- Email: [email protected]
ALPHA1-ANTITRYPSIN PHENOTYPES IN PARAPROTEINÆMIAS
561 to be reduced. However, c.s.F. concentrations of have been reported to be normal in schizophrenia. 12 On the basis of the above results it seems that a G.A.B.A. deficiency in brains from schizophrenics is unlikely to be a general
workers" G.A.B.A.
finding. J. CROSS T. J. CROW A.
Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
F. OWEN
ALPHA1-ANTITRYPSIN PHENOTYPES IN PARAPROTEINÆMIAS
SiR,—o-antitrypsin (
the major
trypsin inhibitor in
blood, has a wide genetic variability.’2 apart from the most common allele, (Pi M) all variants studied so far differ in both Fig. 2-Correlation between G.A.B.A. concentrations and G.A.D. activity in nucleus accumbens of controls (e) and
schizophrenics (0). r=054,r<0001. Brains from controls and
sected, and stored
as
schizophrenics were collected, dispreviously described.2 The two groups did
not differ with respect to age, sex, time from death to necropsy, time of storage at 4°C before necropsy, or length of time deep frozen. Diagnosis of schizophrenia was established only if the information in the case-notes fulfilled both the criteria of the present state examination3 and "probable" or "definite" schizophrenia.4 Brain samples were coded and all assays were done blind. G.A.B.A. was assayed in the nucleus accumbens and thalamus of controls and schizophrenics by a radioreceptor technique5 (fig. 1). There was no significant difference in G.A.B.A. concentrations between controls and schizophrenics in either of the brain regions studied. Moreover, G.A.B.A. concentrations in the nucleus accumbens of controls and schizophrenics were significantly correlated (r=0.54, p<0-001) with G.A.D. activities as previously assessed. In our sample G.A.B.A. concentrations in both brain regions were unrelated to post-
storage time, agonal state, neuroleptic medication, or age. The reason for the discrepancy between our result and that of Perry and colleagues is not clear, although they studied only seven samples of nucleus accumbens. The G.A.B.A. deficiency hypothesis of schizophrenia is based primarily on the interaction between dopaminergic and G.A.B.A.-ergic mechanisms in animals, 6, with little, if any, clinical evidence to support this hypothesis. The putative G.A.B.A. agonist, baclofen, was at one time claimed to be therapeutically effective in schizophrenia,8 but subsequent reports suggest that baclofen is ineffective or even detrimental.9 In addition, the highly specific and potent G.A.B.A. agonist, muscimol, does not alleviate schizophrenic symptoms. 10 In Huntington’s chorea, where a G.A.B.A. deficiency seems to be well established, the concentration of G.A.B.A. in the cerebrospinal fluid has been shown by several groups of
electrophoretic mobility and functional capacity. The clinically relevant allele is Piz which exhibits only 10-20% of normal serum trypsin-inhibitory capacity.’ Homozygotes and heterozygotes for the Pihave been associated with a wide variety of diseases. We have found a high frequency of the PiMZ phenotype among patients with multiple myeloma or lymphoma who have paraproteins in serum and/or urine. The 30 patients with multiple myeloma and 3 with lymphoma were diagnosed and classified on clinical and laboratory findings. Control sera were obtained from 296 cord bloods and most
o-A.T.
PHENOTYPES IN PARAPROTEINAEMIAS AND CONTROLS
mortem
2. Owen,
F., Cross, A. J., Crow, T. J., Longden, A., Poulter, M., Riley, G. J.
Lancet, 1978, ii, 223. 3. Wing, 4
J. K., Cooper, J. E., Sartorius, N. Measurement and Classification of Psychiatric Symptoms. London, 1974. Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. A., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57.
