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SummaryA double-blind trial was carried out in 47 patients with depression to compare the effectiveness of 30 mg mianserin, 60 mg mianserin and 50 mg sustained-release amitriptyline, each given as a single dose at night over a period of 4 weeks. Hamilton Rating Scale scores showed signgcant, progressive improvement from Week 1 with all three regimens. Although the differences between the groups were not significant, the greatest improvement occurred after 60 mg mianserin daily and the order of effectiveness was consistent for various Hamilton Rating Scale items. Patient seu-assessment, using visual analogue scales, gave similar results to the Hamilton Rating Scale with signijicant, progressive improvement in all groups. Once again, a consistent order of effectiveness was evident with most of the items, the greatest improvement being noted with 60 mg mianserin daily and the least with 30 mg mianserin daily. There was a considerable reduction in the number of reports of symptoms recorded before the trial during treatment in all groups. The only increase in symptoms possibly drug-related was of blurred vision in patients receiving amitriptyline.

The individual response to radiation of 166 carcinomata of the cervix uteri, treated since 1938, has been assessed by means of a quantitative histological examination of serial biopsies. The subsequent clinical findings have confirmed the histological assessment in the majority of tumours examined, the proportion of agreements increasing with time after treatment. The histological assessment has, therefore, a useful prognostic value.A further series of 502 carcinomata of the cervix treated radiologically between 1930 and 1939 was classified on a pre-radiation biopsy according to their degree of anaplasia and the results compared with the clinical follow-up which covered a period of at least five years. In this series also it was found that the response of anaplastic tumours to radiation tended to be less satisfactory than that of differentiating tumours.The significance of these observations to radiotherapy is discussed.

1. In a series of over 700 fully treated patients with epithelioma of the uterine cervix, more differentiated tumours than anaplastic ones of the same clinical stage responded favourably to treatment as measured by the five-year symptom free survival rate.2. The incidence of differentiated tumours increased with age of patient.3. The clinical extent of the disease depended on the growth rate of the tumour and on the length of time it had been present. There was no correlation between survival rate and length of history per se.

We are met to commemorate the life and work of Douglas Lea, a member of this Association, whose work in the field of biophysics influenced the thought and changed the direction of experimental procedure in many laboratories scattered over the world.The Council of the Hospital Physicists Association has honoured me by the invitation to speak on behalf of us all on this occasion of the First Memorial Lecture, and I am proud to be able to do so as one of the family. For this occasion is essentially a family affair in which we gather formally to acknowledge our indebtedness to the achievement of a friend and colleague. It is no time for morbid thoughts or regretful memories. We are here to be glad for what has been done by one well known to us all and beloved by one a few.First, then, let us think of D. E. Lea as we knew him personally. Then let us try and view his world by considering the relationship of the physicist with his colleagues. Finally, let us attempt some assessment of Lea's accomplishments during the all too short period of his research career.Douglas Edward Lea was born in Liverpool on February 8, 1910. From Liverpool Collegiate School he went with a scholarship to Trinity College, Cambridge, in 1928.

My brief is to give some account of the early history of experimental radiology and its relevance—if any—to our anniversary celebrations.The beginning can be fixed with precision: the day when Röntgen gave the world something quite new. The date when “early” can be discarded was decided for me by a would-be contributor to our Journal whose paper I refereed. On pointing out to the author that his conclusions were already accepted, and ten years old at that, he replied with engaging unconcern, “That could well be: I never read anything published before 1940.” That fixes the date! Let us see what he had missed.In 1896 a person actively interested in Röntgen's discovery had the choice either of investigating the possibilities of diagnostic radiology or of studying the biological effects of radiation. Some followed one course, unknowingly playing with fire: of these a proportion burnt their fingers and ultimately became danger signals to their followers: among them were the martyrs. Others became radiation biologists, while Rontgen pursued his studies of the physical properties of his discovery and did the job so thoroughly that for years little was left for other physicists to do but confirm his work and acknowledge him as master.

