693 inconsistent, and these studies
were abandoned, overby the description of the hepatitis B antigens and, more recently, by animal and immunoelectronmicroscopic observations pertinent to hepatitis A.
obtained) and our modified co-agglutination test for every test.
were
In neither case would he be using reagents with a short shelflife, Workers who use the co-agglutination method to detect other antigen-antibody reactions may also find that the separate addition of antiserum and staphylococcal strain saves them
shadowed
considerable labour. Cross-Infection Reference Laboratory, Ceniral Public Health Laboratory, London NW9 5HT
W. R. MAXTED ANDROULLA EFSTRATIOU M. T. PARKER
SIR,-In bronchial asthma, exercise-induced symptoms can be a disabling and socially restricting feature of the disease.I At a clinic visit a 38-year-old male patient whose main complaint was of wheezing induced by running, also volunteered that he developed similar symptoms during sexual intercourse. The asthmatic features often interfered with the satisfactory completion of coitus and were causing considerable strain on his marital relationship. After this, three further male patients aged 25-40, with exercise-induced asthma, were asked specifically about the possible onset of symptoms during intercourse. All these patients, surprisingly, admitted to considerable sexual difficulties because of the onset of their typical symptoms of wheezing and dyspnrea. None had been asked previously about this feature of their condition, nor had they wished to mention this aspect because of embarrassment. After prophylactic therapy had been started (two with disodium cromoglycate, two with a steroid aerosol), all had a general improvement in their asthma. Two indicated that while on therapy their sexually induced asthmatic symptoms were eliminated, and in the two others the difficulties were considerably modified. The mechanism of this reaction is unlikely to be different from that of asthma initiated by other forms of exercise such as running or cycling. Anxiety and emotional factors may have played a part, but in this group with exercise-induced features predominating, these factors are unlikely to be significant. It is conceivable, however, that sexual activity in bed, by disturbing the surrounding house-dust mite population may provide an allergen challenge in sensitised individuals. It is only through increased awareness and specific questioning that the frequency of angina pectoris occurring during intercourse in patients with coronary heart-disease has been demonstrated.2 "Sexercise" induced asthma may also be common but overlooked both by the family doctor and the respiratory physician. The successful outcome in this group of patients serves to demonstrate the need for a direct approach in those at risk. IAN S. SYMINGTON
JAMES W. KERR
INHIBITION OF PHYTOHÆMAGGLUTININ TRANSFORMATION BY SERUM OF PATIENTS WITH FULMINANT HEPATITIS
Sn,—Dr Dupuy and his colleagues (Sept. 11,
they
were
It may be that inhibition of P.H.A transformation is associated with hepatitis B (4/6 of Dupuy’s cases were known to be associated with hepatitis B) and that the inconsistency encountered in earlier studies was related to our inability properly to identify octiologically distinct varieties of hepatitis. Virus Laboratory, Department of Microbiology, Institute of Child Health, London WC1N 1EH
SEXERCISE-INDUCED ASTHMA
Department of Respiratory Medicine, Western Infirmary and Knightswood Hospital, Glasgow
as
p.
578)
describe the inhibition of phytohasmagglutinin transformation
oy serum of patients with fulminant viral hepatitis. This was ?1 described by Mella and myself in 1967and 1968.4 Subsequently several attempts were made by my laboratory by others to investigate this finding further. The results 1 McNeill, R S., Nairn, J. R., Millar, J. S., Nairn, C. G. Q. Jl Med. 1966,
137, 55 2 Hellerstein, H. K., Fnedman, E. H. Archs intern. Med. 1970, 125, 987. 3 Mell a. B, Lang, D. J. Science, 1967, 155, 80. 4 Mella B, Lang, D. J. Ann N.Y. Acad Sci 1968, 155, 880.
