1196

stimuli of different intensities delivered at variable rates and durations with the coil centred over a silver/silver-chloride cup electrode. We measured temperature on the skin directly under the electrode by a thermocouple. Skin temperature rose by 3 5°C after 40 stimuli delivered at 4 Hz, and the temperature did not return to baseline for almost 4 min (figure). The temperature increase was dependent on frequency, intensity, and number of stimuli. Delivery of 160 stimuli at 100% output intensity and 1 Hz frequency raised the temperature by 4-4*C. Magnetic stimulation applied over the contact gel or the bare arm without the electrode or over the isolated thermocouple did not lead to any temperature changes. The calculated increase in temperature on the skin surface under a silver/silver-chloride electrode after a single train of magnetic stimuli of 10 s duration at 80% output intensity and 16 Hz2 would be about 9°C. If such trains were to be applied repeatedly over the same position the temperature might increase to the point of burning, unless sufficient time (3-4 min) for cooling were allowed between each stimulation train. The temperature increase is also likely to depend on the size, thickness, and material of the electrodes. Until further studies clarify these issues, we feel that great caution should be taken when applying repetitive magnetic stimulation over surface and

subdurally implanted electrodes. Human Cortical Physiology Unit, Human Motor Control Section, National Institute of Neurological Diseases and Stroke, Bethesda, Maryland 20892, USA

A. PASCUAL-LEONE

Department of Neurology, University of Minnesota

A. DHUNA

Biomedical Engineering and Instrumentation National Institute of Health,

Human Cortical Physiology Unit, NINDS, Bethesda

Program,

B.

J. ROTH

L. COHEN M. HALLETT

1. Gates JR, Cadwell JA, Dhuna AK, Pascual-Leone A. Rapid transcranial magnetic stimulation: a new technique for non-invasive functional cortical mapping. Paper read at Second Cleveland Clinic International Epilepsy Symposium (Cleveland,

Ohio, 1990). 2. Pascual-Leone

A, Gates JR, Dhuna AK Determination of language dominant with rapid transcranial magnetic stimulation (rTMS). Ann Neurol 1990; 28: 223 (abstr).

hemisphere

Simvastatin and

ursodeoxycholic acid for rapid gallstone dissolution

SIR,-Suppression of cholesterol synthesis with HMG CoA reductase inhibitors is now a powerful option in the management of hypercholesterolaemia. These drugs also reduce the cholesterol content of bile.1 Since this is additive to the effect of bile acid therapy,2 combination treatment may be more rapid and efficacious in the dissolving of cholesterol gallstones. A 26-year-old healthy woman who had never been pregnant and with no family history of gallstones began a very-low-fat reducing diet. She quickly lost 10 kg after which her weight became stable at 77-5 kg. After two weeks on the diet she had severe abdominal pain-a new symptom. This recurred and three months later she presented for investigation. Ultrasonography and oral cholecystography showed about 20 radiolucent floating gallbladder stones, 2-3 mm in diameter. She refused surgery, but continued to have severe colic. She was started on simvastatin 20 mg daily and ursodeoxycholic acid 750 mg daily. Her symptoms subsided and disappeared. Repeat investigation after four weeks showed all but 1 stone had gone. Serum cholesterol fell from 7-8 to 6-6 mmol/1. After a further four weeks ultrasonography and oral cholecystography were normal and her stones had been completely dissolved. It is likely that this patient’s biliary symptoms, and possibly the gallstones, were precipitated by a period of relative starvation and rapid weight loss.3 This is ironic since the diet she used had been designed by the author of the slimming book followed who had herself used this approach to control her gallstone symptoms, and who was apparently unaware of the regimen’s potential to cause gallstones.

The patient’s cholesterol gallstones were rapidly dissolved by combination therapy, and the result should prompt rigorous assessment ofHMG-CoA reductase inhibitors, either alone or with bile-acids, in the management of gallstones. General Hospital,

Bishop Auckland,

M. C. BATESON

Co Durham DL14 6AD, UK

Hoogerbrugge VD, Linden N, de Rooy FWH, Jansen H, van Blankenstein M. Effect of pravastatin on biliary lipid composition and bile add synthesis in familial hypercholesterolaemia. Gut 1990; 31: 348-50. 2. Logan GM, Dyane WC. Lovastatin added to UDCA further reduces biliary cholesterol saturation. Gastroenterology 1990; 98: 1572-76. 3. Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight reduction 1.

diet. Arch Intern Med 1989; 149: 1750-53.

