307 causes of condition: the secondary depression, quite as infective such for infections puerperium, example; hepatitis and influenza; Parkinson’s disease; drugs such as reserpine and methyldopa. Secondary mania, however, is much less often encountered, whether it results from some other psychiatric illness, from physical illness or injury, or from drugs. Indeed, Winokur et al. quote Guze and his St Louis group as saying that their studies do not support the concept of secondary mania. In their 1971 study of affective disorder in 253 people they found 95 secondary cases. None of these was manic, though two had mania in close relatives. "Mania", they state, "was not found in patients with secondary affective disorder". A paper by Krauthammer and Klerman" is therefore welcome as a corrective. These workers start by defining the meaning they attach to the term: a condition lasting at least one week; mood elated or irritable; behaviour showing at least two of the following features - hyperactivity, push (pressure) of speech, flight of ideas, grandiosity, decreased sleep, distractibility, lack of judgment. In addition, a clear history of manic-depressive or other affective disease should be absent, as should an accompanying confusional state. These criteria for mania are similar to, though not quite the same as, those laid down by the St Louis school. Provided with this net Krauthammer and Klerman trawl the English and French literature of the past half century. They reconsider the diagnosis after looking again at the original descriptions of the secondary mania attacks they found. Many reports of mania (not just euphoria) after tricyclic drugs and monoamine oxidaseinhibitor antidepressants had to be excluded because the SECONDARY MANIA illness being treated was a primary depression. Many MORE than fifty years after the death of Emil Kraepeother groups of drugs, though much more likely to prolin there is still no wide agreement about the classificaduce confusion or depression, had occasionally led to an tion of affective disorders. Do continuous dimensions or unequivocal manic picture-corticosteroids, for examdo distinct categories best express clinical facts, and if ple, and levodopa and isoniazid. If secondary mania does result from the use of these three drugs, to cease giving categories which ones? Many psychiatrists, particularly in the United States and headed by Guze at Washington them, or in some cases just to reduce the dose, is usually University, St Louis, and Winokur at Iowa City, would sufficient for cure. make a first distinction between primary and secondary Many of the remaining positive reports are single case affective disorders. By secondary disorder they mean studies of manic episodes in conditions such as hxmodiadepressive (and perhaps others would add manic or lysis, influenza, encephalitis and cerebral tumours, or in the course of another associated with surgical operations. Such single cases hypomanic) symptoms arising or in a illness or medical to are open to the objection that they might have resulted illness, response psychiatric from affective illnesses chance coincidence or from a latent tendency to Since Leonhard’s work, primary drug. to into be subdivided have tended unipolar (endogenous primary mania. Krauthammer and Klerman counter this second objection at some length and lament that depression) and bipolar (manic-depressive) types. Unipothere is so far no biochemical marker of "silent" maniclar mania, admittedly rare, still appears in the 9th revision (1977) of the International Classification of Disdepressive disease. One illness surprisingly and conspieases2and in the proposed 3rd Diagnostic and Statistical cuously absent from their list of possible causes is thyrotoXiCoSiS.5 _ Manual of the American Psychiatric Association; but, A fresh point that Krauthammer and Klerman are thanks to Guze and Winokur, in Missouri and Iowa, and able to establish in these secondary cases is that the elsewhere in the United States, it is regarded as part of

Much has been written about the

clues. Among the risk of lymphorwith increased an conditions associated eticular neoplasia are the autoimmune disorders (including s.L.E.), primary immunodeficiency states, and immunosuppression after renal transplantation.3’-40 Despite our imperfect understanding of the mechanisms involved, this immediately suggests that host factorsspecifically immunological status-are relevant in the xtiology of the malignant process. Perhaps the most extreme instance is the rare sex-linked disorder in which the cell proliferation characteristic of infectious mononucleosis is unrestrained so that the victims die in the acute phase of the disease with heavy infiltrates of B lymphoid cells in many internal organs.41,42 Although in this condition the individual cells, do not satisfy the normal histological criteria for malignancy, it can hardly be termed a benign illness. The point at which lymphoproliferation becomes "malignant" may therefore be quite arbitrary in terms of cell biology. In terms of the whole organism, it would have to be defined as the point at which the balance between the proliferative tendency of the lymphoid cells, on the one hand, and the various restraining mechanisms of the body on the other, is tipped in favour of the former. The notion of malignancy as a disturbance in a state of dynamic balance may have validity only for lymphomas or it may prove wildly wrong even for them. What matters in cancer research is that there should be continuing stimulus to develop new concepts and to look afresh at old ones. In providing this, the lymphomas show no signs of declining potency. Once

again,

the

lymphomas offer

manic-depressive illness.

