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CHARACTER OF THE TECTORIAL MEMBRANE
889 In a third boy (case 3) phenylketonuria was diagnosed at the age of two years and three months and treatment was started at the same time. His mental development did not progress either. During the first three months of therapy his head circumference increased from 47-3 to 49 cm. Normally it would not increase at all during this period.
As could be
expected,
treatment
produced the best -
results in the six-month-old boy. We conclude that microcephaly is never a contraindication to a therapeutic trial in this disease, certainly not at an earlv age. Kindergeneeskunde, Rijksuniversiteit Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
F. J.
VAN
5. 6. 7.
Faierman, E. Arch. Dis. Childh. 1960, 35, 285. Bourne, G. L., Benirschke, K. ibid. p. 534. Lewis, A. J. Lancet, 1962, i, 866. Uchida, I. A., Bowman, J. M., Wang, H. C. New Engl. J. Med. 1962, 266, 1198. German, J., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., Beam, A. G. J. Pediat. 1962, 60, 503. Heinrichs, E. H., Allen, S. W. Clin. Pediat. 1963, 2, 25. Dunn, P. M., Fisher, A. M., Koller, H. G. Amer. J. Obstet. Gynec. 1962, 84, 348. DATA ON
Department of Pædiatrics, University Hospital, Sapporo, Hokkaido, Japan.
Hokkaido
4
T. KAJII. M. SHINOHARA K. KIKUCHI S. DOHMEN.
Department of Obstetrics and Gynaecology, Sapporo Medical College, Sapporo. Mitsubishi Tokyo Hospital, Tokyo, Japan.
SPRANG.
THALIDOMIDE AND THE UMBILICAL ARTERY SIR,-We have examined the umbilical cord of 4 cases of thalidomide embryopathy in which the infant died shortly after birth. A single umbilical artery was found in 2 of these 4 cases, an attenuated right umbilical artery was present in 1, and in the remaining case the umbilical arteries were normal. In each case with a single umbilical artery, the iliac and femoral arteries of the side where the umbilical artery was missing were about one third of their normal size, and the intra-abdominal umbilical artery of the same side was lacking. In case 3, in which the right umbilical artery was half its normal size, the intraabdominal umbilical artery of the same side was also attenuated, though the right iliac and femoral arteries were normal. These 3 cases with abnormalities of the umbilical artery had multiple congenital malformations of the internal organs, including the heart and genitourinary system, besides limb deformities. By contrast, the case with normal umbilical arteries showed no malformations of the internal organs. Details of the 4 cases are given in the accompanying table. Studies of the single umbilical artery 12 show increased association of a range of congenital malformations with this circumstance. The 17-18 syndrome has been reported to accompany single umbilical artery.3-6 But an extensive search of published reports on thalidomide embryopathy has revealed no case with a single umbilical artery except one described by Dunn et al. in which there was binovular twin pregnancy. This case presented phocomelia of the upper limbs and a pilonidal sinus. A single umbilical artery is present in 7% of twin pregnancies, compared 1. 2. 3. 4.
with an overall prevalence of 1 %, and it is hard to tell whether in this case the abnormality is attributable to twin pregnancy or to thalidomide. But our finding of abnormalities of the umbilical arteries in 3 out of 4 cases of thalidomide embryopathy suggests that the umbilical cord of every thalidomide baby should be examined for such abnormalities.
M. AKICHIKA.
CHARACTER OF THE TECTORIAL MEMBRANE
SiR,—The results of our analysis of the tectorial membrane1 have prompted us to make a model imitating part of the energy-transducing mechanism of the cochlea. The model consisted of
by
a
an
liquid ion-exchange
agar-gel with electrolyte overlaid
resin
not
miscible with
Polyethylene cells with agar-gel and overlaid
resin
or
water.
saline solu-
tion; A, B, C, and D are indifferent electrodes made of stainless steel rigidly fixed in walls.
(’Amberlite’, LA-1, British Drug Houses.) The resin was diluted with organic solvent, miscible with both water and resin phases, and saturated with water containing the same electrolytes as in the agar-gel. This system was left for a little time to allow the equilibrium distribution of electrolytes for the system to become established. Indifferent electrodes were inserted rigidly into both phases (see accompanying figure). The 1.
resin-gel system
was
contained in
a
small
polyethylene
Naftalin, L., Harrison, M. S., Stephens, A. Lancet, 1963, i,
CASES OF THALIDOMIDE EMBRYOPATHY
1192.
