Health Articles

 

Pii: s0140-6736(98)26032-6

Organ donation and kidney sales Sir—Your decision to publicise conclude that by establishing a Radcliffe-Richards J, Daar AS, J Radcliffe-Richards and colleagues' commercial transplantation service in Guttman RD, et al, for the InternationalForum for Transplant Ethics. The case for (June 27, p 1950)1 case for allowing the famine areas of Sudan, the whole allowing kidney sales. Lancet 1998; 351:
kidney sales reveals the unwillingness kidney transplant waiting lists of the of sectors of medical opinion to accept developed world would disappear Mohamed AS, Velasco N. Kidneys for sale.
the verdict of the professional associa- within a few weeks and that payment of Lancet 1990; 336: 1384.
tions, parliaments, and governments donors could be done cheaply since Bosch X. Spain celebrates leading the world quoted in the paper. The investigators donors would be desperate enough for in organ donation. Lancet 1998; 351: 1868.
Seidelman WE. Nuremberg lamentation: for assume that the provision of trans- any agreement, which would be life- the forgotten victims of medical science.
plantation for patients on dialysis justifies saving anyway.
BMJ 1996; 313: 1463–67.
everything, that ethics are a variable Arguments in favour of the sale concept which depends on fashion, and of kidneys distort facts that usually Sir—The report by J Radcliffe-Richards that objectors to anything would fail to fool people that have deep and colleagues for the International eventually suffer from outrage fatigue.
feelings of repugnance about paying Forum for Transplant Ethics1 I have previously recounted how, in desperate people to undergo a painful refreshing. The carefully worded commercial kidney transplantation in procedure, lose an organ, and take document asks for a careful, unpartial India, not only the recipients did risks associated with surgery. The re-evaluation of the prohibition to poorly, but the donors never received lessons of the defeat of fascism in Nazi accept the sale of kidneys for trans- more than 10% of the funds required Germany have not been learnt when plantation under carefully controlled from the recipients, hardly a way of the exploitation of large numbers escaping their poverty.2 The need for of people judged sub-human at the My colleagues and I have previously an ethical cadaveric and living-related- time, was condoned by the same reported our medical experience with only kidney-transplant programme in sections of the medical establishment Palestinian Arab children who travelled that part of the Middle East was who saw only the so-called scientific from the area of the Palestinian evident then, and with others I was value of such experimentation.4 The authority to Iraq for a commercial renal instrumental in commencing it. Today implication of Radcliffe-Richards and transplant, as more than 100 adult this programme has flourished in the colleagues' proposal is that some Palestinians had done before them.2,3 hands of Saudi doctors with 222 trans- human beings are intrinsically more All the children were on dialysis in the plantations having taken place by the medically worthy than others. Imagine Israeli part of Jerusalem. We end of 1997, with excellent results in the outrage and anger if, with similar cooperated by providing a covering terms of graft and patients' survival. All arguments, we justify child labour, letter on their departure and by the patients and relatives understood child prostitution, or many other accepting them for follow-up the benefits of ethical donation and activities that occur in the context of immediately on their return to our stopped travelling to buy organs.
an economically unequal world. Logic public hospital. The patients lived in an We should strive to increase rates of is not the basis for acceptable area beyond the jurisdiction of Israel transplantation in a way similar to that behaviour, and judging by their and obviously this holds true for the reported by Xavier Bosch in his June 20 proposals I am happy that legislation hospital where the transplants were news item (p 1868)3 about Spanish is not in the hands of doctors who, performed. The donors were adult, after all, are no more ethical than transplantation. He suggested that one consenting, healthy, young men eager anyone else. We should not take for of the reasons for its success was the to sell their kidneys.
granted that our responsibilities as transparency and accountability of the The first journal to which we doctors are limited to looking after submitted our results, refused to accept our individual patients. We are The arguments of Radcliffe-Richards the article because of its ethical accountable for our actions at large and and co-workers are based on the implications. We were accused of there is such a thing as crimes against assumption that poverty is impossible facilitating the sale of kidneys, a to deal with and that the owner of practice which certainly should not be surplus non-vital organs could sell publicised for fear of inducing others to them to escape poverty, and should not follow a similar path. A second try in a be denied such a possibility. With this prominent nephrology journal was type of tunnel vision of mankind and more successful; the same text was Mayday University Hospital, London Road, humanity, one would be expected to Thornton Heath, Surrey CR7 7YE, UK accepted with only a few clarifications.
THE LANCET • Vol 352 • August 8, 1998 My support for the report by travel abroad. Both haemo- and number of organs available for Radcliffe-Richards and co-workers continuous ambulatory peritoneal transplantation. The decline in number does not mean that I have no mixed dialysis demand self-discipline and of cadaveric renal transplants is feelings about commercial transactions commitment from patients and multifactorial. One reason is the with regard to organ transplantation.
families. It is also undeniable that, as in reluctance of relatives of brain-dead Nor do I think that it will be easy to transplantation, the side-effects and patients who could be potential donors.
regulate the practical features of the long-term sequelae of dialysis are Time and again one is faced with sale of kidneys, particularly when causes for concern. However, I do not relatives' refusal to allow retrieval of dealing with developing countries. The believe that I was alone in finding that cadaveric organs. Rather than making a proposal by these researchers will no most of the difficulties I experienced as case for accepting the sale of kidneys by doubt rekindle discussion among the a dialysis patient arose from the live vendors, perhaps a case should first various medical, legal, and religious ignorance, lack of understanding, and be made for remunerating those who forces in Israel, as we seek to find ways prejudice of the general public, allow cadaveric organs of brain-dead to expand the local kidney donor pool.
employers, and some members of the relatives to be used for transplantation.
Reconsideration of the legal supervised medical profession.
sale of kidneys received a certain Few—and certainly not I—would Aberdeen Royal Hospitals NHS Trust, impetus after the unexpected deny that successful transplantation is Aberdeen AB25 2ZN, UK endorsement (in principle) by the chief the treatment of choice for renal failure. But not all transplants are Radcliffe-Richards J, Daar AS, successful and not all patients are Guttman RD, et al, for the InternationalForum for Transplant Ethics. The case for PO Box 8504, Jerusalem 91084, Israel suitable for transplantation. By their allowing kidney sales. Lancet 1998; 351:
unconsidered statement, Radcliffe- Radcliffe-Richards J, Daar AS, Richards and colleagues undermine the Guttman RD, et al, for the International case for kidney sales and do a disservice Sir—I Kennedy and colleagues (May Forum for Transplant Ethics. The case for to renal dialysis patients.
30, p 1650)1 reconsider the ban on the allowing kidney sales. Lancet 1998; 351:
1950–52.
sale of human kidneys, to meet the Frishberg Y, Feinstein S, Drukker A. Living, growing disparity between the waiting unrelated (commercial) renal Medpress, Tubs Hill House, London Road, lists and the availability of organs. They transplantation in children; and ethical Sevenoaks TN13 1BL, UK attribute the foundation upon which dilemma. J Am Soc Nephrol 1998; 9:
1100–03.