5. Enna, S. J., Snyder, S. H. J. Neurochem. 1976, 26, 221. 6. Roberts, E. Neurosci. Res. Progr. Bull. 1972, 10, 468. 7 Fuxe, K., Hökfelt, T., Ljingdahl, Å., Agnati, L., Johansson,
O. E., Perez de la Mora, M. Med Biol. 1975, 53, 177. 8. Fredenksen, P. K. Lancet, 1975, i, 702. 9. Simpson, G. M., Lee, J. H., Shnvastava, R. K., Branchey, M. M. Psychopharmac. Bull. 1978, 14, 16. 10. Tamminga, C. A., Crayton, J. W., Chase, T. N. Am. J. Psychiat. 1978, 135, 746.
*Not including 7
(1.4%) with "other" phenotypes.
219 blood-donors. 1X1-A.T. was measured by immunoturbidometry on a centrifugal analyser. Protease inhibitor (Pi) typing was done by isoelectric focusing on polyacrylamide gel slabs (’Ampholine’) pH range 3.5-5-0; o-A.T. bands were stained with Coomassie brilliant-blue. Paraproteins were demonstrated by zone electrophoresis on cellulose-acetate membranes and on agarose gel. The immunoglobulin and light-chains were identified by immunoelectrophoresis with specific antisera. The most striking feature of the table is the increased frequency of PiMZ in the patients, this phenotype being found in 3 of 33 patients and only 9 of 515 controls. The relative risk for paraproteinxmia in an individual with the PiMZ is roughly 9. Serum-1X1-A.T.values among patients were higher (1-92 g/1) than those of the controls (1-43 g/1), and this difference was statistically significant by thet test. Since paraproteinoemias have a late age onset, this association is likely to represent a portion of the underlying genetic predisposition to disease, since natural selection in maintaining B. S., Vogel, 1975, 12, 380.
11. Glaeser,
W. H.,
Oleweiler, D. B., Hare, T. A. Biochem. Med.
Lichtshtein, D., Dobkin, J., Ebstein, R. P., Biederman, J., Rimon, R., Belmaker, R. H. Br. J. Psychiat. 1978,132, 145. 1. Kueppers, F., Black, L. F. Am. Rev. resp. Dis. 1974, 110, 176. 2. Mittman, C. Trace Components of plasma; p. 261. New York, 1976.
12.
562 the Ct.1-A.T. variability is unlikely to be the cause. An explanation for this association between a genetic system and a disease process has to be sought in the contribution of the gene product to initiation and/or progression of cancer. Proteolytic enzymes enhance cell growth.3 Since otA.T. inhibits proteolytic enzymes it could be argued that people with the Z allelle might have enhanced cell proliferation, thus aiding tumour spread. If this were so, more homozygous ZZ types might be expected among the cancer patients. However, homozygous individuals, being susceptible to neonatal hepatitis4 and chronic obstructive pulmonary disease,5 may succumb to these diseases and thus be excluded from the cancer-predisposed group.
