1067

the N.C.B. study the corresponding correlations were0.76 and 0.60. Heritability estimates have a wide mar-gin of error. The difference between the N.C.B. andother twin studies should not be exaggerated.

With increasing evidence for genetic factors in per-sonality and mental illness,16-19 it seems strange that

genetic influence on intelligence should be so

strenuously denied. There are some parallels with

schizophrenia. Some fifteen years ago Kallmann’s exten-sive work was severely criticised for some of the samereasons as Burt’s, though fraud was never alleged. Whena population-based twin study reported zero concor-dance for schizophrenia in identical twins,2O some

thought the genetic hypothesis had been completely dis-credited. But further careful work on twins and adop-tees led to a better appreciation of the importance ofgenetic predisposition and Kallmann’s work is now seenin truer perspective. Because of the many unansweredquestions, there are sharp differences of opinion,21 buton the whole the discussion is now a little more open-minded than is the current debate concerning intelli-gence.

SUBSTANCE P

IN 1931 von Euler and Gaddum extracted from

equine brain and intestine a material with hypotensiveand smooth-muscle-stimulating properties.22 Initiallydesignated preparation P (for powder), it was laterreferred to as substance P, a non-descriptive name whichit has retained.23 Forty years after its discovery substanceP has finally been fully purified, sequenced,24 and synthe-sised25: it is a small polypeptide of 11 aminoacids. Sub-stance P is widely distributed in the body, with localisa-tion in the central and peripheral nervous system.26-29 Inthe C.N.S. the highest concentrations are in the substan-tia nigra, hypothalamus, pineal gland, and also the dor-sal grey matter of the spinal cord. Immunofluorescencestudies reveal that it is contained predominantly in thecell bodies and processes of a subpopulation of small un-myelinated primary sensory neurons,30 and in nerveextracts it is associated particularly with the synapto-some fractions. 29 When applied directly to single neurons,such as the motor neuron of the ventral horn of thespinal cord, it provokes a slow, long-lasting excitatory res-ponse.3’ Substance P is also present in the dorsal root,though not the ventral root, of the spinal cord. If thedorsal root is sectioned, substance P then accumulatesdistally but disappears from the proximal dorsal horn ofthe cord. 32 On p. 1054 Dr Cuello and his co-workers report

17. Gottesman, I. I., Shields, J. Schizophrenia and Genetics. New York, 1972.18 Mednick, S. A., Schulsinger, F., Higgins, J., Bell, B., eds. Genetics, Environ-

ment and Psychopathology. Amsterdam, 1974.19. Fieve, R. R., Rosenthal, D., Brill, H. (editors) Genetic Research in Psychi-

atry Baltimore, 1975.20. Tienari, P Acta psychiat. scand. 1963, suppl. 171.21. Gottesman, I. I., Shields, J. Schiz. Bull. (in the press).22. von Euler, U S., Gaddum, J. H. J. Physiol., Lond. 1931, 72, 74.23. Chang, H. C., Gaddum, J. H. ibid. 1933, 79, 255.24 Chang, M. M., Leeman, S. E., Niall, H. D. Nature New Biol. 1971, 232, 86.25 Tregear, G. W., Niall, H. D., Potts, J. T., Leeman, S. E., Chang, M. M. ibid.

p. 87.26. Powell, D., Leeman, S., Tregear, G. W., Niall, H. D., Potts, J. T. ibid. 1973,

241, p. 252.27. Takahashi, T , Otsuka, M. Brain Res. 1975, 87, 1.28. Hokfelt, T., Meyerson, B., Nilsson, G., Pernow, B., Sachs, C. ibid. 1976,

104, 181.29. Duffy, M J , Wong, J , Powell, D. Neuropharmacology, 1975, 14, 615.30. Hokfelt, T., Kellerth, O., Nilsson, G., Pernow, B. Science, 1975, 190, 889.31. Takahashi, T., Konishi, S., Powell, D., Leeman, S. E., Otsuka, M. Brain

Res 1974, 73, 59.32. Otsuka, M., Konishi, S., Takahashi, T. Fedn Proc. 1975, 34, 1922.

further evidence that it may have a role as a sensoryneurotransmitter: they found that in the substantia gela-tinosa of the dorsal horn of human spinal cord, fine un-myelinated axons contained immunoreactive substanceP. At the Nobel Symposium on substance P, held inStockholm earlier this year, this substance was said tocause excitation specifically of the sensory spinalneurons that transmit painful stimuli from the peri-phery.33 In contrast, Stewart et al.34 have lately shownthat when substance P is administered intracerebally inmice the response to pain stimuli is much reduced-ina manner similar to that seen after morphine or thenewly discovered analgesic peptides enkephalin andendorphin.35 Animals made tolerant to morphine werealso tolerant to substance P and its effect was blocked bythe morphine antagonist naloxone.34 Thus, while in thecord substance P seems to be involved in pain transmis-sion, in the brain it may play a different role, modulat-ing neuronal activity and reducing pain sensitivity.The importance of substance P in the peripheral ner-

