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Editorials or research. Thirdly, despite scepticism about the origin of the increased incidence of childhood cancer, a prominent aim of research has been to seek charac- teristics, at molecular level, that might signal radiation as the cause of the cancer. So tar no such markers have been identified for any tumour. Such markers would have obvious benefits in helping to determine eligibil- ity for comi~ensation for radiation induced cancers, and this financially motivated aspect of the research has produced an unproductively competitive atmos- phere in some research circles. If the lessons of a disaster on the scale of Cherno- byl are to be learnt an international effort is essential. For the results to be meaningful independence from vested interests must be guaranteed; the compensation issue in America and for the nuclear industry is poten- tially so large that significant sums could be spent to frustrate legitimate research in the hope of avoiding much larger sums in compensation. How can these two objectives be met? After the atomic bombings in Japan a joint Japanese-American study was initiated and continues today as the Radiation Effects Research Foundation. It is the main source of knowledge about the effects of radiation on human health. The situation in Japan, involving only two principals, is simple in comparison with that in Ghernobyl, where three independent states are involved together with tens of international, national, and private agencies. Nevertheless, if the opportunities to learn from this disaster are not to be irretrievably lost some kind of initiative along the lines of the Japan-American foundation is required. Improved coordination has been universally advocated over the past five or six years, yet the position has not improved. Either no one organisation commands both the authority and the confidence of the other organisa- tions to allow it to coordinate effectively, or the partici- pating organisadons do not want m cooperate as their real aims differ from those they proclaim. The humanitarian a~pect to this problem should also not be forgotten. Whatever the decision about an international effort to learn about the course of the epidemic, speculative research to identify a marker of radiation causation will continue-because the rewards are so high. Tl'fis research impinges negatively on the lives of those exposed and is rumoured to have led to a market in turnout tissue. Bringing all research under a single coordinating body would additionally serve to minimise the impact on the affected populations. A significant proportion of the global population, particularly in western Europe and America, obtain electricity from nuclear sources. Had the Chernobyl accident occurred there and affected those populations, they would have ~pected to be compensated, either individually or on the basis of a national health care pro- gramme. Given the economic drcumstances in the former Soviet Union, those ~¢posed have little chance of compensation but would benefit from international help to obtain adequate treatment The global community needs to learn from their experience: those who benefit from the production of nuclear electricity should finance an independent international founda- tion to coordinate research and provide humanitarian Keith Baverstock Radiation~cientist WHO European Cenmg for Envirorunen~ and Hea/th, Rome, Italy Ka~akov VS, Demidchik EP, A~takhova I-N, Bav~t~k ~ Eg[off B, ~chem & et ~ ~)~id ~ ~ Ch~obvk Nat~e 1~59:21-2. B~ ~ R~ G, Shi~u L ~J~ Chfl~ ~id ~cer ~ ~,V~ [~2~59:680- I. ~n ~ Lub~ J, ~dder ,~ ~ffoid ~cer ~ddence..V~ure 1992~60:[ 13, Suj~ V~ Ts~ .~, Tmnko ND, Souch~tch G, Bavmt~k Chfl~ ~id ~c~ s~ce a~id~ at Chemobyl. 1995~ 10:801. j~ob P, Gou~o G, Heide~ei~ ~, L~*~" L e~ ~ ~*~id c~cer ~k to chg~n ~t~ ,Vatt~ 1998:392~ I-2. • Ron F, Lubin J~ Sho~ ~ M~uc~ su~ m ~t~ m~fion: a ~1~ ~Nvsi~ of s~'en sm~ R~icgion Re~t~h 1995; 14 l:259- Robin ~ ~men~ ~l~e of [s~I: ~e ~n rim. Health P~sics 1992:62:487-95. Nafio~ C~c~ [m~m[e. ~t~ted ~ A~wan p~ i~#w- 1 n~r ~ ~ B¢~ MD: Naflon~ ~*cer lmfimte. 