- Email: [email protected]
G.M.C. CENTENARY
1217
outbreaks-for
that due to meat in Essex in 1946 or the milk-borne outbreak in Somerset in 19521112seems pretty clear, but that the most careful investigation fails to reveal the source of the far more numerous minor outbreaks or sporadic individual infections. We know that some infections are derived from meat products, and notably from those which contain pig meat. We know, too, that the mesenteric glands of pigs have been found to be infected on many occasions and in Investigations here have, however, many countries. a lower incidence of infection in pigs than that shown found twenty years ago. Sampling of made-up meat products might usefully be pursued further. Pig meat eaten in this country amounts to many thousands of tons annually; but probably not more than 5 lb. is cultured for salmonella:. Meat is not milk, and our ideas of sampling may be misconceived: there is no evidence that the salmonelloc are distributed evenly through a yard of salami. We know that bakers use large amounts of imported egg (dried or frozen), some of which teems with Salmonella spp. When reconstituted it is sticky and likely to pollute everything and everybody in the bakehouse. Has there been any extensive search for salmonellx in bakery workers ? If this is a dangerous source of infection there are no reasons (except trouble and cost) why this substitute for fresh eggs should not always be pasteurised: already it often is. Bone meal and fish meal of exotic origin have been shown to contain not only the everyday species of Salmonella but many rare and curious ones never seen before in this country. Both these substances are compounded in animal feedingstuffs to produce a flora which is sometimes quite alarming. Were all these species of Salmonella as pathogenic as our native strains we must surely have seen an appalling murrain in our flocks and herds. ROHDE and BISCHOFF 13 have demonstrated that, while these foreign species may be recovered from the fxces and organs of the animals to which they have been fed, they do not seem to cause obvious disease. The absence of disease may be associated with lack of exuberant bacterial multiplication. Nevertheless this imported animal matter is beyond much doubt the ultimate origin of some of the rarer species of Salmonella now found in Englandthough the route by which they infect man can be only
example,
guessed. About the dose of salmonellae necessary to cause disease we know almost nothing. It seems, however, that the infective dose for man of S. typhi is small compared with that of S. typhimurium, and possibly this in turn is much less than that of S. charity or chittagong. We know that not all species of Salmonella are equally infective for all species of animals. It is tempting to classify the genus into three groups. There are those, such as S. typhi or S. pullorum, which are specialised parasites of one species of animal: their infective dose is small and their virulence high. S. typhimurium is the type species of the second group, which includes most of those found commonly in animals and man: some11. Camps, F. E. ibid. 1947, 6, 89. 12. McCall, A. M. Lancet, 1953, i, 1302. 13. Rohde, R., Bischoff, J. Zbl. Bakt. Abt.
I, 1956, 159,
145.
for instance, S. thompson and S. cholerae-suis-seem to have a preference for one host but can cause disease in many others. Different strains of a single species in this group may differ widely in virulence, but as a whole they seldom cause the septicaemic kind of infection common in the first group. The second group shades off indefinitely into the catalogue of romantic names in the Kauffman-White table which represent species of Salmonella found only once or very seldom. Since the published accounts of their discovery often omit the essential information, it is not easy to determine how many of these may cause disease, but at least some have been found only in reptiles or in the bowels of apparently healthy humans. Perhaps for reasons of geography they have not yet run riot under the eyes of the epidemiological laboratory. Perhaps they have been introduced to this country but have not established themselves, for reasons which we do not know; or perhaps they really prefer a saprophytic life in the bowel of a serpent on the banks of the Congo. As long as these and many other questions remain unanswered it would be foolish to suggest that any administrative acts will bring foodpoisoning to an end.
Annotations G.M.C. CENTENARY
meeting of the General Medical Council was held at the Royal College of Physicians of London on Nov. 23, 1858, under the presidency of Sir Benjamin Brodie. The centenary was marked by a dinner at the Mansion House on Nov. 27, when Sir David Campbell, the twelfth president, responding to a toast by the Lord Mayor, reviewed the state of the profession before and THE first
since the enforcement of the Medical Act of 1858. In the first half of the 19th century the profession was in a state approaching chaos: it had no cohesion; it was torn by jealousies and competing interests; and some of its members were half educated-in 1841 more than a third of the practitioners were unqualified. Simon, in 1858, painted an astonishing picture. Titles to practise were obtainable from twenty-one sources-including the Archbishop of Canterbury. There was irresponsible competition between licensing bodies, which had exclusive territorial powers in granting the right to practise: for instance, graduates of London University laid themselves open to prosecution by the Royal College of Physicians. There were several pharmacopoeias with no standard. For help, later, in devising the British Pharmacopaeia the Council was greatly indebted to the pharmaceutical
profession. the first statutory tribunal of a registered profession required to exercise quasijudicial functions; and overseas too, Sir David said, the Council had exercised a helpful influence in setting standards. (Earlier in the day, as we report on p. 1222, he had welcomed to the Council’s centenary session representatives of Commonwealth countries and of Burma.) At home it had helped to create the profession of dentistry, which long remained in its purview; but lately the General Dental Council had been established as the mirror-image of the G.M.C. The G.M.C.
