186
EXAMPLES OF CURRENT AWARENESS SERVICES ON FLOPPY DISK
i
i *Refs 1-5 tRefs 1,2,6,7
i
z
i
These services enable retrieval of articles by author, journal name, and subject, although subject indexing is somewhat basic. Reprint request cards can be generated automatically. These services are reasonably priced and will run on a standard microcomputer without extra hardware. An advantage of both CD-ROM and floppy disk databases is their ability to generate data in a form compatible with a wide range of bibliographic software. Such software enables personal research databases to be created with little effort. In the better packages, data downloaded from electronic databases can be directly imported without any reformatting by the user. Better still, they can be easily retrieved and further reformatted into the different styles needed for submission of articles to journals. The ideal situation for any medical researcher is to have a comprehensive personal database of references available on his or her microcomputer covering specific interests. Such a database can be regularly updated by importing references from the various electronic databases. In this respect the current information provided by floppy disk databases is invaluable and deserves
emphasis. KIERAN DAWSON JOHN COX OWEN SMITH
University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK 1. Brahmi FA. Current contents
on
diskette and reference update MD Comput 1990; 7:
55-58.
Wiggins T, Miller N. Reference update and current contents on diskette a review of two new current awareness services. Med Ref Serv Quart 1990; 9: 1-12. 3. Powell JH Current contents on diskette: a review CD-ROM Prof 1990; 3: 39-44. 4. Harrington J. Optical product review, current contents on diskette. CD-ROM Lib 2
1991; 6: 30-33. on diskette. Blood Coagulat Fibrinol 1991; 2: 579. 6. Matus N, Beutler EB. Reference update and reference manager- personal computer programs for locating and managing references Bio Techniques 1989; 7: 636-39. 7. Francis JL. Reference update. Blood Coagulat Fibrinol 1991; 2: 578.
5. Francis JL. Current contents
Autism and
Asperger syndrome
SIR,-David Taylor’s otherwise splendid review (Dec 14, 1509) of Uta Frith’s Autisna and Asperger Syndrome contains one egregious error that should not go uncorrected. He refers to Kanner’s description of autism "from a psychoanalytic perspective". I rise to defend my teacher against such calumny. If Leo Kanner subscribed to any psychiatric school, it would have been to Adolf Meyer’s psychobiology. Kanner’s 1943 paper, "Autistic disturbances of affective contact", concluded that his patients had "come in to the world with an innate inability to form the usual, biologically provided affective contact with people, just as other children come in to the world with innate physical or intellectual handicaps". That statement, made at the height of psychoanalytic hegemony over American psychiatry, was an act of courage. I agree with Taylor that Frith’s book is a splendid one. All the more reason, then, not to malign one of the great pioneers to p
whose work this book is devoted. Department of Social Medicine, Harvard Medical School, Boston, MA 02115, USA
LEON EISENBERG
Triazolam and
platelet-aggregating factor
SIR,-In a letter in your Nov 2 issue (p 1157) we drew attention to the high rate of reports of inflammation with triazolam and van der Kroefobservation of blistering in 1982. Blistering had in fact been first found by the drug’s manufacturer in 1972. This was at the Upjohn Experimental Clinic, in a clinical trial (Protocol 321) on male prisoners selected for good physical and mental health. One recipient of triazolam 1 mg (subject no 42, aged 35) had severe blistering. Upjohn’s report in 19731 did not disclose this blistering to the US Food and Drug Administration-nor the development in this man of nervousness, persistent tinnitus, apyrexial severe congestion of the chest, difficulty in breathing, hallucinations, talking a lot, and lapses of memory; nor his improvement when triazolam stopped; nor his later being found dead in bed. Dr Jonas from Upjohn denies (Jan 4, p 57) that van der Kroef mentioned blistering from triazolam yet that 1982 paper refers to blisters of the hands and feet ("haaruitval en blaren op handen en voeten") and vesicles or blisters of the tongue ("blazen op de tong"). The interesting experiments of Dr Roberts and Professor Bames (Dec 7, p 1459) with triazolam 0-25 mg and intradermal plateletaggregating factor (PAF) were on only seven subjects. The error bars (SE) indicate that the power of the study was low. They