Document k647J6be4Q0ZMR4dkDJ6vzvyB

iaeiiiisTiiwitwBai Tiaa^wwmOMinlM^ui MMAUMWUUk i ' : j { I I I 4 ( J I 1 I I 1 I I I. The New England Journal of Medicine SatakllaM la UU u TU KIW ENGLAND JOUKNAL OF MEDICINE AMD SUBGEBT PLAINTIFF'S EXHIBIT DUP-1029 VOLUME 306 JUNE 17, 1982 NUMBER 24 Original Articles Editorial Family Management in the Prevention of Exacerbations of Schizophrenia: A Controlled Study...................................... 1. IL H. Falloon, J. L. Boyo, C W McGill, J, Razanl, H. B. Moss, and A. M. Gilocruan The Interaction of AIpha-ThaUsaemta and Homozygous Sickle-Cell Disease.......... D. R. Higgs, B. E. Aldridge, J. Lasix, J. B. Clzgg. D. J. WlATHCRALL. R. J. HaYCS. V. GraXOOON, Y. Lowait, K. P Mason, B. E. Sujrant, and G. R. Scrjeant Exposure to Asbestos and Human Disease MS M. R. BtratAsr Sounding Boards 1441 After Laetrile, What?. m B. R. Casmltth A Futfire Shortage of Residency Training Positions: Dilemma or Opportunity?... D. A Kixmc A.xo N. C. Dunham 1482 1484 Medical Progress The Pathogenesis of Asbestos-Associated Diseases..................................................... J. E. Craighead and B. T. Morshan 1446 Medical Intelligence Drug Therapy: Atenolol and Timolol, Two New Systemic /J*Adrenoceptor Antagonists................................................ W. H. Fushuam 1456 Discordant Cortisol Response to Exogenous ACTH and Insulin-Induced Hypoglycemia in Patients - with Pituitary Disease........ .................... C. C. Bout, H. J. Mioit-sriLDCs, AH J. T. O'BfclAN 1462 Intraventricular Hemorrhage in the Premature Infant: A Changing Outlook...................................................... S. Shirnas, R. A. Moltcju, K. Gammon, B. J. D SoiOx, J. Altman, akoJ. M. Felkman 1464 Hetcrosygote Detection in Cystinosis, Using Leukocytes Exposed to Cystine Dimethyl Ester........................... R. SrtiftMcaz, F. Ttrrzi, T. Tatcite. A. Mooem, W. A Gaiil, amo J. D. Sciiulman 1468 Case Records of the Massachusetts General Hospital A 51`Year-Old Woman with Chronic Asthma and Hemoptysis ........ N. M. Baaslow and E. J. Mark 1471 '.Correspondence Hazard of Ophthalmic Timolol............................... Aplastic Anemia after Parenteral Chloramphenicol: Warning Renewed........... Thrombosis after Pulmonary-Artery Catheterization vii the Internal Jugular Vein......................................... Factitious Sickle-Cell Trait...................................... Folate Levels ia Inflammatory Bowel Disease ... Thyrotropin-Releasing Hormone........................... Possible Alteration of .Metronidazole Metabolism by Phenobarbital................................................ Case 7-1982: Sarcoidosis and Cancer.................... Katie of Arm Span to Height not Usually Increased in Klinefelter's Syndrome.............. Visualization of "CoidM Thyroid Nodules with Nooredioactive Iodine...................................... A Good UtUe Antacid.............................................. Musical Boules............................................................ Do Water Pipes Prevent Transmission of Fungi from Contaminated Marijuana?....................... Methadone Maintenance Programs......................... Financing Long-Term Care........... .......................... Computerized Matching Algorithm for Third- Year .Medical-School Courses ......................... IjKk of Interpersonal Communication in Programmed Learning...................................... 1485 1486 1486 1487 1488 1488 1490 1490 1490 1491 1492 1492 1492 1493 1494 1495 1495 Book Reviews....................................................... 1495 Books Received................................................... 1499 Notices....................................................................... 1501 Special Report The Modular Medical Integrated DUP I 1506 1 2 Curriculum: An Innovation in Medical Education.................................... 1502 A. J, Cu.at.ar, E. H. Blacstun, aadJ 1. Sandson ' c' Owaed. Published, and OCogyrighied. 