DAVID J. LANG
BREAST IS BEST FOR CORONARY PROTECTION
SiR,—Your contributor (Aug. 21, p. 412) has a hunch that "breast is best", but admits his reasons are largely related to the emotional and behavioural bonding of mother and baby. But he overlooks a wealth of circumstantial evidence which points to coronary protection being a likely benefit of breast
feeding. Non-lipid-containing histological changes in the coronary arteries of infants and young children which are almost certainly predisposing to later atherosclerosis have been described by many pathologists, 1-3 notably Osborn.4These changes have been found in children who have died from gastroenteritis, other infections, or any condition associated with dehydration and collapse, and also in those killed accidentally in whom there was no obvious preceding disease. With a variety of associations, but no proof of causation, they must be referred to as non-specific. Often no doubt, and usually in lowrisk countries in which atherosclerosis and its complications are rare, injury is followed by repair. However, given a later unfavourable nutritional environment in the form of a modern Western-type diet, it is probable that the increased permeability of the arterial wall and changes which predispose to the infiltration, retention, and accumulation of low-density lipoproteins predispose to atherosclerosis. Osborn described the pathological changes in 1500 young people aged 0-20 years. Since serial observations in an individual are impossible, conclusions had to be based on the spectrum of pathological changes from the accumulation of mucopolysaccharides to fully developed atherosclerotic plaques. In infants with no history of relevant preceding disease, causes are likely to be nutritional. He closely questioned more than 100 mothers and concluded that the lesions described were more frequent and severe in the predominantly bottlefed and uncommon or mild in those predominantly breast-fed. Clearly only a prospective study can be conclusive. It is therefore reasonable to consider the differences between human and cow’s milk and the likelihood of their being responsible for the early changes in the coronary arteries. Breast milk has evolved as a perfect and all-sufficient food for the first twelve months of life or longer while cow’s milk has evolved for very different needs. The only similarities in the two varieties lie in the water and, perhaps, the sugar. Total protein in cow’s milk is much higher and its constituent aminoacid pattern is very different. Antibodies are present in the blood of many infants and this immunological response could itself damage the arterial wall and also increase platelet adhesiveness and aggregation which can have harmful effects.6 Cow’s milk is grossly deficient in essential fatty acids. They amount to only 25% of the concentration in human milk in 1. Moon, H. D. Circulation, 1957, 16, 268. 2. Daoud, A. et al. Exp. mol. Path. 1964, 3, 475. 3. Pesonen, E. Atherosclerosis, 1974, 20, 173. 4. Osborn, G. R. Incubation Period of Coronary
Thrombosis; p. 177. London,
1963. 5. Osborne, G. R. Colloq. int. C.N.R.S. 1967, no. 169. 6. Davies, D. F. Am. Heart J. 1971, 81, 289. 7. György, P. Am. J. clin. Nutr. 1971, 24, 970.
694 which it constitutes 8% of total calories,? yet are vital for the integrity of the developing arterial wall and later for its maintenance and repair. There are also differences in minerals, vitamins, and trace elements. The Western baby is usually bottle-fed with an unnatural substitute of radically different composition to which sugar or salt is often added to maternal taste and the mixture given in excess. Weaning is then carried out, all too early, onto a modern atherogenic diet, high in saturated fat, cholesterol and refined carbohydrate and deficient in polyunsaturated fat. Full-fat dairy produce is given in excess and also fatty meat and meat products, together with fats and oils which have been hydrogenated by the food industry to change their composition from being high in polyunsaturates to high in saturates. Processing of vegetable oils and their use in many convenience foods contributes to excess, deficiencies, and imbalance of essential nutrients. The links between food, plasma-lipids, atherosclerosis, and coronary disease are strong. Your contributor is not correct in his supposition that "the chances are that even the high serumcholesterol of the atheromatous individual is unrelated to that in the plaque". Lipid in the plaque is mainly derived from that in the plasma and dietary cholesterol can be traced to that in the food.8 The probability of a causal relationship between bottle feeding and these early pathological changes seems high. Cow’s milk should be avoided for as long as possible whilst infant defences are developing and the tissues are becoming less susceptible to dietary insult. If the mother is unable or unwilling to feed her infant, then particular care should be paid to the alternative, humanised as far as possible and not neglecting the balance of fatty acids. This is rarely done in realistic terms. It seems likely that the answer to the coronary problem starts in childhood, with breast feeding followed by appropriate weaning, and infant nutrition based on correction of the radical changes man has made in the food he eats in recent years. Meanwhile, surely consideration should be given to a project which should be feasible and might well provide invaluable information ? If an accurate record of infant and early childhood feeding were made by the cooperation of maternity ward staff, midwives, health visitors, and family doctors in consultation with paediatricians and if the information were centrally stored, pathologists would sometimes have the opportunity to compare the state of the coronary arteries with early nutrition. Edinburgh University, 21 Buccleuch Place, Edinburgh EH8 9L9
R. W. D. TURNER
CLONIDINE OVERDOSE
SIR,-A 48-year-old hypertensive male was admitted to the U.S.A.F. Medical Center, Keesler 3 h after ingesting an estimated twenty-four 0.2 mg clonidine hydrochloride (’Catapres’) tablets and an undetermined amount of alcohol. The patient’s blood-pressure had been controlled with two thiazide-triamterene (’Dyazide’) capsules daily, frusemide (’Lasix’) 40 mg every other day, and clonidine 0-8 mg three times daily for approximately 6 months. On admission he was alert but complained of dizziness on standing. Supine bloodpressure was 110/78 mm Hg with pulse 78/min. On standing the blood-pressure fell to 50/30 mm Hg with pulse increasing to
98/min.
