956 mechanism were normal. The results, however, show that the feedback effect is very small. Myxoedema is not the only chronic deficiency in which acute changes in hormone levels have little effect upon the pituitary hormone concentration. In the castrated female rat oestradiol benzoate (2 x 20 g) produces luteinising-hormone (L.H.) suppression if given within 5 days of castration but significantly higher final levels if given 21-28 days after castration. In the same experiment follicle-stimulating hormone was poorly suppressed at all times.9 Similarly, in oophorectomised monkeys L.H. falls, but not to basal levels, after administration of oestradiol benzoate. 10 All these examples of target-organ hormone deficiency can be explained by secondary pituitary hyperplasia. This is recognised in myxoedema, for enlargement of the pituitary fossa is seen in some patients in whom the disorder is of long standing.ll,’2 This may be partially autonomous and would account for the failure of T.S.H. suppression in our experiment. Indeed it seems that tertiary hyperplasia can occur in this situation, and this would account for the cases of pituitary tumour occasionally reported. The degree of hyperplasia has been assessed in myxoedemic patients. When T.R.H. was infused the total net T.s.H. released averaged 123 mu in normal subjects but 640 mu in hypothyroid patients.7 Measurements of the size of the pituitary fossa have shown that this hyperplasia secondary to myxoedema can improve,12 but it takes time and is not invariable." Secondary hyperplasia with some degree of autonomy would explain our findings in the patients with Addison’s disease. We stopped therapy for 24 hours to mimic the chronic hormone deficiency. This model, however, appears to apply also to patients receiving therapy. Krieger and Gewitz1 found a similar lack of suppressibility although their patients were off treatment for only 12 hours, and in our outpatients A.C.T.H. levels were raised at a time when their cortisol concentrations were within normal limits. This difference in trophic-hormone response between treated myxoedema and treated Addison’s disease can be attributed to the difference in the half-life of the replacement hormones. The half-life of thyroxine is about 6-7 days,14 whereas the half-life of cortisol is 80-115 min." At times the patient with Addison’s disease, especially if he does not always take his steroid medication, will have very low levels of circulating cortisol, and this would be amplified in times of stress. These continuing inadequate levels of cortisol can, we suggest, maintain pituitary
,
We have shown that present treatment regimens for Addison’s disease are insufficient and produce secondary pituitary hyperplasia. We do not know if this is of importance in the management of patients with Addison’s disease, but we believe it is of setiological importance in the genesis of Nelson’s syndrome. The hypothesis could be tested by means of a combination of short-acting and long-acting steroids to mimic the normal cortisol circadian rhythm and by the use of A.C.T.H. concentrations to define the degree of control.
Requests for reprints should be addressed to A. C. B., Department of Medicine, General Hospital, Gwendolen Road, Leicester LE5 4PW. REFERENCES D. T., Gewitz, G. P. J. clin. Endocr. Metab. 1974, 39, 46. Besser, G. M. in Cushing’s Syndrome, Diagnosis and Treatment (edited by C. Binder and P. E. Hall); p. 132. London, 1972. 3. Berson, S. A., Yalow, R. S. J. clin. Invest. 1968, 47, 2725. 4. Murphy, B. E. P. J. clin. Endocr. Metab. 1967, 27, 973. 5. Wilkin, T. J., Storey, B. E., Isles, T. E., Crooks, J., Swanson Back, J. Br med. J. 1977, i, 993. 6. Shenkman, L., Mitsuma, T., Hollander, C. S. J. clin. Invest. 1973, 52, 205. 7. Wartofsky, L., Dimond, R. C., Noel, G. L., Frantz, A. G., Earll, J. M. J. clin. Endocr. Metab. 1976, 42, 443. 8. Saberi, M., Utiger, R. D. ibid. 1974, 39, 923. 9. Martini, L. in Endocrine Function of the Human Ovary (edited by V. H. T.
1. 2.
Krieger,
James, M. Serio, and G. Ginstri); p 119. London, 1976 Yamaj, T., Dierschke, D. J., Hotchkiss, J., Bhattacharya, A. N., Surve, A. H., Knobil, E. Endocrinology, 1971, 89, 1034. 11. Jackson, I. M.D. Proc. R. Soc. Med. 1970, 63, 578. 12. Van Wyk, J. J., Grumback, M. M. J. Pediat. 1960, 57, 416. 13. Reichlin, S., Utiger, R. D. J. clin. Endocr. Metab. 1967, 27, 251. 14. Pittman, C. S., Chambers, J. B., Read, V. M. J. clin. Invest. 1971, 50, 1187. 15. Migeon, C. J., Sandberg, A. A., Decker, H. A, Smith, D. F., Paul, A. C., Samuels, L. T. J. clin. Endocr. Metab. 1956, 16, 1137. 10.
Hypothesis FREE FATTY ACIDS, COMPLEMENT ACTIVATION, AND POLYCLONAL B-CELL STIMULATION AS FACTORS IN THE IMMUNOPATHOGENESIS OF AFRICAN
TRYPANOSOMIASIS I. R. TIZARD R. K. G. ASSOKU K. H. NIELSEN
Department of Veterinary Microbiology and Immunology, University of Guelph, Ontario, Canada
hyperplasia.
Summary
Our work suggests that the only way of defining adequate treatment is by the restoration of A.C.T.H. levels to normal. We accept that this may be difficult to achieve and that secondary hyperplasia may not be of consequence to the patient with Addison’s disease. Whether control would be beneficial to the patient is impossible to know, because it has never been attempted. However, it may be of importance in the genesis of Nelson’s syndrome-a combination of raised A.C.T.H. concentrations, skin pigmentation, and obvious pituitary tumour following bilateral adrenalectomy. In all with bilateral adrenalecpatients Cushing’s syndrome tomy is followed by a rise in A.c.T.H. levels,2 and we suggest that this is the result of pituitary hyperplasia resulting from inadequate replacement therapy.
panosomiasis are characterised by sustained hypocomplementæmia, gross hypergammaglobulinæmia M, and profound immunosuppression. It is suggested that this hypocomplementæmia is probably due to the action of a trypanosome-derived complement-activating factor and that the elevated IgM levels may be the combined result of this decomplementation, together with a subsequent failure of the normal IgM-to-IgG antibody switch mechanism and polyclonal B-lymphocyte activation by a trypanosome-generated mitogen The immunosuppression in this disease may be a result of the collective immunosuppressive effects of trypanosome-derived immune-modulating free fatty acids, polyclonally stimulating B-cell mitogen, and complementactivating factors.
