- Email: [email protected]
THE MYOFIBROBLAST
1290
necessarily of clinical importance. The firmer the original indications for digoxin, the more likely that the patient will deteriorate when it is stopped: even so, withdrawal may be possible in more than half of the patients in sinus rhythm. Unfortunately, clinical trial is the only way of distinguishing which category a particular patient falls into. Overall, then, the availability of serum digoxin concentration measurements does not seem to have resolved many of the problems of digoxin prescribing. Rather it has generated new areas of confusion. The longevity of digitalis drugs indicates continued belief in their worth: there is still much to be done to make them better and safer.
CEREBELLAR STIMULATION FOR EPILEPSY AND CEREBRAL PALSY BEGINNING with the demonstration
by Sherrington
that cerebellar stimulation reduces extensor tone in decerebrate animals, experiments over 70 years or so have indicated that the cerebellum has a regulatory effect on the motor system. Lately the cerebellum has been shown also to influence blood-pressure, and
by Horsley
rate, glucose tolerance, pupillary reflexes, and emotions. 5 years ago Irving Cooper first used cerebellar stimulation to treat spasticity in man. The usual procedure is to place silicon-mesh plates, bearing platinum electrodes, bilaterally on the anterior and posterior lobes. The operation is done under general anxsthesia, via 3 cm diameter craniectomies; subcutaneous leads pass to a subcutaneously implanted receiver which is activated by a radio-frequency signal from a power pack carried by the patient. The best position and number of electrodes, and the best type of pulse, have still to be determined. Stimulation of the anterior lobe of the cerebellum inhibits spinal-cord reflexes ipsilaterally; stimulation of the posterior lobe inhibits the contralateral cerebral cortex; and simultaneous stimulation of both produces greater suppression than stimulation of either alone. The current required to elicit neurophysiological evidence of inhibition varies between patients; and too much may worsen symptoms. Some patients improve despite an absence of neurophysiological changes. When cerebellar stimulation is interrupted, rebound facilitation may be detected at spinal, brainstem, and cortical levels, with maximum effect after 8-11 minutes. This is the basis of a technique in which stimuli are applied for one minute at a time to alternating cerebellar cortical areas, at a pulse width of 500 ms. Chronic cerebellar stimulation (c.c.s.) has been used mainly in the treatment of epilepsy and cerebral palsy. Cooper and Upton have lately reviewed the technique and its possible mechanisms,and a fuller account has now been pub-
respiratory
cephalographic abnormalities, an i.Q. of at least 70, and no evidence of a space-occupying lesion. 18 patients had a good clinical response (at least 50% reduction of seizures) ; some did much better-for example, reduction from 25 to 4 a day. Other benefits included return to employment, reduction or cessation of drugs, increased alertness and concentration, and reduced aggression. 9 patients were therapeutic failures but none was made neurologically worse by the procedure. 1 patient died postoperatively of extradural hxmatoma, and 4 died after 6 weeks, 17 months, 26 months, and 28 months of In the 9 patients specially investigated, cerebellar stimulation inhibited the H reflex and other spinal reflexes, and cortical somatosensory evoked responses, but not visual evoked responses. The same group has experience of c.c.s. in 141 patients with cerebral palsy, age-range 7-55years. The usual cause is birth trauma; 42% had epilepsy and 28% had an abnormal electroencephalogram. The mean i.Q. was 92. 62% were severely spastic and 52% were athetotic. In most cases the electrodes were implanted on the anterior lobe, and the follow-up time was 3-39 months. 1 patient died after operation from embolism and subdural haematoma. Overall improvement was said to be moderate to marked in 46% and mild in 39%. As to more specific indices, spasticity was believed to have lessened in 73% and athetosis in 61%, and about half the patients were judged better able to look after themselves. In 9 patients studied by neurophysiological methods, cerebellar stimulation inhibited spinal responses and somatosensory evoked potentials. There is some evidence that c.c.s. improved visual perception, and Cooper ascribes this either to "enhancement of overall sensorimotor integration" or to reduction of abnormal eye movements. Improvement was noted also in verbal, perceptual, and psychomotor skills. Patients stimulated for a year or more seemed to have gained in alertness and to be less anxious, tense, and depressed than formerly. Clearly this improvement could be secondary to relief of neurological symptoms, but the connection was not always strong. 30 of the 173 patients had cerebellar biopsy specimens taken at operation and 3 of those who died came to necropsy. In patients with epilepsy, pre-existing cerebellar damage was very common, including loss of Purkinje cells. As in animals, the stimulating electrode produced a limited lesion, without fibrosis; there was no evidence of serious harm from c.c.s. These results from Cooper and his colleagues indicate that chronic cerebellar stimulation is ripe for controlled clinical evaluation. In cerebral palsy, electrical stimulation of the cerebellum or spinal cord is the only really promising approach. In epilepsy it is possible that cerebellar stimulation will now save some patients from that last resort, ablative surgery.
