559
This enzyme leads to production of 12-hydroxyeicosatetraenoic acid and leukotriene B4, which are found in substantial amounts in psoriatic skinIn psoriasis, sulphonamides may have a pharmacological effect that warrants further investigation. Rupert Hallam Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
DAVID J. GAWKRODGER
1. Grau EB. Una neuva técnica de tratamiento del psoriasis mediante la asociación triamcinolona-acetazolamida. An Med Espec 1964; 50: 278-91. 2. Gupta AK, Ellis CW, Siegel MT, et al. Sulfasalazine improves psoriasis: a double-blind analysis. Arch Dermatol 1990; 126: 487-93. 3. Sircar JC, Schwender CF, Carethers ME. Inhibition of soyabean lipoxygenase by sulphasalazine and 5-aminosalicylic acid: a possible mode of action in ulcerative colitis. Biochem Pharmacol 1983; 32: 170-73. 4. Grabbe J, Czametzki M, Rosenbach T, et al. Identification of chemotactic lipoxygenase products of arachidonic acid metabolism in psoriatic skin. J Invest Dermatol 1984; 82: 477-79.
Neurofibrillary tangles and olfactory dysgenesis SIR,-In the "olfactory hypothesis" of neurofibrillary tangle formation (NFT) in Alzheimer’s disease (AD) an environmental toxin is transported along olfactory pathways projecting from the nasal epithelium through the cribriform plate to the brain.1.2 The idea stems from the observation that pathological changes in AD and ageing are mainly in structures related anatomically to the olfactory system, such as the amygdala and entorhinal cortex. Furthermore these areas are the preferential site of initial NFT formation,3 the olfactory bulb itself contains substantial NFTs," and the neuroepithelium of the olfactory mucosa develops immunohistochemical changes in AD. We had the opportunity to test this hypothesis when bilateral olfactory dysgenesis was noted incidentally in a 65-year-old patient at post-mortem examination. This woman had had a lifelong inability to smell and lack of interest in foods. She worked as a nurse and had no history of cognitive impairment. Her medical history included alcohol abuse, and hypothyroidism of adult onset. She died of sepsis complicating immunosuppressive treatment for polymyositis. At necropsy the skull was remarkable for a bilaterally imperforate cribriform plate. Both olfactory bulbs and tracts were absent. Small nodules of light tan tissue, covered by leptomeninges, occupied the positions of the normal tracts. The right olfactory sulcus was of normal length but shallow; the left was barely visible. The remainder of the brain was developmentally normal. A small lacunar infarct was present in the right putamen. The olfactory nodules consisted of organised neuronal layers in a gliotic neuropil and these and the presence of mitral and granule cells were strongly suggestive of olfactory bulb architecture. Thioflavine S positive NFT (as many as 7/mmz field) were noted in layer II of entorhinal cortex, in layer III of perirhinal cortex, the CAl/subicular field of the hippocampus, and in the cortical, medial basal, and accessory basal nuclei of the amygdala. Immunohistochemical staining with Alz-50 confirmed these NFT. Senile plaques were not observed with thioflavine S, Cambell-Switzer silver stains, or anti-A4
immunohistochemistry. Olfactory dysgenesis is commonly grouped with the holoprosencephalic malformations; these malformations are usually detected in children, and associated with other developmental anomalies. This patient, however, had no features to suggest that the olfactory dysgenesis was part of a more extensive condition. The abnormal olfactory sulci, imperforate cribriform plate, and lifelong history of anosmia support a prenatal origin for the lesion, and the anomalous nodules probably represent failure of migration of the olfactory bulbs during fetal development.6 The olfactory hypothesis predicts NFT formation in areas closely connected with the olfactory system (figure). In AD these tangles show a specific pattern with severe involvement of limbic cytoarchitectural areas. Studies in young adults with Down’s syndrome and non-demented elderly individuals also highlight the vulnerability to NFT formation of neurons in layer IIof entorhinal cortex, perirhinal cortex, amygdala, and the hippocampal CAl/ subicular zone to develop NFT.3,7,8 The number and anatomical
Main connections of
olfactory pathway. Interruption of circuit in this patient (black diagonal band) and areas where NFT were present (dark boxes) are indicated. Vertical rectangle is cribriform plate. distribution of NFT in our patient is identical to that found in young adults with Down’s syndrome, other elderly, non-demented individuals, and, presumably, individuals in the initial stages of AD. The absence of amyloid plaques is consistent with our findings in other non-demented elderly individuals.9 This patient, with no peripheral olfactory structures and an imperforate cribriform plate, nonetheless had NFTs in the very distribution predicted by the olfactory hypothesis. The vulnerability of neurons in entorhinal and perirhinal cortices, amygdala, and hippocampal CAl-subiculum cannot therefore be ascribed to olfactory connections. An olfactory toxin might accelerate the development of NFT or senile plaques. Nonetheless if an environmental agent is responsible for initial NFT formation it must gain access to the brain by some other route and target entorhinal cortex and related structures by a different mechanism.
