133 genome proliferate and give rise to stable lymphoblastoid cell lines in the laboratory.12 The proportion of cells with this remarkable capacity for replication is probably not high, since 105 to 106 lymph-node cells from an i.M. patient have to be cultured to obtain a cellline.13 Most of the lymphocyte proliferation in i.M. is by T cells14 and is
the
E.B.v.
stimulated by virus-determined antigens which appear on the surface of infected cells.15 The atypical lymphocytes are T cells and infection is normally followed by lifelong immunity and positive laboratory tests for cell-mediated responses to
E.B.V.16 In contrast, the cells which proliferate in the Duncan’s disease patients with Burkitt’s lymphoma or plasmacytoma belong to the B series. Their behaviour is similar to E.B.v.-infected cell lines and, after several years, some of the cells become truly malignant." It is tempting to conclude that this progression results from the failure of T cells to control the E.B.v.-genome-containing B cells}8 The absence of any previous susceptibility to candidiasis or other infections which typically occur in patients with defective cell-mediated immunity is evidence against a pre-existing generalised defect of T cells in the boys with Duncan’s disease. Indeed, the observation of atypical lymphocytes in their blood during the early phases of the illness suggests that they do possess T cells capable of recognising E.B.v. The Duncan hyporesponsiveness to E.B.v. is also unlikely to result from the lack of a putative immune-response gene
(these
genes
are
currently
thought determine the behaviour of macrophages) since in other animals Ir genes are coded-for close to histocompatibility loci, on an autosomal chromosome.2 Abnormal function of B cells is suggested by the patients’ failure to make antibodies to the E.B.v. early antigen or to the viral capsid, although their serum reacted positively in the nonE.B.v.-specific heterophile-antibody test.’ Since the E.B.V. infection is primarily of B cells this defect could well be secondary. One possibility which might be explored is that affected boys have a genetically determined failure to express the lymphocyte-defined membrane antigen,19 which is the target for sensitised T cells. A failure to make B cells bearing specialised surface receptors seems to cause the X-linked immunodeficiency of CBA(N) mice,2o so there is a precedent for an X-chromosome contribution to B-lymphocyte surface antigens. to
12. Nilsson, K., Ponten, J. Int. J. Cancer, 1975, 15, 321. 13. Bechet, J. M., Nilsson, K., Ponten, J. ibid. 1973, 11, 58. 14. Sheldon, P. J., Papamichael, M., Hemsted, E. H., Holborow, E.
J. Lancet, 1973, i, 1153. 15. Rickinson, A. B., Crawford, D., Epstein, M. A. Clin. exp. Immun. 1977, 28, 72.
16. Periman, P., Levine, P. H., Ablashi, D. V.,
Royston, I. Int. J. Cancer, 1977, 20, 506. 17. Nilsson, K., Giovanella, B. G., Stehlin, J. S., Klein, G. ibid. 1977, 19, 337. 18. Thorsley-Lawton, D. A., Chess, L., Strominger, J. L. J. exp. Med. 1977, 146, 495.
19. Jondal, M. Clin. exp. Immun. 1976, 25, 1. 20. Cantor, H., Boyse, E. A. Immun. Rev. 1977, 33, 105.
COMMUNICATING ADVERSE DRUG REACTIONS
164, Dr Burland comments on the publication correspondence columns of isolated case-reports drug side-effects and he suggests that we should modify this practice. Some of his colleagues in the pharmaceutical industry have gone further and complain that The Lancet has double standards-requiring rigorous proof of the efficacy of a drug while flimsy evidence is accepted when a drug’s safety is called into question. But this is not to compare like with like. A well-designed clinical trial can yield convincing data on efficacy even when the number of patients is small and the period of study short. Most patients, even those on placebo, respond one way or another, however slightly, in a clinical trial; but side-effects are rare. The dangers of practolol are no indictment of the quality of the clinical trials done with this drug; in a recent trial of disopyramide urinary retention was not significantly more common in the treated patients, but it now seems to be a real adverse reaction; problems with perhexiline maleate, the subject of a Committee on Safety of Medicines warning, first emerged at the anecdotal level. Various methods for monitoring newly released drugs and the application of epidemiological tools to measurement of side-effects are being discussed, and maybe we shall soon be able to study adverse reactions with the precision with which efficacy can be tested. But there will always be an interval between the availability of a drug and the publication of a study on it by, say, the Boston Collaborative Drug Surveillance Programme. Official bodies (the Committee on Safety of Medicines in the U.K.) will, quite rightly, issue a formal warning to doctors only when they are sure. A letter reporting a drug reaction often draws similar reports, and the side-effect is rapidly ON p.
