177 copper excretion was 540 g. per 24 hours before In the early postoperative period this patient had markedly increased urinary excretion of copper, but after five months a decrease toward normal was noted. At the present time, the urinary copper excretion is 87 g. per day, which is
Urinary
operation.
still slightly elevated.
Initially, caeruloplasmin was virtually absent in the serum of this patient, but within three months after transplantation it increased dramatically and now remains normal (see table). The serum-copper concentration, which was low preoperatively, rapidly increased early postoperatively, then fell to normal. Postoperatively, the patient’s neurological dysfunction has gradually improved and now he has no neurological impairment. The Kayser-Fleischer rings have completely disappeared over a period of two and a half years as determined by several slit-lamp examinations. The complete correction, in our second patient, of all the classical clinical manifestations and biochemical abnormalities of Wilson’s disease has not been reported with other forms of therapy.33 These observations lend support to the contention that this genetic disorder is liver-based. With the provision of a normal liver, excess body-copper is eliminated over a period of years. This work was supported by research grants from the Veterans Administration; by grants AI-AM-08898 and AM-07772 of the National Institutes of Health; and by grants RR-00051 and RR-0069 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of
Health. Departments of Surgery and Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220, U.S.A.
ROBERT W. BEART, JR. CHARLES W. PUTNAM K. A. PORTER THOMAS E. STARZL.
SULPHONE RESISTANCE IN LEPROSY SIR,—The salutary paper by Dr Pearson and his colleagues (July 12, p. 69) confirms a growing suspicion that sulphone-resistant leprosy bacilli may be shown to be appearing with disturbing frequency wherever the investigation of clinical relapse can be supplemented by mouse footpad inoculation. Several instances are known to have arisen in England, in addition to the one reported by Adams and Waters.4 The financial and other constraints which, in most countries, have hitherto made monotherapy in leprosy almost obligatory, must now be reviewed in the light of the findings reported. For patients with lepromatous leprosy, treatment with more than one leprostatic drug should henceforth be the ideal to strive for, if not actually
mandatory.
FUTURE OF CHEMICAL PATHOLOGY SiR,-We read with interest but some alarm your editorial of June 14 (p. 1327) on the future of chemical pathology in this country. Chemical pathology is indeed at the crossroads and a change of direction is vital, but changes are taking place. We have now reached the point where chemical pathology can break loose from the other pathological sciences and can become an exciting and
important subject in its own right. Perhaps fortunately, economic disaster and manpower problems have led many of us to re-examine the whole philosophy of clinical biochemistry. Two types of individual are needed. The professional biochemist is necessary to cope with the complex machinery, automation, and the highly sophisticated apparatus now available, as well as to develop new methodologies, but equally the medically qualified biochemist is necessary both in the laboratory and at the bedside. His presence in the laboratory is vital so that only clinically useful and relevant tests are performed and he has a full role to play in development. His presence at the bedside is necessary to advise on biochemical problems such as fluid balance, intravenous nutrition, hyperlipidasmia, and metabolic disease, to help interpret biochemical results for the clinician, and to advise on appropriate tests. To maintain credibility he will require both a clinical and a biochemical training. This might be best fulfilled by the M.R.C.P. and an M.sc. in clinical biochemistry, together with a certain number of years spent in a chemical pathology department. Rotation of junior staff through general pathology has outlived its usefulness as a means of training, although it may have a role in recruitment. It is - surely more relevant to establish rotations through clinical medicine. The chemical pathology department of the future will probably be controlled in parallel by a top-grade biochemist and a chemical pathologist, the latter also having responsibility for metabolic clinics, being involved in intensive care, acting as a secondary referral service, and controlling a small number of investigative beds. In the district general hospital the chemical pathologist has a vital clinical role to play. You imply that a change to this type of approach is rare. We suggest that the change is already taking place, albeit slowly; that most of us are aware of the need for change; and that the subject of chemical pathology will. shortly become one of the most exciting, rewarding, and intellectually stimulating specialties in clinical medicine. University Department of Chemical Pathology and Human Metabolism, General Hospital, Southampton.
Basingstoke District General Hospital, Basingstoke.
K. G. M. M. ALBERTI G. F. BATSTONE M. NATTRASS. H. PLATT.
While Dr Pearson and his colleagues state that " the long duration of treatment before relapse is very striking ", and cite one patient who relapsed after only 5 years of
intermittent treatment, it should be known that, in
a
Nigerian patient, relapse due to dapsone-resistant organisms occurred after 52 months of regular treatment at a dose of 50 mg. twice weekly.5 Fortunately, no case of relapse due to sulphone-resistant organisms has so far failed to respond to clofazimine.6s Leprosy Study Centre, 57A Wimpole Street, London W1M 7DF. 3.
