108 while the
I describe were seen in the first week of 120 miles away. Centre,
cases
March, 1974, The Health
some
Saltash, Cornwall PL12 6DL.
C.F. RANDALL.
ISCHÆMIA TIMES AND PHENOXYBENZAMINE IN HUMAN CADAVER-KIDNEY DONORS
Sir,-Referring to the importance of warm and cold ischxmia times in preservation of human cadaver kidneys, Hall and his colleagues (March 30, p. 532) observed an increased failure-rate of transplanted kidneys with cold ischemia times greater than 7 t hours. This caused us to review our previous datawhich suggested that kidneys with warm ischemia times greater than 15 minutes and cold ischemia times greater than 7 hours before pulsatile preservation had a higher incidence of acute tubular necrosis (A.T.N.) after transplantation. We used a modified discriminant function procedure, discriminating acute tubular necrosis from normal function on the basis of warm ischemia time, cold ischaemia time, pulsatile preservation time, and presence or absence of phenoxybenzamine pretreatment of donor. The efficacy of the x-adrenergic blocking agent, phenoxybenzamine, was demonstrated experimentally by Belzer et al.The modified procedure consisted of constraining the traditional discriminant function procedure so that the probability of A.T.N. is never less for greater values of the Sterling, W. A., Pierce, J. C., Lee, H. M., Hume, D. M., Hutcher, N. E., Mendez-Picon, G. Surgery Gynec. Obstet. 1972, 135, 589. 2. Belzer, R. O., Reed, T. W., Pryor, J. P., Kountz, S. L., Dunphy, J. E. ibid. 1970, 130, 467. 1.
three times. Rough discrimination boundaries are shown in the accompanying figure for selected values of the four discriminating variables. Arranged in this way it becomes obvious that as pulsatile preservation time increases narrower limits of warm and cold ischaemia times must be observed in order to avoid A.T.N. Pretreatment with phenoxybenzamine seems to increase the tolerance to warm and cold ischaemia times. These data fit the concept that damage from warm ischaemia, cold ischaemia, and pulsatile preservation interval is cumulative and that pretreatment of cadaver donors with phenoxybenzamine is helpful in procurement of cadaver organs. Although discrimination was statistically significant at the 5% level, the paucity of data requires that caution be used when interpreting the exact position of the discrimination boundaries. ’
Departments of Surgery and Biostatistics, University of Alabama Medical Center, University Station, Birmingham, Alabama 35294, U.S.A.
ORAL BACTERIAL VACCINE AND COLDS
SIR,-Both Price and Henleyand your editorial (Dec. 28, p. 1552) overlooked the study2 we made on the effects of oral bacterial vaccine in colds. Unlike them we studied two groups of adults, but we used a strict double-blind trial designed to record all respiratory symptoms in detail. We believe the vaccine and placebo and the regimen were similar to those used by Price and Henley. yet there was no effect on the frequency, duration, or severity of colds. There seem to be two possible explanations. Either the results of one or other trial are capricious, or the results of both are valid and the different results are due to differences in the conditions of the trial. Obvious suggestions are that in the trial in which an effect was seen the subjects were not adults, but children who might not yet have acquired full immunity to common respiratory bacteria; then the effects were apparently in preventing the severer illnesses which it is reasonable to postulate might be partly due to bacteria. We think that although there is little evidence that oral vaccines of this type have a useful effect in healthy adults it might be worth trying to confirm whether in young subjects or those with some tendency to bacterial infections such antigens might be of value. Your editorial suggests that the oral route does not fit in with current ideas of local immunity and it might be more effective to give the vaccine as nasal drops if practicable to administer it by this route. Division of Communicable Diseases, Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
Areas within dark lines represent predicted immediate function for various time intervals of warm ischeemia, cold ischeemia, and pulsatile preservation.
Observed values (0 immediate function, . necrosis) are plotted within predicted areas.
acute
tubular
W. A. STERLING K. A. KIRK M. E. TURNER.
D. A. J. TYRRELL.
ADMISSIONS TO MEDICAL SCHOOLS SiR—You quote (Dec. 14, p. 1466) from the Commonwealth Universities Yearbook 1974 some of the figures for medical-school output and student numbers in Africa and rightly state that beside these statistics for developing Commonwealth countries the problems of medical-school expansion in Britain pale into insignificance. Nevertheless the situation in Great Britain remains disturbing and the problems are interrelated. It was revealed by the Universities Central Council on Admissions report for 1972-73 that only 30% of U.K. applicants to read medicine were admitted. At a time when the N.H.S. is increasingly 1. Price, M. C., Henley, G. Practitioner, 1974, 213, 720. 2. Tyrrell, D. A. J., Nolan, P. S., Reed, S. E., Healy, M. prev. soc. Med. 1972, 26, 129.
