Albendazole for mass treatment of asymptomatic trichuris infections
aminotransferase concentrations when it is used at higher
Over recent years the mortality of young children in
developing countries has been reduced by mass
Forrester and colleagues have examined three
immunisation, but there is no cause for complacency since
anthelmintic regimens (albendazole 400 mg/day for 3
many currently non-immunisable threats to their health
consecutive days, albendazole 400 mg/day once only, or
remain. One major, and previously under-appreciated,
pyrantel once only), each given for three courses with 4-
threat to physical fitness and cognitive development is
month intervals. They followed up patients for 12 months
intestinal nematode infestation. Despite medical advances
after randomisation. For ethical reasons there was no
in other areas, the global prevalence of intestinal
infestation by worms is largely unchanging, while the
albendazole regimen reduced trichuris intensity by 99%,
number of cases is rising.1,2 Recognition that young
compared with reductions of 87% and 67% in the single-
children carry the heaviest burden of intestinal worms,
dose albendazole and pyrantel groups, respectively. Arm
circumference increased more with the 3-day albendazole
accompanied by the availability of cheap and effective
group in the patients with the heaviest trichuris infestation
drugs, hence the calls for periodic mass treatment of high-
(weight, height, and skinfold thickness were no different).
risk populations in developing countries.3
However, in the children with the lightest infestation,
Trichuris trichiura (the “whipworm”) is a common
weight, arm circumference, and skinfold thickness seemed
intestinal nematode in tropical countries and is generally
to be adversely affected by the 3-day albendazole regimen.
accompanied, in the same host, by other parasites,
After careful analysis, but hampered by the lack of control
including Ascaris lumbricoides and hookworm species.
groups, the researchers conclude that asymptomatic
Adult T trichiura inhabit mainly the caecum but can
trichuriasis, and the 3-day course of albendazole, probably
parasitise the whole colon. Light infections are generally
impair growth. What are the implications of this finding on
asymptomatic, but heavy infestation can produce severe
albendazole for mass-treatment programmes?
clinical illness, including anaemia, finger-clubbing, bloody
There is no such thing as a safe drug. It follows that
diarrhoea, and rectal prolapse. The harmful effects of
therapy invariably results from a risk versus benefit
“trichuris-dysentery syndrome” on growth in young
analysis (by patient or physician but preferably both).
children have been reported, as has catch-up growth after
Such analyses are starkest when drugs are taken prophy-
lactically, when the risks of the drug must be small
T trichiura infection are less well understood although, in
compared with those of the disorder being prevented.
general, the assumption has been that the infection is
However, asymptomatic intestinal helminthiasis produces
relatively benign. In today’s Lancet, J E Forrester and
adverse consequences on the health of children, andtreatment improves both growth and cognitive function.
colleagues report that they had set out to examine the
The findings of Forrester and colleagues must be viewed
effect of treatment of asymptomatic trichuriasis on the
in this context. The suggestion that relatively high doses of
growth of young children (with or without other intestinal
albendazole may affect growth deserves further study,
helminths). In the course of their work they found what
ideally in a trial that incorporates matched control groups.
they believe is an unrecognised adverse effect of
However, it should be remembered that the 3-day
albendazole regimen employed by Forrester and
Albendazole is a broad-spectrum anthelmintic that
colleagues is unlikely to see much use in mass-treatment
perturbs tubulin polymerisation in a wide variety of
programmes. Consequently, although the finding provides
a reminder to use drugs with caution and may stimulate
strongyloides, and ascaris. Its oral bioavailability is low, but
further research in this area, it should not deter the use of
single-dose albendazole in mass-treatment programmes
sulphoxide, reaches therapeutic concentrations in plasma
and tissues and is chiefly responsible for the drug’ssystemic effects (eg, against hydatid disease). Although
toxicological findings include weight loss in adult rodents
Department of Pharmacology and Therapeutics, University of Liverpool,
(albeit given high doses over several weeks),6 albendazole
has a large therapeutic index. In human beings adverse
Chan MS. The global burden of intestinal nematode infections—fifty
effects have been mild and have included gastrointestinal
years on. Parasitol Today 1997; 13: 438–43.
upsets when the drug is used at low dose, and raised
Hall A, Orinda V, Bundy D, Broun D. Promoting child health through
THE LANCET • Vol 352 • October 3, 1998
helminth control—a way forward? Parasitol Today 1997; 13: 411–13.
World Health Organization. Health of school children: treatment ofintestinal helminths and schistosomiasis. WHO doc No
Bundy DA, Cooper ES. Trichuris and trichuriasis in humans. Adv Parasitol 1989; 28: 107–73.
Cooper ES, Duff EM, Howell S, Bundy DA. ‘Catch-up’ growth
velocities after treatment for Trichuris dysentery syndrome. Trans R Soc Trop Med Hyg 1995; 89: 653.
Dollery C. Therapeutic drugs. Edinburgh: Churchill Livingstone,
Horton RJ. Chemotherapy of echinococcus infection in man. Trans RSoc Trop Med Hyg 1989; 83: 97–102.
Can oral ␤ agonists cause heart failure?
