1251
islet cell HSP. During polyacrylamide gel electrophoresis, the 64 kD autoantigen (obtained by immunoprecipitation with 64 kD autoantibody-containing patient sera) and the constituently expressed islet cell HSP 65 (identified as 60 kD and obtained with the IT-13 antibody) showed distinct differences in migration. In competition studies, with 64 kD autoantibody-containing sera of IT-13 antibody as preclearing reagents, the 64 kD autoantigen and HSP 65 proteins were immunocompetitively distinct. A physiological difference between the two proteins is also suggested, in that the quantity of the 64 kD islet-cell autoantigen under heat-shock conditions was substantially lower than that obtained by labelling islets at 37°C. Finally, recent data’ indicate that the 64 kD protein corresponds to the enzyme glumatic acid decarboxylase. We have experimental evidence that concurs with this report. Although our experiments do not support the hypothesis that IDDM in man is associated with serological autoimmunity to islet cell HSP or that the 64 kD islet cell autoantigen is an HSP, the question of whether cellular restricted immunity to islet cell HSP exists within the disease process is under
investigation. Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
Department of Surgery, Washington University School of Medicine, St Louis, Missouri
MARK A. ATKINSON NOEL K. MACLAREN
less than that in the adult, the F/M ratio being about 0-2 for guineapig and 0 005-0 04 for monkey cerebrum and cerebellum. 5,6 In the sheep uptake was much the same (2-11 p.g/g) in fetal and maternal cerebrum. Postnatally, mercury in the liver is redistributed and it is excreted by the kidney.? Temporary trapping of Hg in the fetal liver and dilution by the increase in body mass might reduce exposure and avoid concentration peaks in vulnerable organs such as the brain. The assumption by Vimy et aP that from placental histology alone one might expect a human fetus to receive a greater proportion of a given dose of dental amalgam Hg than a sheep fetus is refuted by the experimental F/M ratios reviewed here and by clinical observations. B-Hg has been measured in female dental personnel and their newborn babies and in non-exposed controls.8 Erythrocyte F/M ratios were 1 15 in the exposed group and 1 11 in the controls, and plasma ratios were 0-88 and 0-93, respectively. These results indicate that fetal exposure to metallic mercury does not exceed that of the mother, and that daily uptake of mercury from dental amalgam is very low (2-5 flg),9 occupational exposure also being very 10w.1O Clinical and experimental data do not warrant restriction of amalgam therapy in pregnant patients or work limitations for dental staff in clinics with good occupational hygiene. Department of Odontological Toxicology, Karolinska Institute,
DAVID W. SCHARP
S-141 04
1. 1. Atkinson
MA, Maclaren NK What causes diabetes? Sci Am 1990; 263: 62-67. 2 Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982; 298: 167-69 3. Atkinson MA, Maclaren NK, Scharp DW, Lacy PE, Riley WJ. 64 000 Mr autoantibodies as predictors of insulin dependent diabetes. Lancet 1990; 335: 1357-60. 4. Elias D, Markovits D, Reshef T, van der Zee R, Cohen IR. Induction and therapy of autoimmune diabetes in the non-obese diabetic mouse by a 65-KDa heat shock protein. Proc Nat Acad Sci USA 1990; 87: 1570-80. 5. Results of a World Health Organisation-sponsored workshop to characterise antigens recognised by mcycobacterium-specific monoclonal antibodies. Infect Immun 1986; 51: 719-32. 6 Welch WJ, Mizzen LA, Arrigio AP Structure and function of mammaliam stress proteins. In: Pardue ML, Feramisco JR, Lindquist S, eds. Stress-induced proteins. New York. Alan R Liss, 1989: 187-201. 7 Baekkeskov S, Jan-Aanstoot H, Chnstgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56.
Placental transfer of mercury from
K. S. LARSSON G.-B. SAGULIN
Socialstyrelsens Expertgrupp. Kvicksilver/amalgam halsorisker.
