253
in their period of rapid growth. Much more comparable to the latter were the large population movements in mainland Greece from rural areas to the towns during its civil war, the 1950s and beyond, and about which much has been written. Indeed, the recent urbanisation of Greece has been more rapid than in most countries at a comparable stage of socioeconomic development. In consequence, for example, whereas 27% of the nation lived below an altitude of 100 m in 1951, this had risen to 55% in 1961.3 This could be investigated by examining mortality from childhood leukaemia in Greece in relation to that of other countries in the 1960s, when modem therapy had not yet affected national rates. towns
Department of Public Health and Primary Care, CRC Cancer Epidemiology Research Group, University of Oxford, Radcliffe Infirmary, Oxford 0X2 6HE, UK 1. Kinlen
L. J. KINLEN
LJ, Clarke K, Hudson C. Evidence from population mixing in British new
1946-85 of an infective basis for childhood leukaemia. Lancet 1990; 336: 577-82. 2 Kinlen LJ, Hudson C. Childhood leukaemia and poliomyelitis in relation to military encampments m England and Wales in the period of national military service 1950-63 Br Med J 1991; 303: 1357-62. 3. Carter FW. In Clout HD, ed. Regional development of Western Europe. London: David Fulton, 1987: chap 18. towns
Fashions in
breastfeeding
SiR,-It is often amazing what medical publications are noticed and how their findings are implemented. A new fashion in breastfeeding in Australia is that mothers are being told to feed from only one breast at each feed. The most extreme example of this type of advice was a woman with twins who was told to feed both babies from the same (one) breast at each feed. This fashion seems to come from overinterpretation of studies such as that by Woolridge and Fisher.1 They suggested that failure to thrive in some babies might have resulted from a lack of higher-energy hind-milk if the mother follows the timed feeds on each side routine. But in fact Woolridge and Fisher’ actually stated that the baby should "come off the breast spontaneously before being offered the second breast should the baby still show signs of hunger". Moreover, a recent study has shown that the amount of milk in a breast varies before each feed and that the fat content of breastmilk does not increase substantially until the breast is 40% empty.2Therefore this new fashion will probably have little effect on the average infant’s fat intake at any particular feed whereas it may lead to discomfort for the mother. We seem to have replaced one dogma with another, equally unfounded. Department of Public Health, University of Sydney, NSW 2006, Australia
DOROTHY MACKERRAS
1. Woolridge MW, Fisher C. Colic, "overfeeding", and symptoms of malabsorption in the breast-fed baby: a possible artifact of feed management? Lancet 1987; ii: 382-84. 2 Daly SEJ, Kent JC, Atwood CS, et al. Breastmilk fat content increases with the degree of breast emptying. Proc Nutr Soc Aust 1991; 16: 126.
Catamenial an
epilepsy and goserelin
SIR,-Dr Haider and Professor Barnett (Dec 14, p 1530) report improvement in seizure frequency in catamenial epilepsy treated
with goserelin. They suggest that reduction of serum oestradiol concentrations with this gonadotropin releasing hormone (GnRH) analogue might explain the improvement. We propose that the abolition of cyclical fluctuations of sex steroids might be the mechanism. In premenstrual syndrome (PMS), menstrual migraine, and catamenial epilepsy, the cause of the cyclical features remains elusive. It is recognised, however, that complete suppression of ovarian activity can abolish these symptoms.1,2 The hypo-oestrogenic state induced by GnRH therapy indicates effective ovarian suppression and the clinical improvement described could be due to the elimination of cyclical changes in ovarian hormones. We would caution against long-term therapy with a GnRH analogue, which effectively creates a medical oophorectomy. Prolonged hypo-oestrogenism significantly increases the risk of osteoporosis and cardiovascular disease.3,4Additionally, patients