RR=age and sex adjusted relative risk; CF=cardiac failure;
Despite concern over the cardiovascular safety of the
long-acting ␤ -selective agonists in general medical
especially in patients with heart disease,
safety of oral ␤ -agonists in a general population.
comparative data are limited. Cardiac failure could even
Bambuterol is slowly hydrolysed to terbutaline
underline an “asthmatic death” rather than be a terminal
throughout 24 h by tissue butylcholinesterase. Taken at
event. Another concern with salmeterol has been possible
bedtime, it provides high night-time serum terbutaline
adverse effects on the airways. Detection of these
concentration, which is very useful for the treatment of
uncommon events requires large numbers of patients.
nocturnal symptoms. Concentrations of bambuterol are
about 40% higher in old than in young adults, but
comparison of salmeterol with salbutamol in 16 787
pharmacokinetic studies are lacking in patients with heart
patients was somewhat reassuring with respect to
asthma,1 it lacked the power to detect, at the 0·05 level,
Was the PEM study a fair comparison? Probably not. It
even a four-fold increase in deaths from either drug.2
took nearly 3 years to collect the cohort of those patients
In prescription-event monitoring (PEM), physicians
who preferred, or needed, an oral agent. There were fewer
report monthly “any new adverse events, referral to a
indications for “asthmatic/wheeze” (57·3% vs 70·2% for
consultant, or admission to hospital” when they prescribe
salmeterol) and more “other” indications, such as
a newly launched drug. An excess of a particular event in
the first month over subsequent months further tends to
incriminate that drug. New hypotheses are formulated
Was the heart failure induced by bambuterol? There
from PEM data and prospectively studied.
may be a simpler explanation. The salmeterol cohort
Using the PEM technique, researchers from the Drug
consisted mostly of patients switching to a longer-acting
and Safety Research Unit and the School of Medicine at
agent, and those on nedocromil were mostly switching
Southampton re-examined the safety issue for salmeterol,
from cromolyn. The bambuterol group was more
a long-acting inhaled agent, and of bambuterol, a long-
heterogeneous. With or without asthma, some patients
acting oral agent and prodrug of terbutaline.3 Two
with impending or undiagnosed heart failure may have
presented with dyspnoea, cough, or wheeze and received
salmeterol between September, 1990, and May, 1991,
bambuterol, the true diagnosis becoming evident during
and 8098 patients begun on bambuterol between
February, 1993, and December, 1995, were compared
There is another possibility. A peak increase of 25% in
with a control cohort of 12 294 patients begun on the
oxygen uptake and carbon dioxide production occurs 5
min after 800 g of salbutamol taken by metred-dose
November, 1986, and September, 1998. There was an
inhaler, when systemic absorption peaks.6 Remarkably,
excess of non-fatal “cardiac failure” in the bambuterol
nearly complete tachyphylaxis develops on maintenance
group during the first month, and a lower but increased
dosing. Could such a metabolic demand produce heart
incidence during the second to sixth months, whereas
failure or angina in some older patients given
there was no excess in the salmeterol group (see table).
bambuterol? Systemic terbutaline causes a surprising
Ischaemic heart disease was also commoner in the first
increase in cardiac output; 0·25 mg given subcutaneously
month on bambuterol, but not thereafter. The team
raises cardiac output by 48% in normal young men.7
recommends “caution when prescribing oral ␤ -agonists
In contrast to fenoterol or isoproterenol, terbutaline
to patients at risk of cardiac failure”.
and salbutamol are only partial agonists at ␤ -
In detailed analysis of the 1022 deaths occurring over 1
adrenoceptors.8 When fenoterol and salbutamol were
year in the salmeterol group,4 only 73 deaths, or 7%, were
given by metred-dose inhaler in increasing doses to
judged to be due to asthma, and in these cases, severity of
healthy individuals, the increases in heart rate and the
disease and advanced age were held responsible. 12
QT interval and decreases in QS I (inotropic effect) and
asthmatic deaths occurred in the bambuterol cohort,
K+ were more abrupt and pronounced for fenoterol, but
about half the proportion of those on salmeterol.
still significant for salbutamol. Reports of angina9 and
Concerns over accuracy of the death certificates
prevented detailed analysis, but cardiovascular deaths on
nebulised β agonists dictate that caution is exercised
bambuterol were “in the same positive direction” as the
when exposing elderly people to these agents.
In the failing heart, ␤ -adrenoceptors are evidently
down-regulated by norepinephrine, whereas activity of ␤ -
This PEM paper further establishes the safety of
adrenoceptors remains relatively unchanged and these
salmeterol, but it raises questions over the long-term
receptors assume increased importance in inotropic and
THE LANCET • Vol 352 • October 3, 1998
chronotropic stimulation.11 In six of 20 patients in
advanced congestive heart failure refractory to diureticsand vasodilators, oral salbutamol greatly increased brief
episodes of ventricular tachycardia during the first 36 h,
and a seventh patient developed atrial fibrillation. Inthose continuing on the drug for 4 weeks, the favourablehaemodynamic effects of salbutamol wereundiminished.12 Although these patients had advancedcongestive heart failure, they highlight the risk of
arrhythmias posed by oral, subcutaneous, or high-dose
inhaled ␤ -agonists in diseased hearts.