S. G. BROWNE.
Beam, A. G. in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. J. Fredrickson); p. 1033. New York, 1972. 4. Adams, A. H. D., Waters, M. F. R. Br. med. J. 1966, ii, 892. 5. Browne, S. G. Int. J. Leprosy, 1969, 37, 296. 6. Browne, S. G. Trans. St. John’s Hosp. derm. Soc. 1973, 59, 225.
SiR,—Your editorial raises complex issues and implies that there must be a reversal of "the retreat from the wards " and renewal of what many practised in the 1950s-clinical collaboration based upon the laboratory. My view, shared I think by almost all academic heads in the U.K. at a meeting this year, is that we do require medically qualified clinical biochemists and that, yes, recruitment is possible; indeed many in my own department have science qualifications. The bottlenecks ahead are money, permission for establishment, and space. For the past decade or so in Scotland we have approached staffing on a combined basis. In this way either medical or non-medical graduates can be in administrative charge of the whole of or sections of a large department. Teaching
178 and research benefit from such a multidisciplinary approach, and non-medical graduates become deeply involved and interested in clinical matters. In this way fundamental investigation into the nature of disease (pathology),- as well as clinical investigation, optimally can and should be carried out from major academic departments of clinical bio-
chemistry. In providing an ideal interface between clinical and molecular colleagues we find increasingly that interdisciplinary teams, spanning the scientific and clinical spectrum, not only work well together but also produce inquiries of the highest quality. Such liaisons, nourished by our strong supportive commitment to patient care, also foster excellence in training programmes. On training, many of my colleagues would agree that more clinical experience be required and recognised, and that thought be given to a clinically slanted biochemical examination on the lines of that taken by the hasmatologists. University Department of Pathological
Biochemistry, Royal Infirmary, Glasgow G4 0SF.
H. G. MORGAN.
SIR,-Some time ago we advocated in your pages1 a solution which makes the best of a bad situation and simply involves hospitals cooperating in providing clinical biochemistry services. This was also encouraged by D.H.S.S. in HM 70/50, but perhaps some redefinition of area pathology services might be useful now that reorganisation has taken place. Cooperation is clearly a part of the supraregional service and often enables the relatively betterfunded university departments to play a useful part. The rational use of declining resources by cooperation is now probably the only hope of retaining acceptable standards in the N.H.S. In this, chemical pathology is able, if it desires, to set an example to other disciplinesan opportunity rather different from your implied threat of execution. Department of Chemical Pathology, South Sefton District, Clinical
Laboratories, Fazakerley Hospital, Liverpool L9 7AL.
I.
J. L. GOLDBERG.
a circular results are widespread in published work; many of them taken, with little or no acknowledgment, from the output of routine laboratories. While you regret that this work often comes from physicians and full-time research-workers, you later suggest that the chemical pathologist of the future would hold M.R.C.P., and work in a specialised laboratory. Your future aim is thus revealed as your present problem. The biennial chemical-pathology course, organised by the Postgraduate Medical Federation for those intending to take the final M.R.C.PATH., has recently ended. A notable feature was the almost total inability of the lecturers to see their highly specialised interests within the concept of a balanced clinical-chemistry service. Such a service must combine suitable methodology with suitable equipment, and aim to be medically relevant and provide a rapid turnround. While many scientific staff in clinical chemistry are perfectly able to run laboratories on a static basis, scientists with the acquired ability to discern the medical relevance and priority of test procedures, as opposed to the methodological convenience, derive unique value by a certain rarity.
SIR,-At least part of
argument.
Clinical
your thesis2 involves
chemistry
1. Goldberg, I. J. L., Mitchell, F. L. Lancet, 2. Lancet, 1975, i, 1327.
1970, ii, 1240.
The role of the chemical pathologist the hospital is to keep up a flow of medically relevant general information on the service provided, and on the interpretation of results: also, to react constructively to new and unmet varieties of demand, bringing new techniques to the attention of clinical colleagues. In the near future, he may also have to be the arbiter of severe service reductions. Unfortunately, this role is regarded by many as being too remote from the patient, because inpatient beds are still regarded as the only " Danegeld capable of buying clinical commitment. It cannot have escaped anyone’s notice that hospitals have recently been amalgamated with other branches of the health services. We must cease to regard pathology laboratories (and other similar services) as hospital property, and look at them only in a wider context-usually of a district responsibility. General practitioners, and other extramural doctors, are much less able to make full use of laboratory facilities. This is partly because they rarely require special tests; partly because they form a diffuse group, to which it is difficult to disseminate up-to-date information; and partly because they may refer patients or samples to laboratories in districts other than their own, with which they are unfamiliar. This is a majorarea of importance for the chemical pathologist. He will supervise tests on patients, whether referred from general practitioners or from hospital clinics: he can see patients on direct referral without needing to consume that scarce resource-a hospital bed. The demands for these clinical services are sufficiently low as to make formal clinics and
within
"
waiting-lists
-
unnecessary. Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, M. D. BUCKLEY-SHARP. London W1P 5PR.
