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CORTICOTROPHIN AND SERUM-ZINC
767 HL-A 1 AND 8 IN ORGAN DONORS
SlR,—Dr Stoker and co-workers (July 22 p. 162) demonstrated an increased incidence of HL-A 1 and 8 in adult ccaliac disease when Compared- with a control population comprising 159 healthy subjects and 109 potential Although this report does not indicate organ donors. whether these were related living donors or cadavers, we should like to point out how the use of the cadavers might give a falsely high impression of the incidence of certain antigens. We have analysed the HL-A phenotypes of our cadaver donors (virtually all having irreversible brain damage) who have presented over the past two years and compared these with a group of healthy unrelated subjects typed over the The- results- are summarised in the accomsame period. table and show a considerable variation in the panying FREQUENCY
OF HL-A ANTIGENS IN CADAVER KIDNEY DONORS IN THE
SCOTTISH S.E. REGION
This does not seem to be due to.antigen deletion, since only 14% of our donor population having 4 antigens have the combination, as compared to 57% in controls-a finding which is statistically significant. However, it is conceivable that transfused heterologous lymphocytes may apparently and replace the deletion of 1 and 8 with other specificities, this is suggested by the higher prevalence of " full houses " in the donor group (41% compared with 27%) and the occasional appearance of more than 4 specificities. Another possibility is that HL-A 1 and 8 may transmute to other specificities. A less likely but more intriguing possibility is that persons lacking the HL-A 1 and 8 do not tolerate stress states well and’arc therefore more likely to achieve organdonor status. Perhaps- they are also more prone two fatal
preadventure! With evidence accumulating- to implicate HL-A 8 with disordered immunity 5-8 and transplant" rejection,9 it is important to avoid cadaver donors as controls for such studies, since this group appears to-be particularly deficient in this antigen. South-East Scotland Regional Blood- Tranfusion Centre,
Royal Infirmary, Edinburgh. Department of Surgery, University of Edinburgh.
*
Yates’ correction for small numbers.
Ns=not
significant.
HL-A frequencies between the groups. HL-A 1 and 8- and the combination of these
In are
particular, significantly
depleted. The lability of the HL-A system has been described by Zmijewski 12 with- such minor stresses as overeating, exercise, and alcohol consumption affecting the expression of HL-A antigens. Dick and Steele3 have noted bizarre changes of reactivity in a cadaver donor, and Harris et awl.4 point out the effects on tissue typing of administration of blood or drugs. Most cadaver donors with irreversible cerebral- damage have been prescribed a battery of drugs, have been subjected to surgery and anaesthesia, may have received large transfusions of blood, and in addition, may have been on assisted ventilation. It is not surprising that such severe metabolic stresses may lead to typing changes. Our own observations show that elective surgery, without associated use of blood- or drugs (excluding general anaesthesia), may produce temporary gains or deletions of antigens in the early postoperative period. Typing of transplanted recipients on heavy immunosuppression is also difficult and reminiscent of the cadaver/donor situation. Our potential donors show a significant decrease in the antigens HL-A 1 and HL-A 8 and of the 1+8 combination. 1. 2.
Zmijewski, C. M. Histocompatibility Testing, 1965, p. 193. Zmijewski, C. M., McCloskey, R. V., St. Pierre, R. L. ibid. 1967, p. 397. 3. Dick, H. M., Steele, C. M. Lancet, 1971, i, 1135. 4. Harris, R., Wentzel, J., Cocking, H., Dodsworth, H., Ukaejiofo, E. Q. Histocompatibility. Testing, 1970, p. 603.
