28 age distribution for males is shown in fig. 1. The mean age for males (57 2 ±3 4 years) was approximately 5 years younger than that for females (62 4r:56 years). In fig. 1 the observed age distribution for males is compared with the expected age distribution based on that for primary liver cancer deaths (I.C.D. 155-0) in 1971. Since most cases of angiosarcoma were identified in I.C.D. category 197-8 (liver cancer not specified whether primary or secondary), a further comparison has been made with this cause group-the mean age at death for adult males was 68-2 years and for females 72 4 years. Because were whose deaths certified due to as persons angiosarcoma appeared to die at an earlier age than those certified as dying from primary liver cancer, this does not necessarily
indicate that
an environmental/occupational cause was paramount-but an unusual tumour would be more frequently identified in younger persons if this diagnosis were more assiduously pursued in this age-group. Fig. 2 shows the annual number of cases that were certified between 1963 and 1973. No explanation has yet been found for the apparent peak of ten cases in 1969, which year also saw the highest incidence of death in adults from primary liver cancers in this period, although as is shown in the figure the rise is not as great as that for adult deaths from angiosarcoma. Fig. 2 also shows the annual number of deaths certified as due to benign haemangioendothelioma " (I.C.D. 227’X). There were eight such cases in the 11-year period. This latter group has been given separately because one of the two proven industrially related cases was identified in this group. This death certificate simply recorded hxmangioendothelioma
2-Deaths due to angiosarcoma of the liver and endothelioma (coded as benign).
Fig.
hatmangio-
The trend for primary liver cancers is given to indicate marginal rise in 1968 and 1969. It was calculated by multiplying the number per year by 32/1433 (no. of angiosarcoma 1963-73 divided by total no. of primary liver cancers 1963-71).
"
"
"
which was coded of the liver-verdict of natural causes as benign, I.C.D. 227 X, because there was no mention of malignant". The industrially related case dying in 1974 had Carcinomatosis; angiosarcoma of the liver; " hepatic cirrhosis recorded on his death certificate. "
"
cases of angiosarcoma of the liver were notified E.M.A.S. by Dr A. H. T. Robb-Smith from Radcliffe Infirmary at Oxford. O.P.C.S. could not have been expected to identify these three deaths because the certified causes of death were:
Three
to
Case 1-(c) (a) Bronchopneumonia; (b) ischaemic heartdisease : (II) hypoproteinaemia (I.C.D. 412-3). Case .2—(i) (a) Neoplasm in liver/liver failure; (b) lung
primary growth ?(I.C.D. 1621). Case 3-(t) (a) Pulmonary embolus; (b) deep-vein thrombosis; (c) carcinoma of the liver (I.C.D. 197-8). These three cases along with the case of angiosarcoma codified as benign haemangioendothelioma illustrate the deficiencies of relying on death-certificate data alone. E.M.A.S. has established a panel of pathologists whose initial task is to review material from all suspected possible and probable cases identified in the 11-year period. A retrospective study identifying cases from 1974 onward has been established with the aim of obtaining a more accurate measure of the annual incidence of angiosarcoma of the liver. All the cases identified by this method, including those identified between 1963 and 1973, will be pursued for detailed occupational histories and a register established. Except for the 1972 case, in none of the 1963-73 cases was an occupational exposure indicated by the death certificates. A comprehensive follow-up obtaining a full occupational history in each of these cases is being conducted.
AGE AT DEATH
70-
Employment Medical Advisory Service, Health and Safety Executive, Baynards House, 1 Chepstow Place, London W2 4TF.
MALE PRIMARV LIVER CANCER 1971, MEAN AGE AT DEATH 6. 3
"2 9
YEARS
1
P. J. BAXTER A. J. Fox.
TREATMENT OF SPINA BIFIDA
Sm,—Dr Campbell and his colleagues (June 14, p. 1336) express the view that certain lesions of
spina bifida are I doubt that this is the case if one uses the inoperable " word " inoperable in the usual sense. In my experience, " very, very few such lesions are truly inoperable Whether or not one can justify early emergency neonatal surgery in all cases of large thoracolumbosacral myelomeningocele depends on one’s own particular philosophy, but it is never true to say that such lesions are " dearly inoperable ", and the termination of pregnancy cannot be "
AGE A"" ^f3’..
Ftt. 1—Mttftbtttico of tnmte deaths due to angiosarcoma of the liver and primary liver cancer (I.C.D. t55-8).
