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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 R Soc 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 306: 1610.
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:
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 201: 1–14.
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
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 2: 617–21.
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
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

Source: http://genepi.qimr.edu.au/contents/p/staff/CV218.pdf


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