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Ethics of experiments in animals

SiR,—Your May 22 editorial contains some remarkable

assertions, especially about man’s evolutionary status as championpredator. You should be well aware that evolution can only beviewed with hindsight, and whether our species’ rapaciouspredatory record will prove successful in the long term can only bespeculation. Furthermore, the notion that ethics and morals can bedismissed before the throne of evolution is fascistic. Similar

arguments have been used by white men to justify slavery andgenocide of native peoples.

Turning to the issue of the care of laboratory animals, you suggestthat "the needs of the animal must come first". These needs mustinclude the needs to live a natural life and not be used for invasive

procedures or be kept in restrictive confinement. I have no

knowledge of conditions in the University of Guelph. However,several investigations by animal rights workers in the UK haveuncovered appalling conditions of animal housing that fail to meetHome Office guidelines, inadequate staff training, and poor animalhandling.l,2 In the case of one supplier of primates, this failure hasbeen acknowledged by the UK Home Office.3 The British Unionfor the Abolition of Vivisection does not believe that the needs ofanimals can be adequately met under present UK laws andmonitoring systems. The Lancet should be calling not for slightlyimproved laboratory conditions, but a massive reduction in animaluse, and a shift of resources to issues of relevance to human health.

British Union for the Abolition of Vivisection,16a Crane Grove,London N7 8LB, UK DONAL CRAWFORD

1. British Union for the Abolition of Vivisection. The use of primates for research in theUnited Kingdom. London: BUAV, 1992.

2. Brtitish Union for the Abolition of Vivisection. A report into Wickham LaboratoriesLtd. London: BUAV, 1993.

3. Wardle C. Primates (Allegations) [Written Answer to Parliamentary Question].Official Report, Dec 3, 1992: c215-16.

Femur bone densities

SIR,-Ms Lees and colleagues (March 13, p 673) establish thatthe bone density in femora from 18th and 19th century burials inChrist Church, Spitalfields, London, was greater than that inpresent day women, and relate their data to a current increasedincidence of hip fractures. They suggest that the difference,present at puberty and persisting beyond the menopause, is dueto the greater physical activity imposed on women of the earlierperiod.

Ivanhoe had earlier studied a similar 18th century populationfrom Saint Bride’s columbarium in the Fleet Street area.! Thinsections of the first and third molars allowed him to demonstrate in

roughly half the skeletons the residual lesions of sunlight deficiencyrickets that had developed between infancy and age ten. At that timethe hours of insolation became adequate to the need, and the skeletallesions healed. During healing, rachitic long bones become harderand denser than normal, appearing ebumated or ivory-like to olderpathologists. These robust bones of healed rickets provide anexplanation for Lees and co-workers’ findings. Virchow, it is worthnoting, provided a precedent for the suggestion when he held thatthe simian cast to bones of Neanderthal man reflected not a separateline in the evolution of Homo but rickets in man living during theWiirm ice age.A more comprehensive description of the bones would probably

reinforce one explanation or the other. Did any of the femoraexcluded from the Christ Church study show hip or knee

deformities, bowing, or other stigmata of childhood rickets? Myobserver bias forbids any attempt at interpreting Lees’ fig 1.

Department of Pharmacology,University of California,San Francisco, California 94143, USA FREDERICK H. MEYERS

1. Ivanhoe F. Interglobular dentine in first and third molars: relation to hours of sunshineduring growth in two archeological populations from England. Calcif Tissue Int1982; 34: 136-44.

2. Ivanhoe F. Was Virchow right about Neanderthal? Nature 1970; 227: 577-79.

Paracelsus

SIR,-As an addition to Professor Feder’s thoughtful article onParacelsus (May 29, p 1396), I would like to draw attention to onemost important finding of this giant predecessor of medicine. In histhird "defension" from August 19, 1538, he declared "Everything isa poison, the dose alone makes a thing not a poison".1 Thisstatement contains a central concept of modem experimental andclinical pharmacology and toxicology-namely, the dose-effectrelationship, a principle of relevance not only to theoreticians butalso to clinicians. It appears to be the most durable consequence of,and could well be considered to be a "surviving paradigma" of,Paracelsus.

Zentrum für Kardiovaskulare Pharmakologie,6500 Mainz, Germany GUSTAV G. BELZ

1. Sudhoff K, ed. Theophrast von Hohenheim (Paracelsus): Sieben Defensiones

(Antwort auf etliche Verunglimfungen seiner Misgonner). Leipzig: J A Barth,1915: 25.

Reappraisal of endotoxin in gram-negativesepsis?

