1468
electrolytes were normal except for phosphate (0-33 and potassium (2-7 mmol/1). He was treated with chlormethiazole capsules and vitamin supplementation overnight. By the time the phosphate result was telephoned in the next morning he was free of hallucinosis. In view of this his phosphate was repeated and his electrolytes were then normal with a phosphate of 0-92 and a potassium of 3-7 nmol/1, and replacement therapy was not thought necessary. His hallucinosis did not recur. As with Barbe and colleagues’ patient hallucinosis was closely linked to hypophosphataemia. This was probably caused by hyperventilation leading to respiratory alkalosis, exacerbated by a metabolic alkalosis (as suggested by the hypokalaemia), on a background of alcohol abuse. The relevance of these factors for phosphate has been previously described.3 We agree that plasma phosphate estimation is an essential measurement in patients with both unexplained hallucinosis as well as in those with risk factors for hypophosphataemia such as alcohol and diabetes. Blood
mmol/1)
Department of Psychiatry, Hither Green Hospital, London SE13 6RU, UK
shown). Supernatants stimulated with LT-24 or peak E enhanced IgA secretion from activated blasts in a dose-dependent manner. IgA secretion was not enhanced by the addition of T-cell supernatants stimulated with pure Trp. Moreover, the IgAinducing activity of IL-5 was inhibited by the addition of polyclonal anti-IL-5 antibody but not by neutralising antibody for IgA switch not
factor, transforming growth factor-(31 (TGF-&bgr;l). Owen
al4 have demonstrated IL-5 and increased hypodense in eosinophils the peripheral blood of patients with EMS, findings that accord with the augmented IL-5 production from T cells induced by peak E in vitro reported here. Peak E may be involved in the pathogenesis of EMS through an IL-5-mediated mechanism. et
Department of Medical Zoology, Tokyo Medical and Dental University, Tokyo 113 Japan
K. A. YAMAOKA N. MIYASAKA
Tokyo Women’s Medical College
S. KASHIWAZAKI
RW, Duffy J, Engel AG, et al. The clinical spectrum of the eosinophiliamyalgia syndrome associated with L-tryptophan ingestion. Ann Intern Med 1990;
1. Martin
ADRIAN TRELOAR
Department of Clinical Chemistry, Guy’s Hospital, London
MARTIN CROOK
Department of Psychiatry, Hither Green Hospital
LIZ PARKER ROBERT DOIG
JP. The pathophysiology and clinical characteristics of severe hypophosphataemia. Arch Intern Med 1977; 137: 203-20. 2. Diagnostic and statistical manual of mental disorders, 3rd ed. Revised (DSM-III-R) Washington, DC: Amencan Psychiatry Association, 1987. 3. Betro MG, Pain RW. Hypophosphataemia and hyperphosphataemia in a hospital population. Br Med J 1972; ii: 273-76.
113: 124-34. 2. Slutsker L, Hoesly
FC, Miller L, Williams LP, Watson JC, Fleming DW. Eosinophilia-mylagia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. 3. Mayeno AN, Lin F, Foote CS, et al Characterization of "peak E" a novel amino acid associated with eosinophiha-myalgia syndrome. Science 1990; 250: 1707-08. 4. Owen WF Jr, Petersen J, Sheff DM, et al. Hypodense eosinophils and interleukin 5 activity m the blood of patients with the eosinophilia-myalgia syndrome. Proc Natl Acad Sci USA 1990; 87: 8647-51.
