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A Confusion of Errors
764
valve made of
closely knitted teflon stiffened with polyurethane. The prosthesis is fashioned in the operating-theatre from a standard crimped woven teflon tube; it is sutured to the base of the aortic cusps and to
the aortic wall once the diseased valve has been excised. The advantage of this type of prosthesis is that it can be adapted to the type of cusp deformity found, the artificial cusps replacing the shrivelled cusps of valves which have been freely regurgitant. 7 patients with stenosis and regurgitation have undergone this operation, and in each the absence of an aortic diastolic murmur postoperatively indicated relief of incompetence by the prosthesis. 3 patients died in the first twenty-four hours from causes other than failure of the valve. KAY et al.12 use two types of artificial valve for the relief of aorticvalvular disease. In patients with regurgitation in whom part of the valvular tissue is preserved, plastic prostheses consisting of three leaflets of the same size and shape are fashioned in the theatre to the individual requirements and then sutured in position. When the patient’s valve has to be completely excised (as often in severe calcific stenosis), the three leaflets have to be deeper and are then buttressed with teflon felt. This procedure has been used in 28 patients with aortic regurgitation and in 8 with calcific stenosis; 4 in the first group died, and 3 in the second. Careful follow-up has shown effective function of the prosthetic valves. HARKEN et a1.13 have employed a caged ball-valve in the treatment of 6 patients with aortic-valve disease. 4 died, but in the other 2 the valve was functioning satisfactorily several months after the operation.
Although these reports are promising, much clearly remains to be done before valve replacement can be considered a safe or routine procedure. Until a wholly satisfactory prosthesis can be produced, physician and surgeon will rightly be chary of submitting a patient to such an operation-unless his clinical condition makes prompt surgical relief imperative. Moreover, cardiopulmonary bypass itself carries great hazards in patients with long-standing cardiac failure, myocardial disease, impaired hepatic or renal function, or serious pulmonary-vascular disease. In patients with aortic stenosis the state of the myocardium is of especial importance; years of hypoxia may have induced ischaemic fibrosis, leaving the muscle too poor to cope with the demands of a long perfusion. Selective hypothermia and coronary perfusion 14 can be of great assistance but may not suffice to preserve the patient’s life. The introduction of a satisfactory valve prosthesis would justify operation in healthier patients, but how to ensure the survival of foreign material subjected to constant movement has yet to be discovered. HARKEN et a1.13 have laid down ten criteria which a satisfactory plastic valve must satisfy: It must
lead to thrombosis and embolism; it must be chemically inert and not damaging to blood elements; it must offer no resistance to blood-flow under physiological conditions; it must close promptly; it must remain not
Kay, E. B., Mendelsohm, D., Zimmerman, H. A. Amer. J. Cardiol. 1962, 9, 292. 13. Harken, D. E., Taylor, W. J., Letemine, A. F., Lunzer, S., Low, H. B. C., Cohen, M. L., Jacobey, J. A. ibid. p. 292. 14. El Sayed, H., Melrose, D. G. Lancet, 1962, i, 551. 12.
closed during the appropriate phase of the cardiac cycle; it must be durable, and able to retain its physical and geometrical properties; it must be inserted in a physiological site, generally the normal site; it must be capable of permanent fixation; it must not annoy the patient; and its insertion must be technically practicable.
Little is known of the long-term survival of plastic valves, and at present the immediate hazards of infection, acceptance of the prosthesis, thrombosis, embolism, and blood destruction cannot always be avoided. As far as the incompetent mitral valve is concerned, open repair without valve replacement, as practised by WooLER in this country, seems to be the best procedure where the cusps are still mobile; but many patients need a complete valve prosthesis and the Starr type is the most promising. The physician should entertain sober optimism; but the patient should realise that certain and longstanding cure by valve replacement is a future prospect rather than an immediate reality.
