- Email: [email protected]
Conferences
847
HORMONES AND
A.
CONFERENCE
ATHEROSCLEROSIS
sponsored by the endocrinology
and plasma-phospholipids. The combination of cortisone with cholesterol feeding causes greater hypercholesterolaemia but less atherosclerosis in animals fed cholesterol alone. He suggested that this may be due to a decrease in arterial permeability produced by cortisone, and in support of this the simultaneous administration of hyaluronidase increased the degree of atherosclerosis. Dr. S. 0. BYERS (San Francisco) reported that rats which were intermittently stressed by contact with an electrical charge at varying points in their cages, and were therefore very active physically, had no change in the plasma cholesterol or phospholipids, but had shortened clotting-times when compared with a control group. Dr. MARMORSTON (Los Angeles) reported that in dogs a single injection of corticotrophin (A.C.T.H.) resulted subsequently in a greater hypercholesterolxmic response to cholesterol and thiouracil feeding than if no corticotrophin had been administered. Extensive atheroma developed in these dogs throughout the vascular tree and some even had cerebral haemorrhage. A flaccid paralysis was observed in other dogs, but it was not clear whether this was related to the cerebrovascular lesions. Dr. R. PICK (Chicago) believes that a decrease in the cholesterol/phospholipid ratio is more closely related to the experimental regression of atherosclerotic lesions in the chick than any other lipid measurement. All her experimental observations on the chick have emphasised that the aorta is more sensitive to the production and reduction of lipid-rich lesions than the coronary arteries. Dr. R. H. FURMAN (Oklahoma City) reported a case of biliary cirrhosis in a woman, aged 30, in whom the plasma-cholesterol increased to 3000 mg. per 100 ml. but the cholesterol/phospholipid ratio remained less than unity. At necropsy there was atherosclerosis in the aorta but the coronary arteries were
protein cholesterol,
Conferences
and
heart sections of the National Institutes of Health was held from March 11 to 14 at Brighton, Utah, under the general chairmanship of Dr. GREGORY PINCUS (Worcester,
Mass.). Cholesterol Metabolism Prof. SUNE BERGSTROM (Lund), who considered the influence of intestinal flora on the excretion of cholesterol and bile acid, showed that hypothyroid rats excrete almost pure cholic acid, whereas hyperthyroid rats excrete mostly chenodeoxycholic acid. This difference may be due to stimulation of bacterial floral activity by the thyroid hormones. He agreed that, although the liver is the primary site for cholesterol degradation, all tissues have the capacity to degrade cholesterol into bile acid. Dr. G. S. BOYD (Edinburgh) showed that in rats thiouracil has an extrathyroidal effect in elevating plasma-cholesterol. Triiodothyronine and tri- and tetra-iodothyroacetic acids cause selective increase of the oxygen requirements of isolated myocardium, and the administration of tri-iodothyroacetic acid to hypercholesterolxmic rats reduces both plasma-cholesterol and lipid deposition in the aorta. Dr. J. E. RALL (Bethesda) demonstrated that low concentrations of circulating thyroxine are bound between the alpha-land alpha-2-globulin fractions, but that higher concentrations are apparently attached to albumin. Sex hormones can influence thyroid activity by altering the protein-binding capacity and thus altering the concentration of circulating free thyroxine.
Arterial Wall and Cholesterol Transport No critical level of blood-cholesterol has been observed for the development of experimental atheroma, and hypercholesterolaemia induced by alloxan or detergents is not often followed by atheromatous lesions; these observations, and the irregular distribution of atheromatous lesions, do not accord well, in the opinion of Dr. R. L. HOLMAN (New Orleans), with the filtration theory of the pathogenesis of atheroma. He emphasised the importance of the arterial wall, indicating that atherosclerosis is a gradually progressive process with well-defined histological stages. Dr. N. T. WERTHESSEN (San Antonio) showed that the accumulation of cholesterol in the isolated perfused aorta is directly related to the initial concentration of cholesterol and to the glucose content of the aorta. Dr. D. B. ZILVERSMIT (Memphis) has shown by tracer studies that all phospholipids have a higher specific activity in the aorta than in the plasma. He believes that excess phosphatide in the aorta is probably due to local synthesis. It is possible that once the process of arterial lipogenesis is set into motion, reduction of hypercholesterolxmia will have little effect. Dr. LEON HELLMAN (New York), who has cannulated the left thoracic duct in humans, reported the results of simultaneous analyses of the plasma and lymphatic lipids. In normal
people and in hypercholesterolxmic non-lipaemic patients, the plasma specific activity of 14C-labelled free cholesterol is greater than that of esterified cholesterol, but in hypercholesterolsemic hyperlipemic subjects the specific activity of 14Clabelled ester cholesterol is greater. This might suggest the possibility of a defect at the intestinal level of absorption. Dr. Hellman indicated that the fall in plasma-cholesterol following corn-oil administration is more directly related to excretion of sterols than to that of bile acids. Hormones and Experimental Atherosclerosis Dr. DAVID ADLERSBERG (New York) showed that cortisone and prednisone increase plasma-free-cholesterol, beta-lipo-
healthy. Hormones and the Blood Dr. JOSEPH SEIFTER
Lipids (Philadelphia) reported further studies
lipid-mobilising factor that can be demonstrated in the posterior pituitary of hogs and is apparently independent of known pituitary hormones. Parenteral injection of lipidmobilising factor produces hyperlipxmia in the systemic on a
circulation in the presence of liver damage, but with a this hyperlipaemia is confined to the portal circulation. Dr. R. H. ROSEMAN (San Francisco) reported that the plasma-cholesterol levels were increased and that the clotting-times were decreased in accountants when they were undergoing the stress of having to balance quarterly
healthy liver
accounts.