A. G. WHITE A. J. DA COSTA.
J. B. MORTON.
CORTICOTROPHIN AND SERUM-ZINC SIR,-We cannot agree with Dr. Flynn’s comment letter.1o Our experiments most (July 29, p. 235) on our " certainly do not show a synergism between corticotrophin and adrenal-cortex secretion "’: they may well show an antagonism. We were careful not to report a significant change in serum-zinc concentration, but simply wished to point out that, in man, a rise in concentration was unusual. A rise in concentration of only 8% may well be statistically significant: this does not necessarily imply that it has any bearing on trace-element physiology. We reported the maximum change in zinc concentration during the 24 hours following the corticotrophin injection; and not the change" 24 hours after injection of corticotrophin gel". Venous blood-samples were collected 6, 9, 12, and 24 hours after corticotrophin: the earlier samples did not show a rise in zinc concentration when compared with subsequent samples; in 3 subjects, the greatest fall was found in the first sample collected. If the action of corticotrophin on the serum-zinc is antagonised: by the consequent adrenal-cortex secretion, we would expect that the response to corticotrophin- would be enhanced after adrenal-cortex atrophy in hypophysectomised rats and that it would. not be necessary to use an unphysiological dose of corticotrophin to show an effect significant at only the 5 % level-. We cannot agree that correlations with aldolase and growth hormone " should not be seriously considered ". Dr. Flynn’s original paper 11 showed that trauma- was associated with a rise in zinc concentration, so. that it was entirely logical to use- serum-aldolase as an objective assessment of tissue injury following the corticotrophin injection, and to seek a correlation with the change in serum-zinc concentration. Since the characteristic action of corticotrophin-, to stimulate adrenal-cortex secretion, is presumably not responsible for the rise in serum-zinc Falchuk, Z. M., Rogentine, G. N., Strober, W. J. clin. Invest. 1972, 51, 1602. 6. Thorsby, E., Engeset, A., Lie, S. O. Tissue Antigens, 1971, 1, 147. 7. Falk, J., Osoba, D. Lancet, 1971, ii, 1118. 8. Grumet, F. C., Coukell, A., Bodmer, J. G., Bodmer, W. F., McDevitt, H. O. New Engl. J. Med. 1971, 285, 193. 9. Kissmeyer Neilsen, F., et al. Transplant Proc. 1971, 3, 1019. 10. Tawodzera, P. B. P., Bell, R. M. S., Jones, J. J. Lancet, 1972, i, 1072. 11. Flynn, A., Pories, W. J., Strain, W. H., Hill, O. A.,Jr., Fratianne, R. B. ibid. 1971, ii, 1169. 5.
768 concentration (zinc concentration is depressed by adrenal corticoids) it is reasonable to look for an association between the change in serum-zinc concentration and other known actions of corticotrophin-e.g., growth-hormone release. Godfrey Huggins School of Medicine,
Salisbury, Rhodesia.
TABLE II-ESTIMATED INCIDENCE OF DEATH WITH HYALINE MEMBRANES PER 1000 LIVEBIRTHS
P. B. P. TAWODZERA R. M. S. BELL
J. J. JONES.
HYALINE-MEMBRANE DISEASE
SiR,-Since the experiment of Liggins,l in which the infusion of cortisol into one of twin fetal lambs caused not only premature delivery but also preferential survival of the infused lamb, it has been considered feasible to postulate that the synthesis of lung surfactant is connected with the presence of corticosteroids normally produced by the fetus to promote labour.2,3 For the theory to be tenable one would expect the incidence of hyaline membranes among infants delivered by cxsarean section before the commencement of labour to be greater than the incidence among infants delivered abdominally during labour. The data of the 1958 British Perinatal Mortality Survey were therefore examined in depth to attempt to elucidate the
*
Cases with known
gestation only.
TABLE III--COMPARISON OF OBSERVED AND EXPECTED* NUMBERS OF DEATHS WITH H.M. AMONG THE POPULATION HAVING BEEN DELIVERED ABDOMINALLY AFTER LABOUR HAD
COMMENCED, IF THE INCIDENCE WERE ASSUMED TO BE THE SAME AS AMONG CASES DELIVERED IN THIS WAY BEFORE THE ONSET OF LABOUR
problem. The survey, carried out under the auspices of the National Birthday Trust,4,5 studied in detail the events of pregnancy and delivery of some 7117 singleton stillbirths and neonatal deaths occurring in England, Scotland, and Wales TABLE I-THE DATA
h
* Where Eg
=
10001s the expected
no.
of
cases
of gestation g, ig is the in-
cidence among the cases of c.s. not in labour of gestation g, and ng is the number of livebirths delivered by c.s. in labour at gestation g.
