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CAUSES OF CONGENITAL HEART-DISEASE
168
passing effect on cell turnover unrelated to chronic renal damage ? The effect was not found with dummy tablets, but what about those containing drugs other than analgesics ? The doses used were several times the ordinary amount, save for addicts, and we need to know about the cumulative effects of small doses. Prescott rightly suggests that attention should be paid to aspirin as well as to phenacetin as a potential cause of renal damage, though, on his results, caffeine should also be included, at least for those factory workers who drink ten cups of tea a day. These findings have less direct bearing upon the basic problems cf analgesic nephropathy, though in time such studies may well contribute to their solution. If, as has been suggested, nephropathy is related to some contaminant, such as acetic 4-chloranilide,33 or to the total cumulative dose consumed rather than to the duration of exposure,4there is a need for new methods of investigation more powerful than the epidemiological or cell-excretion techniques available so far. There is, for example, no satisfactory experimental model of the human disease. The unpleasant possibility even exists that one drug may be found to sensitise patients to the ill-effects of another-a difficult proposition to test experimentally. We still do not know how or why chronic nephropathy develops, or its exact relationship " to pyelonephritis ". The new findings help by showing that acute nephrotoxic effects may arise with analgesics, and that their intensity can be measured. As Prescott shows by analogy with peptic ulcer, the acute and chronic effects may be related. As with peptic ulcer, however, such analogies are fraught with logical pitfalls. more
CAUSES OF CONGENITAL HEART-DISEASE
NEW information about the role of rubella in the xtiology of congenital heart-disease was among the subjects discussed by members from fifteen countries at the recent annual meeting of the Association of European Pxdiatric Cardiologists in St. Andrews. Reporting the the the of after Baltimore experience group great epidemic of this disease on the east coast of the United States last year,5 Dr. Catherine Neill emphasised the great advances in knowledge that have been made since it became possible nor only to culture the virus but also to make an exact diagnosis in babies and very small children by cardiac catheterisation combined with selective cineangiocardiography. This American epidemic confirmed what was first demonstrated twenty years ago-that rubella is a source, and indeed may be a terrible source, of congenital wastage. It is now known that a foetus may be affected even when the infection begins before gestation, that the virus remains in the foetus throughout intrauterine life, and that the virus may be excreted or cultured for up to six months after birth. The extraordinary affinity of the rubella virus for the sixth aortic arch has also been confirmed, and the virus is a powerful arterial teratogen causing persistence of the ductus arteriosus and stenosis of the pulmonary arteries. Though it has often been grown from the hearts of those who have died, and there have been several fairly well-documented cases of myocarditis, the virus seems to be rather a weak cardiac teratogen. Prof. John Hay described how information about 3. Harvald, B., Valdorf-Hausen, F., Nielsen, A. ibid. 1960, 4. Moeschlin, S. Schweiz. med. Wschr. 1957, 87, 123. 5. See Lancet, 1965, i, 1208.
i,
303.
possible aetiological factors in congenital malformations is being obtained by the university department of child health in Liverpool, where a central registry has been set up with the cooperation of the Ministry of Health and the local authorities. An elaborate system has been devised to record those malformations (up to 50%) that escape compulsory notification to the central Government. Close and willing cooperation from many hospitals and clinics, plus constant surveillance by social and public-health workers, has ensured that the great majority of congenital defects are available for statistical analysis. A simple method of wall-charting ensures that any increased incidence soon becomes obvious and a search can be made for possible setiological factors that began to operate during the preceding nine months. The thalidomide tragedy was graphically recorded in this way; and tetracycline is at present under investigation, by reference to the National Health Service prescription forms which are kept in a central office of the Ministry of Health. The importance of this awesome administrative task is proved by prescriptions for thalidomide made out to the mothers of some babies without limbs, who said they had taken no tablets and whose doctors denied prescribing them. These carefully controlled investigations should shed new light on infective and chemical factors in the aetiology of congenital malformations, and at the same time determine the true incidence of the various anomalies at birth. A long-term study of babies with congenital heartdisease is already under way and will help to define the size of the diagnostic and therapeutic problem. It should be useful, too, in highlighting, at any rate in this country, the extent to which pxdiatric cardiology has been neglected; and the results will also be of value in planning future services, since the great majority of children who are born with serious congenital heart-disease do not survive their first year of life, and many of those whose hearts fail early are the ones for whom most could be done. TREATMENT OF NEPHROBLASTOMA
ANY treatment of malignant tumours in childhood has usually to be assessed from results in a small number of patients who have been treated by several methods. A plan of treatment which simplifies the assessment of the value of a single agent is therefore welcome. Death from nephroblastoma (Wilms’ tumour) is mainly due to bloodborne metastases, and it has been known for some years that actinomycin D may inhibit the growth of pulmonary metastases of nephroblastoma. Howard1 has reviewed the results of adding actinomycin D to the standard treatment of nephroblastoma at the Royal Children’s Hospital, Melbourne. A total dose of actinomycin of 120 {jt.g. per kg. body-weight was given in 8 equal quantities. Nephrectomy was carried out after the third dose, and postoperative irradiation was delayed until the 26th day. Of 18 consecutive patients treated in this way, 11 (62%) have survived without sign of recurrence for two to five years-a great improvement on the previous survival-rate (11-5%) at the same hospital.2 Howard reminds us of the toxic properties of this antibiotic : depression of bone-marrow, with a risk of aplastic ansemia, macular rashes, epilation of the scalp, and anorexia, vomiting, stomatitis, and bloody diarrhoea. These toxic reactions vary from patient to patient and with 1. 2.
Howard, R. Archs Dis. Childh. 1965, 40, Howard, R. Med. J. Aust. 1957, i, 200.