Dr. DAVID ADLERSBERG (New York) emphasised the association of acute pancreatitis with hyperlipaemia and felt that the role of glucagon in the regulation of lipid metabolism needed considerable clarification. Dr. G. S. BOYD (Edinburgh) did not observe destruction of the alpha-cells following cobalt chloride administration, which resulted in a rise in the plasmacholesterol and a fatty liver in his rabbits. Dr. E. STRISOWER (Berkeley) reported that the concentration of high density decreased after the administration of very large doses of desiccated thyroid, thyroxine, and triiodothyronine to euthyroid patients. Dr. M. F. OLIVER (Edinburgh) had also observed a decrease in the alpha-lipoprotein concentration with large doses of thyroxine and triiodothyronine, but he felt that this might be a dose effect since the alpha-lipoprotein level was actually increased with smaller doses of these thyroid hormones. Dr. HOWARD EDER (New York) reported that a low dose of methyl testosterone did not necessarily produce much change in the total cholesterol in the plasma, although the beta/alphalipoprotein ratio is increased. Similarly, he had observed a decrease in the beta/alpha-lipoprotein ratio without any very significant change in plasma-total-cholesterol following the
lipoproteins
848 administration of certain weak cestrogens. He raised the question whether a compound which allowed a change in the lipoprotein ratio but not in total cholesterol was of any value in influencing atherosclerosis. Clinical Biological Relationship Dr. A. R. P. WALKER (Johannesburg) emphasised the rarity of coronary-artery disease in the Bantu. Cerebral atherosclerosis and hypertension are common and often severe. The principal differences from Western nations are in the diet and physical
activity. There is a higher concentration of unesterified fatty acids, greater fibrinolytic activity, and greater oestrogen excretion in the Bantu than in the White. A third of adult male Bantus had gynaecomastia, but as yet there is no definite correlation with the incidence of liver disease. Liver disease probably contributes to the rarity of atherosclerosis in the Bantu, but this is probably mostly determined by the diet. Dr. M. F. OLIVER (Edinburgh) indicated that various thyroid
analogues decreased the plasma-cholesterol without apparently increasing the basal metabolic rate, but so far these had proved to be unsuitable since the cholesterol-lowering effect could not be maintained beyond a few weeks and angina was aggravated in a quarter of his patients. Following the clinical trial of several weak oestrogens, he concluded that it was not yet possible to dissociate the cholesterol-lowering action from their feminising effects. (Dr. ROGER ROBINSON [Worcester, Mass.] and Dr. VICTOR DRILL [Chicago] had found the same.) Although the administration of ethinyl oestradiol for two and a half years to 50 men with myocardial infarction had reduced the plasma-lipid levels, there was no difference in morbidity and mortality from further coronary episodes between these men and another 50 receiving lactose. Dr. J. STAMLER (Chicago) reported similar results from a group of about 100 men who had receivedPremarin ’ (conjugated oestrogens) over a three-year period. There was no definite evidence, therefore, that the long-continued reduction of the plasma-lipids improved the prognosis.
NEOPLASIA A
Neoplasia organised by the postgraduate medical education committee of the University of Glasgow and the Royal Faculty of Physicians and Surgeons was held on March 26-28. CONFERENCE on
General
Concepts
Dr. PHILIP PEACOCK said that the first rational idea of causawas Percival Pott’s observations on chimney-sweeps’ cancer of the scrotum. Tumours arise in all animals, but some tumours common in man seem to be rare in other animals. Theoretically cancer can start from one cell, but the earliest case which Dr. Peacock has seen was multicentric. In this case, in addition to the definite neoplastic foci there were areas of retained sebaceous secretion, and the possibility of this being carcinogenic must be considered, especially in view of recent suggestions that cholesterol is a carcinogen. Perhaps cholesterol can be transformed into methyl cholanthrene. Except in a few industrial cases the cause of carcinoma is unknown; and even where the carcinogen is recognised, the final process remains to be discovered. Contaminants of so-called carcinogens may be the active agents. Some virus-induced tumours regress spontaneously; the reason for this may be in the hereditary transmission of the tumour, and an additive factor may be involved. Dr. Peacock’s concept of neoplasia is that cancer is an alternative mode of existence for a cell which is threatened by death. It may be due to imbalance of cell constituents.
tion
D.N.A.