Supported by Brookdale Foundation, NIH AG08487 and P50 AG05134, and Educational Commission for Foreign Medical Graduates (ECFMG). We thank P. Davies (New York) for gift of Alz-50 antibody and C. Masters (Melbourne) for anti-A4 antisera. Department of Pathology (Neuropathology) and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
P. V. ARRIAGADA D. N. LOUIS E. T. HEDLEY-WHYTE B. T. HYMAN
1. Pearson RCA, Esin MM, Hiorns RW, Wilcock GK, Powell TPS. Anatomical correlates of the distribution of the pathological changes in the neocortex in Aluheimer’s disease. Proc Natl Acad Sci USA 1985; 82: 4531-34. 2. Roberts E. Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates. Neurobiol Aging 1986; 7: 561-67. 3. Mann DMA, Esin MM. The pattern of acquisition of plaques and tangles in brains under 50 years of age with Down’s syndrome. J Neurol Sci 1989; 89: 169-79. 4. Esiri MM, Wilcock GK. The olfactory bulbs in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1984; 47: 56-60. 5. Talamo BR, Rudel RA, Kosik KS, Lee VYM, Neff S, AdelmanL, Kauer JS. Pathological changes in olfactory neurons in patients with Alzheimer’s disease. Nature 1989; 337: 736-39. 6. Gilles FH. Telencephalon medium and the olfacto-cerebral outpouching. In: Gilles FH, Leviton A, Dooling EC, eds. The developing human brain. Boston: John Wright-PSG, 1983: 59-86. 7. Arriagada PV, Hyman BT. Topographic distribution of Alzheimer neuronal changes in normal aging brains. J Neuropathol Exp Neurol 1990; 49: 336 (abstr). 8. Mann DMA, Yates PO, Marcyniuk B, Ravindra CR. The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 1986; 12: 447-57. 9. Arriagada PV, Hyman BT. Predominance of A-4 over Alz-50 positive plaques in
non-demented elderly. Neurobiol Aging 1900; 11: 324 (abstr).
Virgin birth syndrome SIR,—Clinicians and therapists are aware of the concealed pathology that can present as infertility, such as eating disorder, depression, alcohol and drug abuse, and marital breakdown. However, as a psychotherapist attached to a fertility clinic, I have encountered a situation unique to high-tech fertility treatmentsingle women with no experience of sexual intercourse and with no intention of having a sexual relationship, but who wish to have a child through assisted conception. I report such a patient. A woman aged 32 was referred by her general practitioner for assisted conception. The gynaecologist concluded that she had never been sexually active nor had had other vaginal penetration. The medical view was that for her to have her first vaginal penetration with a speculum by a member of the team who might
560
her could have implications beyond the potential immediate She was therefore referred for counselling, which is standard practice at this hospital for all single people seeking assisted conception as well as for those who require donated semen or gametes. The patient saw nothing unusual in her request. She believed that medical technology would provide the answer to all her dreams, and she pictured her future life abroad with a perfect child, where no-one would know her. She had had one male friend whom she said was unsuitable and did not envisage a future partner, since she was not interested in sexual intercourse. Her view was that it was better to have a child of your choice by this means than to have a child born of rape. She believed that she would be a good parent, as are her own parents, and that this could be jeopardised if she married the wrong man. She became very angry when both the referring consultant and the psychotherapist recommended further counselling before any fertility treatment. She accused the staff of trying to control her decisions when her mind was made up, and said that the treatment procedures were scientific and preferable to sexual relations. My difficulty in counselling these patients is that I am uncertain if I should accept their representations at face value. Are such women genuinely reluctant to enter into a sexual relationship, yet truly want a child? Or does assisted conception represent their desire for sexual relations via technology? In some cases I doubt whether having a child is the primary motivation. I would welcome any comments from other clinicians or therapists, including those who may suspect a similar occurrence in other contexts. treat
trauma.