1982. by the Massachusetts Medical Society Tut Ntw LnglasP Jh snal of Muxon* tISSN 002H-47^>3) is puMulicd wrreLU fiom rduon.il nflx.n si 10 bluuitKk Street. Boston. M,\ 021 IS Subscripttaxi P**f S'lBut jr \car Srctxxl-tbui |wxl si Boston sitd at stldiUofwl mathn* otftcn. PObTMA-Sl LR hend sddrru changes to 1172 C nmmunxrjlth \venuc, M \ 02131. NEJMAG 306(24) 1437*1504 (1982) DU 060383 1480 THE NEW F.NCII.VND JOURNAL OF MEDICINE June 17, 1082 The New England Journal of Medicine Official Or^an of The M&uaduncm Medical Surim Percy W. Wadman. M.U. Pmuknt William B Municr, M.D. Ftmtm Vkt'pmtdtnL ChaHci S, Amorutmu. Jr. Lunurt Sttnurj Putuurco Wuklv by me Committee o* Publications or the Massachusetts Medical Sociei v James F. McDonough, M.D., CJuirm** John I. Sandson, M.D John C. Ayres. M.D William H. Sweet, M.D.. D-Sc William 8 Schwartz. M.D. Frank . Bixby, Jr., M.D. Samuel K. Sccwart, M.D. Arnold S. Reiman, M.D , Eorroa Marcia Angelt, M.D., Ditvty Eorroa Edwin W. Salzman, M.D., Deputy Eorroa AaaooATt Eorroas Jane F. Des/brges, M.D. Norman K. Hollenberg, M.D.. Ph D, Ronald A. Malt, M.D. Morton N. Swartz, M.D Franklin H. Epstein, M.D. Francis D. Moore. M.D., Book Review Eorroa John C. Bailar, III, M.D., Statstical Consultant Joseph J. Elia, Jr., Manage* or EorroatAL OrcaAtiom Emily S. Boro, Assistant Eorroa Marlene A. 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MA CT.'I >3 Business amd bumcatenon Omcts. 1172 Commonwealih Air . Burton, MA 02134 EXPOSURE TO ASBESTOS AND HUMAN DISEASE During the past two decades, ill health resulting from exposure to asbestos has been the subject of in tensive observation and research1 -- probably more intensive than research on any other environmental agent.2 In the most direct target organ, the lung, and in its pleural coverings, there is a wide spectrum of response after exposure; not only acute and chronic inflammatory diseases but also cancer of these organs may occur. Research has been stimulated by the belief that the more complete our understanding of the mechanisms of pathogenesis, the better will be our ability to control the continued use of thts mineral tn today's complex technologic world.3 The review by Craighead and Mossman of the pathogenesis of asbestos-related diseases m this issue of the Jmirnal * which covers recent work in cell biol ogy, is set in the context ofpathology but also discusses the use of these minerals and regulatory consider ations; it complements other recent reviews of the epi demiology of these diseases,5 their impact on public health,9 and current clinical issues.7 Also important is a recent report that provides criteria for grading tjie pathologic changes in the lungs associated with asbes tos exposure.* Systematization of pathological assess ments can only enhance the pooling ofexperience from different centers cr countries by maximizing the com parability ofstudies. The international classification of radiographs of pneumoconiosis9 by the International Labour Office is an example of such systematization, and the dividends associated with its use arc generally recognized. * Perhaps the major contribution of the review by Craighead and Mossman (and this may surprise read ers not familiar with the field) is the emphasis placed on the shortcomings of our present knowledge of the pathogenesis of asbestos-related disease. Considering first the fate of inhaled fibers in the lung, it is now- evident that the dust burden of the lung is primarily in the form of uncoatcd asbestos particles.4 whether or not these conform to the definition of a fiber (i.c., a particle with a length-to-width ratio of 3:1). This defi nition probably originated rather arbitrarily from a need to standardize what was considered a fiber for purposes of industrial hygiene*; it is now widely be lieved that a much higher ratio, perhaps 10:1, would have been a better choice. Both fiber length10 and mineralogic type" arc important determinants of whether a fiber becomes coated and so takes on the familiar appearance of the asbestos body. Most asbes tos bodies found in human lungs contain an amphibole fiber as a core,11 even though chrysotile accounts for the greatest use and presumably the most exposure.7 What permits some particlrs to lie apparently dormant in the lungs for long periods before evoking an organ response is not known, and there is no good explana tion for the fact that all the disease consequent to as bestos exposure (including fibrosis of the lungs and OUP 115061 iT-Fiai' .ecf*iv DU 060384 Voi. 306 No. 24 EDITORIAL 