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mentioned previous failures to recover P cepacia from extensive surveillance cultures of respiratory equipment and environmental surfaces, and the researchers concluded that direct person-to-person transmission of the organism might be the primary means by which transmission occurs. A subsequent prospective study14 with reliable selective media and typing systems showed that colonised patients can their contaminate environment-ie, indirect transmission might occur via contaminated surfaces. Although there is no scientific evidence to confirm that skin contact, respiratory aerosols, sharing food, kissing, or other forms of intimacy increase the risk of acquiring P cepacia, doctors who care for CF patients have come round to the view that kissing and having a colonised sibling probably present special risks. There are calls for policies to reduce the risk of acquisition of P cepacia and to reassure non-colonised patients. Segregation of colonised from non-colonised patients effectively creates "microbiological outcasts". The social effects of segregation on older patients are devastating since their lives often revolve around CF contacts. Meanwhile, non-colonised patients become increasingly anxious about "getting cepacia". Finally, segregation imposes a considerable burden on medical staff in large clinics and needs to be accompanied by advice that social contacts should also be restricted.’s Attitudes to P cepacia are evolving rapidly and it is difficult to give firm guidance about the risks and consequences of colonisation. However, several centres in Europe and North America segregate colonised from non-colonised patients, and a British CF association has produced interim guidelines to reduce the risk of cross-infection.16 An indication of the impact of these recommendations can be appreciated from this section alone: "P cepacia colonised CF individuals should avoid kissing and intimacy with non-colonised CF individuals. They should also refrain from sleeping, exercising or performing physiotherapy in the same room as non-colonised CF individuals. Contact between colonised CF individuals and CF children should be avoided. On current evidence, colonised CF individuals should probably not attend CF conference/holiday camps." For patients and all concerned in their care, the stigma and problems of P cepacia colonisation are very hard to accept. Nevertheless, the risks cannot be ignored. A, Macluskey I, Corey M, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104: 206-10. 2. Thomassen MJ, Demko CA, Klinger JD, Stern RC. Pseudomonas cepacia colonization among patients with cystic fibrosis: a new opportunist. Am Rev Respir Dis 1985; 131: 791-96. 3. Simmonds EJ, Conway SP, Ghoneim ATM, Ross H, Littlewood JM. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom. Arch Dis Child 1990; 1. Isles

65: 874-77. 4. Gladman G, Connor PJ, Williams RF, David TJ. Controlled study of Pseudomonas cepacia and Pseudomonas maltophilia in cystic fibrosis. Arch Dis Child 1992; 67: 192-95. 5. Govan JRW, Glass S. The microbiology and therapy of cystic fibrosis lung infections. Rev Med Microbiol 1990; 11: 19-28.

Sajjan US, Corey M, Karmali MA, Forstner JF. Binding of Pseudomonas cepacia to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis. J Clin Invest 1992; 89: 648-56. 7. Glass S, Govan JRW. Psendomonas cepacia: fatal pulmonary infection in a patient with cystic fibrosis. J Infect 1986; 13: 157-58. 8. Aoki M, Uehara K, Koseki K, et al. An antimicrobial substance produced by Pseudomonas cepacia B5 against the bacterial wilt disease pathogen Pseudomonas solanacearum. Agric Biol Chem 1991; 55: 715-22. 9. Holmes B. The identification of Pseudomonas cepacia and its occurrence in clinical material. J Appl Bact 1986; 61: 299-314. 10. Sokol PA, Lewis CJ, Dennis JJ. Isolation of a novel siderophore from Pseudomonas cepacia. J Med Microbiol 1992; 35: 184-89. 11. Aronoff SC, Lewis FJ, Stern RC. Longitudinal serum IgG response to Pseudomonas cepacia surface antigens in cystic fibrosis. Pediatr 6.

Pulmonol 1991; 11: 289-93. 12. Tablan OC, Martone WJ, Doershuk CF, et al. Colonization of the respiratory tract with Pseudomonas cepacia in cystic fibrosis: risk factors and outcomes. Chest 1987; 91: 527-32. 13. LiPuma JJ, Dasen SE, Nielson DW, Stern RC, Stull TL. Person-toperson transmission of P cepacia between patients with cystic fibrosis. Lancet 1990; 336: 1094-96. 14. Nelson JW, Doherty CJ, Brown PH, et al. Pseudomonas cepacia in inpatients with cystic fibrosis. Lancet 1991; 338: 1525. 15. Smith DL, Smith EG, Gumery LB, Stableforth DE. Pseudomonas cepacia infection in cystic fibrosis. Lancet 1992; 339: 252. 16. Newsletter of the Association of Cystic Fibrosis Adults (UK). April, 1992, no 30, p 2.