".
29 "
grounds of the " inoperability of the fetal lesion. Indeed, mere size alone is of little impor-
justified simply
on
the
in connection with the ease of surgery in these cases. I should add that lesions in the sacral area are not " probably operable "-they all are. One must not confuse the objective fact that nearly all lesions in spina bifida are treatable and operable with one’s subjective judgment as to whether or not the results of such surgery are acceptable or worthwhile. The Children’s Hospital, Western Bank, R. J. BRERETON. Sheffield S10 2TH. tance
COXSACKIE B4 VIRUS INFECTION AND DIABETES
SIR,-The interesting report by Dr Dippe and his colleagues (June 14, p. 1314) has highlighted a difficult but important question concerning the aetiology of juvenileonset diabetes. Although a negative correlation was found between a severe epidemic of CB4 infection and the develop-. of diabetes, notably in the 5-20-year age-group in the community on the Pribilof Islands, this does not exclude viral infection and in particular CB4 as a cause of islet-cell injury in genetically susceptible individuals. It has been shown that individuals possessing HL-A8 or W15 antigens have an approximate 2-3-fold increased risk of developing insulin-dependent diabetes. 1-4 Furthermore, strong evidence that the major locus producing susceptibility to this type of diabetes is in the HL-A chromosomal region has been obtained by study of siblings with " juvenile " diabetes. The fundamental question is what is the mechanism of action of this HL-A-linked diabetogenic gene(s) ? It is likely that different alleles at this locus are interacting with different environmental factors to precipitate clinical disease. The circumstantial evidence for CB4 infection as a possible triggering environmental factor in the U.K. is well known.ó However, this type of epidemiological evidence, together with current estimates of the population incidence of juvenile onset diabetes, suggest that only a small proportion of individuals are likely to develop diabetes as a result of CB4 infection, and the population studied by Dippe et al. may not be large enough to detect this association. If the concept of viruses interacting with HL-A-linked genes to produce diabetes is a real one, a way of investigating this would be to ascertain whether a positive association exists between evidence for recent infection with a particular virus and HL-A8 or W15, these antigens being in linkage disequilibrium with the diabetogenic genes. Thus, HL-A8 might be linked with a gene which interacts with one virus or group of viruses, and W15 with another. If HL-Alinked genes are present in the Aleuts, they might produce susceptibility to diabetes by interacting with viruses other than CB4. Since the national register for diabetic children was started in 1972 under the segis of the British Diabetic Association, 69 blood-samples have been received for virological analysis from new diabetics under the age of 16 years residing in the Liverpool area. Efforts are being made to trace all these children for HL-A typing. From Oct. 1, 1974, all the new cases of diabetes under the age of 30 years (43 cases so far) have been seen within a week of onset of clinical symptoms in order to obtain blood as early as possible for estimation of virus-antibody titres as well as HL-A typing. It is hoped that these retrospective ment
Nerup, J., et al. Lancet, 1974, ii, 864. Cudworth, A. G., Woodrow, J. C. ibid. p. 1153. Cudworth, A. G., Woodrow, J. C. Diabetes, 1975, 24, 345. Cudworth, A. G., Woodrow, J. C. Br. med. J. (in the press). 5. Gamble, D. R. Postgrad. med. J. 1974, 50, suppl. 3, p. 538. 1. 2. 3. 4.
and prospective studies will throw further light on the relative importance of CB4 and other known virological agents in the pathogenesis of juvenile-onset diabetes. University Department of Medicine, A. G. CUDWORTH P.O. Box 147,
Liverpool L69 3BX. Public Health Laboratory, West Park Hospital, Epsom, Surrey.
