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RESPONSIBILITIES AND FUNCTIONS OF CONSULTANTS
978 Whitehead and Cooper 9 recently showed that when folic acid is fed to human subjects it passes through the intestinal wall unchanged. In a series of experiments in our own laboratories, using everted rat intestinal sacs, we have shown that folic acid passes through the intestinal wall unaltered. Although Baker et al. claim that folic acid is unchanged when given intravenously, Whitehead and Cooper9 also showed that when folic acid in the portal vein reached the liver it was rapidly converted into 5-methyltetrahydrofolic acid. It is therefore likely that intravenously injected folic acid would be converted quickly to 5-methyltetrahydrofolic acid. Therefore, it is probable in Dr. Hepner and his colleagues’ experiment that folic acid was being transported against 5-methyltetrahydrofolic acid in the serum, and this invalidates the suggestion that transport took place against a concentration gradient. However, even if we assume that folic acid was being transported against unaltered folic acid in the serum in this experiment, we still have to consider the different concentrations of unionised folic acid (the transportable species) on either side of the intestinal wall because of the different pH values of the intestinal mucosa and serum. At about pH 7 the concentration of unionised folic acid varies by a factor of 102 for each pH unit. If we take the pH of the intestinal mucosa as 5-3 (virtual pHI-3) and that of the serum as 7-4, the concentration of unionised folic acid in the loaded serum was about 1/300 of that at the surface of the intestinal mucosa. Here again Dr. Hepner and his colleagues’ claim to have observed transport against a concentration gradient seems to be in question.
hydrofolic acid,
Much of the paper by Dr. Hepner and his colleagues is devoted to comparing the amounts of folic acid absorbed over a small constant length of the intestine after the infusion of widely different ranges in the concentration of the vitamin. From these data they were able to derive a Michaelis-Menten curve showing saturation kinetics which they claimed to be typical of an active transport process. Dr. Scott and Dr. Orsi (Oct. 5, p. 775) show that a weighted straight line is a better fit to the data than a hyperbola, but, contrary to their statements, this does not establish the transport process as a passive A typical Michaelis-Menten curve is rectilinear for one. substrate concentrations well below the Km value; hence, in this range of concentrations no distinction can be made between active transport and passive diffusion.10 The Kt value 10 for this system cannot be less than 5 (1.g. per ml. and is probably much higher, and the concentrations used were 10, 1, and 0-1(1.g. per ml. Therefore a simple rectilinear relation would be expected for either active transport or passive diffusion. The saturation kinetics observed could be caused by the precipitation of folic acid from solution as it moves from the lumen of gut at a pH of 6-7 to the surface of the intestinal mucosa at a pH of about 5. The solubility of folic acid in water decreases rapidly with increasingly acid pH and at about pH 5 is of the order of 10-100 (1.g. per ml.ll-13 This would give for the maximum velocity of the absorption a concentration of the order of 10-100 (.Lg. per ml., and hence a Kt value of the order of 5-50 (1.g. per ml.
In summary, the evidence given by Dr. Hepner and his colleagues does not unequivocally prove that folic acid is transported across the intestinal wall by an active process, for much of their evidence is consistent with passive transport with a maximum velocity determined by the solubility and percentage ionisation of the vitamin at the surface of the intestinal mucosa.
Department of Biological Sciences. Department of Chemistry, University of Aston in Birmingham, Birmingham 4.
A.
J. MATTY.
J. A. BLAIR.
9. Whitehead V. M., Cooper, B. A. Br. J. Hœmat. 1967, 13, 679. 10. Wilson, T. H. Intestinal Absorption; pp. 43, 83. London, 1962. 11. Hutchings, B. L., Stokstad, E. L. R., Bohonos, N., Sloane, N. H., Subbarow, Y. J. Am. chem. Soc. 1947, 70, 1. 12. Jaenicke, L., Kurszbach, C. Fortschr. Chem. org. Nat. Stoffe, 1963, 21, 201. 13. Hillcoat, B. L., Nixon, P. F., Blakley, R. I. Analyt. Biochem. 1967, 21, 178.
RESPONSIBILITIES AND FUNCTIONS OF CONSULTANTS SIR,-It is gratifying to read in your News columns last week (p. 923) that one representative of non-teaching-hospital consultants has been added to the working-party on responsibilities of the consultant grade. At the same time, one might well wonder what sort of advice to the Ministry caused this body to be set up in the first place without any representative from the overwhelming majority of consultants in this country. It is also worth noting that this committee, like so many others, contains no psychiatrist. Since psychiatry is one of the largest specialties at consultant level, this would be rather surprisingif the same situation were not constantly recurring. I have previously drawn attention1 to the virtual absence of psychiatrists from regional advisers on addictive drugs (a situation which the Ministry has refused to alter), and to the extraordinary omission of anyone with knowledge of mental health from the Health Education Council. These recent events are symptomatic of the grossly unrepresentative character of that small body of doctors-particularly from the older Colleges-who have influence on medical policy at the highest level. It is time that this situation was ended. Salford Royal Hospital, Salford 3, Lancs.