Heart disease: in the

beginning

Norway in the 1970s, Forsdhal was puzzled by the geographical distribution of cardiovascular mortality. Why were there substantial regional differences when the standard and mode of living was reasonably uniform throughout the country? Could these differences be related, he wondered, not to present circumstances but to poverty or deprivation in early life? More recently, Rose has pointed out that In

well-established risk factors for coronary heart

disease--cigarette smoking, high

serum

cholesterol,

and high blood pressure-have very limited ability to predict disease in adults.2 Could childhood influences explain this gap in our understanding of aetiology? Epidemiologists, notably Barker and colleagues in the UK Medical Research Council Environmental Epidemiology Unit at Southampton University, have taken up the challenge by exploring Forsdahl’s hypothesis on childhood deprivation.3 In a series of studies based mainly on national statistics in the UK, the USA, and Norway, adult cardiovascular mortality rates were shown to correlate with indicators of childhood deprivation in earlier years-ie, with infant mortality,4-7 and short adult and childhood height.8,9 There are also correlations with measures suggestive of intrauterine deprivation such as maternal and neonatal mortality.lO,l1 Not content with these statistical comparisons, Barker et al identified, by means of painstaking detective work, two populations that they were able to follow-up retrospectivelyP,13 In 5654 men born in Hertfordshire between 1911 and 1932, they found that the death rate from ischaemic heart disease was related inversely to weight at one year and was higher in men who had weighed less than 5-5 lb (2-5 kg) at birth.12 Furthermore, indicators of early deprivation were associated in the same cohort with cardiovascular risk factors in adult life-blood pressure, plasma

1387

fibrinogen, glucose intolerance, and serum cholesterol and apolipoprotein B concentrations.3 In 449 men and born in Preston about 50 years ago, placental weight-a possible indicator of poor maternal nutrition-was found to be related to blood pressure in adults." These follow-up studies12,13 by the Southampton group have shown how investigative epidemiology can be made to work, by using different measures to tackle the hypothesis, by searching out old records, and by doggedly following up individuals. The investment appears to be paying off: hardly a month goes by without positive results being reported prominently in the general medical press. Behind the scenes, however, a different perspective is being portrayed in specialist epidemiological journals. Elford, Shaper, and Whincup from the Royal Free Hospital, London, have systematically reviewed papers in this area.14,15 They asked how well the associations satisfy certain criteria for causality-ie, strength of association, specificity only for the characteristics under investigation, graded doseresponse relation, consistency of findings between and within studies, and independence from confounding factors. The criteria were assessed separately for ecological studies,15 in which populations are compared between different geographical areas or time periods, and for analytical studies,14 in which individuals are compared in case-control or follow-up studies. Among the ecological studies there were strong dose-response relations between early life experience and adult disease, but overall in the follow-up studies these relations were not as strong nor were they consistent. In the Hertfordshire cohort, for example, the doseresponse relation between weight at one year of age and adult mortality was not observed for birthweight.12 In addition, Elford et al were worried by a lack of specificity-childhood experience has also been related to respiratory disease, cancer, and all-cause mortality. "Cardiovascular mortality appears to have been selected for special treatment in a somewhat arbitrary manner, without any explanation as to why other causes of death were so casually disregarded."ls A serious difficulty in interpreting associations between early life experience and adult disease is possible confounding by social and economic circumstances in later life. Williams et al4 noted that the geographical ranking of infant mortality in England and Wales has remained the same over time, an observation suggesting that associations between childhood and adult disease may have been influenced by persisting social conditions. After adjustment for current deprivation, the correlation between infant mortality and subsequent cardiovascular mortality fell dramatically (from r = 0.72 to r = 0- 19 in men).7 In the Hertfordshire cohort, however, the relations between fetal and infant growth and cardiovascular risk factors were present within each social class and, in the association with plasma fibrinogen, were independent of some important confounders such as cigarette women

