771
patient has latent c.M.v., immunosuppressive treatment after renal transplantation is likely to reactivate it: virus excretion is commoner in patients who were seropositive before transplanIf
a
tation than in those who were not. However, the severe symptoms tend to result from primary infection rather than reactivation, 1-3 7 8 and there is strong circumstantial evidence that the most common source of this primary infection is the donated kidney.2 3 78 Admittedly, sporadic attempts to isolate c.M.v. from the grafted kidney have been unsuccessful. But this is not very surprising : latent herpes-simplex viruses cannot be isolated from dorsal-root ganglia which are known to harbour them, without virus-rescue techniques such as organ culture and co-cultivation.10 11 In Pittsburgh, Ho8 and colleagues detected c.M.v. infection in 10 of 12 seronegative patients given the kidneys of seropositive donors, but in only 3 of 10 given the kidneys of seronegative donors. In Rochester, N.Y., c.M.v. infection, often severe, arose in all of 16 seronegative patients transplanted with kidneys from seropositive donors; by contrast no c.M.v. infections arose in 24 seronegative patients given kidneys from seronegative donors.A further pointer to the kidney as the source of c.M.v. infection is the presence of c.M.v. antibody in the urine of non-proteinuric transplant patients excreting c.M.v. The urine did not contain antibody to other herpes viruses present at the same level in serum,12 so these findings are compatible with local synthesis of antibody associated with replication of C.M.V. in the transplanted kidney. Several dialysis/ transplant units are now screening recipients and donors to ensure that, whenever possible, a seronegative recipient does not receive a kidney from a seropositive donor. Immunofluorescence tests are greatly preferable to the more commonly employed but less sensitive complement-fixation (C.F.) test; commercial c.F. antigens vary considerably in their potency. The more convenient ELISA is potentially useful but unproved. What about screening of blood before transfusion ? Seropositive healthy donors’ blood may contain c.M.v., and infection by c.M.v. is a wellknown hazard after cardiopulmonary bypass operations. 13 14 But cardiac patients are given large volumes of fresh blood, whereas kidney patients tend to receive banked blood. c.M.v. is very rarely detectable in banked blood,15 16 and there is no cor7. Betts, R.
F., Freeman, R. B., Douglas, R. G., Jr., Talley, T. E. Am. J. Dis. 131, 759 8. Ho, M., Suwansirikul, S., Dowling, J. N., Youngblood, L. A., Armstrong, Child. 1977,
J. A. New Engl. JMed. 1975, 293, 1109. Lopez, C., Simmons, R. L., Mauer, S. M., Najarian, J. S., Good, R. A., Gentry, S. Am J. Med. 1974, 56, 280. 10. Stevens, J.C, Cook, M. L. Science, 1971, 173, 843. 11. Bastian, F. O., Rabson, A. S., Yee, C. L. Science, 1972, 178, 306. 12. Mustani, M., Zerbini, M., Fatone, F., Feletti, C., Bonomini, V., La Placa, M. J. med. Microbiol. 1977, 10, 473. 13. Kääriäinen, L., Klemola, E., Paloheimo, J. Br. med. J. 1966, i, 1270. 14 Lang, D. J, Scolnick, E. M., Willerson, J. T. New Engl. J. Med. 1968, 278, 9.
1147.
15
Mirkovic, R., Werch, J., South, 1971, 3, 45.