Stockholm: Modin-
Tryck, 1987 2. Strubelt O, Schiele R, Estler C-J. Zur Frag der Embruotoxizitat von Quecksilber aus Amalgamfullungen. Zanazarztl Mitteil 1988; 78: 641-46. 3. Vimy MJ, Takahashi Y, Lorscheider FL. Maternal-fetal distribution of mercury (203Hg) released from dental amalgam fillings. Am J Physiol 1990; 258: R939-45. 4. Clarkson TW, Magos L, Greenwood MR. The transport of elemental mercury into fetal tissues. Biol Neonat 1972; 21: 239-44. 5. Yoshida M, Yamamura Y, Satoh H Distribution of mercury in guinea pig offspring after in utero exposure to mercury vapor during late gestation. Arch Toxicol 1986; 58: 225-28. 6. Smith RG, et al, 1970 In: Clayton GD, Clayton FE, eds. Patty’s industrial hygiene and toxicology: vol 2A. New York: John Wiley, 1981: 1780-82. 7. Yoshida M, Satoh H, Aoyama H, Kojima S, Yamamura Y. Distribution of mercury in neonatal guinaepigs after exposure to mercury vapor. Bull Envir Contam Toxicol 1989; 43: 697-704. 8. Wannag A, Skjaerasen J. Mercury accumulation in placenta and foetal membranes: a study of dental workers and their babies. Environ Physiol Biochem 1975; 5: 348-52. 9. Langworth S, Kolbeck K-G, Akesson A. Mercury exposure from dental fillings. Swed Dent J 1988; 12: 71-72. 10. Nilsson B, Nilsson B. Mercury in dental practice. Swed Dent J 1986; 10: 1-14.
amalgam
SIR,-An assumption that mercury vapour from dental amalgam poses a teratogenic risk1 was questioned by Strubelt et al. However, Vimy et al, in their study of the placental transfer of mercury from amalgam fillings in pregnant ewes, conclude: "dental amalgam as a tooth restorative material in pregnant women and children should be reconsidered".3 This verdict is referred to in the mass media with
disconcerting frequency. metallic mercury can be expressed as the ratio of fetal (F) to maternal (M) mercury concentration in the blood or in organs such as the liver and brain. Mercury passes biological membranes by passive diffusion so the F/M-ratio for blood mercury (B-Hg) would not be expected to exceed 1. In Vimy’s study twelve amalgam fillings with radioactive mercury (ZO3Hg) were placed in the teeth of five ewes on gestation day 112. The F/M ratio for B-Hg in the sheep3 was 4, in contrast to about 03 in the rat after inhalation for 25 min.4 After inhalation of mercury at 200-300 Ilgfm3 for 2 hours a day for 4, 5, 7, 10, or 11 days the F/M ratio in guineapigs varied from 0to 0-5. A pregnant stumptailed monkey exposed via inhalation to 500 f.lgfm3 for about 20 weeks had a miscarriage; the F/M ratio for B-Hg was 0’16." The F/M ratio in sheep during late gestation indicates that mercury is transported across the placental barrier not only by passive diffusion but also by active transport. In the fetal rat, guineapig, and monkey the only organ in which the Hg concentration exceeded that of the mother was the liver. By contrast, the liver of the lamb showed one-tenth of the maternal hepatic uptake of 1000 pg/g.3 Hg uptake in the fetal brain is much
Fetal exposure to
Huddinge, Sweden
Kaposi’s sarcoma associated with captopril SiR,—Adverse effects reported with captopril include rashes, pemphigus-like lesions, angio-oedema of the face and mucous membranes, pityriasis-like eruption, alopecia, exfoliative dermatitis, photosensitivity, and lichenoid eruption.1,2 All are reversible when the dosage of captopril is reduced or the drug is discontinued.3 We report a 70-year-old Italian heterosexual man who presented with a 2 month history of three nodular angiomatous lesions on his left arm. He had essential hypertension and no history of allergic drug reaction, and had been treated for 6 years with captopril (’Lopril’), 75 mg per day orally, and acebutolol (’Sectral’), 200 mg per day orally, without complication. He had no history of drug product transfusion, intravenous drugs, or opportunistic infections. Clinical and histopathological findings were typical of Kaposi’s sarcoma (KS). No fever, fatigue, anorexia, or lymphadenopathy were associated with the illness. Systems were otherwise unremarkable. Tests for anti-HIV antibody and HIV antigen were negative. T4/T8 lymphocyte ratio was 1.2 with 802 T4 cells/[tl. Captopril was stopped. After 1 month the KS lesions had begun to disappear, and after 3 months no lesions of KS were seen. Biopsy showed residual features of KS. Many factors contribute to the aetiology of KS; captopril has not previously been described as one of these factors. Captopril has in-viv04 in in-vitros immunosuppressive effects. A 50% reduction of lymphocytic proliferation was observed during captopril