1. Knochel
Epipodophyllotoxin-related acute myeloid leukaemia SIR,-Dr Donatini and Dr Krupp (Nov 16, p 1269) misquote our on secondary acute myeloid leukaemia (AML).1 They interpret our findings as supporting their contention that "the role of etoposide in the development of myelodysplasia/AML remains article
L-tryptophan contaminant "peak E" and interleukin-5 production from T cells SIR,-Eosinophilia-myalgia syndrome (EMS), a disease associated with ingestion of L-tryptophan (Trp), is characterised by eosinophilia, myalgia, and subsequently by fasciitis, skin sclerosis and neuropathy.1 Epidemiological study has revealed a strong link between EMS and the intake of particular lots of Trp produced by a single manufacturerA contaminant ("peak E") has been isolated and found to be 1,1’-ethylidenebis(tryptophan).3 Interleukin-5 (IL-5) is a key factor in the activation and differentiation of eosinophilia.4 We have found that implicated Trp (LT-24) and peak E, but not non-implicated, Japanese Pharmacopoeia grade material induces excessive amounts of IL-5 by splenic T cells from a healthy donor. T cells were cultured for 72 h in medium supplemented with pure Trp, LT-24, or peak E. Supernatants of cultures stimulated with LT-24 or peak E contained significant amounts of IL-5 (specific sandwich ELISA, table). The biological activity of IL-5 was evaluated by IgA synthesis in a 7-day culture of lipopolysaccharideactivated human splenic B cells by adding T-cell supernatants (data I L-5 AN D IgA PRODUCTION INDUCED BY TRYPTOPHANS S
unproven". They base their conclusion in part on the assumption that this complication was not seen in the 138 children with germ-cell tumours treated with epipodophyllotoxins at St Jude Hospital. But none of these children received epipodophyllotoxins. If anything, our data support the role of these drugs in the causation of secondary AML. Dr Pedersen-Bjergaard and colleagues (Aug 10, p 359) report a dose-response relation and we have identified an even more important schedule-dependent effect.2 Weekly or twice weekly administration is associated with a higher risk than an alternate week schedule. In our earlier study, the risk of secondary AML was greatly increased in patients with T-cell acute lymphoblastic leukaemia, suggesting an immunophenotype-related carcinogenic effect of epipodophyllotoxins. This relation disappeared after accrual of additional cases and adjustment for the effect of treatment scheduled St Jude’s Children’s Research Hospital,
Memphis, Tennessee 38101, USA, and Memphis College of Medicine, University of Tennessee
CHING-HON PUI
1. Pui C-H, Hancock ML, Raimondi SC, et al. Myeloid neoplasia in children treated for solid tumours. Lancet 1990; 336: 417-21. 2. Pui C-H, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med (in
press). 3. Pui C-H, Behm FG, Raimondi SC, et al. Secondary children treated for acute lymphoid leukemia. N Engl
myeloid leukemia in J Med 1989; 321: 136-42
acute
Cloning of large isoform of human brain glutamic acid decarboxylase SIR,—Type I or insulin-dependent diabetes mellitus (IDDM) is autoimmune disease, with a strong genetic predisposition, directed against antigenic determinants on the human pancreatic P-cell. Attention has lately focused on a j3-cell polypeptide of molecular weight 64 kDa, against which antibodies are present in the sera of a large number of newly diagnosed patients with IDDM and which may be used to predict diabetes;’ these antibodies are also an
*p
electrolytes were normal except for phosphate (0-33 and potassium (2-7 mmol/1). He was treated with chlormethiazole capsules and vitamin supplementation overnight. By the time the phosphate result was telephoned in the next morning he was free of hallucinosis. In view of this his phosphate was repeated and his electrolytes were then normal with a phosphate of 0-92 and a potassium of 3-7 nmol/1, and replacement therapy was not thought necessary. His hallucinosis did not recur. As with Barbe and colleagues’ patient hallucinosis was closely linked to hypophosphataemia. This was probably caused by hyperventilation leading to respiratory alkalosis, exacerbated by a metabolic alkalosis (as suggested by the hypokalaemia), on a background of alcohol abuse. The relevance of these factors for phosphate has been previously described.3 We agree that plasma phosphate estimation is an essential measurement in patients with both unexplained hallucinosis as well as in those with risk factors for hypophosphataemia such as alcohol and diabetes. Blood
mmol/1)
Department of Psychiatry, Hither Green Hospital, London SE13 6RU, UK
shown). Supernatants stimulated with LT-24 or peak E enhanced IgA secretion from activated blasts in a dose-dependent manner. IgA secretion was not enhanced by the addition of T-cell supernatants stimulated with pure Trp. Moreover, the IgAinducing activity of IL-5 was inhibited by the addition of polyclonal anti-IL-5 antibody but not by neutralising antibody for IgA switch not
factor, transforming growth factor-(31 (TGF-&bgr;l). Owen
al4 have demonstrated IL-5 and increased hypodense in eosinophils the peripheral blood of patients with EMS, findings that accord with the augmented IL-5 production from T cells induced by peak E in vitro reported here. Peak E may be involved in the pathogenesis of EMS through an IL-5-mediated mechanism. et
Department of Medical Zoology, Tokyo Medical and Dental University, Tokyo 113 Japan
K. A. YAMAOKA N. MIYASAKA
Tokyo Women’s Medical College
S. KASHIWAZAKI
RW, Duffy J, Engel AG, et al. The clinical spectrum of the eosinophiliamyalgia syndrome associated with L-tryptophan ingestion. Ann Intern Med 1990;
1. Martin
ADRIAN TRELOAR
Department of Clinical Chemistry, Guy’s Hospital, London
MARTIN CROOK
Department of Psychiatry, Hither Green Hospital
LIZ PARKER ROBERT DOIG
JP. The pathophysiology and clinical characteristics of severe hypophosphataemia. Arch Intern Med 1977; 137: 203-20. 2. Diagnostic and statistical manual of mental disorders, 3rd ed. Revised (DSM-III-R) Washington, DC: Amencan Psychiatry Association, 1987. 3. Betro MG, Pain RW. Hypophosphataemia and hyperphosphataemia in a hospital population. Br Med J 1972; ii: 273-76.