DIFFERENTIAL SISTER-CHROMATID STAINING
SIR,-Korenberg and Freedlender demonstrated differential sister-chromatid staining without using the fluorochrome, Hoechst 33258.1 Using the same method, we found that the optimum temperature of the sodium dihydrogen phosphate solution was 79-81 °C as compared to 89 °C where, in our hands, little sister-chromatid differentiation was observed. C and T banded chromosomes were also noted at 89°C. The above determination
made in human shortstimulated leucocyte cultures derived from whole blood of three individuals and incubated for 96 hours at 36-36-5 °C. A total often slides of cells from the three individuals were examined. At least 25 metaphase spreads per slide were studied. Five slides were exposed to 88-89 °C while the remaining slides were incubated at 79-81 °C. Metaphase cells exposed to the higher temperature exhibited differential staining only 0-8% of the time, while those exposed to the lower temperature showed the effect 40-50 % of the time. The remaining cells stained homogeneously with no indication of C or T banding.
term
was
phytohaemagglutinin (P.H.A.)
In addition, all cultures were exposed to 5-bromodeoxyuridine for only the last 24 hours of incubation, according to the method of Perry and Wolff 2 who tested Chinese hamster ovary-cell cultures, in contrast to other reports where the treatment was continous.3,4 This suggests a cell cycle time of 12 hours for human P.H.A.-transformed blastlike cells in our culture system. Finally, the shorter exposure 1. 2. 3. 4.
Korenberg, J. R., Freedlender, E. Chromosoma, 1974, 48, 355. Perry, P., Wolff, S. Nature, 1974, 251, 156. Latt, S. Proc. natn. Acad. Sci. U.S.A. 1974, 71, 3162. Chaganti, R. S. K., Schonberg, S., German, J. ibid. p. 4508.
Urinary
operation.
still slightly elevated.
Initially, caeruloplasmin was virtually absent in the serum of this patient, but within three months after transplantation it increased dramatically and now remains normal (see table). The serum-copper concentration, which was low preoperatively, rapidly increased early postoperatively, then fell to normal. Postoperatively, the patient’s neurological dysfunction has gradually improved and now he has no neurological impairment. The Kayser-Fleischer rings have completely disappeared over a period of two and a half years as determined by several slit-lamp examinations. The complete correction, in our second patient, of all the classical clinical manifestations and biochemical abnormalities of Wilson’s disease has not been reported with other forms of therapy.33 These observations lend support to the contention that this genetic disorder is liver-based. With the provision of a normal liver, excess body-copper is eliminated over a period of years. This work was supported by research grants from the Veterans Administration; by grants AI-AM-08898 and AM-07772 of the National Institutes of Health; and by grants RR-00051 and RR-0069 from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of
Health. Departments of Surgery and Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220, U.S.A.
ROBERT W. BEART, JR. CHARLES W. PUTNAM K. A. PORTER THOMAS E. STARZL.
SULPHONE RESISTANCE IN LEPROSY SIR,—The salutary paper by Dr Pearson and his colleagues (July 12, p. 69) confirms a growing suspicion that sulphone-resistant leprosy bacilli may be shown to be appearing with disturbing frequency wherever the investigation of clinical relapse can be supplemented by mouse footpad inoculation. Several instances are known to have arisen in England, in addition to the one reported by Adams and Waters.4 The financial and other constraints which, in most countries, have hitherto made monotherapy in leprosy almost obligatory, must now be reviewed in the light of the findings reported. For patients with lepromatous leprosy, treatment with more than one leprostatic drug should henceforth be the ideal to strive for, if not actually
mandatory.
