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SERUM-FREE-FATTY-ACIDS AND ARRHYTHMIAS AFTER MYOCARDIAL INFARCTION
1039 LIGNOCAINE FOR ARRHYTHMIAS SIR,-We have seen a patient in whom lignocaine seemed to provoke ventricular tachycardia and ventricular fibrillation in a similar manner to that in the case described by Dr. Kaufmann
(April 20, p. 862). A 57-year-old man was admitted to the coronary-care unit of this hospital after a myocardial infarction. 4 days after to have ventricular extrasystoles at the of 12 per minute. According to our present practice, he was given an intravenous injection of 50 mg. of lignocaine and, since this was without effect over the succeeding few minutes, it was followed by a further dose of 50 mg. At the conclusion of the second injection ventricular tachycardia occurred and this progressed within a few seconds to ventricular fibrillation. External cardiac massage was performed and spontaneous reversion to sinus rhythm took place before electrical defibrillation had been applied. Multiple ventricular ectopic beats continued for the next half-hour and their number increased to more than 20 per minute. In view of our favourable experience with lignocaine in the past we decided to try this drug again and a third dose of 50 mg. was given. Again it provoked ventricular tachycardia which, on this occasion, did not progress to fibrillation. Sinus rhythm was restored by intra-.
admission, he started rate
venous
procainamide.
This adverse reaction may be an extreme case of a more general effect of lignocaine for we have often observed an increase in the number of ventricular extrasystoles as a transient effect while the injection is being given and this may happen even in those patients who respond to the drug, after a further two or three minutes, by the cessation of ectopic beats. The mechanism may be similar to those instances in which ventricular fibrillation is provoked by procainamide and quinidine and perhaps may be analogous to the paraesthesiae caused by local anaesthetics before they block nerve conduction. R. E. NAGLE Selly Oak Hospital, 29. J. PILCHER. Birmingham
SERUM-FREE-FATTY-ACIDS AND ARRHYTHMIAS AFTER MYOCARDIAL INFARCTION SIR,-In their article (April 6, p. 710), Dr. Oliver and his colleagues demonstrated that a high serum concentration of F.F.A. was associated with a high incidence of cardiac arrhythmias. The authors suggest two alternative mechanisms to explain this observation. Firstly, both phenomena may result from a common cause, possibly the increase in level of circulating catecholamines that is known to occur following severe myocardial infarction. Alternatively the association may be due to enhanced myocardial hypoxia, resulting from the obligatory utilisation of F.F.A., a substrate which requires more oxygen for its combustion than does glucose. The authors do not base this latter hypothesis on quantitative estimates, and the following calculations cast doubts on its
validity. The argument depends on whether the oxygen or the substrate becomes rate-limiting when the circulation through the coronary arteries is reduced. From the chemical equation for oxidation to CO2 and H2O of stearic acid, a typical F.F.A., 0-5 meq. of the acid requires 291 ml. 02. 1 litre of blood, assuming full saturation, has an O2 content of 200 ml. Thus at a serum F.F.A. concentration of 1000 fLeq. per litre (corresponding to a blood concentration of 500 fLeq. per litre) there is sufficient O2 to burn only about 65% of the F.F.A. Similarly it can be calculated that blood contains sufficient O2 to burn only about 25% of its glucose content. Clearly therefore, independent of the nature of the substrate, it is the 02 content of the blood that becomes the rate-limiting factor. Table 11 of the article showed that raising the concentration of F.F.A. from 1000 fLeq. per litre serum to 1500 eq. per litre, is associated with an increase in the frequency of arrhythmias. However, since the O2 content of the arterial blood is already the rate-limiting factor, then raising the concentration of F.F.A. becomes irrelevant as regards increasing the degree of hypoxia
in the myocardium, and hence this cannot be the mechanism of the association. The O2 content of the blood as measured by the Pa02 is known to be lowered in the severely ill coronary patient, but no figures for it have been given by the authors. This leads to the key question: is there a greater energy yield when a limited amount of O2 is used to burn F.F.A. as opposed to glucose ? Taking the caloric value of stearic acid as 9-56 and of glucose as 3.74,2 the yield of energy per litre of O2 is 4-65 Kcal, and 50 Kcal. respectively. A difference of less than 10% is not likely to lead to a clear advantage with regard either to energy or to reduced hypoxia as the authors claim. A positive correlation between F.F.A. concentration and the frequency of arrhythmias has been demonstrated in the article; if there is a direct cause-and-effect relationship between the two, the calculations above suggest that it is not likely to occur through an enhancement of hypoxia in the myocardium by the obligatory use of F.F.A. as substrate. Therefore it might be worth considering the possibility of other direct effects of F.F.A. on the
myocardium. Finally, the suggestion that glucose infusion in such patients would be a rational prophylactic against the development of arrhythmias, ignores the fact, established by Shipp et al. and Garland et al.,4 that, even in the presence of a large bloodglucose concentration, a high concentration of F.F.A. inhibits the utilisation of the glucose by the myocardium. Department of Chemical Pathology, Department of Medicine, General Infirmary, University of Leeds, Leeds 2.
