- Email: [email protected]
MITOCHONDRIA, AUTOIMMUNITY, AND ONCOGENESIS
218
recently conducted a random poll of ten Scottish colleagues and none had heard of acetaminophen. However, as might be expected, the invaluable British reference book, Martindale’s Extra Pharmacopaeia gives full information in
amol.
I
both languages. In a recent textbookIa glossary ensures that the American reader will know that paracetamol is the same as
acetaminophen.
Royal Infirmary, Edinburgh EH3 9YW.
RONALD GIRDWOOD.
THE CONSULTANTS’ CONTRACT
SIR,-It is interesting at this time to look back to your editorial on this subject in the summer of 19732 and to the comments of Dr Fearnley3 and myself,4 which you published then. We all drew attention to some of the difficulties inherent in a fixed 10-session contract. You wondered at that time how many consultants really wanted such a contract, and the results of the recent B.M.A. questionary5 show how small is the majority of those who favour a fixed session contract. Among the 70% of senior hospital staff who replied, 46% favoured a 10-session contract and 38% favoured keeping the present wholetime or part-time contract. Further, 84% of respondents considered that consultants should be able to choose, from a number of types of contract, the one which best suits them. At a meeting just held in Aberdeen to discuss the new contract, 77 consultants voted to retain the present wholetime and part-time types of contract (provided they attracted reasonable remuneration) and 7 preferred a 10session fixed contract. It appears, therefore, that there may be a considerable number of consultants who have their doubts about the wisdom of adopting a fixed contract. At the moment it appears that such a contract is to be the only one offered to new consultants, and it seems unlikely that many consultants will want to stay on their present contract if all prospect of new distinction awards are withdrawn. It is not difficult to understand why some consultants with a heavy emergency load have felt impelled to seek a change in their contract, but the arguments against such a contract were spelt out in 1973 and are just as valid today. If 84% of consultants wish to be offered a choice of contract, then, this should be among the aims of our negotiators. There are many, both among present and future consultants, who feel that this attempt to define hours of work bears little relation to the varying load and continuing responsibility of the life consultants have chosen to adopt. It seems, furthermore, distinctly likely that the need to define sessional hours, and to book time worked on emergency duties, could lead to much closer supervision of consultants by administrators. Those who share these doubts should be offered reasonable alternatives to the uncertain benefits of a 10-session type of contract. Royal Aberdeen Children’s Hospital, Cornhill Road, Aberdeen AB9 2ZG.
PETER F. JONES.
SiR,—We paediatricians are indeed fortunate that we have chosen a specialty which gives great satisfaction, both emotional and intellectual. In truth, few of us would really wish there to be a thriving private sector in child health with the implication of inequality of health care amongst children. Still, we are but human, and have the same general expenses, reasonable and unreasonable, as our part-time Alstead, S., Girdwood, R. H. (editors). Textbook of Medical Treatment. Edinburgh, 1974. 2. Lancet, 1973, ii, 546. 3. Fearnley, G. R. ibid. p. 667. 4. Jones, P. F. ibid. p. 796. 5. Br. med. J. 1974, iv, 608. 1.
colleagues, and one cannot help regret that the surgeons and others who represent us on the Owen working-party should make it a pre-condition of agreement that there can be no compensatory payment to full-timers, reducing the gap between our total earnings and theirs. More important than this is the fear that the present work-to-contract is poisoning the wells of goodwill which still exist in this country between the public and the profession. That such goodwill has been lost in the U.S.A. is evidenced by the astronomically high cost of malpraxis insurance there (Jan. 11, p. 94). George Eliot Hospital, College Street, Nuneaton.
B. G. P. MACNAMARA.
SIR,-For many years your leaders have helped to identify and support minority causes-often predictably In the present contract dispute minority anti-B.M.A. building is clearly tough going, even for The Lancet. However, you have less reason than the Government to misread the thoughts of the vast majority of consultants, and your comment that they might be influenced by a medical voice indicates a total lack of insight into present feelings. Your reference (Jan. 11, p. 82) to tentative sounds from the Royal Colleges makes one doubt if the Presidents concerned would regard their quoted comments as other than personal views. Your editorial, in effect, points to the consultants as the guilty party, and in the next sentence decides not to apportion blame!z 84 Nettleham Road, Lincoln LN2 1RR.