Radcliffe-Richards J, Daar AS, these judgments are based to a visceral Friedlaender M. Living unrelated renal Guttman RD, et al, for the International instinct, not capable of clear of tansplantation: principles and practice. In: Forum for Transplant Ethics. The case for Andreuci VE, Fine LG, eds. International allowing kidney sales. Lancet 1998; 351:
There should be no illusion that the Year Book of Nephrology. Oxford UK: Oxford University Press, 1996, pp 153–59.
question they open is an immediate Sir—I applaud the efforts of J and pressing one worldwide: a candid Sir—As a medical journalist and, more Radcliffe-Richards and his colleagues1 admission by the General Secretary of importantly, after, respectively, 9 and 12 to revisit the case for allowing kidney the Indian Medical Organisation, years' experience as a renal dialysis and sales. I believe that they perform a great indicated that commercial trans- transplant patient, I agree with J service for patients with end-stage renal plantation is widespread in at least two Radcliffe-Richards and co-workers1 that disease and for society at large.
states in India;2 César Chelala's March both society in general and the medical However, their arguments would 7 news item (p 735)3 describes a profession in particular should keep an have been equally effective if they had successful FBI operation to sting open mind in the search for solutions to not described dialysis as a "wretched Chinese trade in prisoner's kidneys in the shortage of donor kidneys. For experience for most patients". That New York;2 and most troubling of all, example, this report has inspired interest statement suggests that they have never kidneys are advertised for sale on the at some UK units in the use of organs looked after dialysis patients, otherwise internet, even from states where from living, unrelated (and unpaid) they would not have said this. My point commerce in transplants is forbidden.
donors such as spouses or friends.
is not to argue whether or not dialysis is Without any controversy, a principal It is unfortunate—and surprising a wretched experience (unsuccessful and venerable medical imperative is given their wish to avoid emotional transplantation could be an equally primum non nocere, first of all to do no reactions to the sale of kidneys—that wretched experience for some harm. Yet, paradoxically, transplant Radcliffe-Richards and co-workers base patients), but to point out that donation does require the doing of their argument partly on the transplantation and dialysis are harm to a healthy person, thus unreferenced and emotive statement complementary programmes that help transforming him or her into a patient.
that "dialysis is a wretched experience patients with end-stage renal disease to Under the exceptional circumstances for most patients". How do the lead lives of the best possible quality.
implicit in a living related or unrelated researchers draw this conclusion? Does (spouse or friend) transplant, the donor it apply to all forms of dialysis wherever is regarded as the most important of Department of Medicine, Peritoneal Dialysis performed? Do they have access to patients. The main issue is not free Program, The Toronto Hospital, Western evidence-based information that they Division, Toronto, Ontario, Canada M5T 2S8 consent, it is proper medical practice.
fail to reference? Or have they fallen There is sacred and important trust into the common trap of judging Radcliffe-Richards J, Daar AS, between the donor and the doctors quality of life, not from the point of Guttman RD, et al, for the International handling the transplant, a trust that will Forum for Transplant Ethics. The case for view of those who experience the illness be inexorably undermined by the allowing kidney sales. Lancet 1998; 351:
or disability, but from that of the introduction of such direct commercial interest in the commissioning of harm.
In the UK alone, thousands of Sir—J Radcliffe-Richards and Unlike any other private medical patients on dialysis hold down colleagues1 favour kidney sales by living practice, the donors are paid by the demanding jobs, enjoy family life, and vendors as a way to increase the doctors for substantial potentially life- THE LANCET • Vol 352 • August 8, 1998 threatening harm done to them by the the measures require refinement; the doctor for no reason other than their results, however, indicate the imaging and prediction own financial gain. Will not this prognostic value of behaviourally based violation of trust for commercial assessment since behavioural features interest do irreparable harm to the that are unique to patients who later profession as a whole? This practice is emerge from vegetative state can be as much a deviation from ordinary medical practice as the supervision oftorture in prison or the administration Sir—I welcome the research published of a fatal injection. A risk-benefit by Andreas Kampf and colleagues Department of Psychology, University of analysis analogous with unpaid (June 13, p 1763),1 but as Keith Surrey, Guildford, Surrey GU2 5XH, UK donation is, therefore, inappropriate.
Andrews implies in his accompanying Do the potential benefits of a cash commentary,2 the title of the paper is Kampf A, Schmutzhard E, Franz G, et al.
windfall for the vendor justify any act? optimistic. The overlap between the Prediction of recovery from post-traumatic It is a shame if the only lessons drawn outcome groups renders the margin of vegetative state with cerebral magnetic- from Nuremberg are restricted to error too large for use of these findings resonance imaging. Lancet 1998; 351:
questions of personal autonomy.4 in treatment decisions. What can be Andrews K. Prediction of recovery from The immediate practical con- seen in these data is a significant trend post-traumatic vegetative state. Lancet 1998; sequences of such a policy would be but not a clear-cut relation between 351: 1751.
disastrous for our patients, both findings on cerebral magnetic-resonance Wilson BA. Recovery of cognitive functions recipients and those on the waiting list, imaging (MRI) and prediction of following nonprogressive brain injury. Curr for paid donors and for public outcome in post-traumatic vegetative Opin Neurobiol 1998; 8: 281–87.
Wilson SL, Powell GE, Brock D, confidence in the medical profession.
state. Furthermore, such a finding is Thwaites H. Behavioural differences How is it possible to introduce a central predictable given current knowledge between patients who emerged from regulatory purchase authority for about the normal variations that can be vegetative state and those who did not.
kidney sales, when the commodity is seen between individuals in the relation Brain Injury 1996; 10: 509–16.
regarded as priceless? I Kennedy and between brain structures and Gill-Thwaites H, Wilson SL. Predictingemergence from vegetative state. Proc Br co-workers are naive to suggest that behaviour, and which would be further Psychol Soc 1998; 6: 75.
"all purchasing could be done by a complicated by the effects of recovery central organisation responsible for fair processes after injury, such as plasticity.
distribution". How is the absence of Fenoterol and asthma coercion to be tested? The sale of situation well when she stated: kidneys is most likely in the poorest "Although imaging techniques may countries, the very countries where help us to understand the recovery Sir—Richard Beasley and colleagues safeguards to ensure that consent is free process, it is hard to argue that they (May 9, p 1406)1 reiterate their original and informed are weakest. Reopening help in planning rehabilitation".
view, that there was a causal link this debate provides impetus to the Given the limitations of imaging for between the high-dose preparation of burgeoning trade in organs in some prognostic purposes, are there other fenoterol and the epidemic of asthma developing countries. Technical quality sources of information that could aid deaths in New Zealand in the 1970s is not a key ethical issue, but poor treatment decisions? Vegetative state and further suggest that a smaller results, a high rate of infection in has always been defined by behavioural increase in asthma mortality in Japan recipients, graft loss, and allegations of rather than pathological criteria, so may also be due to fenoterol use.
criminal involvement, including man- behavioural data seem a good place to Beasley and co-workers do not cite or theft and murder, have all been start. Preliminary studies that I have mention the substantial body of reported from such trade.5 These carried out with colleagues4,5 showed scientific evidence that does not factors alone render the report by quantitative and qualitative behavioural support their view.
Kennedy and colleagues irresponsible, differences between patients who Beasley and colleagues discuss two even before any serious consideration emerge from vegetative state and those kinds of evidence: national trends in of its enquiries.
who remain in this condition. One of drug sales and asthma mortality, and Kennedy and co-workers seek to the differences found (with data from epidemiological studies of patients open a box that would make even momentary behaviour sampling) was prescribed fenoterol. With regard to Pandora blush. Resolute confirmation that patients who later emerged showed the former, in New Zealand, asthma of the original judgments is needed to a characteristic pattern of behaviour mortality started to fall in 1979 when safeguard our professional ethics, with after an environmental event, unlike fenoterol sales were still increasing and careful consideration of policing in new those patients who remained in 11 years before restrictions for potential areas of abuse.
vegetative state.4 I have also analysed reimbursement of fenoterol curbed the data collected by Gill-Thwaites and sales. The use of b-agonists as a class 14 Devonshire Road, Colliers Wood, found that patients who later emerged doubled, whereas asthma mortality London SW19 2EN, UK from vegetative state could be declined by 40%.2 Moreover, sales of Kennedy I, Sells RA, Daar AS, et al. The differentiated from those who did not fenoterol in Austria, Belgium, and case for "presumed consent" in organ by the magnitude of changes in scores donation. Lancet 1998; 351: 1650–52.
Germany were similar to those in New between behavioural assessments Bajpai D. The Indian Express. May 13, 1998.
