38

haemopoietic cells persisting in the thymus) and to minor

histocompatibility antigens expressed by haemopoietic cells.Mutual tolerisation also occurs between peripheral T lymphocytesfor T-cell-expressed MHC and minor H antigens by the "vetoeffect"Y All MHC antigens (again, except hybrid determinants)expressed on the thymus epithelium, which imprints MHCrestriction preference,5,6 would be expressed in the pool of

peripheral antigen-presenting cells. HLA typing would not benecessary. (ABO blood group incompatibilities might be containedby plasmapheresis of recipients.)These potential advantages, and the clear advantage of not

needing HLA-typing, suggest that a mixture of both parents’ bonemarrow might be the donor source of choice for some individuals ina disastrous radiation accident, especially if HLA typing cannot bedone properly because of the lack of white blood cells in the patient.

Basel Institute for Immunology,CH-4005 Basel, Switzerland HANS-GEORG RAMMENSEE

1. Ready AR, Jenkinson EJ, Kingston R, Owen JJT. Successful transplantation acrossmajor histocompatibility barrier of deoxyguanosine-treated embryonic thymusexpressing class II antigens. Nature 1984; 310: 231-33.

2. von Boehmer H, Schubiger K. Thymocytes appear to ignore Class I majorhistocompatibility complex antigens expressed on thymus epithelial cells. Eur JImmunol 1984: 1048-52.

3. Miller RG. An immunological suppressor cell inactivating cytotoxic T-lymphocyteprecursor cells recognizing it. Nature 1980; 287: 544-46.

4. Rammensee H-G, Bevan MJ, Fink PJ. Antigen specific suppression of T-cellresponses-the veto concept. Immunol Today 1985; 6: 41-43.

5. Fink PJ, Bevan MJ. Recovery of the cytotoxic T cell response in the presence orabsence of a thymus. In: Watson JD, Marbrough J, eds. Recognition and regulationin cell-mediated immunity. New York: Marcel Dekker, 1985: 107-25.

6. Lo D, Sprent J. Identity of cells that imprint H-2-restricted T cell specificity in thethymus. Nature 1986; 319: 672.

FAST NEUTRONS IN RADIOTHERAPY

SiR,—Your May 24 editorial (p 1189) has a misleadingly generaltitle because it focuses on squamous or epidermoid head-and-neckcancer and fails to discuss the scope and rationale of current clinical

investigations of neutron therapy.I agree that the major reason for starting neutron therapy clinical

studies at the Hammersmith Hospital’s cyclotron unit in the late1960s was the better understanding of the oxygen effect andlaboratory observations that radiosensitivity is less dependent onoxygenation status with neutrons than it is with X rays. It is,however, no longer the major rationale in the biological basis forneutron therapy,! having been overtaken by other factors.2 In someclinical situations, however, the oxygen effect may still be

important-eg, in head-and-neck cancer recurring after surgeryand radiotherapy, where tissues have been compromised and are,presumably, hypoxic.3Neutron therapy has provided a stimulus for research into the

mechanisms of tumour response and the clinical consequences ofradiation treatment.2 Research is continuing to define predictors oftumour response to high LET radiation, better to select tumourtypes and patients for neutron radiotherapy.4Tumour oxygenation and metabolism may be studied using

positron emission tomography and magnetic resonance spec-troscopy. These techniques will have an important role in futurestudies of the response of tumours and normal tissues to neutron

therapy.The reference to Stone’s work (1948, not 1984) implies that the

severe late normal tissue damage was solely a "neutron effect".Much of the morbidity associated with these first neutron clinicalstudies can be attributed to the patients’ inadvertently receivingvery high radiation doses .5Your review of neutron therapy in squamous carcinoma of the

head and neck shows little understanding of the difficulties intreating such patients, highlighted by the negative comment that itis "difficult to be optimistic" about the contribution of neutrontherapy. The difficulties of treating even head-and-neck cancerwith low energy or fixed beam machines are great and so far it hasbeen hard to assess neutron therapy results.’ This alone does notexplain the differences between the Hammersmith and Edinburghresults. In the small study by Griffm,8 however, it was not pointedout that the results were similar to those from the Hammersmith’s,

with complete response rates of 52% and 17% for neutrons andphotons, respectively; 24% of the neutron patients survived for 2years, and there were no photon survivors at 2 years. The only wayto resolve this dilemma is to repeat these head-and-neck trials for

squamous carcinoma using high-energy neutrons. Such trials areplanned with collaboration between high-energy neutron facilitiesin the USA and the Douglas Cyclotron Centre here.