had increased the stringency of their statistical testing to reduce the risk of a falsely positive result, but allowed the chance of a falsely negative result to be high. As it is, their results hint at triazolam as a PAF inhibitor at lower PAF concentrations (see below). Our letter of Nov 2 rested on daily withdrawal effects during repeated triazolam use, the principle having been recognised since 1982 in the US package insert. Dr Kempe and Dr Blank (Jan 4, p 57) do not give related information about their investigational drug WEB 2086. Its sister, brotizolam, a potent PAF inhibitor and rapidly eliminated hypnotic, would be the relevant single-daily dose comparator. In Upjohn’s 1973 report on Protocol 321 only 4 "events" of nervousness (or anxiety or tension) among men on triazolam 1 mg were disclosed,l yet there were over 70.3 In response to Dr Lenox (Dec 7, p 1459) we must point out that when our research demonstrated that triazolam 05 mg caused anxiety and paranoid reactions4 we were replicating what Upjohn had already found (but what the company’s employees have repeatedly denied). Lenox has worked on PAF, in research aided by Upjohn. Early night plasma concentrations of triazolam are some 10 times higher than morning valuess but Lenox misleadingly quotes morning values, of up to 10 nmol/l. Even multiplying by only 5 would give plasma concentations within an order of magnitude of the 0-3 umol/1 that Lenox reports as the in-vitro concentation of triazolam that led to 50% inhibition of PAF’s maximum effects on human platelets (ICso) at unphysiological concentrations ofPAF.6,7 ICgo values rank the potency of competitive inhibitors but vary with the in-vitro conditions-for example, there is a 25-fold difference between the ICgo for triazolam cited by Roberts and that reported by Lenox, even though both relate to human platelets. Moreover, a seven-fold variation in sensitivity to triazolam in platelets from different individuals6 and tissue-specific differences in PAF receptors8 need to be taken into account. Competitive inhibition depends not only upon the concentration of the inhibitor but also upon the concentration of PAF. Lenox and colleagues demonstrated the competitive relation between alprazolam and PAF: raising the in-vitro concentration of the one necessitated a higher concentration of the other to achieve 50% of maximum platelet response.6 The principle has been demonstrated for several PAF receptor inhibitors; for example,1 pmol/1 BN52021 counteracted 0-01 lanol/1 PAF to roughly the same degree as 10 nmol/1 (0-01 f..lII1o1/1) BN52021 counteracted 01 nmol/1 PAF9 Triazolam as a PAF receptor inhibitor in human platelets is of the same order of potency as BN520218 so low concentrations of triazolam of around 10 nmol/1 would compete with physiological levels (01nmol/1 or less) of PAF.’ Lenox and colleagues have reported an ICS° of 0-5 f..lII1o1/1 for alprazolam, indicating a less potent PAF receptor antagonist than triazolam yet write that treatment with alprazolam "was reported to reduce ... commonly used measures of increased platelet activation
187
in vivo".6 They were referring to a clinical study in which there had been a median plasma alprazolam level of only 0 1 umol/1.’" Lenox is thus willing to link alprazolam’s therapeutic actions to its effects on PAF receptors at concentrations well below his own in-vitro research levels. Clinical plasma concentrations of triazolam were well known in 1987, when Lenox wrote that triazolam and alprazolam "are potent and specific antagonists of PAF" and that antagonism by these triazolobenzodiazepines "may be involved in mechanisms underlying the therapeutic effects of these drugs". If triazolam as a PAF antagonist may contribute to desired effects of triazolam then, in the absence of other explanation, we should suspect that triazolam as a PAF antagonist may contribute to the drug’s peculiar mental and physical ill-effects. The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
KIRSTINE ADAM IAN OSWALD
Upjohn. Technical report. U-33030. six-week tolerance study SPSM protocol no 321. Kalamazoo, Michigan: Upjohn, 1973. 2 Van der Kroef C. Het Halcion-syndrom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. 3. Upjohn. Summary of revised medical event analysis for protocol 321. Kalamazoo, Michigan Upjohn, 1991. 4 Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 5 Eberts FS, Philopoulos Y, Reineke LM, Vliek RW Triazolam disposition Clin Pharmacol Therap 1981; 29: 81-93. 6. Komecki E, Ehrlich YH, Lenox RH. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984; 1.
