- Email: [email protected]
INTRAVENOUS IRON
531 been
Surgenor
fig. 3-Thyroid enlargement eight months after discontinuing use of resorcinol ointment. puffiness around the eyes, and scanty hair. Abnormal features were the waxiness of the pallor, and the large, even, non-nodular goitre. Investigations showed, cardioscopic and electrocardiographic features to be compatible with the diagnosis of myxoedema. The disappearance of the goitre on withdrawal of resorcinol from the ointment used on her legs strongly suggests that this was the agent
responsible; further investigation her second admission as the. patient
was was a
impossible on dying woman
with extensive burns. The metabolic changes may be summarised as follows : basal metabolism in lower normal range; serumcholesterol normal; thyroid uptake of radio-iodine increased above normal. This last finding is similar to that seen after treatment with other goitrogens, and may be regarded as a goitrogen effect. These observations are very similar to those reported by Bull and Fraser, but differ considerably from those made in spontaneous
myxoedema. In view of the popularity of resorcinol ointments, it likely that this condition may be more common than is at present realised. F. DUDLEY HART Westminster Hospital, London, S.W.1. N. F. MACLAGAN. seems
INTRAVENOUS IRON
SIR,—Dr. Jean Scott and Dr. A. D. T. Govan share with Nissim and with Slack and Wilkinson the honour of having pioneered the introduction into clinical practice of the intravenous injection of saccharated iron compounds. Their paper in your issue of Feb. 17 is a notable addition to the valuable work they have done. In their searching analysis of the haemoglobin levels in their cases they found that 100 mg. of elemental iron will raise the haemoglobin level of the pregnant woman by 0-3 g. per 100 ml. This figure is very important to the obstetrician, because it shows what response he can hope to achieve in the time remaining before delivery is expected. Studies similar to those of Scott and Govan were carried out in the - antenatal department of the Postgraduate School at Hammersmith. In a smaller series (35 cases) we arrived at a figure slightly higher than that of Scott’ and Govan-namely, 0-4 g. rise of haemoglobin per 100 mg. intravenous iron. When it is considered that haemoglobin levels in pregnancy are notoriously variable, the difference between the figures is hardly significant. I would be happy to accept the 0-3 g. haemoglobin rise suggested by Scott and Govan as the basis of clinical calculations. In some respects their speculations are less fortunate. Their hypothesis of a renal threshold for iron is not new. It was propounded by Monasterio1 in several publications during 1942-43. Unhappily it has already 1.
Monasterio, G., Casini, C. 14, 22.
Rass. Fisiopatol. clin. terap. 1942,
incorrect. The studies of Laurell 2 and of et al.3 have shown that iron is bound to that
proved
fraction of the &bgr;-globulins which Cohn4 designated as rv-4 (8) in 1946. The unsaturated capacity of this protein to bind iron is roughly 2-3 times the normal level of In serum-iron and is raised in pregnancy anaemia. giving 100 mg. of iron Scott and Govan exceeded slightly in some cases the power of globulin rapidly to bind iron. It is this small amount of free iron which spilled over in the urine. There is no renal threshold for iron, because the kidney is unable to excrete iron as it normally exists in the serum-i.e., bound to protein. A further possible explanation of the appearance of iron in the urine lies in the fact that complex saccharated compounds give up their molecular iron to the serum proteins more slowly than do simple iron salts, and therefore some saccharated iron may be excreted by the kidney before the iron can be passed over to the proteins. Scott and Govan will find it difficult to substantiate their suggestion that renal excretion will account for any significant proportion of the iron that disappears from the serum after intravenous administration. Their figure of 5.2 mg. excreted in 24 hours is higher than any hitherto recorded in my experience. The highest excretion in similar work in this unit was 3-5 mg. Accepting their figure, one can account for only 5% of the iron injected. We are all agreed that the remaining 95% disappears from the serum very much more rapidly than it can be incorporated in the hæmoglobin molecule. Where does it go ?’? Itseems reasonable to suppose that the iron goes to storage depots and to the foetus. It is difficult to see why Scott and Govan say they are prepared to " make a definite statement indicating that maternal storage and foetal demands are not entirely responsible for the limited response of anaemic pregnant patients to intravenous iron." The observation that certain cases show a delayed response to intravenous iron is interesting. This phenomenon appears also in the cases investigated at Hammersmith. The explanation that this is due to hæmodilution, which Scott and Govan put forward, is ingenious and attractive. No experimental evidence in terms of blood volumes is adduced. As it stands it is only a shrewd guess which the scientific observer will be chary of accepting. The