732
cell-mediated immunity as well as the absence of progressive T4-cell loss. This approach deserves further investigation. Immuvax, PO Box 481222, Los Angeles CA 90048, USA; Oncologic Institute, Los Angeles, and
MICHAEL SCOLARO ROY DURHAM GEORGE PIECZENIK
Department of Anatomy,
Mount Sinai Medical Center, New York
1. Pieczenik G. Predicting coding function from nucleotide sequence "fitness" of tRNA. Proc Natl Acad Sci USA 1980; 77: 3539-43.
or
survival of
Fetoplacental passage of 2’,3’-dideoxyinosine SIR,-Data have been reported on the fetoplacental passage of zidovudine and of its glucuronide metabolite.l,2 Other nucleoside analogues--eg, ddI (2’,3’-dideoxyinosine)-are known to have antiretroviral activity, but with few adverse effects on haematopoiesis.3 This finding may be important in view of the theoretical toxicity of zidovudine on fetal myelopoiesis. To examine if ddI given during pregnancy would damage the fetus, we attempted both to find out whether the drug crossed the placental barrier and to establish the pharmacokinetics of ddI in pregnant women. Two pregnant women aged 24 and 28 were studied; both were HIV seropositive, Centers for Disease Control stage II, and were scheduled for voluntary pregnancy termination. Length of amenorrhoea was 21 and 24 weeks, respectively. The study was approved by an independent ethical committee and patients gave written consent. Both were treated with a single oral dose of 375 mg ddI. Maternal blood was taken by venepuncture at hours 0 (before administration of ddI), 05,1,2,3,4,5,6,7,8, and 12 (after administration of ddI). Amniotic fluid and fetal blood samples were taken 65 min after treatment in patient 1 and 78 min after treatment in patient 2. Amniotic fluid was sampled by amniocentesis under untrasound control. ddI was measured by
high-performance liquid chromatography. Pregnancies were terminated by mifepristone and prostaglandin analogues. Blood samples of the two women were compared with mean concentrations obtained in non-pregnant patients.4 We found no difference in pharmacokinetics between pregnant and non-pregnant subjects. The half-life of ddI was 0 76 h in patient 1 and 118 h in patient 2. ddl crossed the placental barrier in both patients. Concentrations in fetal blood (ng/ml) were lower than those in maternal blood and the same was Maternal blood
Patient
true
Fetal
blood
for amniotic fluid: Amniotic fluid
These data show that ddI crosses the placental barrier during the second trimester of pregnancy. However, we cannot recommend ddI therapy during pregnancy until we know if the drug is toxic to the fetus.
J. C. PONS
Hôpital, Antoine Béclère 92141, Clamart, France;
Hôpital Bicêtre; and Hôpital Cochin,
Paris
M. C. BOUBON A. M. TABURET E. SINGLAS V. CHAMBRIN R. FRYDMAN E. PAPIERNIK J. F. DELFRAISSY
1. Gillet JY, Garraffo R, Abrar D, Bongain A, Lapalus P, Dellamonica P. Fetoplacental passage of zidovudine. Lancet 1989; ii: 269-70. 2. Pons JC, Taburet AM, Singlas E, Papiernik E, Delfraissy JF. Transplacental passage of azathiothymidine (AZT) during second trimester of pregnancy. Eur J Obstet
Gynaecol Reprod Biol (m press). 3. Yarchoan R, Mitsuya J, Thomas RV, et al. In vivo activity against HIV and favorable toxicity profile of 2’,3’-dideoxyinosine. Science 1989; 245: 412-15. 4.Hartman NR, Yarchoan R, Pluda JM, et al. Pharmacokinetics of 2’,3’ -dideoxyadenosine and 2’,3’-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther 1990; 47: 647-54.
Radon in pottery workshops SiR,—Dr Bowie and Professor Bowie (Feb 16, p 409) discuss the average annual effective dose equivalents from radon indoor levels in the UK and the related risk factors for lung cancer. They stress that a link between indoor radon levels and lung cancer in the general public is not yet proved. However, until the question of the health risk of indoor radon is answered unambiguously a worst-case scenario must be assumed, especially if children are concerned. We have measured a radon level up to 740 Bq/m3 in classrooms for pottery lessons in Innsbruck. This figure is higher by a factor of 30 than the mean indoor radon level in the UK.l Although teachers and pupils are usually in the pottery room for those lessons only, the health risk to children from radon is higher than that for adults.2 A simple and effective way to avoid this risk is frequent ventilation of the rooms by opening the windows and secure storage of pottery materials in otherwise unused rooms. Institute of Medical Physics, University of Innsbruck, A-6020 Innsbruck, Austria
O. ENNEMOSER W. AMBACH
Institute of Radiochemistry, Versuchsstelle fur Strahlenschutz und Kerntechnik, Innsbruck
P. SCHNEIDER P. BRUNNER
1. Wrixon
AD, Green BMR, Lomas PR, et al. Natural radiation exposure in UK dwellings: NRPB-R190. London: HM Stationery Office, 1988. 2. American Academy of Pediatrics. Radon exposure: a hazard to children Pediatrics 1989; 83: 799-802.