Prof. J. N. DAVIDSON reviewed the knowledge of cell substances, notably those of the nucleus. Of these, desoxyribonucleic acid (D.N.A.) is the most important. The amount of
in the cell is remarkably constant in different organs except the liver, where it is increased. Many tumour cells have more D.N.A. than normal cells. D.N.A. may actually alter the characteristics of cultures and even of organisms. For example, D.N.A. from a mutant added to a sensitive culture will produce mutant cells in the culture. D.N.A. from phage ’may alter Escherichia coli, to produce further phage. D.N.A.
Endogenous and Industrial
Tumours
Dr. B. D. PULLINGER said that some tumours now considered may eventually be removed from this group by further research. Squamous carcinoma of the lung may or may not be endogenous, but it seems likely that neoplasia of the scrotum is exogenous, as it occurs mainly in the lower social classes and the agent can probably be washed off. The virus tumours of animals are difficult to classify. Some tumours-notably polyposis coli and retinoblastoma-are hereditary. Some-notably carcinoma of the breast-appear to be familial. It is impossible to study hereditary tumours in man, because of their irregular breeding; but it may be possible to produce tumours in animals which are highly inbred. The reason for tumour formation may be senescence of the cell or the presence of internal substances which irritate the cell. Recently many mammary tumours have been associated with cholesterol deposits. Cholesterol has caused carcinoma in the bladders of mice. It has recently been shown that carcinoma can be produced locally by the injection of oestrogen. Dr. A. T. DOIG spoke of industrial cancer. The possible factors involved are tar, pitch, shale-oil, asbestos, X rays, ultraviolet rays, arsenic, and chromates. Radium and radioactive materials have become important. Latent periods may be long. In some industries non-carcinogenic materials may be substituted, and in some the process can be properly screened. Dr. Doig made a strong plea for the notification of all cases of possible industrial cancer, so that the conditions of work might be inspected.
endogenous
Reticulo-endothelial System Dr. R. 1. SHAW DUNN classified tumours of lymphoid tissue into (1) Hodgkin’s disease, with subdivisions of typical, atypical, Hodgkin’s sarcoma, and Brill’s disease; (2) lymphosarcoma, which may be small- or large-celled; (3) lymphoreticulosarcoma ; (4) reticular cell sarcoma; and (5) miscellaneous. Dr. A. BROWN dealt with the clinical picture of " reticulosis ". Leukxmia is merely a symptom of several different diseases. There has been a gross increase in this condition after atomic bombing, and in radiologists, but its incidence has also increased in the general population over the same period. The prognosis of these diseases of the reticulo-endothelial system is poor, the average survival being two anda half years-though patients with Hodgkin’s disease may survive for several years and those with chronic leukaemia for up to twenty years. The management of these lesions is non-specific. X rays may be used at the local site of a disease; chemotherapy is generally reserved for radioresistant or generalised lesions. Dr. Brown favours nitrogen mustard by injection, but recent results with tretamine (T.E.M.) and busulphan (’Myleran’) are poor. Anti-metabolites, such as folic-acid antagonists and purine derivatives, are giving some beneficial results.
Regional Cancer Prostate
Mr. W.’B. STIRLING said that in prostatic cancer the serumacid-phosphatase is increased in 90%of cases. Only 5% of the patients are suitable for radical prostatectomy; the rest are treated by stilboestrol. Without treatment, the average duration of the disease is fifteen months, with 9% five-year survivals; after stilboestrol the average duration is forty-five months, with 27% five-year survivals. Adrenalectomy and hypophysectomy yield poor results.
849
Liver Prof. J. W. ORR (Birmingham) pointed out that, in Africa, cancer of the liver is found in 1 % of all necropsies, compared with 0-1% in Europe. In South China and in Indonesia it is common in the natives but rare in Europeans. The age and sex distribution is explicable by the survival-rates of these populations. Race seems to have little effect; the Africans in America have lost their tendency to primary liver cancer. This uneven incidence of carcinoma of the liver may be explained by a dietetic deficiency or by a toxic factor. Primary liver tumours are not common in animals, but can be induced by butter yellow and similar substances. The tumours that develop are similar to the primary tumours in man. It seems likely that carcinoma develops on a process of regenera-
primary
tion.
Stomach Prof. C. F. W. ILLINGWORTH remarked on the poor results of the treatment of carcinoma of the stomach-a disease which now causes the death of 300 people a week in the United Kingdom. The five-year survival-rate is only 2-7% in all diagnosed cases, and 12% in those who have had gastric resection. The aetiology is unknown, and tumours cannot be produced in animals by feeding carcinogens. It is unlikely that gastric ulcers lead to cancer in more than 5% of cases of ulcer. In treatment radical total gastrectomy is unsatisfactory, and partial gastrectomy is probably best. Exfoliative cytology does not add many to the cases diagnosed by other means. Routine test of the stool for occult blood may be a useful screening-test for gastric cancer.
