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PYSCHOSOMATIC ILLNESS AND EPIDEMIC ERYTHEMA INFECTIOSUM
930 the oxidase activity of ceruloplasmin. Thiamazole therapy is often accompanied by side-effects-e.g., loss of tastewhich may result in part from abnormalities in Zn" and/or Cu+ metabolism induced by their interaction with the
drug.
On the basis of these findings the low serum-sodium concentration of premature infants may also be due to the limited renal Na+-H+ exchange during the first postnatal weeks. Department of Pædiatrics, University of Pécs, Pécs, Hungary.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, U.S.A.
D. P. HANLON.
ENDRE SULYOK.
PYSCHOSOMATIC ILLNESS AND EPIDEMIC ERYTHEMA INFECTIOSUM
DRUG IDENTIFICATION
SIR,-Regrettably, Joan Ritchie and her colleagues (March 8, p. 552) fail to provide substantive data to support either the accuracy or the efficiency of the method they champion to identify solid medication forms. In our hands-some decade ago-a comparable approach yielded an unacceptable error-rate (44%) and consumed an inordinate amount of time (11-1minutes) per attempt. In contrast, our use of an imprint code reduced the error-rate to less than 5 ;o and the time expended to less than 20 seconds.2 Is it not time for the unfortunate policy decision reached in 1964 by the Committee on Identification of Drugs3 to be rescinded ? An imprint code is the only acceptable technique; anything less is needless .compromise. In the U.S.A., more than 90% of major manufacturers have followed the example of Eli Lilly & Co. and employed an imprint system on solid medication forms; Japan is pursuing a comparable approach. As noted elsewhere, isn’t it time to " encourage the World Health Organisation to move toward developing an international imprinting system, yet another step in the illusion of one world of medicine "?4 Poison Control Center, Children’s Orthopedic Hospital and Medical Center, Seattle, Washington 98105, U.S.A.
Simultaneous reports of skin rashes and pruritus, mainly in female students, were received from a junior-senior high school in Schuylkill county and from a middle school in Bucks county. These two schools are approximately 90 miles apart. Bucks county is a suburb of Philadelphia, whereas Schuylkill county tends to be rural. In the Bucks outbreak approximately 150 students and staff were affected and at the Schuylkill school approximately 75 students were affected.l The complaints included the sudden appearance of a rash on the face, chest, and arms, and itching. Students in special education classes were free of symptoms. There was little evidence of secondary spread to the members of the households of affected students. The mean age of students at the Bucks school was 12 and at the Schuylkill school it was 14. The dates of onset of symptoms were recorded from a sampling of 13 affected students in Schuylkill county and 17 affected students and/or staff in Bucks county:
WILLIAM O. ROBERTSON.
SODIUM HOMŒOSTASIS IN PRETERM INFANTS
Caldwell, J. G., Shoman, A. F., Hurst, J. Am. med. Ass. 1964, 187, 951.
D. B.,
Robertson,
3 adult females (2 teachers and 1 secretary) and 2 male students represented in the Bucks column. The rest of the cases in this group were female. Comparison of the two schools shows the dates of onset to be identical in several instances. are
SIR,-Dr Honour and his colleagues (Nov. 9, p. 1147) described lower plasma-sodium levels lasting for several weeks in symptom-free preterm infants and reported a study of twin infants of birth-weight 1-1and 1-2 kg. respectively. The hyponatrasmia was most striking on the 13th day, and gradually improved. I think it is relevant to mention some earlier observations 5,6 on electrolyte and acid-base balance of low-birth-weight preterm infants during the first six weeks of life. During the first two weeks of life the serum-sodium concentration fell and reached its minimum of 132-6 meq. per 1. in the third week. Later, as a positive sodium balance developed, a continuous rise followed reaching a level of 137-5 meq. per 1. by the end of the observation period. The initially high urinary sodium excretion was coupled with a low renal hydrogen-ion excretion, but the development of renal capacity to excrete hydrogen ion results in a progressive increase in renal Na—_H+ exchange. The similar trend and time course of the blood-total-CO2 content and serumsodium concentration point to a close relationship between the electrolyte and acid-base regulation during early postnatal life. 1.
SIR,—The events ascribed to psychosomatic illness in Berry, Alabama, by Dr Levine and others (Dec. 21, p. 1500) were similar to those in two counties in Pennsylvania during February and March, 1973.