1. The value of tissue culture as research material is discussed.2. Experiments are described showing the effect of gamma radiation from 3·6 gr. of radium on cell division in vitro.3. These experiments show that the biological efficiency of gamma radiation as measured by this particular response is a function of the intensity of radiation. The biological effect increases with increase of intensity up to a certain critical value. Beyond this point the dose of radiation required to produce a given effect remains practically constant.

It would be difficult to define precisely what feelings are uppermost in my mind at this moment. Appreciation, certainly, for the honour of Council's invitation to this office and for your coming here this evening. Apprehension quickly follows, however, lest I fall short of expectations. Anticipation of pleasures to come accompanies that of difficulties to be faced and overcome. But the most encouraging feeling is that of association with each of you as members of a corporate body representing many different interests which, in one way or another, are the concern of us all.But first a word of apology to those who heard the 35th Mackenzie Davidson Memorial Lecture. When I said it was my “swan song” I had failed to reckon with the resource and daring of Council who, shortly after the 1957 Annual Congress, invited me to become junior Vice-President, which is but three short annual steps from the Presidential Chair. Now when the Executive approaches an ordinary member of this Institute and proffers the highest honour in their power to give and, further (in this instance) expresses willingness to regard any medical qualifications one may have accumulated as so much expendable material—no more in fact than mere neutrinos of near zero significance which can come and go as required to make the situation balance—then, discounting all other considerations, it would be churlish to refuse the invitation just from an aversion to eating one's own words.

By means of tissue culture experiments, the direct effect of radiations upon living cells has been demonstrated beyond dispute. As the dose is increased, biological response becomes more complex. Radiosensitivity can be measured by any one of a number of different responses. The ultimate effect of radiation upon a tissue depends upon the power of recovery in the cells exposed to the particular dose of radiation. Different tissues vary in their power of recovery. Experiments have demonstrated a selective action of radiation, and suggest the existence of a differential action as well.So far as correlative experiments have at present gone, the effects of radiation upon cells in vivoare similar to those obtained under the simpler conditions of growth in vitro, but the precise response of embryonic tissue varies according to the presence or absence of a blood supply. So long as the circulation is intact, its action favours recovery from the effects of radiation. Once involved itself, however, the degenerative effects of radiation are enhanced by the generalised destruction which normally follows any interference with blood supply.The data obtained from tissue culture experiments are of the utmost value as a guide for experimentation under the complicated conditions of growth in vivo. The two methods of investigation are complementary the one to the other.

A photographic study has been made of the duration of mitosis in cells in culture before and after exposure to doses of ? rays ranging from 55 r to 1320 r delivered at a dose-rate of 22 r/min. Cultures irradiated under the same conditions were fixed and stained for histological examination. The total mitotic count was appreciably reduced after each exposure.The abnormalities seen in the stained preparations were numerous even after the lowest dose. It would appear, however, that a proportion of cells which on staining show recognisable abnormalities are still able to complete division within the normal time limits.

Mr. President, Ladies and Gentlemen: This is the formal occasion when we meet corporately to recall the life and work of a man whom we delight to honour. Let us, then, first make an act of recollection of Silvanus Thompson as he was in his age and generation; secondly, review the circumstances in which welive and move and have our being; and finally, attempt to relate his philosophy of life to the conditions of to-day (so far as they can be so extrapolated), to get such inspiration, guidance, and perhaps even comfort, as we can for the daily round and common task of 1949.We are met primarily to commemorate the first President of the Röntgen Society—one of the parent bodies of the British Institute of Radiology; and the ardour and zest of our participation is not diminished by the fact that this is the 28th occasion on which this Institute has gathered to perform this ceremony.The procedure to-day follows the customary ritual into which variety is introduced by the selection each year of a different individual to act as mouthpiece for the assembled company. But having thus stated the purpose of our meeting, I would next tender my sincere thanks to the Council for the honour they have done me by the invitation to follow a succession of far more illustrious men who have delivered the preceding Memorial Lectures of this series.

