- Email: [email protected]
THE THIRD STAGE OF LABOUR
954 600 diabetics disclosed that women under 60 often had hyperlipaemia and atherosclerotic complications than men of the same age.6The higher serumcholesterol levels of our women diabetics seem consistent with these findings. R. L. SEARCY J. A. GIDDINGS Departments of Pathology, Los Angeles County General Hospital G. L. DOUGLAS and California College of Medicine, L. M. BERGQUIST. Los Angeles, California.
of
over
more
INSULIN RESPONSE TO FRUCTOSE AND GALACTOSE
SIR,-We have read with interest the article Samols and Dr. Dormandy (March 2).
by Dr.
In 1959 we suggested that hypoglycasmia in hereditary fructose intolerance (H.F.I.) after fructose administration was due to a block of hepatic glucose release, rather than to hyperinsulinism.1 Later, this hypothesis was proved correct for H.F.I. and galactosaemia by Dubois et al.8 9 who found that the glucose-assimilation coefficient in their patients did not increase after fructose or galactose administration, and that, after prior injection of 14C-labelled glucose, the slope of the specific activity of blood-glucose levelled off, at a time when the blood-glucose decreased. Hence we concluded that hypoglycaemia in these patients was not due to insulin action on tissues in vivo, but rather to a block of the glucose release by the liver. We also measured insulin-like activity in serum by the adipose-tissue assay and found a decrease in fructoseinduced hypoglycaemia. 10-13 The primary enzyme disorder of these patients with H.F.I. has been located at the level of the fructose-1-phosphatesplitting liver aldolase, and it seems that hypoglycxmia is due to secondary inhibition of glycolytic enzymes by fructose-1phosphate, which accumulates in liver cells.10 13 We should like to comment on the data of Samols and Dormandy in their bearing on the stimulation of insulin secretion in man by fructose and galactose. Even if fructose and galactose did stimulate the beta islet cells, this effect might be overcompensated in H.F.I. and galactosaemia by the decreasing stimulus of the rapidly falling blood-glucose levels at the time when fructossemia and galactosaemia reach their maximum. Fortunately, Nature has provided a second inborn error of fructose metabolism-i.e., essential fructosuria, in which fructose concentrations in the blood similar to those in H.F.i. are reached without the appearance of hypoglycaemia. If fructose were responsible for hypoglycaemia by way of insulin secretion, hypoglycaemia could also be expected in essential fructosuria. Another important point is that of the nomenclature of these inborn disturbances of fructose metabolism. Essential fructosuria is a harmless, symptomless anomaly in which the hepatic enzyme fructokinase is lacking.14 H.F.I. is characterised by severe hypoglycsemia and vomiting after fructose ingestion, and the clinical syndrome consists of failure to thrive, hepatomegaly, icterus, albuminuria, and hyperaminoaciduria. These symptoms appear as soon as the children are given sucrose or fructose in their food. When feeding of fructose is continued the children usually die." Those who survive become strongly averse to food containing fructose. Cases 3 and 4 of Samols and Dormandy which were described earlier in more detail 15 do not seem to fit into ,
6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
Lowy, A. D., Jr., Barach, J. H. Circulation, 1958, 17, 14. Froesch, E. R., Prader, A., Wolf, H. P., Labhart, A. Helv. pœdiat. Acta, 1959, 14, 99. Dubois, R., Loeb, H., Ooms, H. A., Gillet, P., Bartman, J., Champenois, A. ibid. 1961, 16, 90. Dubois, R., Loeb, H., Ooms, H. A. Rev. frant. Étud. clin. biol. 1962,
7, 509. Froesch, E. R. in Genetic Defects of Biologically Active Proteins (edited by F. Linneweh); p. 242. Berlin, 1962. Froesch, E. R., Wolf, H. P., Baitsch, H., Prader, A., Labhart, A. Amer. J. Med. 1963, 34, 151. Hers, H. G., Joassin, G. Enzymol. biol. clin. 1961, 1, 4. Pitkänen, E., Perheentupa, J. Ann. Pœdiat. Fenn. 1962, 8, 236. Baylon, H., Shapira, F., Wegmann, R., Dreyfus, J. C., Monlias, R., Poyart, C., Coumel, Ph. Rev. franç. Étud. clin. biol. 1962, 7, 531. Dormandy, T. L., Porter, R. J. Lancet, 1961, i, 1189.
the picture of H.F.I.:these patients tolerated fructose perfectly well in childhood, and were even " fond of sweets ". Moreover, the patients also became hypoglyczmic after galactose ingestion. We suggest that the patients were not typical of H.F.I. Other forms of fructose intolerance may yet come to be recognised, and, therefore, each case should be fullv documented. E. R. FROESCH. Metabolic Unit, Department of Medicine. Department of Pediatrics,
University of Zurich, Switzerland.
