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OSSEOUS MALFORMATION IN BABY BORN TO WOMAN ON CYCLOSPORIN
667 Thus
daily active exercise
may retard rather than accelerate
improvement. Ankylosis did not occur in any patient in the splinted group. An initial period of immobilisation of affected joints is of value in controlling pain and muscle spasm and in reducing disease activity. However, such a regimen makes heavy demands on nurses and prolongs bed occupancy. 26A DalhousIe Road,
Eskbank, Dalkeith, Mldlothlan EH22
3AP
J. J.
DUTHIE
SIR,-Professor Blake and colleagues report that exercise of the inflamed knee caused intra-articular pressure to rise above synovial pressure, resulting in intra-articular hypoxia. This observation may answer a question raised by our studies on inflamed and effused knees.’ Quadriceps muscles can be inhibited when the adjacent knee joint is effused, probably by an inhibitory reflex that may contribute to arthrogenous muscle weakness? There have been several attempts to identify the stimuli for the inhibition, which frequently occurs without pain. Stokes and Young" demonstrated a relation between muscle inhibition and acute traumatic effusions; joint aspiration reduced the inhibition, and stretch/pressure receptors were suggested as the mechanism for inhibition. However, in our studies of chronic knee effusions (secondary to inflammatory joint disease) we could not influence the degree of quadriceps inhibition by the aspiration of significant volumes of fluid (although not to dryness; range aspirated 20-300 ml). This suggests that the mechanism for muscle inhibition in these joints is not mediated in the same way as in acutely swollen joints. These apparently contradictory results of the effect of joint effusion on muscle inhibition might be explained if intra-articular hypoxia is a stimulus for reflex muscle inhibition in chronically effused joint conditions. Drainage of an acute effusion from an otherwise normal joint would be expected to abolish inhibition, as was found. However, drainage of an inflammatory effusion would do nothing to change the effects of the inflammatory joint disease and inhibition would still be present, as was the case. From a practical viewpoint the exercise protocol was extreme, since a maximal quadriceps contraction is rarely, if ever, maintained for two minutes under normal conditions. Furthermore, the contractions were done in full extension, when intra-articular joint pressure3 and reflex muscle inhibition1 is greatest. It would be interesting to know whether there is oxidative damage to lipids and IgG after more functional daily activities.
capillary
Department of Physiology, University College London, London WC1E 6BT
DIANNE J. NEWHAM MICHAEL V. HURLEY
Rheumatology Department, Middlesex Hospital, London WC1
85
ml/min. All other biochemical indices were normal. Labour induced in the 38th week and delivery was by forceps. There was no fetal distress (Apgar score 9 at 1 min and 10 at 5 min). This baby weighed 2450 g and was 46 cm long. She had hypoplasia of the right leg and foot, and the right leg was 2 cm shorter than the left. On X-ray the right femur was 8-9 cm and the left 9-1cm, the right tibia and fibula were also shorter than the left (78 cm vs 8-7 cm), and the right superior tibial epiphysis had not begun to ossify. Hypoplasia of the muscles and subcutaneous tissue of the right leg was also observed. The osseous and soft tissue structures of the right foot were also smaller than those of the left, and the right cuboid bone had not begun to ossify. X-rays of the skeleton were otherwise normal. The baby had transient hypocalcaemia between days 8 and 14 and required calcium gluconate infusion. Blood and urine tests were otherwise normal, as was the karyotype. We have found healing in renal osteodystrophy to be slower in renal transplant recipients immunosuppressed with cyclosporin than in those treated with azathioprine.8 Cyclosporin blocks the release of interleukin-2 from activated helper T lymphocytes which is necessary for the proliferation of cytotoxic T cells.9 It has been suggested that lymphocytic interleukin-2 also has a role in the differentiation of osteoclasts and, probably, osteoblasts from the stem cell. 10 Cyclosporin could thus interfere with the modelling and remodelling processes of bone, and this could be the basis for the osseous malformation found in the baby described here. rate was