226: 1454-56
Framingham participants) of low-risk individuals from which high coronary risk cases have been removed. Yet when the MRFIT participants (high-risk hypertensives)3 and total Framingham group2 were analysed aJ or U shaped relation between DBP (or fall in DBP, and CHD was noted. The latest chapter in the saga is a Lancet editorial seeking a "decent burial" for theJ curve on the basis of study data that have not been analysed for the presence or absence and
of such a
1 Samuelsson OG, Wilhelmsen LW, Pennert KM, et al. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years follow-up of treated hypertensives in the primary prevention trial in Gothenburg, Sweden. J Hypertens 1990; 8: 547-55. 2. D’Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. The relation of low diastolic blood pressure to coronary heart disease death in the presence of myocardial infarction: the Framingham Study. Br Med J (in press) 3. Cohen JD, Butler SM, Cutler JA, Neaton JD (for the MRFIT Research Group). Relationship between blood pressure change and mortality among MRFIT hypertensives. Circulation 1991; 84: II-137 4. Coope J. Hypertension the cause of the J-curve. J Hum Hypertens 1990; 4: 1-4 5. Farnett L, Mulrow CD, Linn WD, et al. The J-curve phenomenon and the treatment
6.
7
of hypertension. JAMA 1991; 265: 489-95 Multiple Risk Factor Intervention Trial Research Group Mortality after 10 years for hypertensive participants in the multiple nsk factor intervention trial. Circulation 1990; 82: 1616-28. McMahon S, Peto R, Curler J, et al. Blood pressure, stroke and coronary heart disease I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74.
alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
Measurement of breath alcohol
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 9. Braquet P, Etienne A, Clostre F. Down-regulation of &bgr;2-adrenergic receptors by PAF-acether and its inhibition by the PAF-acether antagonist BN52021. Prostaglandins 1985; 30: 721. 10. Sheehan DV, Coleman JH, Greenblatt DJ, et al. Some biochemical correlates of panic attacks with agoraphobia and their response to a new treatment. J Clin Psychopharmacol 1984; 4: 66-75.
The J
curve
lives
SIR,-Your Nov 23 editorial (p 1299) points out that surrogate endpoints, such as thiazide or beta-blocker-induced changes in plasma lipids or insulin resistance, are an unsound basis for determining management in hypertension. However, you go on to say that the results of the Systolic Hypertension in the Elderly Program (SHEP) study in isolated systolic hypertension drive a stake through the heart of the J-curve hypothesis. The J curve for diastolic blood-pressure (DBP) death from myocardial infarction is not a hypothesis but a fact, though its mechanism may be debated. The curve has been demonstrated in large cohort and population studies and in well-conducted controlled trials in patients with hypertension (refs 1-4 are just examples), and is independent of the coronary risk factors, illness, and left-ventricular functionA recent assessment of the J curve by four independent reviewers5 covering only the highest quality published studies (over 14 000 patients) yielded a "best-fit" that confirmed the curve with a J point in the low-to-mid 80s DBP. The SHEP study has not yet been analysed as a test for theJ curve. A treatment which confers significant overall benefit (ie, low-dose chlorthalidone in SHEP) may be harmful to some patients. This was found in the MRFIT study6 in which patients in the special-care group experienced fewer coronary heart disease (CHD) deaths than those in the referred-care group, yet in the special-care group there was a strikingJ or U shaped relation between fall in DBP and death from myocardial infarctionprobably explained by previous clinical CHD.3 I am amazed at the reluctance of some doctors to accept the self-evident (to me) concept that a vital organ that is fed by a severely narrowed artery will have a much reduced circulatory reserve. Such an organ may be threatened when perfusion pressure is lowered to levels that are tolerated by well-vascularised organs. The concept is accepted for the brain and kidney but not for the heart. A major 1990 Lancet article dismissed theJ curve on the basis of a massive population (over 400 000, comprising mainly MRFIT screenees common
J. M. CRUICKSHANK
Wilmslow SK9 2AY, UK
7 Komecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the
8
curve.