A. PRADER.
THE THIRD STAGE OF LABOUR
SiR,—The time between completion of the second and third stages of a normal labour is the only part of pregnancy which in these careful days is still left largely to chance. I have therefore evolved an amalgam of tried techniques which has greatly reduced the chance of unpleasant surprises. I start the safe delivery of the placenta by ensuring at a
the first antenatal visit that I shall not have to deal with tired " uterus: 1. Good antenatal instruction of the mother will give a
"
relaxed first stage with no pushing. Specialised development of the abdominal muscles-and not just maintenance-throughout pregnancy is urged. The patient is assured at each antenatal visit that the pregnancy is normal. 2. I establish that there is only one baby. 3. As soon as the head is well engaged in the second stage, and the cord cannot prolapse, I slope the mattress by placing pillows under it; hence the route of delivery is downhill (orthodox positions ensure that the baby has to be pushed up a steeply inclined vagina). 4. By antenatal teaching, by encouragement, by pain relievers, and by sedatives (not amine-oxidase inhibitors, because they potentiate many other drugs) I make sure that each uterine contraction is assisted by full use of good voluntary muscles. 5. From this stage on, the baby stays below the uterine level until the cord is clamped. Keeping the baby below the uterine level means that even if separation is complete before the shoulders are delivered there will be no " bleed-back ", and the baby’s pelvis keeps the cervix open. 6. I let the nurse deliver the baby. Gloves are disinfected with chlorhexidine (’Hibitane’). When the head has reached the stage when the face will be free for breathing in half a minute-in a primipara it may be wise to wait until the face is free-I give 0-5 mg. ergometrine intravenously. The moment the baby is delivered the cord is milked towards it, and without any pause the cord is held at the vulva with one hand, the ulnar edge of the other is applied, palm down, to the groove between symphysis and uterus, pressing upwards and backwards sufficiently to equal the pull on the cord with the other hand. The cord is pulled down and backwards steadily towards the anus-not horizontally or towards the pubis. With impressive ease and absence of blood-loss the complete placenta will come out; it is then held well above the baby and the cord is again milked towards it (keeping some for Coombs’ test in Rh-negative mothers). The cord is then clamped.
All this can be done in either the left lateral or lithotomy position; hence no time is lost nor is there any risk in turning the mother from side to back, and one can be on the opposite side of the nurse with a dorsal delivery on a narrow bed. If the cervix is tight because one is too slow amyl nitrite is helpful. If there is doubt about there being more than one baby the risk to the foetus of using X rays must be weighed against the risk of the conventional management of the third stage. The whole process is so smooth that it is hard to believe that the only question before going home is " Is there an inversion ?" But barring a true placenta accreta
955
the placenta is in fact free before one begins to pull on the cord. Even a small dimple of fundal inversion when missed can kill the patient, but my method is no more likely than any other to produce it. Cromer, A. HENRY GREGSON. G Norfolk. AMAUROTIC FAMILY IDIOCY
is said to be of the enzymes in
SIR,—Amaurotic family idiocy (A.F.I.) caused by
a
hereditary
lack of
one
the ganglioside-synthesising pathway. This idea was originally based upon the observation that the level of neuraminic acid, which is one of the components of gangliosides, was increased in the cortical grey matter of the brains of patients with A.F.I.,1 although it was later shown increased in the brains in other
conditions-e.g., multiple only shown to be present in the grey matter in these cases and in normal material, but now gangliosides have been shown in the white matter from patients with Tay-Sachs disease (an infantile form of A.F.I.) with a distribution in grey and white matter in the ratio of 6 :4.3 The suggestion that this accumulation of ganglioto be