Thyroid Dr. E. M. McGiRR said that cancer of the thyroid gland accounted for only 0-4% of deaths from malignant disease. At all ages it affects females more than males. There are three main types: (1) differentiated (papillary follicular, and Hurthlcell adenocarcinoma); (2) non-differentiated; and (3) miscellaneous. Surgery has not given very good results, and radioactive iodine is suitable for only 10% of the cases.
FREEZING AND DRYING THE second international symposium on freezing and drying was held, under the auspices of the Institute of Biology, in London on April 1 and 2. General Topics Dr. H. T. MERYMAN (U.S.A.) discussed the mechanical and biochemical changes during freezing in biological systems. He felt that a balance must be reached between rapid cooling (in which mechanical damage is maximal) and slow cooling (in which biochemical damage is maximal). The use of additives, such as glycerin, may be rendered unnecessary by uniformity in freezing and thawing. The paper by Prof. N. KALABUKHOV (U.S.S.R.) was read by Dr. A. U. Smith. It dealt with the problems of undercooling, freezing, and vitrifying whole animals. Experiments were described in which bats were undercooled to - 5 to — 7°C, and survived storage at these temperatures for periods up to several days. At —43°C the heart-rate of bats was about 8 beats a minute, compared with the normal rate of 400.
Microorganisms Dr. W. J. ScoTT (Australia) discussed the role of protective agents in storing freeze-dried bacteria. One cause of death is the intracellular reaction of carbonyl with amino groupsknown as the browning reaction. This occurs in dried preparations, and the water formed during the reaction accelerates the process. Glucose or ribose in the medium improves the viable count immediately after freeze-drying, but exerts a deleterious effect on stored organisms. Their corresponding reduction compounds (sorbitol and ribitol) give protection without
facilitating the browning reaction. Addition of aminoacids to the freezing-mixtures to compete for the carbonyl groups is another means of protection, Lysine and sodium glutamate have been found useful in this respect. Along similar lines sulphur dioxide, which reacts with ketone and aldehyde groups, exerts a protective action. Dr. R. I. N. GREAVES described some factors which influence the stability of freeze-dried cultures, with particular reference to the browning reaction. Dried cultures have been boiled to assess the effects of various drying media on their stability when stored for long periods. Glucose in the medium gives high initial survival-rates, but the dried cultures are very heatsensitive. The greatest resistance to high temperatures was found in media consisting of 5% sodium glutamate in 5% dextran solution.
Prof. D. GRIEFF (U.S.A.) talked of the effects of freezing, lowtemperature storage, and drying by vacuum sublimation on the activities of viruses and cellular particulates. Viruses showed less loss of infectivity when they were dried from the vitreous, rather than the crystalline, state. The activity of mitochondria, measured by their capacity for oxidative phosphorylation, was better retained after slow than after rapid freezing. This is possibly related to the preservation of the integrity of mitochondrial membranes. Miss B. L. BRADY described observations on the freezedrying of yeasts, which is used as an ancillary method to maintain the national collection of yeast cultures. With freezedrying little difference is noted between the survival-rates of sporing and of non-sporing cells, and between haploid and diploid organisms. There are generic differences in survivalrates. After freeze-drying no change has been noted in vitamin and aminoacid requirements of the yeasts. Grafts Commander G. W. HYATT (U.S.A.) spoke of experience in maintaining a bank of freeze-dried human cadaveric tissues for use in surgery. Skin, dura, fascia, bone, and arteries are removed aseptically from selected sites. The tissues are placed in a medium containing serum and then freeze-dried at 4°C for six weeks, at the end of which the moisture content has fallen to 2-7-3-5%. The materials are stored in sealed vessels at room temperature until needed. Bone stored for up to five years has been used successfully. .
Prof. C. G. ROB described the experience of his surgical unit with freeze-dried arterial grafts. Of the last 394 arterial reconstructions, 178 were carried out with homologous tissue transplants. Frozen arteries were used in 78 of these, and freeze-dried arteries in 100. The two types of material take equally well. The criterion of success is the absence of thrombosis, and anticoagulant drugs are an essential part of postoperative routine. Colonel F. HENAFF (France) discussed freeze-drying associated with corneal grafts. The freeze-dried corneas are undoubtedly non-viable, but both full-thickness and lamellar grafts have successfully been carried out with homologous and heterologous (dog) material. Dr. A. S. PARKES discussed the freeze-drying of viable grafts. Rat ovaries are good test material because when they are grafted they become physiologically active after a few days. Frozen ovaries retain their activity for at least two years when stored in 15% glycerin at -79°C. At this temperature viability has been maintained although the tissues are effectively dry, because their water is in the form of ice. The problems are how to remove the ice, and what to do with the residual glycerin. High concentrations of glycerin are toxic at room temperature. This is therefore an unsuitable component of freeze-drying media. An ideal protective agent would protect against freezing, be non-toxic, and sublimate with ice during the drying process. To this end, methanol has been tested on rat ovarian tissue in freezing experiments. Viable grafts have been obtained after ovaries have been kept for a few hours in methanol at -20°C.