commonly experience flushing, vaginal dryness, and dyspareunia.5 replacement therapy (HRT) can prevent such complications, and we have reported the long-term use of goserelin with continuous combined HRT in a patient with severe endometriosis.6 We used goserelin 3-6 mg every 4 weeks with medroxyprogesterone acetate (’Provera’) 5 mg and conjugated Hormone
(’Premarin’) 0625 mg, both taken daily and continuously. The endometriosis resolved, she remained amenorrhoeic, and preservation of bone-mineral density was confirmed by dual-energy X-ray absorptiometry. No hypooestrogenic symptoms were seen during 12 months of treatment. We propose that continuous combined HRT supplementation6 will not negate the benefits of goserelin. Cyclical changes of ovarian hormones rather than their absolute concentrations are now widely believed to be important in the genesis of menstrually related disorders. Thus, it is not surprising that the combined oral contraceptive pill, with its seven day pill-free interval, was not effective. Premarin 0 625 mg daily is a bone-conserving doseand might protect the cardiovascular system.’ oestrogens
Department of Obstetrics and Gynaecology, St Mary’s Hospital Medical School, London W2 1PG, UK
B. A. REID K. F. GANGAR
Magos A. Advances in the treatment of the premenstrual syndrome. Br J Obstet Gynaecol 1990; 97: 7-11 2. Magos AL, Zilkhar KJ, Studd JWW. Treatment of menstrual migraine by oestradiol implants. J Neurol Neurosurg Psychiatry 1983, 46: 1044. 3. Dodm S, Lemay AS, Maheux R, Dumont M, Turcot-Lemay L. Bone mass in endometriosis patients treated with GnRH agonist implant or danazol. Obstet Gynecol 1991, 77: 410-15. 4. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten year follow-up from the nurses’ health study. N Engl J Med 1991; 325: 756-62. 5. Shaw RW. LHRH analogue in the treatment of endometriosis: comparative results with other treatment. Ballière’s Clin Obstet Gynaecol 1988; ii: 659-75. 6. Reid BA, Gangar KF, Beard RW. Severe endometriosis treated with gonadotrophin releasing hormone agonist and continuous combined hormone replacement therapy. Br J Obstet Gynaecol (in press). 7. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990; 336: 265-69. 1.
Post-transfusion fulminant hepatitis B after screening for hepatitis B virus core antibody SIR,-Since November, 1989, Japanese Red Cross Blood Centres have screened blood for units with high-titre (2) antibody to hepatitis B virus core antigen (HBcAb) in addition to hepatitis B surface antigen (HBsAg) and surface antibody (HBsAb). The aim of the introduction of the additional HBcAb screening is to reduce the frequency of post-transfusion hepatitis B infection, especially of the fulminant type. The Japanese Red Cross Non-A, Non-B Hepatitis Research Group report (Oct 26, p 1040) complete protection from post-transfusion hepatitis B since the introduction of screening for HBcAb. We have seen the first case of posttransfusion fulminant hepatitis B since the start of this screening. A 70-year-old man was admitted to Showa University Fujigaoka Hospital on Sept 19, 1991, because of fever and jaundice. He had undergone resection of the entire transverse colon because of carcinoma on April 12 of that year. At operation he received four units of blood from four donors. His liver disease began with a slight fever and urine colour change at the beginning of September. On admission he was jaundiced, and liver atrophy was confirmed by ultrasonography. Total bilirubin was 110 mg/dl, aspartate aminotransferase 821 U/1, alanine aminotransferase 940 U/1, and prothrombin time (PT) 43-8%. He was positive for HBsAg, HBeAg, IgM HBcAb, and HBV DNA (by polymerase chain reaction (PCR), and negative for HBsAb, HBeAg, IgM HAVAb, and HCVAb (anti-Cl00). Subsequently PT became undetectable, and grade IIcoma developed on Oct 21. He was immediately placed on liver-support treatment, consisting of plasma exchange and haemofiltration.1 After three such treatments he regained clear consciousness with recovery of liver functions. He continued to improve and was discharged on October 26. The original serum samples from the four blood donors were not available for HBV DNA assay by PCR. The donors, however, were traced by the Japanese Red Cross Kawasaki Blood Centre, and they