Zealand near the peak of the epidemic, Chelala C. China's human organ trade carried out every 2 months.5 The but asthma mortality in these countries highlighted by US arrest of "salesmen".
assessment protocol used assessed remained low.2 Thus, there is no visible Lancet 1998; 351: 735.
degree of functioning within vegetative relation between fenoterol sales and Seidelman WE. Nuremberg lamentation: for state by systematic application of asthma mortality. The cause of the the forgotten victims of medical science.
BMJ 1996; 313: 1463–67.
discrete stimuli to each of the senses in asthma epidemic in New Zealand Mohamed AS, Velasco N. Kidneys for sale.
turn. The findings from these two remains unknown, whilst its decline Lancet 1990; 336: 1384.
studies need replication and some of has been attributed to substantial THE LANCET • Vol 352 • August 8, 1998 increases in use of medium-dose and International trends in sales of inhaled because of under-prescribing of inhaled high-dose inhaled steroids, and other fenoterol, all inhaled b-agonists, and asthma corticosteroids, or that the abrupt end mortality, 1970–1992. J Clin Epidemiol improvements in asthma care.3 to the epidemic occurred because of 1997; 50: 321–28.
The 1990–96 survey by the Garrett J, Kolbe J, Richards G, Whitlock T, increased prescribing of inhaled Committee on Asthma Death of the Rea H. Major reduction in asthma morbidity Japanese Society of Pediatric Allergy and continued reduction in asthma mortality In addition to this epidemiological in New Zealand: what lessons have been and Clinical Immunology in patients evidence, clinical studies have shown learned? Thorax 1995; 50: 303–11.
aged up to 26 years examined 123 that fenoterol has greater acute and Garrett JE, Lanes SF, Kolbe J, Rea HH.
asthma deaths, seven of which were Risk of severe life-threatening asthma and chronic adverse effects than other judged to be due to overdose of b-agonist type: an example of confounding b-agonist drugs.1 Thus, the Japanese fenoterol. These data cannot be by severity. Thorax 1996; 51: 1093–99.
data are consistent with an increasing Spitzer WO, Suissa S, Ernst P, et al. The interpreted without knowing the body of evidence that the use of the use of b-agonists and the risk of death and number of cases that would have been near death from asthma. N Engl J Med high-dose (200 mg/puff) preparation of expected to use fenoterol in the absence 1992; 326: 501–06.
fenoterol increases the risk of death in of any causal relation. To get this figure would require a carefully designed control group, which is unavailable. In *Richard Beasley, Sankei Nishima, lieu of a control group, Beasley and Sir—Gerhard Kremer and Bernd Disse Neil Pearce, Julian Crane colleagues substitute data in overall correctly point out that the ideal way to *Wellington Asthma Research Group, market share that disregards age, assess whether fenoterol increases the Department of Medicine, Wellington School ofMedicine, PO Box 7343, Wellington South, asthma severity, and other important risk of death is to undertake a case- New Zealand; and National Minami-Fukuoka factors. Understandably, such shortcuts control study. There have been four Chest Hospital, Minimiku, Fukuoka City, Japan do not yield valid scientific answers.
such case-control studies, all of which According to the judgment on each showed a significantly higher death rate Pearce NE, Beasley R, Crane J, Burgess C.
individual case of the survey by the in patients prescribed fenoterol than in Epidemiology of asthma mortality. In: Busse W, Holgate S, eds. Asthma and Subcommittee on Adverse Drug those prescribed other b-agonists.1 rhinitis. Oxford: Blackwell Scientific, 1995: Reactions of the Japanese Ministry of There is limited evidence of selective Health and Welfare, a causal relation prescribing of fenoterol in the Beasley R, Pearce NE, Burgess C, between excessive use of the drugs populations studied in New Zealand,2 or Woodman K, Crane J. Confounding byseverity does not explain the association involved and asthma death was not in Canada,3 and detailed analyses between fenoterol and asthma death. Clin established, however, the Ministry and indicate that the association between Exp Allergy 1994; 24: 660–68.
Nippon Boehringer Ingelheim agreed fenoterol and deaths from asthma was Pearce N, Beasley R, Crane J, Burgess C.
to issue a warning about overdosing of not due to confounding by severity of Confounding by indication and channelling and over-reliance on fenoterol.
asthma.2 A formal case-control study in over time: the risks of b -agonists. Am J Epidemiol 1997; 146: 885–86.
There have been other formal Japan would be of interest, although the Beasley R, Nishima S, Pearce N, Crane J. epidemiological studies of the risk of available data on asthma mortality and b agonist therapy and asthma mortality in fenoterol. The difficult challenge fenoterol market share in Japan4 accord Japan. Lancet 1998; 351: 1406–07.
confronting these studies is that with the findings of the case-control Pearce N, Beasley R, Crane J, Burgess C, fenoterol has been prescribed studies in New Zealand and Canada.
Jackson R. End of the New Zealand asthma
mortality epidemic. Lancet 1995; 345:
preferentially to patients with severe Trend data are more difficult to Due to the prescribing interpret because many factors affect pattern, fenoterol will be over- mortality time trends. However, it is Sir—Richard Beasley and colleagues1 represented among patients who die noteworthy that the Japanese data are present what seems to be a cogent from asthma. Researchers who have consistent with the time-trend data hypothesis to support an association adjusted appropriately for asthma from New Zealand.5 The New Zealand between the use of fenoterol and severity have shown that high rates of epidemic started when fenoterol was asthma mortality in Japan and New deaths from asthma among fenoterol introduced in 1976, and despite a slight Zealand. However, a more detailed patients are due to underlying severe decrease in the death rate after analysis of risk factors has shown that asthma, and do not point to any publicity about the epidemic and the the positive association between adverse effect of fenoterol.5 dangers of overuse of b-agonists in fenoterol and severe life-threatening Asthma mortality results from an 1981, the New Zealand death rate asthma may be explained by elusive combination of factors, many remained the highest in the world for preferential prescribing to patients with still to be identified. Taken as a whole, more than 10 years, during which time more severe disease.2 neither the epidemiological data on fenoterol maintained a consistent In a study of 257 patient with acute mortality trends nor the analytical market share. After the publication of severe asthma, dose-titration with studies support Beasley and colleagues' our initial case-control study, the death fenoterol (¶3200 mg), or salbutamol belief that an asthma therapy is rate immediately fell by 50% and (¶1600 mg) given via a spacer showed responsible for increases in asthma remained low in 1990. On the other no evidence of any clinically relevant hand, the time-trend data are cardiac arrhythmias, despite the fact that inconsistent with the hypothesis of a the two-fold higher dose of fenoterol *Gerhard Kremer, Bernd Disse role of a class effect of b-agonists in the exhibited greater systemic b -mediated epidemic. There was no association Corporate Department of Therapeutic Areas II, effects.3 None of the patients showed Respiratory, Boehringer Ingelheim GmbH, between total sales of b-agonists and evidence of pronounced prolongation of D-55216 Ingelheim on Rhein, Germany the start of the epidemic, and total sales interval. Although fenoterol of b-agonists actually increased slightly exhibits a higher degree of intrinsic Beasley R, Nishima S, Pearce N, Crane J.
in 1989–90 when the epidemic came to efficacy at systemic b -adrenoceptors -agonist therapy and asthma mortality in an end. The time-trend data are also Japan. Lancet 1998; 351: 1406–07.
than salbutamol,4,5 such differences are Lanes SF, Birmann B, Raiford D, inconsistent with the hypothesis that of small magnitude and unlikely to be of Walker AM. Pharmacoepidemiology report.