37. Mitelman, F. Hereditas, 1971, 69, 155. 38. Ohno,S. Physiol.Rev. 1971, 51, 496. 39 Jackson,R H., Miller, H., Schapira,K.Br. med. J. 1957, i, 480. 40. Green, J.A., Dawson, A. A., Walker, W. Lancet, 1978, ii, 753. 41 Hoover, R., Fraumeni, J. F., Jr. ibid. 1973, ii, 55. 42 Kersty, J H , Spector, B. D. in Persons at High Risk of Cancer (edited by J F. Fraumeni, Jr); p. 55.New York, 1975. 1 Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. A., Winokur, G., Murioz,R. Archsgen.Psychiat. 1972, 26, 57. 2. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death.World Health Organisation, 1977.

physical

common

a

is high, 41, compared with 25 in bipolar illness.6 Again, in contrast with bipolar illness, in which there is a positive family history in 86%,7 family history was positive in only about half.

median age of most series for

onset

3. Guze, S. B., Woodruff, R. A., Clayton, P. J. Psychol. Med. 1971, 1, 426 4. Krauthammer, C.,Klerman, G. L.Archsgen.Psychiat. 1978, 35, 1333. 5. Conybeare’s Textbook of Medicine by W. M. Mann); p. 712. Edin-

(edited

6.

burgh, 1975. Clancy, J., Tsuang, M.-T., Norton, B., Winokur, G. J. Iowa med. Soc. 1974, 64, 394.

7. Johnson,G.F. S.,Leeman,M. M. Archsgen.Psychiat. 1977,

34, 1074.

308

They conclude that mania

is

unusual

syndrome with many causes-biochemical, psychological, structural, and genetic. Perhaps the newer work on peptide transmitters, vasopressin, and naloxone will bring us nearer an

solution. Meanwhile, the message from Krauthamand Klerman is that a first attack of mania in a middle-aged person, with no family history of that illness, demands extra-thoroughinvestigation.

to a mer

’

ASCORBIC ACID: IMMUNOLOGICAL EFFECTS AND HAZARDS

,

VITAMIN C, contrary to the suggestion of Pauling,l does not seem to decrease the incidence of colds and winter illness.2-5 There is some agreement that it may bring about a modest reduction in the severity of the symptoms of the common cold, though interpretation of the trials depends critically on the subdivision of the treated groups on the basis of age and sex. 2,3,6.’ Though there is little evidence of benefit from prophylactic megadoses of ascorbate, some manifestations of the immune response, particularly those concerning leucocyte mobility, do seem dependent on ascorbate intake. Thomas and Holts have reviewed this association and the potential hazards of ascorbate therapy. Control of infection involves polymorphonuclear and mononuclear cells which have high ascorbate levels. These levels fall rapidly during virus infection and return to normal after recovery. Subnormal levels of polymorphonuclear-leucocyte ascorbate have been observed in people with the immune depression of pregnancyl0, 11, ageing, u, 13 and corticosteroid treatment. 9 , Corticosteroid therapy not only depletes leucocyte ascorbate but also inhibits phagocytic activity.9 Dietary supplementation of ascorbate increases phagocytic activity in steroid-treated subjects,14 Similarly, macrophages from scorbutic subjects show depressed migration and do not aggregate normally in silicotic lesions.15 Though mast cells possess high concentrations of ascorbate, immediate hypersensitivity is not clearly influenced by ascorbate. A potentiation of the effects of antihistamines in anaphylaxis has been demonstrated, but this may be mediated through unphysiological mechanisms. A depression of delayed type hypersensitivity, reversible by 1. 2.

Pauling, L. San Francisco, 1970.

Anderson, T. W., Reid, D. B. W., Beaton, G. H. Can. med. Ass. J. 1972, 107, 503. 3. Anderson, T. W., Beaton, G. H., Corey, P. N., Spero, L. ibid. 1975, 112, 823.

