1282
peutic range of 2 to 5 µg/ml. These patients should have early and regular checks of serum C.K., urea, and creatinine and also free and total
C.P.I.B.
We thank Dr J. M. Thorp (Pharmaceuticals Division, I.C.I.) for carrying out the estimations of total and free C.P.LB. and help with the preparation of this report; and Dr A. Martin (Sunderland Royal Infirmary) for allowing us to report case 5. A. M. P. is supported by an M.R.C. grant no. G/973/693C. Requests for reprints should be addressed to A. M. P. University Department of Medicine, Royal Victoria Infirmary, Newcastle upon
Tyne NE1 4LP.
in elucidating the pathogenesis of this which the W.H.O. classifies as fibromatosis.2 condition, The histological similarity to fibrosarcoma is now well recognised although, in the past, mid-thigh amputation has mistakenly been carried out for plantar Dupuytren’s.3 Chromosome abnormalities have been reported in experimental connective-tissue tumours4 5. Cells from the palmar fascia of Dupuytren’s contracture grown in tissue-culture have been karyotyped. We report early findings here.
disappointing
METHOD
REFERENCES 1.
Hunninghake, D. B., Tucker,
D.
R., Azarnoff, D. L. Circulation. 1969, 39,
675. 2.
Smith, A. F., Macfie, W. G., Oliver, M. F. Br. med. J. 1970, ii, 86. 3. Langer, T., Levy, R. I. New Engl. J. Med. 1968, 279, 856. 4. Sekowski, I., Samuel, P. Am. J. Cardiol. 1972, 30, 572. 5. Bridgman, J. F., Rosen, S. M., Thorp, J. M. Lancet, 1972, ii, 506. 6. Fabre, J., Denizot, M. Wildi, E., Micheli, H., Berthoud, S. Praxis, 1973, 62, 732.
Dupuytren tissue, and in three cases skin from the operative site, have been taken from six males selected randomly for palmar fasciectomy. This material was grown in tissue-culture and karyotyped. 60 metaphases from each tissue at second or third passage were analysed after conventional staining. Abnormal karyotypes were precisely identified.
7.
Katsilambros, N., Braaten, J., Ferguson, B. D., Bradley, R. F. New Engl. J. Med. 1972, 286, 1110. 8. Giegel, J. Soloni, F. G., Trinidad, E., Cohen, B., Clema, W. Clin. Chem 1972, 18, 693. 9. Noble, R. P. J. lipid Res. 1968, 9, 963. 10. Wroblewski, F., La Due, J. S. Proc. Soc. exp. Biol. Med. 1955, 90, 210. 11. Henry, R. H., Chiamori, N., Crolub, O. J., Berkman, S. Am. J. clin. Path. 1960, 34, 381. 12. Wroblewski, F., La Due, J. S. Proc. Soc. exp. Biol. Med. 1956, 91, 569. 13. Oliver, J. T. Biochem. J. 1955, 61, 116. 14. Cramp, D. G., Moorhead, J. F., Wills, M. R. Lancet, 1975, i, 672.
RESULTS
All tissues examined had cell lines with normal karyotypes, but four of the six fascial specimens also had one or more cell line with an abnormal karyotype. ABNORMAL KARYOTYPES IN FASCIA
15. Roodvoets, A. P. M.D. thesis, Leiden, 1974. 16. Cotton, R. C. Acta cardiol. 1972, 15, suppl. p. 163. 17. Cotton, R. C., Personal communication. 18. Green, K. G., Margetts, G. Prog. biochem. Pharma. 1967, 2, 378. 19. Phillips, M. E., Eastwood, J. B., Curtis, J. R., Gower, P. E., de Wardener, H. E. Br. med. J. 1974, ii, 149.
Preliminary Communication CHROMOSOME ABNORMALITIES IN DUPUYTREN’S DISEASE S. BOWSER-RILEY
Royal Hospital for
A. D. BAIN Sick
Children, Edinburgh
J. NOBLE Department of Orthopædic Surgery, University of Edinburgh D. W. LAMB Princess Margaret Rose Hospital,
Edinburgh
ing studies.
