PROSTAGLANDINS AND SCHIZOPHRENIA

706 in 1974,1 and all that has happened since then reinforces that evidence. For example, in one current trial (UKALL V) the records to date refer to 148 exposures to varicella for which ZIg was given and to 17 known cases of varicella in which no ZIg had been given because the contact was missed or not apparent. The outcome was: Outcome No disease Fatal Severe Moderate Mild

No

Zlg given 138 0 1 2 7

? 2

(pneumonia) 10 3 2

We do not know how many undetected contacts occurred no resultant disease, but with the present state of awareness there were probably not many. The figures for the severity

of the disease speak for themselves. It is a pity to waste a valuable commodity on those who already have immunity but it would be disastrous if immunoglobulins were to be withheld in circumstances where they are probably life-saving. In the long run the availability of acyclovir2 and the use of varicella vaccines may necessitate a reappraisal of policy, but meanwhile ZIg must be regarded as a life-saver for susceptible children on immunosuppressive treatments.

R. S. LANE

Leukæmia Trials Office (M.R.C.), Chester Beatty Research Institute, Institute of Cancer Research, London SW3 6JB

A. RANKIN H. E. M. KAY on

ASBESTOS FIBRES IN LUNG TISSUE

ZIg

with

Blood Products Laboratory, Elstree

MESOTHELIOMA CASES AND CONTROLS BY TYPE AND AMOUNT OF

behalf of the M.R.C. Working Party on Leukæmia in Childhood

I

*Low=<1000

fibres/mg lung

I

tissue.

High=>

I

1000

fibres/mg lung tis-

sue.

of fibre found in the lungs of controls in this new study by comparison with only 65 out of the previous 135 controls having fibres present. Moreover it would seem that high levels of chrysotile fibre were found as frequently among the amounts

controls as among the cases. We thank Dr F. D.

Pooley

of the

department

of mineral

exploi-

tation, University College, Cardiff, and Mr G. Berry of the M.R.C. Pneumoconiosis Unit, Penarth, for supplying more detailed tabulation of the data than that given by Jones et al.5 M.R.C. Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO9 4XY

E. D. ACHESON M. J. GARDNER

PROSTAGLANDINS AND SCHIZOPHRENIA

SIR,-Dr Mathe and colleagues’ (Jan. 5, p. 16) report of inPOSSIBLE SYNERGISM BETWEEN CHRYSOTILE AND AMPHIBOLE ASBESTOS

SIR,-Recently we suggested that there might be a synergistic interaction between chrysotile asbestos and amphibole asbestos in the production of mesothelioma of the pleura.3 This was based on an analysis of results of electronmicroscopic examination of lung tissue from mesothelioma cases and controls dying from a range of other causes.’ Data from a further casecontrol comparisondo not support our suggestion. This letter sets out briefly the findings in the new material. The electronmicroscopic technique used previously has been modified and the fibre concentrations in lung tissue are now reported as fibres per mg rather than fibres per electronmicroscopic grid. Although this does not permit direct comparison with the earlier analysis a similar assessment of any possible synergism can be made. The new study included 86 mesothelioma cases and 56 controls, 29 of whom died from cerebrovascular disease and 27 from bronchial carcinoma, matched for place of death, age, and sex with the cases. The table gives the distribution, by asbestos type and amount, of fibres in the lungs and shows the estimated relative risks of high exposure to either or both types of fibre. There is no evidence in these data of a synergistic effect of chrysotile and amphibole, whereas in the earlier data the respective relative risks were 1, 6, 12, and 61. A major change appears to be the much larger WD’A. Danger of varicella to immunosuppressed patients. Lancet 1974; ii: 298-99. 2. Selby PJ, Powles RL, Jameson B, et al. Parenteral acycloguanosine therapy for herpes virus infections in man. Lancet 1979; ii: 1267-70. 3. Acheson ED, Gardner MJ. Mesothelioma and exposure to mixtures of chrysotile and amphibole asbestos. Arch Envir Hlth 1979; 34: 240-42. 4. Pooley FD. Mesothelioma in relation to exposure. In: Bogovski P, Gilson JC, Wagner JC, eds. Biological effects of asbestos: I.A.R.C. Sci Publ no 8. I.A.R.C., Lyon, 1973: 222. 5. Jones JSP, Pooley FD, Clark NJ, Owen WG, Pollock DJ, Roberts GH, Smith PG, Wagner JC, Berry G. The pathology and mineral content of lungs in cases of mesothelioma in the United Kingdom in 1976: paper presented to symposium on Biological Effects of Mineral Fibres held at I.A.R.C., 1.