E. P. MORLEY.
MITOCHONDRIA, AUTOIMMUNITY,
AND
ONCOGENESIS MR,—i nave read witn interest letters trom your mitochondriac " correspondents, who have suggested a primary role for mitochondrial D.N.A. in the events leading to oncogenesis 1,2and development of autoimmune disease.3 It has been suggested that mitochondrial D.N.A., which has been liberated as a result of organelle damage, " infects" the nuclear D.N.A., thereby leading to expression of mitochondrial proteins in the cytoplasm. The cytoplasmically expressed proteins may then act as neoantigens and stimulate the development of autoimmune antibodies. However, such speculation is implausible and furthermore it is not necessary to invoke this type of event to explain the production of antimitochondrial antibodies in autoimmune diseases. Mitochondrial genetic information is normally transcribed and translated by mitochondrial specific enzymes (e.g., R.N.A. polymerase 4) and protein synthesis components (e.g., ribosomes 5). These are not normally present in the cytoplasm. The initiation of protein synthesis in mitochondria (but not in the cytoplasm) apparently requires the participation of N-formyl methionine 6 tR.N.A. Even if one accepts (for the sake of argument) the escape of mitochondrial D.N.A. and its insertion into the nuclear D.N.A. it is improbable that the necessary conditions (correct enzymes, components of protein synthesis, and control signals) for the production of mitochondrial proteins in the cytoplasm would be generated. Surely the significant point made by Dr Hickman3 Baum, H. Lancet, 1973, ii, 738. Schumacher, H. R., Szekely, I. E., Fisher, D. R. ibid. 1974, ii, 1207. Hickman, J. A. ibid. p. 1579. Gallerani, R., Saccone, C. in Biogenesis of Mitochondria (edited by A. M. Kroon and C. Saccone); p. 59. London, 1974. 5. Beattie, D. Subcell. Biochem. 1971, 1, 1. 6. Blossey, H. Ch., Kuntzel, H. F.E.B.S.-Letters, 1972, 24, 335
1. 2. 3. 4.
219 is not that rearrangement of the internal genetic organisation of the cell can give rise to the production of mitochondrial " proteins in the cytoplasm but that labilisation of mitochondria might be expected to occur mainly in tissues undergoing trauma." Thus, it is quite probable that the stimulation of antibodies to the normally " hidden " mitochondrial antigens results from tissue breakdown. As such this represents a secondary effect. One must look elsewhere for the primary events in the ’onset of autoimmune disease. The possibility of an inherited abnormality of the immune response, which may contribute to the development of antimitochondrial antibodies (as in primary biliary cirrhosis), has been discussed previously.7 Genetics Laboratory, Department of Biochemistry, South Parks Road, Oxford OX1 3QU.
IAN CRAIG.
that all those attending it are professional men who had, or still have, to face similar problems. There is, thus, no fear of others sitting in judgment or talking down to the newcomer, who cannot but receive very helpful, constructive advice and support from colleagues who, because of their own experiences, are in full empathy. Those doctors who started this group also continue to attend meetings of A.A. and encourage newcomers to join it, and the group is in touch with the International Doctors in A.A. " body (founded in 1949). However, though obviously not in competition with, or a substitute for, A.A., the group is quite independent. Many doctors concerned about their drinking problem should find this doctors’ group extremely helpful. Any doctor with a drinking problem who is interested is invited to write to the undersigned (obviously in the strictest confidence), and he will be put in touch immediately with a member of the group. "
St. Bernard’s Hospital,
Southall, Middlesex.
THE TIME DIMENSION OF THE GENE SiR -Professor Gedda and Dr Brenci (Dec. 14, p. 1455) claim priority for the use in 1964 of the term " chronon for a concept in genetics as against a later use of this word in a different biological field. The chronon refers to a much older concept of an ultimate atomistic unit of time dating back to the Vedas, also described by Maimonides in the Middle Ages as the atom of time, and given the name by modern physicists. It is of the order of 10-24 second. It was described in 1961 both by Prof. G. J. Whitrow in The Natural Philosophy of Time and by Prof. Henry Margenau in Open Vistas.
M. M. GLATT.
"
37 Clifton Hill, St. John’s Wood, London NW8.
HUGH GAINSBOROUGH.