1441 pleura is well as cancer of these organs) may appear differences in the pathogenic potential of the various long after exposure has ceased. fibers tn this mineral group. Of particular concern is Fibrosis of the lung fasbestosis) was recognized bv whether chrysolite (which has accounted for over 90 the first decade of this century and has been the subject per cent of commercial uses during the past several of much research in animal models. Nevertheless, decades) diflers from the two amphibolc fibers, crocid- Craighead and Mossman conclude that the patho oluc and amosite, which were used extensively during genesis of asbestosis remains to be established,4 as World War II and tn the postwar building boom, l hc docs the importance of exposure dose as compared issue has been bedeviled by problems of comparing with individual "susceptibility" in the initiation and like with like,5 by the difficulty of sorting out the rela the progression of the fibrotic reaction. The finding of tive contributions of exposure (duration, level, and an acute inflammatory response in some early human particle size) and fiber type, and bv the diffidences lesions* raises the issue of whether there is a reversible between exposure in the mining and milling of fiber component to the acute response in human beings, as and the secondary application of fibers m manufactur suggested by work in animals.12 Long-term studies in ing. Thus, although it u dear that the rates ofmesothe sheep13 may help to answer this question. As for lioma are different in different exposed populations, it whether asbestos acts as an initiator or as a promoter has usually not been possible to assess the extent to of lung cancer, the authors of the review* favor the which these differences arc due to filler type or to other latter view; pcrltaps particles act as physical carriers of factors. Some clarification has come from the applica other environmental carcinogens to the basal epithe tion ofmodem methods oflung-dust analysis to autop lial cells. It is also possible that more than one mccha-. ' sy material. In two case-control studies of mesotheli nism is involved.7 oma, an excess of amphiboles (amosite in North There is perhaps even more uncertainty about the America and crocidolitc in the United Kingdom) was pathogenesis of pleural reactions than there is about found in the lungs of the eases, whereas chrvsoule parenchymal lesions. For instance, it is not clear how contents were similar in cases and controls.510 In a often acute exudative reactions, such as effusions (pre study of chrysorilc miners in Quebec, almost as much sumably usually clinically silent), precede the more trcmolite (an amphibolc contaminating some of the chronic diffuse or localized fibrotic reactions ofvisceral mined rock deposits) was found in the lungs as chrvso- or parietal pleura. It is also unclear how fibers reach tiic, although the latter was ciearlv the mam environ the parietal pleura and concentrate there in such a wav mental contaminant.17 These results arc consistent as to evoke plaque production after a long delay w hile with what has long been believed on the basis of more leaving the visceral pleura intact; an adequate hypoth tenuous evidence -- that there is preferential clear esis for the pathogenesis of pleural plaques is needed to ance ofchrysotilc, as compared with amphibolc fibers, explain all these features.'* Perhaps even .more puz from body tissues and that this may contribute to the zling is what determines whether the pleural reaction wilt be benign or malignant. Xot all would agree with the view expressed in the article* that malignant mesotheliomas arc pathognomonic of asbestos expo differences in the pathogenic potential of the minerals Epidemiologic evidence for a fiber gradient m I pathogenic potential is strongest for mesothelioma. | with crocidolitc more strongly implicated than clirvso- j sure: these tumors were described by European pa tile, and amosite probably in between. The evidence is j thologists in the 19th century -- long before major also reasonably strong for lung cancer, with crocidolitc ! U- commercial exploration of the asbestos minerals15 -- again more strongly implicated than chrvsoule. For i/4 and there is little evidence even