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PREMATURITY, TETRACYCLINE, AND OXYTETRACYCLINE IN TOOTH DEVELOPMENT
720
editorial of Sept. 9 was also written shor’tly before our European conference. This can hardly be considered a very statesmanlike approach to a difficult problem. Could you not have waited until you had heard the further facts which were reported in Prague this week ? Department of Neurology, Radcliffe Infirmary, Oxford.
W. RITCHIE RUSSELL Chairman of the U.K. Committee for Poliomyelitis.
*
DETERMINISM, RESPONSIBILITY, AND ILLNESS SIR,-I want to thank Dr. Merskey and Mr. Clarke (Sept. 1) for dealing with my questions and stating their
assumptions and preconceptions more fully. It is difficult to be wholly " scientific and objective, and without special pleading "; since the type of scientific method advocated as being of primary importance in the study of human behaviour is itself a form of special pleading. Such bias must always be taken into account, so as not to detract from the value of such scientific findings by a tendency to exclude or minimise other methods of study and findings in this complex field. Discipline and restraint are necessary for the more difficult task of attempting to resolve and reconcile these differences in the quest for more adequate theory, rather than the less exacting procedure of setting up one method and approach as superior and more important than others. The dualistic theory put forward by the authors creates the problem of who or what decides which universe of discourse is appropriate to a given situation. It seems unsatisfactory to leave them as apparently unrelated alternatives. Although the authors finally come down on the side of determinism, is it not really the more difficult question of how much of determinism and free will there is in any given human behaviour ? St. George’s Hospital, Stafford.
H. M. FLANAGAN.
TRAINING OF NURSES
SIR,-The nurses are being urged by the Industrial Court to put their salary structure in order by March 31, 1963. I think it would be equally worth putting the professional strata right at the same time, and I would suggest the following: All hospitals which are medical teaching schools should become the State-enrolled-nurse training schools of the United Kingdom. I suggest this because the great work in surgery, medicine, and specialisation is done in these hospitals, and therefore they are the best training centres for the bedside It would also give the doctors the opportunity of nurse. planning and supervising the clinical teaching of the pupil, and of growing up with the nurses they always say they wantnot the academic, but the practical. All men and women who want to become State-registered nurses would take their training in hospitals geared, not to teaching the future doctors, but to teaching and training the future team-leaders in nursing. These schools of nursing would be the regional-board hospitals, approved by the General Nursing Council, throughout the country. The results would be: (a) Removing a lot of chips from the shoulders of the nurses who have trained in non-medical teaching hospitals, but who believe they are as good nurses but have less kudos. (b) Producing a State-registered nurse with a feeling of equality with all other State-registered nurses trained after March 31, 1963. (c) Producing a State-enrolled nurse who would not have an inferiority complex, and if it is social/matrimonial status the candidate is seeking, State-enrolled nursing will become fashionable. Richmond,
Surrey.
E WALSH E. A A. WALSH. WALSH.
