245
than liver tissue receiving only "pancreatic" blood. That insulin plays a part in controlling hepatic cell size seems incontrovertible. Its role as a stimulus to hepatocellular regeneration is less certain. N. BUCHER and her colleagues claimed that combined administration of insulin and glucagon promoted compensatory hyperplasia after partial hepatectomy in eviscerated rats; but in the same animal U. JUNGE and W. CREUTZFELDT found no effect of insulin and glucagon on hepatic D.N.A. synthesis after partial hepatectomy. Even if insulin and glucagon play a supportive role they are highly unlikely to initiate hepatic regeneration. Firstly, they seem to have no effect on hepatocellular proliferation in animals with intact livers. Secondly, portal-vein insulin concentrations fall after partial hepatectomy even though hepatic regeneration has been stimulated. Finally, changes in systemic plasma insulin and glucagon after partial hepatectomy could surely not account for the stimulation of hepatic D.N.A. synthesis observed in normal recipients in cross-circulation experiments. BUCHER claimed that epidermal growth factor (E.G.F.), a polypeptide similar in size to insulin, can initiate D.N.A. synthesis in the liver of normal rats and that this effect is potentiated by administration of glucagon and insulin. Unfortunately the factors controlling E.G.F. release are unknown, nor do we know whether plasma levels rise after partial hepatectomy. Hyperplasia of the liver occurs in acromegaly and in rats with transplanted pituitary tumours which secrete prolactin as well as growth hormone. But, despite these isolated observations, the factors controlling the size of the liver remain D.N.A.
venous
a
mystery. At present it is difficult
to exploit the hepatotrofor the of patients. BUCHER benefit phic concept and her colleagues found that insulin and glucagon increased survival in mice infected with lethal doses of murine hepatitis virus, and on this basis it has been suggested that patients with severe viral hepatitis should be treated with insulin and glucagon. But there are as yet no clinical studies to support this suggestion, and in rats JUNGE and CREUTZFELDT were unable to demonstrate protection against the lethal effects of hepatic necrosis caused by carbon tetrachloride. It seems sensible to give large amounts of glucose to patients with acute hepatocellular necrosis, orally rather than intravenously. This will stimulate insulin secretion, though glucagon concentrations will probably fall. There are reports of benefit from such treatment, but the evidence is anecdotal. The transplant surgeon now appreciates the requirements of the donor liver for portal blood. But the surgeon performing a portacaval shunt is not yet able to harness portal factors in order to prevent or to lessen the liver damage which may follow surgery; nor can he tell whether the diversion of portal factors
is responsible for the apparent benefits of shunt surgery in some patients with homozygous type II hypercholesterolaemia and in patients with several types of glycogen-storage disease. There has been confusion and controversy in the search for hepatotrophic factors, and for several reasons. Those who have studied the effects of portal diversion have used different animals and different experimental techniques from those who have studied regeneration after hepatic resection. Both groups have relied excessively on indirect evidence. Finally, the mechanisms controlling cell size and division are clearly complex but there has been
tendency to promote simple explanations even though each of them conflicts with experimental data. But the Ciba volume shows clearly that the hepatotrophic sphere is an exciting and challenging one. There is good reason to believe that the portal blood may soon give up more of its secrets. a
Aspirin and Stroke Prevention TRANSIENT cerebral ischaemic attacks
(T.I.A.S), patient, are not important in themselves since, by definition, they cease spontaneously within 24 hours. Their importance lies in the fact that they often give warning of an impending stroke. About a third of the patients will have a stroke, the period of greatest risk being the first