vous system is less clear. It is present in dermal nerves30and in the cell bodies and processes of Auerbach’s andMeissner’s plexuses in the gut.36 Indeed, substance P canbe extracted from almost all the tissues of the body in-cluding salivary glands, thyroid, trachea, pancreas, kid-ney, bladder, and prostate.3’ Thus, any of its variousactions on peripheral tissues that have been character-ised so far may turn out to be of physiological impor-tance. For example, it is a powerful stimulant of salivarysecretion,38 it is a potent vasodilator in adipose tissue andmuscle,39 it greatly stimulates intestinal motility,22 andit inhibits insulin release from the pancreas.4o Whenadministered intravenously to guineapigs substance Pcauses a dose-dependent increase in tracheobronchialsmooth-muscle tone,41 and thus in airways resistance. Inman substance P seems to be normally present in

plasma, albeit in low concentrations.26 42 Much higherlevels have been reported in patients with carcinoidtumours 43 and substantial quantities can be extractedfrom the tumorous tissue.44 Whether substance P is res-

ponsible for any of the as-yet unexplained features of thecarcinoid syndrome awaits further research. SubstanceP is not confined to nervous tissue but is also found in

enterochromaffin-type endocrine cells in the gutmucosa.36 45 It thus joins the growing band of hormonalpeptides found in both brain and peripheral endocrinesystem.46No simple explanation of the role of substance P is

possible. In the brain it seems to be a powerful modula-tor of neuronal activity, and in the cord a sensory neuro-

33. Henry, J. L. Abstr. Nobel Symp. 37; p. 29. Stockholm, 197634. Stewart, J. M., Getto, C. J., Neldner, K., Reeve, E. B., Krivoy, W. A., Zim-

merman, E., Nature, 1976, 262, 784.35. Marx, J. L. Science, 1976, 193, 1227.36. Pearse, A. G. E., Polak, J. M., Histochemistry, 1975, 41, 375.37. Brodin, E., Nilsson, G. Abstr. Nobel Symp. 37; p. 8. Stockholm, 1976.38. Chang, M. M., Leeman, S. E. J. biol. Chem. 1970, 245, 4784.39. Pernow, B., Rosell, S. Acta physiol. scand. 1975, 93, 139.40. Efendic, S., Luft, R., Pernow, B. Abstr. Nobel Symp. 37; p. 32. Stockholm,

1976.

41. Dahlberg, K., Brodin, E., Sundler, F., Nilsson, G., Strandberg, K. ibid. p.15.

42. Powell, D., Skrabanek, P. ibid. p. 7.43. Nilsson, G., Pernow, B., Fischer, G. H., Folkers, K. ibid. p. 8.44. Sundler, F., Bengmark, S., Brodin, E., Hakansson, R., Ingemansson, S.,

Larsson, L. I., Nilsson, G. ibid. p. 12.45. Nilsson, G., Larsson, L. I., Hakanson, R., Brodin, E., Pernow, B., Sundler,

F. Histochemistry, 1975, 43, 97.46. Bryant, M. G., Bloom, S. R., Polak, J. M., Albuquerque, R. H., Modlin, I.,

Pearse, A. G. E. Lancet, 1976, i, 991.

1068

transmitter, while in the periphery its action varies

widely from tissue to tissue. Despite the considerablepotential importance of substance P in physiology and inseveral human diseases it is wise to remember that nota single function is yet fully proven. Thus, after four-and-a-half decades of work it remains only a candidatehormone and a tentative neurotransmitter.

INTRATHECAL ANTIBIOTICS IN PURULENTMENINGITIS

WITH the advent of antimicrobials, the concept of theblood/brain and blood/cerebrospinal-fluid (C.s.F.) bar-riers became important in the treatment of central-ner-vous-system infections. Substances which are highlylipid-soluble enter the brain and c.S.F. rapidly, whereasantibiotics such as penicillin and tetracycline, which areionised at the pH of plasma and thus have very low lipidsolubility, penetrate slowly and in small amounts.’ Atpresent there are no pharmacological agents which cansafely be used to destroy these barriers. The best theore-tical solution would be to modify the drugs in such away as to make them lipid soluble without disturbingtheir antimicrobial activity. Until this is achieved theclinician has only two ways of securing high C.s.F. druglevels. He can give massive intravenous doses in thehope that some will spill over, or he can inject the drugdirectly by the lumbar, cisternal, or ventricular route.Both methods have their advocates. As long ago as 1953,Hoyne2 listed ten reasons why he believed intrathecaltherapy should not be used. Yet it is still recom-

mended in many departments treating meningitis-par-ticularly on the east of the Atlantis. 3 4 Any treatmentshould be avoided either if it can be shown to be harmfulor that as good or better results can be achieved withoutit. Occasionally, intrathecal antibiotics cause transientlocal arachnoiditis, but with correct dosage and the pur-est preparations there is no evidence that this method ofadministration is hazardous.

