- Email: [email protected]
ROLE OF COPPER IN PRIMARY BILIARY CIRRHOSIS
375 metastatic melanoma. None showed an objective remission during treatment and 70% showed disease progression within 30 days of the start of treatment. Tamoxifen is a well-tolerated agent which we have used effectively in the treatment of advanced breast cancer for more than five years. There seems to be no reason why it should not be given a therapeutic trial in selected cases of malignant melanoma which havenot responded to conventional therapy. However, the evidence for its efficacy is weak, both in terms of hormone receptor content in melanoma and clinical response. We doubt if tamoxifen has a significant place in the therapy of malignant melanoma. Department of Surgery, University of Queensland, Brisbane 4067, Queensland, Australia
C. M. FURNIVAL I. R. GOUGH G. S. J. THYNNE
bound to
a
10 000 molecular
weight fraction in PBC that is almost
certainly metallothionein. At an early stage in the disease this form of copper can be easily mobilised which may explain the decrease in liver copper due to penicillamine therapy. At the same symposium, Dr I. Bremner of the Rowett Research Institute, Aberdeen, stated that lysosomal copper may well be polymerised metallothionein. Knowledge of the chemical binding of a trace element is essential in appreciating its role within the cell as trace elements are present both as components of metalloenzymes and also bound to various proteins and other ligands which if abnormal can lead to disease.6 Studies on copper-induced metallothionein in PBC and other accumulating liver diseases would certainly clarify picture and probably explain some anomalies. copper
Department of Pathology, Welsh National School of Medicine, Cardiff CF4 4XN
FORMALDEHYDE IN INSULATED HOUSING
SIR,-Formaldehyde can pollute the air in homes insulated with urea-formaldehyde foam. 1-3 In January of this year 254 apartments built in 1960 in a residential area near Milan were insulated by pumping urea-formaldehyde polymer and water through small holes into the air cavities of the outside main walls. After a few days, seven occupants of two apartments complained of eye irritation, upper-respiratory-tract irritation, cough, malaise, insomnia, and headache. Formaldehyde was suspected. We detected levels of formaldehyde in air of 0 94:t0. 30 and 1.45--tO 42 rng/m3 (mean±SD; n=6) in the two departments. Air was drawn for 4 h through a bubbler containing de-ionised water and formaldehyde was determined by the chromotropic acid colour method. The exposure levels are excessive. The 1980 threshold limit value of the American Conference of Governmental Industrial Hygienists is 3 mg/m3 for 8 h for occupational exposure, and the upper limit recommended by the National Institute of Occupational Safety and Health is 1 -22 mg/m3for any 30 min period. The timing of the symptoms makes it very likely that they were caused by formaldehyde exposure, although we agree with Berger and Lamm4 about the possible role of other unknown substances. Since symptoms are non-specific and since the smell of 2 formaldehyde may be missed because of olfactory accommodation,2 well have more apartments may been polluted. Institute of Occupational Medicine, Catholic University, 00168 Rome, Italy
PIERLUIGI BERNARDINI GIOVANNI CARELLI RIMATORI VALENTINO
ROLE OF COPPER IN PRIMARY BILIARY CIRRHOSIS
SIR,-As someone interested in trace element metabolism, where work has been done in animals, I have read the paper by Dr Epstein and colleagues (June 13, p. 1275) on D-penicillamine in primary biliary cirrhosis (PBC) and Dr Lesna’s letter (July 11, p. 87) most
with interest. There seems to be considerable confusion about the role of copper in the liver in PBC but I have yet to find a mention of the possible detoxifying role of the metal-binding protein metallothionein. The copper data cited by Epstein et al. appear to be based on neutron activation analysis which measures all copper, irrespective of whether it is chemically reactive or bound in the hepatocyte or sequestrated in lysosomes. The histochemical observations made by Lesna give a better picture of chemically reactive copper but in our experience with zinc histochemical techniques only demonstrate a small proportion of the metal present in a cells 5 At the 4th Symposium on Trace Element Metabolism in Man and Animals (TEMA 4) in Perth, Western Australia, a paper on liver copper-binding proteins in disease was presented by Dr E. J. A. van den Hamer (Delft) in which he described an increase in copper 1 Breysse PA The health cost of "tight" homes.JAMA 1981; 245: 267-68. 2. Harris JC, Rmack BH, Aldrich FD. Toxicology of urea formaldehyde and polyurethane foam insulation.JAMA 1981; 245: 243-46. 3 Editorial The health hazard of formaldehyde. Lancet 1981; i: 926-27. 4 Berger JM, Lamm SH. Health hazards of formaldehyde. Lancet 1981; i: 1264. 5 Elmes ME, Jones G. Paneth Cell Zinc: A comparison of Histochemical and microanalytical techniques. Histochem J1981; 13: 335-37.
the
6.
van
MARGARET E. ELMES
den Hamer
analytical
EJA, Houtman JPW. In: Brätter P, Schramel P, eds. Trace element chemistry in medicine and biology. Berlin: Walter Gruyter, 1980:
233-42.