PREMATURITY, TETRACYCLINE, AND OXYTETRACYCLINE IN TOOTH DEVELOPMENT
SIR,-We have reported1 the finding of pigmentation, with or without enamel hypoplasia, in deciduous teeth of children who were given tetracycline in the neonatal period, and the apparent rarity of these complications after oxytetracycline therapy. Prof. M. A. Rushton (May 5), Mr. Stewart (May 5), and Dr. Miller (May 19) suggested that prematurity alone, or the disease for which the drug was given, rather than tetracycline, may have been responsible for the enamel hypoplasia. To elucidate this problem we investigated 46 prematurely born children to determine the incidence of tooth deformity. In a separate survey 21 children who had been given oxytetracycline in the neonatal period were also investigated to assess the effects of this drug on dentition. We examined the records of all babies born at the King Edward Memorial Hospital for Women in Perth in the twelve months from January, 1960, to January, 1961. 46 children whose birthweight was less than 2-5 kg. (this being taken as the criterion of " prematurity ") were traced. The teeth were examined and the gestation period, birthweight, any significant illness, and details of the administration of antibiotics were noted. Enamel hypoplasia was diagnosed when there was naked-eye deformity of the teeth. This was usually manifested in the canines and molars as abnormally sharp cusps and obvious deficiency of the enamel. The average birthweight in this group was 2-06 kg., and the average gestation period was 35-1 weeks. 32 children had normal teeth. 6 of these had illnesses: conjunctivitis (3), respiratory distress (2), and cyanotic attacks (1). None had been given tetracycline. 14 children had abnormal teeth. Of this group, 1 had kemicterus and had received oxytetracycline. He had enamel hypoplasia and slight yellow pigmentation. The other 13 had all been given tetracycline in doses ranging from 120 to 750 mg. 9 had enamel hypoplasia and pigmentation, and 4 had pigmentation alone. The drug was given for respiratory distress in 4 cases, for conjunctivitis in 2, for cyanotic attacks in 2, for pustules in 2, for pneumonia in 1, and prophylactically in 2, 21 children who had been given oxytetracycline in the neonatal period were traced. Most of them had been given the drug in the first week of life. In each instance we recorded the birthweight, gestational age, the dose of oxytetracycline, the duration of treatment, and the reason for giving the drug. This group includes the 8 cases previously
reported.1 Oxytetracycline was given for respiratory distress in 4 cases, for conjunctivitis in 4, for pyrexia in 3, for pustules in 1, for infected umbilicus in 1, for cellulitis in 1, and prophylactically in 7. The average birthweight was 2’82 kg.; the average gestational period was 38 weeks. The average total dose of oxytetracycline was 620 mg. (an average total dose of 210 mg. per kg. with an average daily dose of 38 mg. per kg.). 2 children had abnormal teeth. 1 was a mentally defective child, previously described, who had superficial yellow pigmentation of the teeth which did not fluoresce in ultraviolet light. There was. no associated enamel hypoplasia. The 2nd child had kernicterus due to rhesus incompatibility. 700 mg. of oxytetracycline had been given in the neonatal period. The teeth showed moderate enamel hypoplasia with slight yellow pigmentation. Other than varying degrees of caries, the remaining children had normal teeth. 2 children whose birthweights were 2-2 kg. and 1’6 kg. received 630 and 750 mg. per kg., yet neither had abnormal teeth. Kernicterus is often followed by severe enamel hypoplasia. Forrester and Miller2 examined 13 children who had had kernicterus, and found that all had tooth deformity. They also described enamel hypoplasia in some premature babies, and noted that most of these children 1. 2.
Wallman, I. S., Hilton, H. B. Lancet, 1962, i, 827. Forrester, R. M., Miller, J. Arch. Dis. Childh. 1955, 30, 224.
721
had neurological lesions similar to the kemicterus group. No mention was made of the degree of jaundice in these babies. In our follow-up of 46 premature
babies, abnormal teeth
were
found
only in those who had been given tetracycline (13 cases) and 1 child who had kernicterus. The remaining 32 children had normal teeth. None of these had been given tetracycline, although 6 had neonatal illnesses similar to those in the tetracycline group. We think, therefore, that tetracycline, rather than the illness for which the drug is given, is directly responsible for enamel hypoplasia. There is
experimental evidence that affect the growth of teeth and bone. The drug has been shown to tetracycline
can
inhibit skeletal formation in the larval sand dollar (Echinarachnus parma),3 and when (a) Pustulosis palmaris 4 days after tetracycline (total 5 g.) was discontinued. (b) Same view under ultraviolet light. Yellow tetracycline fluorescence at the margins of the injected into the developing chick embryo rhagades and in the drying pustules formed during treatment. it may produce shortening and deformity of bones.4 Fillipi and Mela5 showed that long-continued administration of tetracycline during the phages.11 The neoplastic cells themselves invariably fail to gestation period of rats resulted in several skeletal anomalies exhibit fluorescence. Thus tetracycline fluorescence is not an in the newborn animals; and Bevelander et al.demonstrated indicator of malignancy but merely an expression of stromal inhibition of calcification of the teeth after giving tetracycline reaction favouring calcification. Experience with experimental 12 and clinical ulcers 5 supports this view. In all kinds of ulcers, to rats. Teeth develop faster during the seventh month of tetracycline fluorescence is confined to the marginal areas of9 necrotic tissue, where calcium salts are known to be deposited. gestation and are probably most susceptible then to Not only frank ulcers but even small rhagades and pustules noxious influences. This would explain the greater fremay display marginal tetracycline fluorescence (see figure). quency of enamel hypoplasia in premature babies than in The fluorescent material for several after
babies born
at term.