today that asbestos is responsible for many eases in men or women outside industrial centers.315 What arc described in the pres pleural reactions (pleural plaques and fibrosis), there I may also be a fiber gradient, although other factors arc i almost certainly involved; for parenchymal fibrosis thcl ent review as "casual" exposures (i.c., usually domes evidence fora fiber gradient is minimal. At present it is tic or neighborhood) arc exposures that are intermit believed that the biologic activity of asbestos particles tent but have often turned out to be to very heavy dust relates to the degree of penetration and the amount of clouds of fine particles.3 deposition in the lower respiratory tract, both of which In spite of considerable current interest in the depend mainly on their physical characteristics, in topic,7 the issue ofwhether asbestos exposure is associ cluding their aerodynamic properties. Particle size ated with airway abnormalities is not addressed by (and particularly length and fineness I may also deter Craighead and Mossman. The involvement of small mine oncogenicity. However, biologic activity is likely airways in the early stages of asbestos-related lung to be modified by the length of time that particles fibrosis has in all likelihood ns clinical counterpart, survive in the lung without denaturing, which inav be although there is no evidence about w Itether these ab related to their chemical characteristics. The most normalities arc reversible nr not. l hc association be plausible explanation for differences in the pathogenic tween asbestos exposure and otherjinnis of attway potential of vaaous libers is that these differences re response, such as bronchitis or rmpliv scuta m the ab sult from dillcrcnccs in both the physical and chemical sence of asbestosis, also remains to lie elariftrtl. as do properties of the libers. the confounding elfcets of cigarette smoking. What is the clinical im|x>rtancc of the issues raised Finally, there is the question of whether there arc by the review in illc Journal? Perhaps the most impnr- DUP 1150614 DU 060385 1483 THE NEW ENGLAND JOURNAL MEDICINE June 17, 1983 urn is that health risks in relation to exposure to ashestos vary according to environmental factors. Some of these factors (such as exposure dose, panicle size, and fiber type) arc known, but there are undoubtedly oth ers not yet recognized. Host characteristics probably also influence the response to exposure. Thus, in con sidering the individual patient with a disease known to be related to asbestos exposure, the wise clinician should avoid regarding any particular exposure as too short, too remote, or at too low a level (even if environ mental counts were in compliance with the present regulations) to have accounted for the disease. Assess ment of the importance of particular environmental exposures is often outside the clinician's expertise; it should be referred to appropriate consultants in indus trial hygiene, engineering, or physics. In lung cancer the statistical probability that a given case is attribut able to asbestos exposure may be estimated from expo sure-response data," which for practical purposes can probably be assumed to be linear, provided that the data available are applicable to the industry in which" the subject was employed. Finally, the unpredictable clinical course of these diseases demands vigilance by the clinician with respect to past exposures, and the most powerful indicator remains the careful, complete, and precise occupational history.7 Whether the dust concentrations permitted by cur rent regulations will in fact eliminatedie future risk of asbestosis, as Craighead and Mossman suggest,4 re mains to be established. Similar suggesdons in the 1930s proved to be premature. Evaluation of the im pact of present controls on health issues is an urgent matter for research. Furthermore, a total ban on use seems unlikely in technologic societies,5 in which it may be considered preferable to retain these versadle minerals for certain uses. Until it is established that asbestos subsututes do not carry health risks," re search into the mechanisms by which asbestos pani cles produce ill health should be vigorously pursued. McCUM'Bnrntfy Moostai. PQ H3A 2B4. Cuki Margaret R. Bccklakc, M.D. References I. Admen ED, GvCmt M. ripam liflum -- dx adMUde crwrji bL McDould JC. td. (Ur** adtwen nm^KtwiI bed*. Filubwib: Cburctull UviftfKoat. 