254
tested again for HBV serum markers. A serum sample from donor (26-year-old man) proved positive for HBsAb and HBcAb. He had been admitted to a nearby hospital because of liver function abnormalities two months after he gave blood. The hospital record clearly showed that he had contracted typical acute hepatitis B infection. These findings show that, as predicted,2 post-transfusion fulminant hepatitis B infection can occur even after the introduction of blood screening for high-titre HBcAb, through blood from donors who, although acutely infected with HBV, are both HBsAg and HBcAb negative at the time of donation. were
one
M. YOSHIBA K. SEKIYAMA F. SUGATA
Division of Gastroenterology, Showa University Fujigaoka Hospital, Midori-Ku, Yokohama 227, Japan
Y. KAWAMOTO
H. MURAOKA M. AOYAMA
Japanese Red Cross, Kawasaki Blood Centre
M, Yamada H, Yoshikawa Y, et al. Hemodiafiltration treatment of deep hepatic coma by protein passing membrane case report. Artif Organs 1986; 10:
1. Yoshiba
used since it was prepared by Distillers Biochemicals from penicillin which, on hydrolysis, yields the D isomer only. In the United States penicillamine for clinical trials was synthesised from D,L-valine and the D and L forms were not separated, hence the case of optic neuritis described by Tu et al.’ After this report D,L-penicillamine was withdrawn and now only the D isomer is available. However, even D-penicillamine can mimic the antipyridoxine action of the L isomer if given in large doses and under certain specific circumstances such as pregnancy or during a growth spurt.4 In 1991 a case of optic neuritis induced by D-penicillamine was reported.s Kean et al seem to imply that the penicillamine-copper chelate is a simple 2-to-lI combination. The evidence suggests many penicillamine molecules binding copper (I) and (II) in a ratio of 14 to 12, though it does not follow that the chelate formed in vitro is was
that which occurs in vivo,7 where other aminoacids and albumin may be involved. Department of Neurology, Middlesex Hospital, London W1 N 8AA, UK
J. M. WALSHE
417-21. 2.
Hoofnagle JH. Editorial: posttransfusion hepatitis B Transfusion 1990; 30:
384-86.
Cyclosporin and muscle SIR,-Arellano and Krupp/ in their review of muscle disorders associated with cyclosporin, referred to three cases of possible muscular toxicity published by our group in 1989.2 In the table they state that biopsy was not done in two of our patients and that all had received prednisone. This is incorrect. Our report noted that biopsy, with examination by electronmicroscopy, was done in all cases, and all three had abnormalities. Moreover prednisone had been discontinued several months before myopathy developed. The statement that electromyograms were normal in our three cases is not true either, since our first case had an abnormal electromyogram. Arellano and Krupp have not read our report carefully, and it is very regrettable that Sandoz’ drug monitoring centre shall have recorded incorrect information, with the risk of the possible myotoxicity of cyclosporin being underrated. Division of
Cardiology and Pathology, CHU Vaudois,
J.-J. GOY J. P. DERUAZ
1011 Lausanne, Switzerland 1. Arellano
F, Krupp
P. Muscular disorders associated with
cyclosporin
Lancet 1991;
337: 915 2.
Goy JJ, Stauffer SC, Deruaz JP, et al. Myopathy cyclosporin. Lancet 1989, i: 1446-47.
as a
possible side-effect of
***This letter has been shown to Dr Arellano and Professor Krupp, reply follows.-ED. L. SIR,-We regret the misquotation of Dr Goy and colleagues’ report. Despite this oversight, we feel that the conclusions in our letter were not inappropriate. Indeed, our review has resulted in amendments to international product information on ’Sandimmun’. Myopathy is now mentioned as a side-effect and colchicine and lovastatin are noted as possible drug interactions leading to muscular toxicity. It was never our intention to underrate the myotoxicity of cyclosporin.
