1092 Thus patients with neuroblastoma are in double jeopardyfrom a malignant tumour and from the substances that it may elaborate which specifically impair their immune responses.
It is not known whether plasma-adrenaline is increased for prolonged periods in neuroblastoma, since only urinary metabolites have been generally studied. Voorhess and Gardnerfound that urinary adrenaline in thirteen patients with neuroblastoma was within the normal range. However, total production or plasma-levels of adrenaline cannot be estimated by examining the urine, since adrenaline and noradrenaline have common metabolites and these hormones can be degraded even before they leave
the
tumour.
Various catecholamine precursors and metabolites are increased in urine from patients with neuroblastomae.g., V.M.A., homovanillic acid, 3,4-dibydroxyphenylalanine, 3,4-dihydroxyphenethylamine, normetanephrine, and metanephrine.8 Even if adrenaline is only of trivial importance in neuroblastoma, one of these compounds may sufficiently resemble adrenaline in structure to stimulate P-adrenergic receptors. To my knowledge, few of these compounds have been tested for this effect. If this hypothesis is correct, adjuvant treatment with P-adrenergic antagonists may improve the prognosis in patients with neuroblastoma. 1188 North Euclid,
Anaheim, California 92801, U.S.A.
LEE WOOD.
ACUTE PANCREATITIS
SIR,-Your editorial of Jan. 25 (p. 205) deals with the roles of glucagon and serum-calcium in acute pancreatitis. These are doubtless critical matters with respect to the pathophysiology of the disorder. From the therapeutic point of view, however, one could wish for more emphasis on those features of the disorder that are clearly involved in death. Thus, there is a large loss of plasma into the retroperitoneal space, as well as into the peritoneal cavity, which cannot be restored because the infusate promptly leaks out through the injured capillary beds. There is also a peritonitis which is chemical at first and septic later. In either case, dead and live bacteria cross the gut wall in abundance, especially from the immediately adjacent transverse colon. The victim, therefore, has an endotoxaemia which promptly weakens the resources for defence, and initiates vascular collapse and increasing pulmonary insufficiency, disseminated intravascular coagulation, and h2emorrhagic ulceration of the intestinal mucosa-common features of the preterminal stage of the disorder. Hence, therapy for the endotoxsemia is necessary, the more so for those who regard the role of calcium as critical in the deterioration, for the endotoxin shifts ionised calcium into the cell.9 Now that there is a test for the presence and amount of the endotoxin in the blood and peritoneal fluid, measures that do not come to grips with this offender should give way to those that do (e.g., continuous peritoneal lavage,10 intra-intestinal bacteriostasis,ll and intra-aortic corticosteroids 12). Center for Advanced Study in the Behavioral Sciences, 202 Junipero Serra Boulevard, Stanford, California 94305, U.S.A
SIR,-Professor Munro and his colleagues1 suggest that, in hepatic coma, increased plasma-insulin concentrations lead to a fall in the plasma concentration of branchedchain aminoacids which compete with tryptophan for transport into the brain. Brain tryptophan thus increases and as tryptophan hydroxylase, which is the rate-limiting for brain 5-hydroxytryptamine (5-H.T.) synthesis, is normally unsaturated with tryptophan5-H.T. synthesis may be increased and alter brain function. We do not dispute the possibility that such changes occur in cirrhosis but considerable evidence, summarised below, indicates that another mechanism which can also influence brain tryptophan may be at least as relevant to her-at;.:: coma. Tryptophan is unique among the plasm aminoacids in being largely bound to albumin. Knott and Curzon4 and Tagliamonte et awl. have proposed that changes in the concentration of the relatively small free fraction of tryptophan in plasma can influence brain tryptophan concentration. The " theory that tryptophan uptake by the brain depends solely on the plasma concentration of free tryptophan ", is wrongly attributed to Knott and Curzon by Munro et al. However, plasma free tryptophan does seem to influence brain tryptophan concentration in many circumstances.
