Skin Disease and the Gut

29 August 1970

Correspondence

Medullary Carcinoma of Breast SIR,-While agreeing with Dr. H. J. G. Bloom and others (25 July, p. 181) that the results of radical treatment for medullary carcinoma of the breast are remarkably good we cannot accept the validity of two of their conclusions. Firstly, there is insufficient evidence to support their view that conservative treatment would not have achieved similar results as compared with a radical approach. In their non-randomized retrospective study only 14 patients out of 104 had either a simple mastectomy or wedge excision. Of these 10 also had postoperative radiotherapy. No attempt was made to explain why the policy of radical surgery was abandoned in these cases. We believe that it is not possible to reach a reasonable conclusion on the results of conservative surgery alone on the basis of four patients. Secondly, we feel that it is very difficult for the authors to make judgements on the importance of the role of possible local defence mechanisms in medullary carcinoma of the breast. This would entail a prospective randomized trial comparing the results of radical treatment, which would involve ablation of the lymph nodes by surgery or radiotherapy, with conservative surgery by itself, which would result in the least interference with regional lymph nodes. Taking cancer of the breast as a whole there is increasing evidence of the importance of local defence mechanisms.' We would agree wholeheartedly with Dr. Bloom and his colleagues when they say that the value of treating the axilla in the initial therapy of early breast cancer awaits the results of well-conducted clinical trials where the comparison of radical and conservative therapy can be made on secure foundations.1-We are, etc., MICEuEL BAUM. M. H. EDWARDS. King's Colleee Hosoital Medical School, London S.E.5. I

REFERENCE Lancer, 1969, 2, 1175.

Contraceptives and Serum Proteins SIR,-We have read with interest the

recent report by Dr. L. W. Powell and others (25 July, p. 194) who have shown that single intramuscular injections of 300 mg. medroxyprogesterone acetate, lasting 120 to 180 days, do not affect serum levels of iron or total iron-binding capacity (T.I.B.C.). This is in contrast to similar women receiving various "sequential" oral contraceptives who showed marked increases in these serum components. On the basis of this difference, Dr. Powell and his colleagues suggest that the elevations in serum iron and T.I.B.C. seen in women taking sequential or combined oral contraceptives are due to the oestrogenic rather than the progestogenic component. They further propose that any effect of the progestogen is due to oestrogenic metabolites from the particular compound used, and that "pure" progestogens, such as medroxyprogesterone acetate, which have no oestrogenic metabolites, are devoid of effect. As these findings are somewhat in contrast to previous studies by ourselves and

Steroid None .Ethinyloestradiol

Norethisterone Acetate

Dm Daily Dose

jg.-

521

p4.1100 ml.

tLg./100 Mi.

T.I.B.C.

Serum Copper

93±25 95±28 96+31

361+35

122 +28

428+49 425+51 465 +65

125± 8 136+10 181±16 227±18 130± 8 152+11 235 ±25

118+25

432+42

128+10

Serum Iron

10 20 50 300 1000

90+30

118 +21

119±30

Ethinyloestradiol + .50

Norethisterone Acetate.+ 1000 d(l)-Norgestrel .1000

355+38 359±32

365±40

&g./100

Mean Values +S.D.

othersl4 and as the matter is of some complexity and open to a number of possible interpretations, we thought we would present the preliminary results of a study, as yet unfinished, in which we have given oral oestrogen and progestogen separately and in combination to groups of 10 to 12 healthy young women who had not previously received steroids of any kind. Results are shown in the Table. The compounds were given in. gelatin capsules or as proprietary preparations daily for three to four weeks. Each patient served as her own controL Assay methods and other techniques are as given in our previous publications.' 5 These results indicate that a combined oral contraceptive containing ethinyloestradiol 50 ,ug. and norethisterone acetate 1,000 pg. (that is, Minovlar) produces a significant increase in all three- serum values, but that ethinyloestradiol, given alone in doses up to 50 pg. daily, signintly increases serum copper values but not serum iron or T.I.B.C In contrast, norethisterone acetate has a marked effect on serum iron and T.I.B.C., but only a slight action on serum copper. The other progstogen used in this study, d(j)-norgestrel, is the 13-homologue of norethisterone, but unlike the latter is virtay free of oestrogenic metabolites in the human.6 This compound significanty increases serum iron and T.I.B.C, but has no effect on serum copper. Our findings stogly suggest that oral oestrogens have no marked effects on serum iron and T.I.B.C, but that oral progestogens stimulate an increase. This finding is in contrast to the conclusion of Dr. Powell and others, who used intramuscular medroxy-

progesterone acetate. A possible explanation of this difference is the route of administration of the steroid. The changes. in blood constituents are probably secondary to effects on the liver synthesis and release of metal-binding proteins. Oral steroids are absorbed into the entero-hepatic circulation and probably reach the liver in far higher concentrations than if given by the intramuscular route. We must also point out that medroxyprogesterone acetate, while devoid of oestrogenic properties, has up to one third of the glucocorticoid activity of hydrocortisone in the human.7 The effect of corticoid-sex hormone interactions on trace element binding proteins in blood is not yet known. We are grateful for the assistance in this work of Dr. J. Austin, Dr. Denise Pullen, Mr. J. E. N. Kelly, and the staff of the Wandsworth F.P.A. Clinic.-We are, etc.,