whose
Drug Monitoring Centre, Sandoz Pharma, 4002 Basle, Switzerland
F. ARELLANO P. KRUPP
Chirality of penicillamine SIR,-In their review on chirality and antirheumatic drugs Dr Kean and colleagues (Dec 21/28, p 1565) pay special attention to the D (or S) and the L (or R) enantiomers of penicillamine and refer to their work to illustrate optic neuritis induced by using D,L-penicillamine. That manifestation of L-penicillamine toxicity had been known since 1963/ and the original description of L-penicillamine toxicity can be traced back to the work of Wilson and Du Vigneaud in 1950/* In my 1956 article on the therapeutic potential of penicillamine for Wilson’s disease I stressed the differential toxicity of the D and L forms and recommended that the D form be used in clinical trials.’ In the UK D-penicillamine only
J-b, Blackwell RQ, Lee P-F. DL-penicillamine as a cause of optic axial neuritis JAMA 1963; 185: 83-86. 2. Wilson JE, Du Vigneaud V. Inhibition of growth in the rat by 1-penicillamine and its prevention by aminoethanol and related compounds J Biol Chem 1950; 312: 63-70. 3. Walshe JM. Penicillamine, a new oral therapy for Wilson’s disease Am J Med 1956, 1. Tu
21: 487-95. 4. Gibbs K, Walshe JM. Interruption of the tryptophan-nicotinic acid pathway by penicillamine induced pyridoxine deficiency in patients with Wilson’s disease and in experimental animals Ann NY Acad Sci 1969; 166: 158-69. 5. Lee A. Lawton NF. Penicillamine treatment of Wilson’s disease and optic neuropathy J Neurol Neurosurg Psychiatry 1991; 58: 746 6. Laurie SH, Prime DN. The formation and nature of the mixed valence copper-dpenicillamine-chloride cluster in aqueous solution and its relevance to the treatment of Wilson’s disease. J Inorgan Biochem 1979; 11: 229-39.
Two types of translucent membrane of caesarean section scar tissue SIR,-Pedowitz and Schwartz have reported that translucent membrane of transverse caesarean section scar tissue and incomplete uterine rupture occurred in 8-3% (22/266) patients at repeat caesarean section.’ We have graded findings at repeat caesarean section as follows: grade 1, neither thinning nor loss of continuity of lower uterine segment; grade II, thinning and loss of continuity but fetal hair not visible; grade III thinning or absence of lower uterine segment and fetal hair visible. The frequency of grade III was 9-1% (18/197) from September, 1982, until now 2-4 a frequency much the same as that recorded by Pedowitz and Schwartz. However, complete rupture of the lower transverse uterine scar is reported in 0-2-3% of planned trials of labour,s so what type of translucent membrane is it that ruptures during trials of labour-and can ultrasound scans distinguish one type from another? Since February, 1989, we have scanned 45 patients with previous caesarean section by high-resolution ultrasound (SSA-250A, Toshiba). 38 patients showed good healing with a thickness more than 1-2 mm throughout and 7 patients showed poor healing with reduced thickness and/or loss of continuity. Of 38 patients with good healing 10 were delivered vaginally and 28 patients had repeat caesarean section for other obstetric indications. Of 7 patients with poor healing 3 showed grade III operative findings (translucent membrane). The thinnest thickness of the lower uterine segment in these 3 patients near term by ultrasound is shown in the figure. Patient I showed great variability of thickness in the short term (5-10 min) and also over time (37-39 weeks) but patient III showed little variability (static thinning). Before repeat caesarean section in patient I thickness was never less than 0-5 mm and we predicted grade II; the thickness, by ophthalmic calipers, was 0-5 mm at operation. In patient III, with static thinning, thickness was 0-3 mm by ultrasound (7-5 MHz linear probe) before operation and 0-2 mm by ophthalmic calipers at operation. The thinnest portion of the lower uterine segment in patient I (variable thinning) showed good preservation of smooth muscle fibres and a little stromal fibrosis while that of the patient with static thinning showed prominent degeneration and atrophy of muscle fibres and severe stromal fibrosis with hyalinisation.