890 pot with a small hole (4 mm. x 2 mm.) in one side, connecting the agar-gel phase only with the same agar-electrolyte in a neighbouring pot. On top of this agar was placed a large brass " stapes " weighing about 2 g. A symmetrical system with electrodes was made on the other side of the " stapes " cell, but this system contained only saline solution and had no resin. A hearing-aid earpiece was held to the stapes and the electrodes were connected either to an oscilloscope or to the input of a tape recorder. All connections were made rigid, and care was taken to avoid earthing or other adventitious potentials. Tuning forks, one at a time, or together, could be recorded both on the oscilloscope and on the tape recorder, when the forks were held about 1 in. in the air above the hearing-aid microphone. When the electrodes in the resin side were connected up there was recording, but not when the saline solution side only was in circuit. We have also recorded the human voice, counting 1 to 10, with a quality of reproduction approaching that of a carbon microphone, distinctive timbre being clearly heard. Similar results, but of much poorer quality, were obtained, for tuning forks only by means of a piece of filter paper appropriately treated with resin-electrolyte. This system fatigued quickly and was accompanied by much adventitious noise. We do not claim that the transduction of acoustic energy to electrical potential in the scala media must be of this nature, but we have shown that an ion-exchange resin system (which maintains by its physico-chemical nature a permanent junction potential) can respond as accurately as a carbon microphone to acoustic vibration and is a possible mode of action in the tectorial membrane. It is relevant here to quote Hallowell Davis.2 " We have sought with the electron microscope for some structure ... that looks as though it might perform the job that we have assigned to it, which is really the job of being a resistance microphone like a carbon-type microphone of a telephone or hearing-aid. So far nothing helpful has been found. The electrical mechanism must be of molecular dimensions ...". The model we have made employs a molecular mechanism, and we derived our idea of it from the analysis of the tectorial membrane. We suggest that this type of transduction should be given serious consideration as a possible mode of conversion of acoustic to electrical energy in the receptor-organ of the cochlea. L. NAFTALIN Biochemistry Laboratory, St. George’s Hospital, A. STEPHENS. Lincoln. -
ANTI-RABIES VACCINE
SIR,-Recently I attended a patient with neuroparalysis following a second course of anti-rabies vaccine (10 injections of carbolised fixed virus vaccine, M.R.I. Colombo no. 1062). The first course had been given three years previously. Despite treatment with cortisone and vitamin B}2} and resort to a respirator, the patient died on the fifth day of the illness. The dog survived. This is the first reported case of its sort in Ceylon, where dogbites are a recognised hazard for planters and estate workers. In view of the fact that, on religious grounds, compulsory immunisation or extermination of stray dogs cannot be applied here, would it not be advisable to make available the duck embryo vaccine (non-nervous tissue),3 which does not give rise to these neuroparalytic accidents ? Such accidents only occur with carbol fixed virus vaccine, when used for second or subsequent courses. One course of the carbol vaccine can be given harmlessly. World figures for these accidents show a most unsatis2. 3.
Davis, H. in Neural Mechanisms of the Auditory and Vestibular Systems (edited by G. L. Rasmussen, W. F. Windle); p. 35. Springfield, 1960. W.H.O. Expert Committee on Rabies: Fourth Report. Tech. Rep. Wld Hlth Org. 1960, no. 201.
factory picture for the carbol vaccine used in a second o: subsequent course: between 1 in 860 and 1 in 8000 0 vaccinated persons have been found to become paralysed and about 30% of those affected die.4 Thus the need for: vaccine without neurotoxic properties seems to be great My
thanks
are
due
to
the director of the Medical Researc
Institute, Ceylon, and Dr. J. Hay Arthur, Estates Health Servia Cevlon. for their kind help.
J. T. DIXON.
Colombo, Ceylon,
BROAD-SPECTRUM REDEFINED
SiR,—Your leading article of Oct. 5 stated: "In urinary infections, its [chloramphenicol’s] undoubted activity against many of the common causal organisms is cancelled by the fact that it appears in the urine mainly as an inactive metabolite." It is true that a relatively large fraction of the administered dose of chloramphenicol is converted to forms not active against bacteria, but, in spite of this, urine concentrations of the active compound are high and peak levels of the antibiotic exceeding 200 g. per ml. have been recorded after a single 1-5 g. oral dose." This is not the whole story, however. It is generally agreed that infection of the urinary tract is primarily in tissue and the objective of therapy is to deliver to the site of infection amounts of a drug that are either bactericidal or bacteriostatic .6With chloramphenicol, the greatest tissue concentration of the drug is observed in the kidney,5 and so, in large part, this objective is achieved. Furthermore, if susceptible bacteria are shed into the urine, the urinary concentration of active drug is more than sufficient to prevent their multiplication providing adequate dosage is given. J. R. ARCHER Manager Parke Davis &
Company, Hounslow, Middlesex.
