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A GENETIC THEORY OF INFLAMMATORY POLYARTHRITIS
151
(’Nardil’) are most often incriminated in man, it is still uncertain whether a structural resemblance to amphetamine, wider usage, or their efficacy as enzyme inhibitors is responsible. Until these matters are clarified, any question concerning the comparative safety of one or other amine-oxidase inhibitor can be rendered redundant by warning all patients taking any of these drugs to shun the substances with which they interact. Better still, patients should be provided with a card (similar to that carried by diabetics) so as to minimise the hazards of polypharmacy and poor communication between doctors. Responsible action by the drug companies is imperative, and doctors should be left in no doubt when a compound is a monoamine-oxidase inhibitor. The purpose of these precautions is not to limit the use or to deny the value of monoamine-oxidase inhibitors but to render them safer and
haemodynamic load or myocardial metabolic alteration. Raab3 has emphasised the myocardial hypoxia resulting from excessive cateacholamine levels, while Lepeschkin4 has described T-wave depression followed by elevation of the T-wave after injection of adrenaline. The progression of electrocardiograph changes in these two cases is consistent with this hypothesis. Abington Memorial Hospital, Abington, Pennsylvania, U.S.A.
A GENETIC THEORY OF INFLAMMATORY POLYARTHRITIS
effective in treatment. Institute of Psychiatry,
more
Maudsley Hospital,
B. BLACKWELL.
London, S.E.5.
SIR,-Since many reports of acute hypertension associated with tranylcypromine have appeared in your journal, I should like to share my experiences with another monoamine-oxidase inhibitor (M.A.o.l.), pargyline hydrochloride e’ Eutonyl ’, Abbott),
an
anti-hypertension
agent.
My experience has been with five patients who have reacted pargyline with amine hypertension. The first patient is a sixty-four-year-old bus-driver who had eaten Sweitzer cheese many times before while under effective therapy with pargyline hydrochloride for his hypertension. This time, within fifteen minutes, he noticed severe substernal chest pain and palpitations. On admission his blood-pressure was 200/114 mm. Hg and pulse-rate 80 per minute. After a profuse sweat his bloodpressure subsided within two hours to 90/60 mm. Hg. Physical examination was normal except for radiological evidence of an old ulcer deformity of the duodenum and electrocardiographic changes described later. The next three patients were on pargyline at the Abington Memorial Hospital outpatient hypertension clinic. Two of these gave a history of headache following ingestion of aged cheese, and the other had a blood-pressure of 240/140 with a The cause of his hypertensive crisis was severe nose-bleed. unknown, but it followed the pattern of amine hypertension. The fifth patient was a transient from the South Pacific under therapy with pargyline, who ate cheese and took one of her husband’s cold capsules with resultant severe occipital headache and chest tightness typical of amine hypertension. One of my private patients experienced electrocardiograph changes while on tranylcypromineafter eating cheese. I will report only the serial changes, which were as follows: May 8, 1961, electrocardiograph before and after amine hypertension in response to tranylcypromine, normal tracing at routine
to
examination; Nov. 26, 1963, nineteen hours after onset of reaction, lowering of T waves in leads I, V5, and Va, and inversion of aVL, Qtc prolonged to 0-45 seconds; Nov. 27 and Dec. 10, 1963, progressive loss of T-wave inversion and finally symmetrically peaked T wave in all leads, Qtc 0-40 seconds. We observed similar but less pronounced electrocardiographic changes in a patient (case 1 2) on pargyline. The findings were as follows: Dec. 11, 1959, before and after amine hypertension in response to pargyline, control tracing normal; Nov. 7, 1963, two hours after onset of reaction, decreased T-wave amplitude in leads i, aVL, V5, and Va, Qtc =0-41; Nov. 14, 1963, T waves increased in height, actually exceeding those of the control
tracing, Qtc=046. Not all patients experience adverse reactions to cheese, and, furthermore, other, at present unidentified, foods may augment sympathetic activity. The metabolic state of the patient (i.e., the catecholamine levels and their availability) may play a role in triggering this reaction. The
electrocardiographic alterations 1. 2.
may
reflect
either
Hutchison, J. C., Kinlaw, W. B. Curr. ther. Res. 1964, 6, 127. Hutchison, J. C., Kenworthy, H. J., Stamps, W. H. ibid. p. 67.