Kay HEM, Maycock

Lyon, 1979. (In press).

creased

E (PGE) levels in the CSF of schizosupports the concept of an abnormality of PG metabolism in schizophrenia. However, there are problems of experimental technique and interpretation. Mathe et al. claim that there is no previous direct experimental evidence of a PG abnormality. Abdullah et al.’ found

prostaglandin

phrenics

that platelets from schizophrenics formed much less PGE, from its precursor dihomogammalinolenic acid (DGLA) than did platelets from non-schizophrenics. When the platelets were stimulated with maximal ADP concentrations the difference between the schizophrenics and the non-schizophrenics was

highly significant. Mathe et al. appear to have measured only PGE (i.e., PGE, plus PGEz). In platelets2 and in smooth muscle from the mesenteric vasculature,3 for example, the actions of these two PGs are different. To interpret changes properly assays specific for PGE1 and PGEz must be used. I have suggested that the primary failure in schizophrenia is failure of PGE1 formation.’ Since PGEinhibits the mobilisation of arachidonic acid it is likely that reduced PGEformation will be accompanied by increased production of PGE2, and this may be what Mathe et

al. have observed. Mathe et al. imply that reduced cAMP formation in response to PGE15 is evidence of exposure to high levels ofPGE1. They argue that exposure of a receptor to high levels of an agonist always desensitises that receptor. However, there are exam1. Abdullah YH, Hamadah K. Effect of ADP on PGE formation in blood platelets from patients with depression, mania and schizophrenia. Br J Psychiat

1975; 127: 591-95. J. Relationship between chemical structure and platelet aggregation activity of prostaglandins. Biochim Biophys Acta 1969; 187: 215-91. 3. Manku MS, Horrobin DF, Cunnane SC et al. Effects of prostaglandins E1,

2. Kloeze

E2

and

I2

in the

rat

mesenteric artery: Evidence for three distinct recep-

Biochem Biophys Res Comm 1978; 83: 295-99. Horrobin DF. Schizophrenia: Reconciliation of the dopamine, prostaglandin, and opioid concepts and the role of the pineal. Lancet 1979; i. tors.

4.

529-31. 5. Rotrosen J, Miller AD, Mandio D, et al. Reduced PGE1 stimulated 3H-cAMP accumulation in platelets from schizophrenics. Life Sci 1978; 23: 1989-96.

707

ples, notably with prolactin and angiotensin,6 where absence of the agonist desensitises the receptor. Four lines of evidence suggest that PGE, behaves like prolactin and angiotensin rather than like insulin: (a) in essential fatty acid deficient rats, in which PGE,formation is reduced, inhibition of aggregation by PGE, is also reduced;’ (b) lithium treatment reduces PGE1 production8 and lowers the cAMP response to PGE1;9 (c) tumour cell lines, which often cannot produce PGE1 because of an enzyme defect,’O often have a poor cAMP response to PGE1;" (d) platelets from schizophrenics, which fail to produce PGE1 normally,’ also fail to generate cAMP normally in 5 response to PGE 1.1 I have argued4that a reduced rate of PGE, formation, possibly due to a lack of melatonin or to an excess of an opioid, will lead to lowered sensitivity of the cAMP response to PGE l’ to increased formation of PGEz because of loss of control of arachidonate mobilisation, and to an increased biological activity of dopamine because opioid excess may lead to dopamine supersensitivity and because dopamine opposes the actions of low concentrations of PGE1 on intracellular calcium movements. This dopamine/PG antagonism seems specific to PGE1 since it is not found with either PGE2 or PGF2&agr; (unpublished). PO Box 10, Nun’s Island, Montreal H3E