The Flat, The Bows, Wilmslow Park,
SIR,-"Be careful about reading health books", said Mark Twain, "you may die of a misprint". I learned from Dr Hahn (Dec 21/28, p 1602) that he and his colleagues have been using ethanol to monitor fluid absorption during TURP since 1986; that it can lead "breath alcohol [concentration of] about 0-25 mg/ml" but that the operation need not be stopped "until 2 litres have been absorbed (breath alcohol about 0-50 mg/ml)". A breath alcohol concentration of 0-50 mg/ml is some 1428 times the legal limit for driving in the UK (which is 35 ug/100 ml, or 0-35 ug/ml, or 0-00035 mg/ml) and would mean that the patients had 100 % ethanol circulating in their veins. I feel sure that there must be a misprint somewhere; but where? And who was responsible for it? Does the fault lie with the author? Is the mistake in the units of volume or of mass? This is not an isolated example of the confusion that can arise as a result of the misuse (or misprinting) of units of measurement. Such errors occur in refereed journals just as often as in unrefereed ones, but do make reports containing such errors potentially, and sometimes positively, harmful. I recall that some years ago some colleagues and I found ourselves unable to reproduce important work published by a very well known group of researchers into experimental hyperlipidaemia until it dawned on us that the amount of substance (cobalt chloride) that they claimed to have used in their experiments was exactly 100 times the amount they actually had used. to a
School of
Biological Sciences, University of Surrey,
VINCENT MARKS
Guildford GU2 5XH, UK
** This letter has been shown follows.-ED. L.
to
Dr Hahn, whose
reply
SIR,-Breath alcohol analysers in Sweden are calibrated to the corresponding blood ethanol concentration. These devices are usually purchased to establish whether drivers are being intoxicated, which is defmed (in Sweden) by a blood alcohol concentration above 0-40 mg/ml. Breath ethanol concentration is consistently 2300 times lower than that of blood ethanol. We have studied the blood-breath partition coefficient for ethanol in TURP patients in an investigation of ethanol monitoring (Acta Anaesthesiol Scand 1991; 35: 393-97), but all papers on ethanol monitoring during irrigating fluid absorption express breath alcohol in terms of the corresponding blood ethanol concentration. I could have avoided
EXAMPLES OF CURRENT AWARENESS SERVICES ON FLOPPY DISK
i
i *Refs 1-5 tRefs 1,2,6,7
i
z
i
These services enable retrieval of articles by author, journal name, and subject, although subject indexing is somewhat basic. Reprint request cards can be generated automatically. These services are reasonably priced and will run on a standard microcomputer without extra hardware. An advantage of both CD-ROM and floppy disk databases is their ability to generate data in a form compatible with a wide range of bibliographic software. Such software enables personal research databases to be created with little effort. In the better packages, data downloaded from electronic databases can be directly imported without any reformatting by the user. Better still, they can be easily retrieved and further reformatted into the different styles needed for submission of articles to journals. The ideal situation for any medical researcher is to have a comprehensive personal database of references available on his or her microcomputer covering specific interests. Such a database can be regularly updated by importing references from the various electronic databases. In this respect the current information provided by floppy disk databases is invaluable and deserves
emphasis. KIERAN DAWSON JOHN COX OWEN SMITH
University Department of Surgery, Royal Free Hospital, London NW3 2QG, UK 1. Brahmi FA. Current contents
on
diskette and reference update MD Comput 1990; 7:
55-58.
Wiggins T, Miller N. Reference update and current contents on diskette a review of two new current awareness services. Med Ref Serv Quart 1990; 9: 1-12. 3. Powell JH Current contents on diskette: a review CD-ROM Prof 1990; 3: 39-44. 4. Harrington J. Optical product review, current contents on diskette. CD-ROM Lib 2
1991; 6: 30-33. on diskette. Blood Coagulat Fibrinol 1991; 2: 579. 6. Matus N, Beutler EB. Reference update and reference manager- personal computer programs for locating and managing references Bio Techniques 1989; 7: 636-39. 7. Francis JL. Reference update. Blood Coagulat Fibrinol 1991; 2: 578.