the epidemic may have occurred any clinical relevance. THE LANCET • Vol 352 • August 8, 1998 Although it is tempting to implicate cardiac impairment, whether cardiomyopathy, since diminished the use of fenoterol with asthma symptomatic or symptomless. However, contractile reserve may predict adverse mortality, this hypothesis is not there is no consensus about the relation clinical outcome in these patients.5 substantiated by data from carefully between plasma concentrations of these controlled pharmacodynamic or peptides and the severity of left- Hiroaki Kitaoka, Jun Takata, ventricular dysfunction.4 Moreover, the Nobuhiko Hitomi, Takashi Furuno, Doctors should follow accepted role of the peptides in dilated asthma-management guidelines in that cardiomyopathy is unknown. Low-dose excessive use of b -agonists including dobutamine infusion has been reported Department of Medicine and Geriatrics, Kochi Medical School, Oko-cho, Nankoku-shi, fenoterol should point to inadequate to be useful in assessment of functional Kochi 783-8505, Japan suppression of the underlying inprovement in regions with rest inflammatory process and the need to asynergy in patients with previous Cowie MR, Struthers AD, Wood DA, et al.
optimise the dose of inhaled myocardial infarction. We tested Value of natriuretic peptides in assessment ofpatients with possible new heart failure in whether plasma concentrations of BNP primary care. Lancet 1997; 350: 1347–51.
and ANP can be used as biochemical McDonaugh TA, Robb SD, Murdoch DR, *Brian Lipworth, Catherine Jackson indicators in the assessment of et al. Biochemical detection of left-ventricular Department of Clinical Pharmacology and contractile reserve of dysfunctional systolic dysfunction. Lancet 1997; 351: 9–13.
Therapeutics, Ninewells Hospital and Medical myocardium in dilated cardio- The Metoprolol in Dilated Cardiomyopathy School, Dundee DD1 9SY, UK (MDC) Trial Study Group. 3-year follow-up of patients randomised in the Metoprolol in 22 patients with dilated Dilated Cardiomyopathy Trial. Lancet 1998; Beasley R, Nishima S, Pearce N, Crane J. cardiomyopathy (age 54 [SD 14] years; b-agonist therapy and asthma mortality in 17 men and five women; left-ventricular Omland T, Aakvaag A, Bonarjee VVS, et al.
Japan. Lancet 1998; 351: 1406–07.
ejection fraction 34 [7]%) had low-dose Plasma brain natriuretic peptides as an Garrett J, Lanes SF, Kolbe J, Rea HH. Risk indicator of left ventricular systolic function dobutamine infusion (5 of severe life threatening asthma and and long-term survival after myocardial b-agonist type: an example of confounding and 10 mg kg-1 min-1) during cardiac infarction. Circulation 1996; 93: 1963–69.
by severity. Thorax 1996; 51: 1093–99.
catheterisation. Plasma concentrations Dubois-Rande JL, Merlet P, Roudot F, et al.
Newhouse MT, Chapman KR, of BNP, ANP, and norepinephrine b-adrenergic contractile reserve as a McCallum AL, et al. Cardiovascular safety predictor of clinical outcome in patients with were analysed in relation to of high doses of inhaled fenoterol and idiopathic dilated cardiomyopathy. Am haemodynamic indices. With low-dose albuterol in acute severe asthma. Chest Heart J 1992; 124: 679–85.
1996; 110: 595–603.
dobutamine infusion, cardiac indices Bremner P, Siebers R, Crane J, Beasley R, increased significantly: 32 (22)% Burgess C. Partial versus full b-receptor increase at 5 mg kg–1 min–1, and 69 agonism: a clinical study of inhaled albuterol (26)% increase at 10 and fenoterol. Chest 1996; 109: 957–62.
mg kg–1 min–1.
Sir—Treatment with b-blockers Lipworth BJ, Newnham DH, Clark RA, Plasma concentrations of BNP, ANP, improves cardiac function in many Dhillon DP, Winter JH, McDevitt DG.
and norepinephrine were slightly raised patients with congestive heart failure.
Comparison of the relative airway and at rest: BNP 91 (93) pg/mL, ANP 39 Our long-term Metoprolol in Dilated systemic potencies of inhaled fenoterol and (31) pg/mL, and norepinephrine 302 Cardiomyopathy (MDC) trial was the salbutamol in asthmatic patients. Thorax
1995; 54: 54–61.
(229) pg/mL. The raised BNP and first large placebo-controlled trial of a ANP concentrations negatively b-blocker in heart failure.1 correlated to percentage increase of Some patients show a poor response cardiac indices by dobutamine infusion to b-blocker therapy, whereas others Natriuretic peptides and at 10 mg kg–1 min–1: (BNP r=–0·55, may display a dramatic improvement.
contractile reserve in p<0·01; ANP r=–0·48, p<0·05), but Several attempts have been made to did not correlate to the degree of identify predictors of a favourable dilated cardiomyopathy impaired ejection fraction at rest.
response. Although some factors have Plasma concentrations of been associated with subsequent Sir—Natriuretic peptides are secreted in norepinephrine did not correlate with improvement, the correlations have response to increased intracardic been only slight. A high heart rate at volume and pressure. The measurement BNP and ANP correlated negatively baseline and an increase in plasma of these peptides in biochemical to the response of the left ventricle to noradrenaline are associated with a assessment of left-ventricular low-dose dobutamine infusion, beneficial response to dysfunction has been reported.1,2 With b-blockers.2,3 The although a raised BNP concentration possibility that a dobutamine stress test regard to the report by the Metoprolol seems to be more accurate than a raised might identify possible responders has in Dilated Cardiomyopathy Trial Study ANP concentration in assessment of been suggested but not proven.
Group (April 18, p 1180),3 contractile reserve in dilated Hiroaki Kitaoka and colleagues wondered if the investigators had the cardiomyopathy. Ejection fraction at suggest that high concentrations of the opportunity to measure natriuretic rest is important in the definition of left- natriuretic peptides ANP and BNP are peptides in the patients in relation to ventricular dysfunction, but is probably associated with left-ventricular treatment with b-blockers, since these unreliable for assessment of reversibility contractile reserve in patients with peptides could have prognostic value indilated cardiomyopathy.
of left-ventricular dysfunction and the dilated cardiomyopathy, as assessed by Raised plasma concentrations of atrial cardiovascular system as a whole in dobutamine stimulation. They question natriuretic peptides (ANP) and B-type relation to compensatory mechanisms.
whether the concentration of natriuretic natriuretic peptide (BNP) have been The ability of the heart to respond to peptide might identify responders to reported in patients with left-ventricular dobutamine infusion may partly reflect b-blocker therapy. When we began the dysfunction after myocardial infarction4 good functional reserve of the MDC study, little was known about and in people with symptomless left- cardiovascular system in patients with natriuretic peptides, and no such data ventricular systolic dysfunction.1,2 dilated cardiomyopathy. These results are available from that study or from Previous studies focused on the role of have clinical importance in the any other b-blocker trial, as far as we these peptides in detection of underlying management of patients with dilated know. Although the question proposed THE LANCET • Vol 352 • August 8, 1998 by Kitaoka and co-workers is pacing-induced heart failure. Am J Physiol dose of 0·05 mg per day, seems to straightforward, the complexity of 1994; 266: H468–75.
produce a bimodal effect: if basal IGF-I Yoshimoto T, Naruse M, Tanabe A, et al.
neurohormones and their relation might is low, an increase during treatment is Potentiation of natriuretic peptide action by be an obstacle to finding an answer.
the beta-adrenergic blocker carvedilol in seen; conversely, if the basal value is Natriuretic peptides are affected by hypertensive rats: a new antihypertensive high, IGF-I tends to fall.5 Overall, atrial distension, left-ventricular filling, mechanism. Endocrinology 1998; 139: 81–88.