enzyme
1. After food intake in human beings Perez-Cruet et al.’ found decreased c.s.F. 5-hydroxyindoleacetic acid (5-H.I.A.A.), which is an index of C.N.S. 5-H.T. turnover, and decreased c.s.F. tryptophan, and these correlated positively with changes in plasma free tryptophan and in the ratio of free tryptophan to competing aminoacids, but not with changes of plasma total tryptophan or of its ratio to competing aminoacids. Other factors may also be important, for Madras et al.’ found that alterations in rat brain tryptophan 2 hours after the ingestion of various diets could not be explained by changes in free tryptophan alone. 2. 24-hour food deprivation in the rat resulted in an increase plasma free tryptophan associated with increases both in brain tryptophan and in 5-H.I.A.A.4 Total plasma tryptophan did not rise. Work on fasted human subjects suggests that altered levels of plasma-insulinor branched-chain aminoacids 9 do not contribute to the brain changes. These changes probably result from the liberation of plasma tryptophan from albumin-binding sites 10 due to the increase in plasma non-esterified fatty acid concentration during starvation. When the latter increase was prevented by nicotinic acid, then the increases in both the plasma free tryptophan and brain tryptophan were opposed.ll
in
3. Immobilisation of rats for 3 hours led to increase of plasma free tryptophan and of brain tryptophan and 5-H.I.A.A.4,12 Plasma total tryptophan did not rise. 4. Increased brain tryptophan after administration of tryptophan5 or of many drugs which alter the binding of tryptophan to plasma albumin 11,13 was explicable on the basis of changes in plasma free tryptophan. 1.
2. 3. 4.
5. 6.
Munro, H. N., Fernstrom, J. D., Wurtman, R. J. Lancet, March 29, 1975, p. 722. Fernstrom, J. D., Wurtman, R. J. Metabolism, 1972, 21, 337. Friedman, P. A., Kappelman, A. H., Kaufman, S. J. biol. Chem., 1972, 247, 4165. Knott, P. J., Curzon, G. Nature, 1972, 239, 452. Tagliamonte, A., Biggio, G., Vargiu, L., Gessa, G. L. Life Sci. 1973, 12, 227. Perez-Cruet, J., Chase, T. N., Murphy, D. L. Nature, 1974, 248, 693.
Madras, B. K., Cohen, E. L., Messing, R., Munro, H. N., Wurtman, R. J. Metabolism, 1974, 23, 1107. 8. Cahill, G. F., Herrera, M. G., Morgan, A. P., Soeldner, J. S., Steinke, J., Levy, P. L., Reichard, G. A., Kipnis, D. M. J. clin. Invest. 1966, 45, 1751. 9. Felig, P., Owen, O. E., Wahren, J., Cahill, G. F. ibid. 1969, 48, 584. 10. Curzon, G., Friedel, J., Knott, P. J. Nature, 1973, 242, 198. 11. Curzon, G., Knott, P. J. Br. J. Pharmac. 1974, 50, 197. 12. Curzon, G., Joseph, M. H., Knott, P. J. J. Neurochem. 1972, 19, 7.
JACOB FINE.
Voorhess, M. L., Gardner, L. I. J. clin. Endocr. Metab. 1962, 22, 126. von Studnitz, W., Käser, H., Sjoerdsma, A. New Engl. J. Med. 1963, 269, 232. 9. Connor, J., et al. Proc. natn. Acad. Sci. 1973, 70, 3201. 10. Caridis, D. T., Cuevas, P., Fine, J. Surgery Gynec. Obstet. 1972, 135, 199. 11. Caridis, D. T., et al. J. reticuloend. Soc. 1974, 14, 513. 12. Woodruff, P., et al. Archs Surg. 1973, 107, 613. 7. 8.
DISTURBED BRAIN TRYPTOPHAN METABOLISM IN HEPATIC COMA
1967.