Academic Unit of Obstetrics and Gynaecology, London Hospital Medical College, London E1 1BB, UK
SUE JENNINGS
Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche) SIR,—The use of 5-fluorouracil (FU) as a continuous infusion 4-5 days at high dose (1 g/m2 daily) has been followed by an increase in the frequency of FU cardiotoxicity from 1-6%1 to about 10%.2,3 It has been suggested that the cardiotoxicity (and neurotoxicity) might be due to conversion of &agr;x-fluoro-&bgr;-alanine (FBAL), the major metabolite of FU, into fluoroacetate (FAC), over
which is highly cardiotoxic and neurotoxic.4,5FAC enters the Krebs cycle, undergoes metabolic conversion to fluorocitrate which inhibits citrate metabolism, resulting in accumulation of citrate.6 To understand the mechanism of FU cardiotoxicity, we treated isolated perfused hearts from rabbits, a species that is especially sensitive to the cardiotoxic effects of FU, with FU Roche (vials of 0-25 g in 5 ml aqueous solution buffered with "tris") at five doses ranging from 0- 11 to 1-4 mmol/kg. Ventricular arrest occurred at about 1 h and 3 h for the highest and lowest doses, respectively. Intracellular citrate rose 40-80-fold. FAC was detected in all perfusates analysed by fluorine-19 nuclear magnetic resonance (NMR) spectroscopy. Surprisingly, however, no cardiotoxicity or marked rise in intracellular citrate was observed when isolated hearts were treated with FBAL (Tokyo Kasei) at doses of 0-35 or 1 -4 mmol/kg over 4 h. Nor was FAC detected in perfusates even though FBAL was found in the heart, demonstrating uptake. Thus the cardiotoxicity induced by FU (Roche) did not result from the metabolic transformation of FBAL into FAC. NMR of FU (Roche) vials revealed, besides FU itself, six fluorinated compounds accounting for 1-1 5mol %. None of them corresponded to FAC or to FC. Two of the four major impurities were fluoride ion and fluoracetaldehyde-acetal, resulting from acetalisation of fluoroacetaldehyde by tris. No fluorinated impurity was detected in FBAL. Since in rats, fluoroacetaldehyde formed by oxidation of fluoroethanol was converted to FACFAC obtained after treatment with FU (Roche) most probably came from the impurity fluoroacetaldehyde, even though the low sensitivity of NMR does not rule out a small amount of metabolic conversion of FBAL into FAC. Four experiments confirmed this finding. When isolated perfused rabbit hearts were treated with FU (Sigma) no fluorinated impurity, at 0-11 or 1-4 mmol/kg no cardiotoxic symptoms ensued, citrate levels did not rise, and FAC
containing
was not observed. Since the liver is the major site of xenobiotic metabolism isolated perfused rat livers were treated with FU (Roche), FU (Sigma), or FBAL at 1 ’5 mmol/kg and FAC detected only for FU (Roche). NMR analysis of urine from rats injected intraperitoneally with FU (Roche), FU (Sigma), or FBAL 1-4 mmol/kg led to similar results, showing that the fluoroacetaldehyde-to-FAC conversion occurred in vivo. When rat liver or rats were treated with FU (Roche) containing an enhanced amount of fluoroacetaldehyde-acetal and the other impurities, the level of FAC increased. The detection of FAC in urine from eight patients treated with continuous infusion of FU (Roche), five with cardiotoxic symptoms and three without, suggested that fluoroacetaldehyde converted to FAC in man also. Variable amounts of FAC in patients and/or differences in individual susceptibility to the cardiotoxicity of FAC might explain this result. LAURENT LEMAIRE Biomedical NMR Group, MARIE C. MALET-MARTINO IMRCP Laboratory, SOPHIE LONGO Paul Sabatier University, ROBERT MARTINO 31062 Toulouse, France
Centre Claudius Regaud, Toulouse
FORNI MICHEL CARTON MARCEL DE