J. M. PUJALS G. FIGUERAS Paediatric Department and Nephrology Department, Hospital GMD l’Esperanca, 08024 Barcelona, Spam
J. M. PUIG J. LLOVERAS J. AUBIA J. MASRAMON
1 Lewis
GJ, Lamont CAR, Lee HA, et al. Successful pregnancy in a renal transplant recipient taking cyclosporme A. Br Med J 1983, 286: 603. 2 Klintmalm G, Althoff P, Appleby G, et al. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984; 38: 198-99. 3 Flechner S, Katz AR, Rogers AJ, et al The presence of cyclosporine m body tissues and fluids during pregnancy. Am J Kidney Dis 1985, 5: 60-63. 4. Pickrell MD, Sawers R, Michael J Pregnancy after renal transplantation severe mtrautenne growth retardation during treatment with cyclosporin A Br MedJ 1988; 296: 825. 5. Al-Khader A, Absy
M, Al-Hasani MK, et al Successful pregnancy in renal transplant recipients treated with cyclosporine. Transplantation 1988; 45: 987-88 6 Ziegenhagen DJ, Crombach G, Dieckmann M, et al Schwangerschaft unter Ciclosporin-Medikation nach nierentransplantation. Dtsch Med Wschr 1988; 113: 260-63. 7. Lau RJ, Scott JR. Pregnancy following renal transplantation, Clin Obstet Gynaecol 1985; 28: 339-50. J, Masramón J, Serrano S, et al. Bone histology in renal transplant patients receiving cyclosporin. Lancet 1988, i: 1048. 9. Bunjes D, Hardt C, Rollinghoff M, et al. Cyclosporine A mediates immunossuppression of primary cytotoxic T cell response by impairing the release 8 Aubia
DAVID W.
JONES
Jones DW, Jones DA, Newham DJ Chronic knee effusion and aspiration the effect on quadriceps inhibition Br J Rheumatol 1987; 26: 370-74. 2. Stokes M, Young A. The contribution of reflex inhibition to arthrogenous muscle weakness Clin Sci 1984; 67: 7-14. 3 Jayson MI, Dixon A StJ Intra-articular pressure in rheumatoid arthritis of the knee III pressure changes during passive joint distension. Ann Rheum Dis 1970, 29: 1
261-65.
OSSEOUS MALFORMATION IN BABY BORN TO WOMAN ON CYCLOSPORIN
SiR,—So far pregnancies in women taking cyclosporin have not been associated with congenital malformations.’-bHowever, intrauterine growth retardation is a common factor in such pregnancies, as it is in women on azathioprine.’
Hypoplasia of the legs is an unusual malformation when present isolation, and no causal agent has hitherto been recognised. A 29-year-old woman had a kidney transplant 9 months before becoming pregnant. She had never had significant renal osteodystrophy or hyperparathyroidism. She had no X-rays during her pregnancy. She took cyclosporin and low-dose prednisone, and tolerated this regimen well. Prednisone had been discontinued 6 months after transplantation. Cyclosporin levels (whole blood, in
Sandoz non-specific radioimmunoassay) averaged 560 ng/ml during the first 3 months after that transplant and 350 ng/ml during pregnancy. No other drugs were administered during pregnancy. Plasma creatinine averaged 123-88 )mol/l and glomerular filtration
of IL-1 and IL-2.
Eur J Immunol 1981; 11: 657-61
10 Baron
R, Vignery A, Horowitz M. Lymphocytes, macrophages and the regulation of bone remodeling. In: Peck W, ed Bone and mineral research annual 2. Amsterdam: Elsevier, 1984 175-225.
CUTANEOUS ALTERNARIOSIS RESPONDING TO KETOCONAZOLE
SIR,-Alternaria alternata is an unusual cause of infection and we of no more than fifty reported cases. Most were cutaneous infections but invasive altemariosis has been described in
are aware
immunocompromised patients.’1 An 80-year-old farmer was admitted to hospital with a history of dermatopolymyositis. He had been well until 4 months earlier when he began to feel tired with progressive weakness of the legs. He could not get up or walk without help. Examination revealed extensive wasting of the muscles proximally with normal sensitivity and tendon reflexes. Muscle biopsy indicated myositis. On his right arm he had a violaceous plaque with dry crusts. He recalled a minor injury from a reed 2 years earlier. The patient started treatment with azathioprine and prednisone and the plaque grew rapidly. Biopsy revealed intradermal
daily active exercise
may retard rather than accelerate
improvement. Ankylosis did not occur in any patient in the splinted group. An initial period of immobilisation of affected joints is of value in controlling pain and muscle spasm and in reducing disease activity. However, such a regimen makes heavy demands on nurses and prolongs bed occupancy. 26A DalhousIe Road,
