not small amounts of residual livevirus which the process was believed to reduce to animmeasurably low and harmless level." We may inferfrom this that the curve describing the inactivation ofpoliomyelitis virus by formaldehyde is not strictly linear,but follows a less readily predictable course. In conse-

quence, it has been found necessary to increase theminimum requirements for vaccine testing to provide asubstantially greater margin of safety.2O These changesprovide for an increase in the number and sensitivity ofthe tests, and the application of the tests at more criticalpoints in the manufacturing process. In addition, a finaltissue-culture test of the finished product has been addedto exclude virus contamination during the bottling pro-cess. The revised requirements will be incorporated inofficial regulations to establish their status as mandatorystandards. There is also to be a considerable expansionin the organisation for controlling the requirements forvaccine production, including the creation of a technicalcommittee on poliomyelitis vaccine, a new Division of

Biological Standards, and increased " on-plant " sur-

veillance and consultation by Public Health Service staffand by consultants drawn largely from university researchcentres.

These, and other similar measures, are sensible secondthoughts which will increase the safety of the vaccineconsiderably. But there is a danger that in navigatingthe narrow channel of formaldehyde treatment, manu-facturers, anxious to keep clear of the Scylla of incom-pletely inactivated virus, may founder on the Charybdisof insufficiently potent vaccine. There are fears too thatthe decision to stop controlled trials of the vaccine willhave obscured the navigational markings in this particulardanger spot ; it will be no easy matter in present cir-cumstances to get a clear idea of the efficacy of differentbatches of vaccine in preventing paralytic poliomyelitis.The report on the 1954 vaccine trial 21 made it clear thatbatches of vaccine prepared by different manufacturersfrom the same formula showed considerable variationsin their immunising potency, and this finding should notbe overlooked in the natural anxiety to ensure that thevaccine is as safe as is humanly possible. This considera-tion becomes all the more important as changes are

introduced here and there into the technique of vaccineproduction.

In Washington last week a panel of 15 experts dis-cussed the situation.22 8 were in favour of continuing thevaccination programme, 5 were opposed to it, and 2abstained from voting. It seems, therefore, that vaccina-tion on a large scale may begin again presently ; but novaccine will be released until it has passed the newsafety tests. It has not yet been announced who willget the vaccine and when.

16. Fanconi, G., Botsztejn, A. Helv. pœdiat. acta, 1948, 3, 264.17. Holzel, A., James, T. Lancet, 1952, i, 441.18. Ibid, 1955, i, 1270.19. New York Times, June 9, 1955.20. Ibid, June 10, 1955.21. See Lancet, 1955, i, 851.22. New York Times, June 26, 1955.

29ANNOTATIONS

MENTAL DISORDERS DUE TO CORTICOTROPHIN

AND CORTISONE

MENTAL disturbances are not uncommonly associatedwith disorders of suprarenal function. The apathy ofpatients with Addison’s disease is well known ; mentaldisturbance is found in many patients with Cushing’ssyndrome 1 2 ; and patients with adrenal virilism mayshow schizoid reactions or have depressive episodes.3-6Thus it is not surprising that mental disturbances arisein patients treated with corticotrophin or cortisone 7-11 ;but the cause of these aberrations remains in doubt.Lewis and Fleminger 12 find no evidence that patientswho have been mentally ill are especially liable to suchaberrations. Quarton et al.13 consider whether cortico-trophin and cortisone in some way directly damagenerve-cells. Cerebral lesions have been described in

Cushing’s &bgr;yndrome 13 and in animals which have receivedlarge doses of corticotrophin or cortisone,14 but in thisexperimental work the dosage was much higher thanthat used therapeutically. Other workers have reportedcerebral vascular lesions after deoxycortone therapy,I516and Selye 15 believes that these can result from adminis-tering corticotrophin or cortisone. It has also beensuggested that multiple small cerebral thrombosesmay be responsible for mental abnormalities duringtreatment with these substances, since there is some

evidence that the blood of such patients shows increasedcoagulability.17There is at present no evidence that pituitary and

adrenocortical hormones can pass the blood-brain barrierand directly affect the metabolism of the brain-thoughin disease the barrier might possibly become abnormallypermeable to them. There is a certain amount of evidencethat the hormones affect the permeability of the barrierto other substances and patients with Cushing’ssyndrome occasionally have elevated protein levels in thecerebrospinal fluid,2 suggesting altered permeability.Electro-encephalographic studies in animals have yieldedabnormal tracings which have been interpreted as

indicating an antagonistic action between cortisone anddeoxycortone on brain excitability ; but the evidence is

conflicting. Similarly it is impossible to draw any conclu-sions from the large mass of experimental work on theeffect of cortisone and corticotrophin on the enzymesystems in the brain. Nor is there any evidence to

support the idea that psychotic symptoms may arisefrom an unbalanced secretion of adrenocortical hormonesin response to corticotrophin, or from the balance beingdisturbed by exogenous cortisone.1. Schlesinger, N. S., Horwitz, W. A. Amer. J. Psychiat. 1940,

96, 1213.2. Trethowan, W. H., Cobb, S. Arch. Neurol. Psychiat. 1952,

67, 283.3. Broster, L. R., Allen, C. E., Vines, H. W. C., Patterson, J.,

Greenwood, A. W., Marrian, G. F., Butler, G. C. The AdrenalCortex and Intersexuality. London, 1938.

