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UNSATURATED FATTY ACIDS AND RENAL TRANSPLANTATION
717 the activity for O.T.C. was outside the 95% confidence limits of normal in one patient, and for c.p.s. in two patients (see accompanying table). Dr Thaler and his colleagues imply that there may -be different types of Reye’s syndrome; since our one specimen with o.2.c. as low as Dr Thaler’s had a significant reduction of c.P.s., we wonder what the c.p.s. was in Dr Thaler’s specimen. If defective o.T.c. called for therapy with ornithine or arginine as Dr Thaler suggested, such therapy might be counterproductive, as Glasgow and Chase3 suggested for
Regarding individual patients,
therapy with citrulline if c.p.s. was reduced also. This work was supported by N.I.H. grant RR 00123 and the Children’s Hospital Research Foundation. Children’s Hospital Research Foundation, Cincinnati, Ohio, U.S.A. Harvard Medical School, Boston, Massachusetts, U.S.A. University of Kansas Medical School, Kansas
City, Kansas, U.S.A.
TED BROWN GEORGE HUG KEVIN BOVE.
ing that linoleic acid (C18 :2) is able to prolong graft survival across a strong histocompatibility barrier. This observation and the finding of a beneficial linoleic-acid effect on experimental allergic encephalomyelitis (Hughes et al., unpublished) give some support for our hypothesis of r.u..n. participation in immunoregulatory mechanisms. The preliminary results of Uldall et al. in human transplantation give further encouragement for extended invitro and in-vivo in immunity.
investigations
A full report of our studies elsewhere.
into the role of P.U.F.A.S
using other in-vivo models will be
published
Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
HENRY BROWN.
J. MERTIN.
PROLACTIN AND MIGRAINE
SIR,-Dr Nader’s reply (July 27, LESTER LANSKY.
UNSATURATED FATTY ACIDS AND RENAL TRANSPLANTATION
SiR,—The results reported by Dr Uldall and others (Aug. 31, p. 514) suggest that polyunsaturated fatty acids (P.u.F.A.s) may be a useful addition to immunosuppressive therapy after renal transplantation. Following up in-vitro fndings of an inhibitory P.U.F.A. action on the lymphocyte
Skin-graft survival in 30 female CBA mice treated with subcutaneous injections of saline (control) and linoleic acid (C18:2), 20 I-I.l. three times per week.
response to P.H.A. and antigen (P.p.D.),4-7 we have now examined P.U.F.A. effects on skin-graft survival in mice. As shown in the figure, we obtained in preliminary experiments an increase in the mean survival-time of female-A strain tail skin grafts applied to female CBA mice, indicatGlasgow, A. M., Chase, H. P. New Engl. J. Med. 1974, 291, 421. Mertin, J., Shenton, B. K., Field, E. J. Br. med. J. 1973, ii, 777. Mertin, J., Hughes, D., Shenton, B. K., Dickinson, J. P. Klin. Wschr. 1974, 52, 248. 6. Mertin, J., Hughes, D. Int. Arch. Allergy (in the press). 7. Offner, H., Clausen, J. Lancet, Aug. 17, 1974, p. 400.
3. 4. 5.
.
in
some
respects inaccurate and
p.
231)
to my
letter is
misleading.