113: 124-34. 2. Slutsker L, Hoesly
FC, Miller L, Williams LP, Watson JC, Fleming DW. Eosinophilia-mylagia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. 3. Mayeno AN, Lin F, Foote CS, et al Characterization of "peak E" a novel amino acid associated with eosinophiha-myalgia syndrome. Science 1990; 250: 1707-08. 4. Owen WF Jr, Petersen J, Sheff DM, et al. Hypodense eosinophils and interleukin 5 activity m the blood of patients with the eosinophilia-myalgia syndrome. Proc Natl Acad Sci USA 1990; 87: 8647-51.
1. Knochel
Epipodophyllotoxin-related acute myeloid leukaemia SIR,-Dr Donatini and Dr Krupp (Nov 16, p 1269) misquote our on secondary acute myeloid leukaemia (AML).1 They interpret our findings as supporting their contention that "the role of etoposide in the development of myelodysplasia/AML remains article
L-tryptophan contaminant "peak E" and interleukin-5 production from T cells SIR,-Eosinophilia-myalgia syndrome (EMS), a disease associated with ingestion of L-tryptophan (Trp), is characterised by eosinophilia, myalgia, and subsequently by fasciitis, skin sclerosis and neuropathy.1 Epidemiological study has revealed a strong link between EMS and the intake of particular lots of Trp produced by a single manufacturerA contaminant ("peak E") has been isolated and found to be 1,1’-ethylidenebis(tryptophan).3 Interleukin-5 (IL-5) is a key factor in the activation and differentiation of eosinophilia.4 We have found that implicated Trp (LT-24) and peak E, but not non-implicated, Japanese Pharmacopoeia grade material induces excessive amounts of IL-5 by splenic T cells from a healthy donor. T cells were cultured for 72 h in medium supplemented with pure Trp, LT-24, or peak E. Supernatants of cultures stimulated with LT-24 or peak E contained significant amounts of IL-5 (specific sandwich ELISA, table). The biological activity of IL-5 was evaluated by IgA synthesis in a 7-day culture of lipopolysaccharideactivated human splenic B cells by adding T-cell supernatants (data I L-5 AN D IgA PRODUCTION INDUCED BY TRYPTOPHANS S
unproven". They base their conclusion in part on the assumption that this complication was not seen in the 138 children with germ-cell tumours treated with epipodophyllotoxins at St Jude Hospital. But none of these children received epipodophyllotoxins. If anything, our data support the role of these drugs in the causation of secondary AML. Dr Pedersen-Bjergaard and colleagues (Aug 10, p 359) report a dose-response relation and we have identified an even more important schedule-dependent effect.2 Weekly or twice weekly administration is associated with a higher risk than an alternate week schedule. In our earlier study, the risk of secondary AML was greatly increased in patients with T-cell acute lymphoblastic leukaemia, suggesting an immunophenotype-related carcinogenic effect of epipodophyllotoxins. This relation disappeared after accrual of additional cases and adjustment for the effect of treatment scheduled St Jude’s Children’s Research Hospital,
Memphis, Tennessee 38101, USA, and Memphis College of Medicine, University of Tennessee
CHING-HON PUI
1. Pui C-H, Hancock ML, Raimondi SC, et al. Myeloid neoplasia in children treated for solid tumours. Lancet 1990; 336: 417-21. 2. Pui C-H, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med (in
press). 3. Pui C-H, Behm FG, Raimondi SC, et al. Secondary children treated for acute lymphoid leukemia. N Engl
myeloid leukemia in J Med 1989; 321: 136-42
acute
Cloning of large isoform of human brain glutamic acid decarboxylase SIR,—Type I or insulin-dependent diabetes mellitus (IDDM) is autoimmune disease, with a strong genetic predisposition, directed against antigenic determinants on the human pancreatic P-cell. Attention has lately focused on a j3-cell polypeptide of molecular weight 64 kDa, against which antibodies are present in the sera of a large number of newly diagnosed patients with IDDM and which may be used to predict diabetes;’ these antibodies are also an
*p