J. R.
Br.
J.
109
dependent
on overseas
doctors
can we
afford
to waste
this
potential ? It is wasteful not only in terms of educational opportunity for these able young people themselves but also because Great Britain continues to absorb the medical graduates of other countries who can surely ill afford to lose them. The Chief Medical Officer of the Department of Health has stated in his annual report that in 1973 the number of N.H.S. doctors rose by 3%, half of them born abroad. Perhaps 50% of doctors at present working in National Health Service hospitals come from abroad. A further relevant and sad statistic revealed by the 197273 U.C.C.A. report is that of 2120 overseas applicants for places in British medical schools only 116 were admitted, If existing medical schools an acceptance rate of 5%. cannot further increase their intake then there seems to be much logic in the proposalby the members of the National Association of Clinical Tutors for a working-party to examine the possibility of utilising the resources of the Open University for preclinical training and those in postgraduate teaching centres in district general hospitals for clinical training. Even post-Illich ! 38 Magdalen Road, Norwich,
JAMES
Norfolk NOR 57P.
BEVERIDGE.
SEASONAL VARIATION OF PATENT DUCTUS ARTERIOSUS
SIR,-Dr Rothman and Dr Fyler reported a seasonal variation in ventricular septal defect (V.S.D.), especially when associated with patent ductus arteriosus (P.D.A.).2 However, Dr Rosenberg and Dr Heinonen (Oct. 12, p. 903) could not demonstrate such a seasonal trend for last menstrual periods in mothers of offspring with either
simple
or
complex
v.s.D.
These contradictory findings prompt me to report a study which did not demonstrate a seasonal variation in P.D.A., as had been suggested by other workers. 3,4 The records of 421 patients, over the age of one month with P.D.A., confirmed by surgery, catheterisation, or necropsy, were reviewed. 135 such patients were treated at the Massachusetts General Hospital of Boston and 286 at the YaleNew Haven Hospital, between 1947 and 1966. Their years of birth ranged from 1893 to 1966. These patients were classified: as (a) having only a P.D.A., (b) as having a P.D.A. associated with another anomaly, (c) as presenting a chromosomal aberration and P.D.A., and (d) as patients known to have been affected in utero by rubella virus. There was no statistically significant seasonal variation in births of patients with P.D.A. of any of the above groups, with the exception of the rubella syndrome. This does not accord with Record and McKeown3 who found that P.D.A. was increased among girls born between May and December, with a peak in July and August. Polani and Campbell4 reached similar conclusions. However, by combining Record’s figures with their own, they found that more girls were born during May to November, with the peak in August, and fewer from December to April. They also found that births of affected boys were equally distributed through the year, except that fewer were born in January, February, and March. Finally, Rutstein et al.5 described an increase in the births of patients with P.D.A. between October and January and correlated these with the high incidence of rubella seven months earlier. My results do not agree with those of the above workers. I believe that the season of birth does not significantly 1. Times, Nov. 8, 1974, p. 17. 2. Rothman, K. J., Fyler, D. C. Lancet, 1974, ii, 193. 3. Record, R. G., McKeown, T. Br. Heart J. 1953, 15, 376. 4. Polani, P. E., Campbell, M. Ann. hum. Genet. 1960, 24, 343. 5. Rutstein, D. D., Nickerson, R. J., Heald, F. P. Am. J. Dis. Child.
1952, 84, 199.
affect the incidence of P.D.A., with the exception of the P.D.A. caused by the rubella virus. The incidence of births of affected infants should reflect the season of the epidemic as in the cases reported (November to January), which followed a spring epidemic. I thank Dr W. W. L. Glenn for his assistance in
allowing
the
study of the Yale records. B. Department of Pediatrics, University of Athens, P.O. Box 3064, Athens, Greece.
CHRISTOS S. BARTSOCAS.