Human and animal forms of African try-
957 INTRODUCTION
THERE is much interest in both the human and animal forms of African trypanosomiasis, not only because of their great economic and public-health importance but also because they are elegant natural disease models for the elucidation of the homoeostatic and regulatory mechanisms of antibody biosynthesis,l immunosuppression in parasitic infections,2,3 and parasite survival in the immunised host. 2,4 These diseases vary according to the species of trypanosome and differences between hosts, but all are characterised by numerous aberrations in functions of the immune system,5 some of the most important being a sustained hypocomplementaemia,6-9 considerably elevated IgM,10-13 a dramatic reduction in IgA and IgE,14 and profound immunosuppression.15-18 The mechanisms underlying these immunological abnormalities and their role in the immunopathogenesis of trypanosome infections have not yet been elucidated, but recent studies suggest a link between the hypocomplementxmia, hypermacroglobulinaemia, and immunological hyporesponsiveness in this disease syndrome. We believe that a combination of the effects of free fatty acids,19-21 complement-activating factors,22-24 and B-cell mitogenic factors,25.26 all generated by the infecting trypanosomes, cause many of the aberrations of the immune system observed in trypanosomiasis. FREE FATTY ACIDS, DISRUPTION OF LYMPHOID-ORGAN ARCHITECTURE, AND IMMUNOSUPPRESSION
We have recently drawn attention to the remarkable resemblance between the immunopathological lesions induced by administration of free fatty acids (F.F.A.) and those observed in trypanosomiasis.2’ F.F.A., both saturated and unsaturated, can significantly modify the immune response,28,29 and several are immunosuppressive.28,30-32 Linoleic acid (C18:2), which has been most extensively studied, can prolong kidney allograft survival in man33 and skin allograft survival in mice34 and rats.3’ Linoleic and arachidonic (C20:4) acids have also been shown to disrupt the architecture of the lymphoid organs in vivo,29 and there is evidence that these F.F.A. may also induce an in-vivo immunosuppressive effect, either by blocking lymphocyte reactivity to mitogens31 or antigens32 or through the production of potent im-
munosuppressive prostaglandins.36,37 Since the in-vivo immunosuppressive effect of F.F.A. can be prevented by splenectomy,38 this may indicate induction of the suppressor-cell population. Jayawardena and Waksman39 have presented evidence that suppressor cells are involved in the suppression of immunity in trypanosomiasis. of
Relatively large quantities (mostly stearic, linoleic, palmitic, and oleic acids) are generated by autolysing trypanosomes.19-21 These F.F.A. are potently cytotoxic and haemolytic in vitro. Since trypanosomes tend to aggregate in dense clusters within capillary beds40 and F.F.A.
may reside in microenvironmental locations within the lymphoid organs,41,42 it is postulated that the immunosuppression and the structural disturbances in these organs in trypanosomiasis42.43 may be partly accounted for by the release of F.F.A. from the various parasitsemic waves of trypanosomes autolysing in vivo which may reach relatively high concentrations in these areas. Although serum-albumin binds fatty acids and largely
neutralises their membrane activity both in vivo and in vitro,44,45 it is possible that this is of reduced significance in trypanosomiasis because of the reasons given above, and also because animals and patients with trypanosomiasis are usually severely hypoalbuminoemic .46 The immunopathological lesions in trypanosomiasis closely resemble those induced by F.F.A. administration. They include disruption of spleen and lymph-node architecture,41-43 depression of the immune responses of lymphocytes to specific antigen4’ and mitogen,17 and evidence for the participation of a population of suppressor cells.39 We therefore suggest that one of the pathogenetic mechanisms of immunosuppression in trypanosomiasis involves the active participation of free fatty acids generated in the host lymphoid microvasculature by autolysing trypanosomes. COMPLEMENT ACTIVATION, HYPOCOMPLEMENTaeMIA, AND IMMUNOSUPPRESSION
One of the commonest immunochemical features of both human and animal trypanosomiasis is a sustained hypocomplementaemia.6-8.48 In addition, the constant finding of concomitant severely depressed C3,’’" C1,9 and properdin9 levels, the appearance of high immunoconglutinin 49 and complement-fixing antitrypanosome antibody,13 and the demonstration of direct activation of (22.24 and C350 in vitro by autolysing trypanosomes are strongly suggestive of the probable activation of complement by both the alternative and the classical pathways in trypanosomiasis. The disease has also been characterised by aberrations in the levels of other serum-proteins.l0-14 Thus, any explanation of the immunosuppression seen in trypanosomiasis is complicated by the concomitant high levels of both specific and non-specific IgM 12 and greatly decreased IgA and IgE levels.14 The immunosuppressive effect of complement activation and hypocomplementaemia has been shown by the demonstration that animals deprived of C3 by injection of cobra-venom factor are only able to mount immune
consisting mainly of IgM,51 and they also have greatly reduced ability to respond to thymus-dependent antigens.52,53 In addition, complement-depleted animals have been shown by Pepys and colleagues54.55 to have greatly reduced IgA54 and IgE55 responses. We therefore suggest that the sustained hypocomplementaemia in patients with African trypanosomiasis is likely to lead to the suppression of IgG, IgA, and IgE production and the disruption of the homoeostatic control of IgM production, resulting in excess biosynthesis of IgM. Indeed, deprivation of complement in animals may lead to failure of the normal IgM-to-IgG antibody switch mechresponses a
anism.sl,56
Complement depletion also has a disorganising effect on lymphoid tissues and the processing of antigens .54,-17 Excess proliferation of plasma-cells and disruption of thymus-dependent areas of lymphoid organs have been noted in African trypanosomiasis.41-43,58 Indeed, such disruption or disorganisation of lymphoid organs in trypanosomiasis, it has been suggested, may interfere with T and B cell cooperation in the immune response.42.58 Regardless of the precise mechanisms involved in trypanosome-induced immunosuppression, we believe that activation of complement may be an important effector arm of this phenomenon and that the observed hypocomplementxmia could account, at least in part, for the immunosuppression described in trypanosomiasis.
