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THERAPEUTIC ABORTION BY LOCAL ADMINISTRATION OF PROSTAGLANDIN
716
Letters
to
the Editor
INCREASING FREQUENCY OF A SYNDROME OF MULTIPLE OSSEOUS DEFECTS ? SIR,-In the past six months we have seen 8 infants and a 6-year-old child with a malformation syndrome affecting primarily the craniofacial skeleton, the tubular bones of the lower extremities, and the axial skeleton. Craniofacial abnormalities include a flat face, hypertelorism, micrognathia, and cleft palate. Deformities of the lower extremities consist of anterior bowing of the femorse and tibiae, bilateral hypoplasia of the fibult, and a calcaneovalgus deformity of the feet. One patient had mild bowing of the radii and ulna;. The most severe bowing, usually in the tibiae, was associated with a subcutaneous dimple. Abnormalities of the axial skeleton include numerical defects of the ribs and hypoplasia of the scapulae, and in some cases ossification defects of the vertebral bodies and posterior elements. All the cases were isolated observations. The patients failed to thrive, and 7 of the 9 children died in early infancy. A search for similar cases in the bone-dysplasia registries of Minneapolis, Paris, and Kiel revealed one similar case, indicating that this syndrome must have been rare in previous years. A literature review revealed three 1-3 and possibly five 4,5 previously reported cases. The appearance of 9 cases in a few months may be fortuitous or may reflect a newly stimulated interest of the authors. (This was true for the 6-year-old patient, who was known previously and whose disease was re-evaluated in the light of the other cases.) A genuine increase in frequency cannot be excluded, and this raises the question of an exogenous cause. We should like to know if any other similar cases have been observed. Department of Pediatrics,
University of Wisconsin. Department of Radiology, University of Minnesota, Minneapolis. Clinique de génétique médicale, Hôpital des Enfants Malades, Paris.
J. SPRANGER. L. O. LANGER. P. MAROTEAUX.
THERAPEUTIC ABORTION BY LOCAL ADMINISTRATION OF PROSTAGLANDIN SIR,-Therapeutic abortion may be induced by intravenous infusion of prostaglandin El (p.G.E1), p.G.E2, and p.G.F2a.6-10 Results from this department indicate that, with a limited infusion-time, the earliest stages of pregnancy (8 weeks or less) are particularly susceptible to the action of prostaglandin, whereas the success-rate is substantially lower in later stages of gestation. 11 ,12
An extended series of clinical trials has been carried out support this conclusion. 22 early pregnant women (at 8 weeks’ gestation or less) were given p.G.F2a by intravenous infusion for an average period of 7-6 hours. There was partial or complete expulsion of the conceptus in 20. In contrast, when p.G.F2a was administered during the 9th to 12th week of pregnancy, pregnancy was terminated successfully in only 6 out of 19 women, despite the fact that an average infusion-time of 13-6 hours was employed. Moreover, intravenous p.G.F2a given to 28 patients in the 13th to 20th week of gestation induced abortion in only 4 cases. These results emphasise the fact that the infusiontime for successful induction of abortion may be comparatively short if p.G.F2a is administered during the early stages of gestation. The frequency of subjective side-effects as related to the dose of P.G.F2a was also carefully analysed. Dysmenorrhceic pain appeared in 50% of cases at a dose of 50 µg.
to
INTRAUTERINE ADMINISTRATION OF PROSTAGLANDINS FOR INDUCTION OF THERAPEUTIC ABORTION
* Only one injection. t Conceptus retained but cervix dilated.
per minute, whereas only 12% had nausea or diarrhcea. At an infusion-rate of 75 .g. per minute 80% complained of dysmenorrhoeic pain and 30% had nausea and/or diarrhoea. When 100 wg. per minute was infused all subjects developed dysmenorrhoea. This means that the dose-range which induces effective uterine contractions (indicated by dysmenorrhaeic pain) but does not cause generalised side-effects (nausea or diarrhoea) is rather limited. Obviously, it would be advantageous if the compounds could be administered so as to give a high local concentration in the myometrium. The compounds may, in fact, be administered directly into the uterine cavity (between the fetal membranes and the uterine wall).
catheter with an outer diameter of introduced through the cervix and p.G.E, or p.G.F2a injected intermittently. The suitable dose-range for each injection varied between 25 and 75 /kg. for P.G.E and 200 and 1000 wg. for P.G.F2a. A thin
1
mm.