HORMONES AND
A.
CONFERENCE
ATHEROSCLEROSIS
sponsored by the endocrinology
and plasma-phospholipids. The combination of cortisone with cholesterol feeding causes greater hypercholesterolaemia but less atherosclerosis in animals fed cholesterol alone. He suggested that this may be due to a decrease in arterial permeability produced by cortisone, and in support of this the simultaneous administration of hyaluronidase increased the degree of atherosclerosis. Dr. S. 0. BYERS (San Francisco) reported that rats which were intermittently stressed by contact with an electrical charge at varying points in their cages, and were therefore very active physically, had no change in the plasma cholesterol or phospholipids, but had shortened clotting-times when compared with a control group. Dr. MARMORSTON (Los Angeles) reported that in dogs a single injection of corticotrophin (A.C.T.H.) resulted subsequently in a greater hypercholesterolxmic response to cholesterol and thiouracil feeding than if no corticotrophin had been administered. Extensive atheroma developed in these dogs throughout the vascular tree and some even had cerebral haemorrhage. A flaccid paralysis was observed in other dogs, but it was not clear whether this was related to the cerebrovascular lesions. Dr. R. PICK (Chicago) believes that a decrease in the cholesterol/phospholipid ratio is more closely related to the experimental regression of atherosclerotic lesions in the chick than any other lipid measurement. All her experimental observations on the chick have emphasised that the aorta is more sensitive to the production and reduction of lipid-rich lesions than the coronary arteries. Dr. R. H. FURMAN (Oklahoma City) reported a case of biliary cirrhosis in a woman, aged 30, in whom the plasma-cholesterol increased to 3000 mg. per 100 ml. but the cholesterol/phospholipid ratio remained less than unity. At necropsy there was atherosclerosis in the aorta but the coronary arteries were
protein cholesterol,
Conferences
and
heart sections of the National Institutes of Health was held from March 11 to 14 at Brighton, Utah, under the general chairmanship of Dr. GREGORY PINCUS (Worcester,
Mass.). Cholesterol Metabolism Prof. SUNE BERGSTROM (Lund), who considered the influence of intestinal flora on the excretion of cholesterol and bile acid, showed that hypothyroid rats excrete almost pure cholic acid, whereas hyperthyroid rats excrete mostly chenodeoxycholic acid. This difference may be due to stimulation of bacterial floral activity by the thyroid hormones. He agreed that, although the liver is the primary site for cholesterol degradation, all tissues have the capacity to degrade cholesterol into bile acid. Dr. G. S. BOYD (Edinburgh) showed that in rats thiouracil has an extrathyroidal effect in elevating plasma-cholesterol. Triiodothyronine and tri- and tetra-iodothyroacetic acids cause selective increase of the oxygen requirements of isolated myocardium, and the administration of tri-iodothyroacetic acid to hypercholesterolxmic rats reduces both plasma-cholesterol and lipid deposition in the aorta. Dr. J. E. RALL (Bethesda) demonstrated that low concentrations of circulating thyroxine are bound between the alpha-land alpha-2-globulin fractions, but that higher concentrations are apparently attached to albumin. Sex hormones can influence thyroid activity by altering the protein-binding capacity and thus altering the concentration of circulating free thyroxine.
Arterial Wall and Cholesterol Transport No critical level of blood-cholesterol has been observed for the development of experimental atheroma, and hypercholesterolaemia induced by alloxan or detergents is not often followed by atheromatous lesions; these observations, and the irregular distribution of atheromatous lesions, do not accord well, in the opinion of Dr. R. L. HOLMAN (New Orleans), with the filtration theory of the pathogenesis of atheroma. He emphasised the importance of the arterial wall, indicating that atherosclerosis is a gradually progressive process with well-defined histological stages. Dr. N. T. WERTHESSEN (San Antonio) showed that the accumulation of cholesterol in the isolated perfused aorta is directly related to the initial concentration of cholesterol and to the glucose content of the aorta. Dr. D. B. ZILVERSMIT (Memphis) has shown by tracer studies that all phospholipids have a higher specific activity in the aorta than in the plasma. He believes that excess phosphatide in the aorta is probably due to local synthesis. It is possible that once the process of arterial lipogenesis is set into motion, reduction of hypercholesterolxmia will have little effect. Dr. LEON HELLMAN (New York), who has cannulated the left thoracic duct in humans, reported the results of simultaneous analyses of the plasma and lymphatic lipids. In normal
people and in hypercholesterolxmic non-lipaemic patients, the plasma specific activity of 14C-labelled free cholesterol is greater than that of esterified cholesterol, but in hypercholesterolsemic hyperlipemic subjects the specific activity of 14Clabelled ester cholesterol is greater. This might suggest the possibility of a defect at the intestinal level of absorption. Dr. Hellman indicated that the fall in plasma-cholesterol following corn-oil administration is more directly related to excretion of sterols than to that of bile acids. Hormones and Experimental Atherosclerosis Dr. DAVID ADLERSBERG (New York) showed that cortisone and prednisone increase plasma-free-cholesterol, beta-lipo-
healthy. Hormones and the Blood Dr. JOSEPH SEIFTER
Lipids (Philadelphia) reported further studies
lipid-mobilising factor that can be demonstrated in the posterior pituitary of hogs and is apparently independent of known pituitary hormones. Parenteral injection of lipidmobilising factor produces hyperlipxmia in the systemic on a
circulation in the presence of liver damage, but with a this hyperlipaemia is confined to the portal circulation. Dr. R. H. ROSEMAN (San Francisco) reported that the plasma-cholesterol levels were increased and that the clotting-times were decreased in accountants when they were undergoing the stress of having to balance quarterly
healthy liver
accounts.
