- Email: [email protected]
INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE
357
AMINES, ALERTING, AND AFFECT SiR,łIwas intrigued to read your recent leader,1 which collaborative work with which I was involved.2-6 7-11 which led seem to be unaware of later work to modifications of some of the earlier conclusions. You also omit to credit Vane 12 13 with the suggestion that the central excitant effects of amines such as amphetamine may be due to their action on central tryptamine receptors-a suggestion that motivated some of the work discussed in the leader and one which was found to apply for some species245711 but not others.14 15 A critic of the earlier work suggests 16 that the doses used and given intravenously in young chickens were " unphysiologically high ". This was not the case. He also suggests that the amines reached sites which they would not normally have access to. This was also unlikely, since in later experiments 11 17 in which the amines were given by microinfusion in 1/100 of the intravenous dose and into different sites of the brain, the effects obtained with catecholamines given intravenously were duplicated by their microinfusion into the hypothalamus but not elsewhere in the brain. The effects obtained were potentiated by monoamine-oxidase inhibition, 17 suggesting that the doses used did not swamp transport and storage mechanisms. Although these effects were elicited in young chicks in which the blood/brain barrier was imperfect, similar results have been obtained by microinjections of catecholamines into the hypothalamus of adult cats 18 19 in which the blood-barrier was fully functional. Institute of Psychiatry,
referred
to
However,
you
De Crespigny Park, London S.E.5.
E. MARLEY.
TREATING BRAIN METASTASES FROM LUNG CANCER SIR,-I read with interest the article by Dr. Deeley and Dr. Edwards.2O The use of steroids and a controlled group of untreated patients are two important points which were not mentioned in the paper. Some patients with metastatic central-nervous-system disease from the lung (and other sites) will often show a dramatic, though temporary, improvement with high doses of steroid therapy (16 mg. per day of dexamethasone [‘ Decadron’] parenterally or orally, usually given in 4 divided doses). This response reflects the dramatic effects of steroids in reducing cerebral oedema.21 This improvement may persist for several months, during which time the dose may be cautiously tapered. I and others have also noted temporary spontaneous remissions from neurological symptoms in centralnervous-system metastases from the lung.22 This may reflect 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Lancet, 1968, i, 1237. Dewhurst, W. G., Marley, E. Ciba Foundation Symposium on Drug Action and Animal Behaviour (edited by H. Steinberg, A. V. S. de Reuck, and A. Knight); p. 175. London, 1964. Dewhurst, W. G., Marley, E. Br. J. Pharmac. Chemother. 1965, 25, 671. Dewhurst, W. G., Marley, E. ibid. p. 682. Dewhurst, W. G., Marley, E. ibid. p. 705. Key, B. J., Marley, E. Electroenceph. clin. Neurophysiol. 1962, 14, 90. Allen, D. J., Marley, E. Br. J. Pharmac. Chemother. 1967, 31, 290. Marley, E. in Studies in Psychiatry (edited by M. Shepherd and D. L. Davies); chap. 13, p. 253. London, 1968. Marley, E. in The Scientific Basis of Medicine Annual Reviews; p. 359. London, 1968. Marley, E., Morse, W. H. Br. J. Pharmac. Chemother. 1967, 31, 367. Marley, E., Stephenson, J. D. J. Physiol., Lond. 1968, 196, 116P. Vane, J. R. in Adrenergic Mechanisms (edited by J. R. Vane, G. E. W. Wolstenholme, and M. O’Connor); p. 356. London, 1960. Vane, J. R., Collier, H. O. J., Corne, S. J., Marley, E., Bradley, P. B. Nature, Lond. 1961, 191, 1068. Bradley, P. B., Marley, E. Br. J. Pharmac. Chemother. 1965, 24, 659. Marley, E., Vane, J. R. ibid. 1967, 31, 447. Weil-Malherbe, H. Lancet, July 27, 1968, p. 219. Marley, E., Stephenson, J. D. Unpublished. Myers, R. D. Can. J. Psychol. 1964, 18, 6. Feldberg, W., Myers, R. D. J. Physiol., Lond. 1965, 177, 239. Deeley, T. J., Edwards, J. M. R. Lancet, 1968, i, 1209. French, L. A., Galicich, J. H. Clin. Neurosurg. 1964, 10, 212. Lesse, S., Metsky, M. G. A.M.A. Archs Neurol. Psychiatry, 1954, 72, 133.