FUTURE OF CHEMICAL PATHOLOGY SiR,-We read with interest but some alarm your editorial of June 14 (p. 1327) on the future of chemical pathology in this country. Chemical pathology is indeed at the crossroads and a change of direction is vital, but changes are taking place. We have now reached the point where chemical pathology can break loose from the other pathological sciences and can become an exciting and
important subject in its own right. Perhaps fortunately, economic disaster and manpower problems have led many of us to re-examine the whole philosophy of clinical biochemistry. Two types of individual are needed. The professional biochemist is necessary to cope with the complex machinery, automation, and the highly sophisticated apparatus now available, as well as to develop new methodologies, but equally the medically qualified biochemist is necessary both in the laboratory and at the bedside. His presence in the laboratory is vital so that only clinically useful and relevant tests are performed and he has a full role to play in development. His presence at the bedside is necessary to advise on biochemical problems such as fluid balance, intravenous nutrition, hyperlipidasmia, and metabolic disease, to help interpret biochemical results for the clinician, and to advise on appropriate tests. To maintain credibility he will require both a clinical and a biochemical training. This might be best fulfilled by the M.R.C.P. and an M.sc. in clinical biochemistry, together with a certain number of years spent in a chemical pathology department. Rotation of junior staff through general pathology has outlived its usefulness as a means of training, although it may have a role in recruitment. It is - surely more relevant to establish rotations through clinical medicine. The chemical pathology department of the future will probably be controlled in parallel by a top-grade biochemist and a chemical pathologist, the latter also having responsibility for metabolic clinics, being involved in intensive care, acting as a secondary referral service, and controlling a small number of investigative beds. In the district general hospital the chemical pathologist has a vital clinical role to play. You imply that a change to this type of approach is rare. We suggest that the change is already taking place, albeit slowly; that most of us are aware of the need for change; and that the subject of chemical pathology will. shortly become one of the most exciting, rewarding, and intellectually stimulating specialties in clinical medicine. University Department of Chemical Pathology and Human Metabolism, General Hospital, Southampton.
Basingstoke District General Hospital, Basingstoke.
K. G. M. M. ALBERTI G. F. BATSTONE M. NATTRASS. H. PLATT.
While Dr Pearson and his colleagues state that " the long duration of treatment before relapse is very striking ", and cite one patient who relapsed after only 5 years of
intermittent treatment, it should be known that, in
a
Nigerian patient, relapse due to dapsone-resistant organisms occurred after 52 months of regular treatment at a dose of 50 mg. twice weekly.5 Fortunately, no case of relapse due to sulphone-resistant organisms has so far failed to respond to clofazimine.6s Leprosy Study Centre, 57A Wimpole Street, London W1M 7DF. 3.
S. G. BROWNE.
Beam, A. G. in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. J. Fredrickson); p. 1033. New York, 1972. 4. Adams, A. H. D., Waters, M. F. R. Br. med. J. 1966, ii, 892. 5. Browne, S. G. Int. J. Leprosy, 1969, 37, 296. 6. Browne, S. G. Trans. St. John’s Hosp. derm. Soc. 1973, 59, 225.
SiR,—Your editorial raises complex issues and implies that there must be a reversal of "the retreat from the wards " and renewal of what many practised in the 1950s-clinical collaboration based upon the laboratory. My view, shared I think by almost all academic heads in the U.K. at a meeting this year, is that we do require medically qualified clinical biochemists and that, yes, recruitment is possible; indeed many in my own department have science qualifications. The bottlenecks ahead are money, permission for establishment, and space. For the past decade or so in Scotland we have approached staffing on a combined basis. In this way either medical or non-medical graduates can be in administrative charge of the whole of or sections of a large department. Teaching
178 and research benefit from such a multidisciplinary approach, and non-medical graduates become deeply involved and interested in clinical matters. In this way fundamental investigation into the nature of disease (pathology),- as well as clinical investigation, optimally can and should be carried out from major academic departments of clinical bio-
chemistry. In providing an ideal interface between clinical and molecular colleagues we find increasingly that interdisciplinary teams, spanning the scientific and clinical spectrum, not only work well together but also produce inquiries of the highest quality. Such liaisons, nourished by our strong supportive commitment to patient care, also foster excellence in training programmes. On training, many of my colleagues would agree that more clinical experience be required and recognised, and that thought be given to a clinically slanted biochemical examination on the lines of that taken by the hasmatologists. University Department of Pathological
Biochemistry, Royal Infirmary, Glasgow G4 0SF.
H. G. MORGAN.
SIR,-Some time ago we advocated in your pages1 a solution which makes the best of a bad situation and simply involves hospitals cooperating in providing clinical biochemistry services. This was also encouraged by D.H.S.S. in HM 70/50, but perhaps some redefinition of area pathology services might be useful now that reorganisation has taken place. Cooperation is clearly a part of the supraregional service and often enables the relatively betterfunded university departments to play a useful part. The rational use of declining resources by cooperation is now probably the only hope of retaining acceptable standards in the N.H.S. In this, chemical pathology is able, if it desires, to set an example to other disciplinesan opportunity rather different from your implied threat of execution. Department of Chemical Pathology, South Sefton District, Clinical
Laboratories, Fazakerley Hospital, Liverpool L9 7AL.