Bedside blood

compatibility testing

SIR,-Diane Blakeley and her colleagues (Oct 6, p 854) have developed a dry blood grouping plate for checking ABO and RhD grouping. Although the use of monoclonal antibodies in a dry plate system may have wide applications, Blakeley et al state that this particular dry instant blood typing plate can be used by "personnel with no specific training" and that the use of such a plate may be important for bedside testing before blood transfusion to ensure ABO compatibility. The introduction of a "veto" by untrained personnel using such a plate would necessitate radical changes in transfusion policy in the UK. UK guidelines for safe transfusion practice, prepared by joint working parties of the British Committee for Standards in Haematology (BCSH) and the British Blood Transfusion Society (BBTS), include quality assurance at every stage from donor collection to recipient transfusion, including training and assessment of staff responsible for compatibility testing.l.2 Samples must be labelled at the bedside immediately after venepuncture with adequate patient identification. Compatibility testing must conform to standard operational procedures, and before a transfusion the recipient must be identified by a double-check system at the bedside to match the patient’s identity and ABO and RhD type with that of the donor unit. Most ABO incompatible transfusions result from clerical errors due to lack of identification or documentation: either the wrong sample is sent for compatibility testing or the transfusion is given to the wrong recipient. Training of doctors and others taking blood samples will prevent the former whereas the correct practice of a double-check system at the bedside will eliminate the latter. To maintain standards of good laboratory practice and transfusion medicine the BCSH task force for blood transfusion "strongly recommends that a blood transfusion committee be established in each hospital to talk through and agree procedures so that there is total agreement of all staff involved in direct patient care".2 The use of a bedside ABO and RhD check presupposes that the assay is 100% accurate, that it is always interpreted correctly by the "user", and that institution of transfusion is not significantly delayed. Furthermore, the cost of testing at the bedside, whether this be slide grouping with conventional reagents or dry plate assays, has financial implications. The dry grouping plate described by Blakeley et al was assessed against a standard clinical assay based on a semiautomated microplate system. The microplate system was not compared with a manual spin tube technique. Indeed the standard clinical assay missed a group A antigen detected by a "more sensitive manual method". New technology must be evaluated with respect to standard methodology if accuracy and precision are to be determined. In two cases, the dry plate assay failed to detect a blood group antigen picked up by the standard clinical assay used in this evaluation. The plate technique, at its present state of development, is not satisfactory. The decision to permit transfusion to proceed would be based on interpretation of the bedside ABO and RhD check and might lead to a critical delay in transfusion. The use of qualified transfusion staff for bedside compatibility testing might avoid that delay but the provision of staff on a 24-hour basis would have important financial implications. The use of untrained staff, as suggested by Blakeley et al, would introduce an element in the transfusion practice not

1197

varying amounts of endotoxin. This contaminant was responsible for the rapid and massive production ofTNF-a in vitro. No TNF-cx induction was measured in endotoxin-free blood-collecting

subject to quality assurance and therefore unacceptable by current UK standards of good laboratory and clinical transfusion practice. Finally, bedside testing with the manipulation of blood in non-designated areas would result in an additional infection hazard to both personnel and ward patients. Department of Haematology, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK

systems.

Recently, we have confirmed and extended the findings of Riches and Gooding. Whole blood, anticoagulated with EDTA or endotoxin-free heparin, was contaminated with 33 pg/ml endotoxin (Escherichia coli 0111 B4). This amount of endotoxin is known to occur in patients with septicaemia. Endotoxin did not induce production of interleukin 1 (IL-1), IL-6, or TNF-cx: in EDTAcontaining tubes, whereas it clearly triggered cytokine synthesis and release in heparinised blood. IL-1, IL-6, and TNF-K were measured with commercially available immunoassays (Medgenix, Fleurus, Belgium). Endotoxin-induced cytokine production increased with prolonged incubation (24 vs 2 h) and higher incubation temperature (37°C vs 21 °C). Cytokine responses were irreversible when EDTA was added to heparinised blood 2 h or more after endotoxin stimulus. Our results confirm that artifactual cytokine production by endotoxin contaminating blood-collecting systems or present in the blood of septicaemic patients must always be considered by investigators. We do not agree with Dr Murch and Dr MacDonald (Sept 15, p 687), who underestimate the role of endotoxin and consider Freeman and colleagues’ observations to be a consequence of the non-specificity of the TNF-a assay. The need for extreme care (cooling of the sample, rapid separation of plasma or serum from cells, and apyrogeny) when sampling blood for measurement of cytokines cannot be overemphasised.

T. BAGLIN W. OUWEHAND

Regional Transfusion and Immunohaematology Centre, Cambridge

D.