different oestrogen preparations renal function, and renin-angiotensin can reduce the wide variations of basal activation. Furthermore, all neurohormones are inter-related, and Hankinson and colleagues showed no Insulin-like growth factor-I natriuretic peptides are increased correlation between IGF-I and breast- secondary to sympathetic or inotropic and risk of breast cancer cancer risk in postmenopausal women, stimulation. Although high even after exclusion of the 165 breast- concentrations of neurohormones Sir—Susan Hankinson and colleagues' cancer cases (54% of postmenopausal predict a poor prognosis in congestive (May 9, p 1393)1 finding of a positive patients) and of a similar number of heart failure, the effects of different relation between the concentration of controls who were on hormone- therapies on neurohormones do not circulating insulin-like growth factor replacement therapy. Nevertheless, generally correlate with the effects on (IGF)-I and risk of breast cancer in breast cancers appearing during mortality. Moreover, whereas the premenopausal women is of interest hormonal therapy might more improvement in cardiac function and a with respect to hormone-replacement frequently be endocrine sensitive and reduction in filling pressures would therapy in postmenopausal women. In responsive to the stimulus of both result in lower concentrations of fact, oestrogen and IGF-I have oestrogens and IGF-I. A rise in basal natriuretic peptides, several studies synergistic effects on cell proliferation2 IGF-I in individuals harbouring such have shown that b -selective and non- and IGF-I is necessary for maximum disease would be hidden by oestrogen- selective b-blockers might increase the oestrogen-receptor activation in cell replacement treatment. Can Hankinson concentration of natriuretic peptides.4 lines in breast cancer.3 and co-workers give details on Natriuretic and vasodilating properties Circulating concentrations of IGF-I menopausal age and IGF-I values of the atrial peptides could be are affected differently by the various in cases and controls on hormone- responsible for some of the positive types of hormone-replacement replacement therapy, and in effects of b-blockers. A proposed mode treatments.4 The use of oral oestrogens postmenopausal women and controls of action is that b-blockade induces a causes about a 25% decrease of not on hormone therapy? down-regulation of the natriuretic circulating IGF-I concentrations peptide-C clearance receptor, leading to through metabolic and hepatocellular *Carlo Campagnoli, Simona Ambroggio, increased peptide plasma actions (enhanced by the first liver Nicoletta Biglia, Clementina Peris, passage), whereas transdermal In this context, it should be oestradiol has on average no such *Department of Endocrinological Gynaecology, emphasised that although most effect.4,5 Oestrogen-mediated reduction "S Anna" Gynaecological Hospital, 10126 neurohormones exert negative long- of IGF-I is opposed by androgenic Turin, Italy; and Department of GynaecologicalOncology University of Turin, Mauriziano progestagens such as norethisterone, term effects on heart failure "Umberto I" Hospital, Turin but not by progestagens such as pathophysiology, the effects of atrial dydrogesterone that have no peptide are beneficial in Hankinson SE, Willett WC, Colditz GA, androgenic action.4 counterbalancing other neuro- et al. Circulating concentrations of insulin- The finding that the effect of hormones. Nevertheless, natriuretic like growth factor-I and risk of breast cancer.
Lancet 1998; 351: 1393–96.
oestrogen-replacement therapy is peptides are probably better predictors Westley BR, May FEB. Role of insulin-like largely dependent on basal IGF-I values of long-term prognosis than other growth factors in steroid modulated is noteworthy, and may help to neurohormones in congestive heart proliferation. J Steroid Biochem Molec Biol interpret Hankinson and colleagues' failure. A study on the ability of these 1994; 51: 1–9.
findings. IGF-I reduction associated peptides to predict b-blocker effects Lee AV, Weng CN, Jackson JG, Yee D.
with oral oestrogen use is pronounced Activation of oestrogen receptor-mediated would be of value.
gene transcription by IGF-I in human breast in most women with high basal values, cancer cells. J Endocrinol 1997; 152: 39–47.
but is not seen in women with low basal Campagnoli C, Biglia N, Peris C, values (figure, unpublished results).
Sismondi P. Potential impact on breast Department of Cardiology, Sahlgrenska Transdermal oestradiol, at the usual cancer risk of circulating insulin-like growth University Hospital, S-413 45 Göteborg,Sweden The Metroprolol in Dilated Cardiomyopathy(MDC) Trial Study Group. 3-year follow-up of patients randomised in the Metoprolol inDilated Cardiomyopathy trial. Lancet 1998; Fisher ML, Gottlieb SS, Plotnick GD, et al.
Beneficial effects of metoprolol in heartfailure associated with coronary arterydisease: a randomized trial. J Am Coll Cardiol 1994; 23: 943–50.
CIBIS Investigators and Committees. A
randomized trial of b-blockade in heart
failure: the Cardiac Insufficiency Bisoprolol
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1765–73.
Levett JM, Marinelli CC, Lund DD, et al.
Serum IGF-I concentrations in 46 postmenopausal women Effects of b-blockade on neurohormonal Basal values and those after 6 months* on oral conjugated equine oestrogens (0·625 mg per day) responses to neurochemical markers in THE LANCET • Vol 352 • August 8, 1998 factor I modifications induced by oral HRT Hankinson SE, Willett WC, Colditz GA, in menopause. Gynecol Endocrinol 1995; 9:
et al. Circulating concentrations of insulin- Sir—The data presented by Carlo like growth factor-1 and risk of breast cancer.
Campagnoli C, Biglia N, Cantamessa C, Lancet 1998; 351: 1393–96.
Campagnoli and colleagues are very Lesca L, Lotano MR, Sismondi P. Insulin- Blake EJ, Adel T, Santoro N. Relationship like growth factor I (IGF-I) serum level interesting. We had noted that in women between insulin-like growth hormone factor- modifications during transdermal oestradiol who had not used postmenopausal I and estradiol in reproductive aging. Fertil treatment in postmenopausal women: a hormones within 3 months of their Steril 1997; 67: 697–701.
possible bimodal effect depending on basal blood collection (thus their IGF-I Klein NA, Battaglia DE, Miller PB, IGF-I values. Gynecol Endocrinol (in press).
Soules MR. Circulating levels of growth concentrations would reflect basal hormone, insulin-like growth factor-I and Sir—Susan Hankinson and colleagues1 values), there was no significant relation growth hormone binding protein in normalwomen of advanced reproductive age. Clin describe an increased risk for breast between plasma IGF-I and breast Endocrinol 1998; 44: 285–92.
cancer in premenopausal women with cancer.1 To assess this issue further, we Van Dessel HJHMT, Chandrasekher Y, raised serum IGF-I concentrations.
evaluated the IGF-I/breast cancer Yap OWS, et al. Serum and follicular fluid This increased risk was not shown in relation in women who had never used levels of insulin-like growth factor 1 (IGF-I), postmenopausal women. Raised postmenopausal hormones (76 cases and IGF-II, and IGF-binding protein-1 and -3during the normal menstrual cycle. J Clin circulating insulin and IGFBP-3 values 189 controls). The relation was not Endocrinol Metab 1996; 81: 1224–31.
are present in premenopausal women2 positive, as was seen in premenopausal Wang HS, Lee JD, Soong YK. Serum levels and can be explained by an underlying women, although the number of cases of insulin-like growth factor I and insulin-like syndrome of insulin resistance. IGF-I is and controls in this analysis was small growth factor-binding protein-1 and -3 inwomen with regular menstrual cycles. Fertil secreted in a circadian fashion, and the confidence limits were wide.