Oxytetracycline does not seem to cause pigmentation or hypoplasia when given in the neonatal period. Only 2 out of 21 children in our series had abnormal teeth, and in neither was the drug thought to be responsible. These effects contrast with those of tetracycline, which we reported as causing pigmented teeth in 46 of 50 children who were given this drug in the neonatal period. The average dose of oxytetracycline-210 mg. per kg. birthweight-is greater than the average dose of tetracycline (189 mg. per kg. birthweight) which gave rise to severe abnormality in the teeth. enamel
Princess Margaret Hospital for Children, Perth, Western Australia.
I. S. WALLMAN H. B. HILTON.
TETRACYCLINES AND DEPOSITION OF CALCIUM SlR,-The affinity of tetracyclines for bone and teeth has aroused lively discussion. On the other hand, in a recent annotationthe selective concentration of
tetracyclines in tumour tissue was emphasised. To me these seemingly unrelated interactions between drug and tissue appear to have a common basis: deposition of a calcium chelate of tetracycline11 in a matrix of collagen and ground substance.’ In bones the fluorescence of tetracyclines is restricted
of matrix calcification 10 and in tumours specifically to tissue debris and to macro-
to areas
to stroma, more
Bevelander, G., Goldberg, L., Nakahara, H. Arch. Orol. Biol. 1960, 2, 127. 4. Bevelander, G., Nakahara, H., Rolle, G. K. Devel. Biol. 1960, 2, 298. 5. Fillipi, B., Mela, V. Minerva chir. 1957, 12, 1, 6. Bevelander, G., Rolle, G. K., Cohlan, S. Q. J. dent. Res. 1961, 40, 1020. 7. Lancet, 1962, i, 1393. 8. Ibsen, K. H., Urist, M. R. Proc. Soc. exp. Biol., N.Y. 1962, 109, 797.
3.
Glimcher, M. J. in Connective Tissue, Thrombosis and Atherosclerosis; (edited by I. Page); p. 97. New York, 1959. 10. Milch, R. A., Tobie, J. E., Robinson, R. A. J. Histochem. Cytochem. 1961, 9, 261.
days persisted tetracycline was discontinued. It was exfoliated within the scab. This means that tetracyclines accumulate and persist at the very sites where they are needed-that is, where the skin barrier against bacteria is broken. This will have therapeutic
consequences if the fluorescent material retains its antibacterial in the skin as well as it does in the bone.13 Moreover, the demarcation of malignant and necrotic lesions by tetracycline fluorescence facilitates their surgical removal. Department of Dermatology, University of Helsinki, K. K. MUSTAKALLIO.
activity
Finland.
TOO MUCH TO DO?
SIR,-" Final-year Student " (Sept. 22) appears surprised and frightened at his discovery that house-officers are expected to work long hours. Presumably he does not yet know that all doctors have to do the same.
even
after their houseman year,
I, personally, regard his estimate of the hours worked as modest and I do not refer only to house-officers; I would suggest that the long hours worked by housemen be regarded as training for the hard work required in subsequent years. The man who cannot work for such periods without neglecting his patients has no place in the profession of medicine. If " Final-year Student " feels that he cannot attain the required standard he should not bother to sit his final examinations but should get out now and take up some more suitable career. The carefree young man who can relax while neglecting his patients has no right to call himself a doctor. It would be a mistake to regard Dr. Schweitzer as being distinguished by his virtue. That great man’s devotion to his patients is, I believe, a characteristic of our profession. Dr. Schweitzer differs from the rest of us in his ability, which 11.
9.
Vassar, P. S., Saunders, 69, 613.
12. 13.
A.
