- Email: [email protected]
ERYTHEMA MULTIFORME EXUDATIVUM
1262
is a desirable alternative to reduction and fixation if it permits early movement and ambulation, and if the artificial hip-joint withstands the stresses and strains imposed on it by these elderly
operation
patients. As things stand, elderly or decrepit patients in whom the blood-supply of the femoral head has been destroyed will probably have a smoother convalescence and better function if the dead head is removed and replaced by a suitable metallic prosthesis. But there is still no agreement on the best way of determining the viability of the Annotations NATURAL SELECTION AND FITNESS
OVER fifty years ago Galton declared that " to replace natural selection by other processes that are more merciful and not less effective, this is precisely the aim of genetics". Dr. P. B. Medawar, F.R.S., in a Darwin lecture delivered in London on May 11, confessed that we do not know enough to recommend any programme of positive eugenics. Perhaps the goal of eugenics should be modified. Superficially, man may seem a highly evolvable creature, but here, Dr. Medawar thought, lay deception, because the devices that make for population stability, such as gene diversity, inhibit changes and encourage conservatism in natural selection. In the old days the ." fitness to survive " of any given group was measured by increase in numbers, net reproductive rate, and intrinsic rate of natural increase. Today geneticists are more cautious, recognising that many of the old concepts of fitness were based on the idea that a
population was homozygous-that is, genetically uniform. It is the very lack of uniformity-the heterozygous genetic structure-that contributes most to survival value. Even breed out certain genetic defects from the race may have unforeseen disadvantages. Sickle-cell anaemia, for instance, an inherited illness with a high mortality in childhood, confers on the sufferer relative immunity to malaria, so that where malaria is endemic the prevalence of sickle-cell anaemia tends to rise. to
Of genetic polymorphism, Dr. Medawar said that it is found wherever it is sought. He instanced blood-groups, haemoglobin differences, and red-cell enzymes. Leucocyte antigenic variants had been found by the study of failure of tissue transplants. Inherited differences were also found in tissue-proteins and y-globulins. As with sicklecell anaemia, it was not known when any one variant might prove to have survival value. That " like begets like " is a fallacy, said Dr. Medawar, in a natural population: it only holds true of an inbred population. The concept has been useful in stockbreeding. With dogs, some breeds have become veritable museums of mutation, showing up the disadvantage of a homozygous population. Even in stockbreeding, where selective breeding has had some success, there has been a swing away from inbreeding, and the value of cross-breeding has become better recognised. A natural population is an evolutionary outcome, and here like does not beget like because of genetic polymorphism. A natural population as a whole may breed true, in that it may keep its genetic pool constant and maintain the same concentration of genetical
femoral head after a fracture of the femoral neck. The injection of dyes 22 or of radio-opaque material 23 into the femoral head, or the systemic injection of radioactive red blood-cells 24 have been used, but no method has yet established itself as being clearly the best. In the younger patient, direct inspection of the head, with correction and avoidance of rotation deformity, may increase the prospects of viability. 22. Price, E. R. ibid. 1962, 44B, 854. 23. Harrison, M. H. M. ibid. 1963, 44B, 858. 24. Boyd, H. B., Calandruccio, R. A. ibid. 1963, 45A, 445.
but the individuals thereof do not. Thus individual can represent the population, nor can a selection of its more spectacularly endowed creatures. This has been proved true of fruit flies, mice, and some birds, and is believed to be true of man.