W. O.
2. Robertson, K. A., Robertson, W. O. Clin. Toxicol. 1974, 7, 83. 3. Pharm. J. 1964, 421. 4. Robertson, W. O. Clin. Toxicol. 1974, 7, 407. 5. Kerpel-Fronius, E., Heim, T., Sulyok, E. Biol. Neonate, 1970, 156. 6. Sulyok, E. ibid. 1971, 17, 227.
Possible
explanations for these outbreaks included a allergen that may have been introduced into both schools, epidemic erythema infectiosum2 (fifth disease), and psychosomatic illness. In Bucks county, many of the cases were first seen in the girls’ gymnasium and a possible allergen was sought.3 Change in soaps, disinfectants, water, and personal towels used by affected students were investigated. Air filters and gymnasium mats were examined, but An important factor no contact allergen was identified. that influenced the consideration of epidemic erythema infectiosum as the cause included the " slapped cheek appearance of the rash in many individuals.1 Erythema infectiosum is thought to be due to a virus, but this has not been confirmed. Nevertheless, the Pennsylvania Bureau of Laboratories tested 28 throat washings (17 affected and 11 non-affected) from the Bucks school and 19 throat washings (13 affected and 6 non-affected) from the Schuylkill school. 12 paired sera (acute and convalescent) were collected from affected students and/or staff at the Bucks school plus 8 sera from non-affected students. 14 paired sera (acute and convalescent) were collected from affected students of the Schuylkill school plus 4 sera from noncontact
"
D. Communicable Diseases Notes, Pennsylvania Departof Health, March 17, 1973. 2. Ager, E. A., Chin. T. D. Y., Poland, J. D. New Engl. J. Med. 1966, 275, 1326. 3. Conway, M., Ottey, P. C. Bucks County Department of Health memorandum, Feb. 22, 1973. 1.
Rimland, ment
15,
931 affected students. All throat washings were negative for virus isolation, and viral serological investigation did not reveal four-fold or greater increases in antibody titres to herpes, measles, or rubella viruses. Psychosomatic illness was considered as a possible explanation, but this was highly unlikely since it did not fully explain the simultaneous rashes and pruritus in two schools at least 90 miles apart and, as far as we know, in no contact with each other during the outbreak. Although there was no virus implicated in our laboratory examinations, that did not mean one did not exist. There are other exanthemas-e.g., exanthem subitum (roseola infantum)-that are believed to be virus diseases, but these viruses have eluded detection. Pennsylvania Bureau of Laboratories, 2100 West Girard Avenue, Philadelphia, Pennsylvania 19130, U.S.A. Division of Communicable Diseases, Harrisburg, Pennsylvania 17120, U.S.A.
WALLACE E. TURNER RICHARD E. BERMAN JAY E. SATZ. WILLIAM E. PARKIN.
CONGENITAL LIMB-REDUCTION DEFORMITIES SIR The data presented by Dr Jaffe and others (March 1, p. 526) are derived from a very small, but interesting, series of cases of congenital limb-reduction deformities. Because the number of cases is so small, it is difficult to appraise their claim that a " cluster ", seasonal or otherwise, has occurred. Although clusters of birth defects can and do occur as the result of unidentified environmental factors, when the number of cases is small a cluster can occur as the result of pure chance. The fact that the Harrow group found no pill failures among their 7 cases is not unexpected. Our series1 yielded only 6 pill failures among 108 cases (5-6%). On the basis of our findings, one would expect only 0-39 cases with a history of pill failure among the Harrow series. The Harrow group found a history of hormone exposure in 2 out of their 7 cases (29%), and this is much higher than we found in our case series (14-0%). Although control data were not presented for the Harrow series, one might speculate that a hormone-exposure rate above 25% would be greater than one would expect to find in any normal control population. The sex of their exposed cases is important. In our series we found 15 cases with a history of exposure to exogenous sex hormones; 12 of these were males, but all 11 cases with a history of orally ingested sex hormones were males. Nora and Nora2 found 10 males among their series of 13 cases. Their data plus the data from the Harrow series show that exposed affected cases are not always male, but the cumulative available data still show a predominance of males among exposed affected cases. Although male unanimity would have provided strong proof of causation, it is not an essential feature of the suspected association. Finally, we should note a small inconsistency in the data from Harrow. 7 cases among the 6980 deliveries occurring during the review period does indeed produce a rate of 1-00 cases per 1000 births. However, 4 cases among the 2750 deliveries which occurred in 1974 would produce a rate, not of 1-81 per 1000 births as they stated, but of 1-45 per 1000 births. If the rate of 1-81 is correct then the denominator value of 2750 births must be inaccurate. New York State Department of
Albany, 1.