Proteolytic enzymes are secreted by transformed celllines.6 Goetze et al.7 found that protease inhibitors inhibit the growth of transformed hamster cell lines, but &agr;1-A.T. was not tested. Furthermore proteases promote tumour growth through the destruction of surrounding tissue.8 It thus seems that antiproteases could play a role in the progression of cancer. The rise in Ct.1-A.T. concentration is predictable since part of the response to malignancy is a rise in antiproteolytic activity9 but must be interpreted with caution since several factors can cause a rise in concentration. In paraproteinsemias Ct.2-macroglobulin levels fall because the metabolic controls over the synthesis of ê.’I.2-macroglobulin are diverted to the production of the abnormal protein.1O Such a mechanism might operate for &agr;1-A.T. synthesis. Department of Genetics,
University of Melbourne, and Department of Chemical Pathology, Prince Henry’s Hospital, Melbourne, Victoria 3004, Australia
R. ANANTHAKRISHNAN B. BIEGLER P. M. DENNIS
PEPTIC ULCER AFTER RENAL TRANSPLANTATION
SIR,-Your editorial (Feb. 17) on peptic ulceration after renal transplantation referred to our use of prophylactic cimetidine in this context. In the twelve months following our publication1 we have done a further sixty-three renal transplants. There has been no upper gastrointestinal haemorrhage in these patients; during this period our maintenance steroid regimen has been modified so that in the first month after transplantation our earlier, higher doses of steroids are avoided. However, acute rejection episodes continue to be treated with 1 g methylprednisolone on three consecutive days, well into the dosage range thought to put patients at risk from peptic ulceration.2
have a series of ninety-three consecutive renal in which no upper gastrointestinal haemorrhage transplants has occurred. Further, in none of the thirty patients we orig- ’ inally reported’ has peptic ulceration subsequently developed and in only one patient out of the sixty-three recent transplants has a duodenal ucler developed, 3 months after cimetidine was stopped. We now believe that the routine use of prophylactic cimetidine after renal transplantation is advisable. We
now
J. RUDGE R. H. JONES
C. Renal Unit,
Kings College Hospital, London SE5
M. BEWICK M. J. WESTON V. PARSONS
3. Pohjanpelto, P. J. Cell Physiol. 1977, 91, 387. 4. Aagenaes, O., and others Postgrad. med. J. 1974, 50, 365. 5. Laurell, C.-B., Ericksson, S. Scand. J. clin. Lab. Invest. 1963,15, 132. 6. Reich, E. in Bayer Symposium V: Proteinase Inhibitors; p. 621. Berlin, 1974. 7. Goetz, I. E., Weinstein, C., Roberts, E. Cancer Res. 1972, 32, 2469. 8. Latner, A. L., Longstaff, E., Pradhan, K. Br. J. Cancer, 1973, 27, 460. 9. Clark, D. G. C., Clifton, E. E., Newton, B. L. Proc. Soc. Biol. Med. 1948,
69, 276. 10. Ritzman, S. E., Daniels, J. C. in Serum Protein Abnormalities,
Boston, 1975. 1. Jones, R. H., Rudge, C. J., Bewick, M. et al. Br. med. J. 1978, i, 398. 2. Conn, H. O, Blitzer, B.L New Engl. J. Med. 1976,294,473.
p. 253.
FALSE-NEGATIVE SMEARS IN GYNÆCOLOGICAL CYTOLOGY
SIR,-Rubiol-3 has reported that cotton-tipped applicators and wooden spatulas trap large numbers of atypical cells when used as cervical smear cytological specimen collectors. He suggested that this may be one of the causes of false-negative smears in exfoliative cytology of the uterine cervix. Six months ago, in response to this concern and, more generally, to professional concern about the frequency of false-negative smears in gynxcological practice 4-1 we asked manufacturers of cell-collecting devices to carry out clinical studies to determine the extent of the problem. The results of these studies confirm Rubio’s conclusions that cotton swabs or cotton-tipped applicators are not suitable for gynaecological cytology. A survey we recently conducted indicates that, in Canada, cotton swabs are generally used only for bacterial sampling. Nevertheless, those who, for some reason, choose to use cotton swabs for cell collection, should be reminded that these devices give a significant number of falsenegative smears and hence may pose an indirect health hazard. The data also revealed that, despite the demonstrated celltrapping characteristics of wooden spatulas, there is no significant difference in clinical performance between the traditionally popular wooden spatulas and the newer plastic cervical smear specimen collectors. Bureau of Medical Devices, Health Protection Branch, Health & Welfare Canada, Ottawa, Ontario, Canada