was
1218
Under the first Medical Act the Council’s powers were indicated rather than defined; but, though these powers were scanty, great things had been achieved in the century. Referring to earlier leaders in the Council, including Brodie, Sir "Donald MacAlister, and Sir We are their debtors for their Herbert Eason, he said: ideal and their example." Lord Cohen of Birkenhead observed that, through the G.M.C., the Governments of Great Britain, Northern Ireland, and Eire met for a common purpose. Reciprocity in registration and temporary registration was one of the most abiding links of friendship with the Commonwealth. The history and present work of the Council are related in booklet by the Registrar, Mr. Walter Pyke-Lees (Centenary of the General Medical Council, 1858-1958). a
SEX AND AGE DIFFERENCES IN RADIATION-INDUCED MUTATION-RATES
A RATHER unexpected finding of the recent surveys of man’s exposure to artificial radiation was that the main Such radiation was source was clinical radiography. a much more important source of exposure of the gonads, in countries where X rays were much used medically, than, at any rate, the external radiation from atomic and thermonuclear devices so far exploded. Efforts, therefore, are now being made to reduce gonad exposure to medical X rays. For these efforts to be well directed it is important to know whether it is men or women who particularly need protection-by, for example, such devices as the ’Armadillo ’, recently described in our columns 1-and to know whether mutation is particularly likely after exposure in foetal, child, or adult life. Experiments in animals and plants show that radiationinduced mutation-rates may vary greatly, not only between male and female but also between different stages in the maturation of the germ cells in the same sex. In man there is no evidence yet on radiation-induced mutationrates, and no evidence even about spontaneous mutationrates for each sex separately. Haldane 2 has pointed out that the family patterns for conditions due to sex-linked mutations may provide evidence on the relative rates of spontaneous mutations; but no conclusive differences have yet been found by this method. Spontaneous mutationrates, too, are of only limited value in estimating the relative rates of radiation-induced mutation, since much, perhaps most, spontaneous mutation is not due to background mutation. Accordingly, Carter3 has designed and performed experiments on radiation-induced mutation-rates by sex and age in the mouse, the most suitable mammal for studies of this kind. In mammals the germ plasm in females is present in oogonia in foetal life, and mainly in oocytes in postnatal life. In males the germ plasm is present in spermatogonia in foetal life, and also in spermatogonia for most of postnatal life, the stages of spermatocyte and spermatozoon lasting, perhaps, only about a year. In mice the mutationrates for a number of gene-loci have already been established for adult males in America by Russell. Using Russell’s strains of mice, Carter looked for mutations in the offspring of irradiated foetal male mice and adult female mice. With the foetal male mice he was able to follow Russell’s method closely, using high-voltage X rays for a short period, though to avoid foetal damage the total 1. Tanner, J. 2. 3.
M., Whitehouse, R. H., Powell, J. H. Lancet, Oct. 11, 1958, p. 779. Haldane, J. B. S. Ann. Eugen. 1947, 13, 262. Carter, T. C. Brit. J. Radiol. 1958, 31, 407.
