- Email: [email protected]
TRACHEOSTOMY FOR SLEEP APNOEA
332 methionine the level of GSH remains at the theshold for toxicity, about 20%. Thus, NAC is effective even after the removal of
paracetamol, presumably by enabling the synthesis of GSH, which then serves as a thiol-reductant. In contrast, both antidotes are effective during the early stages of paracetamol toxicity, due to the generation of GSH which will presumably act largely by detoxifying the reactive metabolite directly. Both methionine and N-acetylcysteine are first converted to L-cysteine. NAC requires only deacetylation and this enzyme seems not to be affected by oxidising agents. In contrast, methionine requires sequential metabolism by five enzymes, at least two of which are inhibited by oxidising agents. It is thus possible that some antidotes, in particular NAC, act by two mechanisms to protect against paracetamol overdose. In the first, there is reduction in the amount of reactive metabolite4 available to cause toxicity, through adduct formation with GSH.4 This is the mechanism upon which most workers have concentrated, and some workers have tried to develop specific inhibitors of the activation pathway.The second mechanism is reduction of oxidised thiol groups in key enzymes permitting reestablishment of calcium homoeostasis. This effect will continue even after most of the paracetamol has been metabolised, and the efficacy of such antidotes will be independent of the formation of the methionine seems to be reactive metabolite. This might explain effective up to only 8 or 9 h after overdose whereas NAC seems to be beneficial for at least 12 h.8
why
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W120HS
L. G. B. TEE A. R. BOOBIS D. S. DAVIES
1. Blair 2.
IA, Boobis AR, Davies DS, Cresp TM. Paracetamol oxidation: synthesis and reactivity of N-acetyl-p-benzoquinoneimine. Tetrahedron Lett 1980; 21: 4947-50. Moore M, Thor H, Moore G, Nelson S, Moldeus P, Orrenius S. The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine (NAPQI) in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2 +. J Biol Chem 1985; 260: 13035-40.
3. Tee LBG, Boobis 4.
AR, Huggett AC, Davies DS. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol (in press). Lauterburg BH, Corcoran GB, Mitchell JR. Mechanism of action of N-acetylcysteine
the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin 1983; 71: 980-91. 5. Miners JO, Drew R, Birkett DJ Mechanism of action of paracetamol protective agents in mice in vivo. Biochem Pharmacol 1984; 33: 2995-3000 6. Mitchell MC, Schenker S, Avant GR, Spieg KV. Cimetidine protects against acetaminophen hepatotoxicity in rats. Gastroenterology 1981; 81: 1052-60. 7. Prescott LF, Park J, Sutherland GR, Smith IJ, Proudfoot AT. Cysteamine, methionine and penicillamine in the treatment of paracetamol poisoning. Lancet 1976; ii: 109-14. 8. Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; ii: 1097-100.
positive airways pressure (CPAP). Unfortunately reported in Australia with this approach has not been achieved in North America so a patient with disabling OSA should be tried with nasal CPAP and/or protriptyline, but if these are not tolerated or are ineffective then tracheostomy may well be nasal continuous
he
success rate
indicated. This may be necessary as weight loss is accomplished or, rarely, Department of Respiratory Medicine, University of Manitoba, and Sleep Laboratory, St Boniface General Hospital, Winnipeg, Manitoba, Canada R2HG 2AG
a
temporary
measure
until
permanently. CHARLES F. GEORGE MORLEY LERTZMAN MEIR H. KRYGER
CONDUCTION BLOCK IN EARLY GUILLAIN-BARRE SYNDROME
SiR,-The importance of conduction block in Guillain-Barre syndrome (GBS) is now being recognised. Mills and Murrayl have re-emphasised the primary role of conduction block in producing the paralysis and other signs of GBS. We have noted conduction block early in GBS, when other physiological signs of demyelination-slowing of conduction velocity and temporal dispersion of the compound muscle action potential-are often not seen.2,3 Mills and Murray have demonstrated proximal conduction block between the spinal cord and axilla in GBS patients using the technique of direct percutaneous ventral root stimulation 4We have recorded proximal conduction block between the cauda equina and the popliteal fossa using direct stimulation of the lumbosacral ventral roots through lumbar puncture needles, insulated, except for their tips and inserted into the lumbar subarachnoid space.2 This proximal conduction block explains why GBS patients have apparently normal distal electrophysiological studies. Department of Clinical Neurological Sciences, Division of Neurology, University Hospital, London, Ontario N6A 5A5, Canada
T. E. FEASBY W. F. BROWN
in
Invest
KR, Murray NMF. Proximal conduction block in early Guillam Barré syndrome Lancet 1985; ii: 659. 2. Brown WF, Feasby TE. Conduction block and denervation in Guillain-Barré polyneuropathy. Brain 1984; 107: 219-39. 3 Brown WF. The physiological and technical basis of electromyography. Boston 1. Mills
Butterworths, 1984. CD, Merton PA, Morton HB.
