KEEP ON TAKING THE TABLETS

266 HERPESVIRUS TYPE 2 INFECTION AND CARCINOMA OF THE CERVIX SIR,-It is now possible to differentiate two types oj herpes-simplex viruses 1,2: type-1 strains cause infection! of the mouth, keratoconjunctivitis, and acute necrotising encephalitis, and type 2 is responsible for herpes genitalis and generalised infections in newborn children. Specific neutralising antibodies to herpesvirus type 2 have been found with greater frequency in patients with carcinoma oj the cervix than in matched controls, random controls, and patients with other types of malignant disease.2,3 The association of genital herpes infection with cervical carcinoma has also been demonstrated by vaginal exfoliative cytology 4; multinuclear cells with intranuclear inclusions typical of hepetic infection can be detected in routine smears. Among women who showed this sign of herpetic infection at least once during the follow-up, 23-7% had cervical anaplasia; this figure was in contrast with the 2-7% incidence of cervical anaplasia in a control group oj apparently non-infected women. These investigations, done in the United States, showed that herpesvirus type 2 is at least one of the environmental factors in the occurrence oi the disease. We have found the same situation in Belgium. OCCURRENCE OF ANTIBODIES TO HERPESVIRUS TYPE 2

Prof. P. Hubinont (Department of Gynaecology and Obstetrics, Hopital St. Pierre), and Prof. R. Vokaer (Department of Gynxcology and Obstetrics, Hopital Brugmann) for permission to study their patients. Institut Pasteur du Brabant,

Hôpital Brugmann, Institut Bordet, Centre anticancereux, and Hôpital St. Pierre, Brussels, Belgium.

S. SPRECHER-GOLDBERGER L. THIRY J. P. CATTOOR R. HOOGHE J. PESTIAU.

RUBELLA VACCINATION

SIR,-The Department of Health has recently issued a letter setting out the Government policy on rubella vaccination. This is to protect girls between 11 and 14 years of age by a mass vaccination scheme. For this purpose rubella vaccine (’ Cendevax’) will be available from local health authorities. We wish to point out that it is perfectly proper in appropriate circumstances for practitioners to immunise women or girls outside this age-group provided that the prospective vaccinee is known not to be pregnant at the time of vaccination and will undertake not to become pregnant during the next two months. For the purpose of such vaccination cendevax is available through ordinary channels of pharmaceutical supply, and mav be prescribed on a form E.C. 10. Smith Kline & French Laboratories Ltd. Welwyn Garden City, Herts.

*** The Department

G. E. PAGET Managing Director. of Health’s letter is summarised on

p. 271.-ED. L.

I

*

I

Rawls et al. do not consider this figure numbers in the series.

Serum-samples were obtained from patients with invasive carcinoma of the cervix (stages i to iv) who were being treated at three university hospitals in Brussels (two gynaecological departments, and one cancer hospital). Serum-samples were also obtained from 2 control groups: (1) women of the same age who had been admitted to the same gynaecological departments for non-malignant diseases ; (2) male and female patients from the cancer hospital who had carcinomas in sites other than the cervix. It is considered that all the patients belonged broadly to the same socio-economic class (low or middle). The sera were assayed for specific antibodies to herpesviruses type 2, using exactly the technique described by Rawls et al. The results obtained by Rawls et al. are compared, in the accompanying table, with those found in Brussels. They clearly confirm that, in Belgium as in the U.S.A., women with invasive carcinoma of the cervix have a very high incidence (83%) of antibodies to herpesvirus type 2, as compared to a lower incidence in matched controls with other gynxcological diseases (29%) or patients with other types of cancer (33%). The similarity between the last two figures indicates clearly that patients from the different hospitals had been exposed to the same risk of genital herpetic infection, and that the high incidence of this infection is genuinely localised among patients with carcinoma of the cervix. We thank Prof. J. Henry (radiological department, Institut J. Bordet), Prof. H. Tagnon (medical department, Institut J. Bordet),

Rawls, W. E., Laurel, D., Melnick, J. L., Glieksman, J. M., Kaufman, R. H. Am. J. Epidem. 1968, 87, 647. 2. Rawls, W. E., Tompkins, W. A. F., Figueroa, M. E., Melnick, J. L. Science, 1968, 161, 1255. 3. Rawls, W. E., Tompkins, W. A. F., Melnick, J. L. Am. J. Epidem. 1969, 89, 547. 4. Naib, Z. H., Nahmias, A. J., Josey, W. E., Kramer, J. H. Cancer, N.Y. 1969, 23, 940. 1.

KEEP ON TAKING THE TABLETS ...