c.c.s.
lished.2 tried in 32 patients with epilepsy. The agewas 14-56 range years, the length of illness 3-49 years, and the follow-up time for c.c.s. 13-53 months. The basis of selection was intractable epilepsy with electroenc.c.s. was
1. Cooper, I. S., Upton, A. R. M. Lancet, 1978, i, 595. 2. Cerebellar Stimulation in Man. Edited by I. S. COOPER. New York: Raven. 1978. pp. 232. $29.25.
THE MYOFIBROBLAST THE nature of the eosinophilic stellate cells in healing wounds remained a puzzle to pathologists for many years. Similarly the mechanism of wound contraction baffled the surgeon. By their site and shape the cells should have been fibroblasts, but, lacking the cytoplasmic basophilia of protein synthesis, they looked more
1291
like muscle cells. These ambivalent cells are now better understood and they are labelled myofibroblasts. The myofibroblast was named in 1971 by Majno, Ryan, and Gabbiani,’ whose group showed that it possessed the apparatus and many of the functional properties of both fibroblast and smooth-muscle cell. Transiently present in young granulation tissue, myofibroblasts shrink the wound and lose their myofibrils as it matures into a scar.2 The plastic surgeon tries to avoid excessive wound contraction by limiting the formation of granulation tissue with skin grafts, corticosteroids, and X rays, but now the hunt is on for pharmacological means of control.3 Myofibroblasts have been demonstrated in various reactive proliferations of connective tissue, including hypertrophic scars,4 ischsemic contractures of intrinsic hand muscles,s stenosing tenosynovitis, and carpal-tunnel syndrome.6 They may also be responsible for some of the progressive, disabling distortion of normal architecture in cirrhosis of the liver and sarcoidosis of the
mucosa.20 For a moment it seems that hope was misplaced in electron microscopy as the means of classifying more accurately the notoriously difficult and debatable
lung.8 Pluripotent cells in the aorta have been identified as myofibroblasts capable of synthesising elastin as well as collagen and matrix,9 and may phagocytose lipid too in atheroma.10 Their importance in elastogenesis is not yet established, though suggested by the fact that as elastic fibres wax in a wound, the myofibrils wane, and that the familiar but unexplained ganglia of the wrist consist of myofibroblasts capable of elastogenesis.11 However, it is not only in reactive proliferations but also in pseudotumorous and even a few frankly neoplastic conditions that myofibroblasts are being found.
VERY-LOW-DENSITY lipoproteins (V.L.D.L.) are secreted mainly by the liver, for transport of triglycerides to peripheral tissues such as muscle and heart. In the periphery they are broken down to low-density lipoproteins (L.D.L..) by catabolic enzymes such as lipoprotein lipase (L.P.L.) and possibly lecithin:cholesterol acyltransferase (L.C.A.T.). L.D.L. delivers cholesterol to peripheral tissues for the renewal of cell membranes and also inhibits the cellular synthesis of cholesterol. Circulating L.D.L. cholesterol thus regulates, by feedback inhibition of cholesterol synthesis, the cellular content of cholesterol. The lipids of the atheromatous plaque (mainly cholesterol, cholesteryl ester, and phospholipids) are derived from the plasma lipoproteins. Arterial cells can degrade lipoproteins; V.L.D.L. is metabolised in endothelial cells by the enzyme L.P.L., and the product particle, L.D.L., can filter through the endothelial barrier to be taken up by smooth-muscle cells in the subintimal space. Epidemiological and experimental evidence suggests, that raised plasma levels of V.L.D.L. and L.D.L. can predispose to atheroma, 1although it is still disputed whether v.L.D.L. acts as an independent variable for the develop7. ment of arterial disease. The fact that V.L.D.L. is converted into L.D.L. perhaps makes this argument specious. The current focus of attention in the development of atheroma is H.D.L. There is good epidemiological evidence to support the view that reduced levels of H.D.L. may retard the development of atheroma. For example, in 1953 Nikkila3 showed that patients with ischsemic heart-disease and normal total plasma-cholesterol concentrations had significantly reduced levels of H.D.L. cholesterol. This observation was largely neglected until 1975 when further evidence was assembled by Miller and Miller4 to suggest that a reduction in plasma-H.D.L. may impair the normal clearance of cholesterol from the arterial wall and thereby accelerate the development of atherosclerosis. Further weight was given to this idea by the Framingham epidemiological study: among 2815
.