Steril 1995; 63: 1204–09.
introducing variability in single-point Among cases and controls who were measurements, which were used in current hormone users, the mean age at Sir—Susan Hankinson and colleagues'1 Hankinson's study. The total serum menopause was 48 (cases) and 49 years report of a positive relation between concentration of IGF-I, as well as in (controls), the median duration of circulating insulin-like growth factor growth hormone and IGFBP-3, depend hormone use was 6 and 5 years, and the (IFG)-I and risk of breast cancer, also on body mass, age, and time of median IGF-I concentrations were reviewed by Jeff Holly in his menstrual cycle.3,4 131 ng/mL and 137 ng/mL, respectively.
commentary,2 raises important issues colleagues adjusted their analysis for Among previous hormone users, the about growth-hormone administration.
body-mass index but not for age and mean age at menopause was 49 years for Concerns have been expressed over time of menstrual cycle. It would be of each group, the median duration of the potential for growth hormone to interest to know how the risk ratio for hormone use was 1·3 years and 1·8 promote cancer, especially in adult breast cancer would change if adjusted years, and the median IGF-I hypopituitarism, since doses used for these indices. Women younger than concentrations were 155 ng/mL and 165 previously may have been higher than age 35 with a higher normal range of ng/mL, respectively. Among those who true replacement.3 In our experience, IGF-I seem to have more aggressive never previously used postmenopausal the use of locally validated age- breast carcinoma.5 Is the risk of breast hormones, the mean age at menopause standardised reference ranges4 cancer in premenopausal women also was 51 years for each group and median plasma IGF-I has helped to show that increased when the age-adjusted IGF-I values were 169 ng/mL and 161 doses of growth hormone previously standard-deviation scores of IGF-I recommended for adult growth- (SDS IGF-I) are used in the regression In our report, the matching factors hormone deficiency may have been (age, month, time of day of blood above the optimum.5 In adult-onset collection, and fasting status) were growth-hormone deficiency, we used controlled in all analyses. As pointed *Oliver Strohm, Karl-Josef Osterziel, these reference ranges to achieve out by Strohm and colleagues, we were optimum continuing growth-hormone not able to control for phase of replacement for individual patients on Universitätsklinikum Charité, MedizinischeFakultät der Humboldt-Universität zu Berlin, menstrual cycle. However, most long-term therapy.
D-13125 Berlin, Germany previous studies2–5 have shown little Further long-term studies of the variation in IGF-I or IGFBP-3 during association between age-standardised Hankinson SE, Willett WC, Colditz GA, the menstrual cycle, thus having IGF-I concentrations and the risks of et al. Circulating concentrations of insulin- untimed samples is unlikely to be a cancer are needed. However, as like growth factor-I and risk of breast cancer.
Lancet 1998; 351: 1393–96.
substantial limitation of the study. We indicated by Holly,2 the fact that the Del Giudice ME, Fantus IG, Ezzat S, did an analysis of age-specific IGF-I Z binding protein, IGFBP-3, increases McKeown Eyssen G, Page D, Goodwin PJ.
scores (in a model controlling for the when growth-hormone is given to Insulin and related factors in premenopausal matching factors plus IGFBP-3) in growth-hormone deficient adults5 may breast cancer risk. Breast Cancer Res Treat premenopausal women younger than be relevant if risk relates to free IGF-I.
1998; 47: 111–20.
Juul A, Dalgaard P, Blum WF, et al. Serum 50 years. Relative risks remained levels of insulin-like growth factor (IGF)- significant (eg, top to bottom tertile *Chris Florkowski, John Livesey, binding protein-3 (IGFBP-3) in healthy contrast relative risk 5·1 [95% CI infants, children, and adolescents: the Department of Endocrinology, Christchurch relation to IGF-I, IGF-II, IGFBP-1, Hospital, Private Bag 4710, Christchurch, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab *Susan E Hankinson, Walter C Willett, 1995; 80: 2534–42.
Frank E Speizer, Michael Pollak Hankinson SE, Willett WC, Colditz GA, Zanker CL, Swaine IL. Bone turnover in et al. Circulating concentrations of insulin- amenorrhoeic and eumenorrhoeic women *Channing Laboratory, Brigham and Women's like growth-factor-I and risk of breast cancer.
Hospital, Harvard Medical School, Boston, distance runners. Scand J Med Sci Sports Lancet 1998; 351: 1393–96.
MA 02115, USA; Department of Epidemiology 1998; 8: 20–26.
Holly J. Insulin-like growth-factor-I and new and Nutrition, Harvard School of Public Health, Winchester DP, Osteen RT, Menck HR.
Boston; and Departments of Medicine and opportunities for cancer prevention. Lancet The National Cancer Data Base report on Oncology, Cancer Prevention Research Unit, 1998; 351: 1373–75.
breast carcinoma characteristics and Lady Davis Institute of the Jewish General Cuneo RC, Judd S, Wallace JD, et al. The outcome in relation to age. Cancer 1996; 78:
Hospital, McGill University, Quebec, Australian multicenter trial of growth hormone (GH) treatment in GH-deficient THE LANCET • Vol 352 • August 8, 1998 adults. J Clin Endocrinol Metab 1998; 83:
the wide variations between individuals strain of S senftenberg that caused an in circulating IGF binding proteins.
outbreak of wound infection in a Rasat R, Livesey JH, Espiner EA, Abbott Free IGF-I probably has greater hospital in India.2 GD, Donald RA. IGF-I and IGFBP-3screening for disorders of Growth Hormone physiological and clinical relevance than Other molecular class A b-lactamases Secretion. NZ Med J 1996; 109: 156–59.
total IGF-I.
have also been found in salmonella, Florkowski CM, Walmsley T, George PM, Circulating concentrations of free sex including CTX-M2 from S typhimurium Livesey JH, Espiner EA, Donald RA.
hormone and total IGF-I are in Argentina. PER-1 b-lactamase, The effect of growth hormone on significantly inter-related. The which was previously seen in only age-standardized IGF-I, IGFBP-3 andbiochemical parameters of bone turnover in associations observed between total Pseudomonas aeruginosa, was found in adult hypopituitarism. Endocrinol Metabol IGF-I concentrations and breast and two S typhimurium strains in Turkey, 1997; 4: 129–34.
prostate cancers could reflect overall one of which caused an outbreak Sir—Plasma-free and albumin-bound sex-steroid activity, although the value of neonatal meningitis. Two concentrations of androgen and of measuring total IGF-I concentrations S typhimurium strains that produced oestrogen are the biologically active to estimate the biologically active PER-type enzymes were reported from fraction of circulating sex-steroids.
moiety of IGF-I is not known.
Argentina, and one that produced an Plasma sex-hormone-binding globulin enzyme that may be related to MEN-1 *J A M J L Janssen, S W J Lamberts (SHBG) is important in the regulation from Russia. An isolate of S enteritidis of plasma-free and albumin-bound Department of Internal Medicine III, University from Saudi Arabia produced a plasmid- Hospital Dijkzigt, Erasmus University, androgen and oestrogen encoded molecular class C b-lactamase Rotterdam, 3015 GD Netherlands concentrations. Gann and colleagues1 (DHA-1) that conferred resistance to reported that high concentrations of Gann PH, Hennekens CH, Ma J, et al.
extended-spectrum cephalosporins and circulating testosterone and low levels Prospective study of sex hormone levels and cephamycins. Another group I enzyme, risk of prostate cancer. J Natl Cancer Inst of SHBG—both within the normal CMY-2, was reported in S senftenberg 1996; 88: 1118–26.
ranges—were associated with increased from Algeria. Two unidentified Chan JM, Stampfer MJ, Giovanucci E, et al.
risks of prostate cancer. In a group of extended-spectrum b-lactamases have Plasma insulin-like growth factor-I and patients, a positive association was prostate cancer risk: a prospective study.
also been reported from Algeria and found between circulating total insulin- Science 1998; 279: 563–66.