A Confusion of Errors UNDER the alluring title of single-enzyme defects a profusion of new diseases is about to transform GARROD’S classically simple concept of inborn metabolic errors into the woolliest of fashionable medical notions. That a single abnormal protein can cause a characteristic clinical syndrome is not in doubt. That a few diseases result from the congenital inability of certain cells to perform a single but apparently crucial enzyme reaction is unproven but is strongly suggested by circumstantial evidence. But to suppose that every single-enzyme defect demonstrated in vitro is necessarily the cause of the illness with which it is associated-or of any illnessis an over-simplification. Isolated enzyme reactions do not occur in living tissue: their existence would defeat the raison d’etre of enzymes. Perpetually on the brink of a chemical explosion, cells rely on these highly specific catalysts to transform bursts of free energy into stepwise successions of minute discharges, and at the same time to convert a haphazard supply of food energy into intracellular fuel stores. Moreover, uptake and expenditure are probably kept in balance by a hierarchy of broad-spectrum metabolic regulators-hormones, coenzymes, vitamins-capable of coupling and uncoupling pairs, sequences, or whole cycles of multi-enzyme reactions. Faults in this coordinating superstructure rather than in individual reactions almost certainly account for most metabolic disorders seen by the clinician and for most so-called single-enzyme defects diagnosed in the laboratory. The family of metabolic errors associated with excessive deposition of glycogen in one or several organs or tissues has long been known to include various clinical syndromes, but only in the past ten years has it been recognised that the biochemical abnormality itself can arise in many different ways.1 Blood, liver, and muscle tissue from these patients is often strikingly deficient in enzyme-like activity. By isolating in vitro a select group of reactions known to be involved in 1.
Lancet, 1961, i, 206.
765 or breakdown, CoRi and other workers were able to pinpoint at least six different and characteristic defects.2-5 They did not suggest that these defects necessarily represented underlying causes, nor that they excluded other biochemical abnormalities. Indeed, since the in-vitro study of isolated tissue-enzyme reactions depends on artificial conditions in which interference or lack of interference from other enzymes is much reduced, such a claim is hardly ever justified. But biochemical pigeonholes being hard to resist, for some years each enzyme defect was equated with a more or less well defined clinical type. Reviewing 8 new cases studied in some detail LowE et al .6 remark that
glycogen synthesis
"we are now faced with a situation in which patients with similar hepatic defects have different aberrations in in which patients with no carbohydrate metabolism demonstrable in-vitro defect of enzymes involved in the early stages of glycogenosis may act clinically as’classic’ cases of glucose-6-phosphatase deficiency and in which siblings do not always have the same hepatic enzyme defect". This last paradox (which is not confined to the liver) is the most puzzling, for it seems to contradict the ...
...
one-gene one-enzyme hypothesis of hereditary disease. The evidence for the paradox is derived from two families-the first carefully investigated two years ago by CALDERBANK et al.in this country, the second recently reported by EBERLEIN et al.8in the United States. The older child in the American family was diagnosed as a case of type-1 glycogen-storage disease at the age of six months, when a liver-biopsy specimen showed glucose-6-phosphatase activity reduced to 5% of normal. Glucose-6-phosphatase catalyses the last step in what is probably the most important (though not the only) pathway of glycogen breakdown to glucose; and, while HERS9 has probably rightly maintained that only total in-vitro deficiency should be accepted as absolute proof, a diagnosis based on a combination of fasting hypoglycxmia, hepatomegaly, raised blood-glycogen, and 95% enzyme failure makes clinical sense. A younger sister was investigated two years later; and her condition proved to be clinically, but not biochemically, closely similar. "Her hepatic " glucose-6-phosphatase activity was only moderately depressed; but when her liver glycogen was exposed to the catalytic action of purified phosphorylase, only about a fifth of the expected number of glucose residues was recovered. This pointed to a deficiency of amylo-1, 6-glucosidase, the debrancher " enzyme concerned in the pathogenesis of Cori’s type-3 glycogenosis.1 The defect was confirmed by assaying specifically for this enzyme in muscle and by finding the red cells of both children loaded with incompletely degraded glycogen or " limit dextrin ". "
Con, G. T., Cori, C. F. J. biol. Chem. 1952, 199, 661. Illingworth, B., Cori, G. T. ibid. p. 653. Recant, L. Amer. J. Med. 1955, 19, 610. 5. Illingworth, B., Cori, G. T., Cori, C. F. J. biol. Chem. 1956, 218, 123. 6. Lowe, C. U., Sokal, J. E, Mosovich, L. L., Sarcione, E. J., Doray, B. H. Amer. J. Med. 1962, 33, 4. 7. Calderbank, A., Kent, P. W., Lorber, J., Manners, D. J., Wright, A. Biochem. J. 1960, 74, 223. 8. Eberlein, W. R., Illingworth, B. A., Sidbury, J. B. Amer. J. Med. 1962, 33, 20. 9. Hers, H. G. Rév. int. Hépatol. 1959, 9, 35.
2. 3. 4.