polymorphism,
no one
ERYTHEMA MULTIFORME EXUDATIVUM
IN 1946 the United States Commission on Acute Respiratory Diseasesdrew attention to an association between primary atypical pneumonia and erythema multiforme exudativum; of 6 patients with the skin eruption, 3 had clinical and radiological evidence suggesting a virus pneumonia, one with a titre of cold hsemagglutinins of 1/256. About the same time, a Canadian report2 described 17 Army personnel with a mucosal
respiratory syndrome comprising conjunctivitis, stomatitis, commonly penile eruptions, and erythema multiforme ; and 14 patients also had pneumonia. It was believed that the pneumonia was due to a virus which was also responsible for the mucocutaneous lesions. Cold haemagglutinins were not raised in the few cases in which they were sought, but the lungs in 2 fatal cases revealed mononuclear-cell infiltration of bronchi and alveoli, suggesting a non-bacterial cause. Finland et al.3 studied 4 patients, 3 of whom died, with severe erythema multiforme exudativum and pneumonia, during the winter of 1942-43, when primary atypical pneumonia was particularly common in Boston. The pneumonia was thought to be viral because it did not respond to sulphonamides, because there was scattered miliary mottling in both lung fields, because cold haemagglutinins were present in titres of 1/640, 1/32, and 1/160, and also because necropsy in 2 cases demonstrated mononuclear-cell exudate in the alveoli and peribronchial and perivascular infiltration with plasma cells. At the time, supporting evidence for the viral aetiology of cold-haemagglutinin pneumonia came from Eaton et a1.4 who had isolated a filterable agent transmissible to cottonrats, hamsters, and chick embryos. Subsequent studies have shown that this Eaton agent is a pleuropneumonia organism,5 Mycoplasma pneumonia. The presence of complement-fixing antibodies to this organism has now been observed in 5 consecutive cases of erythema multiforme,6 thus providing valuable serological evidence in support of the clinical association between the respiratory and mucocutaneous syndromes observed twenty years ago. These observations may prove to be of 2etiological 1. Arch. intern. Med. 1946, 78, 687. 2. Stanyon, J. H., Warner, W. P. Canad. med. Ass. J. 1945, 53, 427. 3. Finland, M., Jolliffe, L. S., Parker, F Jr. Amer. J. Med. 1948, 4,473. 4. Eaton, M. D., Meiklejohn, G., Van Herick, W. J. exp. Med. 1944, 79, 649. 5. Marmion, B. P., Goodburn, G. M. Nature, Lond. 1961, 189, 247. 6. Ludlam, G. B., Bridges, J. B., Benn, E. C. Lancet, May 2, 1964, p. 958.
1263
significance in the Stevens-Johnson syndrome. It would splendid if sera from these previous outbreaks could now be re-examined in the light of this new information. It would often be a good idea to store sera from obscure outbreaks of disease, so that when new techniques are developed they can be used in retrospective investigation. be
ALCOHOL AND THE LIVER
FEW would deny that there is a relationship between chronic alcoholism and cirrhosis of the liver, but despite extensive study of this subject no general agreement has been reached about the fundamental biochemical derangeMost workers accept that an excessive ment. accumulation of fat in the liver cells is characteristic of the precirrhotic phase in man/ and that a similar fatty infiltration can be induced by giving alcohol to laboratory animals. An important subject of study, therefore, in the toxicology of alcohol is the mechanism which leads to this accumulation of intrahepatic fat. In a review of the metabolic effects of alcohol on the liver, Isselbacher and Greenberger,22 discuss five possible biochemical disturbances that could lead to increased fat within the liver cells.
Firstly, an increased mobilisation of fatty acids from the triglycerides of the adipose tissues could lead to their increased reformation to triglycerides within the liver. That this is an important source of the hepatic fat is supported by the positive correlation in the alcoholic fatty liver between the fat content and the level of linoleic acid, an essential unsaturated fatty acid that presumably cannot be synthesed within the liver since it must be provided in the diet. Furthermore, various procedures, such as adrenalectomy or cordotomy, known to interfere with mobilisation of fatty acids from the depots significantly antagonise the ability of alcohol to raise the fat
content
of the liver.
Secondly, both in vivo and in vitro, alcohol increases synthesis of fatty acids by liver cells. This in itself is probably not a major factor in the genesis of a fatty liver, since other substances similarly capable of stimulating fatty-acid synthesis (for example, glucose) do not lead to a comparable accumulation of intrahepatic fat. Fatty acids synthesised in vitro by liver slices in the presence of alcohol are virtually entirely of the saturated kind, whereas the pathological accumulation found in alcoholism is rich in unsaturated fat indicating the relatively greater importance of mobilisation than local production. Thirdly, inhibition of intracellular oxidation of fat could lead to its progressive increase, and observations in the
vitro have indeed shown that such intracellular oxidation is inhibited by alcohol. Nevertheless this too is probably relatively unimportant, since several substances even more inhibitory than alcohol in this respect do not lead to the development of fatty liver.