LEON KATZ I. HINBERG FRANCES WEBER
HYPERCALCÆMIA IN PAGET’S DISEASE OF BONE
SIR The report by Dr Fuss and colleagues9 prompts us to with severe hypercalcxmia. A admitted to hospital having fallen at home and sustained a transverse fracture of the right femur which showed radiological evidence of Paget’s disease. She was immobilised with a Thomas’ splint. She was fully conscious, rational, and normally hydrated on admission. Later polydipsia and polyuria developed and she became increasingly drowsy and confused with hypercalcxmia and renal failure (see table). There was a good clinical and biochemical response to intravenous fluids, calcitonin, and restricted calcium intake, and she subsequently underwent an internal fixation of the fracture without recurrence of the metabolic disturbance. We assumed that the hypercalcxmia was related to the fracture and subsequent immobilisation. The serum-parathyroid-hormone level was not detectable on two occasions, and there was no laboratory evidence of myeloma. A full radiological survey showed Paget’s disease in the left femur also, the rest of the skeleton being clear. Further inquiry revealed that she had taken calcium gluconate 12 g daily for several years, and that this medication had been continued after admission. Although textbooks often refer to hypercalcxmia as a complication of fracture and immobilisation in Paget’s disease, reports since the one by Reifenstein and Albright10 are hard to find, as pointed out by Fuss et al. and also by Nagant de Deuxchaisnes and Krane.11 It is possible that the complication may only develop in particular circumstances. In the present case’
describe
a
76-year-old
similar
patient
woman was
1, Rubio, C. A. Obstet. Gynec. 1977, 49, 576. 2. Rubio, C. A. Acta cytol. 1977, 21, 500. 3. Rubio, C. A. Am. J. Obstet. Gynec. 1977, 128, 687. 4. Frost, J. K. Obstet. gynec. Surv. 1969, 24, 893. 5. Sedlis, A. and others Acta cytol. 1974, 18, 291. 6. Koss, L. G., Hiclin, M. O. Obstet. Gynec. 1974, 43, 792. 7. May, D. Br. J. Cancer. 1974, 29, 106. 8. Myirjesy,I. J. Am. med. Ass. 1972, 222, 691. 9. Fuss, M., Bergans, A., Corvilain, J. Lancet, 1978, ii, 941. 10. Reifenstein, E. C., Albright, F. New Engl. J Med. 1944, 231, 343. 11. Nagant de Deuxchaisnes, C., Krane S. M. Medicine, 1964, 43, 233.
workers" G.A.B.A.
finding. J. CROSS T. J. CROW A.
Division of Psychiatry, Clinical Research Centre, Harrow, Middlesex HA1 3UJ
F. OWEN
ALPHA1-ANTITRYPSIN PHENOTYPES IN PARAPROTEINÆMIAS
SiR,—o-antitrypsin (
the major
trypsin inhibitor in
blood, has a wide genetic variability.’2 apart from the most common allele, (Pi M) all variants studied so far differ in both Fig. 2-Correlation between G.A.B.A. concentrations and G.A.D. activity in nucleus accumbens of controls (e) and
schizophrenics (0). r=054,r<0001. Brains from controls and
sected, and stored
as
schizophrenics were collected, dispreviously described.2 The two groups did
not differ with respect to age, sex, time from death to necropsy, time of storage at 4°C before necropsy, or length of time deep frozen. Diagnosis of schizophrenia was established only if the information in the case-notes fulfilled both the criteria of the present state examination3 and "probable" or "definite" schizophrenia.4 Brain samples were coded and all assays were done blind. G.A.B.A. was assayed in the nucleus accumbens and thalamus of controls and schizophrenics by a radioreceptor technique5 (fig. 1). There was no significant difference in G.A.B.A. concentrations between controls and schizophrenics in either of the brain regions studied. Moreover, G.A.B.A. concentrations in the nucleus accumbens of controls and schizophrenics were significantly correlated (r=0.54, p<0-001) with G.A.D. activities as previously assessed. In our sample G.A.B.A. concentrations in both brain regions were unrelated to post-