J. C. WOODROW. D. R. GAMBLE.
MAGNESIUM AND MYOCARDIAL ISCHÆMIA SIR,-At a symposium held by the E.E.C. in Luxembourg this May, D. G. Clayton described the higher incidence of heart-attacks in the soft-water areas of North-West England and in Scotland in comparison with the hard-water areas of the South-East. The problem is complicated by differences in the social-class structure of the populations, in smoking habits, and in other variables. Nevertheless, many studies have provided evidence that hard water does appear to offer some protection against dying from a heartattack. 2-10 Calcium or magnesium salts seem to be the likeliest factors; for instance, the magnesium in the myocardium has been found to be low after an ischaemic heart-attack." Many thousands of people in Great Britain and Ireland are in the habit of taking effervescent health salts (magnesium sulphate) every morning, and these salts greatly increase their daily intake of magnesium. It would be interesting to find out whether regular takers of salts living in areas of soft water have a lower risk of dying from a heart-attack than the rest of the community. As a previous correspondent pointed out, perhaps those who take " enough to cover a sixpence every morning have been wiser than they realised.12
indicate that
an environmental/occupational cause was paramount-but an unusual tumour would be more frequently identified in younger persons if this diagnosis were more assiduously pursued in this age-group. Fig. 2 shows the annual number of cases that were certified between 1963 and 1973. No explanation has yet been found for the apparent peak of ten cases in 1969, which year also saw the highest incidence of death in adults from primary liver cancers in this period, although as is shown in the figure the rise is not as great as that for adult deaths from angiosarcoma. Fig. 2 also shows the annual number of deaths certified as due to benign haemangioendothelioma " (I.C.D. 227’X). There were eight such cases in the 11-year period. This latter group has been given separately because one of the two proven industrially related cases was identified in this group. This death certificate simply recorded hxmangioendothelioma
2-Deaths due to angiosarcoma of the liver and endothelioma (coded as benign).
Fig.
hatmangio-
The trend for primary liver cancers is given to indicate marginal rise in 1968 and 1969. It was calculated by multiplying the number per year by 32/1433 (no. of angiosarcoma 1963-73 divided by total no. of primary liver cancers 1963-71).
"
"
"
which was coded of the liver-verdict of natural causes as benign, I.C.D. 227 X, because there was no mention of malignant". The industrially related case dying in 1974 had Carcinomatosis; angiosarcoma of the liver; " hepatic cirrhosis recorded on his death certificate. "
"
cases of angiosarcoma of the liver were notified E.M.A.S. by Dr A. H. T. Robb-Smith from Radcliffe Infirmary at Oxford. O.P.C.S. could not have been expected to identify these three deaths because the certified causes of death were:
Three
to
Case 1-(c) (a) Bronchopneumonia; (b) ischaemic heartdisease : (II) hypoproteinaemia (I.C.D. 412-3). Case .2—(i) (a) Neoplasm in liver/liver failure; (b) lung
primary growth ?(I.C.D. 1621). Case 3-(t) (a) Pulmonary embolus; (b) deep-vein thrombosis; (c) carcinoma of the liver (I.C.D. 197-8). These three cases along with the case of angiosarcoma codified as benign haemangioendothelioma illustrate the deficiencies of relying on death-certificate data alone. E.M.A.S. has established a panel of pathologists whose initial task is to review material from all suspected possible and probable cases identified in the 11-year period. A retrospective study identifying cases from 1974 onward has been established with the aim of obtaining a more accurate measure of the annual incidence of angiosarcoma of the liver. All the cases identified by this method, including those identified between 1963 and 1973, will be pursued for detailed occupational histories and a register established. Except for the 1972 case, in none of the 1963-73 cases was an occupational exposure indicated by the death certificates. A comprehensive follow-up obtaining a full occupational history in each of these cases is being conducted.
AGE AT DEATH
70-
Employment Medical Advisory Service, Health and Safety Executive, Baynards House, 1 Chepstow Place, London W2 4TF.
MALE PRIMARV LIVER CANCER 1971, MEAN AGE AT DEATH 6. 3
"2 9
YEARS
1
P. J. BAXTER A. J. Fox.
TREATMENT OF SPINA BIFIDA
Sm,—Dr Campbell and his colleagues (June 14, p. 1336) express the view that certain lesions of
spina bifida are I doubt that this is the case if one uses the inoperable " word " inoperable in the usual sense. In my experience, " very, very few such lesions are truly inoperable Whether or not one can justify early emergency neonatal surgery in all cases of large thoracolumbosacral myelomeningocele depends on one’s own particular philosophy, but it is never true to say that such lesions are " dearly inoperable ", and the termination of pregnancy cannot be "
AGE A"" ^f3’..
Ftt. 1—Mttftbtttico of tnmte deaths due to angiosarcoma of the liver and primary liver cancer (I.C.D. t55-8).
".