2.
Health, York, U.S.A.
New
D. T. JANERICH J. M. PIPER D. M. GLEBATIS.
Janerich, D. T., Piper, J. M., Glebatis, D. M. 1974, 291, 697. Nora, J. J., Nora, A. H. ibid. p. 731.
New
Engl. J. Med.
ORGANIC ACIDURIAS to Dr Gompertz (March 1, p. 552), we of the two questions raised-namely, benzoic " aciduria " caused by bacterial action, and the possible effects of drug therapy-and our studies were to some In a preliminary comextent designed to answer them. munication it was not possible to discuss the significance of each finding or to relate the results in detail to those of other workers. This will be attempted later, but additional information may be of interest now. The possibility that benzoic aciduria is a chance finding or the result of bacterial action has not been excluded. We reported a consistently higher incidence of benzoic aciduria in the mentally subnormal communities compared with our matched ambulant non-hospitalised control populations.1 We also selected certain individuals who excreted levels in excess of the highest values found in the control population range (up to 0-5 µ.g. per µg. of creatinine) and it is these who are included in our tables. These patients do not have gross urinary-tract infections detectable by a dip-slide technique. Further studies are in progress on these patients. We are certainly aware that bacterial action may lead to the appearance of benzoic acid in the urine and that there is a higher incidence of bacteriuria in institutionalised patients. Hansen et al.,=to whose work Dr Gompertz refers, did not study patients with urinarytract infections but only specimens of normal human urine inoculated with various bacterial cultures. These workers found that none of their cultures produced benzoic acid when inoculated urine was stored for 2 hours at 25°C and they emphasise that their results refer to " gross bacterial infection of the urinary tract". In such patients . one might expect concomitant proteinuria and other signs, which were not, however, observed in any of the subjects we studied.33 Also, urine specimens collected in the present studies were all frozen within 140 minutes of collection. The analytical methods used by Hansen and her colleagues,2 which involve solvent or steam-distillation extraction from acidified urine, are known to give poor recoveries45 and to cause artefact formation, such as the hydrolysis of glycine conjugates to the unconjugated compounds .6,7 This would produce benzoic acid from hippuric acid. The results obtained by use of such methods must be treated with great caution. We are also aware of the potential effects of drug therapy on the urinary excretion of organic acids. For example, in the studies of Perry et al. on benzoic aciduria in patients with psychoses,8 the periods of benzoic-acid excretion may be directly related to the periods of administration of reserpine and haloperidol.33 Our studyto which Dr Gompertz refers was on 17 normal subjects who, as stated, were preselected from our general normal survey because they had no evidence of urinary-tract infections and were not receiving drugs that might have influenced the excretion of the volatile organic acids to which the paper refers. In our general survey of normal subjects, however, with which the mentally subnormal survey results were compared, we studied 420 normal subjects of both sexes in an age-range of 1-5 to 83 years. 1,3,4 Of these subjects, 28% were receiving drug therapy of various kinds, from contraceptive pills and ferrous sulphate to reserpine and
SIR--In reply
are aware
Chalmers, R. A., Healy, M. J. R., Lawson, A. M., Tudor Hart, J., Watts, R. W. E. Unpublished. 2. Hansen, S., Perry, T. L., Lesk, D. Clinica chim. Acta, 1972, 39, 71. 3. Chalmers, R. A. PH.D. thesis. Council for National Academic Awards, 1974. 4. Chalmers, R. A., Bickle, S., Watts, R. W. E. Clinica chim. Acta, 1974, 52, 31. 5. Chalmers, R. A., Lawson, A. M. Chem. Brit. (in the press). 6. Gompertz, D. Clinica chim. Acta, 1971, 33, 457. 7. Gompertz, D., Draffan, G. H. in Organic Acidurias (edited by J. Stem and C. Toothill); p. 35. London, 1972. 8. Perry, T. L., Hansen, S., Lesk, D. ibid. p. 99. 1.
drug.
