- Email: [email protected]
COMPARATIVE STUDIES OF CEREBRAL ATHEROSCLEROSIS
1409
have taken great pains to consider the possible effects of misclassification before reaching this conclusion. This raises the question: is yersinia arthritis indeed a new disease, or has its relative importance waxed only because the absolute importance of rheumatic fever has waned ? This is not the popular view, but time will tell; it is only when the tide goes out that the rocks appear, and, like that of acute rheumatic fever, the tide of tuberculous mesenteric lymphadenitis (which is clinically similar to yersinia infection in young people) has also ebbed.
they
As yet there seems no reason to believe that yersinia arthritis has the same grave cardiac sequelx as acute rheumatic fever, although electrocardiographic changes have been described in 5 adults of a series of 25 cases.26 SIEVERS and HALL have, however, been able to follow up 46 of 60 cases of acute rheumatic fever with a mean time-lag between onset of the disease and last examination of 8-7 years, ranging from a minimum of 3-4 to a maximum of 12-3 years. It is well known that the incidence of overt valvular disease depends on the length of follow-up,31 and they recognise this; but the incidence of rheumatic heart-disease among the cases they examined is only 8%, and they point out that this is lower than the rates predicted by HALL in his earlier investigation.22 This leads them to the tentative conclusion " that the decrease in the incidence of rheumatic heart disease is even more pronounced than that of rheumatic fever "-a hopeful one, especially since HALL 22 could find no evidence of a decrease in the incidence of rheumatic heart-disease before 1950.
acute
THE C.C.C.R.—FOUNT OR SUMP?
THE Co-ordinating Committee for Cancer Research (C.C.C.R.) has produced a statement of its first year’s work. 3The formation of the committee, and the fact that representatives of the three principal bodies that sponsor cancer research in Britain meet together to discuss what each is doing and should do, was an important, welcome, and long overdue development. During the first year the committee was mainly concerned with chemotherapy. Here one of the major difficulties is the provision of facilities for the testing and evaluation of new drugs. The organisation of the clinical assessment of cancer chemotherapeutic agents in Britain is less haphazard than it was, but the C.C.C.R. favours the setting up of " oncological centres ", because this would facilitate the planning and execution of clinical trials of new drugs and new treatment regimens. Few would disagree with the
view of the committee that no attempt should be made in the U.K. to duplicate chemotherapy research already being conducted on a large scale in the U.S.A. 31. Bland, E. F., Jones, T. D. Ann. intern. Med. 1952, 37, 1006. 32. Joint Cancer Research Campaign/Imperial Cancer Research Fund/ Medical Research Council Co-ordinating Committee for Cancer Research—Statement on First Year’s Work.
The report on an assessment of the work of Dr. Josef Issels 33 required much time and effort by the C.C.C.R., but the wisdom and humanity expressed in that report give it a general and lasting value that goes far beyond the appraisal of particular forms of treatment practised in the Ringberg Clinic in Bavaria. Most of the rest of the report on the first year’s work consists of rather general statements under headings such as recent advances, prevention of cancer, and improvements from better use of existing knowledge, which could have been written by anyone reasonably well versed in cancer research; it is to be hoped that the committee did not spend much of its time agreeing these parts of its statement. Planning research on a proper scale, preventing duplication, and coordinating parallel approaches are clearly necessary in the overall organisation of cancer research, but the efforts of the C.C.C.R. must not for ever be confined to the better organisation of what is already going on. Scattered throughout the hospitals, medical schools, and universities are a handful of brilliant young men and women with two precious commodities-ideas and energy. These need to become the founts of energy on which the whole future organisational structure of cancer research depends. There is a distinct danger that with the present emphasis on broad planning and on thinking big, these sources of energy will be lost sight of. Surely, the most urgent task before the C.C.C.R. is not simply to plod its way through the rational organisation of wellestablished areas of cancer research but to evolve new and better ways of ensuring that the best use is made of the energy and originality of young scientists. What can be done to attract first-class brains into cancer research ? What are the career prospects for such men ? Should cancer research continue to be largely an area in which doctors and scientists just dabble for a few years as they ascend the career ladders of pathology, Is the organisational surgery, or biochemistry ? structure of universities inappropriately rigid in relation to the organisation of research in such a multidisciplinary exercise ? If the C.C.C.R. can make better use of the manpower supported by cancer funds it might itself come to be regarded as a fount. If it does nothing more than support and protect established lines of research, it will be nothing more than a central sump into which good ideas drain and are lost.