Summary
Palmar
fascia
from
six
men
with
Dupuytren’s contracture has been grown in tissue-culture and examined cytogenetically; and in three of these cases skin was also studied. Four of the six cases showed mosaicism, but only in cultures of the fascia; the mosaicism was therefore unlikely to be an artefact. Since the abnormalities were inconsistent and absent from skin-cultures they are very unlikely to indicate any mechanism of inheritance. Similar chromosome abnormalities have been reported from experimentally induced tumours. INTRODUCTION
LITTLE
case 3 the abnormal cell lines was trisomic, while clones from cases 1, 4, and 5 showed balanced structural rearrangements In case 5 about half the metaphases were tetraploid and 30 of these were scored in addition to 60 diploids 13 of the 30 cells showed an inverted insertion between two chromosomes and, though its possible diploid origin was not seen in the 60 cells analysed, one instance of this was noted during band-
. In
is
known
regarding the aetiology of Dupuytren’s contracture, although Ling’s’ population study showed that its inheritance may be autosomal dominant. Conventional histological studies have proved
DISCUSSION
To the best of our knowledge, this is the first attempt to study Dupuytren’s tissue in this way. The variation of the abnormal findings and their absence from the three control cultures of skin excludes the possibility of this reflecting an inherited abnormality. Littlefield and Mailhes6 have shown abnormal cell lines in cultures of normal skin and, while abnormal cells were noted in skin controls in the present study, the abnormalities were not consistent and therefore the cells were not considered to be clones. All tissues were analysed at the second or third passage-that is, by the sixth week - so that the duration in culture was not excessive. Mycoplasma may cause aberrant clones in tissueculture and, although our cultures were free of contamination as judged by microbial tests, biochemical
1283 assay for
mycoplasma
was not
performed However,
if it was the cause of these abnormalities, then the skin controls would also have been affected. The
histological similarity
to
a stroked This strongly suggests that it is the raised blood-pressure itself which damages blood-vessels and causes
strokes.
fibrosarcoma has been
noted. Chromosome abnormalities have been recognised in cells cultured from experimental connective-tissue tumours,4 5 but there is no question of Dupuytren’s contracture being other than entirely benign. Recent reports? 8 have suggested that different acquired chromosome abnormalities may vary in their prognostic significance and Codish and Paul8 have described the appearance of a specific chromosome which suppresses malignancy. One may speculate that, within the broad range of fibromatoses, the existence and balance of chromosome abnormalities may influence the clinical course. Meanwhile, we suggest that chromosomally abnormal cell lines may arise in the development
of Dupuytren’s disease. We thank Rhona Bauld and Elizabeth Grace for assistance with case 1. Requests for reprints should be addressed to S. B-R., Pathology Department, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF. REFERENCES
Ling, R. G. M. J. Bone Jt. Surg. 1963, 45B, 709. 2. Enzinger, M., Lattes, R., Torloni, H. Types Histologiques des 1.
Tumeurs des Tissue Mous; p. 28. Geneva, 1970. 3. Hueston, J. T. Dupuytren’s Disease; p. 61. Edinburgh, 1974. 4. Rasheed, S., Nelson-Rees, W. A., Toth, E. M., Arnstein, P., Gardner, M. B. Cancer, 1974, 33, 1027. 5. Benedict, W. F., Rucker, N., Mark, C., Kouri, R. E. J. natr. Cancer Inst. 1975, 54, 157. 6. Littlefield, L. G., Mailhes, J. B. Am. J. hum. Genet. 1975, 27, 190. 7. Rowley, J. D. Lancet, 1973, ii, 390. 8. Codish, S. D., Paul, B. Nature, 1974, 252, 610.