Although oral ␤ -agonists have their uses, the route of
The patient is moved slowly through the gantr y during continuous
choice is inhalation. Physicians should not abandon
rotation of the X-ray tube. The pitch is the longitudinal distance the patient travels per tube rotation divided by the chosen thickness. For
efforts to teach patients in the older age-groups to use a
a table movement of 10 mm/s, a tube rotation of 1/s, and a slice
metred-dose inhaler, with a chamber if needed. Failing
thickness of 10 mm, the pitch is 1·0.
this, every effort should be made to rule out cardiacdisease before prescribing an oral ␤ -agonist.
community in a developed country is natural and 15%man-made. Of the man-made sources, about 97% comes
from diagnostic radiology, chiefly CT.
54 PAA-KO Brive, Sandis Park, NM 87047, USA
Surveys of CT practice5–8 have consistently shown that
Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance
the radiation dose from certain CT examinations can be
study: comparison of salmeterol in asthmatic patients who require
regular bronchodilator treatment. BMJ 1993; 306: 1034–37.
examination is in the order of 10 mSv (2·3 mSv for a
Bunney R. Study too small to detect increase in deaths. BMJ 1993;
cranial examination). Such an exposure means that one
Martin MM, Dunn NR, Freemantle SN, Mann RD. Risk of non-fatal
abdominal CT examination carries about the same
cardiac failure and ischaemic heart disease with long acting ␤2
radiation risk as 500 chest radiographs and a background
agonists. Thorax 1998; 53: 558–62.
equivalent radiation time (BERT) of 4·5 years. Relation of
Mann RD, Kubota K, Pearce G, Wilton L. Salmeterol: a study by
the dose to the risk of subsequent cancer is much more
presentation-event monitoring in a UK cohort of 15 407 patients. J Clin Epidemiol 1996; 49: 247–50.
controversial and involves an estimation of stochastic risks.
Sitar DS. Clinical pharmacokinetics of bambuterol. Clin Pharmacokinet
On the assumption that the best estimate of risk of fatal
1996; 314: 246–56.
cancer to the whole population is 5% per Sv,9 an effective
Wilson SR, Amarosa P, Moxham J, Ponte J. Modification of the
dose of 10 mSv corresponds to an excess risk of fatal
thermal effect of acutely inhaled salbutamol by chronic inhalation in normal subjects. Thorax 1993; 48: 886–89.
cancer of 1 in 2000. This risk sounds high until put into
Sackner MA, Dougherty R, Watson H, Wanner A. Hemodynamic
the perspective of the inherent risk of cancer that
effects of epinephrine and terbutaline in normal men. Chest 1975; 68:
everybody carries (approaching 1 in 3). Nevertheless, it
calls for frugal use of CT and adherence to national
Jenne J W. Bronchodilators. In: O’Byrne O, Thomas NC, eds. Manualof asthma management. London: Saunders, 1996: 291–340.
radiological guidelines,10 and avoidance of repeated CT
Higgens RM, Cookson WOCM, Lane DJ, John SM, McCarthy GL,
studies for benign disease in the young patients. Note that,
McCarthy ST. Cardiac arrhythmias caused by nebulised beta-agonist
unlike some high-dose procedures (eg, interventional
therapy. Lancet 1987; ii: 863–64.
radiology11), CT is unlikely to have deterministic effects
10 Kinney EL, Trautlein JJ, Harbaugh CV, Lambert D, Zelib RF.
Ventricular tachycardia after terbutaline. JAMA 1978; 240: 2247.
(ie, those certain to occur when the dose is high enough),
11 Bristow MR, Ginsburg R, Umans V, et al. ␤ - and ␤ -adrenergic-
because rotation of the source spreads out the entrance
receptor subpopulations in non-failing and failing human ventricular
myocardium: coupling of both receptors subtypes to musclecontractions and selective ␤1-receptor down-regulation in heart
Why is the radiation dose from CT so high? And what
failure. Circ Res 1986; 59: 297–309.
steps are being taken to reduce it? The CT image is
12 Mettauer B, Rouleau J-L, Burgess JH. Detrimental arrhythmogenic
constructed from many projections, and at each angle the
and sustained beneficial hemodynamic effects or oral salbutamol in
detector must receive sufficient X-ray photons, so CT
patients with chronic congestive heart failure. Am Heart J 1985: 109: 840–46.