polyethylene
was
Compared with single intravenous injections Middleton, D. S. Edinb. med. J. 1934, 41, 401. Bound, J. P., Finlay, H. V. L., Rose, F. C. Archs Dis. Childh. 1952, 27, 179. 3. Bain, A. D., Barrett, A. H. S. ibid. 1959, 34, 516. 4. Williams, E. R. Br. J. Radiol. 1943, 16, 371. 5. Schudel, P. Helv. pœdiat. Acta, 1968, 23, 659. 6. Embrey, M. B. Br. med. J. 1970, ii, 258. 7. Karim, S. M. M., Filshie, G. M. Lancet, 1970, i, 157. 8. Karim, S. M. M., Filshie, G. M. Br. med. J. 1970, iii, 198. 9. Karim, S. M. ibid. p. 196. 10. Roth-Brandel, U., Bygdeman, M., Wiqvist, N., Bergström, S. Lancet, 1970, i, 190. 11. Wiqvist, N., Bygdeman, M. ibid. p. 889. 12. Wiqvist, N., Bygdeman, M., Kirton, K. Proceedings of Fifteenth Nobel Symposium on Control of Human Fertility (edited by U. Bovell and E. Diczfalusy). Stockholm (in the press). 1. 2.
of similar
doses, intrauterine administration resulted in a less dramatic initial response but a more sustained and effective stimulation of uterine contractility. The duration of the stimulatory response varied between 1 and 3 hours. The effect of intrauterine administration has been assessed in 12 women admitted for therapeutic abortion. The results are shown in the accompanying table. The clinical effectiveness of local administration during pregnancy is comparable with that of intravenous infusion. In addition, the method requires less supervision of the patient. The total dose used in the individual cases was approximately one-tenth of the intravenous dose. The
early
717 most
remarkable difference consisted in the virtually of generalised side-effects.
complete elimination
This work was supported by the Swedish Medical Research Council and the Astra Company. Department of Women’s Diseases, Karolinska Sjukhuset, N. Stockholm 60, Sweden.
WIQVIST
M. BYGDEMAN.
EMERGENCY CALL SERVICE SIR,-Dr. Pinsent (Sept. 19, p. 604) states that on over 80% of occasions on which the call service was contacted no medical emergency was found." If he denies the patient the opportunity to telephone his doctor for advice, the patient will do the only thing he can-ask for a visit. I estimate that at least half of all out-of-hours telephone calls can be dealt with by telephone or the matter left until routine working hours ". I also disagree with Dr. Pinsent’s classification: a child who develops otitis media on Saturday afternoon should not wait until " routine working hours " for treatment. There are many causes of a crying child, among the commoner being earache and abdominal pain: it can be very difficult for an experienced doctor to diagnose the cause of crying; to expect an emotionally involved parent to make a correct diagnosis is less than fair. A two-tier system of doctors and nurses in radio contact may be one way of providing off-duty for doctors. I submit, Sir, that one doctor (on call for his colleagues) who can advise by telephone or arrange to see the patient at a convenient time gives a more economical and more satisfactory service. "
"