sclerosis. Neuraminic acid
was
side in the body of the nerve-cells may be the sole cause of their dysfunction seems too facile. Accumulations of other substances (for example, lipofuscin) seem to be tolerated for a considerable time with apparently slight effects. Thin-layer chromatography of the gangliosides of a patient who had died from Tay-Sachs disease showed an increase in one of the fractions containing neuraminic acid.4 This increase was ascribed to an enzymatic block that had dammed up ganglioside precursors in the metabolic pathway. Gatt and Bermanshowed that there were two sialic acid-free
glycolipids (not containing N-acetylneuraminic acid) not found in normal subjects in the brain-lipids of patients with Tay-Sachs disease. One of these, at least, could well be one of the precursors in the postulated ganglioside-synthesising pathway.6 Anoxia has been shown to greatly diminish the resting membrane potential of isolated slices from the cerebral cortex of guineapigs and cats.’ The hypopolarisation caused by clupein, a basic protein, in similar slices from the guineapig could be counteracted by the addition of gangliosides.8 Other workers have shown that the level of N-acetylneuraminic acid (N.A.N.A.) in gangliosides from the cerebral cortex in man and in cats 9 is greatly reduced by anoxia from whatever cause. AS N.A.N.A. is the only acidic group in the ganglioside structure, its removal from the neuronal membrane (where it has been shown to be probably localised 10) could cause an irreversible alteration in net negative charge. The finding that the removal of N.A.N.A. by the enzyme neuraminidase from erythrocytes 11 changes their electrophoretic mobility and causes a loss of surface negative charge lends support to this view. Almost all the neuraminic acid was found to be accessible to the neuraminidase and was located at the outer membrane surface. Neuraminidase has been found in mammalian brain.12 Its pH range was small and the optimum was between 35 and 40. Anoxia produces a tendency to an acid pH, because of the carbon-dioxide build-up. This favours neuraminidase activity and could account for the reduction in neuraminic acid after anoxia. The lack of incorporation of gangliosides into the neuronal membranes and possibly into the axonal membranes as a 1. Klenk, E., Langerbeins, H. Hoppe-Seyl. Z. 1941, 270, 185. 2. Cumings, J. N. Brain, 1955, 78, 554. 3. Folchi-Pi, J., Lees, M. Amer. J. Dis. Child. 1959, 97, 730. 4. Muldner, H., Wherrett, J. R., Cumings, J. N. J. Neurochem.
9, 607.
1962,
5. Gatt, S., Berman, E. R. ibid. 1963, 10, 43. 6. Burton, R. M. in The Neurochemistry of Nucleotides and Amino Acids (edited by R. O. Brody and D. B. Tower); p. 65. New York, 1960. 7. Li, C. H., McIlwain, H. J. Physiol. 1957, 139, 178. 8. Hillman, H. H. J. Neurochem. 1961, 8, 257. 9. Lowden, J. A., Wolfe, L. S. Nature, Lond. 1963, 197, 771. 10. Wolfe, L. S. Biochem. J. 1961, 79, 348. 11. Eyler, E. H., Madoff, M. A., Brody, O. V., Oncley, J. L. J. biol. Chem. 1962, 237, 1992. 12. Morgan, E. H., Laurell, C. B. Nature, Lond. 1963, 197, 921.
result of the postulated enzyme block, could greatly affect the membrane potential, and the generation of nerve impulses, and hence could explain the dysfunction of the neurones in patients with A.F.I. Other studies on cerebral tissues have shown that the metabolic response to electrical stimulation (like the effect of clupein) is abolished by protamine.13 This effect was reversed by gangliosides and by the anti-trypanosomal drug, suramin, and was shown to be due to the formation of a complex between protamine and gefngliosides. 14 Similar inhibition was also observed with histones, while that caused by basic proteins was reversed by sialo-mucopolysaccharides. These results suggest that the gangliosides in the neuronal membrane may be in the form of a basic protein-ganglioside complex. On this hypothesis, the dysfunction of neurones could be explained by the effect of uncombined basic proteins on the membrane potential. The administration of suramin or gangliosides to patients with A.F.I., assuming that these substances could penetrate to the affected neurones, might prove interesting. National Hospital; Queen Square, London, W.C.1.