patient was given maintenance intravenous fluids, and he slept much of the first 24 h but was easily awakened. There was a variable orthostatic drop in the blood-pressure, systolic greater than diastolic, and a relative bradycardia during the first 24 h. The blood-pressure returned to pre-admission levels 1972, 1, 49.
standing blood-pressure and pulse after clonidine overdose.
the 13th hour after ingestion. On the second hospital day he was given half his usual dose of clonidine. He did not exhibit a hypertensive rebound, and he was discharged on the third hospital day with no untoward effects. Plasma samples were assayed for clonidine hydrochloride by Dr D. Davies, Hammersmith Hospital, London, using gaschromatography/mass-spectrometry. Plasma concentrations were 6.0, 5.25, and 4.9 ng/ml at 4, 6, and 8 h after ingestion. Reported average peak plasma levels 90 min after a single 03 mg dose has been 1.02+0.52ng/mI.1 The dose of clonidine hydrochloride ingested by this patient is the largest single dose
by
reported. U.S.A.F. Medical Center, Keesler Air Force Base, Mississipi, U.S.A.
Keesler,
*Present address: Renal Division, Department of School of Medicine, Winston-Salem, North Carolina
MICHAEL A. MOORE* PAUL PHILLIPI Medicine, Bowman 27103, U.S.A.
Gray
STARTING DIGOXIN
SIR,-When the new specification for digoxin tablets (not less than 75% dissolution in one hour) was introduced in October, 1975, the need for reassessment of dose was stressed. The figure summarises recent experience in the general medical department of a district hospital2 and the renal unit of a teaching hospital,3 using ’Lanoxin’ tablets (Wellcome Medical Division) manufactured in the U.K. It is intended as a guide to the initial choice of dose. Subsequent alteration may be required to achieve the maximum therapeutic effect or avoid symptoms of toxicity. The standard dose is the mean dose required by the general medical patients to achieve therapeutic serum concentrations. Previous studies 4have shown that little of the variation in requirements in patient groups with normal or slightly impaired renal function can be explained by patient variables. ReducC. T., Davies, D. S., Draffan, G. H., Dargie, H. J., Dean, C R. Reid, J. L., Clare, R. A., Murray, S. Clin.Pharmac. Ther. 1976, 19, 11 2. Dobbs, S. M., Rodgers, E. M., Parkes, J., Kenyon, W. L., unpublished obser-
1.