H. E. G. REES.
SOCIAL WORK IN GENERAL PRACTICE
SiR,—The paper by Dr. Harwin and his colleagues (Sept. 12, p. 559) is an important contribution to the reconstruction of medical care in Britain. In an era when the range of domiciliary care has enormously increased and morbidity moved towards a preponderance of degenerative and psychosocial conditions, it is astonishing that the trained social caseworker has as yet found little place in our system of personal medical care. Potentially, she stands in a similar practising relationship to the behavioural sciences as does the doctor to internal medicine. In practice, however, she remains incarcerated largely within the institutional setting. Some of the reasons for this are historical. In the pre-N.H.S. days of fee-paying general practice and of voluntary " and " municipal " hospitals, the hospital represented concentration points of maximum need. In these the social caseworker was strategically placed. But that it remains so after 22 years of the N.H.S. is a measure of the medical profession’s aversion to change. That favourable attitudes to medicosocial teamwork were, in this survey, associated with younger practitioners, is perhaps a sign of hope for the future: but that 50% of practitioners in practice for less than 10 years were " neutral " or unfavourable " to such developments surely tempers any optimism. And that even " a few " doctors are still under the happy illusion of welcoming such teamwork " chiefly because it offered them the hope of freedom from an unwanted burden " tempers it still further. The immediate need is for the provision of much wider experimental attachment of social caseworkers to selected general practices; and the critical assessment, from experience, of how social caseworker and general practitioner work best together. Dr. Harwin remarks " that few doctors had any clear "
"
idea of the function of the social worker
or
of the types of
problems with which her help might be usefully invoked ". Is this surprising ? Our own experience, in a department staffed with a social caseworker of many years’ experience in community work, is that we are only now beginning to learn. We propose that 15-20 such attachments be set up in selected practices, each for a period of, say, three years. This would provide a wealth of basic experience. But it can be achieved only with the support of the Department of Health and Social Security in funding and coordination, and with the cooperation of the Royal College of General Practitioners and the Institute of Medical Social Workers. It is immaterial from which of these three the initiative comes. But if the Department is willing to undertake such a role, there should be no insuperable difficulty in finding
suitable practices. The second need is for changes in the educational pattern of physicians and, perhaps, of social workers also. University departments of general practice will have to accept (as has Manchester) that they have certain responsibilities to cooperate, when requested, in the training of social case-workers and health visitors as well as student physicians. The undergraduate (as well as graduate) physician needs to be introduced not only to the theoretical concepts but also to the practice of social science. Where better to illustrate these than in a group general practice in which a social caseworker is an integral part of the team ? Darbishire House Health Centre, University of Manchester, Manchester M13 OF P.
E. M. INESON H. J. WRIGHT.
S.H. ANTIGEN AND CHRONIC LIVER DISEASE SiR,The continued presence of the serum-hepatitis (s.H.) antigen in some patients with a history of serum hepatitis and in some patients with progressive liver disease raises the possibility of an association between some forms of chronic liver disease and chronic s.H. virus infection.1,2 A survey of thirteen published reports 13-14 reveals that S.H. antigen has been detected, albeit with varying frequency in individual series, in serum in 47/374 cases of chronic active hepatitis, 49/417 cases of cirrhosis (of various types), and in 9/130 cases of carcinoma of the liver. The agar-gel diffusion technique was used to test sera for the 8 presence of s.H. antigen in all but one of these series.8 To evaluate a possible relationship between chronic liver disease and chronic s.H. antigenvemia, we have tested sera from cases of chronic liver disease for the presence of S.H. antigen in a variety of populations. Sera were tested by both agar-gel diffusion 15 and high-voltage immunoelectroosmophoresis (I.E.O.P.).16 The I.E.O.P. method is ten times as sensitive as agar-gel diffusion. 1. 2.
Wright, R., McCollum, R. W., Klatskin, G. Lancet, 1969, ii, 117. Prince, A. M., Hargrove, R. L., Jeffries, G. H. Trans. Am. Ass. Physns, 1969, 82, 265. 3. Okochi, K., Murakami, S. Vox Sang. 1968, 15, 374. 4. Gitnick, G. L., Gleich, G. J., Schoenfield, L. J., Baggenstoss, A. H., Sutnick, A. I., Blumberg, B. S., London, W. T., Summerskill, W. H. J. Lancet, 1969, ii, 285. 5. Fox, R. A., Niazi, S. P., Sherlock, S. ibid. p. 609. 6. Mathews, J. D., Mackay, I. R. Br. med. J. 1970, i, 259. 7. Velasco, M., Katz, R. Lancet, 1970, i, 779. 8. Krassnitzky, O., Pesendorfer, F., Wewalka, F. Dt. med. Wschr. 1970, 95, 249. 9. Hadziyannis, S. J., Merikas, G. E., Afroudakis, A. P. Lancet, July 11, 1970, p. 100. 10. Blumberg, B. S., Sutnick, A. I., London, W. T. Bull. N.Y. Acad. Med. 1968, 44, 1566. 11. Chandra, R. K. Lancet, 1970, i, 537. 12. Reinicke, V., Nordenfelt, E. ibid. p. 141. 13. Guardia, J., Bacardi, R., Gras, J. ibid. p. 1007. 14. Smith, I. B., Blumberg, B. S. ibid. 1969, ii, 953. 15. Prince, A. M. Proc. natn Acad. Sci. 1968, 60, 814. 16. Prince, A. M., Burke, K. Science, 1970, 169, 593.