M. A,
Benyesh-Melnick, M.Infect. Immun.
infection and the number given during or after renal trans4 8 16 Nevertheless, it is possible that plantation.3 transfusion of foreign cells may initiate a host-versus-graft response, or that donated leucocytes may initiate a graft-versus-host response, which in turn activate latent c.M.v. Some of the above potential hazards might be reduced by giving only leucocytedepleted blood to renal-allograft recipients. Although screening is likely to result in a reduction in morbidity associated with primary c.M.v. infections, there is more difficulty in predicting whether such a programme will reduce allograft rejection. Thus, although many c.M.v. infections coincide with rejection episodes, it is not clear whether relation between of units of blood
c.M.v.
c.M.v.
triggers rejection (perhaps by potentiating
the host’s immune response)
whether the hostversus-graft response, which arises to some extent in almost - every patient, reactivates or enhances c.M.v. Studies in mice suggest that c.M.v. infection is in itself immunosuppressive: 17 mice chronically infected with murine c.nt.v. show enhanced virus titres when given skin allografts. 18 Perhaps answers to some of these questions will emerge from the prospective studies now being conducted in England19 and the U.S.A., in which morbidity, including the frequency of rejection episodes, and mortality will be determined in seronegative patients given an attenuated c.M.v. vaccine before transplantation. American patients have had satisfactory humoral and cell-mediated immune responses to the vaccine without systemic reactions or abnormal laboratory findings, and 6 vaccinated patients have so far received renal transplants, 3 from seropositive donors. 2 of these 3 recipients have subsequently excreted c.M.v., but restrictionenzyme studies reveal that the viruses were not the vaccine strains .2’ This suggests that, in immunosuppressed patients, c.M.v. vaccines may not confer absolute protection. It is quite possible however, that vaccination will prevent the more serious manifestations associated with primary infection. or
CLOUDS OVER PAEDIATRIC RESEARCH RESEARCH-WORKERS are troubled by the legality of controlled experiments in paediatrics; they cannot have had much relief from what they heard during a symposium at the Institute of Child Health last week. True; the academic lawyers seemed willing to go along with research-work in children as now practised. Dr P. D. Skegg, for instance, repeated his view that, in the matter of informed consent, parents can speak for their children (or the child for itself in certain circumstances); further16 Pien, F. D., Smith, T. F., Anderson, C F., Webel, M.
Transplantation, 1973, 16, 489. 17. Howard, R. J., Miller, J., Najarian, J. S Clin. exp 18. Wu, B C., Dowling, J N., Armstrong, J. A., Ho, 56. 19. Stern, H. Unpublished 20 Plotkin, S A. Paper read
at
Fourth International
Hague, Aug. 30-Sept. 6, 1978
L, Taswell,
H. F.
Immun 1974, 18, 119. M Science, 1975, 190,
Congress
for
Virology, The
772
his paper had raised no eyebrows among fellow academic lawyers at Oxford. But there was no word from that wary caucus who, in the absence of statute and case-law on the matter, argue that possession of parental consent to a reasonable research procedure on a child would be no guarantee were a research-worker to be sued for assault. Yet it is this opinion, passed on by the Medical Research Council, the defence unions, and the Department of Health, which has caused all the uncertainty. The M.R.C. sometimes sticks to the letter of its own advice. One project involving the monitoring of normal growth by wrist X-rays at low millirad doses had to be abandoned. Another speaker asked if, when biological fluid was sampled for a diagnostic purpose, it was permissible to withdraw a little bit more for tests unrelated to the management of that child’s illness. The M.R.C. answer to this seems unclear. For a child below the age of twelve years "... information requiring the performance of any procedure involving his body would need to be obtained incidentally to and without altering the nature of a procedure intended for his individual benefit".2 Yet do workers in the Council’s own units pay attention to these strictures all the time? Society wants research into childhood illness and the study of normal children to continue. Research-workers are mindful of their responsibilities and of the essential role in all this of the patient’strust, though Dr T. M. Barratt illustrated how, in multicentre trials, this doctor/patient relationship could be altered by restraints from outside. Nor should altruism be suppressed. But why should research-workers be asked to work under the threat that what they are doing may be illegal. What choices have we? Statute law? A non-starter said Mr Godfrey Carter, a Parliamentary