1. Labianca R, Beretta G, Clerici M, Fraschim P, Luporini G. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori 1982; 68: 505-10. 2. Collins C, Welden PL. Cardiotoxicity of 5-fluorouracil. Cancer Treat Rep 1987; 71: 733-36. 3. de Forni M, Bugat R, Sorbette F, Delay M, Bachaud JM, Chevreau C Cardiotoxicité du 5-fluorouracile perfusion intraveineuse continue: étude clinique, prévention, physiopathologie: à propos d’une série de 13 cas. Bull Cancer 1990; 77: 429-38. 4. Koenig H, Patel A. Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate. Arch Neurol 1970; 23: 155-60. 5. Matsubara I, Kamiya J, Imai S. Cardiotoxic effects of 5-fluorouracil in the Guinea pig. Jpn J Pharmacol 1980; 30: 871-79. 6. Pattison FLM, Peters RA. Monofluoro aliphatic compounds. In: Smith FA, ed. Handbook of experimental pharmacology: vol XX, part I. New York: Springer, 1966: 387-458. 7. Tecle B, Casida JE. Enzymatic defluorination and metabolism of fluoroacetate, fluoroacetamide, fluoroethanol, and (-)-erythro-fluorocitrate in rats and mice examined by 19F and 13C NMR. Chem Res Toxicol 1989; 2: 429-35.
Echinococcus multilocularis infestation acquired in UK SIR,-Four species of the cestode genus Echinococcus have been described. E vogeli and E oligarthrus are confined to Central and South America. E granulosus is widely distributed. The principal reservoirs in Britain are hill sheep and sheepdogs. Human cases are seen in the UK in emigrants from regions where the infection is endemic (eg, Cyprus and the Middle East), and in areas with regional reservoirs, the recorded incidence being 1 new case per 1000 per annum in one part of central Powys (Wales) and 1 per 700 in another.1 Lesions are almost always confined to lungs and liver. E multilocularis is a sub-Arctic species, but it is also found in central Europe, including Switzerland.2The natural hosts include the arctic fox and red fox, many species of rodent, cats, and dogs.3 The lifespan of small mammals is short and in its cystic phase in the liver the parasite matures much more quickly than cysts of Egranulosus. Developing cysts infiltrate healthy liver and may metastasise, and in man the infection is ultimately fatal. Drug therapy (principally benzimidazoles) is not notably successful.’* All the evidence at present available suggests only one species in the UK, Egranulosus. E multilocularis has never been identified in the British fox (Vulpes vulpes). (A vigorous debate about whether E granulosus and E multilocularis were the same or not ended, in 1956, in favour of two species, and the two are easy to distinguish.) In 1954, Walshe reported on the death of a London woman, from an infection he described as "echinococcosis alveolaris" and caused by Taenia (Echinococcus) granulosus.5 Subsequently it was appreciated by those interested in this parasite that Walshe had in fact described an infection by E multilocularis. In 1963 I was then asked by the Ministry of Health to reopen the case and to examine the possibility that E multilocularis might be established in the UK. Members of the patient’s family, colleagues from work, members of her church, and landladies were interviewed. Dr Walshe kindly made histology slides available and the Wellcome Museum of
This enzyme leads to production of 12-hydroxyeicosatetraenoic acid and leukotriene B4, which are found in substantial amounts in psoriatic skinIn psoriasis, sulphonamides may have a pharmacological effect that warrants further investigation. Rupert Hallam Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
DAVID J. GAWKRODGER
1. Grau EB. Una neuva técnica de tratamiento del psoriasis mediante la asociación triamcinolona-acetazolamida. An Med Espec 1964; 50: 278-91. 2. Gupta AK, Ellis CW, Siegel MT, et al. Sulfasalazine improves psoriasis: a double-blind analysis. Arch Dermatol 1990; 126: 487-93. 3. Sircar JC, Schwender CF, Carethers ME. Inhibition of soyabean lipoxygenase by sulphasalazine and 5-aminosalicylic acid: a possible mode of action in ulcerative colitis. Biochem Pharmacol 1983; 32: 170-73. 4. Grabbe J, Czametzki M, Rosenbach T, et al. Identification of chemotactic lipoxygenase products of arachidonic acid metabolism in psoriatic skin. J Invest Dermatol 1984; 82: 477-79.
