- Email: [email protected]
MATERNAL LYMPHOCYTE TRANSFER
1266 and respiratory arrest. Immediate resuscitation was successful in restoring cardiac action but he remained unconscious, had several subsequent cardiac arrests and intermittent generalised convulsions, and died 48 hours later following another arrest. At necropsy, the heart was normal apart from 20 ml. serous pericardial fluid, the lungs showed congestion, the bowel and mesenteric vessels were normal. The kidneys were large, swollen, boggy and had a granular appearance; microscopically the glomeruli showed increased mesangial matrix but no cellular proliferation, hyalinisation, or epithelial crescents, and there was no thickening of the capillary basement membranes. We concluded that he had a steroid-resistant nephrotic syndrome which most closely resembled the " minimal change " type, and that he had a cardiac arrest caused by hypersensitivity to frusemide. I have seen no other report of such an occurrence in childhood and have had no other such complication in a number of children who have received this diuretic
agent. The Hospital for Sick Children, Toronto 2, Ontario.
C. P. RANCE.
SURVIVAL-TIMES AFTER CARDIAC ALLOGRAFTS SiR,-Dr. Messmer and his colleagues (May 10, p. 954) ask: " Does cardiac transplantation at the present stage of development prolong the life of patients with advanced, therapyresistant heart-disease ? They conclude, with various qualiit believe that their paper gives a that does. We fications, misleading answer to their question. As Mr. Le Vay notes (May 24, p. 1048), only 2 of 15 transplanted patients were alive at the end of the observation period, while 15 of 42 were alive in the comparison group. Different periods of observation, incomplete follow-ups, and the contribution of preoperative survival to the total survival of the transplanted group question the validity of comparing mean survival-time of potential and actual recipients. A life-table analysis of the data affords a sounder comparison of survival with cardiac transplantation against survival without "
transplantation (see accompanying table). Taking all starters (column P in table), transplant patients appear to have an advantage in cumulative survival up to the end of the fourth month (after which only transplant patients died). This apparent advantage is entirely located in the first-month experience (column p in table). The lower first-month survival of non-transplant patients results from a skewed distribution of deaths: 70% occurred within the first month, half of them during the first week, whereas 50% of the transplant patients had a preoperative waiting-period of at least one week. For those who survived the first month, there is virtually no difference in the cumulative probability of survival (column P’ in table). This is an unavoidable bias, given the comparisons the authors have chosen to present. Of necessity transplant patients had to live until they were operated on; the comparison group was under no compulsion to survive a comparable period. A second problematic element of the comparisons presented
by the authors relates to age-distribution. The mean age of the transplant group was 49 years with a range of 5-62 years; the mean age of the potential recipient " group was 47 years, with a range of 7-60 years. The similarities conceal striking disparities. Among the 15 transplant patients, 1 5-year-old was in the age-group 45 years or less, and 14 were in the older age-group. Among potential recipients 12 of 42 were 45 or less, and 30 were older. These age differences, per se, probably exert a negligible influence on survival over an observation period of 9 months, but they do elaborate the question about the comparability of the transplanted group and the " potential recipient " comparison group. The question of prolongation of life is of course not the only issue to be weighed in the decision to operate. On that particular question, however, the evidence seems inadequate. "
Epidemiology Research Unit, N.Y.S. Department of Mental Hygiene, Division of Epidemiology, Columbia University, New York 10032.
FETAL/MATERNAL
LYMPHOCYTE TRANSFER Walknowska and Sm,-Dr. colleagues (June 7, p. 1119) suggest that "... it may be that the transplacental passage of fetal lymphocytes contributes to the acceptance of the fetus during gestation ". Before accepting this hypothesis, which was proposed in general terms five years ago, 1 it is necessary to demonstrate specific abrogation of transplantation immunity in the mother and to examine the possibility of a mutual effect in the fetus. It is possible that one cell-type of chimsrism in adult mammals may not be accompanied by diminished immunity towards different tissues from the same source as the chimaeric cells, as has been demonstrated in cattle twins3 Direct observations rather than inferences are desirable in such complex situations. Partly published studies 4in five mammalian species have shown that specific depression of immunity towards the histocompatibility antigens of the partner in viviparity exists in the armadillo and the rat, and to lesser degrees in man, dog, and sheep. This has been called " immunological inertia ", because it can be distinguished from similar states such as "paralysis", "tolerance", "antigen overload ", and " desensitisation ", by the characteristic features of partner-specificity, mutuality, evanescence and species-variation. The mechanism of inertia may be cellular transfer, but subcellular material would be equally acceptable for the exchange of information about the profiles of histocompatibility antigens that must occur. Artificial mimicry of the inertia is one method of testing this hypothesis that has 1. 2. 3.