DOCTORS WITH A DRINKING PROBLEM
SiR,—Problem drinking among doctors-an issue raised in-your columns —in our experience constitutes an occupational hazard.9 Its frequency among doctors certainly speaks little for the education of medical undergraduates in what should often be a preventable condition.9 The likelihood that there must be at present many doctors with alcoholism who do not present themselves for treatment is the more regrettable, since in our experience such doctors, with adequate treatment, often do very well.8,9 Moreover, recovered doctors can often be of the greatest assistance to other alcoholics. Corresponding to the complaint frequently heard from alcoholics-though probably often unjustifiedthat their doctor seems to care little for the sufferers from this condition, alcoholic doctors themselves sometimes complain that their non-alcoholic partners do not understand this problem. On the other hand, it is only fair to report that not only wives of alcoholic medical men but also general practitioners with an alcoholic partner often ask in desperation how they can motivate their alcoholic husband or colleague to present himself for treatment. For some reason or other, alcoholic doctors often apparently shy away from asking a doctor for help and from attending Alcoholics Anonymous meetings-though many alcoholic doctors participate closely and successfully in A.A. Under the circumstances, it is very promising that a number of recovered alcoholic doctors have lately formed a group who meet once a month in London, and who are expanding their membership. Not unexpectedly, some alcoholic doctors find it easier to attend these meetings than ordinary Alcoholics Anonymous meetings. Some doctors travel very long distances to attend these meetings, in the knowledge 7. 8. 9.
Doniach, D. Br. med. Bull. 1972, 28, 145. Glatt, M. M. Lancet, 1974, ii, 342. Glatt, M. M. A Guide to Addiction and its Treatment: Drugs, Society and Man. Lancaster, 1974.
ASSESSMENT OF CADAVERIC KIDNEYS FOR
TRANSPLANTATION
SiR,—We read with interest the paper by Mr Baxby and others (Oct. 26, p. 977). Everyone, of course, agrees that " dead" kidneys should not be transplanted. Therefore any method that can assess the viability of kidneys before transplantation is extremely useful. We must, however, disagree with the authors’ statement that delayed function due to acute tubular necrosis after transplantation is detrimental to either patient or later kidney function. At our institution the incidence of acute tubular necrosis (A.T.N.) is approximately 11% in related transplants and 27% in cadaver transplants. The 61 patients (22 living related donors and 39 cadaver donors) who had post-
transplant A.T.N. necessitating haemodialysis were compared with
a
control group matched for age, sex, and time of
transplant. When these two patient groups were compared (patients observed for from 6 months to 4! years) there was no difference in survival, either absolute or cumulated, of functioning kidneys, creatinine, blood-urea nitrogen, rejection episodes, or blood-pressure. We therefore feel that post-transplant A.T.N. is a benign complication that does not adversely affect the outcome of the transplant.I We therefore believe that the results reported by Dr Baxby and others and also by Whittaker et al. are partly due to chance (their material is small and there was no comparison or matching between the patients who experienced A.T.N. and those who did not) and partly the result of employing certain diagnostic procedures. Invasive diagnostic procedures (second-look operations, angiograms, retrograde pyelographies, and biopsies) are to be avoided in the postoperative, immunosuppressed patient. These methods were used by both groups and were believed by Whittaker et al. to contribute to failure in their patients. Dialysis problems also seem to have been causing trouble in the group described by Baxby et al., bleeding, of course, being the most feared. By using a simple method of anticoagulation this has not been a hazard.33 The fear of post-transplant acute tubular necrosis, as might be expected if kidneys are used from cadavers in shock, should not be a deterrent. That would, in our opinion, unnecessarily cut the preciously small supply of cadaver kidneys. We believe that avoiding non-invasive 1.
2.
Kjellstrand, C. M., Simmons, R. L., Shideman, J. R., Buselmeier, T. J., von Hartitzsch, B., Najarian, J. S. Department of Health, Education, and Welfare publ. no. (N.I.H.) 74-608, 1974, p. 329. Whittaker, J. R., Veith, F. J., Soberman, R., Lalezari, P., Tellis, I., Freed, S. Z., Gliedman, M. L. Surgery, Gynec. Obstet. 1973, 136, 919.
3.