958 POLYCLONAL B-CELL
ACTIVATION, ELEVATED IgM LEVELS,
AND IMMUNOSUPPRESSION
A paradoxical finding which has greatly contributed the difficulty in the elucidation of iminunosuppression in African trypanosomiasis is the simultaneous association of a highly active immunological and mononuclear phagocytic system42.43 with an immunosuppressed state to other anigens.4.18 One of the most attractive hypotheses advanced to explain this has been that B cells capable of recognising the introduced antigen may be depleted as a result of polyclonal B-cell activation.4.16,18.25.26 Recent reports have stressed the close functional and causal relationship between the high IgM levels, probable polyclonal B-cell activation, and immunosuppression in African trypanosomiasis.4.25.26.58 Whether a trypanosome-derived mitogen plays a significant part in the immunosuppression, as well as in a spontaneous polyclonal B-cell response in this disease, has yet to be unequivocally established. Nevertheless, there is increasing evidence that a trypanosome-derived B-cell mitogen stimulates B-cell clones to differentiate,4.5.25.26 resulting not only in unregulated clonal expansion and secretion of immunoglobulins with numerous specificities but also in clonal exhaustion and/or paralysis, so that the induction of specific antibody responses is severely depressed. Proof of the existence of such a trypanosome-derived mitogen would undoubtedly have enormous implications for understanding the basis of immune-system dysfunction in the disease. Lately, we have obtained evidence for the generation of a potent B-cell mitogen by autolysing trypanosomes,26 thus confirming the findings of Esuruoso.25 Like Urquhart and colleagues,16 Greenwood and Whittle,8 Esuruoso,25 and Hudson and co-workers,44 we believe that some of the immunological dysfunctions in trypanosomiasis, particularly the immunosuppression and concomitant synthesis of high levels of specific and non-specific IgM immunoglobulins, might be associated with this elaboration of a B-cell mitogen by the parasite.26 This hypothesis would also explain the background IgM responses to the many antigens, recognisable by B cells, which are greatly increased in
to
trypanosomiasis.4 We therefore postulate that trypanosome infection induces polyclonal B-cell activation which, in the presence of continuous and successive waves of blood parasitsemia, is likely to result in a progressive depletion of antigen-reactive B lymphocytes, since these cells would then be activated to change into secretor cells. In this way the immunosuppression in trypanosome infections may also be partially accounted for by the depletion of B cells capable of recognising the introduced antigen. Indeed, a number of B-cell mitogens completely suppress primary immune responses in vivo to sheep erythrocytes.59 If, however, both activation and immunosuppression were polyclonal, it would be expected that the antibody responses to later-appearing trypanosome antigenic variwould also be impaired. Recent support to this view. ants
findings4lend some
The overall mechanisms by which trypanosomes influence the host immune system are obviously complex, and more direct evidence is needed. Nevertheless, from the available data it is a reasonable working hypothesis that the immunoregulatory and immunopathogenic effects of the hypocomplementaemia, high IgM levels,
and immunosuppression in trypanosomiasis are causally linked. We suggest that immunosuppression in this syndrome is the result of the collective immunosuppressive effects of trypanosome-derived immune-modulating free fatty acids, polyclonally stimulating B-cell mitogen, and complement-activating factors. This work is
supported by the International Development Research
Centre, Canada. R. K. G. A. is on sabbatical leave from the University of Ghana.
Requests for reprints should be addressed to 1. R. T. REFERENCES 1. Cohen, S., Sadun, E. H. Immunology of Parasite Infections. Oxford, 1976. 2. Parasites in the Immunized Host: Mechanisms of Survival. Ciba Fdn Symp. 25, new series. Amsterdam, 1974. 3. Neal, R. A., Garnham, P. C., Cohen, S. Br. med. Bull. 1969,25,194. 4. Hudson, D. M., Byner, C., Freeman, J., Terry, R. J. Nature, 1976, 264, 256. 5. Mansfield, J. M., Craig, S. A., Stelzer, G. T. Infect. Immun. 1976, 14, 976. 6. Nagle, R. B., Ward, P. A., Lindsley, H. B., Sadun, E. H., Johnson, A. J., Berkow, R. E., Hildebrandt, P. K. Am. J. trop. Med. Hyg. 1974, 33, 15. 7. Jarvinen, J. A., Dalmasso, A. P. Infect. Immun. 1976, 14, 894. 8. Greenwood, B. M., Whittle, H. C. Clin. exp. Immun. 1976, 24, 133. 9. Nielsen, K. H., Sheppard, J., Holmes, W., Tizard, I. R. Unpublished. 10. Houba, V., Brown, K. N., Allison, A. C. Clin. exp. Immun. 1969, 4, 113. 11. Freeman, T., Smithers, S. R., Targett, G. A. T., Walker, P. J. J. infect. Dis.
1970, 121, 401. Hudson, K. M., Freeman, J. C., Byner, C., Terry, R. J. Trans. R. Soc. trop. Med. Hyg. 1975, 69, 273. 13. Kobayashi, A., Tizard, I. R. Tropenmed. Parasit 1976, 27, 411. 14. Nielsen, K. H., Sheppard, J., Tizard, I. R., Holmes, W. Unpublished. 15. Godwin, L. G., Green, D. G., Guy, M. W., Voller, A. Br. J. exp. Path. 1972,
12.
53, 40. Urquhart,
G. M., Murray, M., Murray, P. K., Jennings, F. W., Bates, E. Trans. R. Soc. trop. Med. Hyg. 1973, 67, 528. 17. Greenwood, B. M., Whittle, H. C., Molyneux, D. H. ibid. p. 846. 18. Murray, P. K., Jennings, F. W., Murray, M., Urquhart, G. M. Immunology, 16.
1974, 27, 825. 19. 20. 21.
Tizard, I. R., Holmes, W. L. Experientia, 1976, 32, 1533.
22. 23.
Nielsen, K. H., Sheppard, J. Experientia, 1977, 33, 769 Nielsen, K. H., Sheppard, J., Tizard, I. R., Holmes, W. L. Exp. Parasit. (in
Tizard, I. R., Holmes, W. L., York, D. A., Mellors, A. ibid. 1977, 33, 901. Tizard, I. R., Mellors, A., Holmes, W. L., Nielsen, K. H. Exp. Parasit. (in the press).
the press).
Nielsen, K. H., Sheppard, J., Tizard, I. R., Holmes, W. L. J. Parasit. (in the press). 25. Esuruoso, G. O. Clin. exp. Immun. 1976, 23, 314. 26. Assoku, R. K. G., Tizard, I. R. Experientia (in the press). 27. Tizard, I. R., Nielsen, K. H., Mellors, A., Assoku, R. K. G. Lancet, 1977, i, 750.