1997. ~1~ ~L H~n ~o~ SO. Glat~ ~)~id ~cer in Noway: influ~ce ofhk~ coho~ ~d time p~o& IntJ C~w 1993:53:183-7. Inflammatory responses and coronary heart disease The "dirty chicken"hypothesis of cardiovascular risk factors The "dirty chicken" hypothesis was proposed by Solomons to explain why children reared in poverty, though appearing healthy and receiv- ing adequate nutrition, end up as short adults.~ Based on the observation that antibiotic supplementation reverses poor growth in chickens reared in over- crowded unhygienic conditions, he suggested that chronic subclinical infection induces a low grade svstemic inflammation and that this produces a qualitatively similar effect to full blown acute inflammation--that is, chronic anorexia and increased basal metabolic rate, with cvtokines being the mediators. What does r_his have to do Mth humans reared in.relatively overcrowded unhygienic conditions and cardiovascular disease? There is an increasing interest in the relation between chronic low grade systemic inflammation, as indicated by serum levels of C reactive protein, and mortality from coronary, heart disease.~ There has, however, been little knowledge of the determinants of this response and ir~ importance in the pathogenesis of atherosclerosis. Chronic subclinical infection with Chla~ny'dia pneumoniae, Heticobacter pylori, chronic bron- chitis, and chronic dental sepsis have been associated with raised values of C reactive protein within the nor- real range~ and have been implicated as risk thctors tbr BM'J VOLL'ME316 28M.-kRCH 1998

Editorials coronary heart disease. Non-infective conventional environmental risk factors also associated with low grade acute phase responses include age, low adult social class, smoking, obesit); and childhood social class (a possible mechanism for the association of short stat- ure and corona_r)" heart disease)? If the dirty chicken hypothesis is true--that is, that qualitatively similar effects are observed during chronic low grade systemic inflammation (occurring in all of us) as in severe acute inflammation--many biological risk factors should be associated with raised serum G reactive protein values in normal subjects. This is indeed the case: raised serum C reactive protein values are associated with raised serum fibrinogen, plasmino- gen, factor VIII, white blood cell count, fasting insulin, and serum trigiyceride values: depressed high density lipoprotein-cholesterol; and raised fasting blood sugar concentrations? 4 (The latter cast light on the pathd- genesis of non-insulin dependent diabetes.) These assodations are not diminished by controlling for body mass index. A common underl,ving mechanism such as inflammation may explain why different types of cardiovascular risk factors cluster in the same .subject-- for example, in syndrome X. It might also explain why many environmental cardiovascular risk fac, tors pro- duce changes in several different biological risk factors--for example, smoking or obesity. Nevertheless, atherosderosis is dearly a multifactorial condition, since not all contributory factors show a dear relation to inflammation--for example, low density lipoprotein cholesterol and hypertension. We have recently extended these observations on inflammation. Interleukin 6 and tumour necrosis factor tz play a key part in regulating the acute phase response by the liver. They also affect lipid metabolism in vivtx Raised serum concentrations of both have similar associations to those observed with serum G reactive protein and were linked to chronic coronary heart disease? Inflammatory type reactions and, particularly, cytokines may not deal only with the body's response to tissue damage or environmental stress. Body mass index is correlated with serum concentrations of turnout necrosis factor ~, which is consistent with increased synthesis of turnout necrosis factor mRNA by adipocytes from obese subjects? Oestrogen has inhibitory effects on interieukin 6 synthesis and on levels of cardiovascular risk factors, perhaps through this mechanism. Alcohol consumption is assodated with diminished serum concentrations of turnout necrosis factor a,s and pol.vunsaturated fatty adds inhibit cytokinc synthesis. Hence levels of inflarnma- tion may respond to metabolic change and be irtfluenccd by various dietary factors But what relation does systemic inflammation gen- erated in response to environmental or metabolic change bear to the risk of