Glycine and neurodegenerative disease SIR,-Excitatory aminoacid neurotransmitters (EAAs) such as glutamate have been implicated in the pathogenesis of certain neurodegenerative disorders. Glutamate analogues such as p-methylaminoalanine, p-N-oxalylamino-L-alanine, and domoic acid are neurotoxic and have been linked to neurological disorders in man." Glutamate and its analogues act at N-methyl-D-aspartate (NMDA) receptors on neurons. Glycine has an established function as an inhibitory neurotransmitter in the brainstem and spinal cord. Glycine binds to a strychnine-sensitive receptor and causes increased chloride conductance and hyperpolarisation in a similar way to y-aminobutyric acid. However, recent evidence suggests that glycine is also an allosteric modulator at the NMDA receptor, where it potentiates activity of EAAs.5 Glycine may enhance NMDA-mediated neurotoxicity. Ketotic and non-ketotic hyperglycinaemia in infants causes severe encephalopathy and seizures, and rare cases of familial non-ketotic hyperglycaemia have been reported in adults who present with a slowly progressive motor neuron disorderWe have shown that patients with sporadic motoneuron disease have increased cerebrospinal fluid (CSF) glycine concentrations and show a reduced rate of clearance of glycine from blood after an oral glycine load.7,sAmong 32 cases of motoneuron disease and 13 neurological disease controls, we found 1 patient with a significantly raised fasting blood glycine concentration. A 59-year-old woman with claustrophobia and panic attacks was treated for a few weeks in 1986 with clomipramine 20 mg at night. A few months later she noticed progressive gait ataxia followed by upper limb ataxia and slurring dysarthria, together with some impairment of memory. In March, 1988, general physical examination was normal but neurological examination revealed slight optic disc pallor, generalised mild spasticity with hyperreflexia, cerebellar signs in the limbs, and striking truncal ataxia. There was no nystagmus, plantar responses were flexor, and higher cerebral functions were intact, although she had pronounced pout and palmomental and glabellar reflexes. Investigations, which included blood film, visual evoked responses, electromyography, . CSF examination, and vitamin E measurements, were normal but brain computed tomography showed mild cerebellar atrophy. There was no evidence of malignant disease. By March, 1990, she was wheelchair-bound. She had phasic nystagmus on lateral gaze and
severe generalised limb weakness. Neuropsychological revealed testing significant cognitive decline compared with premorbid estimates. A glycine challenge test was completed.’I
cell-mediated immunity as well as the absence of progressive T4-cell loss. This approach deserves further investigation. Immuvax, PO Box 481222, Los Angeles CA 90048, USA; Oncologic Institute, Los Angeles, and
MICHAEL SCOLARO ROY DURHAM GEORGE PIECZENIK
Department of Anatomy,
Mount Sinai Medical Center, New York
1. Pieczenik G. Predicting coding function from nucleotide sequence "fitness" of tRNA. Proc Natl Acad Sci USA 1980; 77: 3539-43.
or
survival of
Fetoplacental passage of 2’,3’-dideoxyinosine SIR,-Data have been reported on the fetoplacental passage of zidovudine and of its glucuronide metabolite.l,2 Other nucleoside analogues--eg, ddI (2’,3’-dideoxyinosine)-are known to have antiretroviral activity, but with few adverse effects on haematopoiesis.3 This finding may be important in view of the theoretical toxicity of zidovudine on fetal myelopoiesis. To examine if ddI given during pregnancy would damage the fetus, we attempted both to find out whether the drug crossed the placental barrier and to establish the pharmacokinetics of ddI in pregnant women. Two pregnant women aged 24 and 28 were studied; both were HIV seropositive, Centers for Disease Control stage II, and were scheduled for voluntary pregnancy termination. Length of amenorrhoea was 21 and 24 weeks, respectively. The study was approved by an independent ethical committee and patients gave written consent. Both were treated with a single oral dose of 375 mg ddI. Maternal blood was taken by venepuncture at hours 0 (before administration of ddI), 05,1,2,3,4,5,6,7,8, and 12 (after administration of ddI). Amniotic fluid and fetal blood samples were taken 65 min after treatment in patient 1 and 78 min after treatment in patient 2. Amniotic fluid was sampled by amniocentesis under untrasound control. ddI was measured by
high-performance liquid chromatography. Pregnancies were terminated by mifepristone and prostaglandin analogues. Blood samples of the two women were compared with mean concentrations obtained in non-pregnant patients.4 We found no difference in pharmacokinetics between pregnant and non-pregnant subjects. The half-life of ddI was 0 76 h in patient 1 and 118 h in patient 2. ddl crossed the placental barrier in both patients. Concentrations in fetal blood (ng/ml) were lower than those in maternal blood and the same was Maternal blood
Patient
true
Fetal
blood
for amniotic fluid: Amniotic fluid
These data show that ddI crosses the placental barrier during the second trimester of pregnancy. However, we cannot recommend ddI therapy during pregnancy until we know if the drug is toxic to the fetus.