of Medical Services
J. A. L. GORRINGE Director of Clinical Investigation.
SiR,—Your editorial of Oct. 5 stated, when speaking of chloramphenicol, that " it may still find a place ... in topical treatment of some ocular and aural infections ". This dangerous drug continues to be an important antibiotic in treating some cases of intraocular infection, and your emphasis on topical treatment of eye infection should not be construed as indicating that systemic chloramphenicol has no place in the treatment of infection within t’1P
put-
G. EVERARD HEWSON. JAUNDICE ASSOCIATED WITH HALOPERIDOL
SIR,-Iwish to report a case of jaundice in a patient undergoing treatment with haloperidol (’ Serenace ’). A man of 71 admitted to hospital on July 17, 1963, for a manic illness was found to have signs of chronic bronchitis and emphysema. On July 22 there were signs of an acute exacerbation of the chronic bronchitis. Treatment was instituted with oxytetracycline (’Terramycin’) 250 mg. 6-hourly. The patient’s haemoglobin was 12-3 g. per 100 ml. and the whitecell count was 5750 per c.mm. On July 25 treatment with haloperidol 1-5 mg. t.d.s. was begun and the dose was increased to 1-5 mg. q.d.s. on July 30. Next day the patient became excessively drowsy, and the pulse-rate increased to 160 per minute-at first irregular but reverting later to regular rhythm. Early cor pulmonale was suspected despite absence of raised jugular venous pressure. X-ray of chest confirmed early cor pulmonale, showing considerable pulmonary hilar congestion. Digoxin 0-25 mg. was given 4-hourly and the dose of oxytetraMcFadzean, A. J. S. Trans. R. Soc. trop. Med. Hyg. 1952/53, 47, 372. Smith, G., Wells, C. W. Bulletin 8, Institute of Medical Research Federation of Malaya. Laha, P. N. Brit. med. J. 1957, i, 148. 5. Glazko, A. J., Wolf, L. M., Dill, W. A., Bratton, A. C., Jr. J. Pharmacol exp. Ther. 1949, 96, 445. 6. Antibiot. Chemother. 1961, 11, 681. 4.
As could be
expected,
treatment
produced the best -
results in the six-month-old boy. We conclude that microcephaly is never a contraindication to a therapeutic trial in this disease, certainly not at an earlv age. Kindergeneeskunde, Rijksuniversiteit Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands.
F. J.
VAN
5. 6. 7.
Faierman, E. Arch. Dis. Childh. 1960, 35, 285. Bourne, G. L., Benirschke, K. ibid. p. 534. Lewis, A. J. Lancet, 1962, i, 866. Uchida, I. A., Bowman, J. M., Wang, H. C. New Engl. J. Med. 1962, 266, 1198. German, J., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., Beam, A. G. J. Pediat. 1962, 60, 503. Heinrichs, E. H., Allen, S. W. Clin. Pediat. 1963, 2, 25. Dunn, P. M., Fisher, A. M., Koller, H. G. Amer. J. Obstet. Gynec. 1962, 84, 348. DATA ON
Department of Pædiatrics, University Hospital, Sapporo, Hokkaido, Japan.
Hokkaido
4
T. KAJII. M. SHINOHARA K. KIKUCHI S. DOHMEN.
Department of Obstetrics and Gynaecology, Sapporo Medical College, Sapporo. Mitsubishi Tokyo Hospital, Tokyo, Japan.
SPRANG.
THALIDOMIDE AND THE UMBILICAL ARTERY SIR,-We have examined the umbilical cord of 4 cases of thalidomide embryopathy in which the infant died shortly after birth. A single umbilical artery was found in 2 of these 4 cases, an attenuated right umbilical artery was present in 1, and in the remaining case the umbilical arteries were normal. In each case with a single umbilical artery, the iliac and femoral arteries of the side where the umbilical artery was missing were about one third of their normal size, and the intra-abdominal umbilical artery of the same side was lacking. In case 3, in which the right umbilical artery was half its normal size, the intraabdominal umbilical artery of the same side was also attenuated, though the right iliac and femoral arteries were normal. These 3 cases with abnormalities of the umbilical artery had multiple congenital malformations of the internal organs, including the heart and genitourinary system, besides limb deformities. By contrast, the case with normal umbilical arteries showed no malformations of the internal organs. Details of the 4 cases are given in the accompanying table. Studies of the single umbilical artery 12 show increased association of a range of congenital malformations with this circumstance. The 17-18 syndrome has been reported to accompany single umbilical artery.3-6 But an extensive search of published reports on thalidomide embryopathy has revealed no case with a single umbilical artery except one described by Dunn et al. in which there was binovular twin pregnancy. This case presented phocomelia of the upper limbs and a pilonidal sinus. A single umbilical artery is present in 7% of twin pregnancies, compared 1. 2. 3. 4.