Anderson, J. M., Benirschke, K. Br. med. J. 1964, i, 1534. Anderson, J. M. Nature, Lond. 1965, 206, 786. Stone, W. H., Cragle, R. G., Swanson, E. W., Brown, D. G. Science,
4. 5.
N.Y. 1965, 148, 1335. Anderson, J. M. Transpl. Proc. 1969, 1, 67. Anderson, J. M., Benirschke, K. Ann. N.Y. Acad. Sci. 1962, 99, Art3, 399.
PATIENTS, WITH AND WITHOUT CARDIAC TRANSPLANTATION REDUCING THE STARTING NUMBER BY HALF THE WITHDRAWALS)
SURVIVAL OF END-STAGE HEART-DISEASE
H. HANSEN F. MAROLLA Z. STEIN.
(MISSING
DEATHS ESTIMATED BY
1267 thus far been unhelpful.6 More detailed characterisation of the
LITHIUM-EXCRETION TEST
immunological inertia of viviparity, which is an important feature of the natural solution to what modern surgery has raised as "the transplantation problem", is worth further exploration with a view to the establishment of a specific and clinically safe method of immunosuppression for allografts of tissues and organs. Royal Infirmary, JOHN MAXWELL ANDERSON. Glasgow C.4. LITHIUM RETENTION AND RESPONSE SIR,- This letter has been prompted by the controversy on the value of lithium in various psychiatric syndromes. Much of this controversy- could be resolved if the studies being carried out by various workers were based upon an objectively uniform
population. Cade first showed that lithium had a place in psychiatry in 1949,’ and it was a direct result of his question (whether there was any difference between the manic patients who respond to lithium and those who do not) that the following test was devised. It was felt that, to be practical for disturbed manic patients, the duration of the test should be relatively short. (Trautner et awl. in 1955 showed that lithium appears in the urine 15 minutes after ingestion, and, after a dose of 50 meq. of lithium carbonate over 2 hours (i.e., 1800 mg.), the initial peak in urinary excretion was reached in 6-8 hours, during which 33-66% of the dose was excreted.) The loading dose used was 1200 mg. of lithium carbonate, given in one dose, and the amount excreted in the urine over the next 4 hours was measured. The questions I initially tried to answer were: (1) did manic patients handle this loading dose of lithium-ion differently from non-manic patients ? (2) Were there any differences within the population of patients diagnosed as manic ? The lithium-excretion test is carried out as follows: 1. The subject is asked to void as much urine as possible. 2. The subject is put to bed, partly to standardise the procedure, but more particularly to allow constant supervision and collection of urine samples during the test. If the patient is difficult to manage, or very disturbed, the use of phenothiazines before or during the test is helpful and does not affect the result. 3. The patient is given a loading dose of 1200 mg. of lithium carbonate (4 tablets)-i.e., 33 meq. orally, and the time noted, since this is the beginning of the test proper. 4. Fluids are given liberally during the next 4 hours. This was found to be important, for a urinary excretion of at least 100 ml. is necessary to provide a valid result. 5. Blood is taken 2 hours after the commencement of the test to ensure that the patient had in fact taken the tablets and to obtain a serum-level of lithium. 6. All the urine passed from the commencement of the test is collected, and at the end of 4 hours the patient is encouraged to void as much urine as he can. 7. The volume of urine is collected, and its specific gravity, and total lithium-ion content are measured (the latter using an ’E.E.L.’
flame-photometer). The results of the test are given in the accompanying table. The control patient who excreted over 20 mg. was admitted as a problem of diagnosis, between mania and thyrotoxicosis-she was a lithium excretor, but showed thrice the normal serumprotein-bound-iodine level and twice the normal uptake of radioactive iodine. Certain definite results were obtained. (1) 24 of 30 manic patients excreted less than 11 mg. of lithium in 4 hours (these are referred to as " lithium retainers "). All these patients responded to treatment with lithium carbonate, 600 mg. three times daily, within 10 days, most after 5 days, after which the dose was reduced to 900 mg.
daily. (2) 6. 7. 8.
2 of 30 manic
patients excreted between
11.1and 20 mg.