Fourthly, and almost certainly of greater importance, is the ability of alcohol to lead to the preferential incorporation of intrahepatic fatty acids into triglycerides rather than into phospholipids. The way in which this diversion is produced is unknown but could be related to the antilipotropic effect of alcohol and its antagonism by choline3
constituent of lecithin, quantitatively the most of the hepatic phospholipids. a
important
the normal release of triglyceride by the liver plasma in the form of lipoprotein could be either as a result of diminished formation of the impaired necessary protein or some interference with its passage through the cell membrane. There is little evidence to show whether these functions are impaired by alcohol, but a specific inhibitor of protein synthesis, like puromycin, is known to be an effective producer of a fatty liver.4
Finally,
into the
The known metabolic effects of alcohol on the liver are not, of course, confined to fats and fatty acids: they also include both carbohydrates and proteins as well as other metabolites. But the disturbance of fat metabolism is not only the most conspicuous change: it also seems to be the one most closely related to the subsequent development of cirrhosis. In laboratory animals, especially the rat but also the dog, the production of severe fatty infiltration by purely dietetic methods is consistently followed by the development of hepatic cirrhosis having many of the pathological features of human alcoholic cirrhosis.56The essential feature of the diets used in these experiments is a deficiency of those factors, such as choline and other sources of labile methyl groups, which are needed to prevent abnormal accumulation of fat within the liver cells. A clear antagonism between these factors and alcohol has been shown to operate in rats,3 but a similar relationship in man has yet to be shown. Even in the absence of such a direct antagonism the diet of the chronic alcoholic not infrequently approaches that used specifically for the induction of cirrhosis in laboratory animals, and it is therefore difficult to exclude a significant role for malnutrition in the genesis of human alcoholic cirrhosis. A contributory factor well known to operate with many other hepatotoxic agents is the increased sensitivity of the liver in malnutrition, especially protein malnutrition..7 The defective nutritional state of the chronic alcoholic may well enhance such hepatotoxic effects as alcohol itself seems to
have.
CARDIAC SURGERY IN AUSTRALIA
CARDIAC surgeons have had to undergo long and arduous training; yet they must be reasonably young at the peak of their working life. The units in which they work are elaborate and the equipment is expensive, and, since relatively few patients need heart operations, the units should be strategically placed. In addition, there is the need for continuing research in a rapidly expanding subject. To bring together cardiac patients, cardiac surgeons, cardiac units, and opportunities for cardiac research calls for more than the haphazard workings of the law of demand and supply: there must be some sort of plan.
Recognising this, the National Heart Foundation of Australia appointed a subcommittee in 1962 to examine the country’s present cardiac-surgery establishment and to gauge its future requirements. The result is an admirable reportwhich warrants full appraisal outside Australia.
1.
4. 5. 6.
Robinson, D. S., Seakins, A. Biochem. biophys. Acta, 1962, 62, 163. Connor, C. L. Amer. J. Path. 1938, 14, 347. Glynn, L. E., Himsworth, H. P., Lindan, O. Brit. J. exp. Path. 1948,
2.
7.
Miller, L. L., Ross, J. F., Whipple, G. H. Amer. J. med. Sci. 1940, 200, 739. Cardiovascular Surgery in Australia: A Report by the National Heart Foundation of Australia, Box 691, Canberra City, A.C.T. April, 1964.
Hartroft, W. S. in Progress in Liver Diseases (edited by H. Popper and F. Schaffner); p. 68. New York, 1961. Isselbacher, K. J., Greenberger, N. J. New Engl. J. Med. 1964, 270, 351, 402. 3. Best, C. H., Hartroft, W. S., Lucas, C. C., Ridout, J. H. Brit. med. J. 1949, ii, 1001.