4. Marsden brain:
Percutaneous stimulation of spinal cord pyramidal tract conduction studies in man. J Physiol 1982; 328: 6P
and
FERTILITY GOD IN THE GAMETE LABORATORY
TRACHEOSTOMY FOR SLEEP APNOEA 26 editorial on snoring and sleepiness reinforces of obstructive sleep apnoea (OSA). While the editorial summarised this vast topic very well, we disagree with the view that "tracheostomy has little or no role in the modern treatment of sleep
SiR,-Your Oct
awareness
apnoea". Five years ago tracheostomy was the only effective form of therapy. Awareness and understanding of the disorder was so slight that patients were not identified until disabling daytime sleepiness was manifest and often not until secondary erythrocytosis and/or right heart failure were obvious. With increasing knowledge and the development of sleep laboratories the broad spectrum of severity of OSA was appreciated and it soon became obvious that tracheostomy was too invasive a procedure for a patient with mild or moderate disease. Thus, as discussed in your editorial, other forms of therapy evolved for mild to moderate cases, for which tracheostomy is not the treatment of choice. There are three categories of patient who still may require tracheostomy: the patient with severe OSA related to an underlying anatomical deformity in whom a tracheostomy is the initial treatment of choice until the anatomical deformity can be corrected; those in whom uvulopalatoplasty is to be performed, who should have a tracheostomy preoperatively; and those who do not tolerate
SIR,-While the entire world of in vitro fertilisation (IVF) is struggling to improve the pregnancy rate, we believe that we have made a significant observation. 120 consecutive cycles were studied. All patients underwent essentially identical ovulation stimulation, oocyte retrieval, sperm capacitation, fertilisation, and embryo transfer procedures.’ In the first 75 patients only 7 pregnancies were confirmed after embryo transfer. In the subsequent 45 patients there were 10 pregnancies. The single variable accounting for this improved success rate was the placement of a Cook Islands silver dollar, upon which is imprinted the symbol of a fertility god, on top of the laminar flow hood in the gamete laboratory after the first 75 patients had been treated. We wish to draw this to your readers’ attention, less to extol the virtues of fertility symbols than to make the point that as there are so many variables contributing to success or failure in IVF, any conclusions drawn from similar apparently single
variable studies must be read with caution.
Department of Obstetrics and Gynaecology, Health Sciences
Centre,
University of Calgary, Calgary, Alberta, Canada 1.
T2N 4N1
P. J. TAYLOR S. SERVIS M. MAHADEVAN A. LEADER
Taylor PJ, et al Initial experience with IVF/ET at the University of Calgary/Foothills 1985; 2: 112. Hospital. IVF/ET J
paracetamol, presumably by enabling the synthesis of GSH, which then serves as a thiol-reductant. In contrast, both antidotes are effective during the early stages of paracetamol toxicity, due to the generation of GSH which will presumably act largely by detoxifying the reactive metabolite directly. Both methionine and N-acetylcysteine are first converted to L-cysteine. NAC requires only deacetylation and this enzyme seems not to be affected by oxidising agents. In contrast, methionine requires sequential metabolism by five enzymes, at least two of which are inhibited by oxidising agents. It is thus possible that some antidotes, in particular NAC, act by two mechanisms to protect against paracetamol overdose. In the first, there is reduction in the amount of reactive metabolite4 available to cause toxicity, through adduct formation with GSH.4 This is the mechanism upon which most workers have concentrated, and some workers have tried to develop specific inhibitors of the activation pathway.The second mechanism is reduction of oxidised thiol groups in key enzymes permitting reestablishment of calcium homoeostasis. This effect will continue even after most of the paracetamol has been metabolised, and the efficacy of such antidotes will be independent of the formation of the methionine seems to be reactive metabolite. This might explain effective up to only 8 or 9 h after overdose whereas NAC seems to be beneficial for at least 12 h.8
why
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W120HS
L. G. B. TEE A. R. BOOBIS D. S. DAVIES
1. Blair 2.
IA, Boobis AR, Davies DS, Cresp TM. Paracetamol oxidation: synthesis and reactivity of N-acetyl-p-benzoquinoneimine. Tetrahedron Lett 1980; 21: 4947-50. Moore M, Thor H, Moore G, Nelson S, Moldeus P, Orrenius S. The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine (NAPQI) in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2 +. J Biol Chem 1985; 260: 13035-40.