small vascular
insults, possibly
tumour
emboli,
or
spon-
resolution of oedema. The morbidity and mortality accompanying the use of radiotherapy in this condition are high (27 of 88 patients died
taneous
during course of treatment), and the possible benefits are limited (" significant palliation " averaging over four months in 6 of 16 patients with tissue diagnosis of intracranial metastasis).2O These modest results emphasise the need for a critical and controlled study with a group of non-radiated patients. It would be worthwhile to compare the effects of steroids alone with steroids plus radiotherapy in the palliation of this malignant disease. Department of Neurosurgery, The Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, N.Y. 10032.
RONALD BRISMAN.
INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE SiR,łIread with interest the hypothesis presented by Dr. Stark and his colleagues 23 describing intravascular coagulation (i.c.) as a possible cause of hyaline-membrane disease (H.M.D.). A child (of a fellow medical student) with severe respiratory distress due to H.M.D. was treated by Dr. H. D. Weintraub (who is listed as a reference by Dr. Stark and his colleagues) with urokinase, responded dramatically, and is in good health at present. This success, together with that of Dr. Stark and his colleagues with heparin, makes it seem plausible that i.c. may be the cause of H.M.D. It is well known that premature infants are more likely to develop H.M.D. However, they are also hypoprothrombinxmic because of an immature liver and low vitamin-K intake and synthesis. Since factors 11, VII, ix, and x are vitamin-Kdependent, the premature infant has a built in defence against i.c.I therefore wonder whether vitamin K should be withheld from a premature infant with respiratory distress. State
School of Medicine, University of New York at Buffalo, New York.
GLENN TISMAN.
URINARY INSULIN IN OBESE CHILDREN SIR,-Publication in The Lancet 24 25 and elsewhere 26 of data on insulin in urine in different conditions prompted us to study this problem in obese children, in whom high levels of plasma-insulin have been demonstrated, both in the basal state and after different stimuli.2’ Until now, to our knowledge, there have been no publications on this topic. We studied fifteen children of normal weight (seven boys and eight girls, mean age 9 years 3 months, range 7-13 years), admitted to this department for mild respiratory diseases and submitted to the test just before discharge, and 10 obese children (five boys and five girls) without family history of diabetes, whose mean age was 9 years 6 months (range 5-12 years). In the obese children, mean weight was 64-84% greater than ideal; the duration of obesity varied from 2-3 years. None of the subjects had lost weight for several months before the observation. All these children had normal oral glucose-tolerance tests and apparently normal renal function. After 3 days of standard diet, with carbohydrate 50%, fat 35%, and protein 15% of total calories, the urine was collected for 3 days. Insulin in the urine was estimated by the double-antibody assay method,28 modified by Jorgensen for urine.29 23. Stark, C. R., Abramson, D., Erkan, V. Lancet, 1968, i, 1180. 24. McArthur, K. G., Stimmler, L. ibid. 1966, i, 1236. 25. Lowy, C., Schiff, D. ibid. 1968, i, 225. 26. Trayner, I. M., Wellborn, T. A., Russell Fraser, T. J. Endocr. 1967, 37, 443. 27. Chiumello, G., del Guercio, M. J., Carnelutti, M., Bidone, G. Helv. pœdiat. Acta, 1967, 23, 45. 28. Hales, C. N., Randle, P. J. Biochem. J. 1963, 88, 137. 29. Jorgensen, K. R. Acta endocr., Copenh. 1966, 51, 400.
