221 infection has so far seemed less of a problem than with transfusion at more peripheral sites. The greatest danger is undoubtedly the ease with which the circulation can be overloaded, and this demands a high, but not unattainable, standard of nursing vigilance. The distance to the heart seems to be variable and not directly related to the size of the child, and we have often been surprised to see the tip of the cannula within the heart shadow on X-rays. A transient high concentration of ions, to which cardiac muscle is sensitive, might well be delivered by injection along the catheter or through the drip tubing; but when citrated blood was given rapidly, or when a potassiumrich solution was infused, no adverse effect was noted. On one occasion, however, there was temporary collapse with profound bradycardia after the injection of a small quantity of calcium
gluconate. Given reasonable safeguards, this valuable aid in psediatric surgery.
W. COCHRAN S. H. S. LOVE.
Royal Belfast Hospital for Sick Children, Belfast, 12.
SIR,-In my preliminary communication (Jan. 12) I stated that " the abdomen is usually opened without the use of a relaxant drug, or a relaxant is given by intramuscular injection ". Some of my anaesthetic colleagues are unhappy about this statement since it is not in accord with their practice or teaching to administer relaxant
drugs of any
kind by intramuscular injection., My statement was intended as a general one and not necessarily to reflect the anaesthetic nolicv or Dractice in this hospital. The
Hospital for Sick Children, London, W.C.1.
A. W. WILKINSON.
CHANGES IN CIGARETTE MANUFACTURE SIR,-Mr. Constantinides’ letter of Dec. 29 contains a number of inaccurate statements. The facts are: (1) In countries producing Virginia-type tobacco leaf, flue-curing and machine redrying of the leaf have been established practices for very many years-and certainly throughout the present century. (2) Neither as the result of the two world wars nor for any other reason have there been substantial-let alone " revolutionary "-changes in the curing of tobacco leaf; nor have there been " vast changes " in overseas packing plant, either in Rhodesia or anywhere else. (3) Although the duration of U.K. stocks of tobacco leaf is lower than it was before World War II, manufacturers here still aim to let their tobacco mature in bond for up to 18 months to 2 years before use. (4) Machine-made cigarettes of flue-cured Virginia-type were widely smoked in this country long before World War I.
A. H. MAXWELL Chairman, Tobacco Advisory Committee.
*** We showed Sir Alexander Maxwell’s letter
Mr. Constantinides, whose reply follows.-ED. L.
SIR,-Ins,tead of refuting
some of my points, it seems that Sir Alexander tends to confirm them. When he says, for example, " In countries producing Virginia-type tobacco leaf, flue-curing and machine redrying
of the leaf have been established practices for very many years", he agrees with my statement that " in Rhodesia.... Enormous ovens were erected for drying tobacco as had long been the practice in American tobacco-curing plants":and when he says " Machine-made cigarettes of flue-cured Virginia-type were widely smoked in this country long before World War I ", he again agrees with me that, " The term ’gasper’ was
applied to cigarettes before 1914." But when he says " nor have there been ’vast changes ’ in packing plant, either in Rhodesia or anywhere else ", there, I am afraid, we differ. Because when I went to Salisbury, overseas
Rhodesia, in 1951 to supervise the curing and packing of over 1,000,000 lb. of flue-cured Virginia-type Rhodesian tobacco, I was proudly shown the enormous new ovens in which it would be dried, and I had some fierce arguments about excessive temperatures and over-drying. Finally, when he says: " Although the duration of U.K. stocks of tobacco is lower than it was before World War II, manufacturers here still aim to let their tobacco mature in bond for up to 18 months to 2 years before use ", it surprises me to think they are still only aiming at it so long after the war. If Sir Alexander would refer to the London trade journal, Tobacco, of March, 1951, he would find an article of mine warning the then Chancellor of the Exchequer against just such a situation as has now arisen in regard to cigarette smoking, if he did not raise the permitted minimum of moisture in tobacco at time of landing. And in the same journal six months later, there was an article by Quentin W. Roop, of the Tobacco Branch, U.S. Department of Agriculture, Production and Marketing Administration, to the effect that: " The findings seem to support the thesis of Mr. Constantinides that the present import regulations of Great Britain affect the flavour of the manufactured tobacco produce " ; and that " in drying tobacco it would be entirely possible to remove an unnecessary amount of moisture thereby disturbing or removing " some desirable chemical components of the leaf."