200.
passing effect on cell turnover unrelated to chronic renal damage ? The effect was not found with dummy tablets, but what about those containing drugs other than analgesics ? The doses used were several times the ordinary amount, save for addicts, and we need to know about the cumulative effects of small doses. Prescott rightly suggests that attention should be paid to aspirin as well as to phenacetin as a potential cause of renal damage, though, on his results, caffeine should also be included, at least for those factory workers who drink ten cups of tea a day. These findings have less direct bearing upon the basic problems cf analgesic nephropathy, though in time such studies may well contribute to their solution. If, as has been suggested, nephropathy is related to some contaminant, such as acetic 4-chloranilide,33 or to the total cumulative dose consumed rather than to the duration of exposure,4there is a need for new methods of investigation more powerful than the epidemiological or cell-excretion techniques available so far. There is, for example, no satisfactory experimental model of the human disease. The unpleasant possibility even exists that one drug may be found to sensitise patients to the ill-effects of another-a difficult proposition to test experimentally. We still do not know how or why chronic nephropathy develops, or its exact relationship " to pyelonephritis ". The new findings help by showing that acute nephrotoxic effects may arise with analgesics, and that their intensity can be measured. As Prescott shows by analogy with peptic ulcer, the acute and chronic effects may be related. As with peptic ulcer, however, such analogies are fraught with logical pitfalls. more
CAUSES OF CONGENITAL HEART-DISEASE
NEW information about the role of rubella in the xtiology of congenital heart-disease was among the subjects discussed by members from fifteen countries at the recent annual meeting of the Association of European Pxdiatric Cardiologists in St. Andrews. Reporting the the the of after Baltimore experience group great epidemic of this disease on the east coast of the United States last year,5 Dr. Catherine Neill emphasised the great advances in knowledge that have been made since it became possible nor only to culture the virus but also to make an exact diagnosis in babies and very small children by cardiac catheterisation combined with selective cineangiocardiography. This American epidemic confirmed what was first demonstrated twenty years ago-that rubella is a source, and indeed may be a terrible source, of congenital wastage. It is now known that a foetus may be affected even when the infection begins before gestation, that the virus remains in the foetus throughout intrauterine life, and that the virus may be excreted or cultured for up to six months after birth. The extraordinary affinity of the rubella virus for the sixth aortic arch has also been confirmed, and the virus is a powerful arterial teratogen causing persistence of the ductus arteriosus and stenosis of the pulmonary arteries. Though it has often been grown from the hearts of those who have died, and there have been several fairly well-documented cases of myocarditis, the virus seems to be rather a weak cardiac teratogen. Prof. John Hay described how information about 3. Harvald, B., Valdorf-Hausen, F., Nielsen, A. ibid. 1960, 4. Moeschlin, S. Schweiz. med. Wschr. 1957, 87, 123. 5. See Lancet, 1965, i, 1208.
i,
303.
possible aetiological factors in congenital malformations is being obtained by the university department of child health in Liverpool, where a central registry has been set up with the cooperation of the Ministry of Health and the local authorities. An elaborate system has been devised to record those malformations (up to 50%) that escape compulsory notification to the central Government. Close and willing cooperation from many hospitals and clinics, plus constant surveillance by social and public-health workers, has ensured that the great majority of congenital defects are available for statistical analysis. A simple method of wall-charting ensures that any increased incidence soon becomes obvious and a search can be made for possible setiological factors that began to operate during the preceding nine months. The thalidomide tragedy was graphically recorded in this way; and tetracycline is at present under investigation, by reference to the National Health Service prescription forms which are kept in a central office of the Ministry of Health. The importance of this awesome administrative task is proved by prescriptions for thalidomide made out to the mothers of some babies without limbs, who said they had taken no tablets and whose doctors denied prescribing them. These carefully controlled investigations should shed new light on infective and chemical factors in the aetiology of congenital malformations, and at the same time determine the true incidence of the various anomalies at birth. A long-term study of babies with congenital heartdisease is already under way and will help to define the size of the diagnostic and therapeutic problem. It should be useful, too, in highlighting, at any rate in this country, the extent to which pxdiatric cardiology has been neglected; and the results will also be of value in planning future services, since the great majority of children who are born with serious congenital heart-disease do not survive their first year of life, and many of those whose hearts fail early are the ones for whom most could be done. TREATMENT OF NEPHROBLASTOMA
ANY treatment of malignant tumours in childhood has usually to be assessed from results in a small number of patients who have been treated by several methods. A plan of treatment which simplifies the assessment of the value of a single agent is therefore welcome. Death from nephroblastoma (Wilms’ tumour) is mainly due to bloodborne metastases, and it has been known for some years that actinomycin D may inhibit the growth of pulmonary metastases of nephroblastoma. Howard1 has reviewed the results of adding actinomycin D to the standard treatment of nephroblastoma at the Royal Children’s Hospital, Melbourne. A total dose of actinomycin of 120 {jt.g. per kg. body-weight was given in 8 equal quantities. Nephrectomy was carried out after the third dose, and postoperative irradiation was delayed until the 26th day. Of 18 consecutive patients treated in this way, 11 (62%) have survived without sign of recurrence for two to five years-a great improvement on the previous survival-rate (11-5%) at the same hospital.2 Howard reminds us of the toxic properties of this antibiotic : depression of bone-marrow, with a risk of aplastic ansemia, macular rashes, epilation of the scalp, and anorexia, vomiting, stomatitis, and bloody diarrhoea. These toxic reactions vary from patient to patient and with 1. 2.
Howard, R. Archs Dis. Childh. 1965, 40, Howard, R. Med. J. Aust. 1957, i, 200.
200.