whole process of splitting cases up into those which show a large rapid response and those which show a small slow one is questionable. Scott and Govan make no attempt to show that the difference between the mean of the rapid responders and the mean of the slow responders is statistically significant. The response is comparatively variable within the limits laid down by them. In my own experience a good many cases fall between one type of response and the other. I fear that the distinction is artificial. In view of the fact that it is the clinical impression of -experienced workers, this separation into two types of anaemia response is eminently worthy of respect. But it is no more than opinion until statistically validated. Scott and Govan’s observations on the occasional toxic effects of intravenous iron describe very clearly similar experiences in this unit and the publication of their investigations into this aspect is keenly awaited. Working along this line in London we have estimated the iron-binding capacity of the serum proteins in all our cases. Using rough calculations of plasma volume it would appear that toxic effects only arise when the ironbinding capacity is exceeded in the individual injection. Hence the significance of Scott and Govan’s observation that the reaction " depends on the amount of iron given in a single injection." It does not follow that the toxic reaction is due to free iron. If copper is bound to the same ,
2. Laurell, C. B. Acta physiol. scand. 1947, 14, suppl. 46. 3. Surgenor, D. M., Koechlin, B. H., Strong, L. E. J. clin. Invest. 1949, 28, 73. 4. Cohn, E. J., et al. J. Amer. chem. Soc. 1946, 68, 459.
532 as it very likely is, toxic reactions may be due to the, appearance of copper, selectively displaced from the nrotein substrate bv its saturation with iron. ARNOLD KLOPPER Junior Registrar, Department of Obstetrics and Gynæcology.
protein molecule,
Hammersmith Hospital, London.
DERMATITIS HERPETIFORMIS TREATED WITH CHLORAMPHENICOL SIR,—The report of a case of dermatitis herpetiformis treated with chloramphenicol by Dr. N. A. Thorne (Feb. 17) raises two points. Firstly, chloramphenicol has previously been used in this disease. Beinhauer1 2 of the results 5 which were in cases, reported improved and the rest showed no change. The dosage used in these cases was f500 mg. daily for periods varying from three to six weeks. Secondly, insufficient time has been allowed to elapse before assessing the result of treatment. It is, of course, obvious from the case-history that Dr. Thorne’s patient has materially benefited from the use of chloramphenicol, but what will happen when the drug is discontinued Practically every case of dermatitis herpetiformis controlled by sulphapyridine relapses when the drug is withdrawn, and the same can be said of the few cases reported as showing favourable response to any of the other sulphonamides, or to penicillin or aureomycin. This is certainly my experience and I venture to suggest it may also occur after chloramphenicol. A maintenance dose of the latter may be necessary, and this is not without its disadvantages ; to mention but one complication, pruritus. ani is not uncommon with prolonged chloramphenicol therapy. This apparently occurred in some of Beinhauer’s cases, as he had to take steps to treat it. -I am of the opinion, therefore, that the use of chloramphenicol in dermatitis herpetiformis should be reserved for very severe cases. It should not be used for the milder varieties, which are at present quite adequately controlled by very small doses of sulphapyridine. J. O’D. ALEXANDER Third Assistant, Royal Infirmary, Glasgow, C.4. Department of Dermatology. A CONNECTION BETWEEN THE PREFRONTAL CORTEX AND THE HIPPOCAMPAL FORMATION
of the variable results which have been of prefrontal leucotomy, and the need for a more accurate knowledge of the
SIR,—In view
reported following the operation
efferent connections of the prefrontal cortex, the following observations recently made in this laboratory appear to be of some interest. Ablation of the prefrontal cortex on the medial aspect of the cerebral hemisphere in a monkey (involving areas 9, 10, and 32, and also to a slight extent the medial part of area 6) was found to result in a large number of degenerating fibres in the cingulum. These fibres can be traced as they run back in the medial part of the cingulate fasciculus. Posteriorly, they turn round the splenium of the corpus callosum and can be followed to their termination in the presubicular zone of the hippocampal formation. Many more degenerating fibres were found to be present in the cingulum than can be seen after localised cortical ablations limited to either the anterior or posterior parts of the cortex of the
cingulate
gyrus. The extent of this contribution to the cingulum from the prefrontal cortex seems to have been hitherto unsuspected. Possibly it may explain why, in some cases, a localised removal of the anterior cingulate cortex in the surgical treatment of mental disorders fails to produce significant changes. It also suggests an anatomical basis for the opinion expressed by some American workers that more satisfactory results are to be expected 1.