13. Gessa, G. L., Tagliamonte, A. Adv. biochem. Psychopharmac. 1974
11, 119.
It is not known whether plasma-adrenaline is increased for prolonged periods in neuroblastoma, since only urinary metabolites have been generally studied. Voorhess and Gardnerfound that urinary adrenaline in thirteen patients with neuroblastoma was within the normal range. However, total production or plasma-levels of adrenaline cannot be estimated by examining the urine, since adrenaline and noradrenaline have common metabolites and these hormones can be degraded even before they leave
the
tumour.
Various catecholamine precursors and metabolites are increased in urine from patients with neuroblastomae.g., V.M.A., homovanillic acid, 3,4-dibydroxyphenylalanine, 3,4-dihydroxyphenethylamine, normetanephrine, and metanephrine.8 Even if adrenaline is only of trivial importance in neuroblastoma, one of these compounds may sufficiently resemble adrenaline in structure to stimulate P-adrenergic receptors. To my knowledge, few of these compounds have been tested for this effect. If this hypothesis is correct, adjuvant treatment with P-adrenergic antagonists may improve the prognosis in patients with neuroblastoma. 1188 North Euclid,
Anaheim, California 92801, U.S.A.
LEE WOOD.
ACUTE PANCREATITIS
SIR,-Your editorial of Jan. 25 (p. 205) deals with the roles of glucagon and serum-calcium in acute pancreatitis. These are doubtless critical matters with respect to the pathophysiology of the disorder. From the therapeutic point of view, however, one could wish for more emphasis on those features of the disorder that are clearly involved in death. Thus, there is a large loss of plasma into the retroperitoneal space, as well as into the peritoneal cavity, which cannot be restored because the infusate promptly leaks out through the injured capillary beds. There is also a peritonitis which is chemical at first and septic later. In either case, dead and live bacteria cross the gut wall in abundance, especially from the immediately adjacent transverse colon. The victim, therefore, has an endotoxaemia which promptly weakens the resources for defence, and initiates vascular collapse and increasing pulmonary insufficiency, disseminated intravascular coagulation, and h2emorrhagic ulceration of the intestinal mucosa-common features of the preterminal stage of the disorder. Hence, therapy for the endotoxsemia is necessary, the more so for those who regard the role of calcium as critical in the deterioration, for the endotoxin shifts ionised calcium into the cell.9 Now that there is a test for the presence and amount of the endotoxin in the blood and peritoneal fluid, measures that do not come to grips with this offender should give way to those that do (e.g., continuous peritoneal lavage,10 intra-intestinal bacteriostasis,ll and intra-aortic corticosteroids 12). Center for Advanced Study in the Behavioral Sciences, 202 Junipero Serra Boulevard, Stanford, California 94305, U.S.A
SIR,-Professor Munro and his colleagues1 suggest that, in hepatic coma, increased plasma-insulin concentrations lead to a fall in the plasma concentration of branchedchain aminoacids which compete with tryptophan for transport into the brain. Brain tryptophan thus increases and as tryptophan hydroxylase, which is the rate-limiting for brain 5-hydroxytryptamine (5-H.T.) synthesis, is normally unsaturated with tryptophan5-H.T. synthesis may be increased and alter brain function. We do not dispute the possibility that such changes occur in cirrhosis but considerable evidence, summarised below, indicates that another mechanism which can also influence brain tryptophan may be at least as relevant to her-at;.:: coma. Tryptophan is unique among the plasm aminoacids in being largely bound to albumin. Knott and Curzon4 and Tagliamonte et awl. have proposed that changes in the concentration of the relatively small free fraction of tryptophan in plasma can influence brain tryptophan concentration. The " theory that tryptophan uptake by the brain depends solely on the plasma concentration of free tryptophan ", is wrongly attributed to Knott and Curzon by Munro et al. However, plasma free tryptophan does seem to influence brain tryptophan concentration in many circumstances.
