339 THERAPY FOR ACUTE DIARRHŒA
SiR,-May I be allowed an anecdotal reference, prompted by your leading article (Jan. 11, p. 79) ? You cite some references stressing the management of cholera by simple clinical assessment of dehydration, and its correction by simple intravenous fluid replacement. During the last campaign of the 14th Army in Burma in the 1939-45 war, two Indian sepoys were admitted to the casualty-clearing station in which I was serving under primitive field conditions. They arrived simultaneously, suffering from severe cholera with " washerwoman’s fingers " and extreme prostration, and each was treated with intravenous 5% glucose in normal saline at a rate of one pint an hour for about 48 hours. They both recovered completely without a single biochemical investigation. Conditions prevailing in tropical homes and villages are unlikely to be much worse nowadays than those in my C-C-S-3 and what has been done before can easily be done again. East Glamorgan General Hospital, Church Village, near Pontypridd, Glamorgan. J. DE SWIET.
PHOTOTHERAPY AND HYPERBILIRUBINÆMIA
SiR,-Your editorial on phototherapy (Nov. 2, p. 1056), by overlooking several important studies, was perhaps rather misleading and less illuminating than it could have been.
It was suggested that the diazo-positive pigment which is excreted in the bile of newborn infants during phototherapy 1,2 is a photo-adduct of bilirubin of the type recently synthesised by Garbagnati and Manitto.3 The simplest and most straightforward explanation, which is that the pigment is bilirubin itself, was considered to be less plausible. Plausible or not, there is in fact little doubt that the pigment is bilirubin and that a major effect of phototherapy is to stimulate the excretion of intact unconjugated bilirubin into the bile. This was first demonstrated by Ostrow in his pioneering study of the effect of photoon rats with unconjugated hyperbilirubinxmia.4 Ostrow showed that these animals, which are considered to be a good model for the jaundiced neonate, excrete considerable amounts of unconjugated bilirubin into the bile on treatment with phototherapy. His identification of the pigment as bilirubin was based largely on its visible absorption spectrum and chromatographic properties, and the chromatographic behaviour of its azo-derivatives; fairly convincing evidence, but not unambiguous. I have confirmed Ostrow’s findings and have further identified the pigment as bilirubin ix- oc by thin-layer chromatography on two different adsorbents, by absorption spectroscopy, and by field-desorption mass spectrometry. Although the photo-adducts described by Garbagnati and Manitto are similar to bilirubin in some respects, they do have distinctly different spectroscopic and chromatographic properties and can readily be distinguished from bilirubin by these methods. Greatly enhanced excretion of unconjugated bilirubin during phototherapy has also been observed in the bile of a 3-year-old child with the Crigler-Najjar syndromeand the urine of jaundiced newborns. However, identification of the pigment in these studies was not unequivocal. Photo-adduct formation could account for some of the other pigments which are also excreted during phototherapy, but this possibility seems remote on the
therapy
1. 2. 3. 4. 5. 6.
Lund, H. T., Jacobsen, J. Acta pœdiat. scand. 1972, 61, 693. Lund, H. T., Jacobsen, J. J. Pediat. 1974, 85, 262. Garbagnati, E., Manitto, P. ibid. 1973, 83, 109. Ostrow, J. D. J. clin. Invest. 1971, 50, 707. Thaler, M. M., Dawber, N. H., Krasner, J., Yaffe, S. J., Mosovich, L. Pediat. Res. 1973, 7, 334 (abstr.). Weiss, P. A. M., Rosanelli, K. Wien. klin. Wschr. 1972, 84, 621.
basis of photochemical studies. 3. 7,8 Photo-addition to the bilirubin molecule is, in general, a rather slow reaction, even with the relatively intense lights used for in-vitro studies, and good yields of the adducts are only obtained when the reactions are done anaerobically because the pigment is so prone to photo-oxidation. Therefore it is unlikely that photo-addition is an important process in vivo, where aerobic conditions prevail and relatively low-power lights are used. That visible radiation can cause the liver to excrete unconjugated bilirubin may seem implausible and awkward to explain. But should it be surprising? After all, light can cause strange effects. Transfer a blinded or pinealectomised Japanese quail from a dark to a light environment-and its testicles will grow.’ A second inaccuracy in your editorial concerns the nature of the compounds which are formed on photodegradation of bilirubin in vitro. Contrary to what was stated, these substances have largely been identified.9-14 The major photo-oxidation products formed in the presence of hydroxylic solvents are water-soluble monopyrroles (haematinic acid imide and methyl vinyl maleimide) and dipyrroles (propentdyopent derivatives). None of these have been identified among the in-vivo photoproducts, but it is noteworthy that in rats and humans phototherapy causes a large increase in the urinary excretion of material showing the positive colour-test characteristic of pro-
pentdyopents.4,16,16 Finally, it is perhaps misleading to say that it remains to be determined which type of light is most useful for phototherapy. Admittedly an action spectrum for the response in man has not been determined; ethical reasons alone preclude this. However, animal studies have shown that light with wavelengths corresponding to the visible absorption band of bilirubin (i.e., blue light) is the most effective,17 as expected from theoretical considerations. Certainly the mechanism of phototherapy is obscure, though not so obscure as you suggest. And surely, as they say at the fireworks factory, it is better to curse the darkness than to light the wrong candle. Department of Medicine, University of California, San Francisco, California 94143, U.S.A.