Department of Haematology, St Bartholomew’s Hospital, London EC1

A. H.

National Blood Transfusion Service,

H. H.

Manchester

National director, NBTS

VOAK,

Chairman, BCSH Blood Transfusion Task Force

WATERS,

Chairman, BCSH

GUNSON,

E. LLOYD, Department of Blood Transfusion, Royal Postgraduate Medical School,

Chairman, steering committee for UK External Quality

London W1 2

Assessment Scheme for Blood Group Serology

1. Anon. BCSH guidelines for compatibility testing in hospital blood banks. Clin Lab Haematol 1987; 9: 333-41 (revised in Roberts BE, ed. Standard haematology practice. Oxford: Blackwell Scientific [in press]). 2. Anon. BCSH guidelines on hospital blood bank documentation and procedures. In. Roberts BE, ed. Standard haematology practice. Oxford: Blackwell Scientific (in

press).

Anti-IgA screening and

use

SIR,-Dr McCluskey and colleagues (Oct 6,

of IVIG 874) refer

the increasing use of intravenous gammaglobulin preparations in various forms of immunodeficiency and related conditions. They rightly point out the increasing potential for severe reactions from anti-IgA among these patients, suggesting that all such individuals should be screened for anti-IgA before immunoglobulin therapy. We would point out that, until lately, a major difficulty faced by many transfusion scientists contemplating routine IgA antibody screening was the requirement for highly purified IgA protein preparations for coating red cells used in the passive haemagglutination test, the test of choice for many laboratories. The high grade purification of IgA requires considerable biochemical skill and specialist equipment which is not always readily available to the transfusion scientist. We have, however, shown that the screening and preliminary identification of anti-IgA antibodies can be achieved with diluted unpurified "raw" IgA paraprotein serum provided that "healthy donor" IgA deficient serum is available for the preparation of negative control cells.The method is simple, rapid, and cheap and, in our view, could easily form part of a routine pretransfusion screening protocol for these and similar patient groups. Regional Transfusion Centre, John Radcliffe Hospital, Oxford 0X3 7TN, UK

p

to

production in vitro. We have evaluated the influence of blood-collecting systems tumour necrosis factor

on

(TNF-a) contaminant in serum and plasma.’ Venous blood was collected from 10 healthy volunteers into tubes with and without various anticoagulants, and serum or plasma were recovered after various intervals. It was shown clearly that commercially available heparinised evacuated tubes contained

F. OFFNER A. VERMEULEN

HIV and travel,

-

SIR,- The message of letters from Dr Freeman and colleagues (Aug 4, p 312), Dr Goldin and Dr Hunt, and Dr Riches and Dr Gooding (Sep 15, p 688) is that blood sampling for the study of monocyte functions and monocyte-derived cytokines must be done with great care and requires endotoxin-free blood collection to prevent activation of monocytes and stimulation of cytokine

Department of Internal Medicine, Medical School, University of Gent

G. LEROUX-ROELS

G, Offner F, Philippé J, Vermeulen A. Influence of blood-collecting systems on concentrations of tumour necrosis factor in serum and plasma. Clin Chem 1988; 34: 2373-74.

A. F. HUNT M. I. REED

production of cytokines in blood

J. PHILIPPÉ

1. Leroux-Roels

1. Hunt A, Reed M. A simple protocol for the screening and preliminary identification of antibodies to human IgA using unpurified proteins in the passive haemagglutination test. Vox Sang 1990; 59: 30-33.

In-vitro

Department of Clinical Chemistry, Medical School, University of Gent, 9000 Gent, Belgium

no

rationale for restrictions

SIR,-Several countries have placed travel restrictions on people infected by HIV,1 thus acting against the clear recommendations of the World Health Organisation. "Common sense" says that the spread of AIDS has been facilitated by movements of people from one country to another and some public health authorities believe, presumably, that preventing immigration will stop the epidemic in their countries. This reasoning can be discussed on the basis of the mathematical model we developed to study air traffic and the spread of AIDS.2 This work uses the methodology applied to the time/space dynamics of influenza.3-S As in Rvachev and Longini’s work,’ a set of 52 cities around the world was considered and data on regular air traffic between these cities were used. The model reproduced the global spread of AIDS up to 1990 and made short-term predictions.2 It is easy to use this model to assess the effect of restricting travel, and we have done such an analysis. We assumed that the infected persons travel in the same proportions as non-infected. On the basis of published data,1,6 36 of the 52 cities are now limiting travel for HIV-infected persons. We assumed that these restrictions began in 1989 and halved the flow of infected persons up to the year 2000. This is a very extreme assumption: even Cuba, one of the most extreme countries in terms of travel restrictions, exempts tourists and visitors from testing, and countries such as Spain and the USA, which are modelled here as blocking 50% of infected travellers, probably do not block any at all. We then compared results obtained from the simulations of the HIV epidemic with and without travel restrictions. The percentage reduction between the two simulations in HIV-infected persons in each country by 2000 is presented in the figure. The median reduction is less than 5% and there were no striking differences between cities which make travel restrictions and those that do not. When simulating travel restrictions with less extreme conditions