I

significant, because of the small

SIR,-Your editorial (July 25, p. 195) is a valuable pointer to a major hazard of therapy. Wefound that there was a substantial amount of drug rejection even under a strict regimen, when conscientious nurses handed out the tablets. In particular, we found a statistically significant change of results when tablets were replaced by syrups. If drugs are rejected to such an extent under strict supervision, it is fair to assume that they are rejected even more by outpatients. Indeed, Wilcox2 found that the rate was as high as 70% in depressed outpatients. Reports from the U.K. and the U.S.S.R.3-5 show rejection-rates of between

5% and 32%. Some important points emerge: firstly, clinical trials which do not take possible drug rejection into account cannot be completely reliable; secondly, drug therapy is more hazardous than many doctors realise. Perhaps, when patients do not complain of the known side-effects of a drug, the doctor should suspect that the drug is not being taken in the prescribed dosage. Interrogation can be a most useful method of checking up on the patients’ drug-taking habits. Such questions as, "You don’t really like taking drugs, do you ? ", " You don’t really think these drugs help, do you ? ", " These are not the tablets you really wanted, are they ? ", often reveal that the patient does not take his drugs. Patients appear relieved at these questions, and take the opportunity to tell the doctor of the anxieties associated with taking drugs and the fears and guilt associated with rejection. Armed with the results of our own experiments, we have inquired more frequently about patients’ drug-taking, and have been struck by the number who vary the amount and 1. 2. 3.

Wilson, J. D., Enoch, M. D. E. Br. J. Psychiat. 1967, 113, 209. Wilcox, D. R. C., Gillan, R., Hane, E. H. Br. med. J. 1965, ii, 790. Forrest, F., Forrest, I. S., Mason, A. S. Am. J. Psychiat. 1961, 118, 300.

Puzhinskii, S., Rogovskaya, Ya. Zh. Nevropat. Psikhiat. 1963, 64, no. 3, p. 437. 5. Uspenskaya, L. Ya. ibid. p. 441. 4.

267 "

frequency of the dose. Not only, therefore, can Keep on taking the tablets " be useless advice, but it may also be equally futile to increase the dose merely because there has been no adequate response. In many cases it would be far more useful to inquire whether the patient takes his drugs or not.

It would seem much more valuable now to spend money, time, and energy on research into drug rejection rather than the introduction of yet another thiazine. Royal Salop Infirmary, Shrewsbury. on

antidepressant or phenoM. DAVID ENOCH.

MEIOSIS AND TESTICULAR HISTOLOGY IN XYY MALES SIR,-Your correspondents on meiosis in XYY males 1-4 have provided evidence of XY/XYY sex-chromosome mosaicism of the germ-cell line in patients with a somatic 47,XYY complement. In previous reports on 7 cases of XYY males,5,6 only spermatogonia and primary spermatocytes without the extra Y chromosome were observed. This latter finding was confirmed in our own studyof two XYY subjects. The controversy on this subject prompts us to present observations on meiosis and testicular histology in 4 further XYY males. Lymphocyte cultures revealed, in all 4 subjects, a 47,XYY karyotype without any evidence of somatic mosaicism. The details of the patients are summarised below. Case 1.-A 16-year-old boy, 183 cm. in height; rapid growth the indication for cytogenetic investigation. No psychiatric abnormality. Case 2.-Illegitimate child, 18 years old and 192 cm. in height. He was discovered at routine examination in a hospital for the educationally subnormal. Case 3.-23 years old, and 173 cm. in height. Patient in a security hospital, where he had been committed for sexual assault. Case 4.-35 years old, 182 cm. in height., Divorced; father of one daughter. This man’s abnormal chromosome complement was found in the course of cytogenetic examinations of 58 prison inmates exceeding a height of 180 cm. He was in prison mainly was

for theft, violence, and sexual assaults. A more detailed clinical description of the individual be given elsewhere.8

cases

will

Testicular Histology

testicular-biopsy specimen from case 1 disclosed severe of development of the testis with immature tubules and reduction of the number of spermatogonia. Spermatocytes, and therefore meiotic figures, were comA

impairment pletely

absent. In case 2, most testicular tubules showed lamellar thickening of the basement-membrane. The germ-cells of all stages were diminished. Only very rarely spermatids or mature spermatozoa were found. The

histological diagnosis

was " marked tubular atrophy with very similar to those in case 2 were present in case 3; but in this case the discrepancy between a fair number of spermatogonia and absence of spermatids or mature spermatozoa was even more complete. Case 4 showed a milder degree of tubular atrophy. Nevertheless, some tubules displayed a more advanced spermatogenic arrest. Although the results of the histological examination were not uniform, all four cases revealed different degrees of tubular atrophy with impairment of

spermatogenic arrest ". Changes

1. 2. 3. 4. 5.