Anderson, J. M. (editor) in Biology and Surgery of Tissue Transplantation. Oxford (in the press). Cade, J. F. J. Med. J. Aust. 1949, 36, 349. Trautner, E. M., Morris, R., Noack, C. H., Gershon, S. ibid. 1955, 42, 280.
of lithium
(these form
an
"intermediate
group"). Both
lithium.
responded (3) 4 patients, diagnosed as manic, excreted over 20 mg. of lithium (these are referred to as lithium excretors "). They did not respond to 1800 mg. of lithium carbonate daily for 12-14 days, although they responded to phenothiazines 2-5 days later. The effect is specific to lithium, for both lithium retainers and excretors could not be differentiated after a loading dose of sodium, which they handled identically. The excretion of lithium was independent of the total amount of urine passed during the 4 hours. For example, one lithium retainer passed 6 mg. of lithium in 1120 ml. of urine over 4 hours, while an to
"
intermediate lithium excretor had 19.8 mg. of lithium in 138 ml. of urine over the same period of time. The lithium content of the urine does not alter, even if it is several days before the amount in the specimen is measured. Consequently, a test performed on a Friday will give a reliable result even if the lithium is not estimated until Monday or later. In patients who have had one lithium excretion test, 4 days must elapse before the level of lithium falls sufficiently to allow a repeat of the test without significant interference from the previous test. Repeat tests on the same subject show little alteration (unless there is a change in the clinical statethe patient either becoming manic, or improving), as follows: First
test
(mg.)
Second
test
Time between
Diagnosis (mg.) 15.0 13.7 Depressive state 14-9 15-6 Schizophrenia 25-4 26-5 Personality disorder 25-0 24-3 Schizophrenia 30-5 34-7* Psychotic depression * After six electric, convulsive treatments, and trifluoperazine, 15
(days) 23 39 35 15 14 mg.
daily.
Depression.-5 of 21 depressives tested were lithium retainers. In the past, the criteria for studying the effect of lithium on the treatment or prophylaxis of this group has been a history of recurrent affective illness. Use of a lithium-retaining population would result in uniformity, and perhaps help resolve this controversial problem. One of these depressive lithiumretainers was admitted for the 14th time for depression on the same day as her father, aged 76, was independently admitted for the lst time. He was diagnosed as manic, shown to be a lithium retainer by the test, and responded well to treatment with lithium carbonate. Further evaluation and treatment of this group is to be undertaken. Personality disorders.-Some workers have treated recurrent personality disorders of all types with lithium; 7 of 18 diagnosed as personality disorders were lithium retainers, who had been resistant to often prolonged and multiple types of psychiatric treatment. Careful review of their histories showed a past history of mood fluctuations. 3 of these have been treated with lithium and have shown encouraging results. All the lithium retainers were characterised by aggressive and/or antisocial behaviour, and in 2 there was associated alcoholism. Schizo-affective disorders.-6 out of 11 in this group were lithium retainers. Treatment with lithium alone removed the " euphoric affective element ", but the patients still showed schizophrenic thought disorder, delusions, and hallucinations. These latter symptoms responded to phenothiazines. Lithium does not " unmask " the schizophrenic symptoms-it selectively improves the affective element, leaving the schizophrenic
agent. The Hospital for Sick Children, Toronto 2, Ontario.
C. P. RANCE.
SURVIVAL-TIMES AFTER CARDIAC ALLOGRAFTS SiR,-Dr. Messmer and his colleagues (May 10, p. 954) ask: " Does cardiac transplantation at the present stage of development prolong the life of patients with advanced, therapyresistant heart-disease ? They conclude, with various qualiit believe that their paper gives a that does. We fications, misleading answer to their question. As Mr. Le Vay notes (May 24, p. 1048), only 2 of 15 transplanted patients were alive at the end of the observation period, while 15 of 42 were alive in the comparison group. Different periods of observation, incomplete follow-ups, and the contribution of preoperative survival to the total survival of the transplanted group question the validity of comparing mean survival-time of potential and actual recipients. A life-table analysis of the data affords a sounder comparison of survival with cardiac transplantation against survival without "
transplantation (see accompanying table). Taking all starters (column P in table), transplant patients appear to have an advantage in cumulative survival up to the end of the fourth month (after which only transplant patients died). This apparent advantage is entirely located in the first-month experience (column p in table). The lower first-month survival of non-transplant patients results from a skewed distribution of deaths: 70% occurred within the first month, half of them during the first week, whereas 50% of the transplant patients had a preoperative waiting-period of at least one week. For those who survived the first month, there is virtually no difference in the cumulative probability of survival (column P’ in table). This is an unavoidable bias, given the comparisons the authors have chosen to present. Of necessity transplant patients had to live until they were operated on; the comparison group was under no compulsion to survive a comparable period. A second problematic element of the comparisons presented
by the authors relates to age-distribution. The mean age of the transplant group was 49 years with a range of 5-62 years; the mean age of the potential recipient " group was 47 years, with a range of 7-60 years. The similarities conceal striking disparities. Among the 15 transplant patients, 1 5-year-old was in the age-group 45 years or less, and 14 were in the older age-group. Among potential recipients 12 of 42 were 45 or less, and 30 were older. These age differences, per se, probably exert a negligible influence on survival over an observation period of 9 months, but they do elaborate the question about the comparability of the transplanted group and the " potential recipient " comparison group. The question of prolongation of life is of course not the only issue to be weighed in the decision to operate. On that particular question, however, the evidence seems inadequate. "
Epidemiology Research Unit, N.Y.S. Department of Mental Hygiene, Division of Epidemiology, Columbia University, New York 10032.