with an overall prevalence of 1 %, and it is hard to tell whether in this case the abnormality is attributable to twin pregnancy or to thalidomide. But our finding of abnormalities of the umbilical arteries in 3 out of 4 cases of thalidomide embryopathy suggests that the umbilical cord of every thalidomide baby should be examined for such abnormalities.
M. AKICHIKA.
CHARACTER OF THE TECTORIAL MEMBRANE
SiR,—The results of our analysis of the tectorial membrane1 have prompted us to make a model imitating part of the energy-transducing mechanism of the cochlea. The model consisted of
by
a
an
liquid ion-exchange
agar-gel with electrolyte overlaid
resin
not
miscible with
Polyethylene cells with agar-gel and overlaid
resin
or
water.
saline solu-
tion; A, B, C, and D are indifferent electrodes made of stainless steel rigidly fixed in walls.
(’Amberlite’, LA-1, British Drug Houses.) The resin was diluted with organic solvent, miscible with both water and resin phases, and saturated with water containing the same electrolytes as in the agar-gel. This system was left for a little time to allow the equilibrium distribution of electrolytes for the system to become established. Indifferent electrodes were inserted rigidly into both phases (see accompanying figure). The 1.
resin-gel system
was
contained in
a
small
polyethylene
Naftalin, L., Harrison, M. S., Stephens, A. Lancet, 1963, i,
CASES OF THALIDOMIDE EMBRYOPATHY
1192.
890 pot with a small hole (4 mm. x 2 mm.) in one side, connecting the agar-gel phase only with the same agar-electrolyte in a neighbouring pot. On top of this agar was placed a large brass " stapes " weighing about 2 g. A symmetrical system with electrodes was made on the other side of the " stapes " cell, but this system contained only saline solution and had no resin. A hearing-aid earpiece was held to the stapes and the electrodes were connected either to an oscilloscope or to the input of a tape recorder. All connections were made rigid, and care was taken to avoid earthing or other adventitious potentials. Tuning forks, one at a time, or together, could be recorded both on the oscilloscope and on the tape recorder, when the forks were held about 1 in. in the air above the hearing-aid microphone. When the electrodes in the resin side were connected up there was recording, but not when the saline solution side only was in circuit. We have also recorded the human voice, counting 1 to 10, with a quality of reproduction approaching that of a carbon microphone, distinctive timbre being clearly heard. Similar results, but of much poorer quality, were obtained, for tuning forks only by means of a piece of filter paper appropriately treated with resin-electrolyte. This system fatigued quickly and was accompanied by much adventitious noise. We do not claim that the transduction of acoustic energy to electrical potential in the scala media must be of this nature, but we have shown that an ion-exchange resin system (which maintains by its physico-chemical nature a permanent junction potential) can respond as accurately as a carbon microphone to acoustic vibration and is a possible mode of action in the tectorial membrane. It is relevant here to quote Hallowell Davis.2 " We have sought with the electron microscope for some structure ... that looks as though it might perform the job that we have assigned to it, which is really the job of being a resistance microphone like a carbon-type microphone of a telephone or hearing-aid. So far nothing helpful has been found. The electrical mechanism must be of molecular dimensions ...". The model we have made employs a molecular mechanism, and we derived our idea of it from the analysis of the tectorial membrane. We suggest that this type of transduction should be given serious consideration as a possible mode of conversion of acoustic to electrical energy in the receptor-organ of the cochlea. L. NAFTALIN Biochemistry Laboratory, St. George’s Hospital, A. STEPHENS. Lincoln. -
ANTI-RABIES VACCINE
SIR,-Recently I attended a patient with neuroparalysis following a second course of anti-rabies vaccine (10 injections of carbolised fixed virus vaccine, M.R.I. Colombo no. 1062). The first course had been given three years previously. Despite treatment with cortisone and vitamin B}2} and resort to a respirator, the patient died on the fifth day of the illness. The dog survived. This is the first reported case of its sort in Ceylon, where dogbites are a recognised hazard for planters and estate workers. In view of the fact that, on religious grounds, compulsory immunisation or extermination of stray dogs cannot be applied here, would it not be advisable to make available the duck embryo vaccine (non-nervous tissue),3 which does not give rise to these neuroparalytic accidents ? Such accidents only occur with carbol fixed virus vaccine, when used for second or subsequent courses. One course of the carbol vaccine can be given harmlessly. World figures for these accidents show a most unsatis2. 3.