SIR,-The letter by Dr. Ferrier and others,! drawing attention to the recent discussion on the phenotype of the XY/XO mosaic in man,2-5 prompts us to record another phenotypic male XY/XO mosaic with special features. The patient, whose male sex had never been questioned, was aged 45 and had been happily married for many years but with no children. He had been investigated on three occasions for painless hasmaturia: in 1944, in 1948, and again in 1956. He had congenital hypospadias with a perineal orifice and a bifid scrotum. Only on the last of the three investigations was it . noticed that there was no verumontanum in the posterior urethra, and on withdrawing the endoscope below the triangular ligament a further orifice was discovered which led into a small vagina, at the apex of which was found a cervix which was normal in appearance, except for its reduced size. As the bladder appeared normal, the bleeding was considered to be of uterine origin, though it did not appear in the cyclical intervals of normal menstruation. He had a past history of an operation in 1945 for an ectopic left gonad. The histological report was a " malignant seminoma of undescended testis ". Radiotherapy was given. He was readmitted in 1961, complaining of pain in the lower abdomen. An examination revealed a large tender mass in the pelvis. At laparotomy a uterus was found adherent to the surrounding structures, but it was impossible to determine whether these adhesions were inflammatory or neoplastic at the time of operation. There was a normal rudimentary right fallopian tube and a mass of tissue superficially resembling an ovary. A hysterectomy was performed and a considerable amount of pus was found in an abscess cavity alongside the uterus.
Histological examination of the uterus showed a poorly differentiated columnar-cell adenocarcinoma of the body of the uterus, but the tissue biopsied from the apparent ovary did not reveal any true ovarian tissue. He was readmitted in January, 1962, with extensive metastatic deposits, and a venous sample of blood was taken for chromosome analysis by the method of Moorhead et al.6 Ferrier, P., Ferrier, S., Klein, D., Fernex, C. Lancet, Jan. 5, 1963, p. 54. 2. de La Chapelle, A., Hortling, H. ibid. 1962, ii, 783. 3. Dewhurst, C. J. ibid. 4. Judge, D. L. C., Thompson, J. S., Wilson, D. R., Thompson, M. W. 1.
ibid. p. 407. Willemse, C. H., Van Brink, J. M., Los, P. L. ibid. 1962, i, 488. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. Exp. Cell. Res. 1960, 20, 613.
Thirty cells were found accurately counted:
in which chromosomes could be
8 cells fully analysed of which 4 contained 3 contained 45 chromosomes, and 1 contained 44+2 double
fragments. Cells with 46 chromosomes showed a normal male karyotype with 22 autosomes and sex chromosomes XY. Cells with 45 chromosomes showed 22 autosomes with sex chromosomes XO. Buccal smears were chromatin negative, and in addition the 17-ketosteroid excretion (March 15, 1961) was 7-5 mg. in 24 hr. The patient died on Jan. 6, 1962, and postmortem was refused. Not only is this case of interest as a phenotypic male XY/XO mosaic but also because of the neoplasia in the male gonad and in the uterus, separated by seventeen years. A full report of this
publication. F. J. W. LEWIS J. P. MITCHELL G. L. Foss.
RUBELLA BEFORE CONCEPTION AS A CAUSE OF FŒTAL ABNORMALITY
SIR,-Has not Mr. Whitehouse (Jan. 19) misinterpreted his data and thereby complicated what we know of the effect of rubella virus on the embryo ? It is quite possible that the primigravida’s history was not accurate; that her last menstrual period of June 10 was a decidual bleed; and that conception occurred during early May. The embryo would thus have been subjected to the effects of rubella in the mother "in late May ". The weight of an abnormal foetus may not be a good measure of its maturity; nevertheless a 28-week foetus weighs 1080 g. and a 32-week fcetus 1670 g.,! so that this macerated foetus, weighing 1240 g. was at least 28 and probably more than 30 weeks old. Gross maceration would occur after death in utero during the second week of December and before evacuation in January. The disparity between the true age of the foetus and the estimate of 24-26 weeks obtained from palpation of the fundus might be due to oligohydramnios, associated with agenesis of the kidneys,2 found on pathological examination. A more valid conclusion would be that intrauterine death occurred in a foetus with several malformations. Anephregenesis and associated oligohydramnios were found and the developmental abnormalities were possibly due to maternal rubella at a very early stage of pregnancy.