Hankinson SE, Wilett WC, Colditz GA, like growth factor (IGF)-I Extended-spectrum et al. Circulating concentrations of insulin- concentrations and the subsequent production is usually encoded on like growth factor-I and risk of breast cancer.
relative risk of prostate cancers.2 Lancet 1998; 351: 1393–96.
transmissible plasmids together with a Susan Hankinson and co-workers3 Holly J. Insulin-like growth factor-1 and new range of aminoglycoside-modifying also report a strong association between opportunities for cancer prevention. Lancet enzymes,3 and, therefore, most of these 1998; 351: 1373–74.
circulating total IGF-I concentrations cephalosporin-resistant salmonellas are Janssen JAMJL, Stolk RP, Pols HAP, et al.
and the relative risk of breast cancer in also resistant to aminoglycosides. The Serum free IGF-I, total IGF-I, IGFBP-1 and premenopausal women. Since the IGFBP-3 in an elderly population: relation resistance plasmids have probably been relative risk of prostate and breast to age and sex steroid levels. Clin Endocrinol acquired from other multidrug-resistant 1998; 48: 417–78.
cancer associated with total steroid enterobacteriaceae, especially Klebsiella concentrations has previously been pneumoniae, which are also increasing in reported to be substantially lower than incidence worldwide.4 that observed for total IGF-I We agree with Rankin and Coyn that concentrations and prostate and breast an effective strategy for the containment cancer in the studies by Chan and of antibiotic resistance in foodborne and Hankinson and Sir—The importance of the increasing pathogens is needed, but would add colleagues,3 respectively, Jeff Holly incidence of multiple-antibiotic- that enteric pathogens can also acquire suggests in his May 9 commentary4 that resistant salmonella is noted by Shelley multiple resistances by conjugation with circulating total IGF-I concentrations Rankin and Michael Coyne (June 6, commensal bacteria in the human do not merely reflect sex-steroid status.
p 1740).1 We would add that antibiotic bowel. Although most cases of human We believe that Holly's conclusion resistance in Salmonella spp is no longer illness from Salmonella spp do not need might not be correct or based on restricted to older compounds.
to be treated with cephalosporins or Salmonella spp resistant to second- aminoglycosides, these antibiotics are Breast and prostate are sex-steroid generation and third-generation useful in invasive complications such as dependent tissues. We found an age- cephalosporins and related antibiotics bacteraemias and meningitis.
independent inverse relation between by the production of various extended- *Kevin Shannon, Gary French total IGF-I and SHBG concentrations spectrum b-lactamases are increasingly Department of Microbiology, United Medical in both sexes.5 We also found a positive common worldwide.* and Dental School, St Thomas' Hospital, relation between total concentrations of The reported enzymes include London SE1 7EH, UK IGF-I, IGFBP-3, or both and free- TEM-3 from Salmonella kedougou inFrance and possibly S enteritidis in Rankin SC, Coyne MJ. Multiple antibiotic androgen index (an index of free resistance in Salmonella enterica serotype testosterone) in men and a positive Spain, TEM-25 from S mbandanka enteritidis. Lancet 1998; 351: 1740.
relation between total IGF-I and free imported into France from Algeria, and Revathi G, Shannon KP, Stapleton PD, oestradol index (an index of free TEM-27 from S othmarschen in Spain.
Jain BK, French GL. An outbreak of oestradol) in women.5 However, free There have been two reports of SHV-2 extended-spectrum b-lactamase-producingSalmonella senftenburg in a burns ward.
IGF-I concentrations were not in S mbandanka, S typhimurium, and J Hosp Infect (in press).
associated with free steroid indices in S wien, all associated with Tunisia, Jacoby GA, Sutton L. Properties of plasmids both sexes.5 Free IGF-I concentrations although the S mbandanka strain was responsible for production of extended- probably reflect the bioavailable IGF-I isolated after importation into the UK.
spectrum b-lactamases. Antimicrob Agents We have reported an SHV-5-producing Chemother 1991; 35: 164–69.
better than total IGF-I concentrations.
Livermore DM. b-lactamase-mediated Total IGF-I offers only a crude estimate *Full list of references available from the The resistance and opportunities for its control. of biologically active IGF-I because of Lancet or authors on request.
J Antimicrob Chemother 1998; 41: 25–41.
THE LANCET • Vol 352 • August 8, 1998 Drug approval in Japan different effectiveness from the vaccines and other therapies in confirmed one in related CCTs; such response to the threat of biological are not evidence based.
warfare, several points apply.
Sir—The ministry of Health and We believe that Japanese There has never been a trial of Welfare of Japan (MHW) banned unscientific CCTs and the current efficacy in man for the current US (or four drugs classified as approval system bear the responsibility British) anthrax vaccine,4 and the issue cerebral-metabolism enhancers on for a mountain of ineffective and of whether vaccinations (or their May 25. The drugs—idebenon, potentially harmful products in Japan.
combination) contributed to Many other dubious drugs such as development of Gulf War illnesses has hydrochloride, and bifemelane antiallergic drugs4 or psychotropic yet to be resolved.5 In particular troops hydrochloride—were approved in the drugs5 have been approved by the who were vaccinated in preparation late 1980s because they were believed MHW on the basis of the same GIR.
but never deployed to the Gulf, and to ease symptoms such as emotional Without a radical reform of the therefore lacked other Gulf-related disorders resulting from stroke.
evaluation system, it is difficult to exposures, have developed such However, studies showed that the avoid this kind of scandal.
illnesses. Furthermore, both naturally drugs failed to outperform placebos.
occurring and recombinant strains of Despite the lack of effectiveness, the *Keiji Hayashi, Kentaro Hashimoto, anthrax exist which are antibiotic and total sales of the four drugs reached Motokazu Yanagi, Tadanori Umeda, vaccine resistant. It is such strains that about ¥875 billion (US$6·25 billion) are likely to be used in a biological since their approval.
*Department of Pediatrics, Takatsuki Red attack. If so, the proposed vaccinations Cross Hospital, 1-1-1 Abuno, Takatsuki City, Although their effectiveness had and antibiotics are unlikely to have Japan; Department of Internal Medicine, much impact. To further complicate Yao Municipal Hospital, Yao; Department of dispute the MHW's decision; it is hard Internal Medicine, Takamoto Kyooritu Clinic, matters, the February, 1998, US Food Osaka; Department of Psychiatry, Iwakura to explain to their patients why these and Drug Administration inspection Hospital, Kyoto; and Japan Institute of drugs had been prescribed until the report for the Michigan Biologic Pharmacovigilance for EBHC, Osaka day when then should be stopped. The Products Institute (the sole US vaccine director of the Japan Medical Significance to designate hopatenate manufacturer) lists 11 pages of quality- Association said, "This decision had a calcium as dangerous drug. Informed control failures for anthrax vaccine Prescrib 1989; 4: 17–21.
great impact on the medical service production, including reuse of expired Yanagi M, Hashimoto K, Umeda T, et al.
providers, because it injured badly the vaccine, grossly inadequate testing, Problems on the clinical evaluation mutual trust between doctors and methods with Zenpan Kaizendo. Jap J Clin and use of lots that failed testing.
patients". We believe that this kind of Pharmacol Therapeutics 1995; 26: 115–16
It is generally agreed that a strong (in Japanese).
tragedy will happen again if the MHW biological warfare treaty, one that Hashimoto K, Irie N, Takamoto E.
continues to use the current approval includes full inspections and other Problems on the clinical evaluation system for new drugs.
verification methods, would not be methods of "cerebral-metabolism and We have criticised the approval circulation enhancers". Jap J Clin 100% effective at preventing such system since 1994 because it lacks the Pharmacol Therapeutics 1996; 27: 303–04
warfare. Yet such a treaty would still (in Japanese).
reproducibility. The primary endpoint have great positive effects. The Hayashi K, Hama R. Evaluation of oral of Japanese controlled clinical trials possibility of being inspected without anti-allergic drugs in Japan. Lancet 1996; (CCTs) is called Zenpan Kaizen Do 347: 477.
warning would deter many (the global improvement rating, GIR), Berger D, Fukunishi I. Psychiatric drug programmes. UN inspections in Iraq which were determined subjectively by development in Japan. Science 1996; 273:
have established the usefulness of such physicians. However, the GIR is strategies at uncovering biological similar to a clinical global impression warfare programmes.
of change, and has no structured We should face the fact that micro- criteria; it therefore, has limited organisms might be created against Biological warfare which our therapeutic arsenal would Japanese CCTs of the four drugs be impotent. Therefore, maximum Sir—Richard Wise (May 9, p 1378)1 is have used numerous (30–100) efforts should be made in primary wrong about secondary spread by endpoints assessed by GIR that were prevention such as adding teeth to the anthrax in biological warfare. There is also judged by physicians subjectively.