DAVID HORROBIN

IJ8, Canada

PGE decreases the release of dopamine and noradrenaline (norepinephrine) in both the peripheral nervous system and in the rat cerebral cortex and neostriatum.6 Increased PGE may then represent a response to the postulated increased dopaminergic activity in schizophrenia. Stimulation of afferent peripheral nerves, reticular activating system and somatosensory cortex have been reported as increasing cerebral PG levels.7.8 This could suggest a possible mechanism for the "reducing" pattern seen in schizophrenics on average evoked response testing, a pattern which, Buchsbaum speculates, may reflect a protective response to stimulus flooding.9 PGE’s pronounced and prolonged constrictor effect on the cerebral vasculature10,11 could contribute to the frontal hypoperfusion in schizophrenics.’2 Finally, opiate inhibition of PGE, stimulated adenyl cyclase and paradoxical stimulation of PG biosythesis13 suggests that increased PGE levels could even be epiphenomenological to postulated altered endogenous opiate activity in

schizophrenia.14,15 Mathe et al. are properly cautious in their interpretation of their potentially important preliminary findings and in their desire for its replication in a larger series. Further attempts to elucidate the possible behavioural concomitants of prostaglandin regulation, linked to schizophrenia or not, could prove important in behavioural neuroscience. Section on Psychobiology,

Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland 20014, U.S.A.

SIR The report by colleagues prompts the questions-why might one expect to find abnormal levels of prostaglandins in schizophrenia and how might such a finding be understood in terms of the pathophysiology of this disorder? Prostaglandins modulate neural activity, producing a net increase or decrease in the gain of a cell’s functional response to stimulation. As such, the prostaglandin system serves a regulatory function, the extent of its activity being determined specifically by the local endocrine/chemical’·2 environment and generally by the state of physiological disequilibrium. Thus, one might predict that significant CNS dysfunction would result in activation of components of the PG system with, perhaps, detectable changes in the CSF. Patients with epilepsy, meningoencephalitis, hydrocephalus, and surgical trauma have dramatically increased CSF levels of both PGF2&agr;, and PGE2.3-s The increased CSF PGE reported by Mathe et al. may reflect a compensatory reaction to CNS dysfunction rather than a specific concomitant of schizophrenia. In what ways, other than those discussed by Mathe et al., might PG activity relate to other findings in schizophrenia?

DAVID R. RUBINOW

Dr Mathe and

6. Baxter JD, Funder JW. Hormone receptors. N Engl J Med 1979; 301: 1149-61. 7. Vincent JE, Melai A, Bonta IL. Comparison of the effects of prostaglandin E1 on platelet aggregation in normal and essential fatty acid deficient rats. Prostaglandins 1974; 5: 369-73. 8. Manku MS, Horrobin DF, Karmazyn M, et al. Prolactin and zinc effects on rat vascular reactivity: Possible relationship to dihomogammalinolenic acid and to prostaglandin synthesis. Endocrinology 1979; 104: 774-79. 9. Murphy DL, Donelly C, Moskowitz J. Inihibition by lithium of prostaglandin E1 and norepinephrine effects on cyclic AMP production in human platelets. Clin Pharmacol Ther 1973; 14: 810-14. 10. Dunbar LM, Bailey JM. Enzyme deletions and essential fatty acid metabolism in cultured cells. J Biol Chem 1975; 250: 1152-54. 11. Sheppard JR. Differences in the cyclic adenosine monophosphate levels in normal and transformed cells. Nature New Biol 1972; 236: 14-16. 1. Zusman RM, Keiser HR, Handley JS. Effect of adrenal steroids on vasopressin-stimulated PGE synthesis and water flow. Am J Physiol 1978; 234: 532-40. 2. Stjarne L. Inhibitory effect of prostaglandin E2 on noradrenaline secretion from sympathetic nerves as a function of external calcium. Prostaglandins 1973; 3: 105-09. 3. Latorre E, Patrono C, Fortuna A, Grossi-Belloni D. Role of prostaglandin F2alpha in human cerebral vasospasm. J Neurosurg 1974; 41: 293-99. 4. Carasso RL, Vardi J, Rabay JM, Zor U, Streifler M. Measurement of prostaglandin E2 in cerebrospinal fluid in patients suffering from stroke. J