Neurofibrillary tangles and olfactory dysgenesis SIR,-In the "olfactory hypothesis" of neurofibrillary tangle formation (NFT) in Alzheimer’s disease (AD) an environmental toxin is transported along olfactory pathways projecting from the nasal epithelium through the cribriform plate to the brain.1.2 The idea stems from the observation that pathological changes in AD and ageing are mainly in structures related anatomically to the olfactory system, such as the amygdala and entorhinal cortex. Furthermore these areas are the preferential site of initial NFT formation,3 the olfactory bulb itself contains substantial NFTs," and the neuroepithelium of the olfactory mucosa develops immunohistochemical changes in AD. We had the opportunity to test this hypothesis when bilateral olfactory dysgenesis was noted incidentally in a 65-year-old patient at post-mortem examination. This woman had had a lifelong inability to smell and lack of interest in foods. She worked as a nurse and had no history of cognitive impairment. Her medical history included alcohol abuse, and hypothyroidism of adult onset. She died of sepsis complicating immunosuppressive treatment for polymyositis. At necropsy the skull was remarkable for a bilaterally imperforate cribriform plate. Both olfactory bulbs and tracts were absent. Small nodules of light tan tissue, covered by leptomeninges, occupied the positions of the normal tracts. The right olfactory sulcus was of normal length but shallow; the left was barely visible. The remainder of the brain was developmentally normal. A small lacunar infarct was present in the right putamen. The olfactory nodules consisted of organised neuronal layers in a gliotic neuropil and these and the presence of mitral and granule cells were strongly suggestive of olfactory bulb architecture. Thioflavine S positive NFT (as many as 7/mmz field) were noted in layer II of entorhinal cortex, in layer III of perirhinal cortex, the CAl/subicular field of the hippocampus, and in the cortical, medial basal, and accessory basal nuclei of the amygdala. Immunohistochemical staining with Alz-50 confirmed these NFT. Senile plaques were not observed with thioflavine S, Cambell-Switzer silver stains, or anti-A4
immunohistochemistry. Olfactory dysgenesis is commonly grouped with the holoprosencephalic malformations; these malformations are usually detected in children, and associated with other developmental anomalies. This patient, however, had no features to suggest that the olfactory dysgenesis was part of a more extensive condition. The abnormal olfactory sulci, imperforate cribriform plate, and lifelong history of anosmia support a prenatal origin for the lesion, and the anomalous nodules probably represent failure of migration of the olfactory bulbs during fetal development.6 The olfactory hypothesis predicts NFT formation in areas closely connected with the olfactory system (figure). In AD these tangles show a specific pattern with severe involvement of limbic cytoarchitectural areas. Studies in young adults with Down’s syndrome and non-demented elderly individuals also highlight the vulnerability to NFT formation of neurons in layer IIof entorhinal cortex, perirhinal cortex, amygdala, and the hippocampal CAl/ subicular zone to develop NFT.3,7,8 The number and anatomical
Main connections of
olfactory pathway. Interruption of circuit in this patient (black diagonal band) and areas where NFT were present (dark boxes) are indicated. Vertical rectangle is cribriform plate. distribution of NFT in our patient is identical to that found in young adults with Down’s syndrome, other elderly, non-demented individuals, and, presumably, individuals in the initial stages of AD. The absence of amyloid plaques is consistent with our findings in other non-demented elderly individuals.9 This patient, with no peripheral olfactory structures and an imperforate cribriform plate, nonetheless had NFTs in the very distribution predicted by the olfactory hypothesis. The vulnerability of neurons in entorhinal and perirhinal cortices, amygdala, and hippocampal CAl-subiculum cannot therefore be ascribed to olfactory connections. An olfactory toxin might accelerate the development of NFT or senile plaques. Nonetheless if an environmental agent is responsible for initial NFT formation it must gain access to the brain by some other route and target entorhinal cortex and related structures by a different mechanism.