V. C. BARBER.
STEATORRHŒA IN ADDISON’S DISEASE
SIR,—The article by Dr. McBrien and his colleagues (Jan. 5) is interesting, because a decrease in absorption of fats in this disease is commoner than is generally thought. We have reported an altered ratio of ingested fats to excreted fats in several patients with Addison’s disease, which was due to an increased loss of fat in the fæces. 15 16 This has been further confirmed by our later work and now by McBrien et al. We gave 40 g. of fats, consisting for the most part of glycerides, daily for three days to 18 patients on a controlled diet. After one day on an unrestricted diet, 80 g. of fats was given daily for another three days. The amount of fat in the faeces was determined daily by the method of Monasterio,17 and the ratio of ingested fats to excreted fats was estimated by the formula of Black. 18 In 6 of the 18 patients (33-3%) there was an increase in the amount of fat excreted in the faeces. All 6 had severe Addison’s disease: in 3 the disease was diagnosed for the first time, and therefore no hormonal treatment had been given: the other 3 had been treated inadequately as outpatients. There was an increase in faecal excretion of fat on a daily dose of only 40 g. of fat in patients 1, 2, 3, and 4 (see table): in FÆCAL EXCRETION OF FAT
*
patients lipids.
Normal
5 and 6
(g.)
AFTER INGESTION OF
(30 determinations), an
1-6-9 g.
100 g.
OF FAT *
(mean 4-21 g.)
increase appeared after doses of 80 g. of
The fats in the fasces are undoubtedly of alimentary origin; some of these patients an extra load of triolein 1311 was always followed by greatly increased excretion of the tagged fat. In patients with Addison’s disease-in which there is an increased fscal excretion of fats-the blood-lipids load test displays abnormality after a very slight rise in blood-lipid. Improvement on appropriate endocrine therapy is accompanied by restoration of the normal ratio between ingested lipids and excreted lipids and by a normal blood-lipid load test. 13. Thomson, C. G., McIlwain, H. Biochem. J. 1961, 79, 342. 14. McIlwain, H. ibid. 1961, 78, 24. 15. Guarini, G., Macaluso, M. Corticosurrene e Metabolismo Lipidico; in
p. 26. Turin, 1961. 16. 17. 18.
Guarini, G., Macaluso, M., Pappalardo, A. International Congress on Hormonal Steroids; p. 245. Milan, 1962. Monasterio, G., Gigli, G., Scotti, G. Riv. Gastro-ent. 1953, 5, 63. Black, W. Quoted by Ciauri, G. in Pass. ital. Gastroent. 1959, 9, 527.
of
over
more
INSULIN RESPONSE TO FRUCTOSE AND GALACTOSE
SIR,-We have read with interest the article Samols and Dr. Dormandy (March 2).
by Dr.
In 1959 we suggested that hypoglycasmia in hereditary fructose intolerance (H.F.I.) after fructose administration was due to a block of hepatic glucose release, rather than to hyperinsulinism.1 Later, this hypothesis was proved correct for H.F.I. and galactosaemia by Dubois et al.8 9 who found that the glucose-assimilation coefficient in their patients did not increase after fructose or galactose administration, and that, after prior injection of 14C-labelled glucose, the slope of the specific activity of blood-glucose levelled off, at a time when the blood-glucose decreased. Hence we concluded that hypoglycaemia in these patients was not due to insulin action on tissues in vivo, but rather to a block of the glucose release by the liver. We also measured insulin-like activity in serum by the adipose-tissue assay and found a decrease in fructoseinduced hypoglycaemia. 10-13 The primary enzyme disorder of these patients with H.F.I. has been located at the level of the fructose-1-phosphatesplitting liver aldolase, and it seems that hypoglycxmia is due to secondary inhibition of glycolytic enzymes by fructose-1phosphate, which accumulates in liver cells.10 13 We should like to comment on the data of Samols and Dormandy in their bearing on the stimulation of insulin secretion in man by fructose and galactose. Even if fructose and galactose did stimulate the beta islet cells, this effect might be overcompensated in H.F.I. and galactosaemia by the decreasing stimulus of the rapidly falling blood-glucose levels at the time when fructossemia and galactosaemia reach their maximum. Fortunately, Nature has provided a second inborn error of fructose metabolism-i.e., essential fructosuria, in which fructose concentrations in the blood similar to those in H.F.i. are reached without the appearance of hypoglycaemia. If fructose were responsible for hypoglycaemia by way of insulin secretion, hypoglycaemia could also be expected in essential fructosuria. Another important point is that of the nomenclature