SIR,-We should like to compare the "classical" view on thecourse of events leading to gram-negative sepsis, organ failure, anddeath with that proposed by Dr Hurley (May l,p 1133). Classically,endotoxins are thought to play a central part in gram-negative sepsisby their induction of toxic amounts of cytokines, which cause theclinical symptoms. Hurley suggests that endotoxin in thebloodstream is an epiphenomenon accompanying the transition ofbacteria to their cell-wall deficient L-forms, and that it is theseL-forms that are responsible for the symptoms. Unless one wants todeny the involvement of cytokines in the course of gram-negativesepsis, one is left with the question: which cellular component of theL-form is responsible for the induction of cytokines? L-forms lack arigid cell wall, are deficient in peptidoglycan, and possess a singlemembrane directly surrounding the cytoplasm. This membranecontains endotoxins ; although on a cell-to-cell basis, L-formscontain less, they were sometimes found to be more endotoxic thancomplete bacterial There is evidence that L-forms shed moreendotoxins that parent bacterial Thus, transition to L-fonns is notnecessarily followed by a halt in the release of endotoxins. For theL-form concept to be relevant to the understanding of gram-negative sepsis it is not necessary to dismiss the part played byendotoxin. The word "endotoxin" may be a misnomer, but wethink that there is sufficient evidence obtained by injectingendotoxins into healthy volunteers to prove that it can give rise tothe clinical symptoms of gram-negative sepsis. In our opinion, thenovel hypothesis of Hurley is not a reappraisal of the role ofendotoxins, but a reappraisal of the bacterial form giving rise tothose endotoxins-ie, possibly L-fonns.

Department of Medical Microbiologyand Intensive Care Unit,

Vrije Universiteit,1081 BT Amsterdam, Netherlands

B. J. APPELMELKJ. DE GRAAFFL. G. THIJSD. M. MACLAREN

1. Mattman L. Cell wall deficient forms. Cleveland: CRC Press, 1974:90 and 199.

Tuberculosis in India: question ofcompliance

SiR,—The figure of 500 000 Indians dying every year fromtuberculosis reported by Mangla (May 1, p 1142) makes it clear thatthree decades of National Tuberculosis Control Programme inIndia has achieved little-either in reduction in incidence or

prevalence. However, the reasons for non-compliance reported byMangla are ambiguous. Poor performance of this programme is dueto very high (more than 50%) rate of default in treannent.1-3 Someof the causes of default, such as socioeconomic conditions, cannot bechanged in the foreseeable future. Nevertheless, one importantfactor-prolonged duration of treatment—can be tackled

immediately if short-course chemotherapy is introduced. In fact,

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the Government of India has grudgingly adopted this strategy inselected districts. Motivation of patients during the course oftreatment (yet another factor in default5) can also be maintained iftreatment duration is shortened. Mangla is not explicit about theWorld Bank’s improved drug delivery system. It would be tragic ifWorld Bank assistance is used to pursue the ineffective treatment

regimen.

Departments of Community Medicine and Surgery,All India Institute of Medical Sciences,New Delhi 110 029, India

SHASHI KANTL. R. MURMU

1. Singh MM, Banerji D. A follow up study of patients of pulmonary tuberculosis treatedin an urban clinic. Ind J Tuberc 1968; 15: 157-63.

2. Bhatia JL, Raj B. Twice weekly streptomycin and isoniazid regimen withoutsupervision. Ind J Tuberc 1968; 15: 67-73.

3. Anderson S, Banerji D. A sociological inquiry into an urban Tuberculosis ControlProgramme in India. Bull World Health Organ 1963; 29: 685-700.

4. Griffeths ML, Makgothi MM, Nordesjo G. Tuberculosis management in ruralcommunity-factors in failure. S Afr Med J 1981; 59: 14-16.

5. Pande RV. Treatment default of tuberculosis patients in a domiciliary service scheme.Ind J Tuberc 1968; 15: 107-12.

Heliotrope poisoning in TadjikistanSiR,—The seeds and roots of Heliotropium lasocarpium contain a

pyrrolizidine alkaloid that causes toxic liver injury and occlusion ofcentrolobular veins in the liver.’ In southern Tadjikistan, theFarkhar region was under blockade from May to November, 1992.This led to a famine and a delay in the wheat harvest of 2 months. Atthe same time, a drought affected the area, and heliotrope had timeto grow and go to seed. The wheat was collected with heliotrope,ground, and made into bread.On Oct 15, 6 weeks after consumption of the contaminated bread

started, the first case of liver toxicity was reported to the Farkharhospital and an epidemiological surveillance system was