Supported by Brookdale Foundation, NIH AG08487 and P50 AG05134, and Educational Commission for Foreign Medical Graduates (ECFMG). We thank P. Davies (New York) for gift of Alz-50 antibody and C. Masters (Melbourne) for anti-A4 antisera. Department of Pathology (Neuropathology) and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
P. V. ARRIAGADA D. N. LOUIS E. T. HEDLEY-WHYTE B. T. HYMAN
1. Pearson RCA, Esin MM, Hiorns RW, Wilcock GK, Powell TPS. Anatomical correlates of the distribution of the pathological changes in the neocortex in Aluheimer’s disease. Proc Natl Acad Sci USA 1985; 82: 4531-34. 2. Roberts E. Alzheimer’s disease may begin in the nose and may be caused by aluminosilicates. Neurobiol Aging 1986; 7: 561-67. 3. Mann DMA, Esin MM. The pattern of acquisition of plaques and tangles in brains under 50 years of age with Down’s syndrome. J Neurol Sci 1989; 89: 169-79. 4. Esiri MM, Wilcock GK. The olfactory bulbs in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1984; 47: 56-60. 5. Talamo BR, Rudel RA, Kosik KS, Lee VYM, Neff S, AdelmanL, Kauer JS. Pathological changes in olfactory neurons in patients with Alzheimer’s disease. Nature 1989; 337: 736-39. 6. Gilles FH. Telencephalon medium and the olfacto-cerebral outpouching. In: Gilles FH, Leviton A, Dooling EC, eds. The developing human brain. Boston: John Wright-PSG, 1983: 59-86. 7. Arriagada PV, Hyman BT. Topographic distribution of Alzheimer neuronal changes in normal aging brains. J Neuropathol Exp Neurol 1990; 49: 336 (abstr). 8. Mann DMA, Yates PO, Marcyniuk B, Ravindra CR. The topography of plaques and tangles in Down’s syndrome patients of different ages. Neuropathol Appl Neurobiol 1986; 12: 447-57. 9. Arriagada PV, Hyman BT. Predominance of A-4 over Alz-50 positive plaques in
non-demented elderly. Neurobiol Aging 1900; 11: 324 (abstr).
Virgin birth syndrome SIR,—Clinicians and therapists are aware of the concealed pathology that can present as infertility, such as eating disorder, depression, alcohol and drug abuse, and marital breakdown. However, as a psychotherapist attached to a fertility clinic, I have encountered a situation unique to high-tech fertility treatmentsingle women with no experience of sexual intercourse and with no intention of having a sexual relationship, but who wish to have a child through assisted conception. I report such a patient. A woman aged 32 was referred by her general practitioner for assisted conception. The gynaecologist concluded that she had never been sexually active nor had had other vaginal penetration. The medical view was that for her to have her first vaginal penetration with a speculum by a member of the team who might
560
her could have implications beyond the potential immediate She was therefore referred for counselling, which is standard practice at this hospital for all single people seeking assisted conception as well as for those who require donated semen or gametes. The patient saw nothing unusual in her request. She believed that medical technology would provide the answer to all her dreams, and she pictured her future life abroad with a perfect child, where no-one would know her. She had had one male friend whom she said was unsuitable and did not envisage a future partner, since she was not interested in sexual intercourse. Her view was that it was better to have a child of your choice by this means than to have a child born of rape. She believed that she would be a good parent, as are her own parents, and that this could be jeopardised if she married the wrong man. She became very angry when both the referring consultant and the psychotherapist recommended further counselling before any fertility treatment. She accused the staff of trying to control her decisions when her mind was made up, and said that the treatment procedures were scientific and preferable to sexual relations. My difficulty in counselling these patients is that I am uncertain if I should accept their representations at face value. Are such women genuinely reluctant to enter into a sexual relationship, yet truly want a child? Or does assisted conception represent their desire for sexual relations via technology? In some cases I doubt whether having a child is the primary motivation. I would welcome any comments from other clinicians or therapists, including those who may suspect a similar occurrence in other contexts. treat
trauma.