Benefit from neutron irradiation to other tumour types and siteshas been shown for locally advanced prostatic adenocarcinoma,9salivary gland carcinoma,"" air sinus tumours,12 malignantmelanoma,13 and soft tissue sarcomas.14Our high energy neutron facility has an important part to play in

assessing the role of neutrons in the management of locallyadvanced malignancy. Precise treatment planning is important, butit is a gross oversimplification to see this as the sole key to defmingthe role of neutron therapy. Account has to be taken of some of theproblems encountered in recruiting and caring for patients withlocally advanced malignancy at sites and of histological types oftenconsidered unsuitable for conventional radiotherapy and so withoutany established referral pattern to a radiotherapy centre.1sThe role of cytotoxic chemotherapy, surgery, or combinations of

these in treating such patients also has to be considered. This createsproblems in the planning of clinical trials of neutron therapy.1S Afurther problem in evaluating any benefit from a local treatmentsuch as neutron therapy is the increased incidence in patients withadvanced local disease of relapse with metastatic disease, even iftheir local tumour is controlled. Overall survival therefore may notbe improved, but this should not detract from the benefit to thepatient that improved local tumour control brings, and neutrontherapy may be one way of achieving this.

Douglas Cyclotron Centre,University of Liverpool,Department of Radiation Oncology

and Mersey Regional Centrefor Radiotherapy and Oncology,

Clatterbridge Hospital,Bebington, Merseyside L63 4JY R. D. ERRINGTON

1. Field SB, Fowler JF. The biological basis for neutron therapy. J Eur Radiother 1984; 3:170-75.

2. Withers HR. Neutron radiobiology and clinical consequences. Strahlentherapie 1985;161: 739-45.

3. Errington RD, Catterall M. Re-irradiation of advanced tumours of the head and neckwith fast neutrons. Int J Radiat Oncol Biol Phys 1986, 12: 191-95.

4. Peters LJ, Maor MH, Laramore GE, Griffin TW, Hendrickson FR. Review ofclinical results of fast neutron therapy in the USA. Strahlentherapie 1985; 161:731-38.

5. Brennan JT, Phillips TL. Evaluation of past experience with fast neutron teletherapyand its implications for future applications. Europ J Cancer 1971; 7: 179-225.

6. Catterall M. Results of neutron therapy: differences, comelations and improvements.Int J Radiat Oncol Biol Phys 1982; 8: 2141-44.

7. Catterall M. The assessment of the results of neutron therapy. Int J Radiat Oncol BiolPhys 1982; 8: 1573-80.

8. Griffin TW, Davies R, Hendrickson FR, Maor MH, Laramore GE. Fast neutronradiation therapy for unresectable squamous cell carcinoma of the head and neck:the results of a randomised RTOG study. Int J Radiat Oncol Biol Phys 1984; 10:2217-22.

9. Laramore GE, Krull JM, Thomas FJ, Griffin TW, Maor MH, Hendrickson FR. Fastneutron radiotherapy for locally advanced prostate cancer: results of an RTOGrandomised study. Int J Radiat Oncol Biol Phys 1985; 11: 1621-27.

10. Catterall M, Bewley DK. Fast neutrons in the treatment of cancer. London: AcademicPress, 1979.

11. Kaul R, Hendrickson FR, Cohen L, et al. Fast neutrons in the treatment of salivarygland tumours. Int J Radiat Oncol Biol Phys 1981; 7: 1667-71.

12. Catterall M, Blake PR, Rampling RP. Fast neutron treatment as an alternative toradical surgery for malignant tumours of the facial area. Br Med J 1984; 287:1653-55.

13. Blake PR, Catterall M, Errington RD. Treatment of malignant melanoma by fastneutrons. Br J Surg 1985; 72: 517-19.

14. Wambersie A, Battermann JJ. Review and evaluation of clinical results in the EORTCheavy-particle therapy group. Strahlentherapie 1985; 161: 746-55.

