PATHOGENESIS OF HISTAMINE-TYPE VASCULAR LEAKAGE

99 Dr. Lawson 6 emphasises the effect of the widespread non-pitting oedema and the likelihood of the secondary vesicles being trophic in nature. A further point to be observed in cutaneous anthrax is that although therapy with penicillin is very effective in eradicating the organisms, the lesion itself may extend for a day or two or even longer, after the commencement of therapy. Such an effect, I believe, is due to the impaired blood-supply occasioned by the inflammatory oedema. Gateside Hospital, Greenock, Renfrew,

Scotland.

ROBERT LAMB.

WEST INDIAN ONE-YEAR-OLDS SIR,-The fascinating survey reported by Dr. Pless and Dr. Hoodis disappointing in one respect. Only once in the whole article is any reference made to a family doctor. They have seemingly ignored the vast amount of clinical experience available as the result of the work of general practitioners in Paddington and similar communities; and in reaching their conclusions, which are in general correct, no mention is made of the use of family doctors by West Indian mothers (see their table m)-it should not be assumed that infant-welfare clinics are the only source of advice to mothers about their children. These clinics deal only with well children. Sick children are usually taken to a general practitioner by the mother or referred to- him by the clinic. In table iv, West Indian children are shown to have a significantly larger number of illnesses requiring admission to hospital, though the reason for admission is not stated. Often the reason is not so much the actual severity of the illness as the family doctor’s difficulty in looking after even a moderately ill child in a small room in the same bed as numerous siblings, when the only nurse is an inept mother probably out at work all day (table v). Your contributors have shown that the conditions in which some West Indian children live are appalling. We family doctors will have to cope not only with the present illnesses resulting from these conditions, but with the future disorders arising directly from maternal and environmental deprivation in infancy. D. S. NACHSHEN.

have made

an observation which may provide an answer to this On the electron micrograph of a platelet thrombus, the nucleus of an endothelial cell, underlying the thrombus, had a peculiar appearance. It was rounded, and penetrated by many deep folds of the nuclear membrane, as if it had been originally flat or oblong, and had then been tightly compressed into the shape of a sphere. A deformation of this kind, it seemed reasonable to conclude, could occur only by contraction of the endothelial cell, possibly as a result of serotonin liberated by the platelets. This led us to examine the endothelial cells of venules in a striated muscle, rat cremaster,8 3-6 minutes after injection of histamine, serotonin, and bradykinin, and 2 minutes after mild constriction of the inguinal funiculus (the latter procedure was adopted in order to obtain, by mild venous congestion, a comparable degree of vascular distension in the experimental and in the control tissues). Many of the nuclei in leaking vessels showed folds similar to those just described; this occurred more often in the cells abutting onto the gaps. Folds are also found in the nuclei of normal endothelium, but nuclei with multiple, tight, pinched folds are a characteristic of leaking vessels (see accompanying figure). Bulging of the nucleus into the lumen is common, and this, too, is suggestive of endothelial contraction. A quantitative study of the nuclear folds is under way; preliminary results show an overwhelming difference between normal and leaking venules. Passive recoil of the endothelial cell is most unlikely, for the gaps are too small in relation to the surface area of the cell. We therefore propose the following mechanism of action for histamine-type mediators. The endothelium of the venules is

question.