of these inborn disturbances of fructose metabolism. Essential fructosuria is a harmless, symptomless anomaly in which the hepatic enzyme fructokinase is lacking.14 H.F.I. is characterised by severe hypoglycsemia and vomiting after fructose ingestion, and the clinical syndrome consists of failure to thrive, hepatomegaly, icterus, albuminuria, and hyperaminoaciduria. These symptoms appear as soon as the children are given sucrose or fructose in their food. When feeding of fructose is continued the children usually die." Those who survive become strongly averse to food containing fructose. Cases 3 and 4 of Samols and Dormandy which were described earlier in more detail 15 do not seem to fit into ,
6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
Lowy, A. D., Jr., Barach, J. H. Circulation, 1958, 17, 14. Froesch, E. R., Prader, A., Wolf, H. P., Labhart, A. Helv. pœdiat. Acta, 1959, 14, 99. Dubois, R., Loeb, H., Ooms, H. A., Gillet, P., Bartman, J., Champenois, A. ibid. 1961, 16, 90. Dubois, R., Loeb, H., Ooms, H. A. Rev. frant. Étud. clin. biol. 1962,
7, 509. Froesch, E. R. in Genetic Defects of Biologically Active Proteins (edited by F. Linneweh); p. 242. Berlin, 1962. Froesch, E. R., Wolf, H. P., Baitsch, H., Prader, A., Labhart, A. Amer. J. Med. 1963, 34, 151. Hers, H. G., Joassin, G. Enzymol. biol. clin. 1961, 1, 4. Pitkänen, E., Perheentupa, J. Ann. Pœdiat. Fenn. 1962, 8, 236. Baylon, H., Shapira, F., Wegmann, R., Dreyfus, J. C., Monlias, R., Poyart, C., Coumel, Ph. Rev. franç. Étud. clin. biol. 1962, 7, 531. Dormandy, T. L., Porter, R. J. Lancet, 1961, i, 1189.
the picture of H.F.I.:these patients tolerated fructose perfectly well in childhood, and were even " fond of sweets ". Moreover, the patients also became hypoglyczmic after galactose ingestion. We suggest that the patients were not typical of H.F.I. Other forms of fructose intolerance may yet come to be recognised, and, therefore, each case should be fullv documented. E. R. FROESCH. Metabolic Unit, Department of Medicine. Department of Pediatrics,
University of Zurich, Switzerland.
A. PRADER.
THE THIRD STAGE OF LABOUR
SiR,—The time between completion of the second and third stages of a normal labour is the only part of pregnancy which in these careful days is still left largely to chance. I have therefore evolved an amalgam of tried techniques which has greatly reduced the chance of unpleasant surprises. I start the safe delivery of the placenta by ensuring at a
the first antenatal visit that I shall not have to deal with tired " uterus: 1. Good antenatal instruction of the mother will give a
"
relaxed first stage with no pushing. Specialised development of the abdominal muscles-and not just maintenance-throughout pregnancy is urged. The patient is assured at each antenatal visit that the pregnancy is normal. 2. I establish that there is only one baby. 3. As soon as the head is well engaged in the second stage, and the cord cannot prolapse, I slope the mattress by placing pillows under it; hence the route of delivery is downhill (orthodox positions ensure that the baby has to be pushed up a steeply inclined vagina). 4. By antenatal teaching, by encouragement, by pain relievers, and by sedatives (not amine-oxidase inhibitors, because they potentiate many other drugs) I make sure that each uterine contraction is assisted by full use of good voluntary muscles. 5. From this stage on, the baby stays below the uterine level until the cord is clamped. Keeping the baby below the uterine level means that even if separation is complete before the shoulders are delivered there will be no " bleed-back ", and the baby’s pelvis keeps the cervix open. 6. I let the nurse deliver the baby. Gloves are disinfected with chlorhexidine (’Hibitane’). When the head has reached the stage when the face will be free for breathing in half a minute-in a primipara it may be wise to wait until the face is free-I give 0-5 mg. ergometrine intravenously. The moment the baby is delivered the cord is milked towards it, and without any pause the cord is held at the vulva with one hand, the ulnar edge of the other is applied, palm down, to the groove between symphysis and uterus, pressing upwards and backwards sufficiently to equal the pull on the cord with the other hand. The cord is pulled down and backwards steadily towards the anus-not horizontally or towards the pubis. With impressive ease and absence of blood-loss the complete placenta will come out; it is then held well above the baby and the cord is again milked towards it (keeping some for Coombs’ test in Rh-negative mothers). The cord is then clamped.