smoking.33

Migrant studies provide an opportunity to take of confounding factors later in life, and also to examine the hypothesis that it is not simply childhood deprivation but deprivation followed by affluence that influences the risk of acquiring disease. In the British Regional Heart Study, conducted by the Royal Free group, men who lived in the relatively deprived north of England and Scotland, on moving to the south of England, showed lower rates of coronary artery disease than men who remained at their place of account

birth.16 This observation suggests that adult as well as childhood factors have an important effect on the risks of disease. Elford et al also point out that time trends militate against a causal relation between childhood deprivation and adult disease.14 A substantial decline in infant mortality between 1900 and 1930 has not led to a decreasing incidence of coronary artery disease among men and women born during that period. What can we conclude at this stage? There is no dispute that a relation does exist between childhood influences and adult cardiovascular disease, but the interpretation remains in doubt. Social and economic factors in adult life do not completely explain the association, and who knows what other confounding factors may be at work? Barker et al are pressing ahead with much-needed investigations of the precise nature and timing of early environmental influences (eg, maternal diet and infant feeding) that may affect the programming of metabolism.3 Sceptics would do well to produce more evidence disproving Forsdahl’s hypothesisAlthough early life experiences would be expected to have some biological influence on the risk of acquiring disease, the crucial question is one of degree; the answer will tell us whether we need to make big changes in public health policy and redirect our energy towards maternal and infant nutrition.

1. Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? Br J Prev Soc Med 1977; 31: 91-95. 2. Rose G. Sick individuals and sick populations. Int J Epidemiol 1985; 14: 32-38. 3. Barker DJP, Martyn CN. The maternal and fetal origins of cardiovascular disease. J Epidemiol Commun Health 1992; 46: 1-11. 4. Williams DRR, Roberts SJ, Davies TW. Deaths from ischaemic heart disease and infant mortality in England and Wales. J Epidemiol Commun Health 1979; 33: 199-202. 5. Buck C, Simpson H. Infant diarrhoea and subsequent mortality from heart disease and cancer. J Epidemiol Commun Health 1982; 36: 27-30. 6. Barker DJP, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; i: 1077-81. 7. Ben-Shlomo Y, Davey Smith G. Deprivation in infancy or in adult life: which is more important for mortality risk? Lancet 1991; 337: 530-34. 8. Barker DJP, Osmond C, Golding J. Height and mortality in the counties of England and Wales. Ann Hum Biol 1990; 17: 1-6. 9. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br Med J 1989; 298: 564-67. 10. Barker DJP, Osmond C. Death rates from stroke in England and Wales predicted from past maternal mortality. Br Med J 1987; 295: 83-86. 11. Barker DJP, Osmond C, Law C. The intra-uterine and early postnatal origins of cardiovascular disease and chronic bronchitis. J Epidemiol Commun Health 1989; 43: 237-40. 12. Barker DJP, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989; i: 577-80.

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13. Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. Br Med J 1990; 301: 259-62. 14. Elford J, Whincup P, Shaper AG. Early life experience and adult cardiovascular disease: longitudinal and case-control studies. Int J Epidemiol 1991; 20: 833-44. 15. Elford J, Shaper AG, Whincup P. Early life experience and

cardiac complications. In a review of 25 children with cardiotoxicity, those under the age of 10 years received a median total dose of 480 mg/m, whereas those over 10 years received a median dose of 810

cardiovascular disease—ecological studies. J Epidemiol Commun Health

only now that the long-term implications are being appreciated. In a prospective study of 201 children who had received 200-1725 mg/m2 (total dose) of anthracyclines, 46 (23%) had abnormal cardiac function on non-invasive testing at follow-up 4-20 years after treatment.12 The frequency and severity of abnormal myocardial function increased with length of follow-up. In this study, no patient evaluated 4-6 years after therapy had a fractional shortening (a measure of left ventricular dimensional shortening or contractility) of 20% or less, whereas after 10 years over 50% of patients had moderate or severe abnormalities (fractional shortening

Heart disease: in the beginning.

1386 mentioned previous failures to recover P cepacia from extensive surveillance cultures of respiratory equipment and environmental surfaces, and t...
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