3. Tee LBG, Boobis 4.
AR, Huggett AC, Davies DS. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol (in press). Lauterburg BH, Corcoran GB, Mitchell JR. Mechanism of action of N-acetylcysteine
the protection against the hepatotoxicity of acetaminophen in rats in vivo. J Clin 1983; 71: 980-91. 5. Miners JO, Drew R, Birkett DJ Mechanism of action of paracetamol protective agents in mice in vivo. Biochem Pharmacol 1984; 33: 2995-3000 6. Mitchell MC, Schenker S, Avant GR, Spieg KV. Cimetidine protects against acetaminophen hepatotoxicity in rats. Gastroenterology 1981; 81: 1052-60. 7. Prescott LF, Park J, Sutherland GR, Smith IJ, Proudfoot AT. Cysteamine, methionine and penicillamine in the treatment of paracetamol poisoning. Lancet 1976; ii: 109-14. 8. Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; ii: 1097-100.
positive airways pressure (CPAP). Unfortunately reported in Australia with this approach has not been achieved in North America so a patient with disabling OSA should be tried with nasal CPAP and/or protriptyline, but if these are not tolerated or are ineffective then tracheostomy may well be nasal continuous
he
success rate
indicated. This may be necessary as weight loss is accomplished or, rarely, Department of Respiratory Medicine, University of Manitoba, and Sleep Laboratory, St Boniface General Hospital, Winnipeg, Manitoba, Canada R2HG 2AG
a
temporary
measure
until
permanently. CHARLES F. GEORGE MORLEY LERTZMAN MEIR H. KRYGER
CONDUCTION BLOCK IN EARLY GUILLAIN-BARRE SYNDROME
SiR,-The importance of conduction block in Guillain-Barre syndrome (GBS) is now being recognised. Mills and Murrayl have re-emphasised the primary role of conduction block in producing the paralysis and other signs of GBS. We have noted conduction block early in GBS, when other physiological signs of demyelination-slowing of conduction velocity and temporal dispersion of the compound muscle action potential-are often not seen.2,3 Mills and Murray have demonstrated proximal conduction block between the spinal cord and axilla in GBS patients using the technique of direct percutaneous ventral root stimulation 4We have recorded proximal conduction block between the cauda equina and the popliteal fossa using direct stimulation of the lumbosacral ventral roots through lumbar puncture needles, insulated, except for their tips and inserted into the lumbar subarachnoid space.2 This proximal conduction block explains why GBS patients have apparently normal distal electrophysiological studies. Department of Clinical Neurological Sciences, Division of Neurology, University Hospital, London, Ontario N6A 5A5, Canada
T. E. FEASBY W. F. BROWN
in
Invest
KR, Murray NMF. Proximal conduction block in early Guillam Barré syndrome Lancet 1985; ii: 659. 2. Brown WF, Feasby TE. Conduction block and denervation in Guillain-Barré polyneuropathy. Brain 1984; 107: 219-39. 3 Brown WF. The physiological and technical basis of electromyography. Boston 1. Mills
Butterworths, 1984. CD, Merton PA, Morton HB.
4. Marsden brain:
Percutaneous stimulation of spinal cord pyramidal tract conduction studies in man. J Physiol 1982; 328: 6P
and
FERTILITY GOD IN THE GAMETE LABORATORY
TRACHEOSTOMY FOR SLEEP APNOEA 26 editorial on snoring and sleepiness reinforces of obstructive sleep apnoea (OSA). While the editorial summarised this vast topic very well, we disagree with the view that "tracheostomy has little or no role in the modern treatment of sleep
SiR,-Your Oct
awareness
apnoea". Five years ago tracheostomy was the only effective form of therapy. Awareness and understanding of the disorder was so slight that patients were not identified until disabling daytime sleepiness was manifest and often not until secondary erythrocytosis and/or right heart failure were obvious. With increasing knowledge and the development of sleep laboratories the broad spectrum of severity of OSA was appreciated and it soon became obvious that tracheostomy was too invasive a procedure for a patient with mild or moderate disease. Thus, as discussed in your editorial, other forms of therapy evolved for mild to moderate cases, for which tracheostomy is not the treatment of choice. There are three categories of patient who still may require tracheostomy: the patient with severe OSA related to an underlying anatomical deformity in whom a tracheostomy is the initial treatment of choice until the anatomical deformity can be corrected; those in whom uvulopalatoplasty is to be performed, who should have a tracheostomy preoperatively; and those who do not tolerate
SIR,-While the entire world of in vitro fertilisation (IVF) is struggling to improve the pregnancy rate, we believe that we have made a significant observation. 120 consecutive cycles were studied. All patients underwent essentially identical ovulation stimulation, oocyte retrieval, sperm capacitation, fertilisation, and embryo transfer procedures.’ In the first 75 patients only 7 pregnancies were confirmed after embryo transfer. In the subsequent 45 patients there were 10 pregnancies. The single variable accounting for this improved success rate was the placement of a Cook Islands silver dollar, upon which is imprinted the symbol of a fertility god, on top of the laminar flow hood in the gamete laboratory after the first 75 patients had been treated. We wish to draw this to your readers’ attention, less to extol the virtues of fertility symbols than to make the point that as there are so many variables contributing to success or failure in IVF, any conclusions drawn from similar apparently single
variable studies must be read with caution.
Department of Obstetrics and Gynaecology, Health Sciences
Centre,
University of Calgary, Calgary, Alberta, Canada 1.
T2N 4N1
P. J. TAYLOR S. SERVIS M. MAHADEVAN A. LEADER
Taylor PJ, et al Initial experience with IVF/ET at the University of Calgary/Foothills 1985; 2: 112. Hospital. IVF/ET J