Letters
to
the Editor
INCREASING FREQUENCY OF A SYNDROME OF MULTIPLE OSSEOUS DEFECTS ? SIR,-In the past six months we have seen 8 infants and a 6-year-old child with a malformation syndrome affecting primarily the craniofacial skeleton, the tubular bones of the lower extremities, and the axial skeleton. Craniofacial abnormalities include a flat face, hypertelorism, micrognathia, and cleft palate. Deformities of the lower extremities consist of anterior bowing of the femorse and tibiae, bilateral hypoplasia of the fibult, and a calcaneovalgus deformity of the feet. One patient had mild bowing of the radii and ulna;. The most severe bowing, usually in the tibiae, was associated with a subcutaneous dimple. Abnormalities of the axial skeleton include numerical defects of the ribs and hypoplasia of the scapulae, and in some cases ossification defects of the vertebral bodies and posterior elements. All the cases were isolated observations. The patients failed to thrive, and 7 of the 9 children died in early infancy. A search for similar cases in the bone-dysplasia registries of Minneapolis, Paris, and Kiel revealed one similar case, indicating that this syndrome must have been rare in previous years. A literature review revealed three 1-3 and possibly five 4,5 previously reported cases. The appearance of 9 cases in a few months may be fortuitous or may reflect a newly stimulated interest of the authors. (This was true for the 6-year-old patient, who was known previously and whose disease was re-evaluated in the light of the other cases.) A genuine increase in frequency cannot be excluded, and this raises the question of an exogenous cause. We should like to know if any other similar cases have been observed. Department of Pediatrics,
University of Wisconsin. Department of Radiology, University of Minnesota, Minneapolis. Clinique de génétique médicale, Hôpital des Enfants Malades, Paris.
J. SPRANGER. L. O. LANGER. P. MAROTEAUX.
THERAPEUTIC ABORTION BY LOCAL ADMINISTRATION OF PROSTAGLANDIN SIR,-Therapeutic abortion may be induced by intravenous infusion of prostaglandin El (p.G.E1), p.G.E2, and p.G.F2a.6-10 Results from this department indicate that, with a limited infusion-time, the earliest stages of pregnancy (8 weeks or less) are particularly susceptible to the action of prostaglandin, whereas the success-rate is substantially lower in later stages of gestation. 11 ,12
An extended series of clinical trials has been carried out support this conclusion. 22 early pregnant women (at 8 weeks’ gestation or less) were given p.G.F2a by intravenous infusion for an average period of 7-6 hours. There was partial or complete expulsion of the conceptus in 20. In contrast, when p.G.F2a was administered during the 9th to 12th week of pregnancy, pregnancy was terminated successfully in only 6 out of 19 women, despite the fact that an average infusion-time of 13-6 hours was employed. Moreover, intravenous p.G.F2a given to 28 patients in the 13th to 20th week of gestation induced abortion in only 4 cases. These results emphasise the fact that the infusiontime for successful induction of abortion may be comparatively short if p.G.F2a is administered during the early stages of gestation. The frequency of subjective side-effects as related to the dose of P.G.F2a was also carefully analysed. Dysmenorrhceic pain appeared in 50% of cases at a dose of 50 µg.
to
INTRAUTERINE ADMINISTRATION OF PROSTAGLANDINS FOR INDUCTION OF THERAPEUTIC ABORTION
* Only one injection. t Conceptus retained but cervix dilated.
per minute, whereas only 12% had nausea or diarrhcea. At an infusion-rate of 75 .g. per minute 80% complained of dysmenorrhoeic pain and 30% had nausea and/or diarrhoea. When 100 wg. per minute was infused all subjects developed dysmenorrhoea. This means that the dose-range which induces effective uterine contractions (indicated by dysmenorrhaeic pain) but does not cause generalised side-effects (nausea or diarrhoea) is rather limited. Obviously, it would be advantageous if the compounds could be administered so as to give a high local concentration in the myometrium. The compounds may, in fact, be administered directly into the uterine cavity (between the fetal membranes and the uterine wall).
catheter with an outer diameter of introduced through the cervix and p.G.E, or p.G.F2a injected intermittently. The suitable dose-range for each injection varied between 25 and 75 /kg. for P.G.E and 200 and 1000 wg. for P.G.F2a. A thin
1
mm.