On the basis of these findings the low serum-sodium concentration of premature infants may also be due to the limited renal Na+-H+ exchange during the first postnatal weeks. Department of Pædiatrics, University of Pécs, Pécs, Hungary.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, U.S.A.
D. P. HANLON.
ENDRE SULYOK.
PYSCHOSOMATIC ILLNESS AND EPIDEMIC ERYTHEMA INFECTIOSUM
DRUG IDENTIFICATION
SIR,-Regrettably, Joan Ritchie and her colleagues (March 8, p. 552) fail to provide substantive data to support either the accuracy or the efficiency of the method they champion to identify solid medication forms. In our hands-some decade ago-a comparable approach yielded an unacceptable error-rate (44%) and consumed an inordinate amount of time (11-1minutes) per attempt. In contrast, our use of an imprint code reduced the error-rate to less than 5 ;o and the time expended to less than 20 seconds.2 Is it not time for the unfortunate policy decision reached in 1964 by the Committee on Identification of Drugs3 to be rescinded ? An imprint code is the only acceptable technique; anything less is needless .compromise. In the U.S.A., more than 90% of major manufacturers have followed the example of Eli Lilly & Co. and employed an imprint system on solid medication forms; Japan is pursuing a comparable approach. As noted elsewhere, isn’t it time to " encourage the World Health Organisation to move toward developing an international imprinting system, yet another step in the illusion of one world of medicine "?4 Poison Control Center, Children’s Orthopedic Hospital and Medical Center, Seattle, Washington 98105, U.S.A.
Simultaneous reports of skin rashes and pruritus, mainly in female students, were received from a junior-senior high school in Schuylkill county and from a middle school in Bucks county. These two schools are approximately 90 miles apart. Bucks county is a suburb of Philadelphia, whereas Schuylkill county tends to be rural. In the Bucks outbreak approximately 150 students and staff were affected and at the Schuylkill school approximately 75 students were affected.l The complaints included the sudden appearance of a rash on the face, chest, and arms, and itching. Students in special education classes were free of symptoms. There was little evidence of secondary spread to the members of the households of affected students. The mean age of students at the Bucks school was 12 and at the Schuylkill school it was 14. The dates of onset of symptoms were recorded from a sampling of 13 affected students in Schuylkill county and 17 affected students and/or staff in Bucks county:
WILLIAM O. ROBERTSON.
SODIUM HOMŒOSTASIS IN PRETERM INFANTS
Caldwell, J. G., Shoman, A. F., Hurst, J. Am. med. Ass. 1964, 187, 951.
D. B.,
Robertson,
3 adult females (2 teachers and 1 secretary) and 2 male students represented in the Bucks column. The rest of the cases in this group were female. Comparison of the two schools shows the dates of onset to be identical in several instances. are
SIR,-Dr Honour and his colleagues (Nov. 9, p. 1147) described lower plasma-sodium levels lasting for several weeks in symptom-free preterm infants and reported a study of twin infants of birth-weight 1-1and 1-2 kg. respectively. The hyponatrasmia was most striking on the 13th day, and gradually improved. I think it is relevant to mention some earlier observations 5,6 on electrolyte and acid-base balance of low-birth-weight preterm infants during the first six weeks of life. During the first two weeks of life the serum-sodium concentration fell and reached its minimum of 132-6 meq. per 1. in the third week. Later, as a positive sodium balance developed, a continuous rise followed reaching a level of 137-5 meq. per 1. by the end of the observation period. The initially high urinary sodium excretion was coupled with a low renal hydrogen-ion excretion, but the development of renal capacity to excrete hydrogen ion results in a progressive increase in renal Na—_H+ exchange. The similar trend and time course of the blood-total-CO2 content and serumsodium concentration point to a close relationship between the electrolyte and acid-base regulation during early postnatal life. 1.
SIR,—The events ascribed to psychosomatic illness in Berry, Alabama, by Dr Levine and others (Dec. 21, p. 1500) were similar to those in two counties in Pennsylvania during February and March, 1973.
