homozygous fetus, already unable
rectify his tyrosine, is
aminoacid environment with respect faced with a more deficient aminoacid environment than the normal fetus. If the phenylketonuria gene or both, in homozygous or heteris in fact potentially damaging to the ozygous form, unborn child, this may have far reaching implications, particularly for expectations regarding efficacy of dietary treatment, since the assumption that phenylketonuric children are normal at birth would not be true. Further study of the effect of the phenylketonuria gene, for its own sake and as a paradigm, is clearly desirable. Attempts have lately been initiated to test the strength of correlation between E.E.G. changes and heterozygosity for phenylketonuria based on the hypothesis that heterozygotes with E.E.G. abnormalities are offspring of mothers rather than fathers carrying the phenylketonuria gene. 14 Such abnormalities might be unmasked during load tests. This hypothesis could be linked with the view that the heterozygote mother may provide an unfavourable intrauterine environment-a view, contested by WooLF et aI:J In an article this week (p. 767) Dr FORD and Dr BERMAN extend the scope of heterozygote investigation with respect to the phenylalaninaemias by studying families with either a phenylketonuric or a hyperphenylataninsmic member; they used a phenylalanine tolerance test and measured intelligence on the Wechsler scales. Their findings indicate an association between intellectual strengths and weaknesses and heterozygosity for phenylketonuria and hyperphenylalaninsemia. They make the cautious proviso that "the data do not clearly depict the direction of specificity of the connection between phenylalanine metabolism and intellectual proficiency", but put their findings forward as a basis for speculation. They hark back to the possibility of brain damage in pregnancy due to the possible deleterious effects of the mutant gene. A systematic study of a wide range of clinical effects in families with known autosomal recessive conditions is called for. For example, cystic fibrosis occurs at a frequency much too high to be maintained by fresh mutations, which typically have a frequency of 1 in 100 000 or so; the most plausible hypothesis for this unexplained phenomenon is heterozygote advantage. No such advantage, unfortunately, has yet been demonstrated. A groundwork of unequivocal observations is needed as a base from which to proceed in a study of the heterozygote, if we are to avoid building speculation upon speculation. To date, we have had few solid
in mother or fetus
facts at our disposal. Heterozygosity, depending on the environment, could be an advantage in some individuals and not in others. 14. Cowie, V. A., Harris, R. F., ment.
Def. 1976, p. 281.
Stern, J. Proc.
III Congr. int. Ass. scient. Study
CHLAMYDIA TRACHOMATIS AND THE RESPIRATORY TRACT
Chlamydia trachomatis is the causal agent of three conditions-trachoma, punctate keratitis, and inclusion conjunctivitis. Inclusion conjunctivitis arises from infection from genital-tract carriers of C. trachomatis (where the organism may cause nonspecific urethritis in eye
the male and cervicitis in the and transmission be as in indirect, may swimming-pool conjunctivitis, or direct, as in the inclusion blennorrhoea of infants infected at delivery. It might be expected that C. trachomatis could be isolated from the upper respiratory tract of patients with eye infection, owing to simple drainage via the lacrymal duct, but there has been scant evidence that this agent causes actual respiratory-tract infection. Schachter et al.isolated chlamydise from the sputum of an infant who had had a prolonged attack of conjunctivitis (probably chlamydial since both parents had genital chlamydial infection, the mother being untreated as she was in the last trimester of pregnancy when diagnosed). When thehild was 52 days old pneumonitis developed with cough, tachypncea, and respiratory distress. No respiratory-tract pathogens were isolated but the child was found to have antibodies to chlamydia. More recently Beem and Saxon2 in Chicago have recognised a clinically distinctive pneumonia syndrome in infants and their observation that 2 of these infants had histories of postnatal conjunctivitis led to a search for evidence of chlamydial infection in respiratory disease in these patients. As in the case described by Schachter et al. pneumonia was diagnosed at about the 6th week of life and the history was of symptoms gradually worsening over the previous 3-4 weeks. The infants had tachypnoea and a distinctive spasmodic cough differing from that of pertussis in that series of staccato coughs were separated by a brief inspiration without a whoop. Chest X-ray showed pulmonary hyperexpansion with diffuse interstitial and patchy alveolar infiltrates. Systemic reactions, fever, and malaise were absent but serum IgG and IgM were raised. Infants with this clinical picture were examined for evidence of chlamydial infection. 5 of 8 patients studied retrospectively yielded C. trachomatis from nasopharyngeal aspirates, 2 (1 nasopharynx-positive and 1 nasopharynx-negative) also from tracheal secretions. 12 infants with the syndrome were studied prospectively. Conjunctival cultures from 7 were positive for C. trachomatis but all 12 yielded C. trachomatis from nasopharyngeal aspirates. Tracheal aspirates yielded C. trachomatis from all 11 infants from whom such specimens were taken (although contamination by nasopharyngeal flora could not be excluded). Patients yielded C. trachomatis on many occasions and often in large numbers. No chlamydiae were isolated from lung-biopsy specimens in 2 cases. Although patients with conjunctivitis had antibody to C. trachomatis, those with pneumonia had much higher titres overall. Other microbial agents were sought and 4 of the 12 patients studied prospectively also excreted cytomegalovirus; what this means is uncertain. Beem and Saxon interpret their findings with caution and point out that 10 of 12 children with inclusion conjunctivitis alone had C. trachomatis in nasopharyn1. Schachter. J., Lum. L., Gooding. C. A., Ostler. B. J. Pediat. 1975, 2. Beem, M. O., Saxon, E. M. New Engl. J. Med. 1977, 296, 306.