The incidence of hyaline membranes having been shown inversely with increasing gestation, the data have been considered in 2-week gestation periods (table I). In the population at risk, cxsarean section was rarely performed after labour had commenced if the gestation was low. Consequently one would anticipate that the overall incidence of death with hyaline membranes would be lower among this group than among infants delivered by ctsarean section (c.s.) before the onset of labour. This was indeed observed, the total incidence among live infants delivered by section before labour started being 46 per 1000, compared with only 3 per 1000 among infants delivered abdominally after the commencement of labour, and 2 per 1000 among infants delivered per vaginam.
to vary
* Cases with known gestation only.
the 3-month period March, April, and May, 1958. 68% of these were given a detailed post-mortem examination, the lung histology of the majority of these being independently assessed for consistency of diagnosis by a team under the chairmanship of Dr. A. E. Claireaux. After infants with severe congenital malformations and rhesus isoimmunisation had been excluded, some 339 neonatal deaths with hyaline membranes were identified.s For detailed analysis the population at risk was taken
during Some
be the number of livebirths in the first week of March a factor of 8 (some 16,994 singletons delivered in that week having also been studied in respect of history of pregnancy and delivery 4,5).
to
multiplied by
1. Liggins, G. C. J. Endocr. 1969, 42, 323. 2. Dawes, G. S. 3rd European Perinatal Congress, Lausanne, 1972. 3. de Lemos, R. A., Shermeta, D. W., Knelson, J. H., Kotas, R., Avery, M. E. Am. Rev. resp. Dis. 1970, 102, 459. 4. Butler, N. R., Bonham, D. G. Perinatal Mortality: First Report of the 1958 British Perinatal Mortality Survey. Edinburgh, 1963. 5. Butler, N. R., Alberman, E. D. Perinatal Problems. Second Report of the 1958 British Perinatal Mortality Survey. Edinburgh, 1969. 6. Fedrick, J., Butler, N. R. Biol. Neonat. 1970, 15, 229.
TABLE IV-COMPARISON OF OBSERVED AND EXPECTED NUMBERS OF
DEATHS WITH H.M. AMONG THE POPULATION HAVING BEEK DELIVERED ABDOMINALLY AFTER LABOUR HAD COMMENCED IF THE INCIDENCE WERE ASSUMED TO BE THE SAME AS AMONG CASES DELIVERED VAGINALLY
SlR,—Dr Stoker and co-workers (July 22 p. 162) demonstrated an increased incidence of HL-A 1 and 8 in adult ccaliac disease when Compared- with a control population comprising 159 healthy subjects and 109 potential Although this report does not indicate organ donors. whether these were related living donors or cadavers, we should like to point out how the use of the cadavers might give a falsely high impression of the incidence of certain antigens. We have analysed the HL-A phenotypes of our cadaver donors (virtually all having irreversible brain damage) who have presented over the past two years and compared these with a group of healthy unrelated subjects typed over the The- results- are summarised in the accomsame period. table and show a considerable variation in the panying FREQUENCY
OF HL-A ANTIGENS IN CADAVER KIDNEY DONORS IN THE
SCOTTISH S.E. REGION
This does not seem to be due to.antigen deletion, since only 14% of our donor population having 4 antigens have the combination, as compared to 57% in controls-a finding which is statistically significant. However, it is conceivable that transfused heterologous lymphocytes may apparently and replace the deletion of 1 and 8 with other specificities, this is suggested by the higher prevalence of " full houses " in the donor group (41% compared with 27%) and the occasional appearance of more than 4 specificities. Another possibility is that HL-A 1 and 8 may transmute to other specificities. A less likely but more intriguing possibility is that persons lacking the HL-A 1 and 8 do not tolerate stress states well and’arc therefore more likely to achieve organdonor status. Perhaps- they are also more prone two fatal
preadventure! With evidence accumulating- to implicate HL-A 8 with disordered immunity 5-8 and transplant" rejection,9 it is important to avoid cadaver donors as controls for such studies, since this group appears to-be particularly deficient in this antigen. South-East Scotland Regional Blood- Tranfusion Centre,
Royal Infirmary, Edinburgh. Department of Surgery, University of Edinburgh.
*
Yates’ correction for small numbers.
Ns=not
significant.