PATHOGENESIS OF HISTAMINE-TYPE VASCULAR LEAKAGE SIR,-It is known that histamine and other mediators of vascular leakage such as serotonin, bradykinin, and the Miles factor (PF/dil) cause ultramicroscopic gaps to appear between endothelial cells,8 and that these gaps occur predominantly in the venules.9 Rowley 10 has explained this histamine-type leakage along the lines of the hydrostatic theory of histamine action." According to Rowley, chemical mediators induce contraction of small veins, thus causing mechanical dilatation of venules upstream, and finally dissociation of their endothelium ; but we found that by increasing venous pressure we could not bring about histamine-type leakage.12 Later we studied the effect of chemical mediators in vivo, under direct observation, and failed to detect any venous spasm 13: extensive vascular leakage can occur in the absence of any visible constriction of the small veins. How, then, do the endothelial gaps develop ? By chance we 7. Pless, I. B., Hood, C. Lancet, 1967, i, 1373. 8. Majno, G., Palade, G. E. J. biophys. biochem. Cytol. 1961, 11, 571. 9. Majno, G., Palade, G. E., Schoefl, G. I. ibid. p. 607. 10. Rowley, D. A. Br. J. exp. Path. 1964, 45, 56. 11. Inchley, O. J. Physiol., Lond. 1926, 61, 282. Landis, E. M., Pappenheimer, J. R. in Handbook of Physiology, sect. 2, vol. II; p. 961. American Physiological Society, Washington, D.C., 1963. 12. Majno, G. in ibid. vol. III; p. 2293. American Physiological Society, Washington, D.C., 1965. 13. Majno, G., La Gattuta, M. in Die Entzündung. Munich, 1966.

Electron micrographs of walls of two venules : normal (above), and 6 minutes after local injection of 0’1 ml. 0’1 % histamine phosphate

(below).

L=lumen; P=platelets; R=red blood-cells; N=nuclei of endothelial cells; G=gap in endothelium, containing a red blood-cell and some particles of carbon black (injected intravenously as a tracer); B=basement membrane; X = pericY1:e. After histamine, note folds in the nuclear membrane (arrows), and bulging of the nucleus into the lumen. (x 12,700.)

100 contract; since the intravascular pressure is high concomitant arteriolar dilatation) the result of this contraction is not a narrowing of the lumen, but a limited " tearing apart " of the endothelial cells. Endothelium and smooth muscle are structurally and biologically very closer thus it is not surprising that the endothelium should respond to substances known to cause a contraction of smooth muscle, such

induced

(due

as

to

to

histamine-type mediators.

This mechanism fits all pertinent facts as far as we know them. We hope that it will satisfy all concerned, including those who feel that " contraction " is involved, and especially Sir Ashley Miles, who wondered whether the effect of mediators might not be that " the outraged endothelial cell draws in its skirts." 14 Department of Pathology, GUIDO MAJNO Harvard Medical School, MONIKA LEVENTHAL. Boston, Massachusetts.

These are mainly synthetic substances, differing widely in progestational activity, oestrogenic and anti-cestrogenic activity, and pituitary-suppressing effects. Nevertheless, the size of the series for some compounds is sufficient to allow statistical Thus, in breast carcinoma, norethisterone comparisons. acetate, 70 remissions in 178 cases (39%), and gestonorone caproate, 15 remissions in 33 cases (45%), seem superior to 9-(x-bromo-ll-ketoprogesterone, 12 remissions in 91 cases (13%) and hydroxyprogesterone caproate, 12 remissions in 66 cases (19%). However, for endometrial carcinoma, medroxyprogesterone acetate, 40 remissions in 103 cases (39%), and hydroxyprogesterone caproate, 172 remissions in 578 cases (30%), seem better than medrogestone, 2 remissions in 50 cases (4%), and gestonorone caproate, 2 remissions in 13 cases (15%). For carcinoma of the cervix, the series are too small for comment; for ovarian carcinoma only hydroxyprogesterone caproate, 21 remissions in 65 cases (32%), has been sufficiently used and a comparison with other compounds is

NEONATAL HYPOMAGNESÆMIA SiR,—Iwas interested to read the article by Dr. Friedman and his colleagues (April 1, p. 703). Symptomatic hypomagnesxmia in the neonatal period is poorly understood. In recent years increasing attention has been directed to this problem There is, however, meagre information available on the normal serum-magnesium levels in newborn infants. It seems, therefore, worth while to report these for further study. In my laboratory serum-magnesium concentrations were determined in 122 healthy infants and children by a modification 16 of the fluorometric method of Schachter 17 using ’Multiplier Fluorescence Meter Model 540’ (Photovolt Corporation). The mean values obtained for each age-group, which were somewhat higher than those of other investigators because of the use of the filters instead of spectrofluorometry, were as follows:

The data indicated that serum-magnesium levels were significantly reduced in infants under the age of 2 months, especially in infants aged 6-10 days. All the infants, however, remained symptom-free. "

I am now investigating the mechanism causing hypomagnesaEmia in newborn infants ", and hope to report on this problem in due course.