COMPARATIVE STUDIES OF CEREBRAL ATHEROSCLEROSIS
ATHEROSCLEROSIS of the aorta and of the coronary arteries, in their severity and complications, have been subjected to many comparative studies among different populations, and great differences have been demonstrated. Thus, coronary heart-disease has been shown to be relatively uncommon in Africans, in contrast to its frequency and severity in many Caucasian groups. 3,1 But cerebral arteriosclerotic vascular disease 33. A report
on
the treatment of cancer
at
the
Egern, Bavaria. H.M. Stationery Office, 34. Williams, A. O. J. Path. 1969, 99, 219.
Ringberg-Clinic, Rottach 1971.
1410 TALKING TURKEY
and the resulting complications have been much less closely examined. While the South African Bantu 35,36 seemed to have less coronary and aortic arteriosclerosis, thus producing little clinical disease compared with their White compatriots, the Bantu cerebral vessels seemed to be equally affected by arteriosclerosis, and in the Bantu cerebrovascular occlusive disease was far commoner than coronary occlusive disease. But when the degree of cerebral arteriosclerosis in Nigerians was compared with that of Minnesotans and with Negro and White residents in Alabama, distinct differences
ANY effective treatment for psoriasis should be welcomed, particularly when it does not involve use of the messy ointments which patients find so hard to tolerate. For this reason, the preliminary report by
Spiera and Lefkovits1 of their success with a diet thought to be low in tryptophan was of great interest, and was given publicity in the lay Press. The diet was based on turkey meat as the main source of protein. New treatments for psoriasis, however, must be properly evaluated before they are generally adopted. If even a small proportion of the 2-3% of the population who have psoriasis switched to turkey meat, there would be important economic consequences. Unfortunately, it is notoriously difficult to assess any treatment in psoriasis: the disease is liable to remit spontaneously ; many believe that admission to hospital alone will cause improvement; the effects of local and other systemic therapy must be disentangled from those of the treatment under trial; obvious enthusiasm may speed recovery; and improvement is not easy to measure objectively. Understandably, in the original paper, describing successful treatment of four patients, some of these points were not adequately controlled.
emerged. 34,37,38 In persons from all these communities cerebral It arteriosclerosis showed some similar features. started early in life and increased in extent and severity with age; young males were affected earlier and more severely than females. But at every age the prevalence, extent, and severity of the arteriosclerotic lesions was distinctly less in the Nigerians. Whereas no differences could be detected between the Minnesotans or the Negroes or Whites in Alabama, there were distinct differences between the Alabama Negroes and the
Nigerians. 38 These findings are based on careful comparisons in which the pitfalls in studying necropsy materials have been avoided and the difficulties of measuring atherosclerosis and drawing valid comparisons have been The material studied was certainly surmounted. amount. The results, while directly at in adequate variance with the South African findings, are consistent with earlier comparative studies of atherosclerosis, coronary-artery disease, and venous thrombosis and embolism between Africans and White and Negro citizens of the United States. 39 The U.S. Negro is far closer to the White American in the prevalence and severity of these cardiovascular diseases than he is to the people living in his ancestral homelands. In Nigeria, lesions secondary to cerebral atherosclerosis are relatively rare, as are lesions secondary to coronary atherosclerosis, but while the second point is true of the Bantu, in these peoples the severity and complications of cerebral atherosclerosis are much more evident. Thus, it seems that even in Africa there is a gradation in this respect in the indigenous population as striking as the one between African groups in Africa and in other continents. How far the
differences in
physical and cultural characteristics, dietary habits, genetic constitution, and way of life these differences is unknown. 34 It seems detectable differences in the bloodclotting mechanisms, though perhaps there are in the mechanisms of clot lysis. Hypertension is common in all groups. While blood-cholesterol levels are generally much lower in Africans, it is as hard as ever to see the links between cholesterol and the strikingly variable but localised lesions of atherosclerosis. contribute there are
to
no
35. Reef, H., Isaacson, C. Circulation, 1962, 25, 66. 36. Meyer, B. J., Pepler, W. J., Meyer, A. C., Theron, J. J. ibid. 1964, 29, 415. 37. Baker, A. B., Flora, C. C., Resch, J. A., Loewenson, R. B. J. chron. Dis. 1967, 20, 685. 38. Williams, A. B., Resch, J. A., Loewenson, R. B. E. Afr. med. J. 1971, 48, 152. 39. Thomas, W. A., O’Neal, R. M., Dimakulangan, A. A., Davies, J. N. P. Am. J. Cardiol. 1960, 5, 41.