though alarming
to a
months after the first T.I.A.’ For this reason anticoagulant therapy has been widely used, with2 apparent reduction in the incidence of strokes. Endarterectomy is likewise beneficial in patients with suitable lesions.34 Most T.l.A.s, and indeed many strokes, are believed to be due to emboli arising from the heart or from atheromatous lesions in the great vessels supplying the brain..5-7 The formation of emboli is a complex process but aggregation of platelets and deposition of fibrin are important first steps. One approach has therefore been to try drugs which inhibit platelet aggregation. In 1977 a multicentre, double-blind, randomised trial of 600 mg aspirin twice a day involving 178 patients with T.I.A.S over 37 months, was reported from the United States.Continued T.I.A.S, cerebral or retinal infarction, and death were taken as end-
two
points,
none
showing statistically significant they were combined in
benefit. However, when
1. Whisnant, J. P., Matsumoto, N., Elveback, L. R. Mayo Clin. Proc. 1973, 48, 194. 2. Marshall, J. The Management of Cerebrovascular Disease. Oxford, 1976. 3. Bauer, R. B., Meyer, J. S., Fields, W. S. J. Am. med. Ass. 1969, 208, 509. 4. Wylie, E. J., Ehrenfield, W. T. Extracranial Occlusive Cerebrovascular Disease. Philadelphia 1970. 5. Torvik, A., Jorgensen, L.J. neurol. Sci. 1966, 3, 410. 6. Jorgensen, L., Torvik, A. ibid. p. 490. 7. Jorgensen, L., Torvik, A. ibid. 1969, 9, 285. 8. Fields, W. S., Lemak, N. A., Frankowski, R. F., Hardy, R. J. Stroke, 1977,
8, 301.
246
what
named "a favourable outcome" there significant advantage to the aspirin-treated group. The need to combine such disparate endpoints as death and retinal ischxmia to secure a significant result indicated the need for caution in interpreting the results. Now a cooperative trial from Canaday has been reported which provides clearer indications of the role of aspirin and sulphinpyrazone. 585 patients with T.I.A.S were divided into four groups-sulphinpyrazone plus was
was a
placebo, aspirin plus placebo, sulphinpyrazone plus aspirin, and placebo only. They were followed for 26 months, a follow-up rate of 99% being achieved. The crucial finding was that aspirin reduced the risk of stroke or death by 48% (P
than liver tissue receiving only "pancreatic" blood. That insulin plays a part in controlling hepatic cell size seems incontrovertible. Its role as a stimulus to hepatocellular regeneration is less certain. N. BUCHER and her colleagues claimed that combined administration of insulin and glucagon promoted compensatory hyperplasia after partial hepatectomy in eviscerated rats; but in the same animal U. JUNGE and W. CREUTZFELDT found no effect of insulin and glucagon on hepatic D.N.A. synthesis after partial hepatectomy. Even if insulin and glucagon play a supportive role they are highly unlikely to initiate hepatic regeneration. Firstly, they seem to have no effect on hepatocellular proliferation in animals with intact livers. Secondly, portal-vein insulin concentrations fall after partial hepatectomy even though hepatic regeneration has been stimulated. Finally, changes in systemic plasma insulin and glucagon after partial hepatectomy could surely not account for the stimulation of hepatic D.N.A. synthesis observed in normal recipients in cross-circulation experiments. BUCHER claimed that epidermal growth factor (E.G.F.), a polypeptide similar in size to insulin, can initiate D.N.A. synthesis in the liver of normal rats and that this effect is potentiated by administration of glucagon and insulin. Unfortunately the factors controlling E.G.F. release are unknown, nor do we know whether plasma levels rise after partial hepatectomy. Hyperplasia of the liver occurs in acromegaly and in rats with transplanted pituitary tumours which secrete prolactin as well as growth hormone. But, despite these isolated observations, the factors controlling the size of the liver remain D.N.A.