4. Allen, C., Broster, L. R., Vines, H. W. C., Patterson, J., Green-wood, A. W., Marrian, G. F., Butler, G. C. Brit. med. J. 1939,i, 1220.

5. Allen, C., Broster, L. R. Ibid, 1945, i, 696.6. Greene, R., Paterson, A. S., Pile, G. C. L. Ibid, p. 698.7. Thorn, G. W., Forsham, P. H., Frawley, T. F., Wilson, D. L.,

Renold, A. E., Frederickson, D. S., Jenkins, D. Amer. J. Med.1951, 10, 595.

8. Cleghorn, R. A., Pattee, C. J. J. clin. Endocrin. 1954, 14, 344.9. Clark, L. D., Bauer, W., Cobb, S. New Engl. J. Med. 1952,

246, 204.10. Margolis, H. M., Caplan, P. S. J. Amer. med. Ass. 1951, 145,

382.11. Goolker, P., Schein, J. Psychosom. Med. 1953, 15, 589.12. Lewis, A., Fleminger, J. J. Lancet, 1954, i, 383.13. Quarton, G. C., Clark, L. D., Cobb, S., Bauer, W. Medicine,

Baltimore, 1955, 55, 13.14. Castor, C. W., Baker, B. L., Ingle, D. J., Li, G. H. Proc. Soc.

exp. Biol., N.Y. 1951, 76, 353.15. Selye, H. Stress Acta. Montreal, 1950. 16. Masson, G. M. C., Hazard, J. B., Corcoran, A. C., Page, I. H.

Arch. Path. (Lab. Med.), 1950, 49, 641.17. Cosgriff, S. W. J. Amer. med. Ass. 1951, 147, 924.18. Grenell, R. G., McCawley, E. L. J. Neurosurg. 1947, 4, 508.

A more promising line has been followed by Mirsky 19in work on conditioned behaviour in monkeys. He foundthat monkeys treated with corticotrophin were moreexploratory in their behaviour and reacted more aggress-ively to unpleasant conditioning. Furthermore thetreated animals forgot how to avoid an unpleasant situa-tion more rapidly than an untreated control group.These aberrations of behaviour are not unlike the" denial " in manic patients. It may be significant thathypomanic symptoms have often been described in

patients treated with corticotrophin or cortisone. Anotherpossibility is that patients treated with corticotrophin orcortisone may develop a distorted relationship to them-selves, and, especially when treatment has been pressedto the point of obvious physical change, the alteration oftheir body-image may precipitate mental upset. Thisconception has been developed in connection with

schizophrenia by Macalpine and Hunter,20 and couldundoubtedly explain the mental aberrations in patientswith adrenal virilism.3-6

THE BLOOD-BRAIN BARRIER

MANY years ago German workers drew attention to thedifference in permeability between cerebral and otherblood-vessels. In the normal animal the large-moleculedyes accepted by the histiocytes of liver and spleen andlymph-nodes did not appear in the histiocytes of thebrain, except where the brain was injured or inflamed.This observation gave rise to the conception of the blood-brain barrier. Friedemann and Elkeles 21 studied the

passage of toxins into the brain through this barrier andshowed that factors other than molecular size were con-

cerned-notably the charge and the lipoid solubility.King 22 suggested that a factor beyond the vessel wall-namely, tissue affinity-was involved.The site of the barrier remained obscure. It might be

the walls of the capillaries, though there was no visiblestructural difference between those of the brain andelsewhere ; or it might be the accepting histiocytes,though in view of their activity in phagocytosis onceinflammation had occurred this seemed improbable ; or

it could lie in the intervening ground-substance. Hess 23

points out the correlation in time and place between thebarrier and the presence of a polysaccharide or glyco-protein in the interstitial tissue. In the mouse embryothis substance, assessed histochemically by the periodicacid-Schiff reaction, is absent, and there is no barrier ;in the guineapig embryo the material is present, and sois the barrier. Further, after injury to the rat brain thearea in which the barrier is absent is temporarily free ofglycoprotein, and as healing occurs and the structure ofthe brain reverts to normal the glycoprotein and thebarrier return pari passu. It seems probable that a gelwith a carbohydrate background is formed in the ground-substance, but Hess has not yet completed the histo-chemical identification of the material. His work willbe of great interest to neuropathologists and others con-cerned with the transport of viruses and large moleculesto the brain and their dissemination in the cerebral tissue.

Elkeles 24 has lately shown the importance of electricalcharge and lipoid solubility in the intravital stainingof the adrenal cortex and medulla. Both the brainand the adrenal cortex, rich in lipoid, concentratedneutral-red chloride (a basic dye) from blood-levelswhich did not colour the rest of the body ; whereasacid dyes were taken up by the rest of the body (includingthe adrenal medulla) but not by the brain or adrenalcortex.

19. Mirsky, A. Proceedings of the Third A.C.T.H. Conference.Chicago.

20. Macalpine, I., Hunter, R. A. In Memoirs of My Nervous Illness,by D. P. Schreber. London, 1955.

21. Friedemann, V., Elkeles, A. Lancet, 1934, i, 719.22. King, L. S. Arch. Neurol. Psychiat. 1939, 41, 51.23. Hess, A. Nature, Lond. 1955, 175, 387.24. Elkeles, A. Lancet, 1954, ii, 1153.