6. 7. 8.

Evans, E. P., Ford, C. E., Chaganti, R. S. K., Blank, C. E., Hunter, H. Lancet, 1970, i, 719. Hultén, M. ibid. p. 717. Hsu, L. Y., Shapiro, L. R., Hirschhorn, K. ibid. p. 1173. Lehrnbecher, W., Lucas, G. J. ibid. 1969, ii, 796. Melnyk, J., Thompson, H., Rucci, A. J., Vanasek, F., Hayes, S. ibid. p. 797. Thompson, H., Melnyk, J., Hecht, F. ibid. 1967, ii, 831. Tettenborn, U., Schwinger, E., Gropp, A. Dt. med. Wschr. 1970, 95, 158. Tinnefeld, W. Unpublished.

spermatogenesis

before

or at

least beyond the

secondary-

spermatocyte level. This is in accordance with own previous findingsand with those of Hulténand others. Meiotic preparations were obtained using a slight modification of the air-drying technique of Evans et awl. In case 4 the method described by Meredith 10 was also used.

Spermatogonial Metaphases No spermatocytes 3

were

found in

case

1.

In the other

patients sufficient numbers of analysable spermatogonial

metaphases were obtained. The chromosome numbers of these metaphases were 46 or 47. From the total number of 67 metaphases the majority displayed a 47,XYY karyotype. Only 15 metaphases (12,1, and 2 in cases 2, 3, and 4 respectively) showed a normal 46,XY karyotype. Thus, a gonosomal XY/XYY mosaic of the germinal cells was presumably present in cases 2 to 4. In addition, some cells with higher chromosome-counts, from 48 to 52 (predominantly 52), were also present. Furthermore, three tetraploid spermatogonia with 93 chromosomes were observed in case 3, although these spreads were not of sufficient quality for an evaluation of the number of the Y chromosomes.

Primary Spermatocytes Figures of good quality, permitting unequivocal

identification of bivalents, were obtained from two subjects (case 2 and 4). Among 11 primary spermatocytes from case 2, 9 possessed 22 autosomal bivalents and a normalappearing XY bivalent. 1 primary spermatocyte showed univalents of the X and Y chromosomes. In another cell with 24 elements, an extra bivalent of G-group size was found. It was tentatively identified as XY bivalent. In case 4, 10 primary spermatocytes of sufficient quality were used for analysis. 8 spreads with 23 bivalents had a normal 46,XY karyotype, but 2 primary spermatocytes contained 24 elements. This finding was attributed to the presence of an X univalent and a YY bivalent which, of course, resembles closely a G-group bivalent. Additional results were obtained from a study of metaphases from fibroblast cultures of testicular tissue in case 2. All karyotyped spreads displayed a 47,XYY karyotype. Clearly, the observation of 46,XY spermatogonia corroborates the findings of Melnyk et al., Thompson et al.,6 and our own previous reports.7 However, the present findings also confirm the occurrence of XY/XYY mosaicism in spermatogonia as claimed by Evans et al.,l Hult6nand Hsu et al.3 Furthermore, the observation of Hult6n2 according to which 47,XYY spermatogonia may develop to primary spermatocytes with the extra Y chromosome, gains support. Even though secondary spermatocytes with the extra Y have not yet been observed, they may nevertheless be expected to originate from such primary spermatocytes. Mature spermatozoa with an extra Y would result in abnormal fertilisation products with an XYY or XXY. Therefore, the observation of XYY sons from XYY fathers 11,12 must not necessarily be explained by secondary non-disjunction only. Yet, tubular atrophy and spermatogenic arrest, as found in XYY males, must lead to a severe impairment of maturation of sperms of all segregational types of the gonosomal set. In fact, changes of tubular

atrophy in the testis, of varying degree, seem to be a constant feature in the XYY syndrome. They may range from slight impairment of tubular function to heavy retardation of tubular development, as found in case 1. Conclusions While Melnyk et al. and Thompson et al. advanced the idea of an elimination of the extra Y by a mechanism Evans, E. P., Breckon, G., Ford, C. E. Cytogenetics, 1964, 3, 289. Meredith, R. Chromosoma, 1969, 26, 254. Tsoneva-Maneva, M. T., Bosajieva, E., Petrow, B. Lancet, 1966, i, 1000. 12. Sundequist, U., Hellstrom, E. ibid. 1969, ii, 1367.

9. 10. 11.