JAMES C. HUTCHISON.
a
SIR,-I, too, have had the privilege of seeing the analysis referred to by Dr. Augustin and Dr. Spiers (June 6). Unlike Dr. Burch, however, I agree that their criticisms of his mathematical deductions are entirely justified. The main point at issue is simple but absolutely fundamental, and is exemplified in Dr. Burch’s letter of June 20. He there applies the " law of independent probabilities ", but unfortunately does so incorrectly. The error in his argument is best demonstrated by an example: If a number of pennies are tossed at random on a table, then according to Dr. Burch the chance that 5 of them show heads is p5 where p is the probability that exactly 1 shows a head, and we are apparently to accept this whatever the total number of pennies. Standard theory5 shows, however, that p =m (0-5)m where m is the number of pennies tossed on to the table, and that the chance of exactly 5 of them showing heads is: This is certainly not p5. Similar conclusions hold if we consider p to be the probability that at least one penny shows a head. In the present context the events to be combined by the law of independent probabilities are the states at time t of all the stem-cells, totalling s, not merely those which represent forbidden clones, numbering n. If the probability of a somatic mutation by time t is kt, then the chance that n (and only n) of the s stem-cells have mutated and represent forbidden clones is given by the exnressinn
which is the (n+l)th
term
of the binomial
expansion
[kt+(1-kt)s. It is this correct expression above which, in their analysis of this problem, the Maynard Smiths approximated by Poissonion probabilities, s being very large and kt very small. Medical Research Council Statistical Research Unit, University College Hospital Medical School, London, W.C.1.
M. C. PIKE.
METAL CRUTCHES
I was on crutches. Part of the time the traditional wooden crutch which is not fully adjustable; for the remainder I was fortunate to be lent by my orthopxdic surgeon an experimental metal pair. The difference was remarkable. Since then most of those I have seen on crutches have been struggling with wooden ones of the wrong length.. Today, when much money and time, public and charitable, are being spent on the welfare of the disabled, and
SIR,-Recently
was
spent
on
Raab, W. Hormonal and Neurogenic Cardiovascular Disorders; p. 14. Baltimore, 1953. 4. Lepeschkin, E. Modern Electrocardiography; vol. I. Baltimore, 1951. 5. See Feller, W. An Introduction to Probability Theory and its Applications; p. 104. New York, 1950. 3.
(’Nardil’) are most often incriminated in man, it is still uncertain whether a structural resemblance to amphetamine, wider usage, or their efficacy as enzyme inhibitors is responsible. Until these matters are clarified, any question concerning the comparative safety of one or other amine-oxidase inhibitor can be rendered redundant by warning all patients taking any of these drugs to shun the substances with which they interact. Better still, patients should be provided with a card (similar to that carried by diabetics) so as to minimise the hazards of polypharmacy and poor communication between doctors. Responsible action by the drug companies is imperative, and doctors should be left in no doubt when a compound is a monoamine-oxidase inhibitor. The purpose of these precautions is not to limit the use or to deny the value of monoamine-oxidase inhibitors but to render them safer and
haemodynamic load or myocardial metabolic alteration. Raab3 has emphasised the myocardial hypoxia resulting from excessive cateacholamine levels, while Lepeschkin4 has described T-wave depression followed by elevation of the T-wave after injection of adrenaline. The progression of electrocardiograph changes in these two cases is consistent with this hypothesis. Abington Memorial Hospital, Abington, Pennsylvania, U.S.A.
A GENETIC THEORY OF INFLAMMATORY POLYARTHRITIS
effective in treatment. Institute of Psychiatry,
more
Maudsley Hospital,
B. BLACKWELL.
London, S.E.5.
SIR,-Since many reports of acute hypertension associated with tranylcypromine have appeared in your journal, I should like to share my experiences with another monoamine-oxidase inhibitor (M.A.o.l.), pargyline hydrochloride e’ Eutonyl ’, Abbott),
an
anti-hypertension
agent.