FETAL/MATERNAL
LYMPHOCYTE TRANSFER Walknowska and Sm,-Dr. colleagues (June 7, p. 1119) suggest that "... it may be that the transplacental passage of fetal lymphocytes contributes to the acceptance of the fetus during gestation ". Before accepting this hypothesis, which was proposed in general terms five years ago, 1 it is necessary to demonstrate specific abrogation of transplantation immunity in the mother and to examine the possibility of a mutual effect in the fetus. It is possible that one cell-type of chimsrism in adult mammals may not be accompanied by diminished immunity towards different tissues from the same source as the chimaeric cells, as has been demonstrated in cattle twins3 Direct observations rather than inferences are desirable in such complex situations. Partly published studies 4in five mammalian species have shown that specific depression of immunity towards the histocompatibility antigens of the partner in viviparity exists in the armadillo and the rat, and to lesser degrees in man, dog, and sheep. This has been called " immunological inertia ", because it can be distinguished from similar states such as "paralysis", "tolerance", "antigen overload ", and " desensitisation ", by the characteristic features of partner-specificity, mutuality, evanescence and species-variation. The mechanism of inertia may be cellular transfer, but subcellular material would be equally acceptable for the exchange of information about the profiles of histocompatibility antigens that must occur. Artificial mimicry of the inertia is one method of testing this hypothesis that has 1. 2. 3.
Anderson, J. M., Benirschke, K. Br. med. J. 1964, i, 1534. Anderson, J. M. Nature, Lond. 1965, 206, 786. Stone, W. H., Cragle, R. G., Swanson, E. W., Brown, D. G. Science,
4. 5.
N.Y. 1965, 148, 1335. Anderson, J. M. Transpl. Proc. 1969, 1, 67. Anderson, J. M., Benirschke, K. Ann. N.Y. Acad. Sci. 1962, 99, Art3, 399.
PATIENTS, WITH AND WITHOUT CARDIAC TRANSPLANTATION REDUCING THE STARTING NUMBER BY HALF THE WITHDRAWALS)
SURVIVAL OF END-STAGE HEART-DISEASE
H. HANSEN F. MAROLLA Z. STEIN.
(MISSING
DEATHS ESTIMATED BY
1267 thus far been unhelpful.6 More detailed characterisation of the
LITHIUM-EXCRETION TEST
immunological inertia of viviparity, which is an important feature of the natural solution to what modern surgery has raised as "the transplantation problem", is worth further exploration with a view to the establishment of a specific and clinically safe method of immunosuppression for allografts of tissues and organs. Royal Infirmary, JOHN MAXWELL ANDERSON. Glasgow C.4. LITHIUM RETENTION AND RESPONSE SIR,- This letter has been prompted by the controversy on the value of lithium in various psychiatric syndromes. Much of this controversy- could be resolved if the studies being carried out by various workers were based upon an objectively uniform
population. Cade first showed that lithium had a place in psychiatry in 1949,’ and it was a direct result of his question (whether there was any difference between the manic patients who respond to lithium and those who do not) that the following test was devised. It was felt that, to be practical for disturbed manic patients, the duration of the test should be relatively short. (Trautner et awl. in 1955 showed that lithium appears in the urine 15 minutes after ingestion, and, after a dose of 50 meq. of lithium carbonate over 2 hours (i.e., 1800 mg.), the initial peak in urinary excretion was reached in 6-8 hours, during which 33-66% of the dose was excreted.) The loading dose used was 1200 mg. of lithium carbonate, given in one dose, and the amount excreted in the urine over the next 4 hours was measured. The questions I initially tried to answer were: (1) did manic patients handle this loading dose of lithium-ion differently from non-manic patients ? (2) Were there any differences within the population of patients diagnosed as manic ? The lithium-excretion test is carried out as follows: 1. The subject is asked to void as much urine as possible. 2. The subject is put to bed, partly to standardise the procedure, but more particularly to allow constant supervision and collection of urine samples during the test. If the patient is difficult to manage, or very disturbed, the use of phenothiazines before or during the test is helpful and does not affect the result. 3. The patient is given a loading dose of 1200 mg. of lithium carbonate (4 tablets)-i.e., 33 meq. orally, and the time noted, since this is the beginning of the test proper. 4. Fluids are given liberally during the next 4 hours. This was found to be important, for a urinary excretion of at least 100 ml. is necessary to provide a valid result. 5. Blood is taken 2 hours after the commencement of the test to ensure that the patient had in fact taken the tablets and to obtain a serum-level of lithium. 6. All the urine passed from the commencement of the test is collected, and at the end of 4 hours the patient is encouraged to void as much urine as he can. 7. The volume of urine is collected, and its specific gravity, and total lithium-ion content are measured (the latter using an ’E.E.L.’