AMINES, ALERTING, AND AFFECT SiR,łIwas intrigued to read your recent leader,1 which collaborative work with which I was involved.2-6 7-11 which led seem to be unaware of later work to modifications of some of the earlier conclusions. You also omit to credit Vane 12 13 with the suggestion that the central excitant effects of amines such as amphetamine may be due to their action on central tryptamine receptors-a suggestion that motivated some of the work discussed in the leader and one which was found to apply for some species245711 but not others.14 15 A critic of the earlier work suggests 16 that the doses used and given intravenously in young chickens were " unphysiologically high ". This was not the case. He also suggests that the amines reached sites which they would not normally have access to. This was also unlikely, since in later experiments 11 17 in which the amines were given by microinfusion in 1/100 of the intravenous dose and into different sites of the brain, the effects obtained with catecholamines given intravenously were duplicated by their microinfusion into the hypothalamus but not elsewhere in the brain. The effects obtained were potentiated by monoamine-oxidase inhibition, 17 suggesting that the doses used did not swamp transport and storage mechanisms. Although these effects were elicited in young chicks in which the blood/brain barrier was imperfect, similar results have been obtained by microinjections of catecholamines into the hypothalamus of adult cats 18 19 in which the blood-barrier was fully functional. Institute of Psychiatry,
referred
to
However,
you
De Crespigny Park, London S.E.5.
E. MARLEY.
TREATING BRAIN METASTASES FROM LUNG CANCER SIR,-I read with interest the article by Dr. Deeley and Dr. Edwards.2O The use of steroids and a controlled group of untreated patients are two important points which were not mentioned in the paper. Some patients with metastatic central-nervous-system disease from the lung (and other sites) will often show a dramatic, though temporary, improvement with high doses of steroid therapy (16 mg. per day of dexamethasone [‘ Decadron’] parenterally or orally, usually given in 4 divided doses). This response reflects the dramatic effects of steroids in reducing cerebral oedema.21 This improvement may persist for several months, during which time the dose may be cautiously tapered. I and others have also noted temporary spontaneous remissions from neurological symptoms in centralnervous-system metastases from the lung.22 This may reflect 1. 2.
3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Lancet, 1968, i, 1237. Dewhurst, W. G., Marley, E. Ciba Foundation Symposium on Drug Action and Animal Behaviour (edited by H. Steinberg, A. V. S. de Reuck, and A. Knight); p. 175. London, 1964. Dewhurst, W. G., Marley, E. Br. J. Pharmac. Chemother. 1965, 25, 671. Dewhurst, W. G., Marley, E. ibid. p. 682. Dewhurst, W. G., Marley, E. ibid. p. 705. Key, B. J., Marley, E. Electroenceph. clin. Neurophysiol. 1962, 14, 90. Allen, D. J., Marley, E. Br. J. Pharmac. Chemother. 1967, 31, 290. Marley, E. in Studies in Psychiatry (edited by M. Shepherd and D. L. Davies); chap. 13, p. 253. London, 1968. Marley, E. in The Scientific Basis of Medicine Annual Reviews; p. 359. London, 1968. Marley, E., Morse, W. H. Br. J. Pharmac. Chemother. 1967, 31, 367. Marley, E., Stephenson, J. D. J. Physiol., Lond. 1968, 196, 116P. Vane, J. R. in Adrenergic Mechanisms (edited by J. R. Vane, G. E. W. Wolstenholme, and M. O’Connor); p. 356. London, 1960. Vane, J. R., Collier, H. O. J., Corne, S. J., Marley, E., Bradley, P. B. Nature, Lond. 1961, 191, 1068. Bradley, P. B., Marley, E. Br. J. Pharmac. Chemother. 1965, 24, 659. Marley, E., Vane, J. R. ibid. 1967, 31, 447. Weil-Malherbe, H. Lancet, July 27, 1968, p. 219. Marley, E., Stephenson, J. D. Unpublished. Myers, R. D. Can. J. Psychol. 1964, 18, 6. Feldberg, W., Myers, R. D. J. Physiol., Lond. 1965, 177, 239. Deeley, T. J., Edwards, J. M. R. Lancet, 1968, i, 1209. French, L. A., Galicich, J. H. Clin. Neurosurg. 1964, 10, 212. Lesse, S., Metsky, M. G. A.M.A. Archs Neurol. Psychiatry, 1954, 72, 133.