Obituary GUY FREDERIC MARRIAN C.B.E., D.Sc.Lond., Hon.M.D.Edin., F.R.I.C., F.R.S.
Professor Marrian’s great contribution to medicine was in the field of steroid hormones. He died on July 24 at the age of 77. As a young man at University College London, Marrian began work on oestrin, the active substance producing oestrus in animals. Within days of his 25th birthday, he announced the isolation of crystalline oestriol from human pregnancy urine. The work was entirely his own, leading a fiercely competitive field in which American, German, and Dutch laboratories were involved. Thus began innumerable contributions to steroid biochemistry. Hitherto unknown steroids were isolated, metabolic pathways were traced, and methods for assaying steroids were developed by Marrian and his colleagues. In 1933, Marrian became professor of biochemistry at Toronto, where he continued work on oestrogens. He returned to this country in 1939 to the chair of chemistry in relation to medicine, later biochemistry, in Edinburgh. In the early ’50s, with Gaddum and Dunlop, he established the Medical Research Council’s clinical endocrinology research unit in Edinburgh, and for a while Edinburgh was the Mecca of steroid biochemists and
endrocrinologists. In
1959, Marrian
was appointed director of research at the Cancer Research Fund in London, where he remained until he retired in 1968. He had great hopes of a splendid multidisciplinary research laboratory. These hopes were, however, to some extent frustrated by the many problems of building a large new institute and organising adequate clinical contacts. The splendid laboratories were, however, completed, and the scientific foundations were laid, for others to build upon. Marrian no doubt felt keenly the loss of time for bench work, which was always so important to him. He was a wonderful teacher, and insisted, even as professor, in giving courses of many lectures to science and junior medical students. Many outsiders attended these lectures. Research was, however, his great obsession. In his laboratory, a newcomer soon learned that he went there to work at the bench. The writing of books, papers, or lectures was something to do at home. Most of us will remember Marrian with sleeves rolled high up on his arms, shaking huge funnels of urine and ether or with some tiny flask in his fingers crystallising steroids, when others failed to do so. Trivial research or shoddy work were utterly and outspokenly condemned, in a manner which may have provoked some antagonism. Nevertheless, Marrian was a man who inspired loyalty and hard work. He had great charm, good humour, and excellent manners. The same courtesy was extended to cleaners as to Nobel prize winners.
Imperial
C. M. FURNIVAL I. R. GOUGH G. S. J. THYNNE
bound to
a
10 000 molecular
weight fraction in PBC that is almost
certainly metallothionein. At an early stage in the disease this form of copper can be easily mobilised which may explain the decrease in liver copper due to penicillamine therapy. At the same symposium, Dr I. Bremner of the Rowett Research Institute, Aberdeen, stated that lysosomal copper may well be polymerised metallothionein. Knowledge of the chemical binding of a trace element is essential in appreciating its role within the cell as trace elements are present both as components of metalloenzymes and also bound to various proteins and other ligands which if abnormal can lead to disease.6 Studies on copper-induced metallothionein in PBC and other accumulating liver diseases would certainly clarify picture and probably explain some anomalies. copper
Department of Pathology, Welsh National School of Medicine, Cardiff CF4 4XN
FORMALDEHYDE IN INSULATED HOUSING
SIR,-Formaldehyde can pollute the air in homes insulated with urea-formaldehyde foam. 1-3 In January of this year 254 apartments built in 1960 in a residential area near Milan were insulated by pumping urea-formaldehyde polymer and water through small holes into the air cavities of the outside main walls. After a few days, seven occupants of two apartments complained of eye irritation, upper-respiratory-tract irritation, cough, malaise, insomnia, and headache. Formaldehyde was suspected. We detected levels of formaldehyde in air of 0 94:t0. 30 and 1.45--tO 42 rng/m3 (mean±SD; n=6) in the two departments. Air was drawn for 4 h through a bubbler containing de-ionised water and formaldehyde was determined by the chromotropic acid colour method. The exposure levels are excessive. The 1980 threshold limit value of the American Conference of Governmental Industrial Hygienists is 3 mg/m3 for 8 h for occupational exposure, and the upper limit recommended by the National Institute of Occupational Safety and Health is 1 -22 mg/m3for any 30 min period. The timing of the symptoms makes it very likely that they were caused by formaldehyde exposure, although we agree with Berger and Lamm4 about the possible role of other unknown substances. Since symptoms are non-specific and since the smell of 2 formaldehyde may be missed because of olfactory accommodation,2 well have more apartments may been polluted. Institute of Occupational Medicine, Catholic University, 00168 Rome, Italy