29 "
grounds of the " inoperability of the fetal lesion. Indeed, mere size alone is of little impor-
justified simply
on
the
in connection with the ease of surgery in these cases. I should add that lesions in the sacral area are not " probably operable "-they all are. One must not confuse the objective fact that nearly all lesions in spina bifida are treatable and operable with one’s subjective judgment as to whether or not the results of such surgery are acceptable or worthwhile. The Children’s Hospital, Western Bank, R. J. BRERETON. Sheffield S10 2TH. tance
COXSACKIE B4 VIRUS INFECTION AND DIABETES
SIR,-The interesting report by Dr Dippe and his colleagues (June 14, p. 1314) has highlighted a difficult but important question concerning the aetiology of juvenileonset diabetes. Although a negative correlation was found between a severe epidemic of CB4 infection and the develop-. of diabetes, notably in the 5-20-year age-group in the community on the Pribilof Islands, this does not exclude viral infection and in particular CB4 as a cause of islet-cell injury in genetically susceptible individuals. It has been shown that individuals possessing HL-A8 or W15 antigens have an approximate 2-3-fold increased risk of developing insulin-dependent diabetes. 1-4 Furthermore, strong evidence that the major locus producing susceptibility to this type of diabetes is in the HL-A chromosomal region has been obtained by study of siblings with " juvenile " diabetes. The fundamental question is what is the mechanism of action of this HL-A-linked diabetogenic gene(s) ? It is likely that different alleles at this locus are interacting with different environmental factors to precipitate clinical disease. The circumstantial evidence for CB4 infection as a possible triggering environmental factor in the U.K. is well known.ó However, this type of epidemiological evidence, together with current estimates of the population incidence of juvenile onset diabetes, suggest that only a small proportion of individuals are likely to develop diabetes as a result of CB4 infection, and the population studied by Dippe et al. may not be large enough to detect this association. If the concept of viruses interacting with HL-A-linked genes to produce diabetes is a real one, a way of investigating this would be to ascertain whether a positive association exists between evidence for recent infection with a particular virus and HL-A8 or W15, these antigens being in linkage disequilibrium with the diabetogenic genes. Thus, HL-A8 might be linked with a gene which interacts with one virus or group of viruses, and W15 with another. If HL-Alinked genes are present in the Aleuts, they might produce susceptibility to diabetes by interacting with viruses other than CB4. Since the national register for diabetic children was started in 1972 under the segis of the British Diabetic Association, 69 blood-samples have been received for virological analysis from new diabetics under the age of 16 years residing in the Liverpool area. Efforts are being made to trace all these children for HL-A typing. From Oct. 1, 1974, all the new cases of diabetes under the age of 30 years (43 cases so far) have been seen within a week of onset of clinical symptoms in order to obtain blood as early as possible for estimation of virus-antibody titres as well as HL-A typing. It is hoped that these retrospective ment
Nerup, J., et al. Lancet, 1974, ii, 864. Cudworth, A. G., Woodrow, J. C. ibid. p. 1153. Cudworth, A. G., Woodrow, J. C. Diabetes, 1975, 24, 345. Cudworth, A. G., Woodrow, J. C. Br. med. J. (in the press). 5. Gamble, D. R. Postgrad. med. J. 1974, 50, suppl. 3, p. 538. 1. 2. 3. 4.
and prospective studies will throw further light on the relative importance of CB4 and other known virological agents in the pathogenesis of juvenile-onset diabetes. University Department of Medicine, A. G. CUDWORTH P.O. Box 147,
Liverpool L69 3BX. Public Health Laboratory, West Park Hospital, Epsom, Surrey.
J. C. WOODROW. D. R. GAMBLE.
MAGNESIUM AND MYOCARDIAL ISCHÆMIA SIR,-At a symposium held by the E.E.C. in Luxembourg this May, D. G. Clayton described the higher incidence of heart-attacks in the soft-water areas of North-West England and in Scotland in comparison with the hard-water areas of the South-East. The problem is complicated by differences in the social-class structure of the populations, in smoking habits, and in other variables. Nevertheless, many studies have provided evidence that hard water does appear to offer some protection against dying from a heartattack. 2-10 Calcium or magnesium salts seem to be the likeliest factors; for instance, the magnesium in the myocardium has been found to be low after an ischaemic heart-attack." Many thousands of people in Great Britain and Ireland are in the habit of taking effervescent health salts (magnesium sulphate) every morning, and these salts greatly increase their daily intake of magnesium. It would be interesting to find out whether regular takers of salts living in areas of soft water have a lower risk of dying from a heart-attack than the rest of the community. As a previous correspondent pointed out, perhaps those who take " enough to cover a sixpence every morning have been wiser than they realised.12