in their period of rapid growth. Much more comparable to the latter were the large population movements in mainland Greece from rural areas to the towns during its civil war, the 1950s and beyond, and about which much has been written. Indeed, the recent urbanisation of Greece has been more rapid than in most countries at a comparable stage of socioeconomic development. In consequence, for example, whereas 27% of the nation lived below an altitude of 100 m in 1951, this had risen to 55% in 1961.3 This could be investigated by examining mortality from childhood leukaemia in Greece in relation to that of other countries in the 1960s, when modem therapy had not yet affected national rates. towns
Department of Public Health and Primary Care, CRC Cancer Epidemiology Research Group, University of Oxford, Radcliffe Infirmary, Oxford 0X2 6HE, UK 1. Kinlen
L. J. KINLEN
LJ, Clarke K, Hudson C. Evidence from population mixing in British new
1946-85 of an infective basis for childhood leukaemia. Lancet 1990; 336: 577-82. 2 Kinlen LJ, Hudson C. Childhood leukaemia and poliomyelitis in relation to military encampments m England and Wales in the period of national military service 1950-63 Br Med J 1991; 303: 1357-62. 3. Carter FW. In Clout HD, ed. Regional development of Western Europe. London: David Fulton, 1987: chap 18. towns
Fashions in
breastfeeding
SiR,-It is often amazing what medical publications are noticed and how their findings are implemented. A new fashion in breastfeeding in Australia is that mothers are being told to feed from only one breast at each feed. The most extreme example of this type of advice was a woman with twins who was told to feed both babies from the same (one) breast at each feed. This fashion seems to come from overinterpretation of studies such as that by Woolridge and Fisher.1 They suggested that failure to thrive in some babies might have resulted from a lack of higher-energy hind-milk if the mother follows the timed feeds on each side routine. But in fact Woolridge and Fisher’ actually stated that the baby should "come off the breast spontaneously before being offered the second breast should the baby still show signs of hunger". Moreover, a recent study has shown that the amount of milk in a breast varies before each feed and that the fat content of breastmilk does not increase substantially until the breast is 40% empty.2Therefore this new fashion will probably have little effect on the average infant’s fat intake at any particular feed whereas it may lead to discomfort for the mother. We seem to have replaced one dogma with another, equally unfounded. Department of Public Health, University of Sydney, NSW 2006, Australia
DOROTHY MACKERRAS
1. Woolridge MW, Fisher C. Colic, "overfeeding", and symptoms of malabsorption in the breast-fed baby: a possible artifact of feed management? Lancet 1987; ii: 382-84. 2 Daly SEJ, Kent JC, Atwood CS, et al. Breastmilk fat content increases with the degree of breast emptying. Proc Nutr Soc Aust 1991; 16: 126.
Catamenial an
epilepsy and goserelin
SIR,-Dr Haider and Professor Barnett (Dec 14, p 1530) report improvement in seizure frequency in catamenial epilepsy treated
with goserelin. They suggest that reduction of serum oestradiol concentrations with this gonadotropin releasing hormone (GnRH) analogue might explain the improvement. We propose that the abolition of cyclical fluctuations of sex steroids might be the mechanism. In premenstrual syndrome (PMS), menstrual migraine, and catamenial epilepsy, the cause of the cyclical features remains elusive. It is recognised, however, that complete suppression of ovarian activity can abolish these symptoms.1,2 The hypo-oestrogenic state induced by GnRH therapy indicates effective ovarian suppression and the clinical improvement described could be due to the elimination of cyclical changes in ovarian hormones. We would caution against long-term therapy with a GnRH analogue, which effectively creates a medical oophorectomy. Prolonged hypo-oestrogenism significantly increases the risk of osteoporosis and cardiovascular disease.3,4Additionally, patients