polyethylene
was
Compared with single intravenous injections Middleton, D. S. Edinb. med. J. 1934, 41, 401. Bound, J. P., Finlay, H. V. L., Rose, F. C. Archs Dis. Childh. 1952, 27, 179. 3. Bain, A. D., Barrett, A. H. S. ibid. 1959, 34, 516. 4. Williams, E. R. Br. J. Radiol. 1943, 16, 371. 5. Schudel, P. Helv. pœdiat. Acta, 1968, 23, 659. 6. Embrey, M. B. Br. med. J. 1970, ii, 258. 7. Karim, S. M. M., Filshie, G. M. Lancet, 1970, i, 157. 8. Karim, S. M. M., Filshie, G. M. Br. med. J. 1970, iii, 198. 9. Karim, S. M. ibid. p. 196. 10. Roth-Brandel, U., Bygdeman, M., Wiqvist, N., Bergström, S. Lancet, 1970, i, 190. 11. Wiqvist, N., Bygdeman, M. ibid. p. 889. 12. Wiqvist, N., Bygdeman, M., Kirton, K. Proceedings of Fifteenth Nobel Symposium on Control of Human Fertility (edited by U. Bovell and E. Diczfalusy). Stockholm (in the press). 1. 2.
of similar
doses, intrauterine administration resulted in a less dramatic initial response but a more sustained and effective stimulation of uterine contractility. The duration of the stimulatory response varied between 1 and 3 hours. The effect of intrauterine administration has been assessed in 12 women admitted for therapeutic abortion. The results are shown in the accompanying table. The clinical effectiveness of local administration during pregnancy is comparable with that of intravenous infusion. In addition, the method requires less supervision of the patient. The total dose used in the individual cases was approximately one-tenth of the intravenous dose. The
early
717 most
remarkable difference consisted in the virtually of generalised side-effects.
complete elimination
This work was supported by the Swedish Medical Research Council and the Astra Company. Department of Women’s Diseases, Karolinska Sjukhuset, N. Stockholm 60, Sweden.
WIQVIST
M. BYGDEMAN.
EMERGENCY CALL SERVICE SIR,-Dr. Pinsent (Sept. 19, p. 604) states that on over 80% of occasions on which the call service was contacted no medical emergency was found." If he denies the patient the opportunity to telephone his doctor for advice, the patient will do the only thing he can-ask for a visit. I estimate that at least half of all out-of-hours telephone calls can be dealt with by telephone or the matter left until routine working hours ". I also disagree with Dr. Pinsent’s classification: a child who develops otitis media on Saturday afternoon should not wait until " routine working hours " for treatment. There are many causes of a crying child, among the commoner being earache and abdominal pain: it can be very difficult for an experienced doctor to diagnose the cause of crying; to expect an emotionally involved parent to make a correct diagnosis is less than fair. A two-tier system of doctors and nurses in radio contact may be one way of providing off-duty for doctors. I submit, Sir, that one doctor (on call for his colleagues) who can advise by telephone or arrange to see the patient at a convenient time gives a more economical and more satisfactory service. "
"