Academic Unit of Obstetrics and Gynaecology, London Hospital Medical College, London E1 1BB, UK
SUE JENNINGS
Fluoroacetaldehyde as cardiotoxic impurity in fluorouracil (Roche) SIR,—The use of 5-fluorouracil (FU) as a continuous infusion 4-5 days at high dose (1 g/m2 daily) has been followed by an increase in the frequency of FU cardiotoxicity from 1-6%1 to about 10%.2,3 It has been suggested that the cardiotoxicity (and neurotoxicity) might be due to conversion of &agr;x-fluoro-&bgr;-alanine (FBAL), the major metabolite of FU, into fluoroacetate (FAC), over
which is highly cardiotoxic and neurotoxic.4,5FAC enters the Krebs cycle, undergoes metabolic conversion to fluorocitrate which inhibits citrate metabolism, resulting in accumulation of citrate.6 To understand the mechanism of FU cardiotoxicity, we treated isolated perfused hearts from rabbits, a species that is especially sensitive to the cardiotoxic effects of FU, with FU Roche (vials of 0-25 g in 5 ml aqueous solution buffered with "tris") at five doses ranging from 0- 11 to 1-4 mmol/kg. Ventricular arrest occurred at about 1 h and 3 h for the highest and lowest doses, respectively. Intracellular citrate rose 40-80-fold. FAC was detected in all perfusates analysed by fluorine-19 nuclear magnetic resonance (NMR) spectroscopy. Surprisingly, however, no cardiotoxicity or marked rise in intracellular citrate was observed when isolated hearts were treated with FBAL (Tokyo Kasei) at doses of 0-35 or 1 -4 mmol/kg over 4 h. Nor was FAC detected in perfusates even though FBAL was found in the heart, demonstrating uptake. Thus the cardiotoxicity induced by FU (Roche) did not result from the metabolic transformation of FBAL into FAC. NMR of FU (Roche) vials revealed, besides FU itself, six fluorinated compounds accounting for 1-1 5mol %. None of them corresponded to FAC or to FC. Two of the four major impurities were fluoride ion and fluoracetaldehyde-acetal, resulting from acetalisation of fluoroacetaldehyde by tris. No fluorinated impurity was detected in FBAL. Since in rats, fluoroacetaldehyde formed by oxidation of fluoroethanol was converted to FACFAC obtained after treatment with FU (Roche) most probably came from the impurity fluoroacetaldehyde, even though the low sensitivity of NMR does not rule out a small amount of metabolic conversion of FBAL into FAC. Four experiments confirmed this finding. When isolated perfused rabbit hearts were treated with FU (Sigma) no fluorinated impurity, at 0-11 or 1-4 mmol/kg no cardiotoxic symptoms ensued, citrate levels did not rise, and FAC
containing
was not observed. Since the liver is the major site of xenobiotic metabolism isolated perfused rat livers were treated with FU (Roche), FU (Sigma), or FBAL at 1 ’5 mmol/kg and FAC detected only for FU (Roche). NMR analysis of urine from rats injected intraperitoneally with FU (Roche), FU (Sigma), or FBAL 1-4 mmol/kg led to similar results, showing that the fluoroacetaldehyde-to-FAC conversion occurred in vivo. When rat liver or rats were treated with FU (Roche) containing an enhanced amount of fluoroacetaldehyde-acetal and the other impurities, the level of FAC increased. The detection of FAC in urine from eight patients treated with continuous infusion of FU (Roche), five with cardiotoxic symptoms and three without, suggested that fluoroacetaldehyde converted to FAC in man also. Variable amounts of FAC in patients and/or differences in individual susceptibility to the cardiotoxicity of FAC might explain this result. LAURENT LEMAIRE Biomedical NMR Group, MARIE C. MALET-MARTINO IMRCP Laboratory, SOPHIE LONGO Paul Sabatier University, ROBERT MARTINO 31062 Toulouse, France