commonly experience flushing, vaginal dryness, and dyspareunia.5 replacement therapy (HRT) can prevent such complications, and we have reported the long-term use of goserelin with continuous combined HRT in a patient with severe endometriosis.6 We used goserelin 3-6 mg every 4 weeks with medroxyprogesterone acetate (’Provera’) 5 mg and conjugated Hormone
(’Premarin’) 0625 mg, both taken daily and continuously. The endometriosis resolved, she remained amenorrhoeic, and preservation of bone-mineral density was confirmed by dual-energy X-ray absorptiometry. No hypooestrogenic symptoms were seen during 12 months of treatment. We propose that continuous combined HRT supplementation6 will not negate the benefits of goserelin. Cyclical changes of ovarian hormones rather than their absolute concentrations are now widely believed to be important in the genesis of menstrually related disorders. Thus, it is not surprising that the combined oral contraceptive pill, with its seven day pill-free interval, was not effective. Premarin 0 625 mg daily is a bone-conserving doseand might protect the cardiovascular system.’ oestrogens
Department of Obstetrics and Gynaecology, St Mary’s Hospital Medical School, London W2 1PG, UK
B. A. REID K. F. GANGAR
Magos A. Advances in the treatment of the premenstrual syndrome. Br J Obstet Gynaecol 1990; 97: 7-11 2. Magos AL, Zilkhar KJ, Studd JWW. Treatment of menstrual migraine by oestradiol implants. J Neurol Neurosurg Psychiatry 1983, 46: 1044. 3. Dodm S, Lemay AS, Maheux R, Dumont M, Turcot-Lemay L. Bone mass in endometriosis patients treated with GnRH agonist implant or danazol. Obstet Gynecol 1991, 77: 410-15. 4. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease: ten year follow-up from the nurses’ health study. N Engl J Med 1991; 325: 756-62. 5. Shaw RW. LHRH analogue in the treatment of endometriosis: comparative results with other treatment. Ballière’s Clin Obstet Gynaecol 1988; ii: 659-75. 6. Reid BA, Gangar KF, Beard RW. Severe endometriosis treated with gonadotrophin releasing hormone agonist and continuous combined hormone replacement therapy. Br J Obstet Gynaecol (in press). 7. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990; 336: 265-69. 1.
Post-transfusion fulminant hepatitis B after screening for hepatitis B virus core antibody SIR,-Since November, 1989, Japanese Red Cross Blood Centres have screened blood for units with high-titre (2) antibody to hepatitis B virus core antigen (HBcAb) in addition to hepatitis B surface antigen (HBsAg) and surface antibody (HBsAb). The aim of the introduction of the additional HBcAb screening is to reduce the frequency of post-transfusion hepatitis B infection, especially of the fulminant type. The Japanese Red Cross Non-A, Non-B Hepatitis Research Group report (Oct 26, p 1040) complete protection from post-transfusion hepatitis B since the introduction of screening for HBcAb. We have seen the first case of posttransfusion fulminant hepatitis B since the start of this screening. A 70-year-old man was admitted to Showa University Fujigaoka Hospital on Sept 19, 1991, because of fever and jaundice. He had undergone resection of the entire transverse colon because of carcinoma on April 12 of that year. At operation he received four units of blood from four donors. His liver disease began with a slight fever and urine colour change at the beginning of September. On admission he was jaundiced, and liver atrophy was confirmed by ultrasonography. Total bilirubin was 110 mg/dl, aspartate aminotransferase 821 U/1, alanine aminotransferase 940 U/1, and prothrombin time (PT) 43-8%. He was positive for HBsAg, HBeAg, IgM HBcAb, and HBV DNA (by polymerase chain reaction (PCR), and negative for HBsAb, HBeAg, IgM HAVAb, and HCVAb (anti-Cl00). Subsequently PT became undetectable, and grade IIcoma developed on Oct 21. He was immediately placed on liver-support treatment, consisting of plasma exchange and haemofiltration.1 After three such treatments he regained clear consciousness with recovery of liver functions. He continued to improve and was discharged on October 26. The original serum samples from the four blood donors were not available for HBV DNA assay by PCR. The donors, however, were traced by the Japanese Red Cross Kawasaki Blood Centre, and they