small vascular
insults, possibly
tumour
emboli,
or
spon-
resolution of oedema. The morbidity and mortality accompanying the use of radiotherapy in this condition are high (27 of 88 patients died
taneous
during course of treatment), and the possible benefits are limited (" significant palliation " averaging over four months in 6 of 16 patients with tissue diagnosis of intracranial metastasis).2O These modest results emphasise the need for a critical and controlled study with a group of non-radiated patients. It would be worthwhile to compare the effects of steroids alone with steroids plus radiotherapy in the palliation of this malignant disease. Department of Neurosurgery, The Presbyterian Hospital, Columbia-Presbyterian Medical Center, New York, N.Y. 10032.
RONALD BRISMAN.
INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE SiR,łIread with interest the hypothesis presented by Dr. Stark and his colleagues 23 describing intravascular coagulation (i.c.) as a possible cause of hyaline-membrane disease (H.M.D.). A child (of a fellow medical student) with severe respiratory distress due to H.M.D. was treated by Dr. H. D. Weintraub (who is listed as a reference by Dr. Stark and his colleagues) with urokinase, responded dramatically, and is in good health at present. This success, together with that of Dr. Stark and his colleagues with heparin, makes it seem plausible that i.c. may be the cause of H.M.D. It is well known that premature infants are more likely to develop H.M.D. However, they are also hypoprothrombinxmic because of an immature liver and low vitamin-K intake and synthesis. Since factors 11, VII, ix, and x are vitamin-Kdependent, the premature infant has a built in defence against i.c.I therefore wonder whether vitamin K should be withheld from a premature infant with respiratory distress. State
School of Medicine, University of New York at Buffalo, New York.
GLENN TISMAN.
URINARY INSULIN IN OBESE CHILDREN SIR,-Publication in The Lancet 24 25 and elsewhere 26 of data on insulin in urine in different conditions prompted us to study this problem in obese children, in whom high levels of plasma-insulin have been demonstrated, both in the basal state and after different stimuli.2’ Until now, to our knowledge, there have been no publications on this topic. We studied fifteen children of normal weight (seven boys and eight girls, mean age 9 years 3 months, range 7-13 years), admitted to this department for mild respiratory diseases and submitted to the test just before discharge, and 10 obese children (five boys and five girls) without family history of diabetes, whose mean age was 9 years 6 months (range 5-12 years). In the obese children, mean weight was 64-84% greater than ideal; the duration of obesity varied from 2-3 years. None of the subjects had lost weight for several months before the observation. All these children had normal oral glucose-tolerance tests and apparently normal renal function. After 3 days of standard diet, with carbohydrate 50%, fat 35%, and protein 15% of total calories, the urine was collected for 3 days. Insulin in the urine was estimated by the double-antibody assay method,28 modified by Jorgensen for urine.29 23. Stark, C. R., Abramson, D., Erkan, V. Lancet, 1968, i, 1180. 24. McArthur, K. G., Stimmler, L. ibid. 1966, i, 1236. 25. Lowy, C., Schiff, D. ibid. 1968, i, 225. 26. Trayner, I. M., Wellborn, T. A., Russell Fraser, T. J. Endocr. 1967, 37, 443. 27. Chiumello, G., del Guercio, M. J., Carnelutti, M., Bidone, G. Helv. pœdiat. Acta, 1967, 23, 45. 28. Hales, C. N., Randle, P. J. Biochem. J. 1963, 88, 137. 29. Jorgensen, K. R. Acta endocr., Copenh. 1966, 51, 400.