-
The theoretical basis for the diet had soon to be altered when it was pointed outthat turkey meat is, in truth, well supplied with tryptophan-a fact acknowledged by Spiera and Lefkovits,3 whose analysis had been in error for technical reasons. Spiera and his co-workers4 have now reported again on the original four patients, with eight additional patients. Seven had responded excellently, three moderately, and two not at all to the diet. Eleven patients had received prednisone and eight methotrexate before the study, but the timing of withdrawal was not stated. No mention was made of local treatment; presumably, as in the preliminary report, none was given. In the early investigation, striking improvement was noted in all patients within two weeks; but for the later patients remissions came more slowly, some starting only after two
months. Six other studies on this topic were cited. Of those in favour, two 5,6 were successes with single patients, The one of whom was also taking triamcinolone. report by Carruthersof twelve patients on the " lowtryptophan " diet is complicated by the fact that many were at the same time using conventional therapyindeed some may have been " more assiduous in the use of topical treatment". Of those against, onea may not be strictly relevant, since the discouraging results in seventeen patients were obtained with a true low-tryptophan diet as distinct from the turkey diet. Ellis et aI.9 achieved little with six patients, and Petrozzi and Rosenbloom 10 with three-one admit1. 2. 3. 4.
Spiera, H., Lefkovits, A. M. Lancet, 1967, ii, 137. Farber, E. M., Zackheim, H. ibid. p. 1154. Spiera, H., Lefkovits, A. M. ibid. p. 1418. Spiera, H., Lefkovits, A. M., Oreskes, I. Br. J. Dermat. 1971, 85,
5. 6. 7. 8. 9. 10.
Aukland, ibid. 1969, 81, 388. Portnoy, B. ibid. p. 389. Carruthers, R. Med. J. Aust. 1968, i, 493. Farber, E. M., Zackheim, H. Lancet, 1967, ii, 944. Ellis, J. P., Sanderson, K. V., Savin, J. A. ibid. 1968, i, 1429. Petrozzi, J. W., Rosenbloom, J. J. Am. med. Ass. 1968, 205,
277.
345.
have taken great pains to consider the possible effects of misclassification before reaching this conclusion. This raises the question: is yersinia arthritis indeed a new disease, or has its relative importance waxed only because the absolute importance of rheumatic fever has waned ? This is not the popular view, but time will tell; it is only when the tide goes out that the rocks appear, and, like that of acute rheumatic fever, the tide of tuberculous mesenteric lymphadenitis (which is clinically similar to yersinia infection in young people) has also ebbed.
they
As yet there seems no reason to believe that yersinia arthritis has the same grave cardiac sequelx as acute rheumatic fever, although electrocardiographic changes have been described in 5 adults of a series of 25 cases.26 SIEVERS and HALL have, however, been able to follow up 46 of 60 cases of acute rheumatic fever with a mean time-lag between onset of the disease and last examination of 8-7 years, ranging from a minimum of 3-4 to a maximum of 12-3 years. It is well known that the incidence of overt valvular disease depends on the length of follow-up,31 and they recognise this; but the incidence of rheumatic heart-disease among the cases they examined is only 8%, and they point out that this is lower than the rates predicted by HALL in his earlier investigation.22 This leads them to the tentative conclusion " that the decrease in the incidence of rheumatic heart disease is even more pronounced than that of rheumatic fever "-a hopeful one, especially since HALL 22 could find no evidence of a decrease in the incidence of rheumatic heart-disease before 1950.
acute
THE C.C.C.R.—FOUNT OR SUMP?
THE Co-ordinating Committee for Cancer Research (C.C.C.R.) has produced a statement of its first year’s work. 3The formation of the committee, and the fact that representatives of the three principal bodies that sponsor cancer research in Britain meet together to discuss what each is doing and should do, was an important, welcome, and long overdue development. During the first year the committee was mainly concerned with chemotherapy. Here one of the major difficulties is the provision of facilities for the testing and evaluation of new drugs. The organisation of the clinical assessment of cancer chemotherapeutic agents in Britain is less haphazard than it was, but the C.C.C.R. favours the setting up of " oncological centres ", because this would facilitate the planning and execution of clinical trials of new drugs and new treatment regimens. Few would disagree with the
view of the committee that no attempt should be made in the U.K. to duplicate chemotherapy research already being conducted on a large scale in the U.S.A. 31. Bland, E. F., Jones, T. D. Ann. intern. Med. 1952, 37, 1006. 32. Joint Cancer Research Campaign/Imperial Cancer Research Fund/ Medical Research Council Co-ordinating Committee for Cancer Research—Statement on First Year’s Work.