I.
J. L. GOLDBERG.
a circular results are widespread in published work; many of them taken, with little or no acknowledgment, from the output of routine laboratories. While you regret that this work often comes from physicians and full-time research-workers, you later suggest that the chemical pathologist of the future would hold M.R.C.P., and work in a specialised laboratory. Your future aim is thus revealed as your present problem. The biennial chemical-pathology course, organised by the Postgraduate Medical Federation for those intending to take the final M.R.C.PATH., has recently ended. A notable feature was the almost total inability of the lecturers to see their highly specialised interests within the concept of a balanced clinical-chemistry service. Such a service must combine suitable methodology with suitable equipment, and aim to be medically relevant and provide a rapid turnround. While many scientific staff in clinical chemistry are perfectly able to run laboratories on a static basis, scientists with the acquired ability to discern the medical relevance and priority of test procedures, as opposed to the methodological convenience, derive unique value by a certain rarity.
SIR,-At least part of
argument.
Clinical
your thesis2 involves
chemistry
1. Goldberg, I. J. L., Mitchell, F. L. Lancet, 2. Lancet, 1975, i, 1327.
1970, ii, 1240.
The role of the chemical pathologist the hospital is to keep up a flow of medically relevant general information on the service provided, and on the interpretation of results: also, to react constructively to new and unmet varieties of demand, bringing new techniques to the attention of clinical colleagues. In the near future, he may also have to be the arbiter of severe service reductions. Unfortunately, this role is regarded by many as being too remote from the patient, because inpatient beds are still regarded as the only " Danegeld capable of buying clinical commitment. It cannot have escaped anyone’s notice that hospitals have recently been amalgamated with other branches of the health services. We must cease to regard pathology laboratories (and other similar services) as hospital property, and look at them only in a wider context-usually of a district responsibility. General practitioners, and other extramural doctors, are much less able to make full use of laboratory facilities. This is partly because they rarely require special tests; partly because they form a diffuse group, to which it is difficult to disseminate up-to-date information; and partly because they may refer patients or samples to laboratories in districts other than their own, with which they are unfamiliar. This is a majorarea of importance for the chemical pathologist. He will supervise tests on patients, whether referred from general practitioners or from hospital clinics: he can see patients on direct referral without needing to consume that scarce resource-a hospital bed. The demands for these clinical services are sufficiently low as to make formal clinics and
within
"
waiting-lists
-
unnecessary. Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, M. D. BUCKLEY-SHARP. London W1P 5PR.
DIFFERENTIAL SISTER-CHROMATID STAINING
SIR,-Korenberg and Freedlender demonstrated differential sister-chromatid staining without using the fluorochrome, Hoechst 33258.1 Using the same method, we found that the optimum temperature of the sodium dihydrogen phosphate solution was 79-81 °C as compared to 89 °C where, in our hands, little sister-chromatid differentiation was observed. C and T banded chromosomes were also noted at 89°C. The above determination
made in human shortstimulated leucocyte cultures derived from whole blood of three individuals and incubated for 96 hours at 36-36-5 °C. A total often slides of cells from the three individuals were examined. At least 25 metaphase spreads per slide were studied. Five slides were exposed to 88-89 °C while the remaining slides were incubated at 79-81 °C. Metaphase cells exposed to the higher temperature exhibited differential staining only 0-8% of the time, while those exposed to the lower temperature showed the effect 40-50 % of the time. The remaining cells stained homogeneously with no indication of C or T banding.
term
was
phytohaemagglutinin (P.H.A.)
In addition, all cultures were exposed to 5-bromodeoxyuridine for only the last 24 hours of incubation, according to the method of Perry and Wolff 2 who tested Chinese hamster ovary-cell cultures, in contrast to other reports where the treatment was continous.3,4 This suggests a cell cycle time of 12 hours for human P.H.A.-transformed blastlike cells in our culture system. Finally, the shorter exposure 1. 2. 3. 4.
Korenberg, J. R., Freedlender, E. Chromosoma, 1974, 48, 355. Perry, P., Wolff, S. Nature, 1974, 251, 156. Latt, S. Proc. natn. Acad. Sci. U.S.A. 1974, 71, 3162. Chaganti, R. S. K., Schonberg, S., German, J. ibid. p. 4508.