Beinhauer, L. G.
Arch. Derm. Syph. 1950, 62, 291.
after leucotomy if the lesion extends far medially into white matter of the frontal lobe. Such lesions, of"course, are more likely to involve the fibres which we have found to contribute to the eingulum toaerminate in -the hippoeampal formation. :’ The precise r61e of the hippocampalformation in emotional mechanisms is not yet there is some evidence in experimental- animals..of altered emotionalstates following lesions which involve this structure. Department of Anatomy, W. R. ADEY. University of Oxford.
the
and
.
.
known, but
’.
TREATMENT OF BURNS SiR,-Reporting last week the discussion at the Royal Society of Medicine, you attribute to me the remark " that the present neglect of antisera was unwise." I would be grateful if you would allow me to state that I did not make such a remark, the meaning of which I do not in fact understand. I did intervene very briefly in the discussion to try to make the point that, granted the value of Mr. Wallace’s exposure treatment of burns, practical difficulties might render some form of absorptive evaporative dressing desirable in some cases. I went on to suggest that the use of water-absorbing powders and pastes might be explored for this purpose. In conclusion, may I state also that, from work which we are doing, it seems unlikely that a paste made from glycerin will prove to be the answer, owing to the property of glycerin of attracting and retaining water. An ideal absorptive powder or paste should not only absorb water but also allow of its evaporation. DAVID H. PATEY. London, W.I. --
-
VACCINATION AGAINST SMALLPOX
SIR,—I do not wish to take up your space in prolonging this correspondence ; but as my figures do not fit in with his own pet theories Dr. Millard seeks to belittle the weight of argument concerning the occurrence of mild cases of variola major in the unvaccinated. As I did not quote the mortality-rates of these cases, he " doubts very much " whether they were true variola major. On at least one occasion some cases of this series were seen by an Army medical officer who had had considerable experience of smallpox in India and who stated that they were as severe as anything he had
previously seen. The mortality-rate
in the unvaccinated was 27%, which is about normal for variola major. But it is strange that Dr. Millard should be so ignorant of this, for he personally requested and was sent a reprint of the original articles published in the Journal of Hygiene which gave all the figures. Department of Preventive Medicine C. W. DIXON. and Public Health, Leeds.