islet cell HSP. During polyacrylamide gel electrophoresis, the 64 kD autoantigen (obtained by immunoprecipitation with 64 kD autoantibody-containing patient sera) and the constituently expressed islet cell HSP 65 (identified as 60 kD and obtained with the IT-13 antibody) showed distinct differences in migration. In competition studies, with 64 kD autoantibody-containing sera of IT-13 antibody as preclearing reagents, the 64 kD autoantigen and HSP 65 proteins were immunocompetitively distinct. A physiological difference between the two proteins is also suggested, in that the quantity of the 64 kD islet-cell autoantigen under heat-shock conditions was substantially lower than that obtained by labelling islets at 37°C. Finally, recent data’ indicate that the 64 kD protein corresponds to the enzyme glumatic acid decarboxylase. We have experimental evidence that concurs with this report. Although our experiments do not support the hypothesis that IDDM in man is associated with serological autoimmunity to islet cell HSP or that the 64 kD islet cell autoantigen is an HSP, the question of whether cellular restricted immunity to islet cell HSP exists within the disease process is under
investigation. Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
Department of Surgery, Washington University School of Medicine, St Louis, Missouri
MARK A. ATKINSON NOEL K. MACLAREN
less than that in the adult, the F/M ratio being about 0-2 for guineapig and 0 005-0 04 for monkey cerebrum and cerebellum. 5,6 In the sheep uptake was much the same (2-11 p.g/g) in fetal and maternal cerebrum. Postnatally, mercury in the liver is redistributed and it is excreted by the kidney.? Temporary trapping of Hg in the fetal liver and dilution by the increase in body mass might reduce exposure and avoid concentration peaks in vulnerable organs such as the brain. The assumption by Vimy et aP that from placental histology alone one might expect a human fetus to receive a greater proportion of a given dose of dental amalgam Hg than a sheep fetus is refuted by the experimental F/M ratios reviewed here and by clinical observations. B-Hg has been measured in female dental personnel and their newborn babies and in non-exposed controls.8 Erythrocyte F/M ratios were 1 15 in the exposed group and 1 11 in the controls, and plasma ratios were 0-88 and 0-93, respectively. These results indicate that fetal exposure to metallic mercury does not exceed that of the mother, and that daily uptake of mercury from dental amalgam is very low (2-5 flg),9 occupational exposure also being very 10w.1O Clinical and experimental data do not warrant restriction of amalgam therapy in pregnant patients or work limitations for dental staff in clinics with good occupational hygiene. Department of Odontological Toxicology, Karolinska Institute,
DAVID W. SCHARP
S-141 04
1. 1. Atkinson
MA, Maclaren NK What causes diabetes? Sci Am 1990; 263: 62-67. 2 Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982; 298: 167-69 3. Atkinson MA, Maclaren NK, Scharp DW, Lacy PE, Riley WJ. 64 000 Mr autoantibodies as predictors of insulin dependent diabetes. Lancet 1990; 335: 1357-60. 4. Elias D, Markovits D, Reshef T, van der Zee R, Cohen IR. Induction and therapy of autoimmune diabetes in the non-obese diabetic mouse by a 65-KDa heat shock protein. Proc Nat Acad Sci USA 1990; 87: 1570-80. 5. Results of a World Health Organisation-sponsored workshop to characterise antigens recognised by mcycobacterium-specific monoclonal antibodies. Infect Immun 1986; 51: 719-32. 6 Welch WJ, Mizzen LA, Arrigio AP Structure and function of mammaliam stress proteins. In: Pardue ML, Feramisco JR, Lindquist S, eds. Stress-induced proteins. New York. Alan R Liss, 1989: 187-201. 7 Baekkeskov S, Jan-Aanstoot H, Chnstgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56.
Placental transfer of mercury from
K. S. LARSSON G.-B. SAGULIN
Socialstyrelsens Expertgrupp. Kvicksilver/amalgam halsorisker.