M. H. BRIGGS. MAXINE BRIGGs. Deportment of Biochemistry, University of Zambia, LuSaka, Zambia. REFERENCES

M., and Staniford, M., Lancet, 1969, 2, 742. Musa, B. U., Doe, R. P., and Seal, U. S., Yournal

1 Briggs, 2

of Clinical Endocrinology and Metabolism, 1967, 27, 1463. Lancet, 1969, 2, 847. Mardell, M., Symmonds, C., and Zilva, J. F., of Clinical Endocrinology and MetaboYournal fism, 1969, 29, 1489. M. H., Austin, J., and Staniford, M., Briggs, Nature, 1970, 225, 81. Littleton, P., Fotherby, K., and Dennis, K. J., Yournal of Endocrinology, 1968, 42, 591. Simon, S., Schiffer, M., Glick, S. M., and Schwartz, E., 7ournal of Clinical Endocrinology and Metabolism, 1967, 27, 1633.

3 Zilva, J. F.,

4

5

6 7

Skin Disease and the Gut SIR,-In your leading artidle (1 August, p. 240) you refer tQ the evidence originally presented by Professor S. Shuster's team' that psoriasis may be associated with an abnormality of the intestinal mucosa. You suggest that lack of confirmation of these results by other observers implies that the original findings were at fault due to derivation of the groups of patients and controls from different population areas. In their latest publication on this subject Dr. Marks and Professor Shuster2 themselves argue this case persuasivdy. They show that the incidence of stereomicroscopic abnormalities found in jejunal biopsies from patients with psoriasis in the Newcastle upon Tyne area is no different from that found in control subjects from the same area. There are, of course, more ways than one of demonstrating the presence of an enteropathy, and only some of these were

used by the same workers in their investigation of "dermatogenic enteropathy."3 We' have correlated jejunal mucosal morphology and disaccharidase activities with the results of a lactose tolerance test, glucose/galactose tolerance test, lactose barium meal, and xylose absorption test in 14 patients with psoriasis. There was evidence of an enteropathy in two-thirds of cases. The mucosal lesion appeared extensive in some cases, but it was never severe. Partial villous atrophy was seen but never a completely flat mucosa. Half the patients showed reduction of mucosal disaccharidase levels. Other parameters were abnormal in some cases. Our (unpublished) findings among control subjects, using these same parameters, show a very much lower incidence of abnonnalities. Moreover, most of the individuals we have investigated were serving members of

522

29 August 1970

the British Army, and the rest were their travelling dependants. They came from many different areas. In fact, a more mixed population in terms of their region of origin within the United Kingdom would be hard to imagine.-We are, etc.,

D. M. ROBERTS. British Military Hospital, Miinster, W. Germany.

F. E. PRESTON. Department of Haematologv, Royal Infirmary, Sheffield, Yorks. REFERENCES 1

Correspondence 6-8 weeks the patient now has no oedema of her hands and feet and can now wear rings last worn five years ago. When she was ventilated for 14 days without a subatmospheric phase the oedema rapidly reaccumulated. It has not been possible because of vascular puncture difficulties to undertake haemodynamic studies so that the actual mechanism causing the oedema has not been elucidated.-We are, etc.,

JOHN STYLES. JoHN S. ROBINSON. J. GARETm JoNEs. Department of Anaesthetics,

Shuster, S., Watson, A. J., and Marks, J. British University of Birmingham. Medical Yournal, 1967, 3, 458. 2 Marks, J., and Shuster, S., Gut, 1970, 11, 281. REFERENCES 1 Marks, J., and Shuster, S., Gut, 1970. 11, 292. 4 Roberts, D. M., and Preston, F. E. Scandinavian 1 Drury, D. R., Henry, J. P., and Goodman, J., Yournal of Gastroenterology, 1970, in press. Yournal of Clinical Investigation, 1947, 26, 945. 2 Gauer, 0. H., Henry, J. P., Sieker, H. O., and Wendt, W. E., 7ournal of Clinical Investigation,

1954, 33, 287. Clinical Science, 1960, 19, 377. 4 Paintal, A. S., 7ournal of Physiology, 1953, 120, 596. 5 Guyton, A. C., In Circulatory and Respiratory Mass Transport: CIBA Foundation Symposium, ed. G. E. W. Wolstenholme and J. Knight, p. 4. London, Churchill, 1969. 3 Eliahou, H. E., Clarke, S. D., and Bull, G. M.,