coronary heart disease? Cytokines and activated white blood cells originating in the lungs or gut in response to environmental stress could influence the process through effects on conven- tional risk factors such as fibrinogen. In addition, turnout necrosis factor ct and interleukin 6 generated at these sites could have direct erects which promote atherosclerosis and thrombosis at distant sites) Alternatively, inflammation may be principally located at the site of the atherosderotic lesion, being directly influenced by environmental factors that can reach that location, such as smoking, alcohol, diet, and C pneumonio~, with the systemic inflammatory response being an epiphenomenon of this process. Obesity, H py/ori infection, and chronic bronchitis cannot act directly at the site ofatherosclerotic lesions, supporting the notion that distant inflammation may be impor- tanL Whatever the balance of effects between locally and distantly generated cytokines, agents which can influence inflammatory processes are likely to have important therapeutic effects in atherosclerosis, as has recently been suggested for aspirin? These observations provide new insights into how environment can influence the risk of atherosclerosis and reduce growth in children. Inflammation and inflammatory cytokines play a fundamentM role in the whole body response to environmental stress (infective and non-infective) and metabolic change. These mechanisms are likely to be continuously active, but more so in some who die sooner from coronary heart disease. The dirty chicken hypothesis has the pleasing property of un" ,lfying many previously disparate obser- xations about the clustering of cardiovascular risk factors and also of identifying new risk factors such as chronic bronchitis and dental disease. It suggests simple ways in which a whole set of environmental stressors--infective agents-can be treated to reduce risk of coronary heart disease, as well as providing a mechanism for the association of poverty with coronary heart disease. The growth of dirty, chickens is augmented by antibiotics, and preliminary studies sug- gest that inflammatory responses~ and coronary even& .0 after myocardial infarction are reduced by antibiotic administration. Michael A Mendall Comultant gastroenterologist and senior lecturer Mayday Hospital, Thornton Heath, Surrey CR7 TYE MM is supported by the British Heart Foundation. 1 Solomon N, Mazariego~ M, Brown K, ~g K. The underprivileged. developing country child: environmental contanfinaf~on and growth falk ure revisited. Nutr Rcv 1993;51~7-32. 2 Ridker P. Cushman M. Stampfer M, Tracy R, Hcrmekcm C. Ir,.flammafio~ aspirin, and the risk of cardiov-~mlar disease in apparendy healthy men. N EnglJ Med 1997~336:973-9. 3 Mendall M. Patel P, Ballam L, Straehan D. Northtield T. C reactive protein and itt rotation to cardivw~cular risk factort: a population ba~ed crost sectional study. BIVlJ 1996;312:1061-5. 4 Havea'kate F.Thomp*on S. Duckert E Haemostmi~ factort in angina pec- tot'it: relation to gend~, age, and acute-phase respov..~e.. Re~ula of the ECAT Aagina Pet:tom Study Group. T/womb Haz,most 5 Mendall M, Patel P, A.~ante M, Ballam L, MorrisJ, Str~chan D, et al. Rela- tion of return leveL* of cytoklne~ to cardior~aflar ri~k factor~ and oaronary heart ~ Heart (in Hommi~gii GS, Arner P. Caro JF, Atldmon RL, Spiegelman I~crea~-d adipose dmue expr~ion of minor necrosi~ factor-alpha in human ob~ity and imulin re~istance.J Clin Int*st 199~;93:2409-15. 7 Vallance P, Collier J, Bhagat K. infection, inttammarlon and infarction: do~ acum endothelial dyafunction provide the link~ 1997;349:1591-2. 8 Gupta S, Leatham E, Mendall MA. Ca.mingtort EL Ka*kiJ, Bevan D, et al. The effect of azithromycin in post-myocardial infarction patient, ~th ele',ated Ch/amydia prmonomae anffoody t~tr~. J Am Coll Cardiol 1997',29~mppI A):209A. 9 Gupta S, Leatham E, Garringzon D. Mendall NL~ K~ki j. carom AJ. Elevated CMart~. d/~ gneumonuu anffoodies, cardios-~:ular evenU and azi. thromycin in male mrvivom of myocm'~al irdarction. CirculaUon t997; 96:404-7 I0 Gurfinkel F_ Bozovida G. Daxoca A. Edga~do B. Maumer B. Randomised trial of Roxithromycin in non-Q-wave coronary ss'ndromes: Roxis pilot stud~: Lanca 1997:$50:404-7. 954 BM'J VOLL,'MF.. 316 28 MARCH 1998