ANTHONY F. MCDONAGH.
TREATMENT OF ACROMEGALY SIR,-We were interested to see your leader (Dec. 21, p. 1490) on this subject. We agree that the results of treatment with proton-beam therapy sound promising,"13 but we also feel that comparisons with other forms of treatment are necessary before its place in the management of acromegaly can be fully assessed. The synchrocyclotron at Harwell is of similar design to that used at Harvard for proton-beam therapy, and we are 7. 8.
Manitto, P., Monti, D. Experientia, 1972, 28, 379. Manitto, P., Monti, D., Garbagnati, E. Farmac. Ed. Sci. 1972, 27,
999. 9. Oishi, T., Lauber, J. K. Am. J. Physiol. 1973, 225, 155. 10. Bonnett, R. Ann. N. Y. Acad. Sci. 1973, 206, 722. 11. Bonnett, R., Stewart, J. C. M. J. chem. Soc. chem. Commun. 1972, 596. 12. Lightner, D. A., Quistad, G. B. Nature New Biol. 1972, 236, 203. 13. Lightner, D. A., Quistad, G. B. FEBS Lett. 1972, 25, 94. 14. Fujikaki, M. Nagoya Shiritsu Daigaku Igakkai Zasshi, 1972, 23, 446; Chemical Abstracts, 1973, 79, 122837. 15. Onishi, S., Yamakawa, T. Acta Pœdiat. jap. 1970, 74, 159. (English abstr., Acta Pœdiat. jap. 1970, 12, 36.) 16. Blaschke, T. F., Berk, P. D., Schaarschmidt, B. F., Guyther, R. J., Vergalla, J. M., Waggoner, J. G. Pediat. Res. 1974, 8, 573. 17. Hewitt, J. R., Klein, R. M., Lucey, J. F. Biol. Neonate, 1972, 21, 112. 18. Kjellberg, R. N., Kliman, B. in The Diagnosis and Treatment of Pituitary Tumours (edited by P. O. Kohler and G. T. Ross); p. 234. Excerpta Medica, International Congress Series no. 303. Amsterdam, 1973.
SiR,-May I be allowed an anecdotal reference, prompted by your leading article (Jan. 11, p. 79) ? You cite some references stressing the management of cholera by simple clinical assessment of dehydration, and its correction by simple intravenous fluid replacement. During the last campaign of the 14th Army in Burma in the 1939-45 war, two Indian sepoys were admitted to the casualty-clearing station in which I was serving under primitive field conditions. They arrived simultaneously, suffering from severe cholera with " washerwoman’s fingers " and extreme prostration, and each was treated with intravenous 5% glucose in normal saline at a rate of one pint an hour for about 48 hours. They both recovered completely without a single biochemical investigation. Conditions prevailing in tropical homes and villages are unlikely to be much worse nowadays than those in my C-C-S-3 and what has been done before can easily be done again. East Glamorgan General Hospital, Church Village, near Pontypridd, Glamorgan. J. DE SWIET.
PHOTOTHERAPY AND HYPERBILIRUBINÆMIA
SiR,-Your editorial on phototherapy (Nov. 2, p. 1056), by overlooking several important studies, was perhaps rather misleading and less illuminating than it could have been.
It was suggested that the diazo-positive pigment which is excreted in the bile of newborn infants during phototherapy 1,2 is a photo-adduct of bilirubin of the type recently synthesised by Garbagnati and Manitto.3 The simplest and most straightforward explanation, which is that the pigment is bilirubin itself, was considered to be less plausible. Plausible or not, there is in fact little doubt that the pigment is bilirubin and that a major effect of phototherapy is to stimulate the excretion of intact unconjugated bilirubin into the bile. This was first demonstrated by Ostrow in his pioneering study of the effect of photoon rats with unconjugated hyperbilirubinxmia.4 Ostrow showed that these animals, which are considered to be a good model for the jaundiced neonate, excrete considerable amounts of unconjugated bilirubin into the bile on treatment with phototherapy. His identification of the pigment as bilirubin was based largely on its visible absorption spectrum and chromatographic properties, and the chromatographic behaviour of its azo-derivatives; fairly convincing evidence, but not unambiguous. I have confirmed Ostrow’s findings and have further identified the pigment as bilirubin ix- oc by thin-layer chromatography on two different adsorbents, by absorption spectroscopy, and by field-desorption mass spectrometry. Although the photo-adducts described by Garbagnati and Manitto are similar to bilirubin in some respects, they do have distinctly different spectroscopic and chromatographic properties and can readily be distinguished from bilirubin by these methods. Greatly enhanced excretion of unconjugated bilirubin during phototherapy has also been observed in the bile of a 3-year-old child with the Crigler-Najjar syndromeand the urine of jaundiced newborns. However, identification of the pigment in these studies was not unequivocal. Photo-adduct formation could account for some of the other pigments which are also excreted during phototherapy, but this possibility seems remote on the
therapy
1. 2. 3. 4. 5. 6.