CHEMOPROPHYLAXIS OF MENINGOCOCCAL INFECTION SIR,-I am perturbed by your editorial (Dec. 14, p. 1431) in which you state that minocycline cannot be recommended as a prophylactic agent, firstly because experience is "
limited, and,
more
seriously, because toxic vestibular to 90% of those receiving
effects have been reported in up
the drug." The first criticism may be pertinent when considering British evidence, but is certainly not true of worldwide publications referring to the prophylactic treatment of over
20,000 subjects.1-5 Regarding your second point I agree that minocycline can cause giddiness. However, our own extensive review of the published and unpublished literature has provided us with an estimated overall incidence of about 5%. Guttler,l for example, in his study of 14,800 subjects, did not even consider the incidence of dizziness worthy of special mention, but classified it together with headache and nausea, quoting a total incidence of 7%. In some series,6.? " vestibular " side-effects were totally lacking in patients treated with minocycline. Masterton 8 reported that of 349 patients treated with single doses of 300 mg. and 400 mg. of minocycline for acute gonorrhoea, only 2 (0-6%) complained of giddiness. These figures are totally at variance with those of Williams 9 who in any case treated only 19 patients, 7 of whom received doses far above those recommended. Lederle Laboratories, Fareham Road, Gosport, P.O. Box 7, Hants P013 0AS.
A. YEADON, Medical Director.
TREATMENT OF MALIGNANT MELANOMA
SIR,-Grant et al., 10 reporting results with B.C.G. immunotherapy in malignant melanoma, describe such complications as fever, granulomatous hepatitis, mycobacterial pneumonia, and splenomegaly, suggesting that they are the These and other result of systemic B.C.G. infection. complications have also been attributed to a hypersensitivity reaction.ll Neurological symptoms have, as far as we know, not been reported. A 28-year-old woman with malignant melanoma developed Guillain-Barré syndrome after B.C.G. immunotherapy by the multiple puncture technique. She had melanoma Guttler, R. B. Antimicrob. Ag. Chemother. 1972, 1, 397. Devine, L. F. Am. J. Epidem. 1971, 93, 337. Guttler, R. B. J. infect. Dis. 1971, 124, 199. Devine, L. F. Am. J. Epidem. 1973, 97, 394. 5. Munford, R. S. J. infect. Dis. 1974, 129, 644. 6. Pines, A. Practitioner, 1974, 213, 727. 7. Fowler, W. Br. J. clin. Pract. 1974, 28, 347. 8. Masterton, G., Schofield, C. B. S. Lancet, 1974, ii, 1139. 9. Williams, D. N. ibid. p. 744. 10. Grant, R. M., Cochran, A. J., Hoyle, D., Mackie, R., Murray, E. L., Ross, C. Lancet, 1974, ii, 1096. 11. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell, C. M., Pitch, Y. M., Morton, D. L. New Engl. J. Med. 1973, 289, 827. 1. 2. 3. 4.
I describe were seen in the first week of 120 miles away. Centre,
cases
March, 1974, The Health
some
Saltash, Cornwall PL12 6DL.
C.F. RANDALL.
ISCHÆMIA TIMES AND PHENOXYBENZAMINE IN HUMAN CADAVER-KIDNEY DONORS
Sir,-Referring to the importance of warm and cold ischxmia times in preservation of human cadaver kidneys, Hall and his colleagues (March 30, p. 532) observed an increased failure-rate of transplanted kidneys with cold ischemia times greater than 7 t hours. This caused us to review our previous datawhich suggested that kidneys with warm ischemia times greater than 15 minutes and cold ischemia times greater than 7 hours before pulsatile preservation had a higher incidence of acute tubular necrosis (A.T.N.) after transplantation. We used a modified discriminant function procedure, discriminating acute tubular necrosis from normal function on the basis of warm ischemia time, cold ischaemia time, pulsatile preservation time, and presence or absence of phenoxybenzamine pretreatment of donor. The efficacy of the x-adrenergic blocking agent, phenoxybenzamine, was demonstrated experimentally by Belzer et al.The modified procedure consisted of constraining the traditional discriminant function procedure so that the probability of A.T.N. is never less for greater values of the Sterling, W. A., Pierce, J. C., Lee, H. M., Hume, D. M., Hutcher, N. E., Mendez-Picon, G. Surgery Gynec. Obstet. 1972, 135, 589. 2. Belzer, R. O., Reed, T. W., Pryor, J. P., Kountz, S. L., Dunphy, J. E. ibid. 1970, 130, 467. 1.
three times. Rough discrimination boundaries are shown in the accompanying figure for selected values of the four discriminating variables. Arranged in this way it becomes obvious that as pulsatile preservation time increases narrower limits of warm and cold ischaemia times must be observed in order to avoid A.T.N. Pretreatment with phenoxybenzamine seems to increase the tolerance to warm and cold ischaemia times. These data fit the concept that damage from warm ischaemia, cold ischaemia, and pulsatile preservation interval is cumulative and that pretreatment of cadaver donors with phenoxybenzamine is helpful in procurement of cadaver organs. Although discrimination was statistically significant at the 5% level, the paucity of data requires that caution be used when interpreting the exact position of the discrimination boundaries. ’
Departments of Surgery and Biostatistics, University of Alabama Medical Center, University Station, Birmingham, Alabama 35294, U.S.A.