enzyme
1. After food intake in human beings Perez-Cruet et al.’ found decreased c.s.F. 5-hydroxyindoleacetic acid (5-H.I.A.A.), which is an index of C.N.S. 5-H.T. turnover, and decreased c.s.F. tryptophan, and these correlated positively with changes in plasma free tryptophan and in the ratio of free tryptophan to competing aminoacids, but not with changes of plasma total tryptophan or of its ratio to competing aminoacids. Other factors may also be important, for Madras et al.’ found that alterations in rat brain tryptophan 2 hours after the ingestion of various diets could not be explained by changes in free tryptophan alone. 2. 24-hour food deprivation in the rat resulted in an increase plasma free tryptophan associated with increases both in brain tryptophan and in 5-H.I.A.A.4 Total plasma tryptophan did not rise. Work on fasted human subjects suggests that altered levels of plasma-insulinor branched-chain aminoacids 9 do not contribute to the brain changes. These changes probably result from the liberation of plasma tryptophan from albumin-binding sites 10 due to the increase in plasma non-esterified fatty acid concentration during starvation. When the latter increase was prevented by nicotinic acid, then the increases in both the plasma free tryptophan and brain tryptophan were opposed.ll
in
3. Immobilisation of rats for 3 hours led to increase of plasma free tryptophan and of brain tryptophan and 5-H.I.A.A.4,12 Plasma total tryptophan did not rise. 4. Increased brain tryptophan after administration of tryptophan5 or of many drugs which alter the binding of tryptophan to plasma albumin 11,13 was explicable on the basis of changes in plasma free tryptophan. 1.
2. 3. 4.
5. 6.
Munro, H. N., Fernstrom, J. D., Wurtman, R. J. Lancet, March 29, 1975, p. 722. Fernstrom, J. D., Wurtman, R. J. Metabolism, 1972, 21, 337. Friedman, P. A., Kappelman, A. H., Kaufman, S. J. biol. Chem., 1972, 247, 4165. Knott, P. J., Curzon, G. Nature, 1972, 239, 452. Tagliamonte, A., Biggio, G., Vargiu, L., Gessa, G. L. Life Sci. 1973, 12, 227. Perez-Cruet, J., Chase, T. N., Murphy, D. L. Nature, 1974, 248, 693.
Madras, B. K., Cohen, E. L., Messing, R., Munro, H. N., Wurtman, R. J. Metabolism, 1974, 23, 1107. 8. Cahill, G. F., Herrera, M. G., Morgan, A. P., Soeldner, J. S., Steinke, J., Levy, P. L., Reichard, G. A., Kipnis, D. M. J. clin. Invest. 1966, 45, 1751. 9. Felig, P., Owen, O. E., Wahren, J., Cahill, G. F. ibid. 1969, 48, 584. 10. Curzon, G., Friedel, J., Knott, P. J. Nature, 1973, 242, 198. 11. Curzon, G., Knott, P. J. Br. J. Pharmac. 1974, 50, 197. 12. Curzon, G., Joseph, M. H., Knott, P. J. J. Neurochem. 1972, 19, 7.
JACOB FINE.
Voorhess, M. L., Gardner, L. I. J. clin. Endocr. Metab. 1962, 22, 126. von Studnitz, W., Käser, H., Sjoerdsma, A. New Engl. J. Med. 1963, 269, 232. 9. Connor, J., et al. Proc. natn. Acad. Sci. 1973, 70, 3201. 10. Caridis, D. T., Cuevas, P., Fine, J. Surgery Gynec. Obstet. 1972, 135, 199. 11. Caridis, D. T., et al. J. reticuloend. Soc. 1974, 14, 513. 12. Woodruff, P., et al. Archs Surg. 1973, 107, 613. 7. 8.
DISTURBED BRAIN TRYPTOPHAN METABOLISM IN HEPATIC COMA
1967.
13. Gessa, G. L., Tagliamonte, A. Adv. biochem. Psychopharmac. 1974
11, 119.