Lund, H. T., Jacobsen, J. Acta pœdiat. scand. 1972, 61, 693. Lund, H. T., Jacobsen, J. J. Pediat. 1974, 85, 262. Garbagnati, E., Manitto, P. ibid. 1973, 83, 109. Ostrow, J. D. J. clin. Invest. 1971, 50, 707. Thaler, M. M., Dawber, N. H., Krasner, J., Yaffe, S. J., Mosovich, L. Pediat. Res. 1973, 7, 334 (abstr.). Weiss, P. A. M., Rosanelli, K. Wien. klin. Wschr. 1972, 84, 621.
basis of photochemical studies. 3. 7,8 Photo-addition to the bilirubin molecule is, in general, a rather slow reaction, even with the relatively intense lights used for in-vitro studies, and good yields of the adducts are only obtained when the reactions are done anaerobically because the pigment is so prone to photo-oxidation. Therefore it is unlikely that photo-addition is an important process in vivo, where aerobic conditions prevail and relatively low-power lights are used. That visible radiation can cause the liver to excrete unconjugated bilirubin may seem implausible and awkward to explain. But should it be surprising? After all, light can cause strange effects. Transfer a blinded or pinealectomised Japanese quail from a dark to a light environment-and its testicles will grow.’ A second inaccuracy in your editorial concerns the nature of the compounds which are formed on photodegradation of bilirubin in vitro. Contrary to what was stated, these substances have largely been identified.9-14 The major photo-oxidation products formed in the presence of hydroxylic solvents are water-soluble monopyrroles (haematinic acid imide and methyl vinyl maleimide) and dipyrroles (propentdyopent derivatives). None of these have been identified among the in-vivo photoproducts, but it is noteworthy that in rats and humans phototherapy causes a large increase in the urinary excretion of material showing the positive colour-test characteristic of pro-
pentdyopents.4,16,16 Finally, it is perhaps misleading to say that it remains to be determined which type of light is most useful for phototherapy. Admittedly an action spectrum for the response in man has not been determined; ethical reasons alone preclude this. However, animal studies have shown that light with wavelengths corresponding to the visible absorption band of bilirubin (i.e., blue light) is the most effective,17 as expected from theoretical considerations. Certainly the mechanism of phototherapy is obscure, though not so obscure as you suggest. And surely, as they say at the fireworks factory, it is better to curse the darkness than to light the wrong candle. Department of Medicine, University of California, San Francisco, California 94143, U.S.A.
ANTHONY F. MCDONAGH.
TREATMENT OF ACROMEGALY SIR,-We were interested to see your leader (Dec. 21, p. 1490) on this subject. We agree that the results of treatment with proton-beam therapy sound promising,"13 but we also feel that comparisons with other forms of treatment are necessary before its place in the management of acromegaly can be fully assessed. The synchrocyclotron at Harwell is of similar design to that used at Harvard for proton-beam therapy, and we are 7. 8.
Manitto, P., Monti, D. Experientia, 1972, 28, 379. Manitto, P., Monti, D., Garbagnati, E. Farmac. Ed. Sci. 1972, 27,
999. 9. Oishi, T., Lauber, J. K. Am. J. Physiol. 1973, 225, 155. 10. Bonnett, R. Ann. N. Y. Acad. Sci. 1973, 206, 722. 11. Bonnett, R., Stewart, J. C. M. J. chem. Soc. chem. Commun. 1972, 596. 12. Lightner, D. A., Quistad, G. B. Nature New Biol. 1972, 236, 203. 13. Lightner, D. A., Quistad, G. B. FEBS Lett. 1972, 25, 94. 14. Fujikaki, M. Nagoya Shiritsu Daigaku Igakkai Zasshi, 1972, 23, 446; Chemical Abstracts, 1973, 79, 122837. 15. Onishi, S., Yamakawa, T. Acta Pœdiat. jap. 1970, 74, 159. (English abstr., Acta Pœdiat. jap. 1970, 12, 36.) 16. Blaschke, T. F., Berk, P. D., Schaarschmidt, B. F., Guyther, R. J., Vergalla, J. M., Waggoner, J. G. Pediat. Res. 1974, 8, 573. 17. Hewitt, J. R., Klein, R. M., Lucey, J. F. Biol. Neonate, 1972, 21, 112. 18. Kjellberg, R. N., Kliman, B. in The Diagnosis and Treatment of Pituitary Tumours (edited by P. O. Kohler and G. T. Ross); p. 234. Excerpta Medica, International Congress Series no. 303. Amsterdam, 1973.