Majno themselves described them in Dupuytren’s contracture,12 and the cells have also been found in the musculoaponeurotic fibromatoses (desmoid tumours),13 nodular fasciitis, 14 and Peyronie’s disease,15 They may simply reflect a phase of normal maturation of fibroblastic tissue in the spontaneous regression of multiple congenital mesenchymal hamartomas16 or be part of a change in a neoplasm analogous to the transformation of neuroblastoma into ganglioneuroma. In a small series of truly malignant tumours, 75% of the spindle cells in both fibrosarcomas and malignant fibrous histiocytomas proved to be myofibroblasts,17 and similar claims have been made for single examples of benign neoplasms such as uterine plexiform tumour,18 dermatofibroma, 19 and giant-cell fibroma of oral Gabbiani and
1. Gabbiani, G., Ryan, G. B., Majno, G. Experientia, 1971, 27, 549. 2. Guber, S., Rudolph, R. Surgery Gynec. Obstet. 1978, 146, 641. 3. Madden, J. W., Morton, D., Peacock, E. E. Surgery, 1974, 76, 8. 4. Baur, P. S., Larson, D. L., Stacey, T. R. Surgery Gynec. Obstet. 22. 5. Madden, J. W., Carlson, E. C., Hines, J. ibid. 1975, 140, 509. 6. Madden,J. W. Plast. reconstr. Surg., 1973, 52, 291. 7. Bhatal, P. S. Pathology, 1972, 4, 139.
1975, 141,
8. Judd, P. A., Finnegan, P., Curran, R.C.J. Path. 1975, 115, 191. 9. Wissler, R. W. Circulation, 1967, 36, 1. 10. Moss, N. S., Benditt, E. P. Lab. Invest. 1970, 23, 521. 11. Ghadially, F. N., Mehta, P. N. Ann. rheumat. Dis. 1971, 30, 31. 12. Gabbiani, G, Majno, G. Am. J. Path. 1972, 66, 131. 13. Stiller, D., Katenkamp, D. Virchows Arch. path. Anat. 1975, 369, 155. 14. Wirman, J. A., Cancer, 1976, 38, 2378. 15. Ariyan, S., Enriquez, R., Krizek, T.J. Archs Surg. 1978, 113, 1034. 16. Benjamin, S. P., Mercer, R. D., Hawk, W. A. Cancer, 1977, 40, 2343. 17. Churg, A. M., Kahn, L. B. Hum. Path. 1977, 8, 205. 18. Fisher, E. R., Paulson, J. D., Gregorio, R. M. Archs Path. 1978, 102, 477. 19. Hashimoto, K., Brownstein, M. H., Jakobiec, F. A. Archs Dermat., 1974,
110, 874.
Yet further work may show that feature of immaturity, and one wonders myofibrils whether radiotherapy will diminish them just as it "matures" other tumours, and whether their presence in a spindle-cell tumour will indicate a poorer prognosis than their absence. The dynamic plasticity of mesenchyme has been underlined by the description of the myofibroblast. Its origins are so far unknown and may lie in immigrant cells, blood-vessels, or transformed local fibroblasts, but tissue-culture experiments show that smooth muscle can secrete collagen and elastin. 21
soft-tissue
tumours.
are a
HIGH-DENSITY LIPOPROTEIN AND ATHEROMA
20. Weathers, D. R., Campbell, W. G. Oral Surg. 1974, 38, 550. 21. Ross, R., Klebanoff, S. J. J. Cell Biol. 1971, 50, 159. 1. Carlson, L. A., Bottiger, L. E. Lancet, 1972, i, 865. 2. Kannel, W. B., Castelli, W. P., Gordon, T., McNamara, P. M. Ann. intern. Med. 1971, 74, 1. 3. Nikkilä, E. Scand. J. clin. Lab. Invest. 1953, 5, suppl. 8. 4. Miller, G. J., Miller, N. E. Lancet, 1975, i, 16.
necessarily of clinical importance. The firmer the original indications for digoxin, the more likely that the patient will deteriorate when it is stopped: even so, withdrawal may be possible in more than half of the patients in sinus rhythm. Unfortunately, clinical trial is the only way of distinguishing which category a particular patient falls into. Overall, then, the availability of serum digoxin concentration measurements does not seem to have resolved many of the problems of digoxin prescribing. Rather it has generated new areas of confusion. The longevity of digitalis drugs indicates continued belief in their worth: there is still much to be done to make them better and safer.