J. R. W. DYKES S. H. TAYLOR.
SIR,—The clinical correlation between elevated
serum-
free-fatty-acids and arrhythmias and death in patients with myocardial infarction described by Dr. Oliver and his colleagues is strengthened by experimental observations. Under certain conditions long-chain fatty acids are injurious to cells, aggregate platelets, and initiate blood coagulation. We have observed acute myocardial failure, cardiac arrhythmias, thrombosis, and death when unbound long-chain saturated fatty acids were injected intravenously into dogs.6 Similar results were obtained when elevated plasma-F.F.A. concentrations were produced owing to acute mobilisation of endogenous lipid by corticotrophin in rabbits,’ glucagon in geese,8 and noradrenaline in dogs.9 The high levels of free fatty acids which seemed toxic in experimental animals were similar to the toxic levels reported in this clinical study. Oliver et al. found that F.F.A. concentrations of 1200 pt.eq. per litre or greater were associated with increased mortality and a greater frequency of arrhythmias. In a necropsy study, we found that the group of patients who died following acute myocardial infarction had the highest mean serum-F.F.A. concentration of any group (1164 Eq. per litre ±s.E. 79).10 Plasma-free-fatty-acids are normally transported bound to plasma-albumin. We suggest that, whenever their circulating level exceeds the amount which can be bound to the " tight" binding sites on the albumin molecule, toxic consequences may ensue.5 Then fatty acids are more loosely bound and may more readily injure cells by their high concentration. Current evidence supports the hypothesis that very high plasma concentrations of fatty acids or a decrease in ther ate of oxidation of fatty acids may result in an intracellular accumula1. 2. 3. 4. 5.
6. 7. 8. 9. 10.
McKenzie, G. J., Taylor, S. H., Flenley, D. C., McDonald, A. H., Staunton, H. P., Donald, K. W. Lancet, 1964, ii, 825. Handbook of Chemistry and Physics (edited by C. D. Hodgman); pp. 870, 874. Cleveland, Ohio, 1933. Shipp, J. C., Opie, L. H., Challoner, D. R. Nature, Lond. 1961, 18, 1018. Garland, P. B., Randle, P. J., Newsholme, E. A. ibid. 1963, 20, 169. Connor, W. E., Hoak, J. C., Warner, E. D. Thromb. Diath. hœmorrh. 1966, suppl. 21, p. 193. Hoak, J. C., Connor, W. E., Eckstein, J. W., Warner, E. D. J. Lab. clin. Med. 1964, 63, 791. Hoak, J. C., Poole, J. C. F., Robinson, D. S. Am. J. Path. 1963, 43, 987. Hoak, J. C., Connor, W. E., Warner, E. D. Clin. Res. 1966, 14, 440. Hoak, J. C., Warner, E. D., Connor, W. E. ibid. 1967, 15, 408. Warner, E. D., Hoak, J. C., Connor, W. E. Thromb. Diath. hœmorrh. 1967, suppl. 26, p. 249.
1040 tion of
fatty acids which
structure
may prove detrimental to cellular
and function.
Departments of Internal Medicine and Pathology, University of Iowa, Iowa City, Iowa, U.S.A.
of autologous plasma before addition of P.H.A. It would interesting to know whether the defective transformation they describe can also be improved by the addition of normal human plasma, and whether the patient’s plasma will retard the growth of control cells. traces
be
W. E. CONNOR J. C. VOAK E. D. WARNER.
Department of Anatomy, Royal Free Hospital School of Medicine, London W.C.1.