Dr. DAVID ADLERSBERG (New York) emphasised the association of acute pancreatitis with hyperlipaemia and felt that the role of glucagon in the regulation of lipid metabolism needed considerable clarification. Dr. G. S. BOYD (Edinburgh) did not observe destruction of the alpha-cells following cobalt chloride administration, which resulted in a rise in the plasmacholesterol and a fatty liver in his rabbits. Dr. E. STRISOWER (Berkeley) reported that the concentration of high density decreased after the administration of very large doses of desiccated thyroid, thyroxine, and triiodothyronine to euthyroid patients. Dr. M. F. OLIVER (Edinburgh) had also observed a decrease in the alpha-lipoprotein concentration with large doses of thyroxine and triiodothyronine, but he felt that this might be a dose effect since the alpha-lipoprotein level was actually increased with smaller doses of these thyroid hormones. Dr. HOWARD EDER (New York) reported that a low dose of methyl testosterone did not necessarily produce much change in the total cholesterol in the plasma, although the beta/alphalipoprotein ratio is increased. Similarly, he had observed a decrease in the beta/alpha-lipoprotein ratio without any very significant change in plasma-total-cholesterol following the
lipoproteins
848 administration of certain weak cestrogens. He raised the question whether a compound which allowed a change in the lipoprotein ratio but not in total cholesterol was of any value in influencing atherosclerosis. Clinical Biological Relationship Dr. A. R. P. WALKER (Johannesburg) emphasised the rarity of coronary-artery disease in the Bantu. Cerebral atherosclerosis and hypertension are common and often severe. The principal differences from Western nations are in the diet and physical
activity. There is a higher concentration of unesterified fatty acids, greater fibrinolytic activity, and greater oestrogen excretion in the Bantu than in the White. A third of adult male Bantus had gynaecomastia, but as yet there is no definite correlation with the incidence of liver disease. Liver disease probably contributes to the rarity of atherosclerosis in the Bantu, but this is probably mostly determined by the diet. Dr. M. F. OLIVER (Edinburgh) indicated that various thyroid
analogues decreased the plasma-cholesterol without apparently increasing the basal metabolic rate, but so far these had proved to be unsuitable since the cholesterol-lowering effect could not be maintained beyond a few weeks and angina was aggravated in a quarter of his patients. Following the clinical trial of several weak oestrogens, he concluded that it was not yet possible to dissociate the cholesterol-lowering action from their feminising effects. (Dr. ROGER ROBINSON [Worcester, Mass.] and Dr. VICTOR DRILL [Chicago] had found the same.) Although the administration of ethinyl oestradiol for two and a half years to 50 men with myocardial infarction had reduced the plasma-lipid levels, there was no difference in morbidity and mortality from further coronary episodes between these men and another 50 receiving lactose. Dr. J. STAMLER (Chicago) reported similar results from a group of about 100 men who had receivedPremarin ’ (conjugated oestrogens) over a three-year period. There was no definite evidence, therefore, that the long-continued reduction of the plasma-lipids improved the prognosis.
NEOPLASIA A
Neoplasia organised by the postgraduate medical education committee of the University of Glasgow and the Royal Faculty of Physicians and Surgeons was held on March 26-28. CONFERENCE on
General
Concepts
Dr. PHILIP PEACOCK said that the first rational idea of causawas Percival Pott’s observations on chimney-sweeps’ cancer of the scrotum. Tumours arise in all animals, but some tumours common in man seem to be rare in other animals. Theoretically cancer can start from one cell, but the earliest case which Dr. Peacock has seen was multicentric. In this case, in addition to the definite neoplastic foci there were areas of retained sebaceous secretion, and the possibility of this being carcinogenic must be considered, especially in view of recent suggestions that cholesterol is a carcinogen. Perhaps cholesterol can be transformed into methyl cholanthrene. Except in a few industrial cases the cause of carcinoma is unknown; and even where the carcinogen is recognised, the final process remains to be discovered. Contaminants of so-called carcinogens may be the active agents. Some virus-induced tumours regress spontaneously; the reason for this may be in the hereditary transmission of the tumour, and an additive factor may be involved. Dr. Peacock’s concept of neoplasia is that cancer is an alternative mode of existence for a cell which is threatened by death. It may be due to imbalance of cell constituents.
tion
D.N.A.