dose was 300 and not 600 rads. This technique was useless in adult females, since they were largely sterilised; so he used the same total dosage of 600 rads, but gave it by gamma-radiation over seven weeks. There is no reason to suppose that the lower dosage to the foetal male mice would affect a comparison with Russell’s findings. The comparability of the effects of X-radiation in a little over an hour with the same dose as gamma-radiation over some weeks is uncertain, but may well be valid. Carter’s findings were surprising. With a little over 10,000 offspring in each group he would have expected, if Russell’s findings on adult males applied, between 11 and 12 mutations in the offspring of the irradiated adult females, and 6 in those of the irradiated foetal males. In fact, only 1 mutation was recognised in each group. It is clear that these results need repeating with, if possible, different mammals and different techniques of irradiation. In particular, the question of the comparability of the same dose given at a high rate over a short period, and at a low rate over a long period, needs further investigation, But Carter’s findings already suggest that it is the postnatal male who particularly needs protection from irradiation of the gonads during radiography. It will be fortunate if this proves to be the case, since it is just this group that is most easily protected. THE PROPERDIN SYSTEM
SPECIFIC antigen-antibody reactions are not the only system of immunity in the body. A globulin fraction has been demonstrated in human serum which contributes to the destruction of bacteria of the shigella group, abnormal red blood-cells, and the inhibition of certain viruses.’ Properdin is a p-euglobulin with a high molecular weight; it represents no more than 0-03% of total serum-proteins, It is active only in a system which invokes complement and magnesium ions, and differs from the usual antigenantibody system in its lack of specificity and its ability to inactivate the C’3 component of complement-a component only partly affected by antigen-antibody reactions. This provides the basis for properdin assay: zymosan, consisting of purified cell walls obtained after tryptic digestion of yeast, forms an insoluble polysaccharide complex with properdin, which may thus be removed from serum; a unit of properdin is defined as the smallest amount then required to reduce the C’3 titre in properdindeficient serum from 120 to 0 units.2 The importance of the properdin system lies in its lack of specificity and therefore wide range of defence. Besides shigella, some strains of salmonella, pseudomonas, proteus,1 paracolon bacilli, and escherichia are properdin-sensitive,3! A relationship has been shown between survival and properdin levels in mice infected with Esch. coli and Friedlander’s bacillus; moreover intravenous administration of properdin altered the course of the infection.4 Rowley’5 has injected mice with cell walls prepared from Esch. coli and demonstrated that the animals then die after being infected by as few as 5 Esch. coli, whereas as many as 10,000 organisms may be needed to kill normal animals. This suggests that bacterial cell walls remove properdin just as zymosan does, the corollary being that the properdin system protects by combining with such substances. 1. Pillemer, L., Blum, L., Lepow, I. H., Ross, O. A., Todd, E. W., Wardlaw, A. C. Science, 1954, 120, 279. 2. Pillemer, L., Blum, L., Lepow, I. H., Wurz., L., Todd, E. W. J. Med. 1956, 103, 1. 3. Wardlaw, A. C., Pillemer, L. ibid. p. 553. 4. Pillemer, L. Trans. N. Y. Acad. Sci. 1955, 17, 526. 5. Rowley, D. Lancet, 1955, i, 233.
outbreaks-for
that due to meat in Essex in 1946 or the milk-borne outbreak in Somerset in 19521112seems pretty clear, but that the most careful investigation fails to reveal the source of the far more numerous minor outbreaks or sporadic individual infections. We know that some infections are derived from meat products, and notably from those which contain pig meat. We know, too, that the mesenteric glands of pigs have been found to be infected on many occasions and in Investigations here have, however, many countries. a lower incidence of infection in pigs than that shown found twenty years ago. Sampling of made-up meat products might usefully be pursued further. Pig meat eaten in this country amounts to many thousands of tons annually; but probably not more than 5 lb. is cultured for salmonella:. Meat is not milk, and our ideas of sampling may be misconceived: there is no evidence that the salmonelloc are distributed evenly through a yard of salami. We know that bakers use large amounts of imported egg (dried or frozen), some of which teems with Salmonella spp. When reconstituted it is sticky and likely to pollute everything and everybody in the bakehouse. Has there been any extensive search for salmonellx in bakery workers ? If this is a dangerous source of infection there are no reasons (except trouble and cost) why this substitute for fresh eggs should not always be pasteurised: already it often is. Bone meal and fish meal of exotic origin have been shown to contain not only the everyday species of Salmonella but many rare and curious ones never seen before in this country. Both these substances are compounded in animal feedingstuffs to produce a flora which is sometimes quite alarming. Were all these species of Salmonella as pathogenic as our native strains we must surely have seen an appalling murrain in our flocks and herds. ROHDE and BISCHOFF 13 have demonstrated that, while these foreign species may be recovered from the fxces and organs of the animals to which they have been fed, they do not seem to cause obvious disease. The absence of disease may be associated with lack of exuberant bacterial multiplication. Nevertheless this imported animal matter is beyond much doubt the ultimate origin of some of the rarer species of Salmonella now found in Englandthough the route by which they infect man can be only
example,
guessed. About the dose of salmonellae necessary to cause disease we know almost nothing. It seems, however, that the infective dose for man of S. typhi is small compared with that of S. typhimurium, and possibly this in turn is much less than that of S. charity or chittagong. We know that not all species of Salmonella are equally infective for all species of animals. It is tempting to classify the genus into three groups. There are those, such as S. typhi or S. pullorum, which are specialised parasites of one species of animal: their infective dose is small and their virulence high. S. typhimurium is the type species of the second group, which includes most of those found commonly in animals and man: some11. Camps, F. E. ibid. 1947, 6, 89. 12. McCall, A. M. Lancet, 1953, i, 1302. 13. Rohde, R., Bischoff, J. Zbl. Bakt. Abt.