counsel. Case law? Perhaps it will come to this,3 but whose head is for the block and on what particular issue is the test case to be decided? Ethical committees help but they have no legal force, nor are they consistent (D.H.S.S. advice on this matter4 is so confusing that this inconsistency is hardly surprising). A doctor in the Oxford region’ could not get approval to take blood from healthy children in their own homes; had she been working in London WC1 this obstacle might never have materialised. One speaker reported that an M.R.C. grant for a multicentre project might be withheld unless all the district ethical committees involved gave their approval. Codes are not legal documents either, though in the United States there is considerable agreement on draft regulations, with the force of Federal law, on research involving children.6 This development will be watched with great interest elsewhere, but even in the draft are obscure phrases such as "minor increase of minimal risk". Over the past few years there has been much discussion amongst lawyers and doctors about the legality of research on children, and the leading opinion on this is now more than fifteen years old. The Medical Research Council cannot itself rewrite a view that begins "In the strict view of the law...", but it could ask for a second
more
1. Skegg, P. D. Lancet, 1977, ii, 754. 2. Medical Research Council. Annual Report 1962-63 3. Lancet, 1977,1,1346. 4. D.H.S.S. Supervision of the Ethics of Clinical Research Fetal Research. HSC(IS)153.1975 5. Pratt, H. Lancet, 1977, i, 699. 6 Federal Register, vol 43, no. 141, July 21,1978.
Investigations and
If those asked feel unable to take into account the current academic view or the present arrangements for peer review and ethical scrutiny (including lay involvement), and repeat their former advice, then an attempt on the Statute Book seems warranted. However, an earlier Bill on aspects of this topic was described by one Queen’s counsel’ as demonstrating the "clumsiness of the law as a means of fine control of human endeavour".
opinion.
SUICIDE AND THE SAMARITANS avoidable and particularly distressing cause of death, suicide merits close attention in any society. Prevention of suicide offers a challenge, and despite the obvious reservations about the validity and consistency of the verdicts of coroner’s courts, the death registration process provides a rare opportunity of monitoring variations from place to place and from time to time. Existing evidence suggests that, in England and Wales at least, recent trends have been highly satisfactory, with a fall of about one-third in the recorded suicide-rates for both males and females between 1964 and 1970. A favourable pattern of this kind has not been observed in other countries and there has been a very natural tendency to look for features unique to England and Wales which might explain the observed results. Amongst the many candidates which have been put forward, the Samaritans have commanded the greatest support. Not only do the Samaritans aim specifically to help troubled people (of whom potential suicides represent a small minority) but also the organisation grew very rapidly during the very period when the dramatic fall in suicide-rates took place. The pattern of development of the Samaritans, involving the setting up of new branches in various cities and towns over several years, at first sight provides the opportunity for a "scientific" evaluation of the effectiveness of the service by comparison of changes in suiciderates in similar geographical areas with and without a branch of the Samaritans. The study by BagleyI in 1968 was the first to be carried out in these terms and has been described as a landmark in the history of social science.2 Bagley compared changes in suicide-rates in 15 pairs of towns in England and Wales, one town of each pair being served by the Samaritans whilst the second (control) town was chosen to be as similar as possible in other relevant respects to the first. He found a significant difference between the Samaritan and the control towns which suggested that the Samaritans were in fact effective in preventing suicide. Bagley’s hypothesis was retested by Barraclough and his colleagues34by the same general procedures but with more extensive data and different and more sophisticated methods of choosing control towns. The fact that Barraclough was unable to confirm Bagley’s results has led to considerable discussion. The apparent contradiction raises issues of wide interest in the context of research in the medical and social sciences, much of which must inevitably be As
a
potentially
7. Clothier, C. M. Lancet, 1977, i, 642. 1. Bagley, C. Soc Sci. Med. 1968, 2, 1. 2. Fox, R. R. Soc. Hlth J. 1975, 95, 9 3. Barraclough, B. M., Jennings, C., Moss, J. 4. Jennings, C., Barraclough, B. M., Moss,