254
tested again for HBV serum markers. A serum sample from donor (26-year-old man) proved positive for HBsAb and HBcAb. He had been admitted to a nearby hospital because of liver function abnormalities two months after he gave blood. The hospital record clearly showed that he had contracted typical acute hepatitis B infection. These findings show that, as predicted,2 post-transfusion fulminant hepatitis B infection can occur even after the introduction of blood screening for high-titre HBcAb, through blood from donors who, although acutely infected with HBV, are both HBsAg and HBcAb negative at the time of donation. were
one
M. YOSHIBA K. SEKIYAMA F. SUGATA
Division of Gastroenterology, Showa University Fujigaoka Hospital, Midori-Ku, Yokohama 227, Japan
Y. KAWAMOTO
H. MURAOKA M. AOYAMA
Japanese Red Cross, Kawasaki Blood Centre
M, Yamada H, Yoshikawa Y, et al. Hemodiafiltration treatment of deep hepatic coma by protein passing membrane case report. Artif Organs 1986; 10:
1. Yoshiba
used since it was prepared by Distillers Biochemicals from penicillin which, on hydrolysis, yields the D isomer only. In the United States penicillamine for clinical trials was synthesised from D,L-valine and the D and L forms were not separated, hence the case of optic neuritis described by Tu et al.’ After this report D,L-penicillamine was withdrawn and now only the D isomer is available. However, even D-penicillamine can mimic the antipyridoxine action of the L isomer if given in large doses and under certain specific circumstances such as pregnancy or during a growth spurt.4 In 1991 a case of optic neuritis induced by D-penicillamine was reported.s Kean et al seem to imply that the penicillamine-copper chelate is a simple 2-to-lI combination. The evidence suggests many penicillamine molecules binding copper (I) and (II) in a ratio of 14 to 12, though it does not follow that the chelate formed in vitro is was
that which occurs in vivo,7 where other aminoacids and albumin may be involved. Department of Neurology, Middlesex Hospital, London W1 N 8AA, UK
J. M. WALSHE
417-21. 2.
Hoofnagle JH. Editorial: posttransfusion hepatitis B Transfusion 1990; 30:
384-86.
Cyclosporin and muscle SIR,-Arellano and Krupp/ in their review of muscle disorders associated with cyclosporin, referred to three cases of possible muscular toxicity published by our group in 1989.2 In the table they state that biopsy was not done in two of our patients and that all had received prednisone. This is incorrect. Our report noted that biopsy, with examination by electronmicroscopy, was done in all cases, and all three had abnormalities. Moreover prednisone had been discontinued several months before myopathy developed. The statement that electromyograms were normal in our three cases is not true either, since our first case had an abnormal electromyogram. Arellano and Krupp have not read our report carefully, and it is very regrettable that Sandoz’ drug monitoring centre shall have recorded incorrect information, with the risk of the possible myotoxicity of cyclosporin being underrated. Division of
Cardiology and Pathology, CHU Vaudois,
J.-J. GOY J. P. DERUAZ
1011 Lausanne, Switzerland 1. Arellano
F, Krupp
P. Muscular disorders associated with
cyclosporin
Lancet 1991;
337: 915 2.
Goy JJ, Stauffer SC, Deruaz JP, et al. Myopathy cyclosporin. Lancet 1989, i: 1446-47.
as a
possible side-effect of
***This letter has been shown to Dr Arellano and Professor Krupp, reply follows.-ED. L. SIR,-We regret the misquotation of Dr Goy and colleagues’ report. Despite this oversight, we feel that the conclusions in our letter were not inappropriate. Indeed, our review has resulted in amendments to international product information on ’Sandimmun’. Myopathy is now mentioned as a side-effect and colchicine and lovastatin are noted as possible drug interactions leading to muscular toxicity. It was never our intention to underrate the myotoxicity of cyclosporin.