BRYAN WINTER.
A SLEEP REGIMEN FOR A NEUROLOGIST’S BOOK LIST ACUTE MYOCARDIAL INFARCTION SIR,-Dr. Nixon and his colleagues (April 6, p. 726) present SiR,-Professor Miller (May 4, p. 971) has compiled a an interesting approach to possible prevention of arrhythmias formidable menu, but may I suggest that the budding neurolafter myocardial infarction. However, a great deal of recent ogist, clinical or otherwise, should start off with An Introduction to Neurologv bv Tudson Herrick ? evidence points to the complexity, dangers, and benefits of certain drugs given to patients with cardiovascular disease. F. B. BYROM. During the D state (rapid-eye-movement sleep) which accounts for 20-25% of a normal night’s sleep, variations in blood-pressure, pulse, and respiration, and electroSERUM-Fab FRAGMENTS IN MULTIPLE cardiographic changes such as sT-segment depression and SCLEROSIS AND SUBACUTE SCLEROSING rhythm abnormalities are more common than in other sleep PANENCEPHALITIS - periods. It is important, therefore, that drugs given to patients SiR,ŇThe immunqglobulin synthesis within the central after myocardial infarction not only have no adverse cardionervous system (c.N.s.) has been reported in patients with vascular effects, but also that their effect on the D state should multiple sclerosis (M.S.) 1 and subacute sclerosing panbe considered. For example, chlorpromazine and barbiturates encephalitis (s.S.p.).2 However, immunopathological manidecrease D-time initially followed by a rebound increase in D-time which may be hazardous to the patient during the, festations in serum of M.S. and s.s.p. patients 34 indicate myocardial healing process. Apart from this type of effect, participation of immunologically competent extraneural tissues prolonged sleep induction with drugs may cause mental changes in the pathogenetic mechanisms of these diseases. In more than 6500 immunoelectrophoretic examinations of and even psychotic reactions. serum and cerebrospinal fluid (c.s.F.) in over 450 patients with Antihistamines such as promethazine (used by Nixon et al.) different c.N.s. diseases, I have detected abnormalities in the have not been studied extensively in regard to D-time. Howserum and c.s.F. IgG precipitation arcs in a variety of subacute ever, drugs such as diazepam and chloral hydrate may be more beneficial to patients with recent myocardial infarction since they have little influence on D-time and rebound has not been observed. GERALD ROSENBLATT Sleep and Dream Laboratory, GEORGE ZWILLING Boston State Hospital, ERNEST HARTMANN. Boston, Massachusetts 02124, U.S.A. Splitting of serum-IgG precipitation arc in the cathodic field.
LYMPHOCYTES IN WHIPPLE’S DISEASE SiR,ŇThe report by Dr. Maxwell and his colleagues (April 27, p. 887), concerning lymphocytes in Whipple’s disease, is further evidence of lymphoreticular dysfunction in certain gastrointestinal diseases; the lack of a chronic inflammatory-cell infiltrate in the mucosa, the relative failure of the blood lymphocytes to respond to phytohsmagglutinin (P.H.A.) in vitro, and the mucosal infiltration by macrophages are of interest. Evidence of primary immunoglobulin disturbances and of lymphoreticular dysfunction has been described in idiopathic steatorrhcea1 2; the circulating lymphocytes of some patients do not respond normally when cultured with P.H.A. in autologous plasma.3 As in cirrhosis, where a similar result has been described,3 the response varies between patients, from the normal to the grossly abnormal. The leucocytes of some patients exhibit a similar response, in some respects, to that of a culture without P.H.A.; leucoagglutination is absent, and at 72 hours many neutrophils are present, together with a large number of untransformed cells, some transitional cells, some macrophages, but few blast cells. When, at the outset of culture, the patient’s plasma is replaced with homologous plasma from a healthy donor, the development of D.N.A.-synthesising blast cells is increased and other features of a normal P.H.A. culture return. Completion of the cross-exchange, by placing the control cells in the retards the normal response of the control patient’s plasma, cells to P.H.A.33 Dr. Maxwell and his colleagues seem to have removed all 1. Crabbé, P. A., Heremans, J. F. Gut, 1966, 7, 119. 2. McCarthy, C. F., Fraser, I. D., Evans, K. T., Read, A. E. ibid. p. 140. 3. Winter, G. C. B., McCarthy, C. F., Read, A. E., Yoffey, J. M. Br. J. exp. Path. 1967, 48, 66.