Continuous Ventilation and Oedema SIR,-We should like to record a patient suffering from severe myasthenia gravis who has required assisted ventilation for nine years using a Bamet Mk II ventilator. For the past five years she has required continuous controlled ventilation. A subatmospheric phase was not employed. During the period of continuous ventilation she developed pitting oedema of the face and extremities. The oedema could not be attributed to cardiovascular, renal, or liver disease as her serum proteins, electrolytes, and osmolarity were within normal limits. Hitherto it was believed that the oedema was due in some way to the immobility of the patient. However, a mean intrathoracic pressure resulting from mechanical ventilation of the lungs which is continually maintained above that of atmospheric pressure may possibly cause oedema by two mechanisms. Since 19471 it has been known that continuous pressure breathing causes an antidiuresis and that a diuresis results when the intrathoracic pressure is lowered.2 It was believed that these effects were mediated by changes in the size of the left atrium.3 It seems likely that adaptation to such changes would occur after very prolonged periods of time as has been suggested," and would not be operative in this case. Another mechanism is that based upon the recent observations of Guyton.5 Guyton, using an implanted capsule technique, has produced evidence that the interstitial fluid pressure is subatmospheric, and that if the interstitial fluid pressure rises to atmospheric then there is a considerable increase in the mobility of the fluid in the tissue spaces, so that these spaces balloon outward to fill with fluid. This is the opposite of the compaction of the tissues which is associated with normal subatmospheric interstitial fluid pressure. This appraisal suggested that if a sub-

Catheter Fragment in the Heart SIR,-We read with interest Dr. J. H. N. Bett's letter (1 August, p. 287) concerning the removal of catheter fragments from the heart. On the same day a thirteen-monthold child (weight 9-56 kg.) was referred to the thoracic unit, the Hospital for Sick Children, with a portion of Silastic catheter in the heart. The child was noted to have a thoracolumbar meningomyelocele at birth, and subsequently developed hydrocephalus, for which a Spitz-Holter valve had been inserted in the usual fashion. This had ceased to function, but during the operation for its removal a portion of the distal Silastic catheter became dislodged. The operative radiograph showed the detached portion to be lying within the cardiac silhouette, presumably in the right atrium.

mm atmospheric expiratory phase were employed the mean intrathoracic pressure, the venous, and the capillary pressures would fall, so that the interstitial fluid pressure would return below that of atmosphere and The following day, with the child the oedema disappear. The employment of a subatmospheric expiratory phase sedated, a cardiac catheter was introduced down to -10 cm. H20 led to a gradual into the right long saphenous vein under

diminution of the oedema, so that after local anaesthesia, and passed to the righi

BmnS atrium. By viewing the child in various positions it was then possible to confirm that both the cardiac catheter and the fragment of Silastic catheter lay within the right atrium. A catheter system which allows a variable degree of flexion of the catheter tip was then introduced. (The Muller-U.S.C.I. guide system is routinely used in this department.) The catheter tip was then hooked and the loop of Silastic catheter caught in it. The whole assembly was withdrawn, but the Silastic catheter could only be pulled to the external iliac vein, this limitation being due to the relative diameters of the vein and the created hook. The femoral vein immediately above the sapheno-femoral junction was dissected out through the original incision. The smallest Fogarty catheter available (5F) was then introduced into the femoral vein and passed up until its tip lay alongside the Silastic catheter. With the balloon partly inflated the Silastic catheter was then drawn out of the femoral vein. The venotomy was sutured. There were no complications and the procedure was tolerated well by the child. It is felt that a catheter assembly which makes it possible deliberately to vary the shape of the catheter tip can at times be used successfully in the location and removal of foreign bodies, especially catheter fragments from within the heart, without recourse to thoracotomy. We would like to thank Mr. James Dickson for permission to report this case.

J. F. N. TAYLOR. L. M. GRAVINGHOFF. Department of Clinical Physiology, The Hospital for Sick Children, London W.C.l.

Sleeping Pilis SIR,-The increasing body of evidence that hypnotics cause auite long-term alteration of sleep pattern (8 August, pp. 296 and 310), as well as the mounting wave of gross abuse of barbiturates by young people, must surely raise the question whether it is not time for all barbiturates to be classed under the D.D.A. This may seem a rather sweeping suggestion, but now the only real indications for the use of barbiturates, e.cept very occasionally for the extremely disturbed patient, seem to be in anaesthesia and the small doses of amylobarbitone used in conjunction with high-dosage chlorpromazine in the intensive treatment of schizophrenia. I know many neurologists still use phenobarbitone in epilepsy, but most psychiatrists are painfully aware of the dopiness, paradoxical irritability, and behaviour disturbances that are so common in patients on long-term medication with phenobarbitone and its derivatives. It is neither logical nor desirable to use hypnotics to damp down insomnia caused by pain, cough, depression, anxiety, or even noise in hospital, instead of tackling the causes. Psychiatric units are among the worst offenders in creating and perpetuating dependence on hypnotics, but this really is not necessary. In my last year at my previous hospital I was the ward doctor for a busy short-term admission unit with a patient population liable to range from 16year-old psychopaths to 86-year-old senile