W. O.
2. Robertson, K. A., Robertson, W. O. Clin. Toxicol. 1974, 7, 83. 3. Pharm. J. 1964, 421. 4. Robertson, W. O. Clin. Toxicol. 1974, 7, 407. 5. Kerpel-Fronius, E., Heim, T., Sulyok, E. Biol. Neonate, 1970, 156. 6. Sulyok, E. ibid. 1971, 17, 227.
Possible
explanations for these outbreaks included a allergen that may have been introduced into both schools, epidemic erythema infectiosum2 (fifth disease), and psychosomatic illness. In Bucks county, many of the cases were first seen in the girls’ gymnasium and a possible allergen was sought.3 Change in soaps, disinfectants, water, and personal towels used by affected students were investigated. Air filters and gymnasium mats were examined, but An important factor no contact allergen was identified. that influenced the consideration of epidemic erythema infectiosum as the cause included the " slapped cheek appearance of the rash in many individuals.1 Erythema infectiosum is thought to be due to a virus, but this has not been confirmed. Nevertheless, the Pennsylvania Bureau of Laboratories tested 28 throat washings (17 affected and 11 non-affected) from the Bucks school and 19 throat washings (13 affected and 6 non-affected) from the Schuylkill school. 12 paired sera (acute and convalescent) were collected from affected students and/or staff at the Bucks school plus 8 sera from non-affected students. 14 paired sera (acute and convalescent) were collected from affected students of the Schuylkill school plus 4 sera from noncontact
"
D. Communicable Diseases Notes, Pennsylvania Departof Health, March 17, 1973. 2. Ager, E. A., Chin. T. D. Y., Poland, J. D. New Engl. J. Med. 1966, 275, 1326. 3. Conway, M., Ottey, P. C. Bucks County Department of Health memorandum, Feb. 22, 1973. 1.
Rimland, ment
15,
931 affected students. All throat washings were negative for virus isolation, and viral serological investigation did not reveal four-fold or greater increases in antibody titres to herpes, measles, or rubella viruses. Psychosomatic illness was considered as a possible explanation, but this was highly unlikely since it did not fully explain the simultaneous rashes and pruritus in two schools at least 90 miles apart and, as far as we know, in no contact with each other during the outbreak. Although there was no virus implicated in our laboratory examinations, that did not mean one did not exist. There are other exanthemas-e.g., exanthem subitum (roseola infantum)-that are believed to be virus diseases, but these viruses have eluded detection. Pennsylvania Bureau of Laboratories, 2100 West Girard Avenue, Philadelphia, Pennsylvania 19130, U.S.A. Division of Communicable Diseases, Harrisburg, Pennsylvania 17120, U.S.A.
WALLACE E. TURNER RICHARD E. BERMAN JAY E. SATZ. WILLIAM E. PARKIN.
CONGENITAL LIMB-REDUCTION DEFORMITIES SIR The data presented by Dr Jaffe and others (March 1, p. 526) are derived from a very small, but interesting, series of cases of congenital limb-reduction deformities. Because the number of cases is so small, it is difficult to appraise their claim that a " cluster ", seasonal or otherwise, has occurred. Although clusters of birth defects can and do occur as the result of unidentified environmental factors, when the number of cases is small a cluster can occur as the result of pure chance. The fact that the Harrow group found no pill failures among their 7 cases is not unexpected. Our series1 yielded only 6 pill failures among 108 cases (5-6%). On the basis of our findings, one would expect only 0-39 cases with a history of pill failure among the Harrow series. The Harrow group found a history of hormone exposure in 2 out of their 7 cases (29%), and this is much higher than we found in our case series (14-0%). Although control data were not presented for the Harrow series, one might speculate that a hormone-exposure rate above 25% would be greater than one would expect to find in any normal control population. The sex of their exposed cases is important. In our series we found 15 cases with a history of exposure to exogenous sex hormones; 12 of these were males, but all 11 cases with a history of orally ingested sex hormones were males. Nora and Nora2 found 10 males among their series of 13 cases. Their data plus the data from the Harrow series show that exposed affected cases are not always male, but the cumulative available data still show a predominance of males among exposed affected cases. Although male unanimity would have provided strong proof of causation, it is not an essential feature of the suspected association. Finally, we should note a small inconsistency in the data from Harrow. 7 cases among the 6980 deliveries occurring during the review period does indeed produce a rate of 1-00 cases per 1000 births. However, 4 cases among the 2750 deliveries which occurred in 1974 would produce a rate, not of 1-81 per 1000 births as they stated, but of 1-45 per 1000 births. If the rate of 1-81 is correct then the denominator value of 2750 births must be inaccurate. New York State Department of
Albany, 1.