More cathodically situated arc (arrowed) shows increased density. Antihuman rabbit antiserum (SEVAC, Prague) was used. Serum was diluted with buffer (1/4).
demyelinating diseases including M.S. and pathological changes in serumimmunoelectropherograms of M.S. and s.s.p. patients was pronounced splitting of the IgG precipitation arc, particularly well demonstrated in the cathodic segment (see figure). The component of the abnormal serum-IgG precipitation arc situated more to the cathodic end of the immunoelectropherogram was regularly of increased density. Antihuman rabbit
inflammatory s.s.p.
and
One of the
most common
antiserum and monovalent anti-Fab and IgG antiserum (SEVAC, Prague; Hoechst Co., Kansas City, Missouri) were further simultaneously used in serum-immunoelectrophoretic examinations of our M.S. and s.s.p. patients. The abnormal cathodically situated IgG component with increased density and the Fab-fragments precipitation arc occupied corresponding positions in serum and c.s.F. immunoelectrophero-
grams.5 By electroimmunodiffusion 6 and radial immunodiffusion (Immunoplates, Hyland Labs., Los Angeles), the serum and C.S.F. Fab fragments (lyophilised Fab fragments of IgG were supplied by SEVAC) and IgG concentrations were examined in 101 patients with different C.N.s. disorders. Over 75% of the 19 patients with M.S. and s.s.p. had serum-Fab-fragments concentrations exceeding 250 mg. per 100 ml. (see table). All patients with M.S. and s.s.p. had abnormal raised c.s.F.-Fab1. 2. 3. 4. 5. 6.
Cohen, S., Bannister, R. Lancet, 1967, i, 366. Kolar, O., Zeman, W., Drew, A., Spurgeon, C. ibid. April 6, 1968, p. 759. Kolar, O., Zeman, W. Z. Immun.Forsch. exp. Ther. 1967, 134, 267. Kolar, O. Neurology, Minneap. 1968, 18, 107. Kolar, O. Unpublished. Hartley, T. F. Merril, D. A., Claman, H. N. Archs Neurol., Chicago, 1966, 15, 472.
(April 20, p. 862). A 57-year-old man was admitted to the coronary-care unit of this hospital after a myocardial infarction. 4 days after to have ventricular extrasystoles at the of 12 per minute. According to our present practice, he was given an intravenous injection of 50 mg. of lignocaine and, since this was without effect over the succeeding few minutes, it was followed by a further dose of 50 mg. At the conclusion of the second injection ventricular tachycardia occurred and this progressed within a few seconds to ventricular fibrillation. External cardiac massage was performed and spontaneous reversion to sinus rhythm took place before electrical defibrillation had been applied. Multiple ventricular ectopic beats continued for the next half-hour and their number increased to more than 20 per minute. In view of our favourable experience with lignocaine in the past we decided to try this drug again and a third dose of 50 mg. was given. Again it provoked ventricular tachycardia which, on this occasion, did not progress to fibrillation. Sinus rhythm was restored by intra-.
admission, he started rate
venous
procainamide.