ORAL BACTERIAL VACCINE AND COLDS
SIR,-Both Price and Henleyand your editorial (Dec. 28, p. 1552) overlooked the study2 we made on the effects of oral bacterial vaccine in colds. Unlike them we studied two groups of adults, but we used a strict double-blind trial designed to record all respiratory symptoms in detail. We believe the vaccine and placebo and the regimen were similar to those used by Price and Henley. yet there was no effect on the frequency, duration, or severity of colds. There seem to be two possible explanations. Either the results of one or other trial are capricious, or the results of both are valid and the different results are due to differences in the conditions of the trial. Obvious suggestions are that in the trial in which an effect was seen the subjects were not adults, but children who might not yet have acquired full immunity to common respiratory bacteria; then the effects were apparently in preventing the severer illnesses which it is reasonable to postulate might be partly due to bacteria. We think that although there is little evidence that oral vaccines of this type have a useful effect in healthy adults it might be worth trying to confirm whether in young subjects or those with some tendency to bacterial infections such antigens might be of value. Your editorial suggests that the oral route does not fit in with current ideas of local immunity and it might be more effective to give the vaccine as nasal drops if practicable to administer it by this route. Division of Communicable Diseases, Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
Areas within dark lines represent predicted immediate function for various time intervals of warm ischeemia, cold ischeemia, and pulsatile preservation.
Observed values (0 immediate function, . necrosis) are plotted within predicted areas.
acute
tubular
W. A. STERLING K. A. KIRK M. E. TURNER.
D. A. J. TYRRELL.
ADMISSIONS TO MEDICAL SCHOOLS SiR—You quote (Dec. 14, p. 1466) from the Commonwealth Universities Yearbook 1974 some of the figures for medical-school output and student numbers in Africa and rightly state that beside these statistics for developing Commonwealth countries the problems of medical-school expansion in Britain pale into insignificance. Nevertheless the situation in Great Britain remains disturbing and the problems are interrelated. It was revealed by the Universities Central Council on Admissions report for 1972-73 that only 30% of U.K. applicants to read medicine were admitted. At a time when the N.H.S. is increasingly 1. Price, M. C., Henley, G. Practitioner, 1974, 213, 720. 2. Tyrrell, D. A. J., Nolan, P. S., Reed, S. E., Healy, M. prev. soc. Med. 1972, 26, 129.
J. R.
Br.
J.
109
dependent
on overseas
doctors
can we
afford
to waste
this
potential ? It is wasteful not only in terms of educational opportunity for these able young people themselves but also because Great Britain continues to absorb the medical graduates of other countries who can surely ill afford to lose them. The Chief Medical Officer of the Department of Health has stated in his annual report that in 1973 the number of N.H.S. doctors rose by 3%, half of them born abroad. Perhaps 50% of doctors at present working in National Health Service hospitals come from abroad. A further relevant and sad statistic revealed by the 197273 U.C.C.A. report is that of 2120 overseas applicants for places in British medical schools only 116 were admitted, If existing medical schools an acceptance rate of 5%. cannot further increase their intake then there seems to be much logic in the proposalby the members of the National Association of Clinical Tutors for a working-party to examine the possibility of utilising the resources of the Open University for preclinical training and those in postgraduate teaching centres in district general hospitals for clinical training. Even post-Illich ! 38 Magdalen Road, Norwich,
JAMES
Norfolk NOR 57P.
BEVERIDGE.
SEASONAL VARIATION OF PATENT DUCTUS ARTERIOSUS
SIR,-Dr Rothman and Dr Fyler reported a seasonal variation in ventricular septal defect (V.S.D.), especially when associated with patent ductus arteriosus (P.D.A.).2 However, Dr Rosenberg and Dr Heinonen (Oct. 12, p. 903) could not demonstrate such a seasonal trend for last menstrual periods in mothers of offspring with either
simple
or
complex
v.s.D.