Neurol Psychiat 1977; 40: 967-69. 5. Wolfe LS, Mamer OA. Measurement of prostaglandin F2alpha levels in human cerebrospinal fluid in normal and pathological conditions. Prosta-

glandins 1974; 9: 183-92.

PROBLEM WITH ULTRASONIC FETAL HEART RATE MONITOR

SIR,-Fetal heart rate monitors are in regular use antenatally and in labour. A monitor may produce artifacts when the signal quality is imperfect, which can be confusing, might affect clinical management, and will make numerical analysis impossible. Simultaneous fetal heart records were obtained at 37 weeks from abdominal ECG electrodes, and also from a widebeam ultrasound transducer (Sonicaid FM3). What may be interpreted as decelerations (falls in heart rate below the baseline) were seen on the Sonicaid tracing only. The artifactual signals were present when the transducer was not perfectly adjusted (see figure). They are attributed to "noisy" signals. Inspection often showed rapid descent to a flat plateau, which was easily recognised as artifactual; but there were instances where the descent was gradual and there was no obvious plato term

6. 7.

Bergstrom S, Farnebo L, Fuxe K. Effects of prostaglandin E2 on central and peripheral catecholamine neurons. Eur J Pharmacol 1973; 21: 362-68. Ramwell PS, Shaw JE. Spontaneous and evoked release of prostaglandins from the cerebral cortex of anesthetized cats. Am J Physiol 1966; 211: 125-34.

Samuels GMR, Shaw JE. Correlation of prostaglandin release from the cerebral cortex of cats with electro-cortigram following stimulation of the reticular formation. Br J Pharmacol 1969; 37: 151-57 9. Buchsbaum MS. The average evoked response technique in the differentiation of bipolar, unipolar and schizophrenic disorders. In: Akiskal HS, Webb, W L, eds. Psychiatric diagnosis: Exploration of biological predictors. Spectrum Publication, 1978: 411-31. 10. Pickard JD, MacDonnell LA, MacKenzie ET, Harper AM. Prostaglandininduced effects in the primate cerebral circulation. Eur J Pharmacol 1977; 43: 343-51. 11. Yamamoto YL, Geindel W, Wolfe LS, Katoh H, Hodge CP. Experimental vasoconstriction of cerebral arteries by prostaglandins. J Neurosurg 1972; 37: 385-97. 12. Ingvar DH, Lassen NA. Cerebral function, metabolism, and blood flow: News and trends, 8th international CBF symposium. Acta Neurol Scand 8.

Bradley PB,

1978; 57: 262-69. HOJ, Roy AC. Hypothesis: Inhibitor of E prostaglandin-sensitive adenyl cyclase as the mechanism of morphine analgesia. Prostaglandins 1974; 7: 361-76. 14. Watson SJ, Akil H, Berger PA, Barchas, JD. Some observations on the opiate peptides and schizophrenia. Arch Gen Psychiat 1979, 36: 35-41. 15. Ross M, Berger PA, Goldstein A. Plasma &bgr;-endorphin immunoreactivitly in schizophrenia. Science 1979; 205: 1163-64. 13. Collier