CEREBELLAR STIMULATION FOR EPILEPSY AND CEREBRAL PALSY BEGINNING with the demonstration
by Sherrington
that cerebellar stimulation reduces extensor tone in decerebrate animals, experiments over 70 years or so have indicated that the cerebellum has a regulatory effect on the motor system. Lately the cerebellum has been shown also to influence blood-pressure, and
by Horsley
rate, glucose tolerance, pupillary reflexes, and emotions. 5 years ago Irving Cooper first used cerebellar stimulation to treat spasticity in man. The usual procedure is to place silicon-mesh plates, bearing platinum electrodes, bilaterally on the anterior and posterior lobes. The operation is done under general anxsthesia, via 3 cm diameter craniectomies; subcutaneous leads pass to a subcutaneously implanted receiver which is activated by a radio-frequency signal from a power pack carried by the patient. The best position and number of electrodes, and the best type of pulse, have still to be determined. Stimulation of the anterior lobe of the cerebellum inhibits spinal-cord reflexes ipsilaterally; stimulation of the posterior lobe inhibits the contralateral cerebral cortex; and simultaneous stimulation of both produces greater suppression than stimulation of either alone. The current required to elicit neurophysiological evidence of inhibition varies between patients; and too much may worsen symptoms. Some patients improve despite an absence of neurophysiological changes. When cerebellar stimulation is interrupted, rebound facilitation may be detected at spinal, brainstem, and cortical levels, with maximum effect after 8-11 minutes. This is the basis of a technique in which stimuli are applied for one minute at a time to alternating cerebellar cortical areas, at a pulse width of 500 ms. Chronic cerebellar stimulation (c.c.s.) has been used mainly in the treatment of epilepsy and cerebral palsy. Cooper and Upton have lately reviewed the technique and its possible mechanisms,and a fuller account has now been pub-
respiratory
cephalographic abnormalities, an i.Q. of at least 70, and no evidence of a space-occupying lesion. 18 patients had a good clinical response (at least 50% reduction of seizures) ; some did much better-for example, reduction from 25 to 4 a day. Other benefits included return to employment, reduction or cessation of drugs, increased alertness and concentration, and reduced aggression. 9 patients were therapeutic failures but none was made neurologically worse by the procedure. 1 patient died postoperatively of extradural hxmatoma, and 4 died after 6 weeks, 17 months, 26 months, and 28 months of In the 9 patients specially investigated, cerebellar stimulation inhibited the H reflex and other spinal reflexes, and cortical somatosensory evoked responses, but not visual evoked responses. The same group has experience of c.c.s. in 141 patients with cerebral palsy, age-range 7-55years. The usual cause is birth trauma; 42% had epilepsy and 28% had an abnormal electroencephalogram. The mean i.Q. was 92. 62% were severely spastic and 52% were athetotic. In most cases the electrodes were implanted on the anterior lobe, and the follow-up time was 3-39 months. 1 patient died after operation from embolism and subdural haematoma. Overall improvement was said to be moderate to marked in 46% and mild in 39%. As to more specific indices, spasticity was believed to have lessened in 73% and athetosis in 61%, and about half the patients were judged better able to look after themselves. In 9 patients studied by neurophysiological methods, cerebellar stimulation inhibited spinal responses and somatosensory evoked potentials. There is some evidence that c.c.s. improved visual perception, and Cooper ascribes this either to "enhancement of overall sensorimotor integration" or to reduction of abnormal eye movements. Improvement was noted also in verbal, perceptual, and psychomotor skills. Patients stimulated for a year or more seemed to have gained in alertness and to be less anxious, tense, and depressed than formerly. Clearly this improvement could be secondary to relief of neurological symptoms, but the connection was not always strong. 30 of the 173 patients had cerebellar biopsy specimens taken at operation and 3 of those who died came to necropsy. In patients with epilepsy, pre-existing cerebellar damage was very common, including loss of Purkinje cells. As in animals, the stimulating electrode produced a limited lesion, without fibrosis; there was no evidence of serious harm from c.c.s. These results from Cooper and his colleagues indicate that chronic cerebellar stimulation is ripe for controlled clinical evaluation. In cerebral palsy, electrical stimulation of the cerebellum or spinal cord is the only really promising approach. In epilepsy it is possible that cerebellar stimulation will now save some patients from that last resort, ablative surgery.