I, 1956, 159,
145.
for instance, S. thompson and S. cholerae-suis-seem to have a preference for one host but can cause disease in many others. Different strains of a single species in this group may differ widely in virulence, but as a whole they seldom cause the septicaemic kind of infection common in the first group. The second group shades off indefinitely into the catalogue of romantic names in the Kauffman-White table which represent species of Salmonella found only once or very seldom. Since the published accounts of their discovery often omit the essential information, it is not easy to determine how many of these may cause disease, but at least some have been found only in reptiles or in the bowels of apparently healthy humans. Perhaps for reasons of geography they have not yet run riot under the eyes of the epidemiological laboratory. Perhaps they have been introduced to this country but have not established themselves, for reasons which we do not know; or perhaps they really prefer a saprophytic life in the bowel of a serpent on the banks of the Congo. As long as these and many other questions remain unanswered it would be foolish to suggest that any administrative acts will bring foodpoisoning to an end.
Annotations G.M.C. CENTENARY
meeting of the General Medical Council was held at the Royal College of Physicians of London on Nov. 23, 1858, under the presidency of Sir Benjamin Brodie. The centenary was marked by a dinner at the Mansion House on Nov. 27, when Sir David Campbell, the twelfth president, responding to a toast by the Lord Mayor, reviewed the state of the profession before and THE first
since the enforcement of the Medical Act of 1858. In the first half of the 19th century the profession was in a state approaching chaos: it had no cohesion; it was torn by jealousies and competing interests; and some of its members were half educated-in 1841 more than a third of the practitioners were unqualified. Simon, in 1858, painted an astonishing picture. Titles to practise were obtainable from twenty-one sources-including the Archbishop of Canterbury. There was irresponsible competition between licensing bodies, which had exclusive territorial powers in granting the right to practise: for instance, graduates of London University laid themselves open to prosecution by the Royal College of Physicians. There were several pharmacopoeias with no standard. For help, later, in devising the British Pharmacopaeia the Council was greatly indebted to the pharmaceutical
profession. the first statutory tribunal of a registered profession required to exercise quasijudicial functions; and overseas too, Sir David said, the Council had exercised a helpful influence in setting standards. (Earlier in the day, as we report on p. 1222, he had welcomed to the Council’s centenary session representatives of Commonwealth countries and of Burma.) At home it had helped to create the profession of dentistry, which long remained in its purview; but lately the General Dental Council had been established as the mirror-image of the G.M.C. The G.M.C.
was
1218
Under the first Medical Act the Council’s powers were indicated rather than defined; but, though these powers were scanty, great things had been achieved in the century. Referring to earlier leaders in the Council, including Brodie, Sir "Donald MacAlister, and Sir We are their debtors for their Herbert Eason, he said: ideal and their example." Lord Cohen of Birkenhead observed that, through the G.M.C., the Governments of Great Britain, Northern Ireland, and Eire met for a common purpose. Reciprocity in registration and temporary registration was one of the most abiding links of friendship with the Commonwealth. The history and present work of the Council are related in booklet by the Registrar, Mr. Walter Pyke-Lees (Centenary of the General Medical Council, 1858-1958). a
SEX AND AGE DIFFERENCES IN RADIATION-INDUCED MUTATION-RATES
A RATHER unexpected finding of the recent surveys of man’s exposure to artificial radiation was that the main Such radiation was source was clinical radiography. a much more important source of exposure of the gonads, in countries where X rays were much used medically, than, at any rate, the external radiation from atomic and thermonuclear devices so far exploded. Efforts, therefore, are now being made to reduce gonad exposure to medical X rays. For these efforts to be well directed it is important to know whether it is men or women who particularly need protection-by, for example, such devices as the ’Armadillo ’, recently described in our columns 1-and to know whether mutation is particularly likely after exposure in foetal, child, or adult life. Experiments in animals and plants show that radiationinduced mutation-rates may vary greatly, not only between male and female but also between different stages in the maturation of the germ cells in the same sex. In man there is no evidence yet on radiation-induced mutationrates, and no evidence even about spontaneous mutationrates for each sex separately. Haldane 2 has pointed out that the family patterns for conditions due to sex-linked mutations may provide evidence on the relative rates of spontaneous mutations; but no conclusive differences have yet been found by this method. Spontaneous mutationrates, too, are of only limited value in estimating the relative rates of radiation-induced mutation, since much, perhaps most, spontaneous mutation is not due to background mutation. Accordingly, Carter3 has designed and performed experiments on radiation-induced mutation-rates by sex and age in the mouse, the most suitable mammal for studies of this kind. In mammals the germ plasm in females is present in oogonia in foetal life, and mainly in oocytes in postnatal life. In males the germ plasm is present in spermatogonia in foetal life, and also in spermatogonia for most of postnatal life, the stages of spermatocyte and spermatozoon lasting, perhaps, only about a year. In mice the mutationrates for a number of gene-loci have already been established for adult males in America by Russell. Using Russell’s strains of mice, Carter looked for mutations in the offspring of irradiated foetal male mice and adult female mice. With the foetal male mice he was able to follow Russell’s method closely, using high-voltage X rays for a short period, though to avoid foetal damage the total 1. Tanner, J. 2. 3.