Prof. J. N. DAVIDSON reviewed the knowledge of cell substances, notably those of the nucleus. Of these, desoxyribonucleic acid (D.N.A.) is the most important. The amount of
in the cell is remarkably constant in different organs except the liver, where it is increased. Many tumour cells have more D.N.A. than normal cells. D.N.A. may actually alter the characteristics of cultures and even of organisms. For example, D.N.A. from a mutant added to a sensitive culture will produce mutant cells in the culture. D.N.A. from phage ’may alter Escherichia coli, to produce further phage. D.N.A.
Endogenous and Industrial
Tumours
Dr. B. D. PULLINGER said that some tumours now considered may eventually be removed from this group by further research. Squamous carcinoma of the lung may or may not be endogenous, but it seems likely that neoplasia of the scrotum is exogenous, as it occurs mainly in the lower social classes and the agent can probably be washed off. The virus tumours of animals are difficult to classify. Some tumours-notably polyposis coli and retinoblastoma-are hereditary. Some-notably carcinoma of the breast-appear to be familial. It is impossible to study hereditary tumours in man, because of their irregular breeding; but it may be possible to produce tumours in animals which are highly inbred. The reason for tumour formation may be senescence of the cell or the presence of internal substances which irritate the cell. Recently many mammary tumours have been associated with cholesterol deposits. Cholesterol has caused carcinoma in the bladders of mice. It has recently been shown that carcinoma can be produced locally by the injection of oestrogen. Dr. A. T. DOIG spoke of industrial cancer. The possible factors involved are tar, pitch, shale-oil, asbestos, X rays, ultraviolet rays, arsenic, and chromates. Radium and radioactive materials have become important. Latent periods may be long. In some industries non-carcinogenic materials may be substituted, and in some the process can be properly screened. Dr. Doig made a strong plea for the notification of all cases of possible industrial cancer, so that the conditions of work might be inspected.
endogenous
Reticulo-endothelial System Dr. R. 1. SHAW DUNN classified tumours of lymphoid tissue into (1) Hodgkin’s disease, with subdivisions of typical, atypical, Hodgkin’s sarcoma, and Brill’s disease; (2) lymphosarcoma, which may be small- or large-celled; (3) lymphoreticulosarcoma ; (4) reticular cell sarcoma; and (5) miscellaneous. Dr. A. BROWN dealt with the clinical picture of " reticulosis ". Leukxmia is merely a symptom of several different diseases. There has been a gross increase in this condition after atomic bombing, and in radiologists, but its incidence has also increased in the general population over the same period. The prognosis of these diseases of the reticulo-endothelial system is poor, the average survival being two anda half years-though patients with Hodgkin’s disease may survive for several years and those with chronic leukaemia for up to twenty years. The management of these lesions is non-specific. X rays may be used at the local site of a disease; chemotherapy is generally reserved for radioresistant or generalised lesions. Dr. Brown favours nitrogen mustard by injection, but recent results with tretamine (T.E.M.) and busulphan (’Myleran’) are poor. Anti-metabolites, such as folic-acid antagonists and purine derivatives, are giving some beneficial results.
Regional Cancer Prostate
Mr. W.’B. STIRLING said that in prostatic cancer the serumacid-phosphatase is increased in 90%of cases. Only 5% of the patients are suitable for radical prostatectomy; the rest are treated by stilboestrol. Without treatment, the average duration of the disease is fifteen months, with 9% five-year survivals; after stilboestrol the average duration is forty-five months, with 27% five-year survivals. Adrenalectomy and hypophysectomy yield poor results.
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Liver Prof. J. W. ORR (Birmingham) pointed out that, in Africa, cancer of the liver is found in 1 % of all necropsies, compared with 0-1% in Europe. In South China and in Indonesia it is common in the natives but rare in Europeans. The age and sex distribution is explicable by the survival-rates of these populations. Race seems to have little effect; the Africans in America have lost their tendency to primary liver cancer. This uneven incidence of carcinoma of the liver may be explained by a dietetic deficiency or by a toxic factor. Primary liver tumours are not common in animals, but can be induced by butter yellow and similar substances. The tumours that develop are similar to the primary tumours in man. It seems likely that carcinoma develops on a process of regenera-
primary
tion.
Stomach Prof. C. F. W. ILLINGWORTH remarked on the poor results of the treatment of carcinoma of the stomach-a disease which now causes the death of 300 people a week in the United Kingdom. The five-year survival-rate is only 2-7% in all diagnosed cases, and 12% in those who have had gastric resection. The aetiology is unknown, and tumours cannot be produced in animals by feeding carcinogens. It is unlikely that gastric ulcers lead to cancer in more than 5% of cases of ulcer. In treatment radical total gastrectomy is unsatisfactory, and partial gastrectomy is probably best. Exfoliative cytology does not add many to the cases diagnosed by other means. Routine test of the stool for occult blood may be a useful screening-test for gastric cancer.