15. Cohen L, Hendrickson FR, Kurup PD, Mansell JA, Awschalom M, Rosenberg I,Ten Haken RK. Clinical evaluation of neutron beam therapy. Current results andprospects, 1983. Cancer 1985; 55: 10-17.

ENALAPRIL, ATENOLOL, ANDHYDROCHLOROTHIAZIDE IN HYPERTENSION

SIR,-Dr Helgeland and colleagues (April 19, p 872) report a16 week study on arterial hypertension in 436 patients,conducted by seventy-six general practitioners. Their studyraises a few questions.

39

, There were three active treatments and a single-blindplacebo. How was double-blindness achieved? After four weeksthe dose could be doubled. How often did this happen?

I am impressed that only 3 of the 436 patients did not followthe protocol and that only 5 were lost to follow-up in thismulticentre trial. However, without knowledge of the numberof patients on higher doses and the numerical values of thechanges it is not possible to judge the relevance of the findingthat patients on a higher dose of enalapril did not have an increasein side-effects whereas an increase was noted for the other

drugs. Further, statistical tests should have been done betweendrugs, not within drugs.

Enalapril was "at least" as effective as the other drugs, andthe reduction in systolic blood pressure was greater than withatenolol. Again, no significance test seems to support thedifference. Most important, however, the dose problem was notaccounted for. The thiazide, for example, was not given in adose producing maximal blood pressure lowering effect, noteven after doubling the dose. 1 Therefore, for one drug to be atleast as effective as another becomes less interesting, and theexpression "at least" is not logical since it suggests that the drugwas probably even more useful than the study revealed.The conclusion that enalapril is a viable alternative to

established first-line therapies in mild to moderate

hypertension is questionable; such a conclusion would demandmany years of follow-up in a much larger series. The aim ofantihypertensive treatment is not to lower the blood pressurebut to improve long-term outcome (ie, to avoid disability anddeath).Department of Infectious Diseases,Rigshospitalet,University of Copenhagen,2200 Copenhagen, Denmark PETER C. GØTZSCHE

1. Freis ED. The cardiovascular risks of thiazide diuretics. Clin Pharmacol Ther

1986; 39: 239-44.

SIR,-Dr Helgeland and colleagues state that "the reductionof systolic pressure was greater in the enalapril group than in theatenolol group. Similar results have been reported in previousstudies. 1,2 A possible explanation for this difference might bethat ACE inhibitors reduce the vascular resistance and improvethe blood flow in large arteries3". This last sentence is not ourinterpretation. We showed3 that enalapril and propranololacted differently on large arteries since arterial diameterincreased only with enalapril. However, changes in blood flowand vascular resistance are unable to produce by themselves agreater reduction in systolic than in diastolic pressure.4 Agreater reduction in systolic pressure requires one or several ofthe following haemodynamic mechanisms: reduction inventricular ejection, increase in arterial compliance, andmodification in the timing of reflected waves.4 With ACEinhibitors, ventricular ejection is unmodified but arterial

compliance is increased, as shown both in the systemic and inthe forearm6 circulations. Furthermore, the complianceenhancement is probably related to the effect of the drug onarterial smooth muscle tone rather than to the lower stretch dueto the blood pressure reduction. 7The increase in arterial compliance caused by ACE inhibitors

is probably not the exclusive explanation for the greater systolicblood pressure reduction observed in hypertensive patients.Pulse wave velocity is decreased after administration of ACEinhibitors,7 thus causing an improvement in the timing ofreflected waves with a subsequent predominant decrease insystolic pressure.8For ACE inhibitors to improve systolic more than diastolic

pressure, at least three modifications of large arteries would beneeded-an increase in arterial diameter, an increase in arterialcompliance, and a decrease in pulse wave velocity.Centre de Diagnostic,Hôpital Broussais,75674 Paris, France M. SAFAR

1. O’Connor DT, Mosley CA, Cervenka J, Bernstein KN. Contrasting renal

haemodynamic responses to the angiotensin enzyme inhibitor enalapril and thebeta-adrenergic antagonist metoprolol in essential hypertension. J Hypertens 1984;2 (suppl 2) 89-92.