24.
28. 29. 30.
Berken, A., Benacerraf, B. Proc. Soc. exp. Biol. Med. 1968, 128, 793. Meade, C. J., Mertin, J. Int. Archs Allergy appl. Immun. 1976, 51, 2. Weyman, C., Belin, J., Smith, A. D., Thompson, R. H. S. Lancet, 1973, ii,
33. 31. Mertin, J., Hughes, D. Int. Archs Allergy appl. Immun. 1975, 48, 203. 32. Field, E. J., Shenton, B. K., Joyce, G. Br. med. J. 1974, i, 412. 33. Udall, P. R., Wilkinson, R., McHugh, M. I., Field, E. J., Shenton, B. K., Baxby, R. M., Seifert, J. Lancet, 1974, ii, 514. 34. Smith, A. D., Tsang, W. M., Weyman, C., Belin, J. ibid. 1976, i, 254. 35. Ring, J., Seifert, J., Mertin, J., Brendel, W., ibid. 1974, ii, 1331. 36. Lichteinstein, L. M., Gillespie, E., Bourne, H., Henney, C. S. Prostaglan-
dins, 1972, 2, 519. 37.
Quagliata, F., Lawrence, V. J., Philips-Quagliata, J. 6, 457.
M. Cell. Immun. 1973,
Mertin, J., Meade, C. J., Hunt, R., Sheena, J. Int. Archs Allergy appl. Immun. 1977, 53, 469. 39. Jayawardena, A. N., Waksman, B. H. Nature, 1977, 265, 539. 40. Bungener, W., Muller, G. Tropenmed. Parasit. 1976, 27, 370. 41. Losos, G. J., Ikede, B. O. Vet. Path. 1972, 9, suppl. 1. 42. Murray, M., Murray, P. K., Jennings, F. W., Fisher, E. W., Urquhart, G. W. Res. vet. Sci. 1974, 16, 77. 43. Murray, M. in Progress in Immunology (edited by L. Brent and J. Holborow); II (4), p. 484. Amsterdam, 1974. 44. Willebrands, A. F., terWelle, H. F., Tasseron, S. J. J. molec. cell. Cardiol 1973, 5, 259. 45. Goodman, D. S. J. clin. Invest. 1958,37,1729. 46. Gall, D. J. W. Afr. Sci. Ass. 1956, 2, 152. 47. McKenzie, P. K., Boyt, W. P., Emslie, V. M., Lander, K. P., Swanepoll, R Vet. Rec. 1975, 97, 452. 48. Woodruff, A. W., Ziegler, J. L., Hathaway, A., Gwata, T. Trans. R. Soc. 38.
trop. Med. Hyg. 1973, 67, 329. 49. Ingram, D. G., Soltys, M. S. Parasitology, 1960, 50, 50. Kierszenbaum, F., Weinman, D. Immunology, 1977,
231. 32, 245.
959
pharmacologists. The past decade, however, has seen an awakening of interest in the condition and an improvement in both the quantity and the quality of research. Many important and interesting, but still unsolved, problems connected with the disease have emerged, and its economic and financial consequences are only now beginning to be understood. Moreover, the emergence of penicillin-resistant, -lactamase-producing gonococci has called into question world-wide antibiotic policies, especially the ease with which antibiotics can be obtained without prescription in many countries. This excellent book contains most of what is known of the subject. It is invaluable for all those who treat patients with sexually transmitted diseases, and should be read by postgraduate students in this subject ; it is also an excellent reference book for epidemiologists, physicians in other branches of medicine, and microbiologists. The text is precise, clearly written, and lightened from time to time by Dr Morton’s attractive sense of humour; besides being easy to read it is illustrated by helpful photographs and tables. Each chapter ends with a full list of references. The best sections of the book are those on the history of gonorrhoea, gonococcal septicaemia, and the size and nature of the problem gonorrhoea poses. In his concluding chapter on the control of gonorrhoea, Morton is pessimistic; he believes that modem social, behavioural, and medical trends will result in a high prevalence of the disease for the rest of this century at least. Politicians, health administrators, and all those who plan and
Reviews of Books
Abortion MALCOLM POTTS, PETER DIGGORV, and JOHN PEEL. London and New York. Cambridge University Press. 1977. Pp. 575. 17.50
(paperback 3.95). THIS is a valuable and extensive review of abortion throughout the world and over the course of time. It has a British bias because of the origin of the authors; the sociological evidence is interesting and well analysed; and the book has a uniformity of style and approach. Those who have followed the abortion debate will know from the names of the authors the sort of conclusions which will be reached. They have convinced themselves of the necessity for abortion, judiciously used with contraception, and they wish to convince others of the validity of their case, stated in elaborate detail which is difficult to find in summary elsewhere. Their case is convincing, though that will not be conceded by everyone. They try hard to do justice to their opponents, but Roman Catholic theologians and some doctors are criticised severely, and sometimes with conscious cleverness. This will not rout the dissenters who, nevertheless, should listen to this generally well argued exegesis. Abortion has been used by all societies. It has been, and is a problem which will not go away. Whether society, through its legislators, lawyers, doctors, and moralists, welcomes termination of pregnancy or rejects it is of small consequence. Many women and their helpers have made their decisions known in action, and the evidence is clearly documented here that abortion will probably remain a feature of fertility control for some time to come. The reader can like it or lump it, but if at the moment he can only lump it because of what, to him, are important ethical considerations, then this book may help him to define those more closely and compare them with those of others. There is fodder for all sides of the argument, but interpretation depends on many inexplicit factors not necessarily amenable to reason. Sir Thomas Browne might be allowed the last word on what it is all about. "As Reason is a Rebel unto Faith, so Passion unto Reason: as the propositions of Faith seem absurd unto Reason, so the Theorems of Reason unto Passion, and both unto Reason". Exactly. So the debate must continue, but with the hope that it will be conducted at the high level of tolerance shown in this book. The authors’ bouts of passionate polemic, comparatively rare, might be overlooked in the same spirit.
