1347 It would be interesting to know how many patients in the N.C.I. and Stanford series underwent splenectomy. Indeed, it would be of great theoretical andpractical importance if either positive or negative associations were found between remission-rates or second malignancies and


pretreatment splenectomy. Evangelismos Medical Center, Athens 140, Greece.



term,S whereas those of G.H. are similar to those in the non-pregnant woman (approximately 5 ng. per ml.) and do not change as the pregnancy advances.6 These facts suggest that hypophysectomy was essential, but had termination been delayed the production of H.P.L. would have continued to rise and further progression of disease might have been stimulated. Hypophysectomy had less effect in abolishing secretion of prolactin than G.H. (see table) and it seems, therefore, that prolactin was less important in promoting tumour growth, a finding confirmed in vitro. We believe that this is the first time that dependence of a human breast cancer on placental lactogen has been demonstrated. per ml. at

SIR,—We describe a patient with carcinoma of the was dependent on human placental lactogen.

breast which

A 38-year-old woman presented in April, 1973, with a stage-i carcinoma of the right breast which was treated by simple mastectomy. She remained well until September, 1974, when a right axillary recurrence was found. She was then 7 weeks pregnant, and pain in the right hip, which she had first noticed 4 months previously, had become so severe that she could no longer walk unaided. She felt weak and complained of thirst, anorexia, and nausea. X-rays showed a large metastatic deposit just below the right femoral head and multiple lytic lesions in the Serum calcium was 36 mmol per litre (14-7 mg. per 100 ml.) and bilirubin 45 µmol per litre (2-8 mg. per 100 ml.). It was decided that the pregnancy should be terminated, oophorectomy performed, and a pin and plate inserted in the right femur. Tissue from the deposit in the femur (which was confirmed histologically as metastatic breast carcinoma) was sent to the tumour biology group at the Westminster Hospital where it was cultured according to the method of Salih et all to determine whether it was hormone dependent. The tumour showed dependence on human placental lactogen (H.P.L.) at 40 ng. per ml., growth hormone (G.H.) at 20-40 ng. per ml., and, to a lesser extent, on prolactin at 6-60 ng. per ml. but was independent of oestrogen, androgen, and chorionic gonadotrophin. It was felt that the decision’to terminate the pregnancy had been correct but that hypophysectomy was also necessary to abolish stimulation of the tumour by growth hormone and prolactin. Transethmoidal hypophysectomy was, therefore, carried out on Sept. 26, 1974. Pre- and post-hypophysectomy stress tests were

right rib-cage.

London SW1P 2AR. ‘

performed (see accompanying table). Postoperative recovery was uneventful and pain relief was good. Initially, the patient required oral phosphate to control the hypercalcwmia, but this was discontinued after 2 weeks and serum-calcium did not rise again. She gradually became more mobile.




seen on

Feb. 20, 1975, 5 months post-

operatively, when she was feeling well and walking easily without pain. There was no clinical evidence of recurrent disease. X-rays showed regression of all the bony lesions with pronounced sclerosis of the previously lytic lesions. Serum calcium was 2-9 mmol per litre (10-9 mg. per 100 ml.) and bilirubin 10 µmol per, litre (0-5 mg. per 100 ml.). H.P.L. is produced by trophoblastic tissue and is present in high concentration from 3 weeks’ gestation to term in the placenta, and in urine and serum in increasing concentration as pregnancy advances. In animals it has been shown to have luteotrophic, lactogenic, and G.H.-like activities 2,3 and to stimulate casein synthesis and histological development in organ culture.4 Its action on the human breast is not well defined but may be similar to that of G.H. No clinical improvement was noticed by our patient in the month after oophorectomy, suggesting that the in-vitro finding of oestrogen independence was correct. It is impossible to be sure whether the excellent regression obtained could have been achieved by either termination of pregnancy or hypophysectomy alone. The levels of H.P.L. are relatively low in early pregnancy (500 ng. per ml. at 7 weeks) but rise steadily to a level of around 6000 ng.

1. 2. 3. 4.