Centre Claudius Regaud, Toulouse
FORNI MICHEL CARTON MARCEL DE
1. Labianca R, Beretta G, Clerici M, Fraschim P, Luporini G. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori 1982; 68: 505-10. 2. Collins C, Welden PL. Cardiotoxicity of 5-fluorouracil. Cancer Treat Rep 1987; 71: 733-36. 3. de Forni M, Bugat R, Sorbette F, Delay M, Bachaud JM, Chevreau C Cardiotoxicité du 5-fluorouracile perfusion intraveineuse continue: étude clinique, prévention, physiopathologie: à propos d’une série de 13 cas. Bull Cancer 1990; 77: 429-38. 4. Koenig H, Patel A. Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate. Arch Neurol 1970; 23: 155-60. 5. Matsubara I, Kamiya J, Imai S. Cardiotoxic effects of 5-fluorouracil in the Guinea pig. Jpn J Pharmacol 1980; 30: 871-79. 6. Pattison FLM, Peters RA. Monofluoro aliphatic compounds. In: Smith FA, ed. Handbook of experimental pharmacology: vol XX, part I. New York: Springer, 1966: 387-458. 7. Tecle B, Casida JE. Enzymatic defluorination and metabolism of fluoroacetate, fluoroacetamide, fluoroethanol, and (-)-erythro-fluorocitrate in rats and mice examined by 19F and 13C NMR. Chem Res Toxicol 1989; 2: 429-35.
Echinococcus multilocularis infestation acquired in UK SIR,-Four species of the cestode genus Echinococcus have been described. E vogeli and E oligarthrus are confined to Central and South America. E granulosus is widely distributed. The principal reservoirs in Britain are hill sheep and sheepdogs. Human cases are seen in the UK in emigrants from regions where the infection is endemic (eg, Cyprus and the Middle East), and in areas with regional reservoirs, the recorded incidence being 1 new case per 1000 per annum in one part of central Powys (Wales) and 1 per 700 in another.1 Lesions are almost always confined to lungs and liver. E multilocularis is a sub-Arctic species, but it is also found in central Europe, including Switzerland.2The natural hosts include the arctic fox and red fox, many species of rodent, cats, and dogs.3 The lifespan of small mammals is short and in its cystic phase in the liver the parasite matures much more quickly than cysts of Egranulosus. Developing cysts infiltrate healthy liver and may metastasise, and in man the infection is ultimately fatal. Drug therapy (principally benzimidazoles) is not notably successful.’* All the evidence at present available suggests only one species in the UK, Egranulosus. E multilocularis has never been identified in the British fox (Vulpes vulpes). (A vigorous debate about whether E granulosus and E multilocularis were the same or not ended, in 1956, in favour of two species, and the two are easy to distinguish.) In 1954, Walshe reported on the death of a London woman, from an infection he described as "echinococcosis alveolaris" and caused by Taenia (Echinococcus) granulosus.5 Subsequently it was appreciated by those interested in this parasite that Walshe had in fact described an infection by E multilocularis. In 1963 I was then asked by the Ministry of Health to reopen the case and to examine the possibility that E multilocularis might be established in the UK. Members of the patient’s family, colleagues from work, members of her church, and landladies were interviewed. Dr Walshe kindly made histology slides available and the Wellcome Museum of