Eskbank, Dalkeith, Mldlothlan EH22
3AP
J. J.
DUTHIE
SIR,-Professor Blake and colleagues report that exercise of the inflamed knee caused intra-articular pressure to rise above synovial pressure, resulting in intra-articular hypoxia. This observation may answer a question raised by our studies on inflamed and effused knees.’ Quadriceps muscles can be inhibited when the adjacent knee joint is effused, probably by an inhibitory reflex that may contribute to arthrogenous muscle weakness? There have been several attempts to identify the stimuli for the inhibition, which frequently occurs without pain. Stokes and Young" demonstrated a relation between muscle inhibition and acute traumatic effusions; joint aspiration reduced the inhibition, and stretch/pressure receptors were suggested as the mechanism for inhibition. However, in our studies of chronic knee effusions (secondary to inflammatory joint disease) we could not influence the degree of quadriceps inhibition by the aspiration of significant volumes of fluid (although not to dryness; range aspirated 20-300 ml). This suggests that the mechanism for muscle inhibition in these joints is not mediated in the same way as in acutely swollen joints. These apparently contradictory results of the effect of joint effusion on muscle inhibition might be explained if intra-articular hypoxia is a stimulus for reflex muscle inhibition in chronically effused joint conditions. Drainage of an acute effusion from an otherwise normal joint would be expected to abolish inhibition, as was found. However, drainage of an inflammatory effusion would do nothing to change the effects of the inflammatory joint disease and inhibition would still be present, as was the case. From a practical viewpoint the exercise protocol was extreme, since a maximal quadriceps contraction is rarely, if ever, maintained for two minutes under normal conditions. Furthermore, the contractions were done in full extension, when intra-articular joint pressure3 and reflex muscle inhibition1 is greatest. It would be interesting to know whether there is oxidative damage to lipids and IgG after more functional daily activities.
capillary
Department of Physiology, University College London, London WC1E 6BT
DIANNE J. NEWHAM MICHAEL V. HURLEY
Rheumatology Department, Middlesex Hospital, London WC1
85
ml/min. All other biochemical indices were normal. Labour induced in the 38th week and delivery was by forceps. There was no fetal distress (Apgar score 9 at 1 min and 10 at 5 min). This baby weighed 2450 g and was 46 cm long. She had hypoplasia of the right leg and foot, and the right leg was 2 cm shorter than the left. On X-ray the right femur was 8-9 cm and the left 9-1cm, the right tibia and fibula were also shorter than the left (78 cm vs 8-7 cm), and the right superior tibial epiphysis had not begun to ossify. Hypoplasia of the muscles and subcutaneous tissue of the right leg was also observed. The osseous and soft tissue structures of the right foot were also smaller than those of the left, and the right cuboid bone had not begun to ossify. X-rays of the skeleton were otherwise normal. The baby had transient hypocalcaemia between days 8 and 14 and required calcium gluconate infusion. Blood and urine tests were otherwise normal, as was the karyotype. We have found healing in renal osteodystrophy to be slower in renal transplant recipients immunosuppressed with cyclosporin than in those treated with azathioprine.8 Cyclosporin blocks the release of interleukin-2 from activated helper T lymphocytes which is necessary for the proliferation of cytotoxic T cells.9 It has been suggested that lymphocytic interleukin-2 also has a role in the differentiation of osteoclasts and, probably, osteoblasts from the stem cell. 10 Cyclosporin could thus interfere with the modelling and remodelling processes of bone, and this could be the basis for the osseous malformation found in the baby described here. rate was
J. M. PUJALS G. FIGUERAS Paediatric Department and Nephrology Department, Hospital GMD l’Esperanca, 08024 Barcelona, Spam
