- Email: [email protected]
Homocyst(e)inaemia and bone density in elderly women
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sequences were identical to those in brain. The sequence we have obtained for GAD65 is identical to that reported as GAD-210 while GAD67 has 100% similarity with the partial human testis sequence. Northern blot analysis showed that both transcripts are present at comparable levels in the brain, whereas in the endocrine pancreas GAD65 is expressed at a much higher level than GAD67. These results suggest that GAD, an autoantigen in type I diabetes and SMS, is encoded by the same genes in both human brain and pancreatic islets and that the structure of the mRNAs in the two tissues is the same. GAD transcripts in the islet and in the brain thus differ only quantitatively. Differences in anti-GAD response in the two autoimmune conditions cannot therefore be ascribed to different GAD sequences, although post-translational modifications in the two tissues cannot be excluded. Now that the sequences of both GAD isoforms are known it should be possible to map the epitope(s) recognised by the antibodies and to study B and T lymphocyte reactions to GAD in these two different autoimmune diseases.
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
ROBERTO GIORDA
Department of Immunology, King’s College School of Medicine and Dentistry,
MARK PEAKMAN
London SE5 9PJ, UK
Department of Surgery,
King’s College Hospital,
Homocyst(e)inaemia and bone density in elderly women SIR,—When we reported (Aug 10, p 355) that low bone density associated with stroke mortality in elderly women we speculated that the association might be a result of Moderately hyperhomocyst(e)inaemia. high levels of homocyst(e)ine in blood have been associated with stroke,’-3 and the was
homozygous form of the disorder (homocystinuria) causes premature stroke, myocardial infarction, and severe osteoporosis.4 To test the hypothesis we investigated homocyst(e)ine concentrations in 23 women aged 65-80 randomly selected from participants in our study of osteoporotic fractures whose bone density was in the highest decile for age, and in 23 age-matched (within 1 year) participants whose bone density was in the lowest decile. Bone density was measured at the distal radius by single photon absorptiometry. Serum taken when the bone density measurements were made was frozen at - 20°C for up to 2 weeks and then at -190°C for up to 3 years. Homocyst(e)ine was assayed blindly by high-pressure liquid chromatography with electrochemical detection. ("Homocyst(e)ine", expressed as homocysteine, refers to the sum of homocysteine and the homocysteinyl moieties of the disulphides homocystine and cysteine-homocysteine, whether free or bound to proteins.) Homocyst(e)ine values ranged from 4-95 to 17.49 nmol/ml and the mean (SD) was 8-66 (3-05) in the 23 women in the highest decile of bone density, and 8-31 ( 1 62) nmol/ml in those in the lowest decile (p=0’63 by paired t-test, 95% confidence interval for difference 1 16 to + 1 86). These data, from a small number of women, suggest that hyperhomocyst(e)inemia is not a common cause of low bone density in elderly American women but do not eliminate the possibility that hyperhomocyst(e)inemia may be involved in the association between low bone density and stroke mortality. -
London
Department of Immunology, King’s College School of Medicine and Dentistry,
London
Division of Immunogenetics, Rangos Research Center, Pittsburgh
K. C. TAN
DIEGO VERGANI MASSIMO TRUCCO
1. Editorial The 64K question in diabetes. Lancet
1990; 336: 597-98. 2. Baekkeskov S, Aanstoot H-J, Christgau S, et al. Identification of the 64K autoantigen in insulin dependent diabetes as the GABA-synthesising enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56. 3. Solimena M, Folli F, Dennis-Donmi S, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in Stiff Man Syndrome. N Engl J Med 1990, 322: 1555-60. 4. Julien J-F, Samama P, Mallet J. Rat brain glutamic acid decarboxylase sequence deduced from a cloned cDNA. J Neurochem 1990; 54: 703-05. 5. Katarova Z, Szabo G, Mugnaini E, Greenspan RJ. Molecular identification of the 62 kD form of glutamic acid decarboxylase in the mouse. Eur J Neurosci 1990; 2: 190-202. 6. Kobayashi Y, Kaufman DL, Tobin AJ. Glutamic acid decarboxylase cDNA: nucleotide sequence encoding an enzymatically active fusion protein. J Neurosci
1987; 7: 2768-72. 7. Okada Y, Taniguchi H, Shimada C.