Hypothesis
PATHOLOGICAL CHANGES IN HYPERTENSIVE CEREBRAL VESSELS
Microaneurysms Related to Lipohyalinosis For many years pathologists have sought an underlying pathological process which can explain the increased liability of cerebral arteries both to rupture and to occlusion. It is generally agreed that the walls of the larger cerebral arteries from chronic hypertensive patients show an increased thickening and hyalinisation of the muscle coat when compared with those from normotensive patients. Furthermore, atheroma is more extensive and severe in large arteries.4 In addition, however, there is a distinct pathological change which affects small intracerebral arteries 50-200 m in diameter and consists of multiple microaneurysms arising on segments of dilated artery. In the wall of the microaneurysm the endothelium has ruptured and the media and elastic coats have disappeared and been entirely replaced by connective tissue. A single brain may contain many microaneurysms, and they have a characteristic distribution, being found most frequently in putamen, globus pallidus, external capsule, thalamus, pons, and subcortical white-matter.5 Some of these microaneurysms show a reaction variously known as "fibrinoid necrosis", "lipohyalinosis", or "angionecrosis" consisting in the accumulation within the wall of hyaline material which stains for fibrin and for fat. Around the aneurysm there is frequently evidence of leakage of blood usually in small quantities6 (figs. 1 and 2). Lacunar Infarction Related to Lipohyalinosis
HOW DOES BLOOD-PRESSURE CAUSE STROKE? R. W. Ross RUSSELL National Hospital, Queen Square, London WC1N 3BQ, and St Thomas’ Hospital, London SE1 7EH
In chronic hypertension the specific arterial lesions responsible for brain damage affect the small resistance arteries. The pathological characteristics of these lesions (notably the presence of microaneurysms, intramural fibrin, and lipid) and the location of lesions within the brain all suggest that they arise from mechanical distension, which destroys the integrity of the vessel and allows plasma insudation into the wall (lipohyalinosis), finally leading to occlusion or rupture. The process is analogous to the breakdown in vascular resistance and permeability which occurs in acute hypertension.
Summary
Fisher’ has convincingly shown that lacunes-small, deep cerebral infarcts often found in the brains of chronic hypertensives-are usually associated with occlusions of small intracerebral arteries. The pathological change at the point of occlusion consists of mural destruction, focal expansion, thrombotic occlusion, and fibrinoid deposition, and has progressed to the point of complete disorganisation of the artery and obliteration
EFFECTS OF HYPERTENSION ON THE BRAIN
EPIDEMIOLOGICAL studies have established an association between high blood-pressure and an increased incidence of cerebral vascular disease; this is true for both cerebral haemorrhage and cerebral infarction. Moreover, in severely hypertensive patients a reduction in blood-pressure by medical treatment lowers the incidence of future strokes both in those who have no cerebrovascular symptoms2 and in those who have survived
1—Cross-section of wall.
Fig.
(PTAH; x90.)
microaneurysm showing plasma
insudation of
peutic range of 2 to 5 µg/ml. These patients should have early and regular checks of serum C.K., urea, and creatinine and also free and total
C.P.I.B.
We thank Dr J. M. Thorp (Pharmaceuticals Division, I.C.I.) for carrying out the estimations of total and free C.P.LB. and help with the preparation of this report; and Dr A. Martin (Sunderland Royal Infirmary) for allowing us to report case 5. A. M. P. is supported by an M.R.C. grant no. G/973/693C. Requests for reprints should be addressed to A. M. P. University Department of Medicine, Royal Victoria Infirmary, Newcastle upon
Tyne NE1 4LP.
in elucidating the pathogenesis of this which the W.H.O. classifies as fibromatosis.2 condition, The histological similarity to fibrosarcoma is now well recognised although, in the past, mid-thigh amputation has mistakenly been carried out for plantar Dupuytren’s.3 Chromosome abnormalities have been reported in experimental connective-tissue tumours4 5. Cells from the palmar fascia of Dupuytren’s contracture grown in tissue-culture have been karyotyped. We report early findings here.
disappointing
METHOD
REFERENCES 1.
Hunninghake, D. B., Tucker,
D.
R., Azarnoff, D. L. Circulation. 1969, 39,
675. 2.
Smith, A. F., Macfie, W. G., Oliver, M. F. Br. med. J. 1970, ii, 86. 3. Langer, T., Levy, R. I. New Engl. J. Med. 1968, 279, 856. 4. Sekowski, I., Samuel, P. Am. J. Cardiol. 1972, 30, 572. 5. Bridgman, J. F., Rosen, S. M., Thorp, J. M. Lancet, 1972, ii, 506. 6. Fabre, J., Denizot, M. Wildi, E., Micheli, H., Berthoud, S. Praxis, 1973, 62, 732.
Dupuytren tissue, and in three cases skin from the operative site, have been taken from six males selected randomly for palmar fasciectomy. This material was grown in tissue-culture and karyotyped. 60 metaphases from each tissue at second or third passage were analysed after conventional staining. Abnormal karyotypes were precisely identified.
7.