5. Francis JL. Current contents
Autism and
Asperger syndrome
SIR,-David Taylor’s otherwise splendid review (Dec 14, 1509) of Uta Frith’s Autisna and Asperger Syndrome contains one egregious error that should not go uncorrected. He refers to Kanner’s description of autism "from a psychoanalytic perspective". I rise to defend my teacher against such calumny. If Leo Kanner subscribed to any psychiatric school, it would have been to Adolf Meyer’s psychobiology. Kanner’s 1943 paper, "Autistic disturbances of affective contact", concluded that his patients had "come in to the world with an innate inability to form the usual, biologically provided affective contact with people, just as other children come in to the world with innate physical or intellectual handicaps". That statement, made at the height of psychoanalytic hegemony over American psychiatry, was an act of courage. I agree with Taylor that Frith’s book is a splendid one. All the more reason, then, not to malign one of the great pioneers to p
whose work this book is devoted. Department of Social Medicine, Harvard Medical School, Boston, MA 02115, USA
LEON EISENBERG
Triazolam and
platelet-aggregating factor
SIR,-In a letter in your Nov 2 issue (p 1157) we drew attention to the high rate of reports of inflammation with triazolam and van der Kroefobservation of blistering in 1982. Blistering had in fact been first found by the drug’s manufacturer in 1972. This was at the Upjohn Experimental Clinic, in a clinical trial (Protocol 321) on male prisoners selected for good physical and mental health. One recipient of triazolam 1 mg (subject no 42, aged 35) had severe blistering. Upjohn’s report in 19731 did not disclose this blistering to the US Food and Drug Administration-nor the development in this man of nervousness, persistent tinnitus, apyrexial severe congestion of the chest, difficulty in breathing, hallucinations, talking a lot, and lapses of memory; nor his improvement when triazolam stopped; nor his later being found dead in bed. Dr Jonas from Upjohn denies (Jan 4, p 57) that van der Kroef mentioned blistering from triazolam yet that 1982 paper refers to blisters of the hands and feet ("haaruitval en blaren op handen en voeten") and vesicles or blisters of the tongue ("blazen op de tong"). The interesting experiments of Dr Roberts and Professor Bames (Dec 7, p 1459) with triazolam 0-25 mg and intradermal plateletaggregating factor (PAF) were on only seven subjects. The error bars (SE) indicate that the power of the study was low. They had increased the stringency of their statistical testing to reduce the risk of a falsely positive result, but allowed the chance of a falsely negative result to be high. As it is, their results hint at triazolam as a PAF inhibitor at lower PAF concentrations (see below). Our letter of Nov 2 rested on daily withdrawal effects during repeated triazolam use, the principle having been recognised since 1982 in the US package insert. Dr Kempe and Dr Blank (Jan 4, p 57) do not give related information about their investigational drug WEB 2086. Its sister, brotizolam, a potent PAF inhibitor and rapidly eliminated hypnotic, would be the relevant single-daily dose comparator. In Upjohn’s 1973 report on Protocol 321 only 4 "events" of nervousness (or anxiety or tension) among men on triazolam 1 mg were disclosed,l yet there were over 70.3 In response to Dr Lenox (Dec 7, p 1459) we must point out that when our research demonstrated that triazolam 05 mg caused anxiety and paranoid reactions4 we were replicating what Upjohn had already found (but what the company’s employees have repeatedly denied). Lenox has worked on PAF, in research aided by Upjohn. Early night plasma concentrations of triazolam are some 10 times higher than morning valuess but Lenox misleadingly quotes morning values, of up to 10 nmol/l. Even multiplying by only 5 would give plasma concentations within an order of magnitude of the 0-3 umol/1 that Lenox reports as the in-vitro concentation of triazolam that led to 50% inhibition of PAF’s maximum effects on human platelets (ICso) at unphysiological concentrations ofPAF.6,7 ICgo values rank the potency of competitive inhibitors but vary with the in-vitro conditions-for example, there is a 25-fold difference between the ICgo for triazolam cited by Roberts and that reported by Lenox, even though both relate to human platelets. Moreover, a seven-fold variation in sensitivity to triazolam in platelets from different individuals6 and tissue-specific differences in PAF receptors8 need to be taken into account. Competitive inhibition depends not only upon the concentration of the inhibitor but also upon the concentration of PAF. Lenox and colleagues demonstrated the competitive relation between alprazolam and PAF: raising the in-vitro concentration of the one necessitated a higher concentration of the other to achieve 50% of maximum platelet response.6 The principle has been demonstrated for several PAF receptor inhibitors; for example,1 pmol/1 BN52021 counteracted 0-01 lanol/1 PAF to roughly the same degree as 10 nmol/1 (0-01 f..lII1o1/1) BN52021 counteracted 01 nmol/1 PAF9 Triazolam as a PAF receptor inhibitor in human platelets is of the same order of potency as BN520218 so low concentrations of triazolam of around 10 nmol/1 would compete with physiological levels (01nmol/1 or less) of PAF.’ Lenox and colleagues have reported an ICS° of 0-5 f..lII1o1/1 for alprazolam, indicating a less potent PAF receptor antagonist than triazolam yet write that treatment with alprazolam "was reported to reduce ... commonly used measures of increased platelet activation
187
in vivo".6 They were referring to a clinical study in which there had been a median plasma alprazolam level of only 0 1 umol/1.’" Lenox is thus willing to link alprazolam’s therapeutic actions to its effects on PAF receptors at concentrations well below his own in-vitro research levels. Clinical plasma concentrations of triazolam were well known in 1987, when Lenox wrote that triazolam and alprazolam "are potent and specific antagonists of PAF" and that antagonism by these triazolobenzodiazepines "may be involved in mechanisms underlying the therapeutic effects of these drugs". If triazolam as a PAF antagonist may contribute to desired effects of triazolam then, in the absence of other explanation, we should suspect that triazolam as a PAF antagonist may contribute to the drug’s peculiar mental and physical ill-effects. The Birches, 41 St Ronan’s Terrace, Innerleithen EH44 6RB, UK
KIRSTINE ADAM IAN OSWALD
Upjohn. Technical report. U-33030. six-week tolerance study SPSM protocol no 321. Kalamazoo, Michigan: Upjohn, 1973. 2 Van der Kroef C. Het Halcion-syndrom-een iatrogene epidiemie in Nederland. Tijdschr Alcohol Drugs 1982; 8: 156-62. 3. Upjohn. Summary of revised medical event analysis for protocol 321. Kalamazoo, Michigan Upjohn, 1991. 4 Adam K, Oswald I. Can a rapidly-eliminated hypnotic cause daytime anxiety? Pharmacopsychiatry 1989; 22: 115-19. 5 Eberts FS, Philopoulos Y, Reineke LM, Vliek RW Triazolam disposition Clin Pharmacol Therap 1981; 29: 81-93. 6. Komecki E, Ehrlich YH, Lenox RH. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984; 1.
226: 1454-56
Framingham participants) of low-risk individuals from which high coronary risk cases have been removed. Yet when the MRFIT participants (high-risk hypertensives)3 and total Framingham group2 were analysed aJ or U shaped relation between DBP (or fall in DBP, and CHD was noted. The latest chapter in the saga is a Lancet editorial seeking a "decent burial" for theJ curve on the basis of study data that have not been analysed for the presence or absence and
of such a
1 Samuelsson OG, Wilhelmsen LW, Pennert KM, et al. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years follow-up of treated hypertensives in the primary prevention trial in Gothenburg, Sweden. J Hypertens 1990; 8: 547-55. 2. D’Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. The relation of low diastolic blood pressure to coronary heart disease death in the presence of myocardial infarction: the Framingham Study. Br Med J (in press) 3. Cohen JD, Butler SM, Cutler JA, Neaton JD (for the MRFIT Research Group). Relationship between blood pressure change and mortality among MRFIT hypertensives. Circulation 1991; 84: II-137 4. Coope J. Hypertension the cause of the J-curve. J Hum Hypertens 1990; 4: 1-4 5. Farnett L, Mulrow CD, Linn WD, et al. The J-curve phenomenon and the treatment
6.
7
of hypertension. JAMA 1991; 265: 489-95 Multiple Risk Factor Intervention Trial Research Group Mortality after 10 years for hypertensive participants in the multiple nsk factor intervention trial. Circulation 1990; 82: 1616-28. McMahon S, Peto R, Curler J, et al. Blood pressure, stroke and coronary heart disease I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335: 765-74.
alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. Adv Exp Med Biol 1987;
Measurement of breath alcohol
221: 477-88.
Braquet P, Touqui L, Shen TY, Vargaftig BB. Perspectives in platelet-activating factor research. Pharmacol Rev 1987; 39: 97-145. 9. Braquet P, Etienne A, Clostre F. Down-regulation of &bgr;2-adrenergic receptors by PAF-acether and its inhibition by the PAF-acether antagonist BN52021. Prostaglandins 1985; 30: 721. 10. Sheehan DV, Coleman JH, Greenblatt DJ, et al. Some biochemical correlates of panic attacks with agoraphobia and their response to a new treatment. J Clin Psychopharmacol 1984; 4: 66-75.