inevitably imparts higher doses than does conventionalradiography because exposure times are longer. Improvement in sensitivity of detectors, anode rating
(allowing shorter data acquisitions), and beam filtration
have helped to reduce dose. A recent innovation is
Even though radiology is a continuously evolving specialty,
modulation of the tube current to the patient’s geometry
few people could have predicted the massive resurgence of
and absorption during data acquisition so that no part of
interest in computed tomography (CT) generated by
the patient receives more radiation than absolutely
spiral technology.1 The advances in magnetic resonance
necessary to produce a satisfactory image.12 Also, there are
imaging were made with reduction in radiation risk. But
now well-established procedures for checking that CT
the past decade has seen a plethora of publications
extolling yet further applications of CT. Importantly, many
So why is there continuing concern over doses from
of these relate to mainstream medical (eg, pulmonary
CT? All multicentre surveys to date have shown large
embolus2) and surgical emergencies (eg, renal colic,3
variations in dose for essentially the same examination.6–8
appendicitis4). Thus, demand for spiral CT of the chest
Differences in equipment design account for up to three-
and abdomen for inpatients continues to rise. But few
fold variation in dose, but an eight-fold variation in dose
clinicians realise that CT is responsible for a substantial
has been found for a paediatric abdominal CT protocol
and increasing proportion of all man-made radiation. In
between different centres, and a 14-fold variation was
rough terms, about 85% of the radiation burden to the
found in a survey in East Anglia,7 which covered 12 CT
THE LANCET • Vol 352 • October 3, 1998
systems in 11 hospitals and 11 different examinations. The
Wade JP, Weyman JC, Goldstone KE. CT standard protocols are of
tube current (mAs) and total number of CT slices are
limited value in assessing actual patient dose. Br J Radiol 1997; 70: 1146–51.
critical variables. In the abdomen little can be done about
Scheck RJ, Coppenrath EM, Kellner MW, et al. Radiation dose and
mAs (unlike in the chest where perfectly satisfactory
image quality in spiral computed tomography: multicentre evaluation at
images can be obtained with a low-dose technique14). The
six institutions. Br J Radiol 1998; 71: 734–44.
ICRP Publication 60. 1990 recommendations of the International
number of slices is determined by the radiologist.
Commission on Radiological Protection. Annals of the ICRP 1991; 21
Radiological Protection Board15 has published reference
10 Royal College of Radiologists. Making the best use of a department of
dose levels for all X-ray examinations.
clinical radiology: guidelines for doctors, 4th edn. London: RoyalCollege of Radiologists, 1998.
reccomendations are based on data collected in the late
11 Wagner LK, Eifel PJ, Geise RA. Potential biological effects following
1980s, and it is reassuring to note that, in recent UK
high X-ray dose intervational procedures. J Vasc Interven Radiol
surveys of CT practice, mean doses are lower than
1994; 5: 71–84.
previously estimated and few examinations exceed the
12 Kalender WA, Wolf H, Suess C, Geis M, Hentschel D, Bautz WA. Dose
reduction in CT by anatomically adapted tube current modulation:
reference dose.7 It is also reassuring that a standard spiral
experimental results and first patient studies. Radiology 1997; 205P:
CT examination (eg, 10 mm thick slices at a pitch of 1·0,
see figure) gives the same radiation dose as does the
13 IPEM Report No 77. Recommended standards for the routine
performance testing of diagnostic X-ray imaging systems.York: Institute
conventional CT examination of old (contiguous 10 mm
of Physics & Engineering in Medicine, 1997.
thick slices) for the same body length covered. Indeed
14 Mayo JR, Hartman TE, Lee KS, et al. CT of the chest: minimal tube
many CT units now routinely use a pitch of 1·5 rather
current required for good image quality with the least radiation dose.
than 1·0 (with very little trade-off in image quality),
Am J Roentgenol 1995; 164: 603–07.
15 National Radiological Protection Board. Medical exposure. Guidance
which gives a theoretical dose reduction for spiral CT.
on the 1990 recommendations of the ICRP. Documents of the NRPB
However, spiral CT has opened up many new diagnostic
1993; 4: 43–74. Didcot: NRPB, 1993.
areas, some of which involve a higher radiation burden.
16 Oliver JH, Baron RL. Helical biphasic contrast-enhanced CT of the
liver: technique, indications, interpretation and pitfalls. Radiology 1996;
For example, an enhanced examination of the liver in the
arterial and portal phases16 may involve several passes of
17 Bearcroft PWP. The use of spiral computed tomography in
musculoskeletal radiology of the lower limb: the calcaneus as an
orthopaedic and vascular applications17,18 employ a narrow
example. Eur J Radiol 1998; 28: 30–38.
18 Rankin SC. Spiral CT: vascular applications. Eur J Radiol 1998; 28:
pitch with narrow collimation, again increasing the
radiation burden. Above all, it is increasing clinical use of
19 EU Council Directive 97/43 Euratom of 31 June 1997 on health
CT that is increasing the collective dose to the population.
protection of individuals against the dangers of ionising radiation in
Thus, the following are some questions that a clinician
relation to medical exposures (repealing Directive 84/466 Euratom). Official J Eur Communities 1997; 180: 22.