2. Enalapril in Hypertension Study Group. Enalapril in essential hypertension: acomparative study with propranolol. Br J Clin Pharmacol 1984; 18: 51-56.

3. Simon ACh, Levenson JA, Bouthier JA, et al. Comparison of oral MD 421 andpropranolol in mild to moderate essential hypertension and their effects on arterialand venous vessels of the forearm. Am J Cordiol 1984; 53: 781-85.

4. Safar ME, Bouthier JA, Levenson JA, Simon ACh. Peripheral large arteries and theresponse to antihypertensive treatment. Hypertension 1983; 5 (suppl III): 63-68.

5. Simon ACh, Levenson JA, Bouthier JL, Safar ME. Captopril-induced changes inlarge arteries in essential hypertension. In: Proceedings of Conference on RegionalHemodynamics following Captopnl Therapy. Am J Med 1984; 71-76.

6. Simon ACh, Levenson JA, Bouthier JD, Safar ME. Effects on chronic administrationof enalapril and propranolol on the large arteries in essential hypertension. JCardiovasc Pharmacol 1985; 7: 856-61.

7. Safar ME, Laurent S, Bouthier JA, London GM. Comparative effects of captopril andisosorbide dinitrate on the arterial wall of hypertension human brachial arteries. JCardiovasc Pharmacol (in press).

8. O’Rourke M. Arterial function in health and disease. Edinburgh: Churchill

Livingstone, 1982: 67-224.

**These letters have been shown to Dr Helgeland and colleagues,whose replies follow.—ED. L. ,

-

SiR,—The answers to Dr Gotzsdi6s questions and commentsare:

(1) All medication was supplied in packaging marked only withthe patient’s allocation number and was dispensed, controlled, andordered by the office assistant. The physician was at no stageallowed to see or have information about the medication. We agreethat a reduction in heart rate suggests P-blocker treatment but thiswould not be a discriminant observation: it is a problem for allstudies with (3-blockers.

(2) 45% of those on enalapril, 56% on atenolol, and 4300 onhydrochlorothiazide continued on the initial dose. For theremainder the dose was doubled.

(3) We share the view that dropouts are a major concern in allstudies. Because of this and because of the multicentre nature of the

project, a detailed study protocol and extensive workinginstructions were devised. Clinical monitors closely and regularlyfollowed up study operations at every centre, besides each patientbeing closely monitored by both physician and office assistant. Theoffice assistants had a key role in the follow-up. Even moreimpressive results were achieved in another multicentre study inwhich all 1884 patients were accounted for at the completion of thestudy. 1

(4) Of those patients who received the double dose and who didnot report side-effects on the initial dose, 63% on enalapril, 22% onatenolol, and 19 4% on hydrochlorothiazide reported side-effectson the double dose. The statistical test was performed betweendrugs.

(5) We are confused by Getzsche’s statement that "no signifi-cance test seems to support the difference". Both the text and fig 1refer to significant differences between drugs in the reduction ofsystolic BP. We agree that efficacy must be related to dose used. Forall three drugs titration was in accordance with current packaginglocally. An average "maximal" effect is not obtainable. As goal BP isreached the dose is not increased, and this might hide possibledifferences. The issue of dose-response relationship seems to becontroversial: the suggestion that 50 mg hydrochlorothiazide issuboptimal would be challenged by some workers.2,3 Gatzschecomments on our use of the expression "at least"; we take the point.

(6) We agree that the ultimate aim of antihypertensive treatmentis to prevent cardiovascular complications. However, despiteseveral intervention trials over the past 15 years there is a lot of

uncertainty about the benefit of treating mild hypertension, and nosingle drug seems to offer any particular advantage.’*-’* We also agreethat long-term experience is needed with any new drug, before firmrecommendations can be made. However, uncertainty about thebenefit of long-term treatment seems relevant for practically alldrugs currently used to treat hypertension. Our conclusion does notreflect any view on long-term effects on life-expectancy but wasbased on, and limited to, information available on enalapril.