c.c.s.
lished.2 tried in 32 patients with epilepsy. The agewas 14-56 range years, the length of illness 3-49 years, and the follow-up time for c.c.s. 13-53 months. The basis of selection was intractable epilepsy with electroenc.c.s. was
1. Cooper, I. S., Upton, A. R. M. Lancet, 1978, i, 595. 2. Cerebellar Stimulation in Man. Edited by I. S. COOPER. New York: Raven. 1978. pp. 232. $29.25.
THE MYOFIBROBLAST THE nature of the eosinophilic stellate cells in healing wounds remained a puzzle to pathologists for many years. Similarly the mechanism of wound contraction baffled the surgeon. By their site and shape the cells should have been fibroblasts, but, lacking the cytoplasmic basophilia of protein synthesis, they looked more
1291
like muscle cells. These ambivalent cells are now better understood and they are labelled myofibroblasts. The myofibroblast was named in 1971 by Majno, Ryan, and Gabbiani,’ whose group showed that it possessed the apparatus and many of the functional properties of both fibroblast and smooth-muscle cell. Transiently present in young granulation tissue, myofibroblasts shrink the wound and lose their myofibrils as it matures into a scar.2 The plastic surgeon tries to avoid excessive wound contraction by limiting the formation of granulation tissue with skin grafts, corticosteroids, and X rays, but now the hunt is on for pharmacological means of control.3 Myofibroblasts have been demonstrated in various reactive proliferations of connective tissue, including hypertrophic scars,4 ischsemic contractures of intrinsic hand muscles,s stenosing tenosynovitis, and carpal-tunnel syndrome.6 They may also be responsible for some of the progressive, disabling distortion of normal architecture in cirrhosis of the liver and sarcoidosis of the
mucosa.20 For a moment it seems that hope was misplaced in electron microscopy as the means of classifying more accurately the notoriously difficult and debatable
lung.8 Pluripotent cells in the aorta have been identified as myofibroblasts capable of synthesising elastin as well as collagen and matrix,9 and may phagocytose lipid too in atheroma.10 Their importance in elastogenesis is not yet established, though suggested by the fact that as elastic fibres wax in a wound, the myofibrils wane, and that the familiar but unexplained ganglia of the wrist consist of myofibroblasts capable of elastogenesis.11 However, it is not only in reactive proliferations but also in pseudotumorous and even a few frankly neoplastic conditions that myofibroblasts are being found.
VERY-LOW-DENSITY lipoproteins (V.L.D.L.) are secreted mainly by the liver, for transport of triglycerides to peripheral tissues such as muscle and heart. In the periphery they are broken down to low-density lipoproteins (L.D.L..) by catabolic enzymes such as lipoprotein lipase (L.P.L.) and possibly lecithin:cholesterol acyltransferase (L.C.A.T.). L.D.L. delivers cholesterol to peripheral tissues for the renewal of cell membranes and also inhibits the cellular synthesis of cholesterol. Circulating L.D.L. cholesterol thus regulates, by feedback inhibition of cholesterol synthesis, the cellular content of cholesterol. The lipids of the atheromatous plaque (mainly cholesterol, cholesteryl ester, and phospholipids) are derived from the plasma lipoproteins. Arterial cells can degrade lipoproteins; V.L.D.L. is metabolised in endothelial cells by the enzyme L.P.L., and the product particle, L.D.L., can filter through the endothelial barrier to be taken up by smooth-muscle cells in the subintimal space. Epidemiological and experimental evidence suggests, that raised plasma levels of V.L.D.L. and L.D.L. can predispose to atheroma, 1although it is still disputed whether v.L.D.L. acts as an independent variable for the develop7. ment of arterial disease. The fact that V.L.D.L. is converted into L.D.L. perhaps makes this argument specious. The current focus of attention in the development of atheroma is H.D.L. There is good epidemiological evidence to support the view that reduced levels of H.D.L. may retard the development of atheroma. For example, in 1953 Nikkila3 showed that patients with ischsemic heart-disease and normal total plasma-cholesterol concentrations had significantly reduced levels of H.D.L. cholesterol. This observation was largely neglected until 1975 when further evidence was assembled by Miller and Miller4 to suggest that a reduction in plasma-H.D.L. may impair the normal clearance of cholesterol from the arterial wall and thereby accelerate the development of atherosclerosis. Further weight was given to this idea by the Framingham epidemiological study: among 2815
.