HUGH FREEMAN.
PHENOBARBITONE AND NEONATAL JAUNDICE SIR,-The effect of phenobarbitone on hepatic conjugation of bilirubin in animals 3 and man 4is now becoming well recognised. Its value in the treatment of some patients with congenital familial hyperbilirubinasmia has been established.’I Its value in the treatment of physiological jaundice of the newborn has not yet been definitely shown, though Professor Trolle’s work6 suggests that in selected cases it may prevent the development of significant hyperbilirubinaemia. That this may be of importance is suggested by the earlier work of Boggs et al. relating neonatal hyperbilirubinaemia to poor performance in subsequent tests of psychomotor development. The problem is how to select cases for treatment with phenobarbitone, since it is scarcely practicable to treat all babies or all pregnant women with phenobarbitone against the possibility that the babies may develop significant hyperbilirubinaemia. I have recently completed a small pilot trial of phenobarbitone in the treatment of neonatal jaundice. All neonates in the Woking Maternity Hospital who were found to have serumbilirubin levels above 10 mg. per 100 ml. were allotted to one of two groups on a random basis. Group 1, comprising 12 babies, received phenobarbitone, 5 mg. 8-hourly, by mouth or by nasogastric tube. Group 2, also comprising 12 babies, received no special treatment. Serum-bilirubin estimations were repeated after 3 days, and the difference between the initial serum-bilirubin levels and the levels at 3 days were compared in the two groups. The results are shown in the accompanying table. The mean fall in the total bilirubin for the treated group was 4-9 mg. per 100 ml., that for the control group was 2-6 mg. per 100 ml. The corresponding figures for indirect bilirubin were 5-0 and 2-6 mg. per 100 ml. These differences achieve only a rather low level of significance (P<0-1) but are nevertheless suggestive. As can be seen from the table the two groups were matched for gestational age, birth-weight, and age at entry to the trial. The question of the value of the treatment remains. It canbe concluded from this limited study that this scheme of treatment will prevent the occurrence of significant (from the psychomotor point of view) hyperbilirubinaemia. It can be not
1. 2.
3. 4. 5.
6. 7.
Freeman, H. Lancet, 1968, i, 589. Freeman, H. Br. J. Psychiat. 1968, 114, 1058. Catz, C., Yaffe, S. J. Am. J. Dis. Child. 1962, 104, 516. Crigler, J. F., Gold, N. J. clin. Invest. 1966, 45, 998. Yaffe, S. J., Levy, G., Matsuzawa, T., Baliah, T. New Engl. J. Med. 1966, 275, 1461. Trolle, D., Lancet, 1968, i, 251; ibid. Sept. 28, 1968, p. 705. Boggs, R. R., Hardy, J. B., Frazier, T. M. J. Pœdiat. 1967, 71, 553.
hydrofolic acid,
Much of the paper by Dr. Hepner and his colleagues is devoted to comparing the amounts of folic acid absorbed over a small constant length of the intestine after the infusion of widely different ranges in the concentration of the vitamin. From these data they were able to derive a Michaelis-Menten curve showing saturation kinetics which they claimed to be typical of an active transport process. Dr. Scott and Dr. Orsi (Oct. 5, p. 775) show that a weighted straight line is a better fit to the data than a hyperbola, but, contrary to their statements, this does not establish the transport process as a passive A typical Michaelis-Menten curve is rectilinear for one. substrate concentrations well below the Km value; hence, in this range of concentrations no distinction can be made between active transport and passive diffusion.10 The Kt value 10 for this system cannot be less than 5 (1.g. per ml. and is probably much higher, and the concentrations used were 10, 1, and 0-1(1.g. per ml. Therefore a simple rectilinear relation would be expected for either active transport or passive diffusion. The saturation kinetics observed could be caused by the precipitation of folic acid from solution as it moves from the lumen of gut at a pH of 6-7 to the surface of the intestinal mucosa at a pH of about 5. The solubility of folic acid in water decreases rapidly with increasingly acid pH and at about pH 5 is of the order of 10-100 (1.g. per ml.ll-13 This would give for the maximum velocity of the absorption a concentration of the order of 10-100 (.Lg. per ml., and hence a Kt value of the order of 5-50 (1.g. per ml.
In summary, the evidence given by Dr. Hepner and his colleagues does not unequivocally prove that folic acid is transported across the intestinal wall by an active process, for much of their evidence is consistent with passive transport with a maximum velocity determined by the solubility and percentage ionisation of the vitamin at the surface of the intestinal mucosa.