Davis, H. in Neural Mechanisms of the Auditory and Vestibular Systems (edited by G. L. Rasmussen, W. F. Windle); p. 35. Springfield, 1960. W.H.O. Expert Committee on Rabies: Fourth Report. Tech. Rep. Wld Hlth Org. 1960, no. 201.
factory picture for the carbol vaccine used in a second o: subsequent course: between 1 in 860 and 1 in 8000 0 vaccinated persons have been found to become paralysed and about 30% of those affected die.4 Thus the need for: vaccine without neurotoxic properties seems to be great My
thanks
are
due
to
the director of the Medical Researc
Institute, Ceylon, and Dr. J. Hay Arthur, Estates Health Servia Cevlon. for their kind help.
J. T. DIXON.
Colombo, Ceylon,
BROAD-SPECTRUM REDEFINED
SiR,—Your leading article of Oct. 5 stated: "In urinary infections, its [chloramphenicol’s] undoubted activity against many of the common causal organisms is cancelled by the fact that it appears in the urine mainly as an inactive metabolite." It is true that a relatively large fraction of the administered dose of chloramphenicol is converted to forms not active against bacteria, but, in spite of this, urine concentrations of the active compound are high and peak levels of the antibiotic exceeding 200 g. per ml. have been recorded after a single 1-5 g. oral dose." This is not the whole story, however. It is generally agreed that infection of the urinary tract is primarily in tissue and the objective of therapy is to deliver to the site of infection amounts of a drug that are either bactericidal or bacteriostatic .6With chloramphenicol, the greatest tissue concentration of the drug is observed in the kidney,5 and so, in large part, this objective is achieved. Furthermore, if susceptible bacteria are shed into the urine, the urinary concentration of active drug is more than sufficient to prevent their multiplication providing adequate dosage is given. J. R. ARCHER Manager Parke Davis &
Company, Hounslow, Middlesex.
of Medical Services
J. A. L. GORRINGE Director of Clinical Investigation.
SiR,—Your editorial of Oct. 5 stated, when speaking of chloramphenicol, that " it may still find a place ... in topical treatment of some ocular and aural infections ". This dangerous drug continues to be an important antibiotic in treating some cases of intraocular infection, and your emphasis on topical treatment of eye infection should not be construed as indicating that systemic chloramphenicol has no place in the treatment of infection within t’1P
put-
G. EVERARD HEWSON. JAUNDICE ASSOCIATED WITH HALOPERIDOL
SIR,-Iwish to report a case of jaundice in a patient undergoing treatment with haloperidol (’ Serenace ’). A man of 71 admitted to hospital on July 17, 1963, for a manic illness was found to have signs of chronic bronchitis and emphysema. On July 22 there were signs of an acute exacerbation of the chronic bronchitis. Treatment was instituted with oxytetracycline (’Terramycin’) 250 mg. 6-hourly. The patient’s haemoglobin was 12-3 g. per 100 ml. and the whitecell count was 5750 per c.mm. On July 25 treatment with haloperidol 1-5 mg. t.d.s. was begun and the dose was increased to 1-5 mg. q.d.s. on July 30. Next day the patient became excessively drowsy, and the pulse-rate increased to 160 per minute-at first irregular but reverting later to regular rhythm. Early cor pulmonale was suspected despite absence of raised jugular venous pressure. X-ray of chest confirmed early cor pulmonale, showing considerable pulmonary hilar congestion. Digoxin 0-25 mg. was given 4-hourly and the dose of oxytetraMcFadzean, A. J. S. Trans. R. Soc. trop. Med. Hyg. 1952/53, 47, 372. Smith, G., Wells, C. W. Bulletin 8, Institute of Medical Research Federation of Malaya. Laha, P. N. Brit. med. J. 1957, i, 148. 5. Glazko, A. J., Wolf, L. M., Dill, W. A., Bratton, A. C., Jr. J. Pharmacol exp. Ther. 1949, 96, 445. 6. Antibiot. Chemother. 1961, 11, 681. 4.