Whatever is the significance of similar enzyme defects in different tissues, both the British and the American family confirm doubts about the istinct genetic status of some of the enzymatic types of glycogenosis. Alternative explanations-perhaps a common endocrine basiscome to mind. Secondary biochemical features-the rise in blood-lipids, the tendency to acidsemia, interference with protein synthesis-suggest a distant kinship with diabetes; and the influence of hormones on the course of the disease may be significant. The place of glucagon in diagnosis and treatment has caused a good deal of debate,6 10-12 but little doubt remains that, in patients with liver involvement, response to this hormone is abnormal and that in favourable cases the natural and the induced abnormality partly cancel each other. A course of ’Halotestin ’, a synthetic androgen, brought about remarkable clinical and biochemical improvement in one of the children described by EBERLEIN et al.88 Other still-unidentified hormones could also be involved. Our uncertainty underlines our almost total ignorance of the links between hormones, coenzymes, and enzymes. NAPOLEON observed that no one man can personally command more than ten other men. If Nature organises cell metabolism on the same principle, her chain of command remains one of her
best-guarded secrets. Annotations MEDICAL CENTRE AT KINGSTON
MUCH is heard of division in the medical profession, of lack of understanding and even of respect between doctors in hospital and general practice, and of the responsibility of the National Health Service for these ills. But hitherto, although many people have bewailed the circumstances, few have tried to improve them. The action taken by Kingston Group Hospital Management Committee is the more remarkable-and the more praiseworthy. The committee has inspired the building, at Kingstonupon-Thames, of a medical centre where hospital doctors, general practitioners, medical officers of health, and dentists can meet both socially and professionally. The centre is housed in a new building which has been supplied and furnished by a grant of E42,000 from King Edward’s Hospital Fund. It is to be opened in December. Full membership will be offered to all registered practitioners in the area, to senior medical and dental staff of the hospitals in the Kingston group, and to registered dental practitioners employed in those hospitals. The idea is that medical workers in all branches of the Health Service shall meet, say, over lunch, and follow their meeting with clinical discussion. The centre will have a fully-equipped lecture room and library, besides restaurant and bar. Thus, through knowing each other better, the doctors should better understand each other’s point of view and cooperate more effectively in their practice. So admirable a venture deserves to succeed; but success will depend on the amount of support from practitioners in the area. That the centre should flourish is important, so that other hospital management committees may be prompted to follow Kingston’s example. 10. Hubble, D. Lancet, 1954, ii, 235. 11. Hagen, J. H. J. biol. Chem. 1961, 236, 1023. 12. Van Creveld, S. Arch. Dis. Childh. 1959, 34, 298.
valve made of
closely knitted teflon stiffened with polyurethane. The prosthesis is fashioned in the operating-theatre from a standard crimped woven teflon tube; it is sutured to the base of the aortic cusps and to
the aortic wall once the diseased valve has been excised. The advantage of this type of prosthesis is that it can be adapted to the type of cusp deformity found, the artificial cusps replacing the shrivelled cusps of valves which have been freely regurgitant. 7 patients with stenosis and regurgitation have undergone this operation, and in each the absence of an aortic diastolic murmur postoperatively indicated relief of incompetence by the prosthesis. 3 patients died in the first twenty-four hours from causes other than failure of the valve. KAY et al.12 use two types of artificial valve for the relief of aorticvalvular disease. In patients with regurgitation in whom part of the valvular tissue is preserved, plastic prostheses consisting of three leaflets of the same size and shape are fashioned in the theatre to the individual requirements and then sutured in position. When the patient’s valve has to be completely excised (as often in severe calcific stenosis), the three leaflets have to be deeper and are then buttressed with teflon felt. This procedure has been used in 28 patients with aortic regurgitation and in 8 with calcific stenosis; 4 in the first group died, and 3 in the second. Careful follow-up has shown effective function of the prosthetic valves. HARKEN et a1.13 have employed a caged ball-valve in the treatment of 6 patients with aortic-valve disease. 4 died, but in the other 2 the valve was functioning satisfactorily several months after the operation.
Although these reports are promising, much clearly remains to be done before valve replacement can be considered a safe or routine procedure. Until a wholly satisfactory prosthesis can be produced, physician and surgeon will rightly be chary of submitting a patient to such an operation-unless his clinical condition makes prompt surgical relief imperative. Moreover, cardiopulmonary bypass itself carries great hazards in patients with long-standing cardiac failure, myocardial disease, impaired hepatic or renal function, or serious pulmonary-vascular disease. In patients with aortic stenosis the state of the myocardium is of especial importance; years of hypoxia may have induced ischaemic fibrosis, leaving the muscle too poor to cope with the demands of a long perfusion. Selective hypothermia and coronary perfusion 14 can be of great assistance but may not suffice to preserve the patient’s life. The introduction of a satisfactory valve prosthesis would justify operation in healthier patients, but how to ensure the survival of foreign material subjected to constant movement has yet to be discovered. HARKEN et a1.13 have laid down ten criteria which a satisfactory plastic valve must satisfy: It must
lead to thrombosis and embolism; it must be chemically inert and not damaging to blood elements; it must offer no resistance to blood-flow under physiological conditions; it must close promptly; it must remain not
Kay, E. B., Mendelsohm, D., Zimmerman, H. A. Amer. J. Cardiol. 1962, 9, 292. 13. Harken, D. E., Taylor, W. J., Letemine, A. F., Lunzer, S., Low, H. B. C., Cohen, M. L., Jacobey, J. A. ibid. p. 292. 14. El Sayed, H., Melrose, D. G. Lancet, 1962, i, 551. 12.