ÆTIOLOGY OF CHRONIC GASTRIC ULCER SiR,-Unfortunately I cannot give Dr. Bromage (Feb. 17) the data he seeks. The study of oxygen desaturation in the blood-vessels of the stomach and intestine is one of great interest ; but this problem was not linked to the present investigation, because it appeared that the site, size, and number of the arteriovenous shunts were the most likely factors to be of ætiological importance. For example, if the shunts were of large size and distributed evenly throughout the submucosa, or at the base of the mucous membrane, when they opened the arterial blood would be diverted from the body and fundus as much as from the lesser curvature. In that event the oxyntic cells of the gastric glands would be deprived of their blood-supply and no hydrochloric acid would be secreted. As current opinion considers the presence of an acid gastric juice of fundamental setiological importance, it seemed essential to find out, first of all, whether the " shunts " were distributed in a manner likely to
Surgenor
fig. 3-Thyroid enlargement eight months after discontinuing use of resorcinol ointment. puffiness around the eyes, and scanty hair. Abnormal features were the waxiness of the pallor, and the large, even, non-nodular goitre. Investigations showed, cardioscopic and electrocardiographic features to be compatible with the diagnosis of myxoedema. The disappearance of the goitre on withdrawal of resorcinol from the ointment used on her legs strongly suggests that this was the agent
responsible; further investigation her second admission as the. patient
was was a
impossible on dying woman
with extensive burns. The metabolic changes may be summarised as follows : basal metabolism in lower normal range; serumcholesterol normal; thyroid uptake of radio-iodine increased above normal. This last finding is similar to that seen after treatment with other goitrogens, and may be regarded as a goitrogen effect. These observations are very similar to those reported by Bull and Fraser, but differ considerably from those made in spontaneous
myxoedema. In view of the popularity of resorcinol ointments, it likely that this condition may be more common than is at present realised. F. DUDLEY HART Westminster Hospital, London, S.W.1. N. F. MACLAGAN. seems
INTRAVENOUS IRON
SIR,—Dr. Jean Scott and Dr. A. D. T. Govan share with Nissim and with Slack and Wilkinson the honour of having pioneered the introduction into clinical practice of the intravenous injection of saccharated iron compounds. Their paper in your issue of Feb. 17 is a notable addition to the valuable work they have done. In their searching analysis of the haemoglobin levels in their cases they found that 100 mg. of elemental iron will raise the haemoglobin level of the pregnant woman by 0-3 g. per 100 ml. This figure is very important to the obstetrician, because it shows what response he can hope to achieve in the time remaining before delivery is expected. Studies similar to those of Scott and Govan were carried out in the - antenatal department of the Postgraduate School at Hammersmith. In a smaller series (35 cases) we arrived at a figure slightly higher than that of Scott’ and Govan-namely, 0-4 g. rise of haemoglobin per 100 mg. intravenous iron. When it is considered that haemoglobin levels in pregnancy are notoriously variable, the difference between the figures is hardly significant. I would be happy to accept the 0-3 g. haemoglobin rise suggested by Scott and Govan as the basis of clinical calculations. In some respects their speculations are less fortunate. Their hypothesis of a renal threshold for iron is not new. It was propounded by Monasterio1 in several publications during 1942-43. Unhappily it has already 1.
Monasterio, G., Casini, C. 14, 22.
Rass. Fisiopatol. clin. terap. 1942,
incorrect. The studies of Laurell 2 and of et al.3 have shown that iron is bound to that
proved
fraction of the &bgr;-globulins which Cohn4 designated as rv-4 (8) in 1946. The unsaturated capacity of this protein to bind iron is roughly 2-3 times the normal level of In serum-iron and is raised in pregnancy anaemia. giving 100 mg. of iron Scott and Govan exceeded slightly in some cases the power of globulin rapidly to bind iron. It is this small amount of free iron which spilled over in the urine. There is no renal threshold for iron, because the kidney is unable to excrete iron as it normally exists in the serum-i.e., bound to protein. A further possible explanation of the appearance of iron in the urine lies in the fact that complex saccharated compounds give up their molecular iron to the serum proteins more slowly than do simple iron salts, and therefore some saccharated iron may be excreted by the kidney before the iron can be passed over to the proteins. Scott and Govan will find it difficult to substantiate their suggestion that renal excretion will account for any significant proportion of the iron that disappears from the serum after intravenous administration. Their figure of 5.2 mg. excreted in 24 hours is higher than any hitherto recorded in my experience. The highest excretion in similar work in this unit was 3-5 mg. Accepting their figure, one can account for only 5% of the iron injected. We are all agreed that the remaining 95% disappears from the serum very much more rapidly than it can be incorporated in the hæmoglobin molecule. Where does it go ?’