All this can be done in either the left lateral or lithotomy position; hence no time is lost nor is there any risk in turning the mother from side to back, and one can be on the opposite side of the nurse with a dorsal delivery on a narrow bed. If the cervix is tight because one is too slow amyl nitrite is helpful. If there is doubt about there being more than one baby the risk to the foetus of using X rays must be weighed against the risk of the conventional management of the third stage. The whole process is so smooth that it is hard to believe that the only question before going home is " Is there an inversion ?" But barring a true placenta accreta
955
the placenta is in fact free before one begins to pull on the cord. Even a small dimple of fundal inversion when missed can kill the patient, but my method is no more likely than any other to produce it. Cromer, A. HENRY GREGSON. G Norfolk. AMAUROTIC FAMILY IDIOCY
is said to be of the enzymes in
SIR,—Amaurotic family idiocy (A.F.I.) caused by
a
hereditary
lack of
one
the ganglioside-synthesising pathway. This idea was originally based upon the observation that the level of neuraminic acid, which is one of the components of gangliosides, was increased in the cortical grey matter of the brains of patients with A.F.I.,1 although it was later shown increased in the brains in other
conditions-e.g., multiple only shown to be present in the grey matter in these cases and in normal material, but now gangliosides have been shown in the white matter from patients with Tay-Sachs disease (an infantile form of A.F.I.) with a distribution in grey and white matter in the ratio of 6 :4.3 The suggestion that this accumulation of ganglioto be
sclerosis. Neuraminic acid
was
side in the body of the nerve-cells may be the sole cause of their dysfunction seems too facile. Accumulations of other substances (for example, lipofuscin) seem to be tolerated for a considerable time with apparently slight effects. Thin-layer chromatography of the gangliosides of a patient who had died from Tay-Sachs disease showed an increase in one of the fractions containing neuraminic acid.4 This increase was ascribed to an enzymatic block that had dammed up ganglioside precursors in the metabolic pathway. Gatt and Bermanshowed that there were two sialic acid-free
glycolipids (not containing N-acetylneuraminic acid) not found in normal subjects in the brain-lipids of patients with Tay-Sachs disease. One of these, at least, could well be one of the precursors in the postulated ganglioside-synthesising pathway.6 Anoxia has been shown to greatly diminish the resting membrane potential of isolated slices from the cerebral cortex of guineapigs and cats.’ The hypopolarisation caused by clupein, a basic protein, in similar slices from the guineapig could be counteracted by the addition of gangliosides.8 Other workers have shown that the level of N-acetylneuraminic acid (N.A.N.A.) in gangliosides from the cerebral cortex in man and in cats 9 is greatly reduced by anoxia from whatever cause. AS N.A.N.A. is the only acidic group in the ganglioside structure, its removal from the neuronal membrane (where it has been shown to be probably localised 10) could cause an irreversible alteration in net negative charge. The finding that the removal of N.A.N.A. by the enzyme neuraminidase from erythrocytes 11 changes their electrophoretic mobility and causes a loss of surface negative charge lends support to this view. Almost all the neuraminic acid was found to be accessible to the neuraminidase and was located at the outer membrane surface. Neuraminidase has been found in mammalian brain.12 Its pH range was small and the optimum was between 35 and 40. Anoxia produces a tendency to an acid pH, because of the carbon-dioxide build-up. This favours neuraminidase activity and could account for the reduction in neuraminic acid after anoxia. The lack of incorporation of gangliosides into the neuronal membranes and possibly into the axonal membranes as a 1. Klenk, E., Langerbeins, H. Hoppe-Seyl. Z. 1941, 270, 185. 2. Cumings, J. N. Brain, 1955, 78, 554. 3. Folchi-Pi, J., Lees, M. Amer. J. Dis. Child. 1959, 97, 730. 4. Muldner, H., Wherrett, J. R., Cumings, J. N. J. Neurochem.
9, 607.