closed during the appropriate phase of the cardiac cycle; it must be durable, and able to retain its physical and geometrical properties; it must be inserted in a physiological site, generally the normal site; it must be capable of permanent fixation; it must not annoy the patient; and its insertion must be technically practicable.
Little is known of the long-term survival of plastic valves, and at present the immediate hazards of infection, acceptance of the prosthesis, thrombosis, embolism, and blood destruction cannot always be avoided. As far as the incompetent mitral valve is concerned, open repair without valve replacement, as practised by WooLER in this country, seems to be the best procedure where the cusps are still mobile; but many patients need a complete valve prosthesis and the Starr type is the most promising. The physician should entertain sober optimism; but the patient should realise that certain and longstanding cure by valve replacement is a future prospect rather than an immediate reality.
A Confusion of Errors UNDER the alluring title of single-enzyme defects a profusion of new diseases is about to transform GARROD’S classically simple concept of inborn metabolic errors into the woolliest of fashionable medical notions. That a single abnormal protein can cause a characteristic clinical syndrome is not in doubt. That a few diseases result from the congenital inability of certain cells to perform a single but apparently crucial enzyme reaction is unproven but is strongly suggested by circumstantial evidence. But to suppose that every single-enzyme defect demonstrated in vitro is necessarily the cause of the illness with which it is associated-or of any illnessis an over-simplification. Isolated enzyme reactions do not occur in living tissue: their existence would defeat the raison d’etre of enzymes. Perpetually on the brink of a chemical explosion, cells rely on these highly specific catalysts to transform bursts of free energy into stepwise successions of minute discharges, and at the same time to convert a haphazard supply of food energy into intracellular fuel stores. Moreover, uptake and expenditure are probably kept in balance by a hierarchy of broad-spectrum metabolic regulators-hormones, coenzymes, vitamins-capable of coupling and uncoupling pairs, sequences, or whole cycles of multi-enzyme reactions. Faults in this coordinating superstructure rather than in individual reactions almost certainly account for most metabolic disorders seen by the clinician and for most so-called single-enzyme defects diagnosed in the laboratory. The family of metabolic errors associated with excessive deposition of glycogen in one or several organs or tissues has long been known to include various clinical syndromes, but only in the past ten years has it been recognised that the biochemical abnormality itself can arise in many different ways.1 Blood, liver, and muscle tissue from these patients is often strikingly deficient in enzyme-like activity. By isolating in vitro a select group of reactions known to be involved in 1.
Lancet, 1961, i, 206.
765 or breakdown, CoRi and other workers were able to pinpoint at least six different and characteristic defects.2-5 They did not suggest that these defects necessarily represented underlying causes, nor that they excluded other biochemical abnormalities. Indeed, since the in-vitro study of isolated tissue-enzyme reactions depends on artificial conditions in which interference or lack of interference from other enzymes is much reduced, such a claim is hardly ever justified. But biochemical pigeonholes being hard to resist, for some years each enzyme defect was equated with a more or less well defined clinical type. Reviewing 8 new cases studied in some detail LowE et al .6 remark that
glycogen synthesis
"we are now faced with a situation in which patients with similar hepatic defects have different aberrations in in which patients with no carbohydrate metabolism demonstrable in-vitro defect of enzymes involved in the early stages of glycogenosis may act clinically as’classic’ cases of glucose-6-phosphatase deficiency and in which siblings do not always have the same hepatic enzyme defect". This last paradox (which is not confined to the liver) is the most puzzling, for it seems to contradict the ...