The report on an assessment of the work of Dr. Josef Issels 33 required much time and effort by the C.C.C.R., but the wisdom and humanity expressed in that report give it a general and lasting value that goes far beyond the appraisal of particular forms of treatment practised in the Ringberg Clinic in Bavaria. Most of the rest of the report on the first year’s work consists of rather general statements under headings such as recent advances, prevention of cancer, and improvements from better use of existing knowledge, which could have been written by anyone reasonably well versed in cancer research; it is to be hoped that the committee did not spend much of its time agreeing these parts of its statement. Planning research on a proper scale, preventing duplication, and coordinating parallel approaches are clearly necessary in the overall organisation of cancer research, but the efforts of the C.C.C.R. must not for ever be confined to the better organisation of what is already going on. Scattered throughout the hospitals, medical schools, and universities are a handful of brilliant young men and women with two precious commodities-ideas and energy. These need to become the founts of energy on which the whole future organisational structure of cancer research depends. There is a distinct danger that with the present emphasis on broad planning and on thinking big, these sources of energy will be lost sight of. Surely, the most urgent task before the C.C.C.R. is not simply to plod its way through the rational organisation of wellestablished areas of cancer research but to evolve new and better ways of ensuring that the best use is made of the energy and originality of young scientists. What can be done to attract first-class brains into cancer research ? What are the career prospects for such men ? Should cancer research continue to be largely an area in which doctors and scientists just dabble for a few years as they ascend the career ladders of pathology, Is the organisational surgery, or biochemistry ? structure of universities inappropriately rigid in relation to the organisation of research in such a multidisciplinary exercise ? If the C.C.C.R. can make better use of the manpower supported by cancer funds it might itself come to be regarded as a fount. If it does nothing more than support and protect established lines of research, it will be nothing more than a central sump into which good ideas drain and are lost.
COMPARATIVE STUDIES OF CEREBRAL ATHEROSCLEROSIS
ATHEROSCLEROSIS of the aorta and of the coronary arteries, in their severity and complications, have been subjected to many comparative studies among different populations, and great differences have been demonstrated. Thus, coronary heart-disease has been shown to be relatively uncommon in Africans, in contrast to its frequency and severity in many Caucasian groups. 3,1 But cerebral arteriosclerotic vascular disease 33. A report
on
the treatment of cancer
at
the
Egern, Bavaria. H.M. Stationery Office, 34. Williams, A. O. J. Path. 1969, 99, 219.
Ringberg-Clinic, Rottach 1971.
1410 TALKING TURKEY
and the resulting complications have been much less closely examined. While the South African Bantu 35,36 seemed to have less coronary and aortic arteriosclerosis, thus producing little clinical disease compared with their White compatriots, the Bantu cerebral vessels seemed to be equally affected by arteriosclerosis, and in the Bantu cerebrovascular occlusive disease was far commoner than coronary occlusive disease. But when the degree of cerebral arteriosclerosis in Nigerians was compared with that of Minnesotans and with Negro and White residents in Alabama, distinct differences
ANY effective treatment for psoriasis should be welcomed, particularly when it does not involve use of the messy ointments which patients find so hard to tolerate. For this reason, the preliminary report by
Spiera and Lefkovits1 of their success with a diet thought to be low in tryptophan was of great interest, and was given publicity in the lay Press. The diet was based on turkey meat as the main source of protein. New treatments for psoriasis, however, must be properly evaluated before they are generally adopted. If even a small proportion of the 2-3% of the population who have psoriasis switched to turkey meat, there would be important economic consequences. Unfortunately, it is notoriously difficult to assess any treatment in psoriasis: the disease is liable to remit spontaneously ; many believe that admission to hospital alone will cause improvement; the effects of local and other systemic therapy must be disentangled from those of the treatment under trial; obvious enthusiasm may speed recovery; and improvement is not easy to measure objectively. Understandably, in the original paper, describing successful treatment of four patients, some of these points were not adequately controlled.