These contradictory findings prompt me to report a study which did not demonstrate a seasonal variation in P.D.A., as had been suggested by other workers. 3,4 The records of 421 patients, over the age of one month with P.D.A., confirmed by surgery, catheterisation, or necropsy, were reviewed. 135 such patients were treated at the Massachusetts General Hospital of Boston and 286 at the YaleNew Haven Hospital, between 1947 and 1966. Their years of birth ranged from 1893 to 1966. These patients were classified: as (a) having only a P.D.A., (b) as having a P.D.A. associated with another anomaly, (c) as presenting a chromosomal aberration and P.D.A., and (d) as patients known to have been affected in utero by rubella virus. There was no statistically significant seasonal variation in births of patients with P.D.A. of any of the above groups, with the exception of the rubella syndrome. This does not accord with Record and McKeown3 who found that P.D.A. was increased among girls born between May and December, with a peak in July and August. Polani and Campbell4 reached similar conclusions. However, by combining Record’s figures with their own, they found that more girls were born during May to November, with the peak in August, and fewer from December to April. They also found that births of affected boys were equally distributed through the year, except that fewer were born in January, February, and March. Finally, Rutstein et al.5 described an increase in the births of patients with P.D.A. between October and January and correlated these with the high incidence of rubella seven months earlier. My results do not agree with those of the above workers. I believe that the season of birth does not significantly 1. Times, Nov. 8, 1974, p. 17. 2. Rothman, K. J., Fyler, D. C. Lancet, 1974, ii, 193. 3. Record, R. G., McKeown, T. Br. Heart J. 1953, 15, 376. 4. Polani, P. E., Campbell, M. Ann. hum. Genet. 1960, 24, 343. 5. Rutstein, D. D., Nickerson, R. J., Heald, F. P. Am. J. Dis. Child.
1952, 84, 199.
affect the incidence of P.D.A., with the exception of the P.D.A. caused by the rubella virus. The incidence of births of affected infants should reflect the season of the epidemic as in the cases reported (November to January), which followed a spring epidemic. I thank Dr W. W. L. Glenn for his assistance in
allowing
the
study of the Yale records. B. Department of Pediatrics, University of Athens, P.O. Box 3064, Athens, Greece.
CHRISTOS S. BARTSOCAS.
CHEMOPROPHYLAXIS OF MENINGOCOCCAL INFECTION SIR,-I am perturbed by your editorial (Dec. 14, p. 1431) in which you state that minocycline cannot be recommended as a prophylactic agent, firstly because experience is "
limited, and,
more
seriously, because toxic vestibular to 90% of those receiving
effects have been reported in up
the drug." The first criticism may be pertinent when considering British evidence, but is certainly not true of worldwide publications referring to the prophylactic treatment of over
20,000 subjects.1-5 Regarding your second point I agree that minocycline can cause giddiness. However, our own extensive review of the published and unpublished literature has provided us with an estimated overall incidence of about 5%. Guttler,l for example, in his study of 14,800 subjects, did not even consider the incidence of dizziness worthy of special mention, but classified it together with headache and nausea, quoting a total incidence of 7%. In some series,6.? " vestibular " side-effects were totally lacking in patients treated with minocycline. Masterton 8 reported that of 349 patients treated with single doses of 300 mg. and 400 mg. of minocycline for acute gonorrhoea, only 2 (0-6%) complained of giddiness. These figures are totally at variance with those of Williams 9 who in any case treated only 19 patients, 7 of whom received doses far above those recommended. Lederle Laboratories, Fareham Road, Gosport, P.O. Box 7, Hants P013 0AS.
A. YEADON, Medical Director.
TREATMENT OF MALIGNANT MELANOMA
SIR,-Grant et al., 10 reporting results with B.C.G. immunotherapy in malignant melanoma, describe such complications as fever, granulomatous hepatitis, mycobacterial pneumonia, and splenomegaly, suggesting that they are the These and other result of systemic B.C.G. infection. complications have also been attributed to a hypersensitivity reaction.ll Neurological symptoms have, as far as we know, not been reported. A 28-year-old woman with malignant melanoma developed Guillain-Barré syndrome after B.C.G. immunotherapy by the multiple puncture technique. She had melanoma Guttler, R. B. Antimicrob. Ag. Chemother. 1972, 1, 397. Devine, L. F. Am. J. Epidem. 1971, 93, 337. Guttler, R. B. J. infect. Dis. 1971, 124, 199. Devine, L. F. Am. J. Epidem. 1973, 97, 394. 5. Munford, R. S. J. infect. Dis. 1974, 129, 644. 6. Pines, A. Practitioner, 1974, 213, 727. 7. Fowler, W. Br. J. clin. Pract. 1974, 28, 347. 8. Masterton, G., Schofield, C. B. S. Lancet, 1974, ii, 1139. 9. Williams, D. N. ibid. p. 744. 10. Grant, R. M., Cochran, A. J., Hoyle, D., Mackie, R., Murray, E. L., Ross, C. Lancet, 1974, ii, 1096. 11. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell, C. M., Pitch, Y. M., Morton, D. L. New Engl. J. Med. 1973, 289, 827. 1. 2. 3. 4.