J. M. PUIG J. LLOVERAS J. AUBIA J. MASRAMON
1 Lewis
GJ, Lamont CAR, Lee HA, et al. Successful pregnancy in a renal transplant recipient taking cyclosporme A. Br Med J 1983, 286: 603. 2 Klintmalm G, Althoff P, Appleby G, et al. Renal function in a newborn baby delivered of a renal transplant patient taking cyclosporine. Transplantation 1984; 38: 198-99. 3 Flechner S, Katz AR, Rogers AJ, et al The presence of cyclosporine m body tissues and fluids during pregnancy. Am J Kidney Dis 1985, 5: 60-63. 4. Pickrell MD, Sawers R, Michael J Pregnancy after renal transplantation severe mtrautenne growth retardation during treatment with cyclosporin A Br MedJ 1988; 296: 825. 5. Al-Khader A, Absy
M, Al-Hasani MK, et al Successful pregnancy in renal transplant recipients treated with cyclosporine. Transplantation 1988; 45: 987-88 6 Ziegenhagen DJ, Crombach G, Dieckmann M, et al Schwangerschaft unter Ciclosporin-Medikation nach nierentransplantation. Dtsch Med Wschr 1988; 113: 260-63. 7. Lau RJ, Scott JR. Pregnancy following renal transplantation, Clin Obstet Gynaecol 1985; 28: 339-50. J, Masramón J, Serrano S, et al. Bone histology in renal transplant patients receiving cyclosporin. Lancet 1988, i: 1048. 9. Bunjes D, Hardt C, Rollinghoff M, et al. Cyclosporine A mediates immunossuppression of primary cytotoxic T cell response by impairing the release 8 Aubia
DAVID W.
JONES
Jones DW, Jones DA, Newham DJ Chronic knee effusion and aspiration the effect on quadriceps inhibition Br J Rheumatol 1987; 26: 370-74. 2. Stokes M, Young A. The contribution of reflex inhibition to arthrogenous muscle weakness Clin Sci 1984; 67: 7-14. 3 Jayson MI, Dixon A StJ Intra-articular pressure in rheumatoid arthritis of the knee III pressure changes during passive joint distension. Ann Rheum Dis 1970, 29: 1
261-65.
OSSEOUS MALFORMATION IN BABY BORN TO WOMAN ON CYCLOSPORIN
SiR,—So far pregnancies in women taking cyclosporin have not been associated with congenital malformations.’-bHowever, intrauterine growth retardation is a common factor in such pregnancies, as it is in women on azathioprine.’
Hypoplasia of the legs is an unusual malformation when present isolation, and no causal agent has hitherto been recognised. A 29-year-old woman had a kidney transplant 9 months before becoming pregnant. She had never had significant renal osteodystrophy or hyperparathyroidism. She had no X-rays during her pregnancy. She took cyclosporin and low-dose prednisone, and tolerated this regimen well. Prednisone had been discontinued 6 months after transplantation. Cyclosporin levels (whole blood, in
Sandoz non-specific radioimmunoassay) averaged 560 ng/ml during the first 3 months after that transplant and 350 ng/ml during pregnancy. No other drugs were administered during pregnancy. Plasma creatinine averaged 123-88 )mol/l and glomerular filtration
of IL-1 and IL-2.
Eur J Immunol 1981; 11: 657-61
10 Baron
R, Vignery A, Horowitz M. Lymphocytes, macrophages and the regulation of bone remodeling. In: Peck W, ed Bone and mineral research annual 2. Amsterdam: Elsevier, 1984 175-225.
CUTANEOUS ALTERNARIOSIS RESPONDING TO KETOCONAZOLE
SIR,-Alternaria alternata is an unusual cause of infection and we of no more than fifty reported cases. Most were cutaneous infections but invasive altemariosis has been described in
are aware
immunocompromised patients.’1 An 80-year-old farmer was admitted to hospital with a history of dermatopolymyositis. He had been well until 4 months earlier when he began to feel tired with progressive weakness of the legs. He could not get up or walk without help. Examination revealed extensive wasting of the muscles proximally with normal sensitivity and tendon reflexes. Muscle biopsy indicated myositis. On his right arm he had a violaceous plaque with dry crusts. He recalled a minor injury from a reed 2 years earlier. The patient started treatment with azathioprine and prednisone and the plaque grew rapidly. Biopsy revealed intradermal