M., Culling, C. F. A. Arch. Path.960,
1
Häkkinen, I., Hartiala, K. Ann. Med. exp. Biol. Fenniœ, 1959, 37, 115. Anderson, R. L., Jr., Ferguson, A. B., Jr., Braude, A. I. Surg. Gynec. Obstet. 1959, 108, 65.
editorial of Sept. 9 was also written shor’tly before our European conference. This can hardly be considered a very statesmanlike approach to a difficult problem. Could you not have waited until you had heard the further facts which were reported in Prague this week ? Department of Neurology, Radcliffe Infirmary, Oxford.
W. RITCHIE RUSSELL Chairman of the U.K. Committee for Poliomyelitis.
*
DETERMINISM, RESPONSIBILITY, AND ILLNESS SIR,-I want to thank Dr. Merskey and Mr. Clarke (Sept. 1) for dealing with my questions and stating their
assumptions and preconceptions more fully. It is difficult to be wholly " scientific and objective, and without special pleading "; since the type of scientific method advocated as being of primary importance in the study of human behaviour is itself a form of special pleading. Such bias must always be taken into account, so as not to detract from the value of such scientific findings by a tendency to exclude or minimise other methods of study and findings in this complex field. Discipline and restraint are necessary for the more difficult task of attempting to resolve and reconcile these differences in the quest for more adequate theory, rather than the less exacting procedure of setting up one method and approach as superior and more important than others. The dualistic theory put forward by the authors creates the problem of who or what decides which universe of discourse is appropriate to a given situation. It seems unsatisfactory to leave them as apparently unrelated alternatives. Although the authors finally come down on the side of determinism, is it not really the more difficult question of how much of determinism and free will there is in any given human behaviour ? St. George’s Hospital, Stafford.
H. M. FLANAGAN.
TRAINING OF NURSES
SIR,-The nurses are being urged by the Industrial Court to put their salary structure in order by March 31, 1963. I think it would be equally worth putting the professional strata right at the same time, and I would suggest the following: All hospitals which are medical teaching schools should become the State-enrolled-nurse training schools of the United Kingdom. I suggest this because the great work in surgery, medicine, and specialisation is done in these hospitals, and therefore they are the best training centres for the bedside It would also give the doctors the opportunity of nurse. planning and supervising the clinical teaching of the pupil, and of growing up with the nurses they always say they wantnot the academic, but the practical. All men and women who want to become State-registered nurses would take their training in hospitals geared, not to teaching the future doctors, but to teaching and training the future team-leaders in nursing. These schools of nursing would be the regional-board hospitals, approved by the General Nursing Council, throughout the country. The results would be: (a) Removing a lot of chips from the shoulders of the nurses who have trained in non-medical teaching hospitals, but who believe they are as good nurses but have less kudos. (b) Producing a State-registered nurse with a feeling of equality with all other State-registered nurses trained after March 31, 1963. (c) Producing a State-enrolled nurse who would not have an inferiority complex, and if it is social/matrimonial status the candidate is seeking, State-enrolled nursing will become fashionable. Richmond,
Surrey.
E WALSH E. A A. WALSH. WALSH.
PREMATURITY, TETRACYCLINE, AND OXYTETRACYCLINE IN TOOTH DEVELOPMENT
SIR,-We have reported1 the finding of pigmentation, with or without enamel hypoplasia, in deciduous teeth of children who were given tetracycline in the neonatal period, and the apparent rarity of these complications after oxytetracycline therapy. Prof. M. A. Rushton (May 5), Mr. Stewart (May 5), and Dr. Miller (May 19) suggested that prematurity alone, or the disease for which the drug was given, rather than tetracycline, may have been responsible for the enamel hypoplasia. To elucidate this problem we investigated 46 prematurely born children to determine the incidence of tooth deformity. In a separate survey 21 children who had been given oxytetracycline in the neonatal period were also investigated to assess the effects of this drug on dentition. We examined the records of all babies born at the King Edward Memorial Hospital for Women in Perth in the twelve months from January, 1960, to January, 1961. 46 children whose birthweight was less than 2-5 kg. (this being taken as the criterion of " prematurity ") were traced. The teeth were examined and the gestation period, birthweight, any significant illness, and details of the administration of antibiotics were noted. Enamel hypoplasia was diagnosed when there was naked-eye deformity of the teeth. This was usually manifested in the canines and molars as abnormally sharp cusps and obvious deficiency of the enamel. The average birthweight in this group was 2-06 kg., and the average gestation period was 35-1 weeks. 