Chalmers, T. C. Am.J. Med. 1975, 58, 532. Tyrrell, D. A. J., Craig, J. W., Meade, T. W., White, T. Br. J. prev. soc: Med. 1977, 31, 189. 6. Coulehan, J. L., Reisinger, K. S., Rogers, K. D., Bradley, D. W. New Engl. J. Med. 1974, 290, 6. 7. Kinlen, L., Peto, R. Lancet, 1973, i, 944. 8. Thomas, W. R., Holt, P. G. Clin. exp. Immun. 1978, 32, 370. 9. Chetien, J. H., Garagusi, V. F. J. reticuloendoth. Soc. 1973, 14, 280. 10. Baines, M. G., Pross, H. F., Millar, K. G. Clin. exp. Immun. 1977, 28, 453. 11. Barton, G. M. G., Roath, O. S. Int. Z. Vitamin Forshch. 1976, 46, 271. 12. Wilson, C. W. M., Loh, H. S. Lancet, 1973, i, 638. 13. Milne, J. S., Lonergan, M. E., Williamson, J., McMaster, R., Percy, N. Br. med. J. 1971, iv, 383. 14. Stankova, L., Gerhardt, N. B., Nagel, L., Bigley, R. H. Infect. Immun. 1975, 12, 252. 15. Goetzl, E. J., Wasserman, S. I., Gigli, I., Austen, K. F. J. clin. Invest. 1974, 4. 5.

53, 813.

ascorbate supplementation, has been demonstrated in scorbutic animals, possibly due to defective migration of recruited cells to the site of challenge rather than a central defect in lymphocyte function. Whatever the basic defect, normal skin-graft rejection seems dependent upon adequate ascorbate intake.8 The links between ascorbate intake and interferon are tenuous, but interferon production is increased in mice fed on ascorbate supplemented diets, and human embryonic fibroblasts show a similar response.16 To date, studies of the relationship between ascorbate and antibody production and ascorbate and complement have produced contradictory results.8 The theoretically harmful effects of megadose ascorbate are as numerous as the potentially beneficial effects. Calcium oxalate and urate calculi, decreased vitamin-B12 availability, and hypovitaminosis C after withdrawal of ascorbate probably matter little in the absence of familial disturbances of metabolism. Gastrointestinal symptoms are usually reversible on withdrawal of ascorbate; pentosuria may be confused with glycosuria and effects on prothrombin time during oral anticoagulation are potentially dangerous.l’ Of greater concern are the as yet unconfirmed reports of alterations in fetal metabolism as a result of maternal megatherapy,8 enhancement of metal toxicity, decreased tolerance of a rapid rise to high altitude,18 potentation of aspirininduced mucosal ulceration,19 interactions with drug metabolism and mutagenic properties of ascorbate metabolites.8 There seems at present little justification for long-term ascorbate megatherapy in cold prophylaxis in the general population. Perhaps it will be possible to define a subpopulation in which the benefits justify the risks.

EXAMINATION OF IMMIGRANTS LAST week The Guardian reported that a 35-year-old Indian lady, arriving at Heathrow airport as an immigrant, had been examined by a doctor in an attempt to test statements about her marital condition which concerned her application for admission. The Home Secretary promptly instructed immigration officers not to ask for medical examinations whose object was to determine whether or not female immigrants had had sexual intercourse or had borne children. It is to be hoped that Mr Rees is pursuing his inquiries into how this shameful incident arose. No doubt the zeal of some immigration officers led them to believe that their duty lay in making every conceivable effort to disprove the evidence presented by a new arrival. Perhaps the view at Heathrow is that this practice is merely one way of meeting the Government’s wishes on the conditions to be fulfilled by immigrants. If so, this impression will now have been forcefully dispelled. It is sad to know that a doctor agreed to comply with the immigration officer’s request. When allegiances are divided, a doctor’s decisions are not always simple. But certainly the best course here would have been to refuse to conduct an unjustified examination at the instigation of a presumptuous official. 16. Siegel, B. V. Nature, 1975, 254, 531. 17. Barness, L. A. Ann. N.Y. Acad. Sci. 1975, 258, 523. 18. Schrauzer, G. N., Ishmael, D., Kieter, G. W. ibid. 1975, 258, 377. 19. Lo, G. Y., Konishi, F. Am. J. clin. Nutr., 1978, 31, 1397.