(and even a well-informed patient) might ask before a CTexamination:
● Can the diagnostic information be obtained by other
radiological means at a lower radiation dose? Answer,see Radiological Guidelines.10
There is plenty of evidence that breastfeeding is beneficial,
● Is the CT machine operating satisfactorily? See reports
and the practice has been encouraged by many health-
promoting organisations.1,2 For the mother, the benefits
● Are the protocols optimum? See audit compared with
include lower rates of breast and ovarian cancers. For the
child, they include lower rates of diarrhoea, otitis media,
All these factors will assume even greater importance in
and lower-respiratory and other infections (which mean
the light of impending UK legislation based on a recently
that parents need take less time off work to meet their
revised European Union directive on protection of the
patient.19 Nevertheless, the over-riding fact is that a skilled
mothers, especially after an initial learning period, enjoy
CT team can provide unique diagnostic information of
considerable help to both the referring clinician and the
Despite these benefits, there is a cost: breastfeeding
requires mothers’ time, a point that has added fuel to theperennial debate on maternal employment. A recent study
of middle-class mothers by S B Fein and B Roe3 has shown
*Departments of Radiology and Medical Physics, Addenbrooke’s Hospital
that, among mothers employed part-time at 3 months after
and the University of Cambridge, Cambridge CB2 2QQ, UK
birth, duration of breastfeeding was only marginally shorterthan that for non-employed mothers, but that it was
Kalender WA, Seissler W, Kltoz E, Vock P. Spiral volumetric CT withsingle-breath-hold technique, continuous transport and continuous
reduced more substantially among those employed full
scanner rotation. Radiology 1990; 176: 181–83.
time. Non-employed mothers breastfed an average of 25·1
Cross JJL, Kemp PM, Walsh CG, Flower CDR, Dixon AK. A
weeks, those employed 1–19 h per week breastfed for 24·4
randomised trial of spiral CT and ventilation perfusion scintigraphy for
weeks, and those working 20–34 h breastfed for 22·5 weeks
the diagnosis of pulmonary embolism. Clin Radiol 1998; 53: 177–82.
Smith RC, Rosenfield AT, Choe KA, et al. Acute flank pain:
(p>0·05 for differences). Those working more than 34 h
comparison of non-contrast-enhanced CT and intravenous urography.
per week breastfed for shorter durations than did those not
Radiology 1995; 194: 789–94.
employed or those employed part-time (p<0·05), but still
Rao PM, Rhea JT, Novelline RA, et al. Helical CT technique for the
for an average of 16·5 weeks. From these data, the
diagnosis of appendicitis: prospective evaluation of a focused appendix CT examination. Radiology 1997; 202: 139–44.
investigators’ single major conclusion was that “part-time
Shrimpton PC, Jones DG, Hillier MC, Wall BF, Letteron JC,
work is an effective strategy to help mothers combine
Faulkner K. Survey of CT practice in the UK, part 2: dosimetric
aspects. Chilton: NRPB-R249. London: H M Stationery Office, 1991.
This is one reasonable conclusion. Young children need
Shrimpton PC, Wall BF. The increasing importance of X-ray computed
consistent, loving, and abundant attention, and frequent
tomography as a source of medical exposure. Radiation Protection Dosimetry 1995; 57: 413–15.
feedings, and mothers are biologically well suited for and
THE LANCET • Vol 352 • October 3, 1998
American Academy of Pediatrics Work Group on Breastfeeding.
usually interested in these tasks. Despite this, in the USA
Breastfeeding and the use of human milk. Pediatrics 1997; 100: 1035–39.
where the study was conducted, and where society is said
Fein SB, Roe B. The effect of work status on initiation and duration of
to promote “family values”, there are many family-hostile
breast-feeding. Am J Public Health 1998; 88: 1042–46.
components. In Norway, mothers may receive 100% pay
Scariti PD, Grummer-Strawn LM, Fein SB. A longitudinal analysis ofinfant morbidity and the extent of breastfeeding in the United States.
for 42 weeks’ maternity leave, or 80% pay for 52 weeks, an
Pediatrics 1997; 99: e5.
arrangement highly conducive to healthy child
Spangler A. Breastfeeding: a parent’s guide. Atlanta: Amy Spangler
development. By contrast, the law in the USA stipulates
only 12 weeks of unpaid leave. Thus Fein and Roe’sfindings suggest that employers and families should
consider whether mothers would gain from returning towork only part-time.
There are, however, at least four other possible
The hypothesis that genes affect the timing of the end of
conclusions from these data. First, all of the mothers in the
reproductive life has been around a long time. There is a
study, irrespective of employment status, breastfed for an
strong evolutionary rationale to ideas about the reason for
average of substantially less than a year, the minimum
the length of human female reproductive life (and also the
recommended by the American Academy of Pediatrics.2
reason why the postmenopausal phase in women is longer
This finding suggests that, apart from employment, there
than that of females of other species). The end of
are social, pragmatic, or other factors that discourage
reproductive life is of considerable interest for diverse
reasons—not only because women may wish to postpone
Second, breastfeeding, particularly after establishment of
lactation in the first few months, need not include daytime
demographers, and biometricians have an interest in
feedings (although the benefits of breastfeeding are dose
describing and predicting fertility trends. Obstetricians,
related4). Mothers can enjoy years of early morning and
gynaecologists, endocrinologists, and associated scientists
evening breastfeeding, without daytime pumping or
are interested in furthering options for individual and
breastfeeding. Availability of suitable written information5
general fertility. Epidemiologists and statisticians look for
or of lactation consultants may help parents become aware
predictors of fertility, and for factors that reduce fertility.