The
8 Connor, W. E., Connor, S. L. Prev. Med.
Serial
Dollery,
vations. 3. Dobbs, S. M., Mawer, G. E., Rodgers, E. M., Woodcock, B. G., Lucas, S B.Br. J.clin.Pharmac. 1976, 3, 231. 4. Peck, C. G., Sheiner, L. B., Martin, C. M., Combs, D. T., Melmon, K L N.Engl. J.Med. 1973, 289, 441. 5. Wagner, J. G., Yates, J. D., Willis, P. W., Sakmar, E., Stoll, R G Clin. Pharmac. Ther. 1974, 15, 291.
were abandoned, overby the description of the hepatitis B antigens and, more recently, by animal and immunoelectronmicroscopic observations pertinent to hepatitis A.
obtained) and our modified co-agglutination test for every test.
were
In neither case would he be using reagents with a short shelflife, Workers who use the co-agglutination method to detect other antigen-antibody reactions may also find that the separate addition of antiserum and staphylococcal strain saves them
shadowed
considerable labour. Cross-Infection Reference Laboratory, Ceniral Public Health Laboratory, London NW9 5HT
W. R. MAXTED ANDROULLA EFSTRATIOU M. T. PARKER
SIR,-In bronchial asthma, exercise-induced symptoms can be a disabling and socially restricting feature of the disease.I At a clinic visit a 38-year-old male patient whose main complaint was of wheezing induced by running, also volunteered that he developed similar symptoms during sexual intercourse. The asthmatic features often interfered with the satisfactory completion of coitus and were causing considerable strain on his marital relationship. After this, three further male patients aged 25-40, with exercise-induced asthma, were asked specifically about the possible onset of symptoms during intercourse. All these patients, surprisingly, admitted to considerable sexual difficulties because of the onset of their typical symptoms of wheezing and dyspnrea. None had been asked previously about this feature of their condition, nor had they wished to mention this aspect because of embarrassment. After prophylactic therapy had been started (two with disodium cromoglycate, two with a steroid aerosol), all had a general improvement in their asthma. Two indicated that while on therapy their sexually induced asthmatic symptoms were eliminated, and in the two others the difficulties were considerably modified. The mechanism of this reaction is unlikely to be different from that of asthma initiated by other forms of exercise such as running or cycling. Anxiety and emotional factors may have played a part, but in this group with exercise-induced features predominating, these factors are unlikely to be significant. It is conceivable, however, that sexual activity in bed, by disturbing the surrounding house-dust mite population may provide an allergen challenge in sensitised individuals. It is only through increased awareness and specific questioning that the frequency of angina pectoris occurring during intercourse in patients with coronary heart-disease has been demonstrated.2 "Sexercise" induced asthma may also be common but overlooked both by the family doctor and the respiratory physician. The successful outcome in this group of patients serves to demonstrate the need for a direct approach in those at risk. IAN S. SYMINGTON
JAMES W. KERR
INHIBITION OF PHYTOHÆMAGGLUTININ TRANSFORMATION BY SERUM OF PATIENTS WITH FULMINANT HEPATITIS
Sn,—Dr Dupuy and his colleagues (Sept. 11,
they
were
It may be that inhibition of P.H.A transformation is associated with hepatitis B (4/6 of Dupuy’s cases were known to be associated with hepatitis B) and that the inconsistency encountered in earlier studies was related to our inability properly to identify octiologically distinct varieties of hepatitis. Virus Laboratory, Department of Microbiology, Institute of Child Health, London WC1N 1EH
SEXERCISE-INDUCED ASTHMA
Department of Respiratory Medicine, Western Infirmary and Knightswood Hospital, Glasgow
as
p.
578)
describe the inhibition of phytohasmagglutinin transformation
oy serum of patients with fulminant viral hepatitis. This was ?1 described by Mella and myself in 1967and 1968.4 Subsequently several attempts were made by my laboratory by others to investigate this finding further. The results 1 McNeill, R S., Nairn, J. R., Millar, J. S., Nairn, C. G. Q. Jl Med. 1966,
137, 55 2 Hellerstein, H. K., Fnedman, E. H. Archs intern. Med. 1970, 125, 987. 3 Mell a. B, Lang, D. J. Science, 1967, 155, 80. 4 Mella B, Lang, D. J. Ann N.Y. Acad Sci 1968, 155, 880.