Biological Weapons Convention. Yet no person-to-person spread of anthrax: In the statistical analysis, the CCTs the USA and some other nations the only reported case of such spread used the significance of p=0·05 for continue to hold out against surprise was when a loofa was shared. in fact, every endpoint; this analysis is inspections and full verification in the this is one reason why anthrax is a erroneous in the multiple comparison.
protocol to the convention that is now classic choice for such warfare: it only For instance, we found a CCT of being negotiated. Before we get caught affects the area in which it is used and indeloxazine hydrochloride that had up in a frenzy of stockpiling and use of does not spread back toward the only three significant (p=0·05) vaccines, antibiotics, and other perpertrator. Anthrax can however, endpoints out of 54. In the Japanese therapies, a careful evaluation needs to mimic landmines, recurring CCTs, so many patients were be made of their actual benefits and unpredictably in the future from a soil excluded that most endpoints were costs. And strategies for prevention assessed in half of the eligible must be moved to the forefront of this Anthrax was developed as a patients.3 Consequently, we found that biological weapon by Japan in the significantly different endpoints 1930s,2 by the USA and Great Britain differed from one study to another; in the 1940s, and by other nations which proves that the Japanese CCTs Parkview Hospital, Brunswick, MN 04011, since. Yet in the intervening 60 years, lacked reproducibility. Moreover, the only very limited use of it for biological statements of virtues of the cerebral- warfare has been documented.2,3 With Wise R. Bioterrorism: thinking the metabolism enhancers claimed respect to the administration of unthinkable. Lancet 1998; 351: 1378.
THE LANCET • Vol 352 • August 8, 1998 Williams P and Wallace D. Unit 731, New implementation of efficient We developed a model to assess the York: Free Press, 1989.
interventions and have also yielded costs and benefits of exercise2 with Nass M. Anthrax epizootic in useful correctional elements for regional estimates of the relative risks in Zimbabwe, 1978–1980: due to deliberatespread? Phys Soc Responsibility Quart 1992; health policy.
exercisers and non-exercisers of the Research results are systematically chronic diseases that have been shown Brachman PS and Friedlander AM.
disseminated during official to benefit from exercise,3 and the Anthrax. In: Plotkin SA, Mortimer EA, eds.
presentations to regional, and national injury risks and treatment costs of Vaccines, 2nd edn. Philadelphia: WB health decision-makers, and to bilateral exercise-related morbidity,4 published Saunders, 1994.
Butler D Admission on Gulf War vaccines and multilateral aid agencies. Research in the scientific literature. The main spurs debate on medical records. Nature reports are also distributed. Publication outcome measure was the impact for 1997; 390: 3–4.
in professional journals requires a the health services of direct costs large effort in the areas of conception incurred and costs avoided by exercise, and composition, but is one of the in a total exercising population. We Health research in the objectives of the PSA's research found that clear health and economic benefits are achievable by encouragingexercise in older populations, but that Sir—In response to Ivan Wolffers and the reverse is true for younger adults.
colleagues' (May 30, p 1652)1 This somewhat surprising conclusion discussion of tropical medicine in the Abidjan Health Project (Projet Santé Abidjan,PSA), BP 1839 Abidjan 01, Côte d'Ivoire (which is similar to the results reported South, we wish to report on the work of in a study of a Dutch population5) rests the Abidjan Health Project (Project on the assumption that the costs and Santé Abidjan, PSA) in Côte d'Ivoire.
Wolffers I, Adjei S, van der Drift R. Health benefits of exercise are contiguous.
The PSA aims to improve the supply of research in the tropics. Lancet 1998; 351:
Thus, the health benefits in terms of health care in Abidjan both qualitatively reducing the risk of the onset of and quantitatively. From the time of its chronic diseases in previously conception, the PSA has included a sedentary individuals who take up research and development component I'll take the health exercise in middle age are the same as that supports the implementation of the those resulting from lifelong different elements of the project. In the benefits of exercise participation in exercise. This past 5 years, 26 research projects have without the risks please assumption is confirmed by the British been completed in various disciplines Regional Heart Study. The added Sir—Preferring in middle age to follow health bonus for delayed exercisers, health economics, health sciences), not a sedentary lifestyle, I am greatly however, is that they can maximise the only in tropical medicine.
comforted to learn from the study by health benefits of exercise and The definition of priorities within the Goya Wannamethee and colleagues minimise the health and direct health- framework of the PSA focuses on the (May 30, p 1603)1 that if guilt for my care costs4 by avoiding exposure to orientations specified in the National complacency gets too much to bear I high-risk sports in which younger Health Plan (Plan National de can invest in regular exercise and adults participate.
Développement Sanitaire) in secure immediate protection for my collaboration with national partners.
health in later years. Their study shows The research projects are executed by that changing my lifestyle from inactive School of Health and Related Research, national research institutions, according to one which includes at least Medical Care Research Unit, University of to terms of reference defined by the occasional light active participation in Sheffield, Sheffield S1 4DA, UK project. These research institutions exercise, will reduce the fully adjusted frequently use local researchers, and risk of my all cause mortality to 0·55 Goya Wannamethee S, Shaper AG,Walker M. Changes in physical activity, occasionally young French researchers (0·36–0·84) relative to the risk of those mortality, and incidence of coronary heart working on a masters or doctoral thesis.
of my colleagues who remain inactive.
disease in older men. Lancet 1998; 351:
The remuneration of researchers is My initial feelings of comfort, contractual and is fixed in relation to however, become almost smug when I Nicholl JP, Coleman P, Brazier JE. Health consider that late investment derived and healthcare costs and benefits of experience acquired and employment exercise. PharmacoEconomics 1994; 5:
status. The amount is calculated from such slight changes in lifestyle according to government salaries and will reduce my risk to below that of Fentem PH, Bassey EJ, Turnbull JB. The varies between US$400 per month for a other colleagues whose continuous new case for exercise. London: Sports junior level civil servant to US$1300 for active participation in sports since their Council and Health Education Authority,1988.
an independent senior level private now distant youths has been Nicholl JP, Coleman P, Williams BT.
consultant. The fee scale is identical for interrupted only by periods of enforced Injuries in sport and exercise: main report.
local and expatriate researchers.
abstinence due to the many injuries London: Sports Council, 1993.
The implementation of research they have sustained (relative risk 0·58).
Reijnen J, Velthuijsen JW. Economic results is a major goal and is facilitated The clear message from this latest aspects of health through sport. ConferenceProceedings: sport an economic force in by a way in which the research contribution from the British Regional Europe. Lilleshall, UK, November, 1989.
component is integrated into the project Heart Study1 that exercise is beneficial as a whole. An operating committee is to health in older men and that small convened whenever necessary to ensure changes away from inactivity are DEPARTMENT OF ERROR that the results are used to improve the immediately associated with a reduced targeting of public-health initiatives. In risk of major chronic diseases, is Disclosure of novel autoantigens in human most cases, the results are used at obviously one to be welcomed.
autoimmunity—In this Commentary by Rita regional level, but sometimes they are Mirakian and colleagues (July 25, p 255) the However, the results also support the last sentence of the fourth paragraph should used to elaborate national strategies.
findings from our earlier study which read: "One thing is certain: autoantibodies to The results obtained since 1993 from are more controversial and have been intracellular autoantigens are not our research have allowed the less well received.
pathogenetic. . " THE LANCET • Vol 352 • August 8, 1998

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