40

We agree with Professor Safar that possible explanations for thedifference in reduction of systolic BP that we found may becomplex. Our intention was merely to suggest one possibleexplanation. This was not further discussed because we found itbeyond the scope of the article. We did not intend to discuss possibledifferences in effect on systolic and on diastolic BP reduction butdifferences in systolic BP reduction for different drugs.

Department of Pharmacotherapeutics,University of Oslo;

and Horten, Sandefjord,and Bekkestua, Norway

ANDERS HELGELAND*CARL H. HAGELUNDROLF STRØMMENSTEINAR TRETLI

*Present address: Health Service of Norwegian Telecom, 0153 Oslo 1, Norway.

1. The Norwegian Multicentre Study Group. Timolol-induced reduction in mortalityand reinfarction in patients surviving acute myocardial infarction. N Engl J Med1981; 304: 801-07.

2. Bengtson C, Johansson G, Sannerstedt R, Werke L. Effect of different doses ofchlorthalidone on blood pressure, serum potassium and serum urate. Br Med J1975; 1: 197-99.

3. Berglund G, Anderson O. Low doses of hydrochlorothiazide in hypertension. Eur JClin Pharmacol 1976; 10: 177-82.

4. Medical Research Council Working Party. MRC trial of treatment of mild

hypertension: Principal results. Br Med J 1985; 291: 97-104.5. The IPPPSH Collaborative Group. Cardiovascular risk and risk-factors in a

randomized trial of treatment based on the beta-blocker oxprenolol. J Hypertension1985; 3: 379-92.

VIRUSES IN ACUTE CHILDHOODENCEPHALOPATHY

SiR,—In explanation of their finding that some common viruseshave a major role in unselected acute encephalopathies in children,Dr Kennedy and colleagues (May 3, p 989) suggest that thepathogenesis might be attributable to a hyperactive immuneresponse by the child. They found that levels of total serum IgGwere higher in patients than in healthy controls.

If this non-specific response occurred in parallel with theintrathecal and serum responses to twenty-three viruses in 25patients, this explanation might be sufficient. If not, the increasecould instead reflect another response, not necessarily hyperactive,to some other antigen or agent acquired around the time of infectionwith one of their ten species of virus.These viruses, identified in seven isolates and by twenty-three or

more rises in specific titres, are all so prevalent as to be sometimesubiquitous. Acute encephalopathy is very rare. The salient

question, in this as in other complications of commonplaceinfections, is why do a very small minority of children acquireencephalopathy and why do most children escape? If the immu-nological answer suggested by Kennedy et al is insufficient, it isappropriate to consider other antecedent or concomitant factors-ie, genetic, congenital, perinatal, neonatal, and post-neonatalevents. There is evidence that multiple sclerosis and several geneticneurological disorders are activated or aggravated by viral infec-tion. In the National Childhood Encephalopathy Study all of thefirst 1000 patients selected for admission with acute encephalopathyor severe neurological incidents were "previously abnormal" invarious neurological ways. Of 569 children who were previouslynormal neurologically, 23 (4%) had received triple vaccine duringthe 7 days before onset of symptoms: a significant increase over the13 (1-2%) matched controls. In children admitted with "convul-sions or encephalopathy" there were significant excesses ofvaccinations with triple antigen within 72 h and of measles vaccinewithin 7-14 days of the onset of symptoms. In 1 of 6 severe casesassociated with triple vaccine, Coxsackie virus was isolated from theCSF while 1 other died from an overwhelming infection withrhinovirus, which is seldom if ever a lethal virus in its own right.

Concurrent or consequent Coxsackie infections in children withacute encephalopathies or severe convulsions after quadruple (tripleplus polio) vaccine have been reported in 4 cases by Hannik3 and in 1case by Cavanagh et al.4 It is unlikely that the experiencedNorthwick Park/Guy’s Hospital team has overlooked the possibilitythat prior neurological disorder or antigenic stimulation might havecontributed to encephalopathy in their patients, but there is noreference to this in their report.

Springwell,High Down,Totland, Isle of Wight P039 0HY GORDON T. STEWART

1. Behan PO. Postviral neurological syndromes. Br Med J 1983; 287: 853-54.2. National Childhood Encephalopathy Study in Whooping Cough. Reports from the

Committee on the Safety of Medicines and the Joint Committee on Vaccinationand Immunisation. London: HMSO, 1981.