DAVID J. LANG
BREAST IS BEST FOR CORONARY PROTECTION
SiR,—Your contributor (Aug. 21, p. 412) has a hunch that "breast is best", but admits his reasons are largely related to the emotional and behavioural bonding of mother and baby. But he overlooks a wealth of circumstantial evidence which points to coronary protection being a likely benefit of breast
feeding. Non-lipid-containing histological changes in the coronary arteries of infants and young children which are almost certainly predisposing to later atherosclerosis have been described by many pathologists, 1-3 notably Osborn.4These changes have been found in children who have died from gastroenteritis, other infections, or any condition associated with dehydration and collapse, and also in those killed accidentally in whom there was no obvious preceding disease. With a variety of associations, but no proof of causation, they must be referred to as non-specific. Often no doubt, and usually in lowrisk countries in which atherosclerosis and its complications are rare, injury is followed by repair. However, given a later unfavourable nutritional environment in the form of a modern Western-type diet, it is probable that the increased permeability of the arterial wall and changes which predispose to the infiltration, retention, and accumulation of low-density lipoproteins predispose to atherosclerosis. Osborn described the pathological changes in 1500 young people aged 0-20 years. Since serial observations in an individual are impossible, conclusions had to be based on the spectrum of pathological changes from the accumulation of mucopolysaccharides to fully developed atherosclerotic plaques. In infants with no history of relevant preceding disease, causes are likely to be nutritional. He closely questioned more than 100 mothers and concluded that the lesions described were more frequent and severe in the predominantly bottlefed and uncommon or mild in those predominantly breast-fed. Clearly only a prospective study can be conclusive. It is therefore reasonable to consider the differences between human and cow’s milk and the likelihood of their being responsible for the early changes in the coronary arteries. Breast milk has evolved as a perfect and all-sufficient food for the first twelve months of life or longer while cow’s milk has evolved for very different needs. The only similarities in the two varieties lie in the water and, perhaps, the sugar. Total protein in cow’s milk is much higher and its constituent aminoacid pattern is very different. Antibodies are present in the blood of many infants and this immunological response could itself damage the arterial wall and also increase platelet adhesiveness and aggregation which can have harmful effects.6 Cow’s milk is grossly deficient in essential fatty acids. They amount to only 25% of the concentration in human milk in 1. Moon, H. D. Circulation, 1957, 16, 268. 2. Daoud, A. et al. Exp. mol. Path. 1964, 3, 475. 3. Pesonen, E. Atherosclerosis, 1974, 20, 173. 4. Osborn, G. R. Incubation Period of Coronary
Thrombosis; p. 177. London,
1963. 5. Osborne, G. R. Colloq. int. C.N.R.S. 1967, no. 169. 6. Davies, D. F. Am. Heart J. 1971, 81, 289. 7. György, P. Am. J. clin. Nutr. 1971, 24, 970.
694 which it constitutes 8% of total calories,? yet are vital for the integrity of the developing arterial wall and later for its maintenance and repair. There are also differences in minerals, vitamins, and trace elements. The Western baby is usually bottle-fed with an unnatural substitute of radically different composition to which sugar or salt is often added to maternal taste and the mixture given in excess. Weaning is then carried out, all too early, onto a modern atherogenic diet, high in saturated fat, cholesterol and refined carbohydrate and deficient in polyunsaturated fat. Full-fat dairy produce is given in excess and also fatty meat and meat products, together with fats and oils which have been hydrogenated by the food industry to change their composition from being high in polyunsaturates to high in saturates. Processing of vegetable oils and their use in many convenience foods contributes to excess, deficiencies, and imbalance of essential nutrients. The links between food, plasma-lipids, atherosclerosis, and coronary disease are strong. Your contributor is not correct in his supposition that "the chances are that even the high serumcholesterol of the atheromatous individual is unrelated to that in the plaque". Lipid in the plaque is mainly derived from that in the plasma and dietary cholesterol can be traced to that in the food.8 The probability of a causal relationship between bottle feeding and these early pathological changes seems high. Cow’s milk should be avoided for as long as possible whilst infant defences are developing and the tissues are becoming less susceptible to dietary insult. If the mother is unable or unwilling to feed her infant, then particular care should be paid to the alternative, humanised as far as possible and not neglecting the balance of fatty acids. This is rarely done in realistic terms. It seems likely that the answer to the coronary problem starts in childhood, with breast feeding followed by appropriate weaning, and infant nutrition based on correction of the radical changes man has made in the food he eats in recent years. Meanwhile, surely consideration should be given to a project which should be feasible and might well provide invaluable information ? If an accurate record of infant and early childhood feeding were made by the cooperation of maternity ward staff, midwives, health visitors, and family doctors in consultation with paediatricians and if the information were centrally stored, pathologists would sometimes have the opportunity to compare the state of the coronary arteries with early nutrition. Edinburgh University, 21 Buccleuch Place, Edinburgh EH8 9L9
R. W. D. TURNER
CLONIDINE OVERDOSE
SIR,-A 48-year-old hypertensive male was admitted to the U.S.A.F. Medical Center, Keesler 3 h after ingesting an estimated twenty-four 0.2 mg clonidine hydrochloride (’Catapres’) tablets and an undetermined amount of alcohol. The patient’s blood-pressure had been controlled with two thiazide-triamterene (’Dyazide’) capsules daily, frusemide (’Lasix’) 40 mg every other day, and clonidine 0-8 mg three times daily for approximately 6 months. On admission he was alert but complained of dizziness on standing. Supine bloodpressure was 110/78 mm Hg with pulse 78/min. On standing the blood-pressure fell to 50/30 mm Hg with pulse increasing to
98/min.