storage time, agonal state, neuroleptic medication, or age. The reason for the discrepancy between our result and that of Perry and colleagues is not clear, although they studied only seven samples of nucleus accumbens. The G.A.B.A. deficiency hypothesis of schizophrenia is based primarily on the interaction between dopaminergic and G.A.B.A.-ergic mechanisms in animals, 6, with little, if any, clinical evidence to support this hypothesis. The putative G.A.B.A. agonist, baclofen, was at one time claimed to be therapeutically effective in schizophrenia,8 but subsequent reports suggest that baclofen is ineffective or even detrimental.9 In addition, the highly specific and potent G.A.B.A. agonist, muscimol, does not alleviate schizophrenic symptoms. 10 In Huntington’s chorea, where a G.A.B.A. deficiency seems to be well established, the concentration of G.A.B.A. in the cerebrospinal fluid has been shown by several groups of
electrophoretic mobility and functional capacity. The clinically relevant allele is Piz which exhibits only 10-20% of normal serum trypsin-inhibitory capacity.’ Homozygotes and heterozygotes for the Pihave been associated with a wide variety of diseases. We have found a high frequency of the PiMZ phenotype among patients with multiple myeloma or lymphoma who have paraproteins in serum and/or urine. The 30 patients with multiple myeloma and 3 with lymphoma were diagnosed and classified on clinical and laboratory findings. Control sera were obtained from 296 cord bloods and most
o-A.T.
PHENOTYPES IN PARAPROTEINAEMIAS AND CONTROLS
mortem
2. Owen,
F., Cross, A. J., Crow, T. J., Longden, A., Poulter, M., Riley, G. J.
Lancet, 1978, ii, 223. 3. Wing, 4
J. K., Cooper, J. E., Sartorius, N. Measurement and Classification of Psychiatric Symptoms. London, 1974. Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. A., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57.
5. Enna, S. J., Snyder, S. H. J. Neurochem. 1976, 26, 221. 6. Roberts, E. Neurosci. Res. Progr. Bull. 1972, 10, 468. 7 Fuxe, K., Hökfelt, T., Ljingdahl, Å., Agnati, L., Johansson,
O. E., Perez de la Mora, M. Med Biol. 1975, 53, 177. 8. Fredenksen, P. K. Lancet, 1975, i, 702. 9. Simpson, G. M., Lee, J. H., Shnvastava, R. K., Branchey, M. M. Psychopharmac. Bull. 1978, 14, 16. 10. Tamminga, C. A., Crayton, J. W., Chase, T. N. Am. J. Psychiat. 1978, 135, 746.
*Not including 7
(1.4%) with "other" phenotypes.
219 blood-donors. 1X1-A.T. was measured by immunoturbidometry on a centrifugal analyser. Protease inhibitor (Pi) typing was done by isoelectric focusing on polyacrylamide gel slabs (’Ampholine’) pH range 3.5-5-0; o-A.T. bands were stained with Coomassie brilliant-blue. Paraproteins were demonstrated by zone electrophoresis on cellulose-acetate membranes and on agarose gel. The immunoglobulin and light-chains were identified by immunoelectrophoresis with specific antisera. The most striking feature of the table is the increased frequency of PiMZ in the patients, this phenotype being found in 3 of 33 patients and only 9 of 515 controls. The relative risk for paraproteinxmia in an individual with the PiMZ is roughly 9. Serum-1X1-A.T.values among patients were higher (1-92 g/1) than those of the controls (1-43 g/1), and this difference was statistically significant by thet test. Since paraproteinoemias have a late age onset, this association is likely to represent a portion of the underlying genetic predisposition to disease, since natural selection in maintaining B. S., Vogel, 1975, 12, 380.
11. Glaeser,
W. H.,
Oleweiler, D. B., Hare, T. A. Biochem. Med.
Lichtshtein, D., Dobkin, J., Ebstein, R. P., Biederman, J., Rimon, R., Belmaker, R. H. Br. J. Psychiat. 1978,132, 145. 1. Kueppers, F., Black, L. F. Am. Rev. resp. Dis. 1974, 110, 176. 2. Mittman, C. Trace Components of plasma; p. 261. New York, 1976.