R. Lancet, 1977, ii, 237. J. R. Psychol. Med. 1978, 8, 413.
patient has latent c.M.v., immunosuppressive treatment after renal transplantation is likely to reactivate it: virus excretion is commoner in patients who were seropositive before transplanIf
a
tation than in those who were not. However, the severe symptoms tend to result from primary infection rather than reactivation, 1-3 7 8 and there is strong circumstantial evidence that the most common source of this primary infection is the donated kidney.2 3 78 Admittedly, sporadic attempts to isolate c.M.v. from the grafted kidney have been unsuccessful. But this is not very surprising : latent herpes-simplex viruses cannot be isolated from dorsal-root ganglia which are known to harbour them, without virus-rescue techniques such as organ culture and co-cultivation.10 11 In Pittsburgh, Ho8 and colleagues detected c.M.v. infection in 10 of 12 seronegative patients given the kidneys of seropositive donors, but in only 3 of 10 given the kidneys of seronegative donors. In Rochester, N.Y., c.M.v. infection, often severe, arose in all of 16 seronegative patients transplanted with kidneys from seropositive donors; by contrast no c.M.v. infections arose in 24 seronegative patients given kidneys from seronegative donors.A further pointer to the kidney as the source of c.M.v. infection is the presence of c.M.v. antibody in the urine of non-proteinuric transplant patients excreting c.M.v. The urine did not contain antibody to other herpes viruses present at the same level in serum,12 so these findings are compatible with local synthesis of antibody associated with replication of C.M.V. in the transplanted kidney. Several dialysis/ transplant units are now screening recipients and donors to ensure that, whenever possible, a seronegative recipient does not receive a kidney from a seropositive donor. Immunofluorescence tests are greatly preferable to the more commonly employed but less sensitive complement-fixation (C.F.) test; commercial c.F. antigens vary considerably in their potency. The more convenient ELISA is potentially useful but unproved. What about screening of blood before transfusion ? Seropositive healthy donors’ blood may contain c.M.v., and infection by c.M.v. is a wellknown hazard after cardiopulmonary bypass operations. 13 14 But cardiac patients are given large volumes of fresh blood, whereas kidney patients tend to receive banked blood. c.M.v. is very rarely detectable in banked blood,15 16 and there is no cor7. Betts, R.
F., Freeman, R. B., Douglas, R. G., Jr., Talley, T. E. Am. J. Dis. 131, 759 8. Ho, M., Suwansirikul, S., Dowling, J. N., Youngblood, L. A., Armstrong, Child. 1977,
J. A. New Engl. JMed. 1975, 293, 1109. Lopez, C., Simmons, R. L., Mauer, S. M., Najarian, J. S., Good, R. A., Gentry, S. Am J. Med. 1974, 56, 280. 10. Stevens, J.C, Cook, M. L. Science, 1971, 173, 843. 11. Bastian, F. O., Rabson, A. S., Yee, C. L. Science, 1972, 178, 306. 12. Mustani, M., Zerbini, M., Fatone, F., Feletti, C., Bonomini, V., La Placa, M. J. med. Microbiol. 1977, 10, 473. 13. Kääriäinen, L., Klemola, E., Paloheimo, J. Br. med. J. 1966, i, 1270. 14 Lang, D. J, Scolnick, E. M., Willerson, J. T. New Engl. J. Med. 1968, 278, 9.
1147.
15
Mirkovic, R., Werch, J., South, 1971, 3, 45.