H. E. G. REES.
SOCIAL WORK IN GENERAL PRACTICE
SiR,—The paper by Dr. Harwin and his colleagues (Sept. 12, p. 559) is an important contribution to the reconstruction of medical care in Britain. In an era when the range of domiciliary care has enormously increased and morbidity moved towards a preponderance of degenerative and psychosocial conditions, it is astonishing that the trained social caseworker has as yet found little place in our system of personal medical care. Potentially, she stands in a similar practising relationship to the behavioural sciences as does the doctor to internal medicine. In practice, however, she remains incarcerated largely within the institutional setting. Some of the reasons for this are historical. In the pre-N.H.S. days of fee-paying general practice and of voluntary " and " municipal " hospitals, the hospital represented concentration points of maximum need. In these the social caseworker was strategically placed. But that it remains so after 22 years of the N.H.S. is a measure of the medical profession’s aversion to change. That favourable attitudes to medicosocial teamwork were, in this survey, associated with younger practitioners, is perhaps a sign of hope for the future: but that 50% of practitioners in practice for less than 10 years were " neutral " or unfavourable " to such developments surely tempers any optimism. And that even " a few " doctors are still under the happy illusion of welcoming such teamwork " chiefly because it offered them the hope of freedom from an unwanted burden " tempers it still further. The immediate need is for the provision of much wider experimental attachment of social caseworkers to selected general practices; and the critical assessment, from experience, of how social caseworker and general practitioner work best together. Dr. Harwin remarks " that few doctors had any clear "
"
idea of the function of the social worker
or
of the types of
problems with which her help might be usefully invoked ". Is this surprising ? Our own experience, in a department staffed with a social caseworker of many years’ experience in community work, is that we are only now beginning to learn. We propose that 15-20 such attachments be set up in selected practices, each for a period of, say, three years. This would provide a wealth of basic experience. But it can be achieved only with the support of the Department of Health and Social Security in funding and coordination, and with the cooperation of the Royal College of General Practitioners and the Institute of Medical Social Workers. It is immaterial from which of these three the initiative comes. But if the Department is willing to undertake such a role, there should be no insuperable difficulty in finding
suitable practices. The second need is for changes in the educational pattern of physicians and, perhaps, of social workers also. University departments of general practice will have to accept (as has Manchester) that they have certain responsibilities to cooperate, when requested, in the training of social case-workers and health visitors as well as student physicians. The undergraduate (as well as graduate) physician needs to be introduced not only to the theoretical concepts but also to the practice of social science. Where better to illustrate these than in a group general practice in which a social caseworker is an integral part of the team ? Darbishire House Health Centre, University of Manchester, Manchester M13 OF P.
E. M. INESON H. J. WRIGHT.
S.H. ANTIGEN AND CHRONIC LIVER DISEASE SiR,The continued presence of the serum-hepatitis (s.H.) antigen in some patients with a history of serum hepatitis and in some patients with progressive liver disease raises the possibility of an association between some forms of chronic liver disease and chronic s.H. virus infection.1,2 A survey of thirteen published reports 13-14 reveals that S.H. antigen has been detected, albeit with varying frequency in individual series, in serum in 47/374 cases of chronic active hepatitis, 49/417 cases of cirrhosis (of various types), and in 9/130 cases of carcinoma of the liver. The agar-gel diffusion technique was used to test sera for the 8 presence of s.H. antigen in all but one of these series.8 To evaluate a possible relationship between chronic liver disease and chronic s.H. antigenvemia, we have tested sera from cases of chronic liver disease for the presence of S.H. antigen in a variety of populations. Sera were tested by both agar-gel diffusion 15 and high-voltage immunoelectroosmophoresis (I.E.O.P.).16 The I.E.O.P. method is ten times as sensitive as agar-gel diffusion. 1. 2.
Wright, R., McCollum, R. W., Klatskin, G. Lancet, 1969, ii, 117. Prince, A. M., Hargrove, R. L., Jeffries, G. H. Trans. Am. Ass. Physns, 1969, 82, 265. 3. Okochi, K., Murakami, S. Vox Sang. 1968, 15, 374. 4. Gitnick, G. L., Gleich, G. J., Schoenfield, L. J., Baggenstoss, A. H., Sutnick, A. I., Blumberg, B. S., London, W. T., Summerskill, W. H. J. Lancet, 1969, ii, 285. 5. Fox, R. A., Niazi, S. P., Sherlock, S. ibid. p. 609. 6. Mathews, J. D., Mackay, I. R. Br. med. J. 1970, i, 259. 7. Velasco, M., Katz, R. Lancet, 1970, i, 779. 8. Krassnitzky, O., Pesendorfer, F., Wewalka, F. Dt. med. Wschr. 1970, 95, 249. 9. Hadziyannis, S. J., Merikas, G. E., Afroudakis, A. P. Lancet, July 11, 1970, p. 100. 10. Blumberg, B. S., Sutnick, A. I., London, W. T. Bull. N.Y. Acad. Med. 1968, 44, 1566. 11. Chandra, R. K. Lancet, 1970, i, 537. 12. Reinicke, V., Nordenfelt, E. ibid. p. 141. 13. Guardia, J., Bacardi, R., Gras, J. ibid. p. 1007. 14. Smith, I. B., Blumberg, B. S. ibid. 1969, ii, 953. 15. Prince, A. M. Proc. natn Acad. Sci. 1968, 60, 814. 16. Prince, A. M., Burke, K. Science, 1970, 169, 593.