in of
our
confirmed. Sometimes there is no confirmation; and publication of such reports, the industry argues, is unfair because the stigma remains. On the whole, though, the human cost of suppressing an early hint is greater than that of publicising an association that turns out to be invalid.
NEW CELLS FOR OLD
THE remarkable regenerative capacity of the liver after acute hepatic necrosis has encouraged development of biological and artificial systems for temporary hepatic support. Even in the most severe cases where the lobular architecture is so distorted as to mimic cirrhosis, regeneration and remodelling can almost completely restore liver structure and function. Indeed, after recovery from fulminant hepatic failure progression to cirrhosis is remarkably rare.2 Although the long-term outlook is so good, the harsh reality is that about 90% of patients with hepatic necrosis severe enough to be associated with grade-IV hepatic coma die in the acute phase of their illness,3-5 either before effective regeneration has begun or because there are no surviving liver cells from 1.
Portmann, B., Talbot, K., Day, D. W., Davidson, A. R., Murray-Lyon, I. M., Williams, R. J. Path. 1975, 117, 169. 2. Karvountzis, G. G., Redeker, A. G., Peters, R. L. Gastroenterology, 1974, 67, 870. 3. Benhamou, J. P., Rueff, B., Sicot,.C. Rev. fr. Etud. clin. biol. 1968, 12, 651. 4. Trey, C., Davidson, C. S. in Progress in Liver Disease (edited by H. Popper and F. Schaffner); vol. III, p. 282. New York, 1970. 5. Saunders, S., Hickman, R., MacDonald, R., Terblanche, J. ibid. vol. IV, p.333. New York, 1972.
the
E.B.v.
stimulated by virus-determined antigens which appear on the surface of infected cells.15 The atypical lymphocytes are T cells and infection is normally followed by lifelong immunity and positive laboratory tests for cell-mediated responses to
E.B.V.16 In contrast, the cells which proliferate in the Duncan’s disease patients with Burkitt’s lymphoma or plasmacytoma belong to the B series. Their behaviour is similar to E.B.v.-infected cell lines and, after several years, some of the cells become truly malignant." It is tempting to conclude that this progression results from the failure of T cells to control the E.B.v.-genome-containing B cells}8 The absence of any previous susceptibility to candidiasis or other infections which typically occur in patients with defective cell-mediated immunity is evidence against a pre-existing generalised defect of T cells in the boys with Duncan’s disease. Indeed, the observation of atypical lymphocytes in their blood during the early phases of the illness suggests that they do possess T cells capable of recognising E.B.v. The Duncan hyporesponsiveness to E.B.v. is also unlikely to result from the lack of a putative immune-response gene
(these
genes
are
currently
thought determine the behaviour of macrophages) since in other animals Ir genes are coded-for close to histocompatibility loci, on an autosomal chromosome.2 Abnormal function of B cells is suggested by the patients’ failure to make antibodies to the E.B.v. early antigen or to the viral capsid, although their serum reacted positively in the nonE.B.v.-specific heterophile-antibody test.’ Since the E.B.V. infection is primarily of B cells this defect could well be secondary. One possibility which might be explored is that affected boys have a genetically determined failure to express the lymphocyte-defined membrane antigen,19 which is the target for sensitised T cells. A failure to make B cells bearing specialised surface receptors seems to cause the X-linked immunodeficiency of CBA(N) mice,2o so there is a precedent for an X-chromosome contribution to B-lymphocyte surface antigens. to
12. Nilsson, K., Ponten, J. Int. J. Cancer, 1975, 15, 321. 13. Bechet, J. M., Nilsson, K., Ponten, J. ibid. 1973, 11, 58. 14. Sheldon, P. J., Papamichael, M., Hemsted, E. H., Holborow, E.