Genetic epidemiologists can enhance the value of
Third, employers can set up potentially mutually
epidemiological research by incorporating information
about genetic differences in risk into accurate statistical
breastfeeding or breast-pumping breaks and on-site day
prediction of the time of menopause.
care, or by the introduction of telecommuting. Fein and
The paper by Harold Snieder and colleagues from the
Roe are now examining data to evaluate the effectiveness of
Twin Research Unit at St Thomas’ Hospital, London, is
the first to identify a substantial proportion of variance of
Finally, although the benefits of breastfeeding are clear,
age at natural menopause attributable to genetic
what are the maternal and other costs? As mentioned
influences.1 The investigators used twin data to assess thereasons for individual differences in age at natural
above, enlightened employer practices can reduce conflicts
menopause, in history of hysterectomy, and in two
between full-time maternal employment and day-time
particular indications for this operation (namely, uterine
lactation. However, to some mothers the cost to their
fibroids and menorrhagia). They were also able to assess
career of daytime breastfeeding or pumping is still too high,
the phenotypic relation between age at menarche and age
especially in the first few months after the immediate
at menopause, and they found no significant correlation.
postpartum period (when the benefits to the baby are
The samples of twins used for their analyses were subsets
highest)—overnight travel is difficult; colleagues’ regard
of 275 monozygotic and 353 dizygotic twin pairs
may diminish when they hear of (or hear) the pumping;
identified through a media campaign in the UK. Snieder
and the mother may be embarrassed by milk letdown that
and colleagues reported substantial heritabilities for age
is copious and uncontrollable. Although some mothers are
at menopause, having had a hysterectomy, and age at
reluctant to abandon the benefits and joys of breastfeeding,
other mothers may decide that despite the benefits babies
The classic twin study provides the ideal natural
obtain from mother’s milk, the resentment the mothers
experimental situation for assessment of genetic
might feel (especially for extended breastfeeding) offsets
influences on human traits,2 although large numbers of
the benefits. Women have little choice but to endure the
twin pairs are needed for such studies,3 especially for
physiological and professional compromises of pregnancy,
those in which data are subject to censoring, as is the case
and may wish to reclaim their bodies and professional
with the menopause. Results from other twin studies will
stature soon after the birth of the baby.
shortly follow. Volunteer twin registries such as the St
Breastfeeding and employment are both worthwhile, and
Thomas’ UK adult twin register and that in Australia
both deserve familial, professional, and societal support.
(panel) provide an invaluable resource for genetic
Women in this time of substantial life-change should
receive such support, irrespective of variability in decisions
Snieder and colleagues themselves point out,
about how and whether to combine these two valuable
substantial in terms of primary prevention of and early
intervention for diseases related to decreased oestrogen
concentrations. Risk of such diseases escalates after the
Department of Family and Preventive Medicine, Emory University School of
menopause. Although difficulty in measuring similarity of
twins’ lifelong environments has to be acknowledged, theonset of menopause (or more accurately the permanent
Healthy People 2000: National Health Promotion and Disease
cessation of menses) generally in mid-life offers greater
Prevention Objectives. US DHSS oublication no. (PHS) 91-50212. Washington, DC: Government Printing Office, 1990: 379–80.
opportunity for genetic and environmental factors (even
THE LANCET • Vol 352 • October 3, 1998
Twin-pair correlations for age at menopause and related conditions
*Intraclass correlations for UK data, polychoric correlations for Australia data except for age at menarche, age at menopause (Pearson product-momentcorrelations). †Estimate of heritability. ‡Unpublished data
age itself) to influence the menopause than a disease or
may not equate with hormonal menopause) as
physiological state occurring early in life.
components of the same phenomenon. Viewing them in
Views of the advantages or otherwise of reproductive
this way may obscure their apparently different causal,
senescence differ. Many researchers have sought to
probably genetic, mechanisms. The same can be said for
explain the end of female reproductive potential on the
age at menopause and age at menarche.
basis of depletion of ovarian follicles.4–6 However, ovarian
Finally, studies by all methods have concluded that age
follicles can be depleted by numerous causes, the most
at menopause is closer between monozygotic twins than
drastic being surgical removal. There is evidence that the
between dizygotic twins, even after adjustment for
final “unnatural” curtain on reproductive potential,
confounders that are correlated within families and
drawn by surgical intervention in the form of
twinships. Statistical research in this area is both
hysterectomy, is also influenced by genes. Snieder and
theoretically complicated and computationally intensive.
colleagues’ findings confirm our report7 that genetic
One way to address the problem of treating covariates as
influences were operating on liability to hysterectomy.
fixed effects is to develop multivariate Markov Chain
Evidence for this process was the much higher
Monte Carlo methods that can incorporate a mixture of
concordance between monozygotic twin sisters than
censored and non-censored observations.
between dizygotic twin sisters for hysterectomy (panel).