Intrathecal treatment is recommended mainly for

pneumococcal meningitis, for gram-negative infections(which are commonest in the neonatal period), and fortuberculous meningitis. In one trial, pneumococcal men-ingitis treated with daily intrathecal penicillin for a

minimum of 5 days had a mortality-rate of 12%,4 com-pared with a mortality of 20-25% in series treated withhigh-dosage intravenous ampicillin or penicillin. 5Hence, although these groups were not strictly compar-able, the evidence has so far favoured intrathecal treat-ment.

A controlled trial was needed, and McCracken andMize6 now report just such a study of neonatal gram-negative meningitis. Both groups received ampicillinand gentamicin, and one group was given in additiongentamicin intrathecally. There was no differencebetween the two groups in mortality, morbidity, ornumber of days the C.s.F. remained positive. Unfortuna-tely the intrathecal dose, 1 mg daily for at least threedays, was considerably smaller than that usually recom-mended, 2 mg daily until at least four consecutive nega-

1. Schanker, L. S. Antimicrob. Agents Chemother. 1966, 5, 1044.2. Hoyne, A. L. Med. Clins N. Am. 1953, 37, 329.3. Lorber, J. Prescribers’ J. 1976, 4, 82.4. McKendrick, G. D. W. Jl. Neurol. Neurosurg. Psychiat. 1968, 31, 528.5. Mathies, A. W. Jl R. Coll. Physs, Lond. 1972, 6, 139.6. McCracken Jr., G. H., Mize, S. G. J. Pediat. 1976, 89, 66.

tive cultures have been obtained and this difference

may account for the lack of advantage in the intrathecalgroup. Though in adults the geometric mean half-life ofgentamicin in the C.s.F. near the site of introduction isunder six hours,7 local gentamicin is undoubtedly valu-able in specific circumstances; for example, after remo-val of an infected ventriculoatrial shunt intraventricular

injection cured meningitis when dosage by the lumbarroute had been unsuccessful.8 Persistent ventriculitis isa known cause of treatment failure in neonatal men-

ingitis. Yeung9 has also produced evidence that ventricu-litis of different aaiologies may respond to intraventricu-lar antibiotics when administration by the lumbar routehas failed. He states that the neonatal-meningitis morta-lity in his hospital has fallen from 70% to 20% since theintroduction of intrathecal therapy.

In tuberculous meningitis, intrathecal streptomycin is

employed less often than formerly. It is not needed in pa-tients in stage I and probably not in those in early stageII. It does, however, lessen mortality in patients with dis-turbed consciousness at the onset of treatment." Nor-mally, ten intrathecal injections are adequate"-onedaily for 7 days, followed, if the improvement is satisfac-tory, by three further injections every other day.

There are clear difficulties in getting a scientificanswer to the necessity for intrathecal therapy. Largewell-designed double-blind multicentre trials are neededto produce statistical evidence of its value in pneumococ-cal and gram-negative infections. Until such results areavailable it seems wise to continue with intrathecal ther-

apy in severe infections. The practice of injecting peni-cillin at the diagnostic lumbar puncture in all ill patientswith purulent meningitis also remains a sensible routinewhich will sometimes save a second lumbar puncture onthe same day.

JUSTICE FOR ALL

A CASE heard in the Court of Appeal last week andreported on p. 1094 concerned the death of a patient inMarch, 1971, and his widow’s efforts to claim damagesfor negligent treatment. The unsatisfactory conclusionwas that no fair trial was possible after so long a lapseof time. The Court’s judgment spoke of the need tobring such actions quickly to trial and of the failure oflawyers to comply with the time rules of the SupremeCourt.When a claim such as this fails on time alone, the doc-

tors concerned are left with the suggestion of negligencehanging in the air (despite the fact that in this case anopinion sought on the widow’s behalf had declared thatthere was no evidence whatsoever of negligence); andthose who bring the claim feel that a proper hearing hasbeen denied to them. It may be that when lawyers havedoubts about the wisdom of pursuing a claim brought tothem, some delay is inevitable while the client seeksother advice. But a point should come, sooner ratherthan later, when the determination of a complainant tocontinue is recognised on both sides, so that the mattermay be put to trial-in the interests of all concerned.

7. Rahal, Jr., J. J., Hyams, P. J., Simberkoff, M. S., Rubenstein, E. New Engl.J. Med. 1974, 290, 1394.

8. Mœllering Jr., R. C., Fischer, E, E. G. J. Pediat. 1972, 81, 534.9. Yeung, C. Y. Archs. Dis. Child. 1976, 51, 686.

10. Freiman, I., Geefhuysen, J., J. Pediat. 1970, 76, 895.11. Lorber, J., Br. med. J. 1960, i, 1309.