(1) He has misread the reference 1. The rise in plasma-prolactin in normal females injected with chlorpromazine has a mean of 30 ng. per ml. and not 23 ng. per ml. as he states: he has misunderstood the table in the paper which quotes a change and not an absolute peak. (2) It is extremely misleading to claim that the paper by himself and others (July 6, p. 17) shows a mean change of 20 ng. per ml. in the migrainous patients following chlorpromazine. The peak to which he is referring occurred 2-5 hours after the chlorpromazine injection and 1-5 hours after a bolus injection of a large quantity of glucose. The effect of glucose on plasma-prolactin is poorly documented: rises, falls, and lack of change have all been reported.The variability may perhaps be related to osmotic effects since it is now established that a hypertonic saline injection is a potent stimulus to prolactin secretion.3Dr Nader is therefore not justified in quoting the figures at 2-5 hours. He should have quoted the figure 1 hour after the chlorpromazine before the glucose was given. Fortunately this is the time when other workers have reported the mean peak response to chlorpromazine injection. The rise in plasma-prolactin found by Dr Nader and his colleagues after 1 hour appears to be about 10 ng. per ml., approximately one third of the normal rise reported by Tolis et al.1 It is therefore possible that there may be some difference between migrainous patients and normals in their response to chlorpromazine or that the assay is less sensitive than some others. A control group would have settled this point. (3) Dr Nader claims that because in controls alcohol failed to raise plasma-prolactin 1 hour after ingestion then it is unlikely that alcohol caused a surge of prolactin secretion in migrainous individuals: this reasoning justified the lack of sampling in the migrainous patients until 2 hours after alcohol ingestion. Dr Nader may well be right, but he has certainly not proved it with any data. Since this group of migrainous patients was selected because they differed from normal in their response to alcohol it is strange to justify a lack of information on the grounds that they probably did behave like normals. (4) Dr Nader does not adequately distinguish between the various hypotheses he and his group appear to be testing. There are at least five explicit or implicit in their paper: a. That chlorpromazine can precipitate migraine in susceptible patients. Even this, the simplest of the five, had not been adequately tested because all the patients received glucose as well as
chlorpromazine.
a sudden rise in plasma-prolactin can precipitate migraine in susceptible individuals. This also has not been adequately tested for reasons discussed in my previous letter and in paragraph 2. Furthermore, it might be sensible to test the effect of a rise in prolactin secretion produced by an injection of
b. That
saline which does not have such profound effects on catecholamines as chlorpromazine. c. That alcohol precipitates migraine attacks in susceptible individuals by elevating prolactin levels. Tentative evidence
hypertonic
1. Tolis, G., Goldstein, M., Friesen, H. G.J. clin. Invest. 1973, 52, 783. 2. Horrobin, D. F. Prolactin: Physiology and Clinical Significance. Lancaster, 1973. 3. Buckman, M. T., Peake, G. T. Science, 1973, 181, 755.
Regarding individual patients,
therapy with citrulline if c.p.s. was reduced also. This work was supported by N.I.H. grant RR 00123 and the Children’s Hospital Research Foundation. Children’s Hospital Research Foundation, Cincinnati, Ohio, U.S.A. Harvard Medical School, Boston, Massachusetts, U.S.A. University of Kansas Medical School, Kansas
City, Kansas, U.S.A.
TED BROWN GEORGE HUG KEVIN BOVE.
ing that linoleic acid (C18 :2) is able to prolong graft survival across a strong histocompatibility barrier. This observation and the finding of a beneficial linoleic-acid effect on experimental allergic encephalomyelitis (Hughes et al., unpublished) give some support for our hypothesis of r.u..n. participation in immunoregulatory mechanisms. The preliminary results of Uldall et al. in human transplantation give further encouragement for extended invitro and in-vivo in immunity.
investigations
A full report of our studies elsewhere.
into the role of P.U.F.A.S
using other in-vivo models will be
published
Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ.
HENRY BROWN.
J. MERTIN.
PROLACTIN AND MIGRAINE
SIR,-Dr Nader’s reply (July 27, LESTER LANSKY.