patient was given maintenance intravenous fluids, and he slept much of the first 24 h but was easily awakened. There was a variable orthostatic drop in the blood-pressure, systolic greater than diastolic, and a relative bradycardia during the first 24 h. The blood-pressure returned to pre-admission levels 1972, 1, 49.
standing blood-pressure and pulse after clonidine overdose.
the 13th hour after ingestion. On the second hospital day he was given half his usual dose of clonidine. He did not exhibit a hypertensive rebound, and he was discharged on the third hospital day with no untoward effects. Plasma samples were assayed for clonidine hydrochloride by Dr D. Davies, Hammersmith Hospital, London, using gaschromatography/mass-spectrometry. Plasma concentrations were 6.0, 5.25, and 4.9 ng/ml at 4, 6, and 8 h after ingestion. Reported average peak plasma levels 90 min after a single 03 mg dose has been 1.02+0.52ng/mI.1 The dose of clonidine hydrochloride ingested by this patient is the largest single dose
by
reported. U.S.A.F. Medical Center, Keesler Air Force Base, Mississipi, U.S.A.
Keesler,
*Present address: Renal Division, Department of School of Medicine, Winston-Salem, North Carolina
MICHAEL A. MOORE* PAUL PHILLIPI Medicine, Bowman 27103, U.S.A.
Gray
STARTING DIGOXIN
SIR,-When the new specification for digoxin tablets (not less than 75% dissolution in one hour) was introduced in October, 1975, the need for reassessment of dose was stressed. The figure summarises recent experience in the general medical department of a district hospital2 and the renal unit of a teaching hospital,3 using ’Lanoxin’ tablets (Wellcome Medical Division) manufactured in the U.K. It is intended as a guide to the initial choice of dose. Subsequent alteration may be required to achieve the maximum therapeutic effect or avoid symptoms of toxicity. The standard dose is the mean dose required by the general medical patients to achieve therapeutic serum concentrations. Previous studies 4have shown that little of the variation in requirements in patient groups with normal or slightly impaired renal function can be explained by patient variables. ReducC. T., Davies, D. S., Draffan, G. H., Dargie, H. J., Dean, C R. Reid, J. L., Clare, R. A., Murray, S. Clin.Pharmac. Ther. 1976, 19, 11 2. Dobbs, S. M., Rodgers, E. M., Parkes, J., Kenyon, W. L., unpublished obser-
1.
The
8 Connor, W. E., Connor, S. L. Prev. Med.
Serial
Dollery,
vations. 3. Dobbs, S. M., Mawer, G. E., Rodgers, E. M., Woodcock, B. G., Lucas, S B.Br. J.clin.Pharmac. 1976, 3, 231. 4. Peck, C. G., Sheiner, L. B., Martin, C. M., Combs, D. T., Melmon, K L N.Engl. J.Med. 1973, 289, 441. 5. Wagner, J. G., Yates, J. D., Willis, P. W., Sakmar, E., Stoll, R G Clin. Pharmac. Ther. 1974, 15, 291.