Salih, H., Flax, H., Brander, W., Hobbs, J. R. Lancet, 1972, ii, 1103. Josimovich, J. B., Maclaren, J. A. Endocrinology, 1962, 71, 209. Josimovich, J. B., Atwood, B. L., Goss, D. A. ibid. 1963, 73, 410. Chomczynski, P., Topper, Y. J. Biochem. biophys. Res. Commun. 1974, 60, 56.


Department of Chemical Pathology, Westminster Medical School, 17 Page Street,



SIR,—We should like to draw attention to an unusual of joint infection by Pasteurella multocida in a patient


with rheumatoid arthritis after A


skin laceration from

a cat.

had a ten-year history of 64-year-old English seropositive rheumatoid arthritis. She had widespread joint disease and had undergone a left geomedic total knee replacement six months before admission, with a good result and no postoperative problems. She was admitted with a three-day history of pain and swelling in the left knee, severe enough to prevent her walking, which had developed two days after receiving an extensive skin laceration on the left shin from her neighbour’s woman


The knee


yielded thick


acutely inflamed and needle aspiration Culture of the pus produced a pure growth of Pasteurella multocida, a gram-negative bacillus, commensal in was

the upper respiratory tract of cats. The laceration from the cat scratch was 6 in. above the left lateral melleolus, well away from the knee, and, though surrounded immediately by erythema, the skin between the scratch and the knee was normal.

Though many lesions, ranging from brain abscess to pyelonephritiso have been reported as being caused by this organism, only one previous report of 2 patients with pyarthrosis after animal assault has been noted.8 The cause of the other two previously reported joint infections with the organism was not determined.9,lo Both Barth’s8 patients and our own had rheumatoid arthritis and had been taking corticosteroids for at least five years, one at a dose of 9 mg. per day of prednisolone, ,

1-2 mg. per day of betamethasone, and 5 mg. per day of prednisolone.

one on

The joint infection in


ours on

patient settled promptly with

5. Chard, T. Medical Monograph. 8. The Radiochemical Centre, 1973. 6. Yen, S. S. C., Samaan, N., Pearson, O. H. J. clin. Endocr. 1967, 27, 1341. 7. Swartz, M. N., Junz, L. J. New Engl. J. Med. 1959, 261, 889. 8. Barth, N. T., Healey, L. A., Decker, J. L. Arthr. Rheum. 1968, 2, 344. 9. Robinson, R. Br. med. J. 1944, ii, 725. 10. Pizey, N. C. D. Lancet, 1953, ii, 324.

ampicillin-the organism is unusually susceptible to penicillin, an antibiotic not often employed either for gram-negative infections or join infections, especially if there is a prosthesis in situ. Some months after the infection the patient has still a satisfactory result from the total knee replacement with no evidence of continuing infection or loosening of the prosthesis. Nuffield Orthopaedic Centre,

Headington, Oxford OX3 7LD.


CHRONIC LOW-LEVEL LEAD EXPOSURE AND MENTAL RETARDATION SIR,-While accepting the cumulation of evidence on the harmful effects of lead and the seriousness of unacceptable lead levels in drinking-water, I should like to comment on the main statistical inference in the paper (March 15, p. 589) by Dr Beattie and his colleagues. The evidence given in support of a relationship between lead exposure and mental retardation was the observation of 11 retarded children, but not their controls, in the water-lead range upwards of 800 µg. per 1. That finding may itself have been worth reporting, but if we wish to examine it with the help of a statistical test it is proper that the test should take account of the variability of the lead measurements in the data as a whole. On this ground, Dr Beattie’s test, based on the comparison between the numbers of cases above and below the diagonal in table iv, is open to criticism. Dr Beattie’s test is a test of symmetry in the 3 x 3 contingency table, and it disregards information from those pairs in which the retarded child and the control are in the same water-lead range. The unfairness of this can be illustrated by considering a situation in which ten times as The many pairs are present in the diagonal squares. authors’ test result would be the same, but would they have come to the same conclusion ? Readers of the paper may wonder whether the choice of water-lead ranges and indeed of the test itself were made before the data were seen. At the outset of an investigation of this kind it would be surprising to condemn a Student’s t test or an equivalent non-parametric test on the differences to be gathered from all of the pairs as " unlikely to be illuminating ". I was sorry that the authors did not give the result of such a test and hope that they will do so yet. .