UNSATURATED FATTY ACIDS AND RENAL TRANSPLANTATION
SiR,—The results reported by Dr Uldall and others (Aug. 31, p. 514) suggest that polyunsaturated fatty acids (P.u.F.A.s) may be a useful addition to immunosuppressive therapy after renal transplantation. Following up in-vitro fndings of an inhibitory P.U.F.A. action on the lymphocyte
Skin-graft survival in 30 female CBA mice treated with subcutaneous injections of saline (control) and linoleic acid (C18:2), 20 I-I.l. three times per week.
response to P.H.A. and antigen (P.p.D.),4-7 we have now examined P.U.F.A. effects on skin-graft survival in mice. As shown in the figure, we obtained in preliminary experiments an increase in the mean survival-time of female-A strain tail skin grafts applied to female CBA mice, indicatGlasgow, A. M., Chase, H. P. New Engl. J. Med. 1974, 291, 421. Mertin, J., Shenton, B. K., Field, E. J. Br. med. J. 1973, ii, 777. Mertin, J., Hughes, D., Shenton, B. K., Dickinson, J. P. Klin. Wschr. 1974, 52, 248. 6. Mertin, J., Hughes, D. Int. Arch. Allergy (in the press). 7. Offner, H., Clausen, J. Lancet, Aug. 17, 1974, p. 400.
3. 4. 5.
.
in
some
respects inaccurate and
p.
231)
to my
letter is
misleading.
(1) He has misread the reference 1. The rise in plasma-prolactin in normal females injected with chlorpromazine has a mean of 30 ng. per ml. and not 23 ng. per ml. as he states: he has misunderstood the table in the paper which quotes a change and not an absolute peak. (2) It is extremely misleading to claim that the paper by himself and others (July 6, p. 17) shows a mean change of 20 ng. per ml. in the migrainous patients following chlorpromazine. The peak to which he is referring occurred 2-5 hours after the chlorpromazine injection and 1-5 hours after a bolus injection of a large quantity of glucose. The effect of glucose on plasma-prolactin is poorly documented: rises, falls, and lack of change have all been reported.The variability may perhaps be related to osmotic effects since it is now established that a hypertonic saline injection is a potent stimulus to prolactin secretion.3Dr Nader is therefore not justified in quoting the figures at 2-5 hours. He should have quoted the figure 1 hour after the chlorpromazine before the glucose was given. Fortunately this is the time when other workers have reported the mean peak response to chlorpromazine injection. The rise in plasma-prolactin found by Dr Nader and his colleagues after 1 hour appears to be about 10 ng. per ml., approximately one third of the normal rise reported by Tolis et al.1 It is therefore possible that there may be some difference between migrainous patients and normals in their response to chlorpromazine or that the assay is less sensitive than some others. A control group would have settled this point. (3) Dr Nader claims that because in controls alcohol failed to raise plasma-prolactin 1 hour after ingestion then it is unlikely that alcohol caused a surge of prolactin secretion in migrainous individuals: this reasoning justified the lack of sampling in the migrainous patients until 2 hours after alcohol ingestion. Dr Nader may well be right, but he has certainly not proved it with any data. Since this group of migrainous patients was selected because they differed from normal in their response to alcohol it is strange to justify a lack of information on the grounds that they probably did behave like normals. (4) Dr Nader does not adequately distinguish between the various hypotheses he and his group appear to be testing. There are at least five explicit or implicit in their paper: a. That chlorpromazine can precipitate migraine in susceptible patients. Even this, the simplest of the five, had not been adequately tested because all the patients received glucose as well as
chlorpromazine.
a sudden rise in plasma-prolactin can precipitate migraine in susceptible individuals. This also has not been adequately tested for reasons discussed in my previous letter and in paragraph 2. Furthermore, it might be sensible to test the effect of a rise in prolactin secretion produced by an injection of
b. That
saline which does not have such profound effects on catecholamines as chlorpromazine. c. That alcohol precipitates migraine attacks in susceptible individuals by elevating prolactin levels. Tentative evidence
hypertonic
1. Tolis, G., Goldstein, M., Friesen, H. G.J. clin. Invest. 1973, 52, 783. 2. Horrobin, D. F. Prolactin: Physiology and Clinical Significance. Lancaster, 1973. 3. Buckman, M. T., Peake, G. T. Science, 1973, 181, 755.