2.
Health, York, U.S.A.
New
D. T. JANERICH J. M. PIPER D. M. GLEBATIS.
Janerich, D. T., Piper, J. M., Glebatis, D. M. 1974, 291, 697. Nora, J. J., Nora, A. H. ibid. p. 731.
New
Engl. J. Med.
ORGANIC ACIDURIAS to Dr Gompertz (March 1, p. 552), we of the two questions raised-namely, benzoic " aciduria " caused by bacterial action, and the possible effects of drug therapy-and our studies were to some In a preliminary comextent designed to answer them. munication it was not possible to discuss the significance of each finding or to relate the results in detail to those of other workers. This will be attempted later, but additional information may be of interest now. The possibility that benzoic aciduria is a chance finding or the result of bacterial action has not been excluded. We reported a consistently higher incidence of benzoic aciduria in the mentally subnormal communities compared with our matched ambulant non-hospitalised control populations.1 We also selected certain individuals who excreted levels in excess of the highest values found in the control population range (up to 0-5 µ.g. per µg. of creatinine) and it is these who are included in our tables. These patients do not have gross urinary-tract infections detectable by a dip-slide technique. Further studies are in progress on these patients. We are certainly aware that bacterial action may lead to the appearance of benzoic acid in the urine and that there is a higher incidence of bacteriuria in institutionalised patients. Hansen et al.,=to whose work Dr Gompertz refers, did not study patients with urinarytract infections but only specimens of normal human urine inoculated with various bacterial cultures. These workers found that none of their cultures produced benzoic acid when inoculated urine was stored for 2 hours at 25°C and they emphasise that their results refer to " gross bacterial infection of the urinary tract". In such patients . one might expect concomitant proteinuria and other signs, which were not, however, observed in any of the subjects we studied.33 Also, urine specimens collected in the present studies were all frozen within 140 minutes of collection. The analytical methods used by Hansen and her colleagues,2 which involve solvent or steam-distillation extraction from acidified urine, are known to give poor recoveries45 and to cause artefact formation, such as the hydrolysis of glycine conjugates to the unconjugated compounds .6,7 This would produce benzoic acid from hippuric acid. The results obtained by use of such methods must be treated with great caution. We are also aware of the potential effects of drug therapy on the urinary excretion of organic acids. For example, in the studies of Perry et al. on benzoic aciduria in patients with psychoses,8 the periods of benzoic-acid excretion may be directly related to the periods of administration of reserpine and haloperidol.33 Our studyto which Dr Gompertz refers was on 17 normal subjects who, as stated, were preselected from our general normal survey because they had no evidence of urinary-tract infections and were not receiving drugs that might have influenced the excretion of the volatile organic acids to which the paper refers. In our general survey of normal subjects, however, with which the mentally subnormal survey results were compared, we studied 420 normal subjects of both sexes in an age-range of 1-5 to 83 years. 1,3,4 Of these subjects, 28% were receiving drug therapy of various kinds, from contraceptive pills and ferrous sulphate to reserpine and
SIR--In reply
are aware
Chalmers, R. A., Healy, M. J. R., Lawson, A. M., Tudor Hart, J., Watts, R. W. E. Unpublished. 2. Hansen, S., Perry, T. L., Lesk, D. Clinica chim. Acta, 1972, 39, 71. 3. Chalmers, R. A. PH.D. thesis. Council for National Academic Awards, 1974. 4. Chalmers, R. A., Bickle, S., Watts, R. W. E. Clinica chim. Acta, 1974, 52, 31. 5. Chalmers, R. A., Lawson, A. M. Chem. Brit. (in the press). 6. Gompertz, D. Clinica chim. Acta, 1971, 33, 457. 7. Gompertz, D., Draffan, G. H. in Organic Acidurias (edited by J. Stem and C. Toothill); p. 35. London, 1972. 8. Perry, T. L., Hansen, S., Lesk, D. ibid. p. 99. 1.