Gonorrhcea R. S. MORTON, F.R.C.P.E., The Royal Infirmary, Sheffield. London and Philadelphia: Saunders. 1977. Pp 292. [,10.
has risen
the past twenty than 250 000 000 mfections with gonorrhoea a year throughout the world. Control measures have clearly failed. The disease has, until lately, THE incidence of
gonorrhoea
years and it is estimated that there
been neglected by
over
are more
physicians, microbiologists, epidemiologists,
51 Nielsen, K.H., White, R.G.Nature, 1974, 250, 234. 52 Pepys, M. B. ibid. 1972, 237, 157 53 Pepys, M.B J. exp.Med. 1974, 140, 126. 54 Pepys, M.B. Transplantn Rev. 1976, 32, 93. 55 Pepys, M. B., Brighton, W. D., Hewitt, B. E., Bryant, D. E., Pepys, J. Clin. exp.Immun.1977, 27, 397. 56 Crane, C. G., Rowley, M. J., Warburton, M. F., Mackay, I. R. Clin. Sci. 1972, 43, 869. 57 Papamichail, M., Gutierrez, C., Embling, P., Johnson, P., Holborow, E. J., Pepys, M.B.Scand. J.Immun. 1975, 4, 343. 58 Terry, R. J., Freeman, J., Hudson, K. M., Longstaffe, J. A. Trans. R. Soc. trop Med.Hyg. 1973, 67, 263. 59 Diamantstein, T., Keppler, W., Blitstein-Willinger, E., Ben-Effraim, S. Immunology, 1976, 30, 401.
health-care services should heed his words and ensure that modern facilities for diagnosis and treatment are available, including contact tracing and improved health education.
Medical Selection of Life Risks R. D. C.
1977.
BRACKENRIDGE,
F.R.C.P.E.
London: Undershaft Press.
Pp. 765.[15.
WHILST most doctors frequently fill up forms on their patients for the benefit of life-insurance schemes, few have much idea of what happens next-or how the risk is calculated. The insurance companies turn in healthy profits and few become bankrupt, so their methods must be efficient from a business point of view. Dr Brackenridge’s survey of the medical side of life insurance is an up-to-date and well-written account of how risk is calculated. Since his first review 15 years ago the results of many long-term epidemiological studies concerned with mortality risk have made a reference manual for the insurance medical officer a necessity-and this book is it. However, it is also relevant to other disciplines. The first part of the book deals with the principles of selection and the rating systems used by insurance medical officers on "substandard" lives. The second part provides a detailed analysis of the prognosis of a wide spectrum of treated and untreated disease-each section ending with practical advice to the examining doctor as to how to assess the risk. Despite the fact that there is a measurable difference between the mortality of "insured lives" (upon which most of the vital statistics presented are based) and that of the general population, the book provides a useful reference for people concerned with prospective surveys of mortality and morbidity and the review of world literature appears comprehensive. For this reason too, clinicians will find useful tables of prognostication to compare with their own experience and to help in advising patients and their relatives of the likely outcome of particular diagnosis and operations. The statistics apply to groups of patients, and the art is knowing how to apply them to the individual case. To help the clinician the author includes between the tables and the risk-rating paragraphs, good clinical sections on each disease, highlighting the prognostic features. His philosophy with regard to minor ailments and their relationship to the whole patient is stimulating and his attitude towards stress-related illness enlightened. The book is well presented; and the tables, with one or two exceptions, are easy to understand, and there is a comprehensive index.
,
We have shown that present treatment regimens for Addison’s disease are insufficient and produce secondary pituitary hyperplasia. We do not know if this is of importance in the management of patients with Addison’s disease, but we believe it is of setiological importance in the genesis of Nelson’s syndrome. The hypothesis could be tested by means of a combination of short-acting and long-acting steroids to mimic the normal cortisol circadian rhythm and by the use of A.C.T.H. concentrations to define the degree of control.
Requests for reprints should be addressed to A. C. B., Department of Medicine, General Hospital, Gwendolen Road, Leicester LE5 4PW. REFERENCES D. T., Gewitz, G. P. J. clin. Endocr. Metab. 1974, 39, 46. Besser, G. M. in Cushing’s Syndrome, Diagnosis and Treatment (edited by C. Binder and P. E. Hall); p. 132. London, 1972. 3. Berson, S. A., Yalow, R. S. J. clin. Invest. 1968, 47, 2725. 4. Murphy, B. E. P. J. clin. Endocr. Metab. 1967, 27, 973. 5. Wilkin, T. J., Storey, B. E., Isles, T. E., Crooks, J., Swanson Back, J. Br med. J. 1977, i, 993. 6. Shenkman, L., Mitsuma, T., Hollander, C. S. J. clin. Invest. 1973, 52, 205. 7. Wartofsky, L., Dimond, R. C., Noel, G. L., Frantz, A. G., Earll, J. M. J. clin. Endocr. Metab. 1976, 42, 443. 8. Saberi, M., Utiger, R. D. ibid. 1974, 39, 923. 9. Martini, L. in Endocrine Function of the Human Ovary (edited by V. H. T.
1. 2.
Krieger,
James, M. Serio, and G. Ginstri); p 119. London, 1976 Yamaj, T., Dierschke, D. J., Hotchkiss, J., Bhattacharya, A. N., Surve, A. H., Knobil, E. Endocrinology, 1971, 89, 1034. 11. Jackson, I. M.D. Proc. R. Soc. Med. 1970, 63, 578. 12. Van Wyk, J. J., Grumback, M. M. J. Pediat. 1960, 57, 416. 13. Reichlin, S., Utiger, R. D. J. clin. Endocr. Metab. 1967, 27, 251. 14. Pittman, C. S., Chambers, J. B., Read, V. M. J. clin. Invest. 1971, 50, 1187. 15. Migeon, C. J., Sandberg, A. A., Decker, H. A, Smith, D. F., Paul, A. C., Samuels, L. T. J. clin. Endocr. Metab. 1956, 16, 1137. 10.
Hypothesis FREE FATTY ACIDS, COMPLEMENT ACTIVATION, AND POLYCLONAL B-CELL STIMULATION AS FACTORS IN THE IMMUNOPATHOGENESIS OF AFRICAN
TRYPANOSOMIASIS I. R. TIZARD R. K. G. ASSOKU K. H. NIELSEN
Department of Veterinary Microbiology and Immunology, University of Guelph, Ontario, Canada
hyperplasia.