32 children had normal teeth. 6 of these had illnesses: conjunctivitis (3), respiratory distress (2), and cyanotic attacks (1). None had been given tetracycline. 14 children had abnormal teeth. Of this group, 1 had kemicterus and had received oxytetracycline. He had enamel hypoplasia and slight yellow pigmentation. The other 13 had all been given tetracycline in doses ranging from 120 to 750 mg. 9 had enamel hypoplasia and pigmentation, and 4 had pigmentation alone. The drug was given for respiratory distress in 4 cases, for conjunctivitis in 2, for cyanotic attacks in 2, for pustules in 2, for pneumonia in 1, and prophylactically in 2, 21 children who had been given oxytetracycline in the neonatal period were traced. Most of them had been given the drug in the first week of life. In each instance we recorded the birthweight, gestational age, the dose of oxytetracycline, the duration of treatment, and the reason for giving the drug. This group includes the 8 cases previously
reported.1 Oxytetracycline was given for respiratory distress in 4 cases, for conjunctivitis in 4, for pyrexia in 3, for pustules in 1, for infected umbilicus in 1, for cellulitis in 1, and prophylactically in 7. The average birthweight was 2’82 kg.; the average gestational period was 38 weeks. The average total dose of oxytetracycline was 620 mg. (an average total dose of 210 mg. per kg. with an average daily dose of 38 mg. per kg.). 2 children had abnormal teeth. 1 was a mentally defective child, previously described, who had superficial yellow pigmentation of the teeth which did not fluoresce in ultraviolet light. There was. no associated enamel hypoplasia. The 2nd child had kernicterus due to rhesus incompatibility. 700 mg. of oxytetracycline had been given in the neonatal period. The teeth showed moderate enamel hypoplasia with slight yellow pigmentation. Other than varying degrees of caries, the remaining children had normal teeth. 2 children whose birthweights were 2-2 kg. and 1’6 kg. received 630 and 750 mg. per kg., yet neither had abnormal teeth. Kernicterus is often followed by severe enamel hypoplasia. Forrester and Miller2 examined 13 children who had had kernicterus, and found that all had tooth deformity. They also described enamel hypoplasia in some premature babies, and noted that most of these children 1. 2.
Wallman, I. S., Hilton, H. B. Lancet, 1962, i, 827. Forrester, R. M., Miller, J. Arch. Dis. Childh. 1955, 30, 224.
721
had neurological lesions similar to the kemicterus group. No mention was made of the degree of jaundice in these babies. In our follow-up of 46 premature
babies, abnormal teeth
were
found
only in those who had been given tetracycline (13 cases) and 1 child who had kernicterus. The remaining 32 children had normal teeth. None of these had been given tetracycline, although 6 had neonatal illnesses similar to those in the tetracycline group. We think, therefore, that tetracycline, rather than the illness for which the drug is given, is directly responsible for enamel hypoplasia. There is
experimental evidence that affect the growth of teeth and bone. The drug has been shown to tetracycline
can
inhibit skeletal formation in the larval sand dollar (Echinarachnus parma),3 and when (a) Pustulosis palmaris 4 days after tetracycline (total 5 g.) was discontinued. (b) Same view under ultraviolet light. Yellow tetracycline fluorescence at the margins of the injected into the developing chick embryo rhagades and in the drying pustules formed during treatment. it may produce shortening and deformity of bones.4 Fillipi and Mela5 showed that long-continued administration of tetracycline during the phages.11 The neoplastic cells themselves invariably fail to gestation period of rats resulted in several skeletal anomalies exhibit fluorescence. Thus tetracycline fluorescence is not an in the newborn animals; and Bevelander et al.demonstrated indicator of malignancy but merely an expression of stromal inhibition of calcification of the teeth after giving tetracycline reaction favouring calcification. Experience with experimental 12 and clinical ulcers 5 supports this view. In all kinds of ulcers, to rats. Teeth develop faster during the seventh month of tetracycline fluorescence is confined to the marginal areas of9 necrotic tissue, where calcium salts are known to be deposited. gestation and are probably most susceptible then to Not only frank ulcers but even small rhagades and pustules noxious influences. This would explain the greater fremay display marginal tetracycline fluorescence (see figure). quency of enamel hypoplasia in premature babies than in The fluorescent material for several after
babies born
at term.