PIERLUIGI BERNARDINI GIOVANNI CARELLI RIMATORI VALENTINO
ROLE OF COPPER IN PRIMARY BILIARY CIRRHOSIS
SIR,-As someone interested in trace element metabolism, where work has been done in animals, I have read the paper by Dr Epstein and colleagues (June 13, p. 1275) on D-penicillamine in primary biliary cirrhosis (PBC) and Dr Lesna’s letter (July 11, p. 87) most
with interest. There seems to be considerable confusion about the role of copper in the liver in PBC but I have yet to find a mention of the possible detoxifying role of the metal-binding protein metallothionein. The copper data cited by Epstein et al. appear to be based on neutron activation analysis which measures all copper, irrespective of whether it is chemically reactive or bound in the hepatocyte or sequestrated in lysosomes. The histochemical observations made by Lesna give a better picture of chemically reactive copper but in our experience with zinc histochemical techniques only demonstrate a small proportion of the metal present in a cells 5 At the 4th Symposium on Trace Element Metabolism in Man and Animals (TEMA 4) in Perth, Western Australia, a paper on liver copper-binding proteins in disease was presented by Dr E. J. A. van den Hamer (Delft) in which he described an increase in copper 1 Breysse PA The health cost of "tight" homes.JAMA 1981; 245: 267-68. 2. Harris JC, Rmack BH, Aldrich FD. Toxicology of urea formaldehyde and polyurethane foam insulation.JAMA 1981; 245: 243-46. 3 Editorial The health hazard of formaldehyde. Lancet 1981; i: 926-27. 4 Berger JM, Lamm SH. Health hazards of formaldehyde. Lancet 1981; i: 1264. 5 Elmes ME, Jones G. Paneth Cell Zinc: A comparison of Histochemical and microanalytical techniques. Histochem J1981; 13: 335-37.
the
6.
van
MARGARET E. ELMES
den Hamer
analytical
EJA, Houtman JPW. In: Brätter P, Schramel P, eds. Trace element chemistry in medicine and biology. Berlin: Walter Gruyter, 1980:
233-42.
Obituary GUY FREDERIC MARRIAN C.B.E., D.Sc.Lond., Hon.M.D.Edin., F.R.I.C., F.R.S.
Professor Marrian’s great contribution to medicine was in the field of steroid hormones. He died on July 24 at the age of 77. As a young man at University College London, Marrian began work on oestrin, the active substance producing oestrus in animals. Within days of his 25th birthday, he announced the isolation of crystalline oestriol from human pregnancy urine. The work was entirely his own, leading a fiercely competitive field in which American, German, and Dutch laboratories were involved. Thus began innumerable contributions to steroid biochemistry. Hitherto unknown steroids were isolated, metabolic pathways were traced, and methods for assaying steroids were developed by Marrian and his colleagues. In 1933, Marrian became professor of biochemistry at Toronto, where he continued work on oestrogens. He returned to this country in 1939 to the chair of chemistry in relation to medicine, later biochemistry, in Edinburgh. In the early ’50s, with Gaddum and Dunlop, he established the Medical Research Council’s clinical endocrinology research unit in Edinburgh, and for a while Edinburgh was the Mecca of steroid biochemists and
endrocrinologists. In
1959, Marrian
was appointed director of research at the Cancer Research Fund in London, where he remained until he retired in 1968. He had great hopes of a splendid multidisciplinary research laboratory. These hopes were, however, to some extent frustrated by the many problems of building a large new institute and organising adequate clinical contacts. The splendid laboratories were, however, completed, and the scientific foundations were laid, for others to build upon. Marrian no doubt felt keenly the loss of time for bench work, which was always so important to him. He was a wonderful teacher, and insisted, even as professor, in giving courses of many lectures to science and junior medical students. Many outsiders attended these lectures. Research was, however, his great obsession. In his laboratory, a newcomer soon learned that he went there to work at the bench. The writing of books, papers, or lectures was something to do at home. Most of us will remember Marrian with sleeves rolled high up on his arms, shaking huge funnels of urine and ether or with some tiny flask in his fingers crystallising steroids, when others failed to do so. Trivial research or shoddy work were utterly and outspokenly condemned, in a manner which may have provoked some antagonism. Nevertheless, Marrian was a man who inspired loyalty and hard work. He had great charm, good humour, and excellent manners. The same courtesy was extended to cleaners as to Nobel prize winners.
Imperial