Traditional biological limitations on fertility, such as
Why should there be such concordance for a surgical
the menopause, may well become increasingly irrelevant
procedure? Snieder and colleagues highlighted uterine
with new reproductive techniques and with the increasing
fibroids and menorrhagia as two of the key reasons for
widespread use of hormone-replacement therapies.
hysterectomy, and showed substantial genetic influences
Nevertheless, investigation of this important human
on these disorders. Strong genetic influences on uterine
milestone has important implications for the prevalence
fibroids as a reason for hysterectomy have been found, as
of cardiovascular and other diseases such as osteoporosis.
have such influences on endometriosis (panel). Genetic
Delaying the menopause to postpone these disorders has
covariation requires further exploration. Estimation of
a more immediate impact than has talk of any future
genetic correlations between age at natural menopause
advantage, related to “grandmothering”, of a longer
and postmenopausal cardiovascular disease, osteoporosis,
postmenopausal life. Hence opportunities for collecting
and reproductive cancers is currently possible only when
sound uncontam-inated data on the menopause are
sufficiently large numbers of elderly female twins
*Susan A Treloar, Kim-Anh Do, Nicholas G Martin
Assessment of the menopause prospectively is the ideal,
*Cooperative Research Centre for Discover y of Genes for Common
albeit chronologically convoluted, approach. It is also
Human Diseases, Queensland Institute of Medical Research, PO Royal
logistically difficult because only after an interval of 12
Brisbane Hospital, Queensland 4029, Australia
months can a woman vouch that a menstrual period wasindeed the last, and because women then may no longer
Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of
see the importance of participating in research on the
a woman’s reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 1998; 83: 1875–80.
menopause.8 In addition, validation and differential
Neale M, Cardon L. Methodology for genetic studies of twins and
diagnosis of vaginal bleeding is a difficulty, since vaginal
families. NATO ASI Series. Dordrecht: Kluwer Academic Publishers,
bleeding may be non-menopausal. To maintain samples of
potential study participants prospectively in sufficiently
Martin N, Eaves L, Kearsey M, Davies P. The power of the classical twin study. Heredity 1978; 40: 97–116.
large numbers to provide adequate power is impossible,
Gosden RG. Follicular status at the menopause. Human Reprod 1987;
so researchers commonly have to be satisfied with
Martin N, Healey S, Pangan T, Heath A, Turner G. Do mothers of
The timing of onset of reproductive potential (age at
dizygotic twins have earlier menopause? A role for fragile X? Am J Med Genet 1997; 69: 114–16.
menarche) has been found to be under genetic influence
Faddy MJ, Gosden RG. A model conforming the decline in follicle
resembling dominance or epistasis (non-allelic
numbers to the age of menopause in women. Hum Reprod 1996; 11:
interaction),9 both of which give rise to non-additive
effects. Snieder and colleagues found a similar genetic
Treloar S, Martin N, Dennerstein L, Raphael B, Heath A. Pathways tohysterectomy: insights from longitudinal twin research. Am J Obstet
influence in their data, which also raises questions of
Gynecol 1992; 167: 82–88.
fitness and selection, because traits that exhibit a large
Treloar AE, Boynton RE, Behn BG. Variation of the human
degree of genetic “non-additivity” have repeatedly been
menstrual cycle through reproductive life. Int J Fertil 1967; 12:
shown to have been subject to intense natural selection
Treloar S, Martin NG. Age at menarche as a fitness trait: non additive
during evolutionary time. The temptation may be to view
genetic variance detected in a large twin sample. Am J Hum Genet
age at natural menopause and age at hysterectomy (which
1990; 47: 137–48.
THE LANCET • Vol 352 • October 3, 1998
be viewed as merely a baseline. The statistical power was
inadequate for the detection of differences in disease
progression afforded by the various medicines used to
The development of potent medicines for the treatment
of rheumatoid arthritis (RA) has made effective
multidisciplinary therapeutic approaches to RA have
palliation of pain and reduction of disease activity
changed, the impact of the newer treatments has not yet
possible for many patients. In addition, the overall
severity of the disease seems to be decreasing,1 possibly
anaesthetic techniques, as well as in the durability and
because of modern multidisciplinary therapy. Neverthe-
functional properties of prostheses, have altered both the
less, a report by F Wolfe and S H Zwillich2 provides a
risks and the benefits of arthroplasty and have probably
timely reminder that RA is still a devastating disease and
affected the overall arthroplasty rate, thereby influencing
that progressive destruction continues despite aggressive
the surrogate marker without necessarily reflecting
treatment by experienced rheumatologists.