Oxytetracycline does not seem to cause pigmentation or hypoplasia when given in the neonatal period. Only 2 out of 21 children in our series had abnormal teeth, and in neither was the drug thought to be responsible. These effects contrast with those of tetracycline, which we reported as causing pigmented teeth in 46 of 50 children who were given this drug in the neonatal period. The average dose of oxytetracycline-210 mg. per kg. birthweight-is greater than the average dose of tetracycline (189 mg. per kg. birthweight) which gave rise to severe abnormality in the teeth. enamel
Princess Margaret Hospital for Children, Perth, Western Australia.
I. S. WALLMAN H. B. HILTON.
TETRACYCLINES AND DEPOSITION OF CALCIUM SlR,-The affinity of tetracyclines for bone and teeth has aroused lively discussion. On the other hand, in a recent annotationthe selective concentration of
tetracyclines in tumour tissue was emphasised. To me these seemingly unrelated interactions between drug and tissue appear to have a common basis: deposition of a calcium chelate of tetracycline11 in a matrix of collagen and ground substance.’ In bones the fluorescence of tetracyclines is restricted
of matrix calcification 10 and in tumours specifically to tissue debris and to macro-
to areas
to stroma, more
Bevelander, G., Goldberg, L., Nakahara, H. Arch. Orol. Biol. 1960, 2, 127. 4. Bevelander, G., Nakahara, H., Rolle, G. K. Devel. Biol. 1960, 2, 298. 5. Fillipi, B., Mela, V. Minerva chir. 1957, 12, 1, 6. Bevelander, G., Rolle, G. K., Cohlan, S. Q. J. dent. Res. 1961, 40, 1020. 7. Lancet, 1962, i, 1393. 8. Ibsen, K. H., Urist, M. R. Proc. Soc. exp. Biol., N.Y. 1962, 109, 797.
3.
Glimcher, M. J. in Connective Tissue, Thrombosis and Atherosclerosis; (edited by I. Page); p. 97. New York, 1959. 10. Milch, R. A., Tobie, J. E., Robinson, R. A. J. Histochem. Cytochem. 1961, 9, 261.
days persisted tetracycline was discontinued. It was exfoliated within the scab. This means that tetracyclines accumulate and persist at the very sites where they are needed-that is, where the skin barrier against bacteria is broken. This will have therapeutic
consequences if the fluorescent material retains its antibacterial in the skin as well as it does in the bone.13 Moreover, the demarcation of malignant and necrotic lesions by tetracycline fluorescence facilitates their surgical removal. Department of Dermatology, University of Helsinki, K. K. MUSTAKALLIO.
activity
Finland.
TOO MUCH TO DO?
SIR,-" Final-year Student " (Sept. 22) appears surprised and frightened at his discovery that house-officers are expected to work long hours. Presumably he does not yet know that all doctors have to do the same.
even
after their houseman year,
I, personally, regard his estimate of the hours worked as modest and I do not refer only to house-officers; I would suggest that the long hours worked by housemen be regarded as training for the hard work required in subsequent years. The man who cannot work for such periods without neglecting his patients has no place in the profession of medicine. If " Final-year Student " feels that he cannot attain the required standard he should not bother to sit his final examinations but should get out now and take up some more suitable career. The carefree young man who can relax while neglecting his patients has no right to call himself a doctor. It would be a mistake to regard Dr. Schweitzer as being distinguished by his virtue. That great man’s devotion to his patients is, I believe, a characteristic of our profession. Dr. Schweitzer differs from the rest of us in his ability, which 11.
9.
Vassar, P. S., Saunders, 69, 613.
12. 13.
A.
M., Culling, C. F. A. Arch. Path.960,
1
Häkkinen, I., Hartiala, K. Ann. Med. exp. Biol. Fenniœ, 1959, 37, 115. Anderson, R. L., Jr., Ferguson, A. B., Jr., Braude, A. I. Surg. Gynec. Obstet. 1959, 108, 65.