Stockholm: Modin-
Tryck, 1987 2. Strubelt O, Schiele R, Estler C-J. Zur Frag der Embruotoxizitat von Quecksilber aus Amalgamfullungen. Zanazarztl Mitteil 1988; 78: 641-46. 3. Vimy MJ, Takahashi Y, Lorscheider FL. Maternal-fetal distribution of mercury (203Hg) released from dental amalgam fillings. Am J Physiol 1990; 258: R939-45. 4. Clarkson TW, Magos L, Greenwood MR. The transport of elemental mercury into fetal tissues. Biol Neonat 1972; 21: 239-44. 5. Yoshida M, Yamamura Y, Satoh H Distribution of mercury in guinea pig offspring after in utero exposure to mercury vapor during late gestation. Arch Toxicol 1986; 58: 225-28. 6. Smith RG, et al, 1970 In: Clayton GD, Clayton FE, eds. Patty’s industrial hygiene and toxicology: vol 2A. New York: John Wiley, 1981: 1780-82. 7. Yoshida M, Satoh H, Aoyama H, Kojima S, Yamamura Y. Distribution of mercury in neonatal guinaepigs after exposure to mercury vapor. Bull Envir Contam Toxicol 1989; 43: 697-704. 8. Wannag A, Skjaerasen J. Mercury accumulation in placenta and foetal membranes: a study of dental workers and their babies. Environ Physiol Biochem 1975; 5: 348-52. 9. Langworth S, Kolbeck K-G, Akesson A. Mercury exposure from dental fillings. Swed Dent J 1988; 12: 71-72. 10. Nilsson B, Nilsson B. Mercury in dental practice. Swed Dent J 1986; 10: 1-14.
amalgam
SIR,-An assumption that mercury vapour from dental amalgam poses a teratogenic risk1 was questioned by Strubelt et al. However, Vimy et al, in their study of the placental transfer of mercury from amalgam fillings in pregnant ewes, conclude: "dental amalgam as a tooth restorative material in pregnant women and children should be reconsidered".3 This verdict is referred to in the mass media with
disconcerting frequency. metallic mercury can be expressed as the ratio of fetal (F) to maternal (M) mercury concentration in the blood or in organs such as the liver and brain. Mercury passes biological membranes by passive diffusion so the F/M-ratio for blood mercury (B-Hg) would not be expected to exceed 1. In Vimy’s study twelve amalgam fillings with radioactive mercury (ZO3Hg) were placed in the teeth of five ewes on gestation day 112. The F/M ratio for B-Hg in the sheep3 was 4, in contrast to about 03 in the rat after inhalation for 25 min.4 After inhalation of mercury at 200-300 Ilgfm3 for 2 hours a day for 4, 5, 7, 10, or 11 days the F/M ratio in guineapigs varied from 0to 0-5. A pregnant stumptailed monkey exposed via inhalation to 500 f.lgfm3 for about 20 weeks had a miscarriage; the F/M ratio for B-Hg was 0’16." The F/M ratio in sheep during late gestation indicates that mercury is transported across the placental barrier not only by passive diffusion but also by active transport. In the fetal rat, guineapig, and monkey the only organ in which the Hg concentration exceeded that of the mother was the liver. By contrast, the liver of the lamb showed one-tenth of the maternal hepatic uptake of 1000 pg/g.3 Hg uptake in the fetal brain is much
Fetal exposure to
Huddinge, Sweden
Kaposi’s sarcoma associated with captopril SiR,—Adverse effects reported with captopril include rashes, pemphigus-like lesions, angio-oedema of the face and mucous membranes, pityriasis-like eruption, alopecia, exfoliative dermatitis, photosensitivity, and lichenoid eruption.1,2 All are reversible when the dosage of captopril is reduced or the drug is discontinued.3 We report a 70-year-old Italian heterosexual man who presented with a 2 month history of three nodular angiomatous lesions on his left arm. He had essential hypertension and no history of allergic drug reaction, and had been treated for 6 years with captopril (’Lopril’), 75 mg per day orally, and acebutolol (’Sectral’), 200 mg per day orally, without complication. He had no history of drug product transfusion, intravenous drugs, or opportunistic infections. Clinical and histopathological findings were typical of Kaposi’s sarcoma (KS). No fever, fatigue, anorexia, or lymphadenopathy were associated with the illness. Systems were otherwise unremarkable. Tests for anti-HIV antibody and HIV antigen were negative. T4/T8 lymphocyte ratio was 1.2 with 802 T4 cells/[tl. Captopril was stopped. After 1 month the KS lesions had begun to disappear, and after 3 months no lesions of KS were seen. Biopsy showed residual features of KS. Many factors contribute to the aetiology of KS; captopril has not previously been described as one of these factors. Captopril has in-viv04 in in-vitros immunosuppressive effects. A 50% reduction of lymphocytic proliferation was observed during captopril