Kjellstrand, C. M., Buselmeier, T. J. Surgery, 1972, 72,
630.
recently conducted a random poll of ten Scottish colleagues and none had heard of acetaminophen. However, as might be expected, the invaluable British reference book, Martindale’s Extra Pharmacopaeia gives full information in
amol.
I
both languages. In a recent textbookIa glossary ensures that the American reader will know that paracetamol is the same as
acetaminophen.
Royal Infirmary, Edinburgh EH3 9YW.
RONALD GIRDWOOD.
THE CONSULTANTS’ CONTRACT
SIR,-It is interesting at this time to look back to your editorial on this subject in the summer of 19732 and to the comments of Dr Fearnley3 and myself,4 which you published then. We all drew attention to some of the difficulties inherent in a fixed 10-session contract. You wondered at that time how many consultants really wanted such a contract, and the results of the recent B.M.A. questionary5 show how small is the majority of those who favour a fixed session contract. Among the 70% of senior hospital staff who replied, 46% favoured a 10-session contract and 38% favoured keeping the present wholetime or part-time contract. Further, 84% of respondents considered that consultants should be able to choose, from a number of types of contract, the one which best suits them. At a meeting just held in Aberdeen to discuss the new contract, 77 consultants voted to retain the present wholetime and part-time types of contract (provided they attracted reasonable remuneration) and 7 preferred a 10session fixed contract. It appears, therefore, that there may be a considerable number of consultants who have their doubts about the wisdom of adopting a fixed contract. At the moment it appears that such a contract is to be the only one offered to new consultants, and it seems unlikely that many consultants will want to stay on their present contract if all prospect of new distinction awards are withdrawn. It is not difficult to understand why some consultants with a heavy emergency load have felt impelled to seek a change in their contract, but the arguments against such a contract were spelt out in 1973 and are just as valid today. If 84% of consultants wish to be offered a choice of contract, then, this should be among the aims of our negotiators. There are many, both among present and future consultants, who feel that this attempt to define hours of work bears little relation to the varying load and continuing responsibility of the life consultants have chosen to adopt. It seems, furthermore, distinctly likely that the need to define sessional hours, and to book time worked on emergency duties, could lead to much closer supervision of consultants by administrators. Those who share these doubts should be offered reasonable alternatives to the uncertain benefits of a 10-session type of contract. Royal Aberdeen Children’s Hospital, Cornhill Road, Aberdeen AB9 2ZG.
PETER F. JONES.
SiR,—We paediatricians are indeed fortunate that we have chosen a specialty which gives great satisfaction, both emotional and intellectual. In truth, few of us would really wish there to be a thriving private sector in child health with the implication of inequality of health care amongst children. Still, we are but human, and have the same general expenses, reasonable and unreasonable, as our part-time Alstead, S., Girdwood, R. H. (editors). Textbook of Medical Treatment. Edinburgh, 1974. 2. Lancet, 1973, ii, 546. 3. Fearnley, G. R. ibid. p. 667. 4. Jones, P. F. ibid. p. 796. 5. Br. med. J. 1974, iv, 608. 1.
colleagues, and one cannot help regret that the surgeons and others who represent us on the Owen working-party should make it a pre-condition of agreement that there can be no compensatory payment to full-timers, reducing the gap between our total earnings and theirs. More important than this is the fear that the present work-to-contract is poisoning the wells of goodwill which still exist in this country between the public and the profession. That such goodwill has been lost in the U.S.A. is evidenced by the astronomically high cost of malpraxis insurance there (Jan. 11, p. 94). George Eliot Hospital, College Street, Nuneaton.
B. G. P. MACNAMARA.
SIR,-For many years your leaders have helped to identify and support minority causes-often predictably In the present contract dispute minority anti-B.M.A. building is clearly tough going, even for The Lancet. However, you have less reason than the Government to misread the thoughts of the vast majority of consultants, and your comment that they might be influenced by a medical voice indicates a total lack of insight into present feelings. Your reference (Jan. 11, p. 82) to tentative sounds from the Royal Colleges makes one doubt if the Presidents concerned would regard their quoted comments as other than personal views. Your editorial, in effect, points to the consultants as the guilty party, and in the next sentence decides not to apportion blame!z 84 Nettleham Road, Lincoln LN2 1RR.