29, 1. 8.
is a desirable alternative to reduction and fixation if it permits early movement and ambulation, and if the artificial hip-joint withstands the stresses and strains imposed on it by these elderly
operation
patients. As things stand, elderly or decrepit patients in whom the blood-supply of the femoral head has been destroyed will probably have a smoother convalescence and better function if the dead head is removed and replaced by a suitable metallic prosthesis. But there is still no agreement on the best way of determining the viability of the Annotations NATURAL SELECTION AND FITNESS
OVER fifty years ago Galton declared that " to replace natural selection by other processes that are more merciful and not less effective, this is precisely the aim of genetics". Dr. P. B. Medawar, F.R.S., in a Darwin lecture delivered in London on May 11, confessed that we do not know enough to recommend any programme of positive eugenics. Perhaps the goal of eugenics should be modified. Superficially, man may seem a highly evolvable creature, but here, Dr. Medawar thought, lay deception, because the devices that make for population stability, such as gene diversity, inhibit changes and encourage conservatism in natural selection. In the old days the ." fitness to survive " of any given group was measured by increase in numbers, net reproductive rate, and intrinsic rate of natural increase. Today geneticists are more cautious, recognising that many of the old concepts of fitness were based on the idea that a
population was homozygous-that is, genetically uniform. It is the very lack of uniformity-the heterozygous genetic structure-that contributes most to survival value. Even breed out certain genetic defects from the race may have unforeseen disadvantages. Sickle-cell anaemia, for instance, an inherited illness with a high mortality in childhood, confers on the sufferer relative immunity to malaria, so that where malaria is endemic the prevalence of sickle-cell anaemia tends to rise. to
Of genetic polymorphism, Dr. Medawar said that it is found wherever it is sought. He instanced blood-groups, haemoglobin differences, and red-cell enzymes. Leucocyte antigenic variants had been found by the study of failure of tissue transplants. Inherited differences were also found in tissue-proteins and y-globulins. As with sicklecell anaemia, it was not known when any one variant might prove to have survival value. That " like begets like " is a fallacy, said Dr. Medawar, in a natural population: it only holds true of an inbred population. The concept has been useful in stockbreeding. With dogs, some breeds have become veritable museums of mutation, showing up the disadvantage of a homozygous population. Even in stockbreeding, where selective breeding has had some success, there has been a swing away from inbreeding, and the value of cross-breeding has become better recognised. A natural population is an evolutionary outcome, and here like does not beget like because of genetic polymorphism. A natural population as a whole may breed true, in that it may keep its genetic pool constant and maintain the same concentration of genetical
femoral head after a fracture of the femoral neck. The injection of dyes 22 or of radio-opaque material 23 into the femoral head, or the systemic injection of radioactive red blood-cells 24 have been used, but no method has yet established itself as being clearly the best. In the younger patient, direct inspection of the head, with correction and avoidance of rotation deformity, may increase the prospects of viability. 22. Price, E. R. ibid. 1962, 44B, 854. 23. Harrison, M. H. M. ibid. 1963, 44B, 858. 24. Boyd, H. B., Calandruccio, R. A. ibid. 1963, 45A, 445.
but the individuals thereof do not. Thus individual can represent the population, nor can a selection of its more spectacularly endowed creatures. This has been proved true of fruit flies, mice, and some birds, and is believed to be true of man.