This adverse reaction may be an extreme case of a more general effect of lignocaine for we have often observed an increase in the number of ventricular extrasystoles as a transient effect while the injection is being given and this may happen even in those patients who respond to the drug, after a further two or three minutes, by the cessation of ectopic beats. The mechanism may be similar to those instances in which ventricular fibrillation is provoked by procainamide and quinidine and perhaps may be analogous to the paraesthesiae caused by local anaesthetics before they block nerve conduction. R. E. NAGLE Selly Oak Hospital, 29. J. PILCHER. Birmingham
SERUM-FREE-FATTY-ACIDS AND ARRHYTHMIAS AFTER MYOCARDIAL INFARCTION SIR,-In their article (April 6, p. 710), Dr. Oliver and his colleagues demonstrated that a high serum concentration of F.F.A. was associated with a high incidence of cardiac arrhythmias. The authors suggest two alternative mechanisms to explain this observation. Firstly, both phenomena may result from a common cause, possibly the increase in level of circulating catecholamines that is known to occur following severe myocardial infarction. Alternatively the association may be due to enhanced myocardial hypoxia, resulting from the obligatory utilisation of F.F.A., a substrate which requires more oxygen for its combustion than does glucose. The authors do not base this latter hypothesis on quantitative estimates, and the following calculations cast doubts on its
validity. The argument depends on whether the oxygen or the substrate becomes rate-limiting when the circulation through the coronary arteries is reduced. From the chemical equation for oxidation to CO2 and H2O of stearic acid, a typical F.F.A., 0-5 meq. of the acid requires 291 ml. 02. 1 litre of blood, assuming full saturation, has an O2 content of 200 ml. Thus at a serum F.F.A. concentration of 1000 fLeq. per litre (corresponding to a blood concentration of 500 fLeq. per litre) there is sufficient O2 to burn only about 65% of the F.F.A. Similarly it can be calculated that blood contains sufficient O2 to burn only about 25% of its glucose content. Clearly therefore, independent of the nature of the substrate, it is the 02 content of the blood that becomes the rate-limiting factor. Table 11 of the article showed that raising the concentration of F.F.A. from 1000 fLeq. per litre serum to 1500 eq. per litre, is associated with an increase in the frequency of arrhythmias. However, since the O2 content of the arterial blood is already the rate-limiting factor, then raising the concentration of F.F.A. becomes irrelevant as regards increasing the degree of hypoxia
in the myocardium, and hence this cannot be the mechanism of the association. The O2 content of the blood as measured by the Pa02 is known to be lowered in the severely ill coronary patient, but no figures for it have been given by the authors. This leads to the key question: is there a greater energy yield when a limited amount of O2 is used to burn F.F.A. as opposed to glucose ? Taking the caloric value of stearic acid as 9-56 and of glucose as 3.74,2 the yield of energy per litre of O2 is 4-65 Kcal, and 50 Kcal. respectively. A difference of less than 10% is not likely to lead to a clear advantage with regard either to energy or to reduced hypoxia as the authors claim. A positive correlation between F.F.A. concentration and the frequency of arrhythmias has been demonstrated in the article; if there is a direct cause-and-effect relationship between the two, the calculations above suggest that it is not likely to occur through an enhancement of hypoxia in the myocardium by the obligatory use of F.F.A. as substrate. Therefore it might be worth considering the possibility of other direct effects of F.F.A. on the
myocardium. Finally, the suggestion that glucose infusion in such patients would be a rational prophylactic against the development of arrhythmias, ignores the fact, established by Shipp et al. and Garland et al.,4 that, even in the presence of a large bloodglucose concentration, a high concentration of F.F.A. inhibits the utilisation of the glucose by the myocardium. Department of Chemical Pathology, Department of Medicine, General Infirmary, University of Leeds, Leeds 2.
J. R. W. DYKES S. H. TAYLOR.
SIR,—The clinical correlation between elevated
serum-
free-fatty-acids and arrhythmias and death in patients with myocardial infarction described by Dr. Oliver and his colleagues is strengthened by experimental observations. Under certain conditions long-chain fatty acids are injurious to cells, aggregate platelets, and initiate blood coagulation. We have observed acute myocardial failure, cardiac arrhythmias, thrombosis, and death when unbound long-chain saturated fatty acids were injected intravenously into dogs.6 Similar results were obtained when elevated plasma-F.F.A. concentrations were produced owing to acute mobilisation of endogenous lipid by corticotrophin in rabbits,’ glucagon in geese,8 and noradrenaline in dogs.9 The high levels of free fatty acids which seemed toxic in experimental animals were similar to the toxic levels reported in this clinical study. Oliver et al. found that F.F.A. concentrations of 1200 pt.eq. per litre or greater were associated with increased mortality and a greater frequency of arrhythmias. In a necropsy study, we found that the group of patients who died following acute myocardial infarction had the highest mean serum-F.F.A. concentration of any group (1164 Eq. per litre ±s.E. 79).10 Plasma-free-fatty-acids are normally transported bound to plasma-albumin. We suggest that, whenever their circulating level exceeds the amount which can be bound to the " tight" binding sites on the albumin molecule, toxic consequences may ensue.5 Then fatty acids are more loosely bound and may more readily injure cells by their high concentration. Current evidence supports the hypothesis that very high plasma concentrations of fatty acids or a decrease in ther ate of oxidation of fatty acids may result in an intracellular accumula1. 2. 3. 4. 5.