12.
562 the Ct.1-A.T. variability is unlikely to be the cause. An explanation for this association between a genetic system and a disease process has to be sought in the contribution of the gene product to initiation and/or progression of cancer. Proteolytic enzymes enhance cell growth.3 Since otA.T. inhibits proteolytic enzymes it could be argued that people with the Z allelle might have enhanced cell proliferation, thus aiding tumour spread. If this were so, more homozygous ZZ types might be expected among the cancer patients. However, homozygous individuals, being susceptible to neonatal hepatitis4 and chronic obstructive pulmonary disease,5 may succumb to these diseases and thus be excluded from the cancer-predisposed group.
Proteolytic enzymes are secreted by transformed celllines.6 Goetze et al.7 found that protease inhibitors inhibit the growth of transformed hamster cell lines, but &agr;1-A.T. was not tested. Furthermore proteases promote tumour growth through the destruction of surrounding tissue.8 It thus seems that antiproteases could play a role in the progression of cancer. The rise in Ct.1-A.T. concentration is predictable since part of the response to malignancy is a rise in antiproteolytic activity9 but must be interpreted with caution since several factors can cause a rise in concentration. In paraproteinsemias Ct.2-macroglobulin levels fall because the metabolic controls over the synthesis of ê.’I.2-macroglobulin are diverted to the production of the abnormal protein.1O Such a mechanism might operate for &agr;1-A.T. synthesis. Department of Genetics,
University of Melbourne, and Department of Chemical Pathology, Prince Henry’s Hospital, Melbourne, Victoria 3004, Australia
R. ANANTHAKRISHNAN B. BIEGLER P. M. DENNIS
PEPTIC ULCER AFTER RENAL TRANSPLANTATION
SIR,-Your editorial (Feb. 17) on peptic ulceration after renal transplantation referred to our use of prophylactic cimetidine in this context. In the twelve months following our publication1 we have done a further sixty-three renal transplants. There has been no upper gastrointestinal haemorrhage in these patients; during this period our maintenance steroid regimen has been modified so that in the first month after transplantation our earlier, higher doses of steroids are avoided. However, acute rejection episodes continue to be treated with 1 g methylprednisolone on three consecutive days, well into the dosage range thought to put patients at risk from peptic ulceration.2
have a series of ninety-three consecutive renal in which no upper gastrointestinal haemorrhage transplants has occurred. Further, in none of the thirty patients we orig- ’ inally reported’ has peptic ulceration subsequently developed and in only one patient out of the sixty-three recent transplants has a duodenal ucler developed, 3 months after cimetidine was stopped. We now believe that the routine use of prophylactic cimetidine after renal transplantation is advisable. We
now
J. RUDGE R. H. JONES
C. Renal Unit,
Kings College Hospital, London SE5
M. BEWICK M. J. WESTON V. PARSONS
3. Pohjanpelto, P. J. Cell Physiol. 1977, 91, 387. 4. Aagenaes, O., and others Postgrad. med. J. 1974, 50, 365. 5. Laurell, C.-B., Ericksson, S. Scand. J. clin. Lab. Invest. 1963,15, 132. 6. Reich, E. in Bayer Symposium V: Proteinase Inhibitors; p. 621. Berlin, 1974. 7. Goetz, I. E., Weinstein, C., Roberts, E. Cancer Res. 1972, 32, 2469. 8. Latner, A. L., Longstaff, E., Pradhan, K. Br. J. Cancer, 1973, 27, 460. 9. Clark, D. G. C., Clifton, E. E., Newton, B. L. Proc. Soc. Biol. Med. 1948,
69, 276. 10. Ritzman, S. E., Daniels, J. C. in Serum Protein Abnormalities,
Boston, 1975. 1. Jones, R. H., Rudge, C. J., Bewick, M. et al. Br. med. J. 1978, i, 398. 2. Conn, H. O, Blitzer, B.L New Engl. J. Med. 1976,294,473.
p. 253.