High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma. Science 1976;
194: 620-22. 8. Erlander MG, Tillakaratne NJK, Feldblum S, Patel N, Tobin AJ. Two genes encode distinct glutamate decarboxylases. Neuron 1991; 7: 91-100. 9. Persson H, Pelto-Huikko M, Metsis M, et al Expression of the neurotransmittersynthesising enzyme glutamic acid decarboxylase in male germ cells. Mol Cell Biol
Division of Clinical Epidemiology, University of California at San Francisco, San Francisco, California 94105, USA
W. S. BROWNER
Primate Center,
Oregon Regional Beaverton, Oregon
M. R. MALINOW
MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated concentration as a possible independent risk factor for stroke. Stroke 1990; 21: 572-76. 2. Brattstrom L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest (m press). 3. Clarke R, Kaly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-55. 4. Mudd SH, Levy HL, Skovby F. Disorders of transulfuration. In: Scriver CS, Beaudet AL, Sly WL, Valle D, eds. The metabolic basis of inherited disease, 5th ed. New York: McGraw-Hill, 1983: 522-59. 5. Malinow MR, Kang SS, Taylor LM, et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989; 79: 1180-88. 1. Coull BM, Malinow
plasma homocyst(e)ine
CORRECTION
1990; 10: 4701-11. 10. Karlsen AE, Hagopian WA, Grubin CE, et al. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci USA 1991; 58: 8337-41.
Upper airway obstruction during nasal intermittent positive-pressure hyperventilation in sleep.-In this article by Dr P. Delguste and colleagues (Nov 23, p 1295), the figure on p 1296 showing continuous polygraphic tracing during sleep was reproduced poorly in some copies of the London edition, and is reprinted below.
sequences were identical to those in brain. The sequence we have obtained for GAD65 is identical to that reported as GAD-210 while GAD67 has 100% similarity with the partial human testis sequence. Northern blot analysis showed that both transcripts are present at comparable levels in the brain, whereas in the endocrine pancreas GAD65 is expressed at a much higher level than GAD67. These results suggest that GAD, an autoantigen in type I diabetes and SMS, is encoded by the same genes in both human brain and pancreatic islets and that the structure of the mRNAs in the two tissues is the same. GAD transcripts in the islet and in the brain thus differ only quantitatively. Differences in anti-GAD response in the two autoimmune conditions cannot therefore be ascribed to different GAD sequences, although post-translational modifications in the two tissues cannot be excluded. Now that the sequences of both GAD isoforms are known it should be possible to map the epitope(s) recognised by the antibodies and to study B and T lymphocyte reactions to GAD in these two different autoimmune diseases.