J. C. PONS
Hôpital, Antoine Béclère 92141, Clamart, France;
Hôpital Bicêtre; and Hôpital Cochin,
Paris
M. C. BOUBON A. M. TABURET E. SINGLAS V. CHAMBRIN R. FRYDMAN E. PAPIERNIK J. F. DELFRAISSY
1. Gillet JY, Garraffo R, Abrar D, Bongain A, Lapalus P, Dellamonica P. Fetoplacental passage of zidovudine. Lancet 1989; ii: 269-70. 2. Pons JC, Taburet AM, Singlas E, Papiernik E, Delfraissy JF. Transplacental passage of azathiothymidine (AZT) during second trimester of pregnancy. Eur J Obstet
Gynaecol Reprod Biol (m press). 3. Yarchoan R, Mitsuya J, Thomas RV, et al. In vivo activity against HIV and favorable toxicity profile of 2’,3’-dideoxyinosine. Science 1989; 245: 412-15. 4.Hartman NR, Yarchoan R, Pluda JM, et al. Pharmacokinetics of 2’,3’ -dideoxyadenosine and 2’,3’-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther 1990; 47: 647-54.
Radon in pottery workshops SiR,—Dr Bowie and Professor Bowie (Feb 16, p 409) discuss the average annual effective dose equivalents from radon indoor levels in the UK and the related risk factors for lung cancer. They stress that a link between indoor radon levels and lung cancer in the general public is not yet proved. However, until the question of the health risk of indoor radon is answered unambiguously a worst-case scenario must be assumed, especially if children are concerned. We have measured a radon level up to 740 Bq/m3 in classrooms for pottery lessons in Innsbruck. This figure is higher by a factor of 30 than the mean indoor radon level in the UK.l Although teachers and pupils are usually in the pottery room for those lessons only, the health risk to children from radon is higher than that for adults.2 A simple and effective way to avoid this risk is frequent ventilation of the rooms by opening the windows and secure storage of pottery materials in otherwise unused rooms. Institute of Medical Physics, University of Innsbruck, A-6020 Innsbruck, Austria
O. ENNEMOSER W. AMBACH
Institute of Radiochemistry, Versuchsstelle fur Strahlenschutz und Kerntechnik, Innsbruck
P. SCHNEIDER P. BRUNNER
1. Wrixon
AD, Green BMR, Lomas PR, et al. Natural radiation exposure in UK dwellings: NRPB-R190. London: HM Stationery Office, 1988. 2. American Academy of Pediatrics. Radon exposure: a hazard to children Pediatrics 1989; 83: 799-802.
Glycine and neurodegenerative disease SIR,-Excitatory aminoacid neurotransmitters (EAAs) such as glutamate have been implicated in the pathogenesis of certain neurodegenerative disorders. Glutamate analogues such as p-methylaminoalanine, p-N-oxalylamino-L-alanine, and domoic acid are neurotoxic and have been linked to neurological disorders in man." Glutamate and its analogues act at N-methyl-D-aspartate (NMDA) receptors on neurons. Glycine has an established function as an inhibitory neurotransmitter in the brainstem and spinal cord. Glycine binds to a strychnine-sensitive receptor and causes increased chloride conductance and hyperpolarisation in a similar way to y-aminobutyric acid. However, recent evidence suggests that glycine is also an allosteric modulator at the NMDA receptor, where it potentiates activity of EAAs.5 Glycine may enhance NMDA-mediated neurotoxicity. Ketotic and non-ketotic hyperglycinaemia in infants causes severe encephalopathy and seizures, and rare cases of familial non-ketotic hyperglycaemia have been reported in adults who present with a slowly progressive motor neuron disorderWe have shown that patients with sporadic motoneuron disease have increased cerebrospinal fluid (CSF) glycine concentrations and show a reduced rate of clearance of glycine from blood after an oral glycine load.7,sAmong 32 cases of motoneuron disease and 13 neurological disease controls, we found 1 patient with a significantly raised fasting blood glycine concentration. A 59-year-old woman with claustrophobia and panic attacks was treated for a few weeks in 1986 with clomipramine 20 mg at night. A few months later she noticed progressive gait ataxia followed by upper limb ataxia and slurring dysarthria, together with some impairment of memory. In March, 1988, general physical examination was normal but neurological examination revealed slight optic disc pallor, generalised mild spasticity with hyperreflexia, cerebellar signs in the limbs, and striking truncal ataxia. There was no nystagmus, plantar responses were flexor, and higher cerebral functions were intact, although she had pronounced pout and palmomental and glabellar reflexes. Investigations, which included blood film, visual evoked responses, electromyography, . CSF examination, and vitamin E measurements, were normal but brain computed tomography showed mild cerebellar atrophy. There was no evidence of malignant disease. By March, 1990, she was wheelchair-bound. She had phasic nystagmus on lateral gaze and
severe generalised limb weakness. Neuropsychological revealed testing significant cognitive decline compared with premorbid estimates. A glycine challenge test was completed.’I