J. Lancet, 1973, i, 1153. 15. Rickinson, A. B., Crawford, D., Epstein, M. A. Clin. exp. Immun. 1977, 28, 72.
16. Periman, P., Levine, P. H., Ablashi, D. V.,
Royston, I. Int. J. Cancer, 1977, 20, 506. 17. Nilsson, K., Giovanella, B. G., Stehlin, J. S., Klein, G. ibid. 1977, 19, 337. 18. Thorsley-Lawton, D. A., Chess, L., Strominger, J. L. J. exp. Med. 1977, 146, 495.
19. Jondal, M. Clin. exp. Immun. 1976, 25, 1. 20. Cantor, H., Boyse, E. A. Immun. Rev. 1977, 33, 105.
COMMUNICATING ADVERSE DRUG REACTIONS
164, Dr Burland comments on the publication correspondence columns of isolated case-reports drug side-effects and he suggests that we should modify this practice. Some of his colleagues in the pharmaceutical industry have gone further and complain that The Lancet has double standards-requiring rigorous proof of the efficacy of a drug while flimsy evidence is accepted when a drug’s safety is called into question. But this is not to compare like with like. A well-designed clinical trial can yield convincing data on efficacy even when the number of patients is small and the period of study short. Most patients, even those on placebo, respond one way or another, however slightly, in a clinical trial; but side-effects are rare. The dangers of practolol are no indictment of the quality of the clinical trials done with this drug; in a recent trial of disopyramide urinary retention was not significantly more common in the treated patients, but it now seems to be a real adverse reaction; problems with perhexiline maleate, the subject of a Committee on Safety of Medicines warning, first emerged at the anecdotal level. Various methods for monitoring newly released drugs and the application of epidemiological tools to measurement of side-effects are being discussed, and maybe we shall soon be able to study adverse reactions with the precision with which efficacy can be tested. But there will always be an interval between the availability of a drug and the publication of a study on it by, say, the Boston Collaborative Drug Surveillance Programme. Official bodies (the Committee on Safety of Medicines in the U.K.) will, quite rightly, issue a formal warning to doctors only when they are sure. A letter reporting a drug reaction often draws similar reports, and the side-effect is rapidly ON p.
in of
our
confirmed. Sometimes there is no confirmation; and publication of such reports, the industry argues, is unfair because the stigma remains. On the whole, though, the human cost of suppressing an early hint is greater than that of publicising an association that turns out to be invalid.
NEW CELLS FOR OLD
THE remarkable regenerative capacity of the liver after acute hepatic necrosis has encouraged development of biological and artificial systems for temporary hepatic support. Even in the most severe cases where the lobular architecture is so distorted as to mimic cirrhosis, regeneration and remodelling can almost completely restore liver structure and function. Indeed, after recovery from fulminant hepatic failure progression to cirrhosis is remarkably rare.2 Although the long-term outlook is so good, the harsh reality is that about 90% of patients with hepatic necrosis severe enough to be associated with grade-IV hepatic coma die in the acute phase of their illness,3-5 either before effective regeneration has begun or because there are no surviving liver cells from 1.
Portmann, B., Talbot, K., Day, D. W., Davidson, A. R., Murray-Lyon, I. M., Williams, R. J. Path. 1975, 117, 169. 2. Karvountzis, G. G., Redeker, A. G., Peters, R. L. Gastroenterology, 1974, 67, 870. 3. Benhamou, J. P., Rueff, B., Sicot,.C. Rev. fr. Etud. clin. biol. 1968, 12, 651. 4. Trey, C., Davidson, C. S. in Progress in Liver Disease (edited by H. Popper and F. Schaffner); vol. III, p. 282. New York, 1970. 5. Saunders, S., Hickman, R., MacDonald, R., Terblanche, J. ibid. vol. IV, p.333. New York, 1972.