3. Hannik CA. Major reactions after DPT-polio vaccinations in the Netherlands. SympSer Immunobiol Standard 1970; 13: 161-70.

4. Cavanagh NPC, Brett EM, Marshall WC, Wilson J. The possible adjuvant role ofBordetella pertussis and pertussis vaccine in causing severe encephalopathic illness: apresentation of three case histories. Neuropediatrics 1981; 12: 374-81.

BANNING PHENACETIN TO PREVENT ANALGESICNEPHROPATHY?

SiR,—The Federal Health Office in West Germany is removingphenacetin from the pharmaceutical market as a response to

increased awareness of analgesic nephropathy, which now accountsfor about 13% of the dialysis and transplantation population(ranging regionally up to 50%). 0’2-0-7% of the normal populationis suspected of severe analgesic abuse. West Germany thus ranksthird in analgesic abuse in Europe, after Switzerland and Belgium.However, the abuse of phenacetin, which is only available in

mixed compounds, plays only a minor role in analgesic intake. Sincethe 1960s, phenacetin has progressively been replaced byparacetamol (acetaminophen) in analgesic mixtures. While theper-caput consumption of phenacetin decreased from 3 43 g in 1976to 1-37 g in 1983, paracetamol consumption increased in the sameperiod from 2-19 g to 4-48 g.l Two-thirds of analgesic consumptionis self-medication (ie, not on prescription). 80% of the more than420 analgesic drugs are mixed compounds, most of them containingsalicylates, antipyrine, aminopyrine, or non-steroidal anti-

inflammatory drugs, and codeine or caffeine. Because the renaldamage is very probably caused by combined chronic toxicity of theingredients of these mixed compounds,2,3 the current policy onphenacetin can be seen as reflecting a historical misunderstanding ofthe pathogenesis of analgesic nephropathy.Nephrology Department,Humboldt Krankenhaus,D-1000 Berlin 27, West Germany

WOLFGANG POMMERMARTIN MOLZAHN

1. Pommer W, Bronder E, Offerman G, Schwarz A, Molzahn M. Analgesicconsumption and analgesic-associated nephropathy: Extent, prevalence, and costs:Data from the Federal Republic of Germany and Berlin (West). Munch Med Wschr1986; 128: 220-23.

2. Prescott LF. Analgesic nephropathy: a reassessment of the role of phenacetin and otheranalgesics. Drugs 1982; 23: 75-149.

3. Garella S, Matarese RA. Renal effects of prostaglandins and clinical adverse effects ofnonsteroidal anti-inflammatory agents. Medicine 1984; 63: 165-81.

PRESCRIPTIONS, ADVERSE REACTIONS, AND THEELDERLY

Sin—Dr Weber and Dr Griffin (May 24, p 1220) calculate thatthere are no more reports of suspected adverse reactions (ADRs)received by the Committee on Safety of Medicines (CSM) for theover-65s than might be expected from the large volume ofprescription drugs used in the elderly. This applies for severalindividual drugs, as well as for all drugs added together (table).Where there was an apparent excess of reports in the elderly, as withthe non-steroidal anti-inflammatory agents (NSAIDs), there wasusually an even greater excess of prescriptions.However, great caution is needed before it can be concluded that

this means that the elderly are not more susceptible overall toADRs. The prescription figures available may not be an accuratereflection of drug use, for example. More importantly, the CSMasks to be sent suspected associations of drug therapy and adverseevents, and while not all the reports it receives will be true drugADRs, it appears that many more drug ADRs are not reported.Even for serious events, under-reporting appears to outweigh falseassociations. In 1984 the CSM received only 409 reports (including54 of fatal reactions) of upper gastrointestinal bleeding associatedwith NSAIDs and this is only 13% of the probable number of UKcases calculated from the Nottingham experience.1 In choosingwhich adverse event associated with drug therapy to report, doctorsmay well be influenced by the patient’s age. A far higher proportionof the reports received by the CSM for the elderly are for serious orfatal reactions (figure), suggesting that only serious events may be