Summary
Our work suggests that the only way of defining adequate treatment is by the restoration of A.C.T.H. levels to normal. We accept that this may be difficult to achieve and that secondary hyperplasia may not be of consequence to the patient with Addison’s disease. Whether control would be beneficial to the patient is impossible to know, because it has never been attempted. However, it may be of importance in the genesis of Nelson’s syndrome-a combination of raised A.C.T.H. concentrations, skin pigmentation, and obvious pituitary tumour following bilateral adrenalectomy. In all with bilateral adrenalecpatients Cushing’s syndrome tomy is followed by a rise in A.c.T.H. levels,2 and we suggest that this is the result of pituitary hyperplasia resulting from inadequate replacement therapy.
panosomiasis are characterised by sustained hypocomplementæmia, gross hypergammaglobulinæmia M, and profound immunosuppression. It is suggested that this hypocomplementæmia is probably due to the action of a trypanosome-derived complement-activating factor and that the elevated IgM levels may be the combined result of this decomplementation, together with a subsequent failure of the normal IgM-to-IgG antibody switch mechanism and polyclonal B-lymphocyte activation by a trypanosome-generated mitogen The immunosuppression in this disease may be a result of the collective immunosuppressive effects of trypanosome-derived immune-modulating free fatty acids, polyclonally stimulating B-cell mitogen, and complementactivating factors.
Human and animal forms of African try-
957 INTRODUCTION
THERE is much interest in both the human and animal forms of African trypanosomiasis, not only because of their great economic and public-health importance but also because they are elegant natural disease models for the elucidation of the homoeostatic and regulatory mechanisms of antibody biosynthesis,l immunosuppression in parasitic infections,2,3 and parasite survival in the immunised host. 2,4 These diseases vary according to the species of trypanosome and differences between hosts, but all are characterised by numerous aberrations in functions of the immune system,5 some of the most important being a sustained hypocomplementaemia,6-9 considerably elevated IgM,10-13 a dramatic reduction in IgA and IgE,14 and profound immunosuppression.15-18 The mechanisms underlying these immunological abnormalities and their role in the immunopathogenesis of trypanosome infections have not yet been elucidated, but recent studies suggest a link between the hypocomplementxmia, hypermacroglobulinaemia, and immunological hyporesponsiveness in this disease syndrome. We believe that a combination of the effects of free fatty acids,19-21 complement-activating factors,22-24 and B-cell mitogenic factors,25.26 all generated by the infecting trypanosomes, cause many of the aberrations of the immune system observed in trypanosomiasis. FREE FATTY ACIDS, DISRUPTION OF LYMPHOID-ORGAN ARCHITECTURE, AND IMMUNOSUPPRESSION
We have recently drawn attention to the remarkable resemblance between the immunopathological lesions induced by administration of free fatty acids (F.F.A.) and those observed in trypanosomiasis.2’ F.F.A., both saturated and unsaturated, can significantly modify the immune response,28,29 and several are immunosuppressive.28,30-32 Linoleic acid (C18:2), which has been most extensively studied, can prolong kidney allograft survival in man33 and skin allograft survival in mice34 and rats.3’ Linoleic and arachidonic (C20:4) acids have also been shown to disrupt the architecture of the lymphoid organs in vivo,29 and there is evidence that these F.F.A. may also induce an in-vivo immunosuppressive effect, either by blocking lymphocyte reactivity to mitogens31 or antigens32 or through the production of potent im-
munosuppressive prostaglandins.36,37 Since the in-vivo immunosuppressive effect of F.F.A. can be prevented by splenectomy,38 this may indicate induction of the suppressor-cell population. Jayawardena and Waksman39 have presented evidence that suppressor cells are involved in the suppression of immunity in trypanosomiasis. of
Relatively large quantities (mostly stearic, linoleic, palmitic, and oleic acids) are generated by autolysing trypanosomes.19-21 These F.F.A. are potently cytotoxic and haemolytic in vitro. Since trypanosomes tend to aggregate in dense clusters within capillary beds40 and F.F.A.
may reside in microenvironmental locations within the lymphoid organs,41,42 it is postulated that the immunosuppression and the structural disturbances in these organs in trypanosomiasis42.43 may be partly accounted for by the release of F.F.A. from the various parasitsemic waves of trypanosomes autolysing in vivo which may reach relatively high concentrations in these areas. Although serum-albumin binds fatty acids and largely
neutralises their membrane activity both in vivo and in vitro,44,45 it is possible that this is of reduced significance in trypanosomiasis because of the reasons given above, and also because animals and patients with trypanosomiasis are usually severely hypoalbuminoemic .46 The immunopathological lesions in trypanosomiasis closely resemble those induced by F.F.A. administration. They include disruption of spleen and lymph-node architecture,41-43 depression of the immune responses of lymphocytes to specific antigen4’ and mitogen,17 and evidence for the participation of a population of suppressor cells.39 We therefore suggest that one of the pathogenetic mechanisms of immunosuppression in trypanosomiasis involves the active participation of free fatty acids generated in the host lymphoid microvasculature by autolysing trypanosomes. COMPLEMENT ACTIVATION, HYPOCOMPLEMENTaeMIA, AND IMMUNOSUPPRESSION
One of the commonest immunochemical features of both human and animal trypanosomiasis is a sustained hypocomplementaemia.6-8.48 In addition, the constant finding of concomitant severely depressed C3,’’" C1,9 and properdin9 levels, the appearance of high immunoconglutinin 49 and complement-fixing antitrypanosome antibody,13 and the demonstration of direct activation of (22.24 and C350 in vitro by autolysing trypanosomes are strongly suggestive of the probable activation of complement by both the alternative and the classical pathways in trypanosomiasis. The disease has also been characterised by aberrations in the levels of other serum-proteins.l0-14 Thus, any explanation of the immunosuppression seen in trypanosomiasis is complicated by the concomitant high levels of both specific and non-specific IgM 12 and greatly decreased IgA and IgE levels.14 The immunosuppressive effect of complement activation and hypocomplementaemia has been shown by the demonstration that animals deprived of C3 by injection of cobra-venom factor are only able to mount immune
consisting mainly of IgM,51 and they also have greatly reduced ability to respond to thymus-dependent antigens.52,53 In addition, complement-depleted animals have been shown by Pepys and colleagues54.55 to have greatly reduced IgA54 and IgE55 responses. We therefore suggest that the sustained hypocomplementaemia in patients with African trypanosomiasis is likely to lead to the suppression of IgG, IgA, and IgE production and the disruption of the homoeostatic control of IgM production, resulting in excess biosynthesis of IgM. Indeed, deprivation of complement in animals may lead to failure of the normal IgM-to-IgG antibody switch mechresponses a
anism.sl,56
Complement depletion also has a disorganising effect on lymphoid tissues and the processing of antigens .54,-17 Excess proliferation of plasma-cells and disruption of thymus-dependent areas of lymphoid organs have been noted in African trypanosomiasis.41-43,58 Indeed, such disruption or disorganisation of lymphoid organs in trypanosomiasis, it has been suggested, may interfere with T and B cell cooperation in the immune response.42.58 Regardless of the precise mechanisms involved in trypanosome-induced immunosuppression, we believe that activation of complement may be an important effector arm of this phenomenon and that the observed hypocomplementxmia could account, at least in part, for the immunosuppression described in trypanosomiasis.