Majno themselves described them in Dupuytren’s contracture,12 and the cells have also been found in the musculoaponeurotic fibromatoses (desmoid tumours),13 nodular fasciitis, 14 and Peyronie’s disease,15 They may simply reflect a phase of normal maturation of fibroblastic tissue in the spontaneous regression of multiple congenital mesenchymal hamartomas16 or be part of a change in a neoplasm analogous to the transformation of neuroblastoma into ganglioneuroma. In a small series of truly malignant tumours, 75% of the spindle cells in both fibrosarcomas and malignant fibrous histiocytomas proved to be myofibroblasts,17 and similar claims have been made for single examples of benign neoplasms such as uterine plexiform tumour,18 dermatofibroma, 19 and giant-cell fibroma of oral Gabbiani and
1. Gabbiani, G., Ryan, G. B., Majno, G. Experientia, 1971, 27, 549. 2. Guber, S., Rudolph, R. Surgery Gynec. Obstet. 1978, 146, 641. 3. Madden, J. W., Morton, D., Peacock, E. E. Surgery, 1974, 76, 8. 4. Baur, P. S., Larson, D. L., Stacey, T. R. Surgery Gynec. Obstet. 22. 5. Madden, J. W., Carlson, E. C., Hines, J. ibid. 1975, 140, 509. 6. Madden,J. W. Plast. reconstr. Surg., 1973, 52, 291. 7. Bhatal, P. S. Pathology, 1972, 4, 139.
1975, 141,
8. Judd, P. A., Finnegan, P., Curran, R.C.J. Path. 1975, 115, 191. 9. Wissler, R. W. Circulation, 1967, 36, 1. 10. Moss, N. S., Benditt, E. P. Lab. Invest. 1970, 23, 521. 11. Ghadially, F. N., Mehta, P. N. Ann. rheumat. Dis. 1971, 30, 31. 12. Gabbiani, G, Majno, G. Am. J. Path. 1972, 66, 131. 13. Stiller, D., Katenkamp, D. Virchows Arch. path. Anat. 1975, 369, 155. 14. Wirman, J. A., Cancer, 1976, 38, 2378. 15. Ariyan, S., Enriquez, R., Krizek, T.J. Archs Surg. 1978, 113, 1034. 16. Benjamin, S. P., Mercer, R. D., Hawk, W. A. Cancer, 1977, 40, 2343. 17. Churg, A. M., Kahn, L. B. Hum. Path. 1977, 8, 205. 18. Fisher, E. R., Paulson, J. D., Gregorio, R. M. Archs Path. 1978, 102, 477. 19. Hashimoto, K., Brownstein, M. H., Jakobiec, F. A. Archs Dermat., 1974,
110, 874.
Yet further work may show that feature of immaturity, and one wonders myofibrils whether radiotherapy will diminish them just as it "matures" other tumours, and whether their presence in a spindle-cell tumour will indicate a poorer prognosis than their absence. The dynamic plasticity of mesenchyme has been underlined by the description of the myofibroblast. Its origins are so far unknown and may lie in immigrant cells, blood-vessels, or transformed local fibroblasts, but tissue-culture experiments show that smooth muscle can secrete collagen and elastin. 21
soft-tissue
tumours.
are a
HIGH-DENSITY LIPOPROTEIN AND ATHEROMA
20. Weathers, D. R., Campbell, W. G. Oral Surg. 1974, 38, 550. 21. Ross, R., Klebanoff, S. J. J. Cell Biol. 1971, 50, 159. 1. Carlson, L. A., Bottiger, L. E. Lancet, 1972, i, 865. 2. Kannel, W. B., Castelli, W. P., Gordon, T., McNamara, P. M. Ann. intern. Med. 1971, 74, 1. 3. Nikkilä, E. Scand. J. clin. Lab. Invest. 1953, 5, suppl. 8. 4. Miller, G. J., Miller, N. E. Lancet, 1975, i, 16.