polymorphism,
no one
ERYTHEMA MULTIFORME EXUDATIVUM
IN 1946 the United States Commission on Acute Respiratory Diseasesdrew attention to an association between primary atypical pneumonia and erythema multiforme exudativum; of 6 patients with the skin eruption, 3 had clinical and radiological evidence suggesting a virus pneumonia, one with a titre of cold hsemagglutinins of 1/256. About the same time, a Canadian report2 described 17 Army personnel with a mucosal
respiratory syndrome comprising conjunctivitis, stomatitis, commonly penile eruptions, and erythema multiforme ; and 14 patients also had pneumonia. It was believed that the pneumonia was due to a virus which was also responsible for the mucocutaneous lesions. Cold haemagglutinins were not raised in the few cases in which they were sought, but the lungs in 2 fatal cases revealed mononuclear-cell infiltration of bronchi and alveoli, suggesting a non-bacterial cause. Finland et al.3 studied 4 patients, 3 of whom died, with severe erythema multiforme exudativum and pneumonia, during the winter of 1942-43, when primary atypical pneumonia was particularly common in Boston. The pneumonia was thought to be viral because it did not respond to sulphonamides, because there was scattered miliary mottling in both lung fields, because cold haemagglutinins were present in titres of 1/640, 1/32, and 1/160, and also because necropsy in 2 cases demonstrated mononuclear-cell exudate in the alveoli and peribronchial and perivascular infiltration with plasma cells. At the time, supporting evidence for the viral aetiology of cold-haemagglutinin pneumonia came from Eaton et a1.4 who had isolated a filterable agent transmissible to cottonrats, hamsters, and chick embryos. Subsequent studies have shown that this Eaton agent is a pleuropneumonia organism,5 Mycoplasma pneumonia. The presence of complement-fixing antibodies to this organism has now been observed in 5 consecutive cases of erythema multiforme,6 thus providing valuable serological evidence in support of the clinical association between the respiratory and mucocutaneous syndromes observed twenty years ago. These observations may prove to be of 2etiological 1. Arch. intern. Med. 1946, 78, 687. 2. Stanyon, J. H., Warner, W. P. Canad. med. Ass. J. 1945, 53, 427. 3. Finland, M., Jolliffe, L. S., Parker, F Jr. Amer. J. Med. 1948, 4,473. 4. Eaton, M. D., Meiklejohn, G., Van Herick, W. J. exp. Med. 1944, 79, 649. 5. Marmion, B. P., Goodburn, G. M. Nature, Lond. 1961, 189, 247. 6. Ludlam, G. B., Bridges, J. B., Benn, E. C. Lancet, May 2, 1964, p. 958.
1263
significance in the Stevens-Johnson syndrome. It would splendid if sera from these previous outbreaks could now be re-examined in the light of this new information. It would often be a good idea to store sera from obscure outbreaks of disease, so that when new techniques are developed they can be used in retrospective investigation. be
ALCOHOL AND THE LIVER
FEW would deny that there is a relationship between chronic alcoholism and cirrhosis of the liver, but despite extensive study of this subject no general agreement has been reached about the fundamental biochemical derangeMost workers accept that an excessive ment. accumulation of fat in the liver cells is characteristic of the precirrhotic phase in man/ and that a similar fatty infiltration can be induced by giving alcohol to laboratory animals. An important subject of study, therefore, in the toxicology of alcohol is the mechanism which leads to this accumulation of intrahepatic fat. In a review of the metabolic effects of alcohol on the liver, Isselbacher and Greenberger,22 discuss five possible biochemical disturbances that could lead to increased fat within the liver cells.
Firstly, an increased mobilisation of fatty acids from the triglycerides of the adipose tissues could lead to their increased reformation to triglycerides within the liver. That this is an important source of the hepatic fat is supported by the positive correlation in the alcoholic fatty liver between the fat content and the level of linoleic acid, an essential unsaturated fatty acid that presumably cannot be synthesed within the liver since it must be provided in the diet. Furthermore, various procedures, such as adrenalectomy or cordotomy, known to interfere with mobilisation of fatty acids from the depots significantly antagonise the ability of alcohol to raise the fat
content
of the liver.
Secondly, both in vivo and in vitro, alcohol increases synthesis of fatty acids by liver cells. This in itself is probably not a major factor in the genesis of a fatty liver, since other substances similarly capable of stimulating fatty-acid synthesis (for example, glucose) do not lead to a comparable accumulation of intrahepatic fat. Fatty acids synthesised in vitro by liver slices in the presence of alcohol are virtually entirely of the saturated kind, whereas the pathological accumulation found in alcoholism is rich in unsaturated fat indicating the relatively greater importance of mobilisation than local production. Thirdly, inhibition of intracellular oxidation of fat could lead to its progressive increase, and observations in the
vitro have indeed shown that such intracellular oxidation is inhibited by alcohol. Nevertheless this too is probably relatively unimportant, since several substances even more inhibitory than alcohol in this respect do not lead to the development of fatty liver.