FALSE-NEGATIVE SMEARS IN GYNÆCOLOGICAL CYTOLOGY
SIR,-Rubiol-3 has reported that cotton-tipped applicators and wooden spatulas trap large numbers of atypical cells when used as cervical smear cytological specimen collectors. He suggested that this may be one of the causes of false-negative smears in exfoliative cytology of the uterine cervix. Six months ago, in response to this concern and, more generally, to professional concern about the frequency of false-negative smears in gynxcological practice 4-1 we asked manufacturers of cell-collecting devices to carry out clinical studies to determine the extent of the problem. The results of these studies confirm Rubio’s conclusions that cotton swabs or cotton-tipped applicators are not suitable for gynaecological cytology. A survey we recently conducted indicates that, in Canada, cotton swabs are generally used only for bacterial sampling. Nevertheless, those who, for some reason, choose to use cotton swabs for cell collection, should be reminded that these devices give a significant number of falsenegative smears and hence may pose an indirect health hazard. The data also revealed that, despite the demonstrated celltrapping characteristics of wooden spatulas, there is no significant difference in clinical performance between the traditionally popular wooden spatulas and the newer plastic cervical smear specimen collectors. Bureau of Medical Devices, Health Protection Branch, Health & Welfare Canada, Ottawa, Ontario, Canada
LEON KATZ I. HINBERG FRANCES WEBER
HYPERCALCÆMIA IN PAGET’S DISEASE OF BONE
SIR The report by Dr Fuss and colleagues9 prompts us to with severe hypercalcxmia. A admitted to hospital having fallen at home and sustained a transverse fracture of the right femur which showed radiological evidence of Paget’s disease. She was immobilised with a Thomas’ splint. She was fully conscious, rational, and normally hydrated on admission. Later polydipsia and polyuria developed and she became increasingly drowsy and confused with hypercalcxmia and renal failure (see table). There was a good clinical and biochemical response to intravenous fluids, calcitonin, and restricted calcium intake, and she subsequently underwent an internal fixation of the fracture without recurrence of the metabolic disturbance. We assumed that the hypercalcxmia was related to the fracture and subsequent immobilisation. The serum-parathyroid-hormone level was not detectable on two occasions, and there was no laboratory evidence of myeloma. A full radiological survey showed Paget’s disease in the left femur also, the rest of the skeleton being clear. Further inquiry revealed that she had taken calcium gluconate 12 g daily for several years, and that this medication had been continued after admission. Although textbooks often refer to hypercalcxmia as a complication of fracture and immobilisation in Paget’s disease, reports since the one by Reifenstein and Albright10 are hard to find, as pointed out by Fuss et al. and also by Nagant de Deuxchaisnes and Krane.11 It is possible that the complication may only develop in particular circumstances. In the present case’
describe
a
76-year-old
similar
patient
woman was
1, Rubio, C. A. Obstet. Gynec. 1977, 49, 576. 2. Rubio, C. A. Acta cytol. 1977, 21, 500. 3. Rubio, C. A. Am. J. Obstet. Gynec. 1977, 128, 687. 4. Frost, J. K. Obstet. gynec. Surv. 1969, 24, 893. 5. Sedlis, A. and others Acta cytol. 1974, 18, 291. 6. Koss, L. G., Hiclin, M. O. Obstet. Gynec. 1974, 43, 792. 7. May, D. Br. J. Cancer. 1974, 29, 106. 8. Myirjesy,I. J. Am. med. Ass. 1972, 222, 691. 9. Fuss, M., Bergans, A., Corvilain, J. Lancet, 1978, ii, 941. 10. Reifenstein, E. C., Albright, F. New Engl. J Med. 1944, 231, 343. 11. Nagant de Deuxchaisnes, C., Krane S. M. Medicine, 1964, 43, 233.