? Itseems reasonable to suppose that the iron goes to storage depots and to the foetus. It is difficult to see why Scott and Govan say they are prepared to " make a definite statement indicating that maternal storage and foetal demands are not entirely responsible for the limited response of anaemic pregnant patients to intravenous iron." The observation that certain cases show a delayed response to intravenous iron is interesting. This phenomenon appears also in the cases investigated at Hammersmith. The explanation that this is due to hæmodilution, which Scott and Govan put forward, is ingenious and attractive. No experimental evidence in terms of blood volumes is adduced. As it stands it is only a shrewd guess which the scientific observer will be chary of accepting. The whole process of splitting cases up into those which show a large rapid response and those which show a small slow one is questionable. Scott and Govan make no attempt to show that the difference between the mean of the rapid responders and the mean of the slow responders is statistically significant. The response is comparatively variable within the limits laid down by them. In my own experience a good many cases fall between one type of response and the other. I fear that the distinction is artificial. In view of the fact that it is the clinical impression of -experienced workers, this separation into two types of anaemia response is eminently worthy of respect. But it is no more than opinion until statistically validated. Scott and Govan’s observations on the occasional toxic effects of intravenous iron describe very clearly similar experiences in this unit and the publication of their investigations into this aspect is keenly awaited. Working along this line in London we have estimated the iron-binding capacity of the serum proteins in all our cases. Using rough calculations of plasma volume it would appear that toxic effects only arise when the ironbinding capacity is exceeded in the individual injection. Hence the significance of Scott and Govan’s observation that the reaction " depends on the amount of iron given in a single injection." It does not follow that the toxic reaction is due to free iron. If copper is bound to the same ,
2. Laurell, C. B. Acta physiol. scand. 1947, 14, suppl. 46. 3. Surgenor, D. M., Koechlin, B. H., Strong, L. E. J. clin. Invest. 1949, 28, 73. 4. Cohn, E. J., et al. J. Amer. chem. Soc. 1946, 68, 459.
532 as it very likely is, toxic reactions may be due to the, appearance of copper, selectively displaced from the nrotein substrate bv its saturation with iron. ARNOLD KLOPPER Junior Registrar, Department of Obstetrics and Gynæcology.
protein molecule,
Hammersmith Hospital, London.
DERMATITIS HERPETIFORMIS TREATED WITH CHLORAMPHENICOL SIR,—The report of a case of dermatitis herpetiformis treated with chloramphenicol by Dr. N. A. Thorne (Feb. 17) raises two points. Firstly, chloramphenicol has previously been used in this disease. Beinhauer1 2 of the results 5 which were in cases, reported improved and the rest showed no change. The dosage used in these cases was f500 mg. daily for periods varying from three to six weeks. Secondly, insufficient time has been allowed to elapse before assessing the result of treatment. It is, of course, obvious from the case-history that Dr. Thorne’s patient has materially benefited from the use of chloramphenicol, but what will happen when the drug is discontinued Practically every case of dermatitis herpetiformis controlled by sulphapyridine relapses when the drug is withdrawn, and the same can be said of the few cases reported as showing favourable response to any of the other sulphonamides, or to penicillin or aureomycin. This is certainly my experience and I venture to suggest it may also occur after chloramphenicol. A maintenance dose of the latter may be necessary, and this is not without its disadvantages ; to mention but one complication, pruritus. ani is not uncommon with prolonged chloramphenicol therapy. This apparently occurred in some of Beinhauer’s cases, as he had to take steps to treat it. -I am of the opinion, therefore, that the use of chloramphenicol in dermatitis herpetiformis should be reserved for very severe cases. It should not be used for the milder varieties, which are at present quite adequately controlled by very small doses of sulphapyridine. J. O’D. ALEXANDER Third Assistant, Royal Infirmary, Glasgow, C.4. Department of Dermatology. A CONNECTION BETWEEN THE PREFRONTAL CORTEX AND THE HIPPOCAMPAL FORMATION
of the variable results which have been of prefrontal leucotomy, and the need for a more accurate knowledge of the
SIR,—In view
reported following the operation
efferent connections of the prefrontal cortex, the following observations recently made in this laboratory appear to be of some interest. Ablation of the prefrontal cortex on the medial aspect of the cerebral hemisphere in a monkey (involving areas 9, 10, and 32, and also to a slight extent the medial part of area 6) was found to result in a large number of degenerating fibres in the cingulum. These fibres can be traced as they run back in the medial part of the cingulate fasciculus. Posteriorly, they turn round the splenium of the corpus callosum and can be followed to their termination in the presubicular zone of the hippocampal formation. Many more degenerating fibres were found to be present in the cingulum than can be seen after localised cortical ablations limited to either the anterior or posterior parts of the cortex of the
cingulate
gyrus. The extent of this contribution to the cingulum from the prefrontal cortex seems to have been hitherto unsuspected. Possibly it may explain why, in some cases, a localised removal of the anterior cingulate cortex in the surgical treatment of mental disorders fails to produce significant changes. It also suggests an anatomical basis for the opinion expressed by some American workers that more satisfactory results are to be expected 1.