E. P. MORLEY.
MITOCHONDRIA, AUTOIMMUNITY,
AND
ONCOGENESIS MR,—i nave read witn interest letters trom your mitochondriac " correspondents, who have suggested a primary role for mitochondrial D.N.A. in the events leading to oncogenesis 1,2and development of autoimmune disease.3 It has been suggested that mitochondrial D.N.A., which has been liberated as a result of organelle damage, " infects" the nuclear D.N.A., thereby leading to expression of mitochondrial proteins in the cytoplasm. The cytoplasmically expressed proteins may then act as neoantigens and stimulate the development of autoimmune antibodies. However, such speculation is implausible and furthermore it is not necessary to invoke this type of event to explain the production of antimitochondrial antibodies in autoimmune diseases. Mitochondrial genetic information is normally transcribed and translated by mitochondrial specific enzymes (e.g., R.N.A. polymerase 4) and protein synthesis components (e.g., ribosomes 5). These are not normally present in the cytoplasm. The initiation of protein synthesis in mitochondria (but not in the cytoplasm) apparently requires the participation of N-formyl methionine 6 tR.N.A. Even if one accepts (for the sake of argument) the escape of mitochondrial D.N.A. and its insertion into the nuclear D.N.A. it is improbable that the necessary conditions (correct enzymes, components of protein synthesis, and control signals) for the production of mitochondrial proteins in the cytoplasm would be generated. Surely the significant point made by Dr Hickman3 Baum, H. Lancet, 1973, ii, 738. Schumacher, H. R., Szekely, I. E., Fisher, D. R. ibid. 1974, ii, 1207. Hickman, J. A. ibid. p. 1579. Gallerani, R., Saccone, C. in Biogenesis of Mitochondria (edited by A. M. Kroon and C. Saccone); p. 59. London, 1974. 5. Beattie, D. Subcell. Biochem. 1971, 1, 1. 6. Blossey, H. Ch., Kuntzel, H. F.E.B.S.-Letters, 1972, 24, 335
1. 2. 3. 4.
219 is not that rearrangement of the internal genetic organisation of the cell can give rise to the production of mitochondrial " proteins in the cytoplasm but that labilisation of mitochondria might be expected to occur mainly in tissues undergoing trauma." Thus, it is quite probable that the stimulation of antibodies to the normally " hidden " mitochondrial antigens results from tissue breakdown. As such this represents a secondary effect. One must look elsewhere for the primary events in the ’onset of autoimmune disease. The possibility of an inherited abnormality of the immune response, which may contribute to the development of antimitochondrial antibodies (as in primary biliary cirrhosis), has been discussed previously.7 Genetics Laboratory, Department of Biochemistry, South Parks Road, Oxford OX1 3QU.
IAN CRAIG.
that all those attending it are professional men who had, or still have, to face similar problems. There is, thus, no fear of others sitting in judgment or talking down to the newcomer, who cannot but receive very helpful, constructive advice and support from colleagues who, because of their own experiences, are in full empathy. Those doctors who started this group also continue to attend meetings of A.A. and encourage newcomers to join it, and the group is in touch with the International Doctors in A.A. " body (founded in 1949). However, though obviously not in competition with, or a substitute for, A.A., the group is quite independent. Many doctors concerned about their drinking problem should find this doctors’ group extremely helpful. Any doctor with a drinking problem who is interested is invited to write to the undersigned (obviously in the strictest confidence), and he will be put in touch immediately with a member of the group. "
St. Bernard’s Hospital,
Southall, Middlesex.
THE TIME DIMENSION OF THE GENE SiR -Professor Gedda and Dr Brenci (Dec. 14, p. 1455) claim priority for the use in 1964 of the term " chronon for a concept in genetics as against a later use of this word in a different biological field. The chronon refers to a much older concept of an ultimate atomistic unit of time dating back to the Vedas, also described by Maimonides in the Middle Ages as the atom of time, and given the name by modern physicists. It is of the order of 10-24 second. It was described in 1961 both by Prof. G. J. Whitrow in The Natural Philosophy of Time and by Prof. Henry Margenau in Open Vistas.
M. M. GLATT.
"
37 Clifton Hill, St. John’s Wood, London NW8.
HUGH GAINSBOROUGH.