Department of Paediatrics, University of Tokyo, Tokyo, Japan.

AKIO KOBAYASHI.

SEX HORMONES IN FEMALE CANCER

SIR,-In an attempt to assess the relative worth of progestogens (either alone or in combination with an oestrogen) in the of cancer in women, we have searched the published reports and also contacted leading workers in this specialty, who have made available to us unpublished case-records. We have found data on 1602 patients. Of these, 453 (28-3%) were said to have shown objective remissions, as follows (according to site of the primary tumour): breast, 157 remissions in 634 cases (24-7%), endometrium, 256 remissions in 822 cases (31-1%); ovary, 22 remissions in 80 cases (27-5%), cervix, 18 remissions in 66 cases (27-2%). The significance of these results is difficult to assess because 20 chemically different progestogens have been used.

treatment

14. Miles, A. A. Lect. scient. Basis Med. 1958-59, 8, 198. 15. Clarke, P. C. N., Carré, I. J. J. Pediat. 1967, 70, 806. 16. Kobayashi, A., Shiraki, K. Archs Dis. Childh. (in the press). 17. Schachter, D. J. Lab. clin. Med. 1961, 58, 495.

feasible. It is clear that, if compounds which yield poor results are removed from our series, the rate of objective remissions in the treatment of advanced cancer in women by progestogens is about 35%, which compares favourably with other forms of not

treatment.

The data in

Hospital

on which this letter is based will be Medicine.

published

in full

M. H. BRIGGS A. D. S. CALDWELL A. G. PITCHFORD.

Pharmaceutical Division, Schering Chemicals Ltd., Burgess Hill, Sussex.

PULMONARY HYPERTENSION AFTER ANGIOCARDIOGRAPHY SIR,-Watson’s articleand the letter commenting on it by Coleman and Sweet2 stimulated my co-workers and me to study the vasomotor action of the different contrast media ordinarily used for angiocardiography, in various concentra-

tions, in dogs. In our investigation, heparinised dog’s blood was injected into the donor dog. Electrocardiographs were taken and pressures in the pulmonary and femoral arteries were recorded simultaneously for at least ten minutes after the ending of the injection. We concluded that concentrations of the dyes are important in determining the pathophysiological disorders that follow their injection. However, we think that the importance of the volume of the dye has been overlooked. Even when using heparinised blood, the injection of 1-5 or more ml. per kg. per second with a pressure higher than 100 lb. per square inch produces changes in the pressure in the pulmonary vascular tree and in systemic arteries as well. Finally, we think that to ensure the fewest pathophysiological disorders in the pulmonary vascular tree, it is much better to use a small amount (1 ml. per kg. per second) of concentrated dye or contrast medium than a larger volume of lower concentration. We injected automatically a new dye (107% concentration) at a pressure of 200 Ib. per square inch, with little vasomotor effect on the pulmonary circulation. At the same time, the cardiac chambers and great vessels were sharply outlined. In conclusion, the amount of dye injected and the speed of the injection are factors to be considered in diminishing the reactions described by many investigators since 1933 when Heathcote and Gartnerreported an experimental investigation using ’Per-Abrodil ’-the dye I used for obtaining good angiocardiograms in normal infants and children with congenital malformation of the heart in 1937. Our full

findings will

be

Research Department, Variety Children’s Hospital 6125 S. W. 31st Street, Miami, Florida 33155. 1. 2. 3.

published

later.

AUGUSTIN W. CASTELLANOS.

Watson, H. Lancet, 1964, ii, 732. Coleman, E. N., Sweet, E. M. ibid. p. 913. Heathcote, R. St. A., Gardner, R. A. Br. J. Radiol.

1933, 6, 304.