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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

188

confusion by using the phrase "breath alcohol corresponding to a blood alcohol concentration of ..." or by writing "blood alcohol" instead of "breath alcohol". Department of Anaesthesiology, Huddinge University Hospital, S-141 86 Huddinge, Sweden

ROBERT HAHN

latex test for diagnosis of invasive aspergillosis

Aspergillus antigen

SiR,—Dr Warnock and his colleagues have drawn attention (Oct 19, p 1023) to defects in the performance of the ’Pastorex Aspergillus’ latex agglultination test introduced for detection of

antigenaemia when invasive aspergillosis is suspected. Our findings are similar to theirs. In one series latex tests were positive in 32 out of 277 sera from 74 neutropenic patients on chemotherapy for haematological malignancy. On retesting with a different batch, only 18 samples remained positive. All were from patients on prophylactic amphotericin B. Invasive aspergillosis was considered possible on clinical grounds in only 1 of the 13 patients involved. The loss of reactivity on retesting noted by Warnock et al has proved to be both common and troublesome, rendering interpretation impossible. Another difficulty is dual reactivity of sera to tests marketed for aspergillosis and candidosis. Sera giving positive tests for aspergillosis may also be positive for candidosis. In our series, coexisting infection could not always be ruled out, but the frequency of dual reactions strongly suggested a cross-reaction. Indeed, the manufacturers state that sera containing high levels (microgram range per ml) of aspergillus galactomannan will also with the candida latex reagent. we have observed positive reactions in the ’Pastorex Candida’ test with sera from a patient with myeloma who had no evidence of systemic candidosis. False-positive reactions with sera containing high levels of paraprotein might readily occur in the latex-based system, and inclusion of a control latex in the new test kit should perhaps have been considered. Rapid and reliable tests for invasive infections caused by aspergillus and candida are needed, and the marketing of kits designed to do this was very welcome. Warnock’s group and ours conclude that performance of the tests has so far been disappointing. Aspergillus galactomannan is an important target molecule for antigenaemia tests, and latex procedures, because of their rapidity and simplicity, have considerable attractions to the routine screening of patients at risk. It is therefore greatly to be hoped that the manufacturers will develop these tests further so that they fulfill their earlier promise.

react

Moreover,

Mycological Reference Laboratory, Central Public Health Laboratory, London NW9 5HT, UK

FRANCES KNIGHT D. W. R. MACKENZIE

*** This letter has been shown to the manufacturers, whose reply to it and to an earlier one follows.-ED. L. SIR,-Dr Warnock and colleagues and Mrs Knight and Professor Mackenzie report defects in the performance of ’Pastorex’ (Diagnostics Pasteur) latex agglutination tests for the detection of circulating antigens in invasive aspergillosis and candidosis. Both groups of investigators observed that positive samples had become negative on later retesting, and Knight and Mackenzie found sera reacting in both tests. When a positive sample is negative on retesting it is either a true positive turned false negative or false positive turned true negative. In the first paper on the aspergillus test Dupont et aP reported that samples from patients with invasive aspergillosis may turn negative

during storage in a freezer, and when we re-tested 15 positive plasma samples from guineapigs with experimental invasive aspergillosis after 13 months of conservation at - 30°C, 6 had unchanged titres,1 increased by 1 dilution, but 8 dropped by 1, 2, or 3 dilution steps. Given the usually low amounts of circulating galactomannan in patients, this instability during storage may account for true-positive samples turning negative. It is difficult to estimate how far this might explain the observations of your correspondents since the clinical information provided does not tell us how many patients definitely had an invasive aspergillus infection.

Both letters do contain evidence that many of the positive reactions were false positives. Pastorex latex agglutination tests have very low detection limits and a drawback of this high sensitivity is increased susceptibility to interference. Good results can only be obtained under good test conditions. Warnock et al did not follow the manufacturer’s instructions. Volumes of samples and latex reagent were halved to 20 pl and 5 ul, respectively. During development of this test special attention was paid to volumes, and they cannot be changed without altering the characteristics of the test itself. Halving the volumes makes it more difficult to homogenise samples and latex suspension and to read the result, and it increases the risk of false-positive reactions as a result of desiccation. By reducing test volumes Warnock et al could do more tests with every kit. They either recycled the disposable agglutination cards and the mixing sticks or used material from other sources; both practices risk introducing errors (eg, mixing with wooden toothpicks may cause false positives). We know that to save money many UK users of these kits halve test volumes. We discourage this very strongly. False-positive agglutination may also occur when latex reagents are not equilibrated to room temperature. We also recommend the use of microcentrifuge tubes that remain well closed during the boiling step of serum treatment; we have observed false positives when water from the water bath enters opened tubes. Finally, the serum should be of good quality. Bacterial contamination causes false-positive reactions.! Serum must be separated from the clot within 24 h of sampling. Transport should be avoided if possible; this can interfere with the reliability of the tests done in reference

laboratories. The dual reactivity described by Knight and Mackenzie has three possible explanations, two of which they mention-namely, double infection (possible but rare) and cross-reactivity. The candida test kit does react with aspergillus galactomannan but only in the Ilgjml range, levels rarely seen in patients. The third explanation is false agglutination, and whenever dual reactivity is frequently observed all the above-mentioned potential causes of false reactions should be

explored. Pastorex candida and aspergillus agglutination tests do require precautions than most latex tests, this being an unfortunate consequence of the very low detection limits that have to be achieved. We now realise that potential interferences deserve more emphasis in the package insert. Some are already mentioned and those that are not will soon be included. We shall also recommend that positive results be re-tested immediately for confirmation. Despite the problems raised by Warnock et al and by Knight and Mackenzie, we believe that both tests are satisfactory if the manufacturer’s protocol is followed and if the pitfalls are avoided. A multicentre study underway in France proves that under those conditions false-positive results are negligible or even non-existent.

more

Sanofi Diagnostics Pasteur, B-3600 Genk, Belgium

D. STYNEN L. MEULEMANS

Sanofi

Diagnostics Pasteur, Marnes-la-Coquette, France

M. L. GARRIGUES

1. Dupont B, Improvisi L, Provost F. Detection de galactomannane dans les aspergilloses invasives humaines et animales avec un test au latex. Bull Soc Fr Mycol Méd 1990; 19: 35-42.

Rise in intracranial pressure with intravenous adenosine SIR,-Adenosine, a purine nucleoside has recently received a product licence (Sanofi) for treatment of paroxysmal supraventricular tachycardia (PSVT). Recognised side-effects include facial flushing, nausea, chest tightness, dizziness, and lightheadedness, this last perhaps as a consequence of either arterial hypotension or cerebral vasodilatation, as reported by Sollevi.1 We report a rise in intracranial pressure after intravenous adenosine. A 58-year-old man was admitted with head injuries after a fall. A subdural haematoma was evacuated, and intracranial pressure monitoring was started perioperatively. Initial intracranial pressure (ICP) measurements ranged from 15-20 cm cerebrospinal fluid (CSF) for 4 days, at which time SVT developed, with associated