6. 7. 8. 9. 10.
McKenzie, G. J., Taylor, S. H., Flenley, D. C., McDonald, A. H., Staunton, H. P., Donald, K. W. Lancet, 1964, ii, 825. Handbook of Chemistry and Physics (edited by C. D. Hodgman); pp. 870, 874. Cleveland, Ohio, 1933. Shipp, J. C., Opie, L. H., Challoner, D. R. Nature, Lond. 1961, 18, 1018. Garland, P. B., Randle, P. J., Newsholme, E. A. ibid. 1963, 20, 169. Connor, W. E., Hoak, J. C., Warner, E. D. Thromb. Diath. hœmorrh. 1966, suppl. 21, p. 193. Hoak, J. C., Connor, W. E., Eckstein, J. W., Warner, E. D. J. Lab. clin. Med. 1964, 63, 791. Hoak, J. C., Poole, J. C. F., Robinson, D. S. Am. J. Path. 1963, 43, 987. Hoak, J. C., Connor, W. E., Warner, E. D. Clin. Res. 1966, 14, 440. Hoak, J. C., Warner, E. D., Connor, W. E. ibid. 1967, 15, 408. Warner, E. D., Hoak, J. C., Connor, W. E. Thromb. Diath. hœmorrh. 1967, suppl. 26, p. 249.
1040 tion of
fatty acids which
structure
may prove detrimental to cellular
and function.
Departments of Internal Medicine and Pathology, University of Iowa, Iowa City, Iowa, U.S.A.
of autologous plasma before addition of P.H.A. It would interesting to know whether the defective transformation they describe can also be improved by the addition of normal human plasma, and whether the patient’s plasma will retard the growth of control cells. traces
be
W. E. CONNOR J. C. VOAK E. D. WARNER.
Department of Anatomy, Royal Free Hospital School of Medicine, London W.C.1.
BRYAN WINTER.
A SLEEP REGIMEN FOR A NEUROLOGIST’S BOOK LIST ACUTE MYOCARDIAL INFARCTION SIR,-Dr. Nixon and his colleagues (April 6, p. 726) present SiR,-Professor Miller (May 4, p. 971) has compiled a an interesting approach to possible prevention of arrhythmias formidable menu, but may I suggest that the budding neurolafter myocardial infarction. However, a great deal of recent ogist, clinical or otherwise, should start off with An Introduction to Neurologv bv Tudson Herrick ? evidence points to the complexity, dangers, and benefits of certain drugs given to patients with cardiovascular disease. F. B. BYROM. During the D state (rapid-eye-movement sleep) which accounts for 20-25% of a normal night’s sleep, variations in blood-pressure, pulse, and respiration, and electroSERUM-Fab FRAGMENTS IN MULTIPLE cardiographic changes such as sT-segment depression and SCLEROSIS AND SUBACUTE SCLEROSING rhythm abnormalities are more common than in other sleep PANENCEPHALITIS - periods. It is important, therefore, that drugs given to patients SiR,ŇThe immunqglobulin synthesis within the central after myocardial infarction not only have no adverse cardionervous system (c.N.s.) has been reported in patients with vascular effects, but also that their effect on the D state should multiple sclerosis (M.S.) 1 and subacute sclerosing panbe considered. For example, chlorpromazine and barbiturates encephalitis (s.S.p.).2 However, immunopathological manidecrease D-time initially followed by a rebound increase in D-time which may be hazardous to the patient during the, festations in serum of M.S. and s.s.p. patients 34 indicate myocardial healing process. Apart from this type of effect, participation of immunologically competent extraneural tissues prolonged sleep induction with drugs may cause mental changes in the pathogenetic mechanisms of these diseases. In more than 6500 immunoelectrophoretic examinations of and even psychotic reactions. serum and cerebrospinal fluid (c.s.F.) in over 450 patients with Antihistamines such as promethazine (used by Nixon et al.) different c.N.s. diseases, I have detected abnormalities in the have not been studied extensively in regard to D-time. Howserum and c.s.F. IgG precipitation arcs in a variety of subacute ever, drugs such as diazepam and chloral hydrate may be more beneficial to patients with recent myocardial infarction since they have little influence on D-time and rebound has not been observed. GERALD ROSENBLATT Sleep and Dream Laboratory, GEORGE ZWILLING Boston State Hospital, ERNEST HARTMANN. Boston, Massachusetts 02124, U.S.A. Splitting of serum-IgG precipitation arc in the cathodic field.