flame-photometer). The results of the test are given in the accompanying table. The control patient who excreted over 20 mg. was admitted as a problem of diagnosis, between mania and thyrotoxicosis-she was a lithium excretor, but showed thrice the normal serumprotein-bound-iodine level and twice the normal uptake of radioactive iodine. Certain definite results were obtained. (1) 24 of 30 manic patients excreted less than 11 mg. of lithium in 4 hours (these are referred to as " lithium retainers "). All these patients responded to treatment with lithium carbonate, 600 mg. three times daily, within 10 days, most after 5 days, after which the dose was reduced to 900 mg.
daily. (2) 6. 7. 8.
2 of 30 manic
patients excreted between
11.1and 20 mg.
Anderson, J. M. (editor) in Biology and Surgery of Tissue Transplantation. Oxford (in the press). Cade, J. F. J. Med. J. Aust. 1949, 36, 349. Trautner, E. M., Morris, R., Noack, C. H., Gershon, S. ibid. 1955, 42, 280.
of lithium
(these form
an
"intermediate
group"). Both
lithium.
responded (3) 4 patients, diagnosed as manic, excreted over 20 mg. of lithium (these are referred to as lithium excretors "). They did not respond to 1800 mg. of lithium carbonate daily for 12-14 days, although they responded to phenothiazines 2-5 days later. The effect is specific to lithium, for both lithium retainers and excretors could not be differentiated after a loading dose of sodium, which they handled identically. The excretion of lithium was independent of the total amount of urine passed during the 4 hours. For example, one lithium retainer passed 6 mg. of lithium in 1120 ml. of urine over 4 hours, while an to
"
intermediate lithium excretor had 19.8 mg. of lithium in 138 ml. of urine over the same period of time. The lithium content of the urine does not alter, even if it is several days before the amount in the specimen is measured. Consequently, a test performed on a Friday will give a reliable result even if the lithium is not estimated until Monday or later. In patients who have had one lithium excretion test, 4 days must elapse before the level of lithium falls sufficiently to allow a repeat of the test without significant interference from the previous test. Repeat tests on the same subject show little alteration (unless there is a change in the clinical statethe patient either becoming manic, or improving), as follows: First
test
(mg.)
Second
test
Time between
Diagnosis (mg.) 15.0 13.7 Depressive state 14-9 15-6 Schizophrenia 25-4 26-5 Personality disorder 25-0 24-3 Schizophrenia 30-5 34-7* Psychotic depression * After six electric, convulsive treatments, and trifluoperazine, 15
(days) 23 39 35 15 14 mg.
daily.
Depression.-5 of 21 depressives tested were lithium retainers. In the past, the criteria for studying the effect of lithium on the treatment or prophylaxis of this group has been a history of recurrent affective illness. Use of a lithium-retaining population would result in uniformity, and perhaps help resolve this controversial problem. One of these depressive lithiumretainers was admitted for the 14th time for depression on the same day as her father, aged 76, was independently admitted for the lst time. He was diagnosed as manic, shown to be a lithium retainer by the test, and responded well to treatment with lithium carbonate. Further evaluation and treatment of this group is to be undertaken. Personality disorders.-Some workers have treated recurrent personality disorders of all types with lithium; 7 of 18 diagnosed as personality disorders were lithium retainers, who had been resistant to often prolonged and multiple types of psychiatric treatment. Careful review of their histories showed a past history of mood fluctuations. 3 of these have been treated with lithium and have shown encouraging results. All the lithium retainers were characterised by aggressive and/or antisocial behaviour, and in 2 there was associated alcoholism. Schizo-affective disorders.-6 out of 11 in this group were lithium retainers. Treatment with lithium alone removed the " euphoric affective element ", but the patients still showed schizophrenic thought disorder, delusions, and hallucinations. These latter symptoms responded to phenothiazines. Lithium does not " unmask " the schizophrenic symptoms-it selectively improves the affective element, leaving the schizophrenic