1962,
5. Gatt, S., Berman, E. R. ibid. 1963, 10, 43. 6. Burton, R. M. in The Neurochemistry of Nucleotides and Amino Acids (edited by R. O. Brody and D. B. Tower); p. 65. New York, 1960. 7. Li, C. H., McIlwain, H. J. Physiol. 1957, 139, 178. 8. Hillman, H. H. J. Neurochem. 1961, 8, 257. 9. Lowden, J. A., Wolfe, L. S. Nature, Lond. 1963, 197, 771. 10. Wolfe, L. S. Biochem. J. 1961, 79, 348. 11. Eyler, E. H., Madoff, M. A., Brody, O. V., Oncley, J. L. J. biol. Chem. 1962, 237, 1992. 12. Morgan, E. H., Laurell, C. B. Nature, Lond. 1963, 197, 921.
result of the postulated enzyme block, could greatly affect the membrane potential, and the generation of nerve impulses, and hence could explain the dysfunction of the neurones in patients with A.F.I. Other studies on cerebral tissues have shown that the metabolic response to electrical stimulation (like the effect of clupein) is abolished by protamine.13 This effect was reversed by gangliosides and by the anti-trypanosomal drug, suramin, and was shown to be due to the formation of a complex between protamine and gefngliosides. 14 Similar inhibition was also observed with histones, while that caused by basic proteins was reversed by sialo-mucopolysaccharides. These results suggest that the gangliosides in the neuronal membrane may be in the form of a basic protein-ganglioside complex. On this hypothesis, the dysfunction of neurones could be explained by the effect of uncombined basic proteins on the membrane potential. The administration of suramin or gangliosides to patients with A.F.I., assuming that these substances could penetrate to the affected neurones, might prove interesting. National Hospital; Queen Square, London, W.C.1.
V. C. BARBER.
STEATORRHŒA IN ADDISON’S DISEASE
SIR,—The article by Dr. McBrien and his colleagues (Jan. 5) is interesting, because a decrease in absorption of fats in this disease is commoner than is generally thought. We have reported an altered ratio of ingested fats to excreted fats in several patients with Addison’s disease, which was due to an increased loss of fat in the fæces. 15 16 This has been further confirmed by our later work and now by McBrien et al. We gave 40 g. of fats, consisting for the most part of glycerides, daily for three days to 18 patients on a controlled diet. After one day on an unrestricted diet, 80 g. of fats was given daily for another three days. The amount of fat in the faeces was determined daily by the method of Monasterio,17 and the ratio of ingested fats to excreted fats was estimated by the formula of Black. 18 In 6 of the 18 patients (33-3%) there was an increase in the amount of fat excreted in the faeces. All 6 had severe Addison’s disease: in 3 the disease was diagnosed for the first time, and therefore no hormonal treatment had been given: the other 3 had been treated inadequately as outpatients. There was an increase in faecal excretion of fat on a daily dose of only 40 g. of fat in patients 1, 2, 3, and 4 (see table): in FÆCAL EXCRETION OF FAT
*
patients lipids.
Normal
5 and 6
(g.)
AFTER INGESTION OF
(30 determinations), an
1-6-9 g.
100 g.
OF FAT *
(mean 4-21 g.)
increase appeared after doses of 80 g. of
The fats in the fasces are undoubtedly of alimentary origin; some of these patients an extra load of triolein 1311 was always followed by greatly increased excretion of the tagged fat. In patients with Addison’s disease-in which there is an increased fscal excretion of fats-the blood-lipids load test displays abnormality after a very slight rise in blood-lipid. Improvement on appropriate endocrine therapy is accompanied by restoration of the normal ratio between ingested lipids and excreted lipids and by a normal blood-lipid load test. 13. Thomson, C. G., McIlwain, H. Biochem. J. 1961, 79, 342. 14. McIlwain, H. ibid. 1961, 78, 24. 15. Guarini, G., Macaluso, M. Corticosurrene e Metabolismo Lipidico; in
p. 26. Turin, 1961. 16. 17. 18.
Guarini, G., Macaluso, M., Pappalardo, A. International Congress on Hormonal Steroids; p. 245. Milan, 1962. Monasterio, G., Gigli, G., Scotti, G. Riv. Gastro-ent. 1953, 5, 63. Black, W. Quoted by Ciauri, G. in Pass. ital. Gastroent. 1959, 9, 527.