...
one-gene one-enzyme hypothesis of hereditary disease. The evidence for the paradox is derived from two families-the first carefully investigated two years ago by CALDERBANK et al.in this country, the second recently reported by EBERLEIN et al.8in the United States. The older child in the American family was diagnosed as a case of type-1 glycogen-storage disease at the age of six months, when a liver-biopsy specimen showed glucose-6-phosphatase activity reduced to 5% of normal. Glucose-6-phosphatase catalyses the last step in what is probably the most important (though not the only) pathway of glycogen breakdown to glucose; and, while HERS9 has probably rightly maintained that only total in-vitro deficiency should be accepted as absolute proof, a diagnosis based on a combination of fasting hypoglycxmia, hepatomegaly, raised blood-glycogen, and 95% enzyme failure makes clinical sense. A younger sister was investigated two years later; and her condition proved to be clinically, but not biochemically, closely similar. "Her hepatic " glucose-6-phosphatase activity was only moderately depressed; but when her liver glycogen was exposed to the catalytic action of purified phosphorylase, only about a fifth of the expected number of glucose residues was recovered. This pointed to a deficiency of amylo-1, 6-glucosidase, the debrancher " enzyme concerned in the pathogenesis of Cori’s type-3 glycogenosis.1 The defect was confirmed by assaying specifically for this enzyme in muscle and by finding the red cells of both children loaded with incompletely degraded glycogen or " limit dextrin ". "
Con, G. T., Cori, C. F. J. biol. Chem. 1952, 199, 661. Illingworth, B., Cori, G. T. ibid. p. 653. Recant, L. Amer. J. Med. 1955, 19, 610. 5. Illingworth, B., Cori, G. T., Cori, C. F. J. biol. Chem. 1956, 218, 123. 6. Lowe, C. U., Sokal, J. E, Mosovich, L. L., Sarcione, E. J., Doray, B. H. Amer. J. Med. 1962, 33, 4. 7. Calderbank, A., Kent, P. W., Lorber, J., Manners, D. J., Wright, A. Biochem. J. 1960, 74, 223. 8. Eberlein, W. R., Illingworth, B. A., Sidbury, J. B. Amer. J. Med. 1962, 33, 20. 9. Hers, H. G. Rév. int. Hépatol. 1959, 9, 35.
2. 3. 4.
Whatever is the significance of similar enzyme defects in different tissues, both the British and the American family confirm doubts about the istinct genetic status of some of the enzymatic types of glycogenosis. Alternative explanations-perhaps a common endocrine basiscome to mind. Secondary biochemical features-the rise in blood-lipids, the tendency to acidsemia, interference with protein synthesis-suggest a distant kinship with diabetes; and the influence of hormones on the course of the disease may be significant. The place of glucagon in diagnosis and treatment has caused a good deal of debate,6 10-12 but little doubt remains that, in patients with liver involvement, response to this hormone is abnormal and that in favourable cases the natural and the induced abnormality partly cancel each other. A course of ’Halotestin ’, a synthetic androgen, brought about remarkable clinical and biochemical improvement in one of the children described by EBERLEIN et al.88 Other still-unidentified hormones could also be involved. Our uncertainty underlines our almost total ignorance of the links between hormones, coenzymes, and enzymes. NAPOLEON observed that no one man can personally command more than ten other men. If Nature organises cell metabolism on the same principle, her chain of command remains one of her
best-guarded secrets. Annotations MEDICAL CENTRE AT KINGSTON
MUCH is heard of division in the medical profession, of lack of understanding and even of respect between doctors in hospital and general practice, and of the responsibility of the National Health Service for these ills. But hitherto, although many people have bewailed the circumstances, few have tried to improve them. The action taken by Kingston Group Hospital Management Committee is the more remarkable-and the more praiseworthy. The committee has inspired the building, at Kingstonupon-Thames, of a medical centre where hospital doctors, general practitioners, medical officers of health, and dentists can meet both socially and professionally. The centre is housed in a new building which has been supplied and furnished by a grant of E42,000 from King Edward’s Hospital Fund. It is to be opened in December. Full membership will be offered to all registered practitioners in the area, to senior medical and dental staff of the hospitals in the Kingston group, and to registered dental practitioners employed in those hospitals. The idea is that medical workers in all branches of the Health Service shall meet, say, over lunch, and follow their meeting with clinical discussion. The centre will have a fully-equipped lecture room and library, besides restaurant and bar. Thus, through knowing each other better, the doctors should better understand each other’s point of view and cooperate more effectively in their practice. So admirable a venture deserves to succeed; but success will depend on the amount of support from practitioners in the area. That the centre should flourish is important, so that other hospital management committees may be prompted to follow Kingston’s example. 10. Hubble, D. Lancet, 1954, ii, 235. 11. Hagen, J. H. J. biol. Chem. 1961, 236, 1023. 12. Van Creveld, S. Arch. Dis. Childh. 1959, 34, 298.