Beinhauer, L. G.
Arch. Derm. Syph. 1950, 62, 291.
after leucotomy if the lesion extends far medially into white matter of the frontal lobe. Such lesions, of"course, are more likely to involve the fibres which we have found to contribute to the eingulum toaerminate in -the hippoeampal formation. :’ The precise r61e of the hippocampalformation in emotional mechanisms is not yet there is some evidence in experimental- animals..of altered emotionalstates following lesions which involve this structure. Department of Anatomy, W. R. ADEY. University of Oxford.
the
and
.
.
known, but
’.
TREATMENT OF BURNS SiR,-Reporting last week the discussion at the Royal Society of Medicine, you attribute to me the remark " that the present neglect of antisera was unwise." I would be grateful if you would allow me to state that I did not make such a remark, the meaning of which I do not in fact understand. I did intervene very briefly in the discussion to try to make the point that, granted the value of Mr. Wallace’s exposure treatment of burns, practical difficulties might render some form of absorptive evaporative dressing desirable in some cases. I went on to suggest that the use of water-absorbing powders and pastes might be explored for this purpose. In conclusion, may I state also that, from work which we are doing, it seems unlikely that a paste made from glycerin will prove to be the answer, owing to the property of glycerin of attracting and retaining water. An ideal absorptive powder or paste should not only absorb water but also allow of its evaporation. DAVID H. PATEY. London, W.I. --
-
VACCINATION AGAINST SMALLPOX
SIR,—I do not wish to take up your space in prolonging this correspondence ; but as my figures do not fit in with his own pet theories Dr. Millard seeks to belittle the weight of argument concerning the occurrence of mild cases of variola major in the unvaccinated. As I did not quote the mortality-rates of these cases, he " doubts very much " whether they were true variola major. On at least one occasion some cases of this series were seen by an Army medical officer who had had considerable experience of smallpox in India and who stated that they were as severe as anything he had
previously seen. The mortality-rate
in the unvaccinated was 27%, which is about normal for variola major. But it is strange that Dr. Millard should be so ignorant of this, for he personally requested and was sent a reprint of the original articles published in the Journal of Hygiene which gave all the figures. Department of Preventive Medicine C. W. DIXON. and Public Health, Leeds.
ÆTIOLOGY OF CHRONIC GASTRIC ULCER SiR,-Unfortunately I cannot give Dr. Bromage (Feb. 17) the data he seeks. The study of oxygen desaturation in the blood-vessels of the stomach and intestine is one of great interest ; but this problem was not linked to the present investigation, because it appeared that the site, size, and number of the arteriovenous shunts were the most likely factors to be of ætiological importance. For example, if the shunts were of large size and distributed evenly throughout the submucosa, or at the base of the mucous membrane, when they opened the arterial blood would be diverted from the body and fundus as much as from the lesser curvature. In that event the oxyntic cells of the gastric glands would be deprived of their blood-supply and no hydrochloric acid would be secreted. As current opinion considers the presence of an acid gastric juice of fundamental setiological importance, it seemed essential to find out, first of all, whether the " shunts " were distributed in a manner likely to