363 accept the fact that British mothers choose bottle feeding using the three most common but "dangerous" powdered milks. If these unmodified milks are to be withdrawn from circulation can all families afford the recommended but highly priced "humanised" milks? Surely the answer must be for the Government to make a firm decision in the very near future to improve N.D.M. and to ensure that it will continue to be relatively cheap. must

Children’s Hospital, Durham Road,


Sunderland SR3 4AF


reduced (by about 50%). His initial plasma-cA.M.p. estimations were above our normal range, but there was a clear response after the P.T.H. which was completely abolished by chlorpropa-

mide therapy. It would seem, therefore, that chlorpropamide does indeed reduce the urinary and plasma CA.M.p. response to P.T.H. in man, but is of no therapeutic value in reducing serum-calcium in primary hyperparathyroidism. We found the plasma-cA.M.p. response to be less sensitive than the urine response. Department of Medicine, Wellcome Research Laboratories, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP.

SIR,-The paper by Dr Tomlinson and his colleagues (Jan. 10, p. 62) concerning the plasma-cA.M.P. response to para-

thyroid hormone (P.T.H.) in pseudo hypoparathyroidism may have important clinical implications. However, the urinary and p!asma-cA.M.P. response to P.T.H. is also reduced in other conditions such as primary hyperparathyroidism and chronic renal failure’ and by some drugs. No

drug therapy



Urinary and plasma cA.M.P. propamide therapy.

response to P.T.H. before and after chlor-

Chlorpropamide has an antidiuretic action which is probably due to an increase in renal medullary adenylate-cyclase activity in response to antidiuretic hormone It has also been shown to reduce, rather than increase, the urinary CA.M.P. response to P.T.H. in parathyroidectomised rats.3 We have recently used chlorpropamide in a patient with confirmed primary hyperparathyroidism in an attempt to reduce his serumcalcium while he awaited surgery. Before and during his fourweek course of chlorpropamide 250 mg daily he received a 300 unit infusion of P.T.H. over 15 min, and we monitored his plasma and urinary CA.M.P. response. These results are shown 10 the figure. There was no change in serum-calcium levels mean 10.8 mg/dl). His urinary CA.M.P. output was low at first but increased almost 50-fold after the P.T.H. infusion. This response is, however, below normal, as frequently happens in patients with primary hyperparathyroidism. After chlorpropamide therapy the urinary CA.M.P. response is even further


SIR,-We would like to suggest that the main effect of the abnormal processes underlying affective disorder is on synthesis of synaptic vesicles in serotoninergic (5-H.T.) neurones. The steps in the proposed working hypothesis are as follows: (1) We have evidence that the concentration of tryptophan in the cells, the flux of tryptophan from the extracellular to the intracellular space, and the turnover of this aminoacid in the affective body are reduced in patients subject to unipolar disorder regardless of whether they are ill or well.1 (2) The smaller pool of tryptophan in cells is regarded as the factor which determines the individual’s constitutional susceptibility to illness. (3) Any agent inducing a further loss of tryptophan from the body will produce a situation where extracellular levels of tryptophan cannot be maintained because replacement from the already attenuated intracellular pool will be inadequate. The concentration of free tryptophan in plasma will fall, putting it at a disadvantage with respect to other neutral aminoacids for transport across the blood-brain barrier. As a result, transport of tryptophan into the brain will decrease and levels of tryptophan in the brain will fall.23 (4) It is suggested that, of all the cells in the brain, serotoninergic neurones are uniquely vulnerable to a period of scarcity of tryptophan because ribosomal protein synthesis and tryptophan hydroxylase (5-H.T. synthesis) compete for a limited supply of tryptophan in the cytoplasm of their cell bodies. Thus production of proteins in these particular cells will be reduced. (5) We propose that the most important effect of a period of scarcity of tryptophan will be to curtail the formation of those functional proteins with high turnover-rates and that this will include those producing the synaptic vesicles.

(6) Although 5-H.T. synthesis will fall, the amount available should be adequate for the smaller population of vesicles. (7) Synaptic vesicles in aminergic neurones may have the ability to take up and release transmitter into the synaptic cleft for only tens of hours, continuing thereafter as storage depots, and have a total half-life in the region of several weeks.4 It follows that most synaptic vesicles must have only the storage function, presumably to maintain adequate 5-H.T. levels in the young vesicles. Thus a period of scarcity of tryptophan in the brain, induced by the triggering process, may have to persist for many weeks before the original population of storage vesicles has been depleted to a degree which produces a significant loss of function in serotoninergic pathways. Traces of a triggering process may have disappeared in some individuals at the onset of clinical symptoms.

Shaw, D. M., Johnson, A. L., Tidmarsh, S. F., MacSweeney, D. A., Hewland, H. R., Woolcock, N. E. Psychol. Med. 1974, 5, 206. 2. Kiely, M., Sourkes, r. L. J. Neurochem. 1972, 19, 2863. 3. Fernstrom, J. D., Wurtman, R. J. Science, 1972, 178, 414. 4. Dahlström, A., Häggendal, J., Atack, C. in Serotonin and Behaviour (edited by J. Barchas and E. Usdin), p. 87. New York, 1973. 1.

1 Lahenfield-Toal, H., Hesch, R. D., Hufner, M., McIntosh, C.

K. Hormone

metab. Res. 1974, 6, 314. Lozada, E S , Gauaux, J., Franklin, N. J. clin. Endocr. 1972, 34, 704. Numann, P. J., Moses, A. M. Surgery, 1974, 75, 869.


Letter: Parathyroid hormone and adenylate cyclase.

363 accept the fact that British mothers choose bottle feeding using the three most common but "dangerous" powdered milks. If these unmodified milks a...
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