My experience has been with five patients who have reacted pargyline with amine hypertension. The first patient is a sixty-four-year-old bus-driver who had eaten Sweitzer cheese many times before while under effective therapy with pargyline hydrochloride for his hypertension. This time, within fifteen minutes, he noticed severe substernal chest pain and palpitations. On admission his blood-pressure was 200/114 mm. Hg and pulse-rate 80 per minute. After a profuse sweat his bloodpressure subsided within two hours to 90/60 mm. Hg. Physical examination was normal except for radiological evidence of an old ulcer deformity of the duodenum and electrocardiographic changes described later. The next three patients were on pargyline at the Abington Memorial Hospital outpatient hypertension clinic. Two of these gave a history of headache following ingestion of aged cheese, and the other had a blood-pressure of 240/140 with a The cause of his hypertensive crisis was severe nose-bleed. unknown, but it followed the pattern of amine hypertension. The fifth patient was a transient from the South Pacific under therapy with pargyline, who ate cheese and took one of her husband’s cold capsules with resultant severe occipital headache and chest tightness typical of amine hypertension. One of my private patients experienced electrocardiograph changes while on tranylcypromineafter eating cheese. I will report only the serial changes, which were as follows: May 8, 1961, electrocardiograph before and after amine hypertension in response to tranylcypromine, normal tracing at routine
to
examination; Nov. 26, 1963, nineteen hours after onset of reaction, lowering of T waves in leads I, V5, and Va, and inversion of aVL, Qtc prolonged to 0-45 seconds; Nov. 27 and Dec. 10, 1963, progressive loss of T-wave inversion and finally symmetrically peaked T wave in all leads, Qtc 0-40 seconds. We observed similar but less pronounced electrocardiographic changes in a patient (case 1 2) on pargyline. The findings were as follows: Dec. 11, 1959, before and after amine hypertension in response to pargyline, control tracing normal; Nov. 7, 1963, two hours after onset of reaction, decreased T-wave amplitude in leads i, aVL, V5, and Va, Qtc =0-41; Nov. 14, 1963, T waves increased in height, actually exceeding those of the control
tracing, Qtc=046. Not all patients experience adverse reactions to cheese, and, furthermore, other, at present unidentified, foods may augment sympathetic activity. The metabolic state of the patient (i.e., the catecholamine levels and their availability) may play a role in triggering this reaction. The
electrocardiographic alterations 1. 2.
may
reflect
either
Hutchison, J. C., Kinlaw, W. B. Curr. ther. Res. 1964, 6, 127. Hutchison, J. C., Kenworthy, H. J., Stamps, W. H. ibid. p. 67.
JAMES C. HUTCHISON.
a
SIR,-I, too, have had the privilege of seeing the analysis referred to by Dr. Augustin and Dr. Spiers (June 6). Unlike Dr. Burch, however, I agree that their criticisms of his mathematical deductions are entirely justified. The main point at issue is simple but absolutely fundamental, and is exemplified in Dr. Burch’s letter of June 20. He there applies the " law of independent probabilities ", but unfortunately does so incorrectly. The error in his argument is best demonstrated by an example: If a number of pennies are tossed at random on a table, then according to Dr. Burch the chance that 5 of them show heads is p5 where p is the probability that exactly 1 shows a head, and we are apparently to accept this whatever the total number of pennies. Standard theory5 shows, however, that p =m (0-5)m where m is the number of pennies tossed on to the table, and that the chance of exactly 5 of them showing heads is: This is certainly not p5. Similar conclusions hold if we consider p to be the probability that at least one penny shows a head. In the present context the events to be combined by the law of independent probabilities are the states at time t of all the stem-cells, totalling s, not merely those which represent forbidden clones, numbering n. If the probability of a somatic mutation by time t is kt, then the chance that n (and only n) of the s stem-cells have mutated and represent forbidden clones is given by the exnressinn
which is the (n+l)th
term
of the binomial
expansion
[kt+(1-kt)s. It is this correct expression above which, in their analysis of this problem, the Maynard Smiths approximated by Poissonion probabilities, s being very large and kt very small. Medical Research Council Statistical Research Unit, University College Hospital Medical School, London, W.C.1.
M. C. PIKE.
METAL CRUTCHES
I was on crutches. Part of the time the traditional wooden crutch which is not fully adjustable; for the remainder I was fortunate to be lent by my orthopxdic surgeon an experimental metal pair. The difference was remarkable. Since then most of those I have seen on crutches have been struggling with wooden ones of the wrong length.. Today, when much money and time, public and charitable, are being spent on the welfare of the disabled, and
SIR,-Recently
was
spent
on
Raab, W. Hormonal and Neurogenic Cardiovascular Disorders; p. 14. Baltimore, 1953. 4. Lepeschkin, E. Modern Electrocardiography; vol. I. Baltimore, 1951. 5. See Feller, W. An Introduction to Probability Theory and its Applications; p. 104. New York, 1950. 3.