ASCERTAINMENT OF MALFORMATIONS SIR,-The special article by Dr. Leck and Dr. Smithells (Jan. 12) is very timely. There is one point which I wish to question. Their series includes 33 infants with major limb defects as compared with an expected figure of 18-20 calculated from the Ministry of Health figures. They say there is a chance of less than 1 in 200 of obtaining a figure so much greater than that expected as a result of random variation (my italics). The incidence of limb malformations presumably bears relation to the amount of thalidomide prescribed. The sale of this drug in different regions cannot have been made in a random fashion, because, amongst other factors, it must have depended on the enthusiasm of local representatives and the attitude of hospital physicians in recommending the drug to general practitioners. 3-7% of Scottish births 1. 2.
Arey, L. B. Developmental Anatomy. Philadelphia, 1949. Baird, D. Combined Textbook of Obstetrics and Gynæcology. Edin-
in Stirlingshire, but 11 infants with major limb defects whose mothers took, or may have taken, thalidomide were born alive in this area out of a total of 511 in Scotland-i.e., 22%. This extreme variation makes the random distribution of these cases even less likely. I agree with Dr. Leck and Dr. Smithells, however, that the national figures are unsatisfactory, especially as they tend to be invested with an air of authority. For instance, it is odd that all the deaths in Scotland should have occurred in Stirlingshire. Thus, according to the official figures, of 51 infants born to mothers who took, or may have taken, thalidomide, 14 are still alive. Of the 11 such infants liveborn in this area, only 4 are still alive.
Royal Infirmary, Stirling.
A. L. SPEIRS.
PITFALLS IN TESTS FOR TERATOGENICITY
SIR,-The statement of Dr. Fraser and others2 that the of malformations depends on several interacting factors is undoubtedly of great importance. Nevertheless, I think that from a practical standpoint-i.e., in screening the possibly teratogenic drug-this is of minor interest.
The question is not quantitative but exclusively qualitative. Whether one finds 6% or 72% of malformations, the conclusion must be the same: the drug should not be released for clinical use. In fact, the pitfall is that, having found no teratogenic effect in a " sufficient number of different species of laboratory animals ", one can still not be sure of the effect on the human foetus, which is always the ultimate purpose of investigation.
MOGENS NYMARK. MECLOZINE AND FŒTAL ABNORMALITIES SIR,-The Fetal Life Study,3 a prospective survey of pregnancy, began to record in February, 1953, the nature and amount of drugs utilised. On the weekend of Nov. 24, 1962, several articles appeared in the New York City lay
Press reporting concern that meclizine (see figure) (or’meclozine as it is known in Britain) might be con-
formations. A preliminary report of the epidemic observation unit of the College of General Practitioners4 and a letter circulated bv the Swedish Medical Board have expressed caution in the use of meclizine during pregnancy. Weicker et al. have pre1. 2. 3.
Lancet, 1962, ii, 986. ibid.p. 1116. McIntosh, R., Mellin, G. W. Bull. Sloane Hosp. Women, December, 1956, 2, 95. 4. Watson, G. I. Brit. med. J. 1962, ii, 1446. 5. Weicker, H., Bachmann, K. D., Pfeiffer, R. A., Gleiss, J. Dtsch. med. Wschr. 1962, 87, 1597. TABLE I-PROPRIETARY NOMENCLATURE
Meclizine : Ancolan Bonamine Bonine Navicalm Neo-Istafene Postafene Meclizine and pyridoxine: Ancoloxin Bonadoxin Postadoxin
Dimenhydrinate: Amosyt Anautine
Andramine Diamarin Dramamine Dramarin
Menhydrinate Nevamin Travelin Travelmin Xamamina