Department of Biological Sciences. Department of Chemistry, University of Aston in Birmingham, Birmingham 4.
A.
J. MATTY.
J. A. BLAIR.
9. Whitehead V. M., Cooper, B. A. Br. J. Hœmat. 1967, 13, 679. 10. Wilson, T. H. Intestinal Absorption; pp. 43, 83. London, 1962. 11. Hutchings, B. L., Stokstad, E. L. R., Bohonos, N., Sloane, N. H., Subbarow, Y. J. Am. chem. Soc. 1947, 70, 1. 12. Jaenicke, L., Kurszbach, C. Fortschr. Chem. org. Nat. Stoffe, 1963, 21, 201. 13. Hillcoat, B. L., Nixon, P. F., Blakley, R. I. Analyt. Biochem. 1967, 21, 178.
RESPONSIBILITIES AND FUNCTIONS OF CONSULTANTS SIR,-It is gratifying to read in your News columns last week (p. 923) that one representative of non-teaching-hospital consultants has been added to the working-party on responsibilities of the consultant grade. At the same time, one might well wonder what sort of advice to the Ministry caused this body to be set up in the first place without any representative from the overwhelming majority of consultants in this country. It is also worth noting that this committee, like so many others, contains no psychiatrist. Since psychiatry is one of the largest specialties at consultant level, this would be rather surprisingif the same situation were not constantly recurring. I have previously drawn attention1 to the virtual absence of psychiatrists from regional advisers on addictive drugs (a situation which the Ministry has refused to alter), and to the extraordinary omission of anyone with knowledge of mental health from the Health Education Council. These recent events are symptomatic of the grossly unrepresentative character of that small body of doctors-particularly from the older Colleges-who have influence on medical policy at the highest level. It is time that this situation was ended. Salford Royal Hospital, Salford 3, Lancs.
HUGH FREEMAN.
PHENOBARBITONE AND NEONATAL JAUNDICE SIR,-The effect of phenobarbitone on hepatic conjugation of bilirubin in animals 3 and man 4is now becoming well recognised. Its value in the treatment of some patients with congenital familial hyperbilirubinasmia has been established.’I Its value in the treatment of physiological jaundice of the newborn has not yet been definitely shown, though Professor Trolle’s work6 suggests that in selected cases it may prevent the development of significant hyperbilirubinaemia. That this may be of importance is suggested by the earlier work of Boggs et al. relating neonatal hyperbilirubinaemia to poor performance in subsequent tests of psychomotor development. The problem is how to select cases for treatment with phenobarbitone, since it is scarcely practicable to treat all babies or all pregnant women with phenobarbitone against the possibility that the babies may develop significant hyperbilirubinaemia. I have recently completed a small pilot trial of phenobarbitone in the treatment of neonatal jaundice. All neonates in the Woking Maternity Hospital who were found to have serumbilirubin levels above 10 mg. per 100 ml. were allotted to one of two groups on a random basis. Group 1, comprising 12 babies, received phenobarbitone, 5 mg. 8-hourly, by mouth or by nasogastric tube. Group 2, also comprising 12 babies, received no special treatment. Serum-bilirubin estimations were repeated after 3 days, and the difference between the initial serum-bilirubin levels and the levels at 3 days were compared in the two groups. The results are shown in the accompanying table. The mean fall in the total bilirubin for the treated group was 4-9 mg. per 100 ml., that for the control group was 2-6 mg. per 100 ml. The corresponding figures for indirect bilirubin were 5-0 and 2-6 mg. per 100 ml. These differences achieve only a rather low level of significance (P<0-1) but are nevertheless suggestive. As can be seen from the table the two groups were matched for gestational age, birth-weight, and age at entry to the trial. The question of the value of the treatment remains. It canbe concluded from this limited study that this scheme of treatment will prevent the occurrence of significant (from the psychomotor point of view) hyperbilirubinaemia. It can be not
1. 2.
3. 4. 5.
6. 7.
Freeman, H. Lancet, 1968, i, 589. Freeman, H. Br. J. Psychiat. 1968, 114, 1058. Catz, C., Yaffe, S. J. Am. J. Dis. Child. 1962, 104, 516. Crigler, J. F., Gold, N. J. clin. Invest. 1966, 45, 998. Yaffe, S. J., Levy, G., Matsuzawa, T., Baliah, T. New Engl. J. Med. 1966, 275, 1461. Trolle, D., Lancet, 1968, i, 251; ibid. Sept. 28, 1968, p. 705. Boggs, R. R., Hardy, J. B., Frazier, T. M. J. Pœdiat. 1967, 71, 553.