venous
a
mystery. At present it is difficult
to exploit the hepatotrofor the of patients. BUCHER benefit phic concept and her colleagues found that insulin and glucagon increased survival in mice infected with lethal doses of murine hepatitis virus, and on this basis it has been suggested that patients with severe viral hepatitis should be treated with insulin and glucagon. But there are as yet no clinical studies to support this suggestion, and in rats JUNGE and CREUTZFELDT were unable to demonstrate protection against the lethal effects of hepatic necrosis caused by carbon tetrachloride. It seems sensible to give large amounts of glucose to patients with acute hepatocellular necrosis, orally rather than intravenously. This will stimulate insulin secretion, though glucagon concentrations will probably fall. There are reports of benefit from such treatment, but the evidence is anecdotal. The transplant surgeon now appreciates the requirements of the donor liver for portal blood. But the surgeon performing a portacaval shunt is not yet able to harness portal factors in order to prevent or to lessen the liver damage which may follow surgery; nor can he tell whether the diversion of portal factors
is responsible for the apparent benefits of shunt surgery in some patients with homozygous type II hypercholesterolaemia and in patients with several types of glycogen-storage disease. There has been confusion and controversy in the search for hepatotrophic factors, and for several reasons. Those who have studied the effects of portal diversion have used different animals and different experimental techniques from those who have studied regeneration after hepatic resection. Both groups have relied excessively on indirect evidence. Finally, the mechanisms controlling cell size and division are clearly complex but there has been
tendency to promote simple explanations even though each of them conflicts with experimental data. But the Ciba volume shows clearly that the hepatotrophic sphere is an exciting and challenging one. There is good reason to believe that the portal blood may soon give up more of its secrets. a
Aspirin and Stroke Prevention TRANSIENT cerebral ischaemic attacks
(T.I.A.S), patient, are not important in themselves since, by definition, they cease spontaneously within 24 hours. Their importance lies in the fact that they often give warning of an impending stroke. About a third of the patients will have a stroke, the period of greatest risk being the first
though alarming
to a
months after the first T.I.A.’ For this reason anticoagulant therapy has been widely used, with2 apparent reduction in the incidence of strokes. Endarterectomy is likewise beneficial in patients with suitable lesions.34 Most T.l.A.s, and indeed many strokes, are believed to be due to emboli arising from the heart or from atheromatous lesions in the great vessels supplying the brain..5-7 The formation of emboli is a complex process but aggregation of platelets and deposition of fibrin are important first steps. One approach has therefore been to try drugs which inhibit platelet aggregation. In 1977 a multicentre, double-blind, randomised trial of 600 mg aspirin twice a day involving 178 patients with T.I.A.S over 37 months, was reported from the United States.Continued T.I.A.S, cerebral or retinal infarction, and death were taken as end-
two
points,
none
showing statistically significant they were combined in
benefit. However, when
1. Whisnant, J. P., Matsumoto, N., Elveback, L. R. Mayo Clin. Proc. 1973, 48, 194. 2. Marshall, J. The Management of Cerebrovascular Disease. Oxford, 1976. 3. Bauer, R. B., Meyer, J. S., Fields, W. S. J. Am. med. Ass. 1969, 208, 509. 4. Wylie, E. J., Ehrenfield, W. T. Extracranial Occlusive Cerebrovascular Disease. Philadelphia 1970. 5. Torvik, A., Jorgensen, L.J. neurol. Sci. 1966, 3, 410. 6. Jorgensen, L., Torvik, A. ibid. p. 490. 7. Jorgensen, L., Torvik, A. ibid. 1969, 9, 285. 8. Fields, W. S., Lemak, N. A., Frankowski, R. F., Hardy, R. J. Stroke, 1977,
8, 301.
246
what
named "a favourable outcome" there significant advantage to the aspirin-treated group. The need to combine such disparate endpoints as death and retinal ischxmia to secure a significant result indicated the need for caution in interpreting the results. Now a cooperative trial from Canaday has been reported which provides clearer indications of the role of aspirin and sulphinpyrazone. 585 patients with T.I.A.S were divided into four groups-sulphinpyrazone plus was
was a
placebo, aspirin plus placebo, sulphinpyrazone plus aspirin, and placebo only. They were followed for 26 months, a follow-up rate of 99% being achieved. The crucial finding was that aspirin reduced the risk of stroke or death by 48% (P