958 POLYCLONAL B-CELL
ACTIVATION, ELEVATED IgM LEVELS,
AND IMMUNOSUPPRESSION
A paradoxical finding which has greatly contributed the difficulty in the elucidation of iminunosuppression in African trypanosomiasis is the simultaneous association of a highly active immunological and mononuclear phagocytic system42.43 with an immunosuppressed state to other anigens.4.18 One of the most attractive hypotheses advanced to explain this has been that B cells capable of recognising the introduced antigen may be depleted as a result of polyclonal B-cell activation.4.16,18.25.26 Recent reports have stressed the close functional and causal relationship between the high IgM levels, probable polyclonal B-cell activation, and immunosuppression in African trypanosomiasis.4.25.26.58 Whether a trypanosome-derived mitogen plays a significant part in the immunosuppression, as well as in a spontaneous polyclonal B-cell response in this disease, has yet to be unequivocally established. Nevertheless, there is increasing evidence that a trypanosome-derived B-cell mitogen stimulates B-cell clones to differentiate,4.5.25.26 resulting not only in unregulated clonal expansion and secretion of immunoglobulins with numerous specificities but also in clonal exhaustion and/or paralysis, so that the induction of specific antibody responses is severely depressed. Proof of the existence of such a trypanosome-derived mitogen would undoubtedly have enormous implications for understanding the basis of immune-system dysfunction in the disease. Lately, we have obtained evidence for the generation of a potent B-cell mitogen by autolysing trypanosomes,26 thus confirming the findings of Esuruoso.25 Like Urquhart and colleagues,16 Greenwood and Whittle,8 Esuruoso,25 and Hudson and co-workers,44 we believe that some of the immunological dysfunctions in trypanosomiasis, particularly the immunosuppression and concomitant synthesis of high levels of specific and non-specific IgM immunoglobulins, might be associated with this elaboration of a B-cell mitogen by the parasite.26 This hypothesis would also explain the background IgM responses to the many antigens, recognisable by B cells, which are greatly increased in
to
trypanosomiasis.4 We therefore postulate that trypanosome infection induces polyclonal B-cell activation which, in the presence of continuous and successive waves of blood parasitsemia, is likely to result in a progressive depletion of antigen-reactive B lymphocytes, since these cells would then be activated to change into secretor cells. In this way the immunosuppression in trypanosome infections may also be partially accounted for by the depletion of B cells capable of recognising the introduced antigen. Indeed, a number of B-cell mitogens completely suppress primary immune responses in vivo to sheep erythrocytes.59 If, however, both activation and immunosuppression were polyclonal, it would be expected that the antibody responses to later-appearing trypanosome antigenic variwould also be impaired. Recent support to this view. ants
findings4lend some
The overall mechanisms by which trypanosomes influence the host immune system are obviously complex, and more direct evidence is needed. Nevertheless, from the available data it is a reasonable working hypothesis that the immunoregulatory and immunopathogenic effects of the hypocomplementaemia, high IgM levels,
and immunosuppression in trypanosomiasis are causally linked. We suggest that immunosuppression in this syndrome is the result of the collective immunosuppressive effects of trypanosome-derived immune-modulating free fatty acids, polyclonally stimulating B-cell mitogen, and complement-activating factors. This work is
supported by the International Development Research
Centre, Canada. R. K. G. A. is on sabbatical leave from the University of Ghana.
Requests for reprints should be addressed to 1. R. T. REFERENCES 1. Cohen, S., Sadun, E. H. Immunology of Parasite Infections. Oxford, 1976. 2. Parasites in the Immunized Host: Mechanisms of Survival. Ciba Fdn Symp. 25, new series. Amsterdam, 1974. 3. Neal, R. A., Garnham, P. C., Cohen, S. Br. med. Bull. 1969,25,194. 4. Hudson, D. M., Byner, C., Freeman, J., Terry, R. J. Nature, 1976, 264, 256. 5. Mansfield, J. M., Craig, S. A., Stelzer, G. T. Infect. Immun. 1976, 14, 976. 6. Nagle, R. B., Ward, P. A., Lindsley, H. B., Sadun, E. H., Johnson, A. J., Berkow, R. E., Hildebrandt, P. K. Am. J. trop. Med. Hyg. 1974, 33, 15. 7. Jarvinen, J. A., Dalmasso, A. P. Infect. Immun. 1976, 14, 894. 8. Greenwood, B. M., Whittle, H. C. Clin. exp. Immun. 1976, 24, 133. 9. Nielsen, K. H., Sheppard, J., Holmes, W., Tizard, I. R. Unpublished. 10. Houba, V., Brown, K. N., Allison, A. C. Clin. exp. Immun. 1969, 4, 113. 11. Freeman, T., Smithers, S. R., Targett, G. A. T., Walker, P. J. J. infect. Dis.
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the press).
Nielsen, K. H., Sheppard, J., Tizard, I. R., Holmes, W. L. J. Parasit. (in the press). 25. Esuruoso, G. O. Clin. exp. Immun. 1976, 23, 314. 26. Assoku, R. K. G., Tizard, I. R. Experientia (in the press). 27. Tizard, I. R., Nielsen, K. H., Mellors, A., Assoku, R. K. G. Lancet, 1977, i, 750.
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trop. Med. Hyg. 1973, 67, 329. 49. Ingram, D. G., Soltys, M. S. Parasitology, 1960, 50, 50. Kierszenbaum, F., Weinman, D. Immunology, 1977,
231. 32, 245.