The modern history of RA care has been punctuated
The important perspective reinforced by reports such
by the discovery and widespread adoption of treatments
as Wolfe and Zwillich’s is that the natural history of RA
that yield striking results both in short-term studies and
spans decades; short-term palliation of inflammatory
in early clinical experience, but which are disappointing
flares is important and helpful, but ultimately, decisions
in the long-term maintenance of joint function. This
must be based on long-term prospects. Although the
history began with the early use of glucocorticoids,
pace of joint destruction is most rapid in the first years
which were initially thought to be potentially curative.
of the disease,3,6 lengthy RA remissions are rare,7 and the
Only with time did their therapeutic limitations and
actuarial survival among RA patients remains
adverse metabolic effects become apparent.
substantially poorer than normal.3 The data presented by
dissonance between the encouraging early results and the
Wolfe and Zwillich are valuable not because they
poor long-term efficacy of RA treatment is due, in part,
contribute to the assessment of prognosis for individual
to the methods of trials in RA. Virtually every controlled
patients, but because they present a unique perspective
study of RA treatment has been limited to less than 24
on the natural history of well-treated RA at the end of
months,3 clearly insufficient for a chronic disease. Wolfe
the 20th century. Documenting true alterations in the
and Zwillich have added to the understanding of RA by
natural history of RA may take decades, and it will be
exploring the natural history of treated RA in a
years before any of the newer agents can be said to be
longitudinal study encompassing nearly 25 years and by
“disease modifying”. Meanwhile, Wolfe and Zwillich
taking joint replacement as a marker of poor outcome.
have laid a foundation that will permit a comparison of
Their finding of an overall 25% risk of arthroplasty by 22
current treatment with a well-described historical
years after onset of RA in a homogeneous midwestern
US population of patients is similar to the 20% rate of
large-joint arthroplasty reported for a population of
Section of Rheumatology, Rush-Presbyterian-St Luke’s Medical Center,
Finnish RA patients.4 These findings indicate that,
although early control of inflammation is important for
Abdel-Nasser AM, Rasker JJ, Valkenburg HA. Epidemiological and
clinical aspects relating to the variability of rheumatoid arthritis. Semin Arthritis Rheum 1997; 27: 123–40.
The absence of universally effective therapy for
Wolfe F, Zwillich SH. The long-term outcomes of rheumatoidarthritis: a 23-year prospective, longitudinal study of total joint
inducing remission in RA has fostered an intensive
replacement and its predictors in 1600 patients with rheumatoid
search for risk factors to permit early identification of
arthritis. Arthritis Rheum 1998; 41: 1072–82.
patients whose poor prognosis would justify an
Pincus T. Long-term outcomes in rheumatoid arthritis. Br J
aggressive approach to treatment. Several factors, such as
Rheumatol 1995; 34 (suppl 2): 59–73.
Hakala M, Nieminen P, Kovisto O. More evidence from a community
poor functional indices, high numbers of affected joints,
based series of better outcome in rheumatoid arthritis: data on the
and inflammatory markers, are associated with poorer
effect of multidisciplinary care on the retention of functional ability.
outcomes in RA.3,5,6 Wolfe and Zwillich’s study also
J Rheumatol 1994; 21: 1432–37.
showed that likelihood of arthroplasty, their surrogate
Van der Heijde DMFM, van Riel PLCM, van Rijswijk MH, van dePutte LBA. Influence of prognostic features on the final outcome in
marker of joint failure, was related largely to disease
rheumatoid arthritis: a review of the literature. Semin Arthritis Rheum
1988; 17: 284–92.
arthroplasty were at high risk of repeat surgery. Anaemia,
Sherrer YS, Bloch DA, Mitchell DM,Young DY, Fries JF. Thedevelopment of disability in rheumatoid arthritis. Arthritis Rheum
leucocyte count, and absence of smoking history were
1986; 29: 494–500.
also identified as somewhat unexpected risk factors.2
Wolfe F, Hawley DJ. Remission in rheumatoid arthritis. J Rheumatol
Although none of the findings was completely
1985; 12: 254–52.
surprising, and despite the lack of prognostic powerapplicable to individual patients, Wolfe and Zwillich have
provided a unique glimpse of the natural history oftreated RA in a closely monitored group of patients.
This week The Lancet pauses briefly to reflect on 175
They were able to do so because of their extensive
years of continuous publication. We are holding a small
database and careful follow-up of a large clinical
party in the journal and publishing an accompanying
population of RA patients referred to their specialty
supplement to signal the occasion. You are invited to join
clinic over the past quarter century; this database alone is
us. Guests are always welcome. We hope that you (and
a rare resource, especially in the USA, where geographic
we) will be around to participate in the journal’s 200th
mobility and medical insurance exigencies typically result
in a rapid loss of continuity of care.
The results generated by this analysis, however, must
THE LANCET • Vol 352 • October 3, 1998
MSE Policy Review in Nepal: Current Reform Process in Government Prof. Dinesh P. Chapagain 1. Conceptualization: MSE Value Chain for Development Poverty reduction has been the foremost development objective of Nepal since it embarked on planned development efforts almost half a century ago. Given the country’s geo-political condition and small economic scale, the micro a
DELHI ELECTRICITY REGULATORY COMMISSION Viniyamak Bhawan, „C‟ Block, Shivalik, Malviya Nagar, New Delhi – 110 017 Ref. F.11(598)/DERC/2010-11/C.F.No. 2581/6436 Petition No. 75/2010 In the matter of: Complaint under Section 142 of the Electricity Act, 2003. In the matter of : Ms. Gargi Mukherjee B-2/2312, Vasant Kunj, New Delhi-110 070 BSES Rajdhani Power Ltd. Through