Katsilambros, N., Braaten, J., Ferguson, B. D., Bradley, R. F. New Engl. J. Med. 1972, 286, 1110. 8. Giegel, J. Soloni, F. G., Trinidad, E., Cohen, B., Clema, W. Clin. Chem 1972, 18, 693. 9. Noble, R. P. J. lipid Res. 1968, 9, 963. 10. Wroblewski, F., La Due, J. S. Proc. Soc. exp. Biol. Med. 1955, 90, 210. 11. Henry, R. H., Chiamori, N., Crolub, O. J., Berkman, S. Am. J. clin. Path. 1960, 34, 381. 12. Wroblewski, F., La Due, J. S. Proc. Soc. exp. Biol. Med. 1956, 91, 569. 13. Oliver, J. T. Biochem. J. 1955, 61, 116. 14. Cramp, D. G., Moorhead, J. F., Wills, M. R. Lancet, 1975, i, 672.
RESULTS
All tissues examined had cell lines with normal karyotypes, but four of the six fascial specimens also had one or more cell line with an abnormal karyotype. ABNORMAL KARYOTYPES IN FASCIA
15. Roodvoets, A. P. M.D. thesis, Leiden, 1974. 16. Cotton, R. C. Acta cardiol. 1972, 15, suppl. p. 163. 17. Cotton, R. C., Personal communication. 18. Green, K. G., Margetts, G. Prog. biochem. Pharma. 1967, 2, 378. 19. Phillips, M. E., Eastwood, J. B., Curtis, J. R., Gower, P. E., de Wardener, H. E. Br. med. J. 1974, ii, 149.
Preliminary Communication CHROMOSOME ABNORMALITIES IN DUPUYTREN’S DISEASE S. BOWSER-RILEY
Royal Hospital for
A. D. BAIN Sick
Children, Edinburgh
J. NOBLE Department of Orthopædic Surgery, University of Edinburgh D. W. LAMB Princess Margaret Rose Hospital,
Edinburgh
ing studies.
Summary
Palmar
fascia
from
six
men
with
Dupuytren’s contracture has been grown in tissue-culture and examined cytogenetically; and in three of these cases skin was also studied. Four of the six cases showed mosaicism, but only in cultures of the fascia; the mosaicism was therefore unlikely to be an artefact. Since the abnormalities were inconsistent and absent from skin-cultures they are very unlikely to indicate any mechanism of inheritance. Similar chromosome abnormalities have been reported from experimentally induced tumours. INTRODUCTION
LITTLE
case 3 the abnormal cell lines was trisomic, while clones from cases 1, 4, and 5 showed balanced structural rearrangements In case 5 about half the metaphases were tetraploid and 30 of these were scored in addition to 60 diploids 13 of the 30 cells showed an inverted insertion between two chromosomes and, though its possible diploid origin was not seen in the 60 cells analysed, one instance of this was noted during band-
. In
is
known
regarding the aetiology of Dupuytren’s contracture, although Ling’s’ population study showed that its inheritance may be autosomal dominant. Conventional histological studies have proved
DISCUSSION
To the best of our knowledge, this is the first attempt to study Dupuytren’s tissue in this way. The variation of the abnormal findings and their absence from the three control cultures of skin excludes the possibility of this reflecting an inherited abnormality. Littlefield and Mailhes6 have shown abnormal cell lines in cultures of normal skin and, while abnormal cells were noted in skin controls in the present study, the abnormalities were not consistent and therefore the cells were not considered to be clones. All tissues were analysed at the second or third passage-that is, by the sixth week - so that the duration in culture was not excessive. Mycoplasma may cause aberrant clones in tissueculture and, although our cultures were free of contamination as judged by microbial tests, biochemical
1283 assay for
mycoplasma
was not
performed However,
if it was the cause of these abnormalities, then the skin controls would also have been affected. The
histological similarity
to
a stroked This strongly suggests that it is the raised blood-pressure itself which damages blood-vessels and causes
strokes.
fibrosarcoma has been
noted. Chromosome abnormalities have been recognised in cells cultured from experimental connective-tissue tumours,4 5 but there is no question of Dupuytren’s contracture being other than entirely benign. Recent reports? 8 have suggested that different acquired chromosome abnormalities may vary in their prognostic significance and Codish and Paul8 have described the appearance of a specific chromosome which suppresses malignancy. One may speculate that, within the broad range of fibromatoses, the existence and balance of chromosome abnormalities may influence the clinical course. Meanwhile, we suggest that chromosomally abnormal cell lines may arise in the development
of Dupuytren’s disease. We thank Rhona Bauld and Elizabeth Grace for assistance with case 1. Requests for reprints should be addressed to S. B-R., Pathology Department, Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF. REFERENCES
Ling, R. G. M. J. Bone Jt. Surg. 1963, 45B, 709. 2. Enzinger, M., Lattes, R., Torloni, H. Types Histologiques des 1.