HL-A frequencies between the groups. HL-A 1 and 8- and the combination of these
In are
particular, significantly
depleted. The lability of the HL-A system has been described by Zmijewski 12 with- such minor stresses as overeating, exercise, and alcohol consumption affecting the expression of HL-A antigens. Dick and Steele3 have noted bizarre changes of reactivity in a cadaver donor, and Harris et awl.4 point out the effects on tissue typing of administration of blood or drugs. Most cadaver donors with irreversible cerebral- damage have been prescribed a battery of drugs, have been subjected to surgery and anaesthesia, may have received large transfusions of blood, and in addition, may have been on assisted ventilation. It is not surprising that such severe metabolic stresses may lead to typing changes. Our own observations show that elective surgery, without associated use of blood- or drugs (excluding general anaesthesia), may produce temporary gains or deletions of antigens in the early postoperative period. Typing of transplanted recipients on heavy immunosuppression is also difficult and reminiscent of the cadaver/donor situation. Our potential donors show a significant decrease in the antigens HL-A 1 and HL-A 8 and of the 1+8 combination. 1. 2.
Zmijewski, C. M. Histocompatibility Testing, 1965, p. 193. Zmijewski, C. M., McCloskey, R. V., St. Pierre, R. L. ibid. 1967, p. 397. 3. Dick, H. M., Steele, C. M. Lancet, 1971, i, 1135. 4. Harris, R., Wentzel, J., Cocking, H., Dodsworth, H., Ukaejiofo, E. Q. Histocompatibility. Testing, 1970, p. 603.
A. G. WHITE A. J. DA COSTA.
J. B. MORTON.
CORTICOTROPHIN AND SERUM-ZINC SIR,-We cannot agree with Dr. Flynn’s comment letter.1o Our experiments most (July 29, p. 235) on our " certainly do not show a synergism between corticotrophin and adrenal-cortex secretion "’: they may well show an antagonism. We were careful not to report a significant change in serum-zinc concentration, but simply wished to point out that, in man, a rise in concentration was unusual. A rise in concentration of only 8% may well be statistically significant: this does not necessarily imply that it has any bearing on trace-element physiology. We reported the maximum change in zinc concentration during the 24 hours following the corticotrophin injection; and not the change" 24 hours after injection of corticotrophin gel". Venous blood-samples were collected 6, 9, 12, and 24 hours after corticotrophin: the earlier samples did not show a rise in zinc concentration when compared with subsequent samples; in 3 subjects, the greatest fall was found in the first sample collected. If the action of corticotrophin on the serum-zinc is antagonised: by the consequent adrenal-cortex secretion, we would expect that the response to corticotrophin- would be enhanced after adrenal-cortex atrophy in hypophysectomised rats and that it would. not be necessary to use an unphysiological dose of corticotrophin to show an effect significant at only the 5 % level-. We cannot agree that correlations with aldolase and growth hormone " should not be seriously considered ". Dr. Flynn’s original paper 11 showed that trauma- was associated with a rise in zinc concentration, so. that it was entirely logical to use- serum-aldolase as an objective assessment of tissue injury following the corticotrophin injection, and to seek a correlation with the change in serum-zinc concentration. Since the characteristic action of corticotrophin-, to stimulate adrenal-cortex secretion, is presumably not responsible for the rise in serum-zinc Falchuk, Z. M., Rogentine, G. N., Strober, W. J. clin. Invest. 1972, 51, 1602. 6. Thorsby, E., Engeset, A., Lie, S. O. Tissue Antigens, 1971, 1, 147. 7. Falk, J., Osoba, D. Lancet, 1971, ii, 1118. 8. Grumet, F. C., Coukell, A., Bodmer, J. G., Bodmer, W. F., McDevitt, H. O. New Engl. J. Med. 1971, 285, 193. 9. Kissmeyer Neilsen, F., et al. Transplant Proc. 1971, 3, 1019. 10. Tawodzera, P. B. P., Bell, R. M. S., Jones, J. J. Lancet, 1972, i, 1072. 11. Flynn, A., Pories, W. J., Strain, W. H., Hill, O. A.,Jr., Fratianne, R. B. ibid. 1971, ii, 1169. 5.
768 concentration (zinc concentration is depressed by adrenal corticoids) it is reasonable to look for an association between the change in serum-zinc concentration and other known actions of corticotrophin-e.g., growth-hormone release. Godfrey Huggins School of Medicine,
Salisbury, Rhodesia.