Mitotic and degenerate cell counts were made on the eye and brain of frog tadpoles exposed to three different doses of a rays and the results compared with those already known for a small dose of ? rays. Whereas with the lowest a-ray dose the relation between mitosis and degeneration does not differ from that which would be expected to follow a relatively small dose of radiation, after the two larger a-ray doses degeneration far exceeds this amount. It would seem that a rays cause the degeneration of potential dividing cells in considerable numbers.

(1) Suspensions of B. mesentericus spores and of B. coli were exposed to gradually increased doses of neutrons and the lethal dose observed.(2) The curve obtained by plotting the proportion of surviving bacteria as a function of dose was exponential in form.(3) B. coli were more sensitive to neutron radiation than the spores of B. mesentericus and in this respect the results resemble those already obtained with gamma rays, but differ from them in degree.(4) The ratio of the gamma-ray dose to the neutron dose required to produce a 50 per cent. lethal effect was 3·2 for B. coli and 5·3 for spores of B. mesentericus.

1. Immature rats were exposed to a beam of neutrons (over a dose range of 2·5 nup to 60 n) and their retinas examined histologically.2. Irradiation produced an initial fall in mitosis which was followed by a return of cell division characterised by a distortion of the normal phase ratio. Degenerate cells appeared between 1 and 3 hours after exposure.3. The results suggest that the degenerate cell count is made up partly by cells killed outright and partly by injured cells which die when mitosis is subsequently attempted.4. The effects of neutron irradiation on the developing rat retina are compared with those obtained by exposing similar tissue to gamma radiation.

A quantitative comparison has been made of the action of fast neutrons (2·8 MEV) and γ rays in inhibiting mitosis in tissue cultures of chick embryo fibroblasts and in the root of the broad bean. The method of dose measurement used makes it possible to compare the effects of equal amounts of γ-ray and neutron energy absorbed per unit volume of tissue. In the case of both tissue cultures and bean roots, the curve relating residual mitosis and dose was found to be approximately exponential, and in the former case the shape of the curve was significantly different from that of the corresponding γ-ray curve, which is of the usual sigmoid type. No intensity dependence was observed. The exponential nature of the neutron curve suggests that the inhibition of mitosis is brought about by one, or at most a few, recoil protons, and the magnitude of the neutron dose which reduces mitosis to 37 per cent. then shows that the volumes within which these particles must pass to be effective, if spherical, have radii of about 2 μ or 3 μ respectively for the two tissues studied. The results indicate that in each case the same number of ions have to be produced within these volumes whichever radiation is used. The difference between both shape and magnitude of the mitosis-dose curves for γ rays and neutrons is then accounted for quantitatively by the fact that in the former case the ionisation would be produced by several hundred secondary electrons, and in the latter by a single recoil proton.Other quantitative studies of the biological effects of fast neutrons are reviewed, and an hypothesis is advanced to account for the large relative efficiency of neutron compared with γ-ray energy which has been observed in some cases. The hypothesis is elaborated in some detail for the case of the lethal action of neutrons on broad bean roots (γ/N = 11), and it is shown that both the high efficiency and the shape of the mortality curve may be accounted for by simple and plausible assumptions.

Tadpoles were exposed to a given dose of gamma radiation and the changes seen over a subsequent period of ten weeks have been described.It has been found that radiation is followed by (a) a reduction in cell division; (b) alteration in the ratio of the different phases of mitosis; and (c) the appearance of degenerate cells.The degenerating cells were found to be mitotic or pre-mitotic cells which the irradiation had unfitted for the ordeal of mitosis.With the dose used, animals were capable of recovery. Those in which the process of metamorphosis had begun showed a recovery rate twice that of younger animals.The quantitative results obtained from this amphibian material, so far as they apply to cell division, closely resemble those already obtained from experiments on avian fibroblasts in vitroand mammalian tissue in vivo.