Fourthly, and almost certainly of greater importance, is the ability of alcohol to lead to the preferential incorporation of intrahepatic fatty acids into triglycerides rather than into phospholipids. The way in which this diversion is produced is unknown but could be related to the antilipotropic effect of alcohol and its antagonism by choline3
constituent of lecithin, quantitatively the most of the hepatic phospholipids. a
important
the normal release of triglyceride by the liver plasma in the form of lipoprotein could be either as a result of diminished formation of the impaired necessary protein or some interference with its passage through the cell membrane. There is little evidence to show whether these functions are impaired by alcohol, but a specific inhibitor of protein synthesis, like puromycin, is known to be an effective producer of a fatty liver.4
Finally,
into the
The known metabolic effects of alcohol on the liver are not, of course, confined to fats and fatty acids: they also include both carbohydrates and proteins as well as other metabolites. But the disturbance of fat metabolism is not only the most conspicuous change: it also seems to be the one most closely related to the subsequent development of cirrhosis. In laboratory animals, especially the rat but also the dog, the production of severe fatty infiltration by purely dietetic methods is consistently followed by the development of hepatic cirrhosis having many of the pathological features of human alcoholic cirrhosis.56The essential feature of the diets used in these experiments is a deficiency of those factors, such as choline and other sources of labile methyl groups, which are needed to prevent abnormal accumulation of fat within the liver cells. A clear antagonism between these factors and alcohol has been shown to operate in rats,3 but a similar relationship in man has yet to be shown. Even in the absence of such a direct antagonism the diet of the chronic alcoholic not infrequently approaches that used specifically for the induction of cirrhosis in laboratory animals, and it is therefore difficult to exclude a significant role for malnutrition in the genesis of human alcoholic cirrhosis. A contributory factor well known to operate with many other hepatotoxic agents is the increased sensitivity of the liver in malnutrition, especially protein malnutrition..7 The defective nutritional state of the chronic alcoholic may well enhance such hepatotoxic effects as alcohol itself seems to
have.
CARDIAC SURGERY IN AUSTRALIA
CARDIAC surgeons have had to undergo long and arduous training; yet they must be reasonably young at the peak of their working life. The units in which they work are elaborate and the equipment is expensive, and, since relatively few patients need heart operations, the units should be strategically placed. In addition, there is the need for continuing research in a rapidly expanding subject. To bring together cardiac patients, cardiac surgeons, cardiac units, and opportunities for cardiac research calls for more than the haphazard workings of the law of demand and supply: there must be some sort of plan.
Recognising this, the National Heart Foundation of Australia appointed a subcommittee in 1962 to examine the country’s present cardiac-surgery establishment and to gauge its future requirements. The result is an admirable reportwhich warrants full appraisal outside Australia.
1.
4. 5. 6.
Robinson, D. S., Seakins, A. Biochem. biophys. Acta, 1962, 62, 163. Connor, C. L. Amer. J. Path. 1938, 14, 347. Glynn, L. E., Himsworth, H. P., Lindan, O. Brit. J. exp. Path. 1948,
2.
7.
Miller, L. L., Ross, J. F., Whipple, G. H. Amer. J. med. Sci. 1940, 200, 739. Cardiovascular Surgery in Australia: A Report by the National Heart Foundation of Australia, Box 691, Canberra City, A.C.T. April, 1964.
Hartroft, W. S. in Progress in Liver Diseases (edited by H. Popper and F. Schaffner); p. 68. New York, 1961. Isselbacher, K. J., Greenberger, N. J. New Engl. J. Med. 1964, 270, 351, 402. 3. Best, C. H., Hartroft, W. S., Lucas, C. C., Ridout, J. H. Brit. med. J. 1949, ii, 1001.
29, 1. 8.