788 did 2 of 15 other infants with other illAll 47 infants studied, both cases and controls, were Black and it is not clear whether the clinic dealt exclusively with a Black population or whether this syndrome has been observed only in Black patients. Nevertheless, it will be of interest to see if other workers are able to confirm that infants (whether Black or White) with prolonged cough, ofen hitherto thought to be infected with Mycoplasma pneumonia or Bordetella pertussis, are indeed suffering from C. trachomatis infection.
a true statement of law, many people will feel that a company has a moral responsibility to compensate patients for harm sustained from a drug which they have persuasively encouraged doctors to prescribe (and sometimes even patients themselves to request) with attractive claims of safety. But one difficulty, in every case,is to prove a causal association-particularly if some parts of the drug reaction, as with the practolol syndrome, are not uncommon in the absence of drug ingestion. I.C.L’s offer of compensation, before questions of litigation were formally raised, is an admirable gesture; but there might have been some advantage in allowing matters to proceed to the courts. Unfortunately the practolol affair is unlikely to be the last of its kind, and clarification of the law would have been useful.
COMPENSATION FOR UNFORESEEN ADVERSE DRUG REACTIONS AT the last county I.C.I. had compensated 300 of the 1000 individuals claiming to have been harmed by the beta blocker, practolol. This episode eobkes memories of thalidomide, but there are important differences. Unlike thalidomide, practolol had been assessed by an official body-the Committee on Safety of Medicines-which had pronounced itself satisfied with the drug’s experimental and early clinical toxicity record. Furthermore, the nature of the practolol reaction is not understood, and there seem no animal or in-vitro tests which could have predicted it. Do these changes in drug-control practice influence the responsibility of a pharmaceutical company to compensate patients who suffer adverse reactions? A small group discussed this question last year at the Royal College of Physicians and their deliberations have just been published. Davey2 stressed the unforeseen nature of the practolol reaction: he reckoned that, assuming that there was a species of laboratory animal suitable for its detection, clear demonstration of such an association might demand experiments on 50 000 to 100 000 animals. It was also evident that, although clinical-trial methodology has developed to a high degree, assisted by the growth of clinical pharmacology as a scientific disciplinesand despite the earlywarning systems now operating to detect adverse effects at an early stage in the life of a drug,4 drug reactions easily escape notice when not predictable from known pharmacological actions of a drug or when they do not fall into a recognised syndrome of such reactions. But it is the legal aspect of the practolol episode which is the most perplexing. A lawyer5 interpreted the present position in law to be that, in guarding against risks, "a manufacturer of drugs must take such care as a reasonably careful and skilful drug manufacturer would take ... In English law he will not be negligent if he has acted in accordance with a practice accepted as proper by a responsible body of his peers skilled in the particular skill in which his field of activity lies... If he has performed all the tests contemporary science has devised and nevertheless something then goes wrong, he will escape liability in this country". While this may well be 1. Lancet, March 26, 1977, p. 709. 2. Davey, D. G. Jl R. Coll. Physns, 1977,
3. Dollery, C. T. ibid. p. 226. 4. Crooks, J. ibid. p. 239. 5. Wilmers, J. ibid. p. 247.
PATHOGENESIS OF SYDENHAM’S CHOREA MOST recover
people who acquire a streptococcal sore throat completely, while 3% or less proceed to rheu-
matic fever and even fewer to chorea. Chorea is twice as in girls as in boys and there is a slight familial trend.’ Taranta and Uhr2noted that siblings in one family tended to have chorea, whereas those in another family had only joint involvement and/or carditis; a study of HLA types might show whether Sydenham’s chorea, like Huntington’s, does indeed have a genetic basis. The organism precipitating rheumatic fever is restricted by the carbohydrate antigen of the p-haemolytic streptococcus to group A, but is not limited to any particular M protein serotype. The precipitating infection is normally in the throat, very rarely elsewhere.3 An abnormal host response presumably underlies rheumatic fever and its choreic complications. In rheumatic carditis there is no lack of hypotheses and observations bearing on the pathogenesis. Immunofluorescence techniques have displayed deposits of rglobulin and complement in the auricles and antimyocardial antibodies in the serum. These antibodies react with a subsarcolemmal antigen and can be absorbed with streptococci. Since they are present more frequently and in higher titre in patients with rheumatic fever than in those with common
uncomplicated streptococcal infection, they are judged relevant to the pathogenesis of rheumatic carditis.3 The hypothesis that the damage is caused by antibody to streptococcal antigens cross-reacting with myocardium and other body tissues is more attractive than the hypotheses implicating immune-complex deposition or an antibody reaction to bacterial antigen fixed in the an
tissues. The attempt to extend this hypothesis to Sydenham’s chorea is complicated by scarcity of neuropathological material. Deaths from Sydenham’s chorea are rare and patients who die have had unusually extensive cerebral disease clinically and tend to show generalised encepha1. Lessof, M. H. Guy’s Hosp. Rep. 1958, 107, 185. 2. Taranta, A., Uhr. H. W. in Immunological Diseases (edited by M. Samter), p. 601. Boston, 1971. 3. Glynn, L. E., Lachmann, P. J. in Clinical Aspects of Immunology (edited by P. G. H. Gell, R. R. A. Coombs, and P. J. Lachmann); p. 1079. Oxford,