M., Whitehouse, R. H., Powell, J. H. Lancet, Oct. 11, 1958, p. 779. Haldane, J. B. S. Ann. Eugen. 1947, 13, 262. Carter, T. C. Brit. J. Radiol. 1958, 31, 407.
dose was 300 and not 600 rads. This technique was useless in adult females, since they were largely sterilised; so he used the same total dosage of 600 rads, but gave it by gamma-radiation over seven weeks. There is no reason to suppose that the lower dosage to the foetal male mice would affect a comparison with Russell’s findings. The comparability of the effects of X-radiation in a little over an hour with the same dose as gamma-radiation over some weeks is uncertain, but may well be valid. Carter’s findings were surprising. With a little over 10,000 offspring in each group he would have expected, if Russell’s findings on adult males applied, between 11 and 12 mutations in the offspring of the irradiated adult females, and 6 in those of the irradiated foetal males. In fact, only 1 mutation was recognised in each group. It is clear that these results need repeating with, if possible, different mammals and different techniques of irradiation. In particular, the question of the comparability of the same dose given at a high rate over a short period, and at a low rate over a long period, needs further investigation, But Carter’s findings already suggest that it is the postnatal male who particularly needs protection from irradiation of the gonads during radiography. It will be fortunate if this proves to be the case, since it is just this group that is most easily protected. THE PROPERDIN SYSTEM
SPECIFIC antigen-antibody reactions are not the only system of immunity in the body. A globulin fraction has been demonstrated in human serum which contributes to the destruction of bacteria of the shigella group, abnormal red blood-cells, and the inhibition of certain viruses.’ Properdin is a p-euglobulin with a high molecular weight; it represents no more than 0-03% of total serum-proteins, It is active only in a system which invokes complement and magnesium ions, and differs from the usual antigenantibody system in its lack of specificity and its ability to inactivate the C’3 component of complement-a component only partly affected by antigen-antibody reactions. This provides the basis for properdin assay: zymosan, consisting of purified cell walls obtained after tryptic digestion of yeast, forms an insoluble polysaccharide complex with properdin, which may thus be removed from serum; a unit of properdin is defined as the smallest amount then required to reduce the C’3 titre in properdindeficient serum from 120 to 0 units.2 The importance of the properdin system lies in its lack of specificity and therefore wide range of defence. Besides shigella, some strains of salmonella, pseudomonas, proteus,1 paracolon bacilli, and escherichia are properdin-sensitive,3! A relationship has been shown between survival and properdin levels in mice infected with Esch. coli and Friedlander’s bacillus; moreover intravenous administration of properdin altered the course of the infection.4 Rowley’5 has injected mice with cell walls prepared from Esch. coli and demonstrated that the animals then die after being infected by as few as 5 Esch. coli, whereas as many as 10,000 organisms may be needed to kill normal animals. This suggests that bacterial cell walls remove properdin just as zymosan does, the corollary being that the properdin system protects by combining with such substances. 1. Pillemer, L., Blum, L., Lepow, I. H., Ross, O. A., Todd, E. W., Wardlaw, A. C. Science, 1954, 120, 279. 2. Pillemer, L., Blum, L., Lepow, I. H., Wurz., L., Todd, E. W. J. Med. 1956, 103, 1. 3. Wardlaw, A. C., Pillemer, L. ibid. p. 553. 4. Pillemer, L. Trans. N. Y. Acad. Sci. 1955, 17, 526. 5. Rowley, D. Lancet, 1955, i, 233.