959
pharmacologists. The past decade, however, has seen an awakening of interest in the condition and an improvement in both the quantity and the quality of research. Many important and interesting, but still unsolved, problems connected with the disease have emerged, and its economic and financial consequences are only now beginning to be understood. Moreover, the emergence of penicillin-resistant, -lactamase-producing gonococci has called into question world-wide antibiotic policies, especially the ease with which antibiotics can be obtained without prescription in many countries. This excellent book contains most of what is known of the subject. It is invaluable for all those who treat patients with sexually transmitted diseases, and should be read by postgraduate students in this subject ; it is also an excellent reference book for epidemiologists, physicians in other branches of medicine, and microbiologists. The text is precise, clearly written, and lightened from time to time by Dr Morton’s attractive sense of humour; besides being easy to read it is illustrated by helpful photographs and tables. Each chapter ends with a full list of references. The best sections of the book are those on the history of gonorrhoea, gonococcal septicaemia, and the size and nature of the problem gonorrhoea poses. In his concluding chapter on the control of gonorrhoea, Morton is pessimistic; he believes that modem social, behavioural, and medical trends will result in a high prevalence of the disease for the rest of this century at least. Politicians, health administrators, and all those who plan and
Reviews of Books
Abortion MALCOLM POTTS, PETER DIGGORV, and JOHN PEEL. London and New York. Cambridge University Press. 1977. Pp. 575. 17.50
(paperback 3.95). THIS is a valuable and extensive review of abortion throughout the world and over the course of time. It has a British bias because of the origin of the authors; the sociological evidence is interesting and well analysed; and the book has a uniformity of style and approach. Those who have followed the abortion debate will know from the names of the authors the sort of conclusions which will be reached. They have convinced themselves of the necessity for abortion, judiciously used with contraception, and they wish to convince others of the validity of their case, stated in elaborate detail which is difficult to find in summary elsewhere. Their case is convincing, though that will not be conceded by everyone. They try hard to do justice to their opponents, but Roman Catholic theologians and some doctors are criticised severely, and sometimes with conscious cleverness. This will not rout the dissenters who, nevertheless, should listen to this generally well argued exegesis. Abortion has been used by all societies. It has been, and is a problem which will not go away. Whether society, through its legislators, lawyers, doctors, and moralists, welcomes termination of pregnancy or rejects it is of small consequence. Many women and their helpers have made their decisions known in action, and the evidence is clearly documented here that abortion will probably remain a feature of fertility control for some time to come. The reader can like it or lump it, but if at the moment he can only lump it because of what, to him, are important ethical considerations, then this book may help him to define those more closely and compare them with those of others. There is fodder for all sides of the argument, but interpretation depends on many inexplicit factors not necessarily amenable to reason. Sir Thomas Browne might be allowed the last word on what it is all about. "As Reason is a Rebel unto Faith, so Passion unto Reason: as the propositions of Faith seem absurd unto Reason, so the Theorems of Reason unto Passion, and both unto Reason". Exactly. So the debate must continue, but with the hope that it will be conducted at the high level of tolerance shown in this book. The authors’ bouts of passionate polemic, comparatively rare, might be overlooked in the same spirit.
Gonorrhcea R. S. MORTON, F.R.C.P.E., The Royal Infirmary, Sheffield. London and Philadelphia: Saunders. 1977. Pp 292. [,10.
has risen
the past twenty than 250 000 000 mfections with gonorrhoea a year throughout the world. Control measures have clearly failed. The disease has, until lately, THE incidence of
gonorrhoea
years and it is estimated that there
been neglected by
over
are more
physicians, microbiologists, epidemiologists,
51 Nielsen, K.H., White, R.G.Nature, 1974, 250, 234. 52 Pepys, M. B. ibid. 1972, 237, 157 53 Pepys, M.B J. exp.Med. 1974, 140, 126. 54 Pepys, M.B. Transplantn Rev. 1976, 32, 93. 55 Pepys, M. B., Brighton, W. D., Hewitt, B. E., Bryant, D. E., Pepys, J. Clin. exp.Immun.1977, 27, 397. 56 Crane, C. G., Rowley, M. J., Warburton, M. F., Mackay, I. R. Clin. Sci. 1972, 43, 869. 57 Papamichail, M., Gutierrez, C., Embling, P., Johnson, P., Holborow, E. J., Pepys, M.B.Scand. J.Immun. 1975, 4, 343. 58 Terry, R. J., Freeman, J., Hudson, K. M., Longstaffe, J. A. Trans. R. Soc. trop Med.Hyg. 1973, 67, 263. 59 Diamantstein, T., Keppler, W., Blitstein-Willinger, E., Ben-Effraim, S. Immunology, 1976, 30, 401.
health-care services should heed his words and ensure that modern facilities for diagnosis and treatment are available, including contact tracing and improved health education.
Medical Selection of Life Risks R. D. C.
1977.
BRACKENRIDGE,
F.R.C.P.E.
London: Undershaft Press.
Pp. 765.[15.
WHILST most doctors frequently fill up forms on their patients for the benefit of life-insurance schemes, few have much idea of what happens next-or how the risk is calculated. The insurance companies turn in healthy profits and few become bankrupt, so their methods must be efficient from a business point of view. Dr Brackenridge’s survey of the medical side of life insurance is an up-to-date and well-written account of how risk is calculated. Since his first review 15 years ago the results of many long-term epidemiological studies concerned with mortality risk have made a reference manual for the insurance medical officer a necessity-and this book is it. However, it is also relevant to other disciplines. The first part of the book deals with the principles of selection and the rating systems used by insurance medical officers on "substandard" lives. The second part provides a detailed analysis of the prognosis of a wide spectrum of treated and untreated disease-each section ending with practical advice to the examining doctor as to how to assess the risk. Despite the fact that there is a measurable difference between the mortality of "insured lives" (upon which most of the vital statistics presented are based) and that of the general population, the book provides a useful reference for people concerned with prospective surveys of mortality and morbidity and the review of world literature appears comprehensive. For this reason too, clinicians will find useful tables of prognostication to compare with their own experience and to help in advising patients and their relatives of the likely outcome of particular diagnosis and operations. The statistics apply to groups of patients, and the art is knowing how to apply them to the individual case. To help the clinician the author includes between the tables and the risk-rating paragraphs, good clinical sections on each disease, highlighting the prognostic features. His philosophy with regard to minor ailments and their relationship to the whole patient is stimulating and his attitude towards stress-related illness enlightened. The book is well presented; and the tables, with one or two exceptions, are easy to understand, and there is a comprehensive index.