whose
Drug Monitoring Centre, Sandoz Pharma, 4002 Basle, Switzerland
F. ARELLANO P. KRUPP
Chirality of penicillamine SIR,-In their review on chirality and antirheumatic drugs Dr Kean and colleagues (Dec 21/28, p 1565) pay special attention to the D (or S) and the L (or R) enantiomers of penicillamine and refer to their work to illustrate optic neuritis induced by using D,L-penicillamine. That manifestation of L-penicillamine toxicity had been known since 1963/ and the original description of L-penicillamine toxicity can be traced back to the work of Wilson and Du Vigneaud in 1950/* In my 1956 article on the therapeutic potential of penicillamine for Wilson’s disease I stressed the differential toxicity of the D and L forms and recommended that the D form be used in clinical trials.’ In the UK D-penicillamine only
J-b, Blackwell RQ, Lee P-F. DL-penicillamine as a cause of optic axial neuritis JAMA 1963; 185: 83-86. 2. Wilson JE, Du Vigneaud V. Inhibition of growth in the rat by 1-penicillamine and its prevention by aminoethanol and related compounds J Biol Chem 1950; 312: 63-70. 3. Walshe JM. Penicillamine, a new oral therapy for Wilson’s disease Am J Med 1956, 1. Tu
21: 487-95. 4. Gibbs K, Walshe JM. Interruption of the tryptophan-nicotinic acid pathway by penicillamine induced pyridoxine deficiency in patients with Wilson’s disease and in experimental animals Ann NY Acad Sci 1969; 166: 158-69. 5. Lee A. Lawton NF. Penicillamine treatment of Wilson’s disease and optic neuropathy J Neurol Neurosurg Psychiatry 1991; 58: 746 6. Laurie SH, Prime DN. The formation and nature of the mixed valence copper-dpenicillamine-chloride cluster in aqueous solution and its relevance to the treatment of Wilson’s disease. J Inorgan Biochem 1979; 11: 229-39.
Two types of translucent membrane of caesarean section scar tissue SIR,-Pedowitz and Schwartz have reported that translucent membrane of transverse caesarean section scar tissue and incomplete uterine rupture occurred in 8-3% (22/266) patients at repeat caesarean section.’ We have graded findings at repeat caesarean section as follows: grade 1, neither thinning nor loss of continuity of lower uterine segment; grade II, thinning and loss of continuity but fetal hair not visible; grade III thinning or absence of lower uterine segment and fetal hair visible. The frequency of grade III was 9-1% (18/197) from September, 1982, until now 2-4 a frequency much the same as that recorded by Pedowitz and Schwartz. However, complete rupture of the lower transverse uterine scar is reported in 0-2-3% of planned trials of labour,s so what type of translucent membrane is it that ruptures during trials of labour-and can ultrasound scans distinguish one type from another? Since February, 1989, we have scanned 45 patients with previous caesarean section by high-resolution ultrasound (SSA-250A, Toshiba). 38 patients showed good healing with a thickness more than 1-2 mm throughout and 7 patients showed poor healing with reduced thickness and/or loss of continuity. Of 38 patients with good healing 10 were delivered vaginally and 28 patients had repeat caesarean section for other obstetric indications. Of 7 patients with poor healing 3 showed grade III operative findings (translucent membrane). The thinnest thickness of the lower uterine segment in these 3 patients near term by ultrasound is shown in the figure. Patient I showed great variability of thickness in the short term (5-10 min) and also over time (37-39 weeks) but patient III showed little variability (static thinning). Before repeat caesarean section in patient I thickness was never less than 0-5 mm and we predicted grade II; the thickness, by ophthalmic calipers, was 0-5 mm at operation. In patient III, with static thinning, thickness was 0-3 mm by ultrasound (7-5 MHz linear probe) before operation and 0-2 mm by ophthalmic calipers at operation. The thinnest portion of the lower uterine segment in patient I (variable thinning) showed good preservation of smooth muscle fibres and a little stromal fibrosis while that of the patient with static thinning showed prominent degeneration and atrophy of muscle fibres and severe stromal fibrosis with hyalinisation.