established. At the request of the Tadjik government, theAssociation Europeenne de Developpement de Sante, andMededns Sans Frontieres, we reviewed data collected in thehospitals of Farkhar and the ten surrounding kolkhozes (state-runfarms serving 5000-10 000 people). Toxic liver injury was definedas such if recorded in the log book of the hospitals. Up to March,1993, 3906 cases were recorded, an attack rate of 4%. The attackrates were respectively 0-4%, 54%, 40%, 28%, and 1 -5% for theage groups less than 1,1-14,15-30, 31-50, and older than 50 years.Within the same age groups, case fatality ratio increased with age:respectively 0%, 0-8%, 1 -3%, 2-3%, and 5-9%, and the overall casefatality ratio was 1 3%. 2 of the 10 kolkhozes contributed 83-3% ofthe cases (figure) with attack rates up to 16°9% and 23-6%,compared with less than 3% for each of the 8 others. Clinical signsand symptoms were recorded in 1102 cases. Four stages of illnesswere defined: I, abdominal pain, nausea or vomiting, and weakness;II, hepatomegaly; III, ascites; and IV, alteration of consciousness.Each stage was represented, respectively, by 55-5%, 29-9%, 13-7%,and 0-9% of the cases. The last case was reported on March 4,1993.At the time of the investigation, 300 cases were still in hospital and itis not known how many will later develop cirrhosis of the liver, towhich veno-occlusive disease is known to be contributory factor.2

Toxic liver injury: hospital admissions 1992-93.

The population was informed of the danger of eatingcontaminated bread early in the outbreak. However, because of theblockade and the related famine, they continued to eat thecontaminated flour until the local authorities started an exchange foruncontaminated flour in mid-December, 1992. Similar outbreakshave been observed previously (India, 1977,3 Afghanistan, 1975,4 4

Iraq, 1970, South Africa and Jamaica in the 1950s, and USSR in the1930s). Owing to the difficult political and economic situation facedby ex-USSR nations, such outbreaks may occur again. They shouldbe detected early and recorded both to increase the awareness of thelocal population and to motivate prompt reaction from theinternational community.Unité de Recherche Biomathématiques et

Biostatistiques,INSERM U263,Paris, France PIERRE CHAUVIN

Institut National d’Agronomie,Départment de Nutrition Humaine,Paris-Grignon, France JEAN-CLAUDE DILLON

Epicentre, Paris, France ALAIN MOREN

General Hospital,Farkhar, Tadjikistan SAIDOV TALBAK

Institute of Gastroenterology,Dushambe, Tadjikistan SALAM BARAKAEV

1. International Programme on Chemical Safety. Pyrrolizidine alkaloids and humanhealth (Environmental Health Criteria 80). Geneva: WHO, 1988: 13-17.

2. Gupta PS, Gupta GD, Sharma ML. Veno-occlusive disease of the liver. BMJ 1963; i:1184-86.

3. Tandon BN, Tandon HD, Koshy A, et al. Epidemiological, clinical, biochemical andhemodynamic study of veno-occlusive disease of the liver due to crotalaria alkaloidsin India. J All Ind Inst Med Sci 1977; 3: 165-75.

4. Mohabbat O, Srivastava RN, Younos MS, et al. An outbreak of hepatic veno-occlusivedisease in north-western Afghanistan. Lancet 1976; ii: 269-71.

Adverse reactions and sumatriptanSIR,-I was interested in the two case-reports of Dr Luman and

Dr Grey (April 24, p 1091). They correctly point out "that thehalf-life of sumatriptan is 2 hours" and "the intervals between drugadministration and cerebral infarction of 1 week in the first case and12 hours in the second, exonerate sumatriptan", but they then go onto state "no other risk factor for vascular disease was identified inour patients". However, migraine itself seems to be a risk factor.They also state that "the hemiparesis in the second case was on theopposite cortical side from the. migraine-associated"hypoaesthesia", but in their case-report both the numbness andthe hemiparesis were right-sided.London Neurological Centre,110 Harley Street,London W1N 1AF, UK F. CLIFFORD ROSE

Author’s replySIR,-We thank Dr Rose for his letter. Neither of our patients

had typical migrainous headache before their hemiplegia. However,their headache could have been relieved by sumatriptan, though weare unable to explain the failure of sumatriptan to preventmigraine-induced hemiplegia (if this was indeed the case).With regard to the second patient, recent correspondence with

her general practitioner reveals that she initially developedintermittent leftsided headache and right hypoaesthesia withoutmotor signs 3 years ago when she was in her first pregnancy. Thesame symptom recurred a year later when she took the oral

contraceptive pill. Before her mentioned admission she developedleftsided numbness on re-introduction of oral contraceptive andsubsequently left hemiparesis 12 hours later after sumatriptantreatment. She was well on review a month later and did not have

any residual motor or sensory signs. Her GP informed us that shehas had a further recurrence of left hemiparesis and, after

investigation, the provisional diagnosis is demyelination. Thisinformation was not available at the time of the report in April.The Committee on Safety of Medicines has received other

reports of suspected neurological reactions, including hemiparesis,facial palsy, dysphasia, dysarthria, paraesthesia, and hemianopia