TABLE II-ESTIMATED INCIDENCE OF DEATH WITH HYALINE MEMBRANES PER 1000 LIVEBIRTHS
P. B. P. TAWODZERA R. M. S. BELL
J. J. JONES.
HYALINE-MEMBRANE DISEASE
SiR,-Since the experiment of Liggins,l in which the infusion of cortisol into one of twin fetal lambs caused not only premature delivery but also preferential survival of the infused lamb, it has been considered feasible to postulate that the synthesis of lung surfactant is connected with the presence of corticosteroids normally produced by the fetus to promote labour.2,3 For the theory to be tenable one would expect the incidence of hyaline membranes among infants delivered by cxsarean section before the commencement of labour to be greater than the incidence among infants delivered abdominally during labour. The data of the 1958 British Perinatal Mortality Survey were therefore examined in depth to attempt to elucidate the
*
Cases with known
gestation only.
TABLE III--COMPARISON OF OBSERVED AND EXPECTED* NUMBERS OF DEATHS WITH H.M. AMONG THE POPULATION HAVING BEEN DELIVERED ABDOMINALLY AFTER LABOUR HAD
COMMENCED, IF THE INCIDENCE WERE ASSUMED TO BE THE SAME AS AMONG CASES DELIVERED IN THIS WAY BEFORE THE ONSET OF LABOUR
problem. The survey, carried out under the auspices of the National Birthday Trust,4,5 studied in detail the events of pregnancy and delivery of some 7117 singleton stillbirths and neonatal deaths occurring in England, Scotland, and Wales TABLE I-THE DATA
h
* Where Eg
=
10001s the expected
no.
of
cases
of gestation g, ig is the in-
cidence among the cases of c.s. not in labour of gestation g, and ng is the number of livebirths delivered by c.s. in labour at gestation g.
The incidence of hyaline membranes having been shown inversely with increasing gestation, the data have been considered in 2-week gestation periods (table I). In the population at risk, cxsarean section was rarely performed after labour had commenced if the gestation was low. Consequently one would anticipate that the overall incidence of death with hyaline membranes would be lower among this group than among infants delivered by ctsarean section (c.s.) before the onset of labour. This was indeed observed, the total incidence among live infants delivered by section before labour started being 46 per 1000, compared with only 3 per 1000 among infants delivered abdominally after the commencement of labour, and 2 per 1000 among infants delivered per vaginam.
to vary
* Cases with known gestation only.
the 3-month period March, April, and May, 1958. 68% of these were given a detailed post-mortem examination, the lung histology of the majority of these being independently assessed for consistency of diagnosis by a team under the chairmanship of Dr. A. E. Claireaux. After infants with severe congenital malformations and rhesus isoimmunisation had been excluded, some 339 neonatal deaths with hyaline membranes were identified.s For detailed analysis the population at risk was taken
during Some
be the number of livebirths in the first week of March a factor of 8 (some 16,994 singletons delivered in that week having also been studied in respect of history of pregnancy and delivery 4,5).
to
multiplied by
1. Liggins, G. C. J. Endocr. 1969, 42, 323. 2. Dawes, G. S. 3rd European Perinatal Congress, Lausanne, 1972. 3. de Lemos, R. A., Shermeta, D. W., Knelson, J. H., Kotas, R., Avery, M. E. Am. Rev. resp. Dis. 1970, 102, 459. 4. Butler, N. R., Bonham, D. G. Perinatal Mortality: First Report of the 1958 British Perinatal Mortality Survey. Edinburgh, 1963. 5. Butler, N. R., Alberman, E. D. Perinatal Problems. Second Report of the 1958 British Perinatal Mortality Survey. Edinburgh, 1969. 6. Fedrick, J., Butler, N. R. Biol. Neonat. 1970, 15, 229.
TABLE IV-COMPARISON OF OBSERVED AND EXPECTED NUMBERS OF
DEATHS WITH H.M. AMONG THE POPULATION HAVING BEEK DELIVERED ABDOMINALLY AFTER LABOUR HAD COMMENCED IF THE INCIDENCE WERE ASSUMED TO BE THE SAME AS AMONG CASES DELIVERED VAGINALLY