Thyroid Dr. E. M. McGiRR said that cancer of the thyroid gland accounted for only 0-4% of deaths from malignant disease. At all ages it affects females more than males. There are three main types: (1) differentiated (papillary follicular, and Hurthlcell adenocarcinoma); (2) non-differentiated; and (3) miscellaneous. Surgery has not given very good results, and radioactive iodine is suitable for only 10% of the cases.
FREEZING AND DRYING THE second international symposium on freezing and drying was held, under the auspices of the Institute of Biology, in London on April 1 and 2. General Topics Dr. H. T. MERYMAN (U.S.A.) discussed the mechanical and biochemical changes during freezing in biological systems. He felt that a balance must be reached between rapid cooling (in which mechanical damage is maximal) and slow cooling (in which biochemical damage is maximal). The use of additives, such as glycerin, may be rendered unnecessary by uniformity in freezing and thawing. The paper by Prof. N. KALABUKHOV (U.S.S.R.) was read by Dr. A. U. Smith. It dealt with the problems of undercooling, freezing, and vitrifying whole animals. Experiments were described in which bats were undercooled to - 5 to — 7°C, and survived storage at these temperatures for periods up to several days. At —43°C the heart-rate of bats was about 8 beats a minute, compared with the normal rate of 400.
Microorganisms Dr. W. J. ScoTT (Australia) discussed the role of protective agents in storing freeze-dried bacteria. One cause of death is the intracellular reaction of carbonyl with amino groupsknown as the browning reaction. This occurs in dried preparations, and the water formed during the reaction accelerates the process. Glucose or ribose in the medium improves the viable count immediately after freeze-drying, but exerts a deleterious effect on stored organisms. Their corresponding reduction compounds (sorbitol and ribitol) give protection without
facilitating the browning reaction. Addition of aminoacids to the freezing-mixtures to compete for the carbonyl groups is another means of protection, Lysine and sodium glutamate have been found useful in this respect. Along similar lines sulphur dioxide, which reacts with ketone and aldehyde groups, exerts a protective action. Dr. R. I. N. GREAVES described some factors which influence the stability of freeze-dried cultures, with particular reference to the browning reaction. Dried cultures have been boiled to assess the effects of various drying media on their stability when stored for long periods. Glucose in the medium gives high initial survival-rates, but the dried cultures are very heatsensitive. The greatest resistance to high temperatures was found in media consisting of 5% sodium glutamate in 5% dextran solution.
Prof. D. GRIEFF (U.S.A.) talked of the effects of freezing, lowtemperature storage, and drying by vacuum sublimation on the activities of viruses and cellular particulates. Viruses showed less loss of infectivity when they were dried from the vitreous, rather than the crystalline, state. The activity of mitochondria, measured by their capacity for oxidative phosphorylation, was better retained after slow than after rapid freezing. This is possibly related to the preservation of the integrity of mitochondrial membranes. Miss B. L. BRADY described observations on the freezedrying of yeasts, which is used as an ancillary method to maintain the national collection of yeast cultures. With freezedrying little difference is noted between the survival-rates of sporing and of non-sporing cells, and between haploid and diploid organisms. There are generic differences in survivalrates. After freeze-drying no change has been noted in vitamin and aminoacid requirements of the yeasts. Grafts Commander G. W. HYATT (U.S.A.) spoke of experience in maintaining a bank of freeze-dried human cadaveric tissues for use in surgery. Skin, dura, fascia, bone, and arteries are removed aseptically from selected sites. The tissues are placed in a medium containing serum and then freeze-dried at 4°C for six weeks, at the end of which the moisture content has fallen to 2-7-3-5%. The materials are stored in sealed vessels at room temperature until needed. Bone stored for up to five years has been used successfully. .
Prof. C. G. ROB described the experience of his surgical unit with freeze-dried arterial grafts. Of the last 394 arterial reconstructions, 178 were carried out with homologous tissue transplants. Frozen arteries were used in 78 of these, and freeze-dried arteries in 100. The two types of material take equally well. The criterion of success is the absence of thrombosis, and anticoagulant drugs are an essential part of postoperative routine. Colonel F. HENAFF (France) discussed freeze-drying associated with corneal grafts. The freeze-dried corneas are undoubtedly non-viable, but both full-thickness and lamellar grafts have successfully been carried out with homologous and heterologous (dog) material. Dr. A. S. PARKES discussed the freeze-drying of viable grafts. Rat ovaries are good test material because when they are grafted they become physiologically active after a few days. Frozen ovaries retain their activity for at least two years when stored in 15% glycerin at -79°C. At this temperature viability has been maintained although the tissues are effectively dry, because their water is in the form of ice. The problems are how to remove the ice, and what to do with the residual glycerin. High concentrations of glycerin are toxic at room temperature. This is therefore an unsuitable component of freeze-drying media. An ideal protective agent would protect against freezing, be non-toxic, and sublimate with ice during the drying process. To this end, methanol has been tested on rat ovarian tissue in freezing experiments. Viable grafts have been obtained after ovaries have been kept for a few hours in methanol at -20°C.