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
ROBERTO GIORDA
Department of Immunology, King’s College School of Medicine and Dentistry,
MARK PEAKMAN
London SE5 9PJ, UK
Department of Surgery,
King’s College Hospital,
Homocyst(e)inaemia and bone density in elderly women SIR,—When we reported (Aug 10, p 355) that low bone density associated with stroke mortality in elderly women we speculated that the association might be a result of Moderately hyperhomocyst(e)inaemia. high levels of homocyst(e)ine in blood have been associated with stroke,’-3 and the was
homozygous form of the disorder (homocystinuria) causes premature stroke, myocardial infarction, and severe osteoporosis.4 To test the hypothesis we investigated homocyst(e)ine concentrations in 23 women aged 65-80 randomly selected from participants in our study of osteoporotic fractures whose bone density was in the highest decile for age, and in 23 age-matched (within 1 year) participants whose bone density was in the lowest decile. Bone density was measured at the distal radius by single photon absorptiometry. Serum taken when the bone density measurements were made was frozen at - 20°C for up to 2 weeks and then at -190°C for up to 3 years. Homocyst(e)ine was assayed blindly by high-pressure liquid chromatography with electrochemical detection. ("Homocyst(e)ine", expressed as homocysteine, refers to the sum of homocysteine and the homocysteinyl moieties of the disulphides homocystine and cysteine-homocysteine, whether free or bound to proteins.) Homocyst(e)ine values ranged from 4-95 to 17.49 nmol/ml and the mean (SD) was 8-66 (3-05) in the 23 women in the highest decile of bone density, and 8-31 ( 1 62) nmol/ml in those in the lowest decile (p=0’63 by paired t-test, 95% confidence interval for difference 1 16 to + 1 86). These data, from a small number of women, suggest that hyperhomocyst(e)inemia is not a common cause of low bone density in elderly American women but do not eliminate the possibility that hyperhomocyst(e)inemia may be involved in the association between low bone density and stroke mortality. -
London
Department of Immunology, King’s College School of Medicine and Dentistry,
London
Division of Immunogenetics, Rangos Research Center, Pittsburgh
K. C. TAN
DIEGO VERGANI MASSIMO TRUCCO
1. Editorial The 64K question in diabetes. Lancet
1990; 336: 597-98. 2. Baekkeskov S, Aanstoot H-J, Christgau S, et al. Identification of the 64K autoantigen in insulin dependent diabetes as the GABA-synthesising enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-56. 3. Solimena M, Folli F, Dennis-Donmi S, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in Stiff Man Syndrome. N Engl J Med 1990, 322: 1555-60. 4. Julien J-F, Samama P, Mallet J. Rat brain glutamic acid decarboxylase sequence deduced from a cloned cDNA. J Neurochem 1990; 54: 703-05. 5. Katarova Z, Szabo G, Mugnaini E, Greenspan RJ. Molecular identification of the 62 kD form of glutamic acid decarboxylase in the mouse. Eur J Neurosci 1990; 2: 190-202. 6. Kobayashi Y, Kaufman DL, Tobin AJ. Glutamic acid decarboxylase cDNA: nucleotide sequence encoding an enzymatically active fusion protein. J Neurosci
1987; 7: 2768-72. 7. Okada Y, Taniguchi H, Shimada C.
High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma. Science 1976;
194: 620-22. 8. Erlander MG, Tillakaratne NJK, Feldblum S, Patel N, Tobin AJ. Two genes encode distinct glutamate decarboxylases. Neuron 1991; 7: 91-100. 9. Persson H, Pelto-Huikko M, Metsis M, et al Expression of the neurotransmittersynthesising enzyme glutamic acid decarboxylase in male germ cells. Mol Cell Biol
Division of Clinical Epidemiology, University of California at San Francisco, San Francisco, California 94105, USA
W. S. BROWNER
Primate Center,
Oregon Regional Beaverton, Oregon
M. R. MALINOW
MR, Beamer N, Sexton G, Nordt F, de Garmo P. Elevated concentration as a possible independent risk factor for stroke. Stroke 1990; 21: 572-76. 2. Brattstrom L, Lindgren A, Israelsson B, Malinow MR, Norrving B, Upson B. Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. Eur J Clin Invest (m press). 3. Clarke R, Kaly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-55. 4. Mudd SH, Levy HL, Skovby F. Disorders of transulfuration. In: Scriver CS, Beaudet AL, Sly WL, Valle D, eds. The metabolic basis of inherited disease, 5th ed. New York: McGraw-Hill, 1983: 522-59. 5. Malinow MR, Kang SS, Taylor LM, et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989; 79: 1180-88. 1. Coull BM, Malinow
plasma homocyst(e)ine
CORRECTION
1990; 10: 4701-11. 10. Karlsen AE, Hagopian WA, Grubin CE, et al. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci USA 1991; 58: 8337-41.
Upper airway obstruction during nasal intermittent positive-pressure hyperventilation in sleep.-In this article by Dr P. Delguste and colleagues (Nov 23, p 1295), the figure on p 1296 showing continuous polygraphic tracing during sleep was reproduced poorly in some copies of the London edition, and is reprinted below.