LYMPHOCYTES IN WHIPPLE’S DISEASE SiR,ŇThe report by Dr. Maxwell and his colleagues (April 27, p. 887), concerning lymphocytes in Whipple’s disease, is further evidence of lymphoreticular dysfunction in certain gastrointestinal diseases; the lack of a chronic inflammatory-cell infiltrate in the mucosa, the relative failure of the blood lymphocytes to respond to phytohsmagglutinin (P.H.A.) in vitro, and the mucosal infiltration by macrophages are of interest. Evidence of primary immunoglobulin disturbances and of lymphoreticular dysfunction has been described in idiopathic steatorrhcea1 2; the circulating lymphocytes of some patients do not respond normally when cultured with P.H.A. in autologous plasma.3 As in cirrhosis, where a similar result has been described,3 the response varies between patients, from the normal to the grossly abnormal. The leucocytes of some patients exhibit a similar response, in some respects, to that of a culture without P.H.A.; leucoagglutination is absent, and at 72 hours many neutrophils are present, together with a large number of untransformed cells, some transitional cells, some macrophages, but few blast cells. When, at the outset of culture, the patient’s plasma is replaced with homologous plasma from a healthy donor, the development of D.N.A.-synthesising blast cells is increased and other features of a normal P.H.A. culture return. Completion of the cross-exchange, by placing the control cells in the retards the normal response of the control patient’s plasma, cells to P.H.A.33 Dr. Maxwell and his colleagues seem to have removed all 1. Crabbé, P. A., Heremans, J. F. Gut, 1966, 7, 119. 2. McCarthy, C. F., Fraser, I. D., Evans, K. T., Read, A. E. ibid. p. 140. 3. Winter, G. C. B., McCarthy, C. F., Read, A. E., Yoffey, J. M. Br. J. exp. Path. 1967, 48, 66.
More cathodically situated arc (arrowed) shows increased density. Antihuman rabbit antiserum (SEVAC, Prague) was used. Serum was diluted with buffer (1/4).
demyelinating diseases including M.S. and pathological changes in serumimmunoelectropherograms of M.S. and s.s.p. patients was pronounced splitting of the IgG precipitation arc, particularly well demonstrated in the cathodic segment (see figure). The component of the abnormal serum-IgG precipitation arc situated more to the cathodic end of the immunoelectropherogram was regularly of increased density. Antihuman rabbit
inflammatory s.s.p.
and
One of the
most common
antiserum and monovalent anti-Fab and IgG antiserum (SEVAC, Prague; Hoechst Co., Kansas City, Missouri) were further simultaneously used in serum-immunoelectrophoretic examinations of our M.S. and s.s.p. patients. The abnormal cathodically situated IgG component with increased density and the Fab-fragments precipitation arc occupied corresponding positions in serum and c.s.F. immunoelectrophero-
grams.5 By electroimmunodiffusion 6 and radial immunodiffusion (Immunoplates, Hyland Labs., Los Angeles), the serum and C.S.F. Fab fragments (lyophilised Fab fragments of IgG were supplied by SEVAC) and IgG concentrations were examined in 101 patients with different C.N.s. disorders. Over 75% of the 19 patients with M.S. and s.s.p. had serum-Fab-fragments concentrations exceeding 250 mg. per 100 ml. (see table). All patients with M.S. and s.s.p. had abnormal raised c.s.F.-Fab1. 2. 3. 4. 5. 6.
Cohen, S., Bannister, R. Lancet, 1967, i, 366. Kolar, O., Zeman, W., Drew, A., Spurgeon, C. ibid. April 6, 1968, p. 759. Kolar, O., Zeman, W. Z. Immun.Forsch. exp. Ther. 1967, 134, 267. Kolar, O. Neurology, Minneap. 1968, 18, 107. Kolar, O. Unpublished. Hartley, T. F. Merril, D. A., Claman, H. N. Archs Neurol., Chicago, 1966, 15, 472.