The J
curve
lives
SIR,-Your Nov 23 editorial (p 1299) points out that surrogate endpoints, such as thiazide or beta-blocker-induced changes in plasma lipids or insulin resistance, are an unsound basis for determining management in hypertension. However, you go on to say that the results of the Systolic Hypertension in the Elderly Program (SHEP) study in isolated systolic hypertension drive a stake through the heart of the J-curve hypothesis. The J curve for diastolic blood-pressure (DBP) death from myocardial infarction is not a hypothesis but a fact, though its mechanism may be debated. The curve has been demonstrated in large cohort and population studies and in well-conducted controlled trials in patients with hypertension (refs 1-4 are just examples), and is independent of the coronary risk factors, illness, and left-ventricular functionA recent assessment of the J curve by four independent reviewers5 covering only the highest quality published studies (over 14 000 patients) yielded a "best-fit" that confirmed the curve with a J point in the low-to-mid 80s DBP. The SHEP study has not yet been analysed as a test for theJ curve. A treatment which confers significant overall benefit (ie, low-dose chlorthalidone in SHEP) may be harmful to some patients. This was found in the MRFIT study6 in which patients in the special-care group experienced fewer coronary heart disease (CHD) deaths than those in the referred-care group, yet in the special-care group there was a strikingJ or U shaped relation between fall in DBP and death from myocardial infarctionprobably explained by previous clinical CHD.3 I am amazed at the reluctance of some doctors to accept the self-evident (to me) concept that a vital organ that is fed by a severely narrowed artery will have a much reduced circulatory reserve. Such an organ may be threatened when perfusion pressure is lowered to levels that are tolerated by well-vascularised organs. The concept is accepted for the brain and kidney but not for the heart. A major 1990 Lancet article dismissed theJ curve on the basis of a massive population (over 400 000, comprising mainly MRFIT screenees common
J. M. CRUICKSHANK
Wilmslow SK9 2AY, UK
7 Komecki E, Lenox RH, Hardwick DH, Bergdahl JA, Ehrlich YH. Interactions of the
8
curve.
The Flat, The Bows, Wilmslow Park,
SIR,-"Be careful about reading health books", said Mark Twain, "you may die of a misprint". I learned from Dr Hahn (Dec 21/28, p 1602) that he and his colleagues have been using ethanol to monitor fluid absorption during TURP since 1986; that it can lead "breath alcohol [concentration of] about 0-25 mg/ml" but that the operation need not be stopped "until 2 litres have been absorbed (breath alcohol about 0-50 mg/ml)". A breath alcohol concentration of 0-50 mg/ml is some 1428 times the legal limit for driving in the UK (which is 35 ug/100 ml, or 0-35 ug/ml, or 0-00035 mg/ml) and would mean that the patients had 100 % ethanol circulating in their veins. I feel sure that there must be a misprint somewhere; but where? And who was responsible for it? Does the fault lie with the author? Is the mistake in the units of volume or of mass? This is not an isolated example of the confusion that can arise as a result of the misuse (or misprinting) of units of measurement. Such errors occur in refereed journals just as often as in unrefereed ones, but do make reports containing such errors potentially, and sometimes positively, harmful. I recall that some years ago some colleagues and I found ourselves unable to reproduce important work published by a very well known group of researchers into experimental hyperlipidaemia until it dawned on us that the amount of substance (cobalt chloride) that they claimed to have used in their experiments was exactly 100 times the amount they actually had used. to a
School of
Biological Sciences, University of Surrey,
VINCENT MARKS
Guildford GU2 5XH, UK
** This letter has been shown follows.-ED. L.
to
Dr Hahn, whose
reply
SIR,-Breath alcohol analysers in Sweden are calibrated to the corresponding blood ethanol concentration. These devices are usually purchased to establish whether drivers are being intoxicated, which is defmed (in Sweden) by a blood alcohol concentration above 0-40 mg/ml. Breath ethanol concentration is consistently 2300 times lower than that of blood ethanol. We have studied the blood-breath partition coefficient for ethanol in TURP patients in an investigation of ethanol monitoring (Acta Anaesthesiol Scand 1991; 35: 393-97), but all papers on ethanol monitoring during irrigating fluid absorption express breath alcohol in terms of the corresponding blood ethanol concentration. I could have avoided