Tumeurs des Tissue Mous; p. 28. Geneva, 1970. 3. Hueston, J. T. Dupuytren’s Disease; p. 61. Edinburgh, 1974. 4. Rasheed, S., Nelson-Rees, W. A., Toth, E. M., Arnstein, P., Gardner, M. B. Cancer, 1974, 33, 1027. 5. Benedict, W. F., Rucker, N., Mark, C., Kouri, R. E. J. natr. Cancer Inst. 1975, 54, 157. 6. Littlefield, L. G., Mailhes, J. B. Am. J. hum. Genet. 1975, 27, 190. 7. Rowley, J. D. Lancet, 1973, ii, 390. 8. Codish, S. D., Paul, B. Nature, 1974, 252, 610.
Hypothesis
PATHOLOGICAL CHANGES IN HYPERTENSIVE CEREBRAL VESSELS
Microaneurysms Related to Lipohyalinosis For many years pathologists have sought an underlying pathological process which can explain the increased liability of cerebral arteries both to rupture and to occlusion. It is generally agreed that the walls of the larger cerebral arteries from chronic hypertensive patients show an increased thickening and hyalinisation of the muscle coat when compared with those from normotensive patients. Furthermore, atheroma is more extensive and severe in large arteries.4 In addition, however, there is a distinct pathological change which affects small intracerebral arteries 50-200 m in diameter and consists of multiple microaneurysms arising on segments of dilated artery. In the wall of the microaneurysm the endothelium has ruptured and the media and elastic coats have disappeared and been entirely replaced by connective tissue. A single brain may contain many microaneurysms, and they have a characteristic distribution, being found most frequently in putamen, globus pallidus, external capsule, thalamus, pons, and subcortical white-matter.5 Some of these microaneurysms show a reaction variously known as "fibrinoid necrosis", "lipohyalinosis", or "angionecrosis" consisting in the accumulation within the wall of hyaline material which stains for fibrin and for fat. Around the aneurysm there is frequently evidence of leakage of blood usually in small quantities6 (figs. 1 and 2). Lacunar Infarction Related to Lipohyalinosis
HOW DOES BLOOD-PRESSURE CAUSE STROKE? R. W. Ross RUSSELL National Hospital, Queen Square, London WC1N 3BQ, and St Thomas’ Hospital, London SE1 7EH
In chronic hypertension the specific arterial lesions responsible for brain damage affect the small resistance arteries. The pathological characteristics of these lesions (notably the presence of microaneurysms, intramural fibrin, and lipid) and the location of lesions within the brain all suggest that they arise from mechanical distension, which destroys the integrity of the vessel and allows plasma insudation into the wall (lipohyalinosis), finally leading to occlusion or rupture. The process is analogous to the breakdown in vascular resistance and permeability which occurs in acute hypertension.
Summary
Fisher’ has convincingly shown that lacunes-small, deep cerebral infarcts often found in the brains of chronic hypertensives-are usually associated with occlusions of small intracerebral arteries. The pathological change at the point of occlusion consists of mural destruction, focal expansion, thrombotic occlusion, and fibrinoid deposition, and has progressed to the point of complete disorganisation of the artery and obliteration
EFFECTS OF HYPERTENSION ON THE BRAIN
EPIDEMIOLOGICAL studies have established an association between high blood-pressure and an increased incidence of cerebral vascular disease; this is true for both cerebral haemorrhage and cerebral infarction. Moreover, in severely hypertensive patients a reduction in blood-pressure by medical treatment lowers the incidence of future strokes both in those who have no cerebrovascular symptoms2 and in those who have survived
1—Cross-section of wall.
Fig.
(PTAH; x90.)
microaneurysm showing plasma
insudation of