Operational Research and Economics Division, Water Research Centre, Medmenham Laboratory, P.O. Box 16,

Ferry Lane, Medmenham, Marlow SL7 2HD.


*, * This letter has been shown to the Glasgow workers, reply follows.-ED. L.


SIR,—Mr Lacey takes issue with the test of symmetry in the 3 x 3 contingency table (table iv in our paper). He says that the test should take account of the variability of the lead measurements in the whole data; that it is unfair to disregard the information in the diagonal cells; and that the test, or at least the grouping into three ranges of water lead, may have been chosen after the data were scrutinised. We answer these points in turn, after stating the classical principle of significance testing-namely, that, subject to the significance level (0-05) being maintained when the null hypothesis is true, one should choose a test

with high power (i.e., high probability of achieving significance when the null hypothesis is false).1 Water-lead values for retarded and control members of a pair would be positively correlated, because of the matching. The null hypothesis that water lead has nothing to do with mental retardation specifies symmetry of the distribution of retarded and control values. We had to choose a test which would be powerful against each of two alternative hypotheses-namely, (a) that, other things being equal, the probability of a child being retarded would increase with the water-lead level, and (b) that there could be a threshold level governing the exhibition of retardation. Both hypotheses are valid in dose-response relationships, and our colleagues2 had suggested that toxic effects might become statistically noticeable at levels between 400 and 1000 µg. per litre. Our alternative hypotheses predicted more retarded than control children from homes with water-lead values in this range and above. On the other hand the probability of retardation was not expected to change very much within the range 0-400 µg. per litre. Detailed study of pairs for whom both water-lead values were less than 400 µg. per litre would have done little to discriminate between the null and alternative hypotheses. On the contrary, it would have contributed additional random error. Because we expected many such pairs (in the event there were 37 out of 64), a sign test would lose substantial power compared with the test based on coarse grouping of data (table iv). We ignored the numbers 37, 6, 0 in the diagonal cells because the null hypothesis of symmetry made no prediction about these frequencies. Mr Lacey further asks for our reaction to similar data with diagonal frequencies ten times as large. This would not affect the validity of our test. However, with a sample size as large as that, one would gain power by using a finer grouping of the data, perhaps as a 7 x 7 table. Had we chosen the form of our test or the water-lead levels in table iv after careful inspection of the data this would indeed have been a well-known form of statistical cheating. However, if we had wanted to produce spurious significance in this way we should not have been content with the modest significance level of 0- ’039; condensation of table iv to a 2 x 2 table with value 800 µg. and 0 and 11 would litre of per off-diagonal frequencies have yielded a (spurious) one-tailed significance level of (½)11 (i.e., 00005). We might also have claimed significance, as others have done,3 from our data by estimating relative risks. We rejected this approach (also in advance) because it took no account of distribution and assumed that we recognised a threshold value for water lead. We have explained above how the nature of the alternative hypotheses, together with the evidence of the earlier study,2 made our form of test preferable to the sign test or other conventional tests. This was clear before the data were examined. 800 µg. per litre is a fairly typical value of water lead when the house has a lead-lined tank, and 400 µg. per litre separates most such houses from most houses without lead-lined tanks.2 We had to choose boundary values for grouping low enough for a number of observed values to exceed them, but high enough for any harmful effects of lead to become plain. Sensible grouping was essential for informative interval estimation (table v) quite as much as for establishing significance. We chose boundary values of 400 and 800 µg. per litre about halfway through the series, and we would concede that for statistical perfection our test should have been applied only to cases in the second half of the series. With this in mind, as well"


1. 2. 3.

Neyman, J., Pearson, E. S. Biometrika, 1928, 20A, 175, 263. Beattie, A. D., Moore, M. R., Devenay, W. T., Miller, A. R., Goldberg, A. Br. med. J. 1972, ii, 491. Leviton, A., Needleman, H. L. Lancet, 1975, i, 983.

Letter: Joint infection by Pasteurella multocida.

1347 It would be interesting to know how many patients in the N.C.I. and Stanford series underwent splenectomy. Indeed, it would be of great theoretic...
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