M. A,
Benyesh-Melnick, M.Infect. Immun.
infection and the number given during or after renal trans4 8 16 Nevertheless, it is possible that plantation.3 transfusion of foreign cells may initiate a host-versus-graft response, or that donated leucocytes may initiate a graft-versus-host response, which in turn activate latent c.M.v. Some of the above potential hazards might be reduced by giving only leucocytedepleted blood to renal-allograft recipients. Although screening is likely to result in a reduction in morbidity associated with primary c.M.v. infections, there is more difficulty in predicting whether such a programme will reduce allograft rejection. Thus, although many c.M.v. infections coincide with rejection episodes, it is not clear whether relation between of units of blood
c.M.v.
c.M.v.
triggers rejection (perhaps by potentiating
the host’s immune response)
whether the hostversus-graft response, which arises to some extent in almost - every patient, reactivates or enhances c.M.v. Studies in mice suggest that c.M.v. infection is in itself immunosuppressive: 17 mice chronically infected with murine c.nt.v. show enhanced virus titres when given skin allografts. 18 Perhaps answers to some of these questions will emerge from the prospective studies now being conducted in England19 and the U.S.A., in which morbidity, including the frequency of rejection episodes, and mortality will be determined in seronegative patients given an attenuated c.M.v. vaccine before transplantation. American patients have had satisfactory humoral and cell-mediated immune responses to the vaccine without systemic reactions or abnormal laboratory findings, and 6 vaccinated patients have so far received renal transplants, 3 from seropositive donors. 2 of these 3 recipients have subsequently excreted c.M.v., but restrictionenzyme studies reveal that the viruses were not the vaccine strains .2’ This suggests that, in immunosuppressed patients, c.M.v. vaccines may not confer absolute protection. It is quite possible however, that vaccination will prevent the more serious manifestations associated with primary infection. or
CLOUDS OVER PAEDIATRIC RESEARCH RESEARCH-WORKERS are troubled by the legality of controlled experiments in paediatrics; they cannot have had much relief from what they heard during a symposium at the Institute of Child Health last week. True; the academic lawyers seemed willing to go along with research-work in children as now practised. Dr P. D. Skegg, for instance, repeated his view that, in the matter of informed consent, parents can speak for their children (or the child for itself in certain circumstances); further16 Pien, F. D., Smith, T. F., Anderson, C F., Webel, M.
Transplantation, 1973, 16, 489. 17. Howard, R. J., Miller, J., Najarian, J. S Clin. exp 18. Wu, B C., Dowling, J N., Armstrong, J. A., Ho, 56. 19. Stern, H. Unpublished 20 Plotkin, S A. Paper read
at
Fourth International
Hague, Aug. 30-Sept. 6, 1978
L, Taswell,
H. F.
Immun 1974, 18, 119. M Science, 1975, 190,
Congress
for
Virology, The
772
his paper had raised no eyebrows among fellow academic lawyers at Oxford. But there was no word from that wary caucus who, in the absence of statute and case-law on the matter, argue that possession of parental consent to a reasonable research procedure on a child would be no guarantee were a research-worker to be sued for assault. Yet it is this opinion, passed on by the Medical Research Council, the defence unions, and the Department of Health, which has caused all the uncertainty. The M.R.C. sometimes sticks to the letter of its own advice. One project involving the monitoring of normal growth by wrist X-rays at low millirad doses had to be abandoned. Another speaker asked if, when biological fluid was sampled for a diagnostic purpose, it was permissible to withdraw a little bit more for tests unrelated to the management of that child’s illness. The M.R.C. answer to this seems unclear. For a child below the age of twelve years "... information requiring the performance of any procedure involving his body would need to be obtained incidentally to and without altering the nature of a procedure intended for his individual benefit".2 Yet do workers in the Council’s own units pay attention to these strictures all the time? Society wants research into childhood illness and the study of normal children to continue. Research-workers are mindful of their responsibilities and of the essential role in all this of the patient’strust, though Dr T. M. Barratt illustrated how, in multicentre trials, this doctor/patient relationship could be altered by restraints from outside. Nor should altruism be suppressed. But why should research-workers be asked to work under the threat that what they are doing may be illegal. What choices have we? Statute law? A non-starter said Mr Godfrey Carter, a Parliamentary counsel. Case law? Perhaps