1911.237.49. 2- NsrGA. ftn 81 Sows*booko* ntantan*. N*w YoA: GarWd STEM fins. 1990.AI.ICU 3. Gtoeg D. Aibcssoe -- cm it be mmi ufety? if MatJ. URL H15JI-3. . A Cwfte4 JE. Moimm IT. The pufcofctmu of abaroe-cuocuaBd div **. N E*#l J Med. 19*2; 30*1*46-55. J. McDowU JC. Aibrwi wlnM dmttc art epidemiological rtvw*. In. Wt$rm JC. H. itoktpai effect! af nmeni 6bm Lyon. Imcnuoonat Afcncy for Rcwvcfe on Cmcct. 1990517-601. (IARC temttae pubtica* mm. JO). 4. LiddeU 0, Asbmm and public fcealtfi. Thom, rttl; 36:2*1 *4 7. RcrHibe MR. Aibtuot related ditcua of the toag and pteun. ctfrent (bocal liiwi. Am Rev Rctptr Ota. (m pm*) I. Craighead JE. Abraham JL. Charg A. et al. The pathology of asheoow tuociatad 6xiiet of the luag* and pleura) canon. Arch Pathol Lab Med. (in pmt) 9. lmcmnuonai Labour Office Guideline* for the ma of ** ILO tmematiou] ChutAcanon of radiographs of pncumonconiOMs Genri inumatioiuJ Labour Office. 1990,1-44 (OctupatiaaaJ teakh and safety smn no. 22). 10. MorgM A. Hdfaw A. CoK*nirion* and dimewiom ofcoated and oncoat* of athnani fibre* in the human to''! Br ) Ind Mud. 1910. 3? 15-32. It. Otarf AM. *anack ML. A<dewu* and other femiginoui bod**. o*o- formattoo and chntcaJ ugnitiesnct. Am J Pathol 199 \, 102 447-36 12. Hied DM. Eapcnmenui obnttisu. an mvcaugatioA of functional and pai lofted docartuncct. I Method*, control ammaii and eapoturv cowJinom Ir J tad Med 1971. 35 129-M 13. Begin R. PleucayAblu M. Mane S. et al Asbeun-tateeg lung j\wy die vwep model, the imctaJ aleo(Ki< Environ Res. (in press) 14. HiUcidal C The pathugennn of pleural plaques and pulmonary tibe-uasu: posidnliuo end impossibilities Eur J Rctpir Ou I9S0. 61.119-31 15. McDonald JC. McDonald AD EpnlermokJiy of mesottehooa from esotamd incidence Pm Med f9T* 6-426-46 16. McDonald AD. McOonaid JC. Poofcy FD Mineral fibre content of the lung in maortwlnl mmoun m Norm America. Atm Occup Hyg. (m pros). 17. Rowland* N. Gibb* GW. McDonakf AD Asbestos fibers m Ore tongs of chryioate aunen and milkn -- a preliminary report. Ann Occup Hyg. (ut pros). It. Enaerttne PC. AcmbaabiUty m te fast of Mccramcy Chest- I960. 7t: Suppt <Aufwt):377*9. 19. Wagrar JC. EJmes PC. The mineral fibre problem (n: McDonald JC. ed Recent advatcaa m occupational health Edinbarfh. Churchill Ltvtnptune. 19VL1-13. SOUNDING BOARDS AFTER LAETRILE, WHAT? Laetrile was moribund before Mocrtcl ct al. laid it to rest with the recent report of their prospective clini cal trial.1,2 It had been replaced in popularity by an approach unusual in the annals of unorthodox cancer therapy --one that represents more of a challenge than did Laetrile or its predecessors. This is the "natu ral" approach to malignant disease, which emphasizes cure through purifleation and the body's capacirv to heal itself. The currently popular alternative approach is rooted in homeopathic and naturopathic beliefs, Indian and Oriental philosophy, and 19th-century theories of intestinal putrefaction. Promoters often evoke the time-worn conspiracy dogma, which states that the medical system, the Food and Drug Adminis tration, and the federal government withhold true cures from the public, thereby perpetuating therapeu tically useless and biologically harmful cancer treat ments in order to further the Establishment's econom ic interests.5,4 Alternative cancer therapies in vogue today differ importantly from Laetrile and from other unproved remedies of the past. Previous unorthodox treatments were "medicines" or at least "medicinal." Examples were Dr. Bye's Combination Oil Cure, Dr. Chamlee's remedy for removing cancer viruses from the blood, Dr. Leach's Cancerol, Dr. Koch's glyoxylide, and manv others that attained great prominence in their day.* They came in ampules, vials, or syringes, mim icking standard medications, and they were sold and administered in the usual clinical fashion by people in white coats. Today's alternative remedies explicitly reject associ ation with standard treatments, environments, and paraphernalia. These are anti-medicines, emphasizing purification through dietary regimens, detoxification DUP 1150615 DU 060386