In a previous paper (Spear and Glücksmann, 1938) the effect of a single γ-ray exposure on the tissues of the normal tadpole were described. It was shown that radiation had a special effect upon cells in the “mitotic areas,” and quantitative results were given of the changes observed in the brain and eye of exposed animals. These indicated that radiation caused a diminution in cell division, followed by the appearance of degeneration (Fig. 1). The sequence of events was explained as an effect of radiation upon potential dividing cells, unfitting many of them for the ordeal of mitosis, and leading to their breakdown.To determine more precisely the relation between disturbance of cell division and the occurrence of degeneration, some preliminary attempts were made to vary the mitotic activity in unirradiated tadpoles: (a) by fasting, and (b) by low temperature. It was found that animals could survive in tap water without food for more than three weeks, and that during this period they showed a steady diminution in cell division, which eventually reached zero.It was also found that tadpoles could live for some time at temperatures as low as 0·5°C. to 0·3°C. Under such conditions proliferative activity was considerably modified; there were fewer cells in prophase, and the actual process of mitosis, especially the metaphase, was prolonged.

(i) The number of cells in mitosis in tissue cultures in vitrowas found to increase up to a maximum which was maintained for a period of approximately 20 hours.(ii) Exposure of tissue cultures in vitroto gamma rays of radium produced a fall in the number of cells in mitosis.(iii) Under certain conditions the fall was followed by a rise which was almost exactly compensatory.(iv) A delayed lethal effect followed prolonged exposure to gamma rays, the average period of survival varying with the duration of exposure.(v) The effect of gamma rays on mitosis and on the survival period after prolonged irradiation, was more marked with 300 mg. radium than with 100 mg., alteration in the duration of exposure being made so as to give a constant value to the product of time and intensity.

We are met to commemorate with thankfulness the life and work of James Mackenzie Davidson, sometime President both of the Röntgen Society and of our Institute prior to the incorporation, and described by a contemporary as “Head of the British School of Radiology”. He was a man of study common sense with an eager and receptive mind and the possessor of a singular charm of manner. It is not, however, merely by the personal qualities which endear a man to his fellows that he lives on in the minds of posterity. It is rather by his power to impress, to be remarkable, or for some reason unique in his day and generation that he earns his right to be commemorated. Mackenzie Davidson come to London in 1897 when he was 41 years old and was present at the inaugural meeting of the Röntgen Society. Up to that time he had made his career in surgery and ophthalmology, spending his leisure time experimenting with electricity and light. Yet it was in radiology that he made his lasting reputation. The pioneer work, for which he became famous (Bruce, 1906) as Thurston Holland (Holland, 1919) reminds us, was done at the time when apparatus was primitive: the mercury break, known by his name, was a great advance at the time of its invention, while his X-ray couch was a stage in the evolution of modern equipment. His methods of stereoscopic radiography and of localising foreign bodies survive to the present day.

Some calculation of gamma-ray intensities published in a previous paper are compared with recent measurements made with an elektron metal Sievert condenser-chamber.It is shown that the relativevalues agree to within 2 per cent, but that the observed values are 24 per cent higher than the calculated.It is found that the Optimum intensityfor reducing mitosis in tissue cultures is in the region of 77 Imc.

In the first paper of this series (Spear and Glücksmann, 1938) it was shown that exposure of the normal brain and eye of the frog tadpole to radiation is followed by (a) a reduction in cell division; (b) alteration in the ratio of the different phases of mitosis, and (c) the appearance of degenerate cells in the germinative zone. The particular stage of mitosis at which the break-down occurred varied with the experimental conditions. This degeneration could be accounted for by assuming that the irradiation had affected cells approaching division at the time of exposure, unfitting them for the ordeal of mitosis and causing them to break down when division was attempted. (See also Tansley, Spear and Glücksmann, 1937.)To test this interpretation of the results a further series of experiments was made (Glücksmann and Spear, 1939), in which the mitotic activity of the tissue was varied by lowering the temperature and by fasting. It was found that when mitotic activity was reduced before exposure, degeneration did not follow radiation until cells were in a position to attempt division again. The results thus confirmed the conclusion drawn from earlier experiments that the degeneration seen after relatively small doses of γ rays (268 r) is correlated with the presence, at the time of exposure, of potential dividing cells which are unable to accomplish mitosis, owing to damage caused by the radiation and break down on attempting division.