it will come to this,3 but whose head is for the block and on what particular issue is the test case to be decided? Ethical committees help but they have no legal force, nor are they consistent (D.H.S.S. advice on this matter4 is so confusing that this inconsistency is hardly surprising). A doctor in the Oxford region’ could not get approval to take blood from healthy children in their own homes; had she been working in London WC1 this obstacle might never have materialised. One speaker reported that an M.R.C. grant for a multicentre project might be withheld unless all the district ethical committees involved gave their approval. Codes are not legal documents either, though in the United States there is considerable agreement on draft regulations, with the force of Federal law, on research involving children.6 This development will be watched with great interest elsewhere, but even in the draft are obscure phrases such as "minor increase of minimal risk". Over the past few years there has been much discussion amongst lawyers and doctors about the legality of research on children, and the leading opinion on this is now more than fifteen years old. The Medical Research Council cannot itself rewrite a view that begins "In the strict view of the law...", but it could ask for a second
more
1. Skegg, P. D. Lancet, 1977, ii, 754. 2. Medical Research Council. Annual Report 1962-63 3. Lancet, 1977,1,1346. 4. D.H.S.S. Supervision of the Ethics of Clinical Research Fetal Research. HSC(IS)153.1975 5. Pratt, H. Lancet, 1977, i, 699. 6 Federal Register, vol 43, no. 141, July 21,1978.
Investigations and
If those asked feel unable to take into account the current academic view or the present arrangements for peer review and ethical scrutiny (including lay involvement), and repeat their former advice, then an attempt on the Statute Book seems warranted. However, an earlier Bill on aspects of this topic was described by one Queen’s counsel’ as demonstrating the "clumsiness of the law as a means of fine control of human endeavour".
opinion.
SUICIDE AND THE SAMARITANS avoidable and particularly distressing cause of death, suicide merits close attention in any society. Prevention of suicide offers a challenge, and despite the obvious reservations about the validity and consistency of the verdicts of coroner’s courts, the death registration process provides a rare opportunity of monitoring variations from place to place and from time to time. Existing evidence suggests that, in England and Wales at least, recent trends have been highly satisfactory, with a fall of about one-third in the recorded suicide-rates for both males and females between 1964 and 1970. A favourable pattern of this kind has not been observed in other countries and there has been a very natural tendency to look for features unique to England and Wales which might explain the observed results. Amongst the many candidates which have been put forward, the Samaritans have commanded the greatest support. Not only do the Samaritans aim specifically to help troubled people (of whom potential suicides represent a small minority) but also the organisation grew very rapidly during the very period when the dramatic fall in suicide-rates took place. The pattern of development of the Samaritans, involving the setting up of new branches in various cities and towns over several years, at first sight provides the opportunity for a "scientific" evaluation of the effectiveness of the service by comparison of changes in suiciderates in similar geographical areas with and without a branch of the Samaritans. The study by BagleyI in 1968 was the first to be carried out in these terms and has been described as a landmark in the history of social science.2 Bagley compared changes in suicide-rates in 15 pairs of towns in England and Wales, one town of each pair being served by the Samaritans whilst the second (control) town was chosen to be as similar as possible in other relevant respects to the first. He found a significant difference between the Samaritan and the control towns which suggested that the Samaritans were in fact effective in preventing suicide. Bagley’s hypothesis was retested by Barraclough and his colleagues34by the same general procedures but with more extensive data and different and more sophisticated methods of choosing control towns. The fact that Barraclough was unable to confirm Bagley’s results has led to considerable discussion. The apparent contradiction raises issues of wide interest in the context of research in the medical and social sciences, much of which must inevitably be As
a
potentially
7. Clothier, C. M. Lancet, 1977, i, 642. 1. Bagley, C. Soc Sci. Med. 1968, 2, 1. 2. Fox, R. R. Soc. Hlth J. 1975, 95, 9 3. Barraclough, B. M., Jennings, C., Moss, J. 4. Jennings, C., Barraclough, B. M., Moss,
R. Lancet, 1977, ii, 237. J. R. Psychol. Med. 1978, 8, 413.