emerged. 34,37,38 In persons from all these communities cerebral It arteriosclerosis showed some similar features. started early in life and increased in extent and severity with age; young males were affected earlier and more severely than females. But at every age the prevalence, extent, and severity of the arteriosclerotic lesions was distinctly less in the Nigerians. Whereas no differences could be detected between the Minnesotans or the Negroes or Whites in Alabama, there were distinct differences between the Alabama Negroes and the
Nigerians. 38 These findings are based on careful comparisons in which the pitfalls in studying necropsy materials have been avoided and the difficulties of measuring atherosclerosis and drawing valid comparisons have been The material studied was certainly surmounted. amount. The results, while directly at in adequate variance with the South African findings, are consistent with earlier comparative studies of atherosclerosis, coronary-artery disease, and venous thrombosis and embolism between Africans and White and Negro citizens of the United States. 39 The U.S. Negro is far closer to the White American in the prevalence and severity of these cardiovascular diseases than he is to the people living in his ancestral homelands. In Nigeria, lesions secondary to cerebral atherosclerosis are relatively rare, as are lesions secondary to coronary atherosclerosis, but while the second point is true of the Bantu, in these peoples the severity and complications of cerebral atherosclerosis are much more evident. Thus, it seems that even in Africa there is a gradation in this respect in the indigenous population as striking as the one between African groups in Africa and in other continents. How far the
differences in
physical and cultural characteristics, dietary habits, genetic constitution, and way of life these differences is unknown. 34 It seems detectable differences in the bloodclotting mechanisms, though perhaps there are in the mechanisms of clot lysis. Hypertension is common in all groups. While blood-cholesterol levels are generally much lower in Africans, it is as hard as ever to see the links between cholesterol and the strikingly variable but localised lesions of atherosclerosis. contribute there are
to
no
35. Reef, H., Isaacson, C. Circulation, 1962, 25, 66. 36. Meyer, B. J., Pepler, W. J., Meyer, A. C., Theron, J. J. ibid. 1964, 29, 415. 37. Baker, A. B., Flora, C. C., Resch, J. A., Loewenson, R. B. J. chron. Dis. 1967, 20, 685. 38. Williams, A. B., Resch, J. A., Loewenson, R. B. E. Afr. med. J. 1971, 48, 152. 39. Thomas, W. A., O’Neal, R. M., Dimakulangan, A. A., Davies, J. N. P. Am. J. Cardiol. 1960, 5, 41.
-
The theoretical basis for the diet had soon to be altered when it was pointed outthat turkey meat is, in truth, well supplied with tryptophan-a fact acknowledged by Spiera and Lefkovits,3 whose analysis had been in error for technical reasons. Spiera and his co-workers4 have now reported again on the original four patients, with eight additional patients. Seven had responded excellently, three moderately, and two not at all to the diet. Eleven patients had received prednisone and eight methotrexate before the study, but the timing of withdrawal was not stated. No mention was made of local treatment; presumably, as in the preliminary report, none was given. In the early investigation, striking improvement was noted in all patients within two weeks; but for the later patients remissions came more slowly, some starting only after two
months. Six other studies on this topic were cited. Of those in favour, two 5,6 were successes with single patients, The one of whom was also taking triamcinolone. report by Carruthersof twelve patients on the " lowtryptophan " diet is complicated by the fact that many were at the same time using conventional therapyindeed some may have been " more assiduous in the use of topical treatment". Of those against, onea may not be strictly relevant, since the discouraging results in seventeen patients were obtained with a true low-tryptophan diet as distinct from the turkey diet. Ellis et aI.9 achieved little with six patients, and Petrozzi and Rosenbloom 10 with three-one admit1. 2. 3. 4.
Spiera, H., Lefkovits, A. M. Lancet, 1967, ii, 137. Farber, E. M., Zackheim, H. ibid. p. 1154. Spiera, H., Lefkovits, A. M. ibid. p. 1418. Spiera, H., Lefkovits, A. M., Oreskes, I. Br. J. Dermat. 1971, 85,
5. 6. 7. 8. 9. 10.
Aukland, ibid. 1969, 81, 388. Portnoy, B. ibid. p. 389. Carruthers, R. Med. J. Aust. 1968, i, 493. Farber, E. M., Zackheim, H. Lancet, 1967, ii, 944. Ellis, J. P., Sanderson, K. V., Savin, J. A. ibid. 1968, i, 1429. Petrozzi, J. W., Rosenbloom, J. J. Am. med. Ass. 1968, 205,
277.
345.