DOCTORS WITH A DRINKING PROBLEM
SiR,—Problem drinking among doctors-an issue raised in-your columns —in our experience constitutes an occupational hazard.9 Its frequency among doctors certainly speaks little for the education of medical undergraduates in what should often be a preventable condition.9 The likelihood that there must be at present many doctors with alcoholism who do not present themselves for treatment is the more regrettable, since in our experience such doctors, with adequate treatment, often do very well.8,9 Moreover, recovered doctors can often be of the greatest assistance to other alcoholics. Corresponding to the complaint frequently heard from alcoholics-though probably often unjustifiedthat their doctor seems to care little for the sufferers from this condition, alcoholic doctors themselves sometimes complain that their non-alcoholic partners do not understand this problem. On the other hand, it is only fair to report that not only wives of alcoholic medical men but also general practitioners with an alcoholic partner often ask in desperation how they can motivate their alcoholic husband or colleague to present himself for treatment. For some reason or other, alcoholic doctors often apparently shy away from asking a doctor for help and from attending Alcoholics Anonymous meetings-though many alcoholic doctors participate closely and successfully in A.A. Under the circumstances, it is very promising that a number of recovered alcoholic doctors have lately formed a group who meet once a month in London, and who are expanding their membership. Not unexpectedly, some alcoholic doctors find it easier to attend these meetings than ordinary Alcoholics Anonymous meetings. Some doctors travel very long distances to attend these meetings, in the knowledge 7. 8. 9.
Doniach, D. Br. med. Bull. 1972, 28, 145. Glatt, M. M. Lancet, 1974, ii, 342. Glatt, M. M. A Guide to Addiction and its Treatment: Drugs, Society and Man. Lancaster, 1974.
ASSESSMENT OF CADAVERIC KIDNEYS FOR
TRANSPLANTATION
SiR,—We read with interest the paper by Mr Baxby and others (Oct. 26, p. 977). Everyone, of course, agrees that " dead" kidneys should not be transplanted. Therefore any method that can assess the viability of kidneys before transplantation is extremely useful. We must, however, disagree with the authors’ statement that delayed function due to acute tubular necrosis after transplantation is detrimental to either patient or later kidney function. At our institution the incidence of acute tubular necrosis (A.T.N.) is approximately 11% in related transplants and 27% in cadaver transplants. The 61 patients (22 living related donors and 39 cadaver donors) who had post-
transplant A.T.N. necessitating haemodialysis were compared with
a
control group matched for age, sex, and time of
transplant. When these two patient groups were compared (patients observed for from 6 months to 4! years) there was no difference in survival, either absolute or cumulated, of functioning kidneys, creatinine, blood-urea nitrogen, rejection episodes, or blood-pressure. We therefore feel that post-transplant A.T.N. is a benign complication that does not adversely affect the outcome of the transplant.I We therefore believe that the results reported by Dr Baxby and others and also by Whittaker et al. are partly due to chance (their material is small and there was no comparison or matching between the patients who experienced A.T.N. and those who did not) and partly the result of employing certain diagnostic procedures. Invasive diagnostic procedures (second-look operations, angiograms, retrograde pyelographies, and biopsies) are to be avoided in the postoperative, immunosuppressed patient. These methods were used by both groups and were believed by Whittaker et al. to contribute to failure in their patients. Dialysis problems also seem to have been causing trouble in the group described by Baxby et al., bleeding, of course, being the most feared. By using a simple method of anticoagulation this has not been a hazard.33 The fear of post-transplant acute tubular necrosis, as might be expected if kidneys are used from cadavers in shock, should not be a deterrent. That would, in our opinion, unnecessarily cut the preciously small supply of cadaver kidneys. We believe that avoiding non-invasive 1.
2.
Kjellstrand, C. M., Simmons, R. L., Shideman, J. R., Buselmeier, T. J., von Hartitzsch, B., Najarian, J. S. Department of Health, Education, and Welfare publ. no. (N.I.H.) 74-608, 1974, p. 329. Whittaker, J. R., Veith, F. J., Soberman, R., Lalezari, P., Tellis, I., Freed, S. Z., Gliedman, M. L. Surgery, Gynec. Obstet. 1973, 136, 919.
3.
Kjellstrand, C. M., Buselmeier, T. J. Surgery, 1972, 72,
630.