lated disease in chrysotile miners and millers. Am Rev Respir Dis. 1984;148:25â31. 11. Dufresne A, Bégin R, Churg A, Massé. Mineral fiber content of lungs in.
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Equally important, the results suggest that premenopausal and postmenopausal women using HRT do not differ on SDB risk. This is a message of particular relevance to premenopausal women with undiagnosed SDB: neither their decision to seek help nor the decision by primary care providers to refer them for SDB evaluation should be negatively influenced by their premenopausal status. The impressive work of Bixler and colleagues provides encouragement for a more intense focus on prevention and intervention as a means of reducing SDB prevalence. I look forward eagerly to further studies on menopause as a modifiable cause of SDB—and to strong data that may lead to an intervention trial. Bixler and colleagues have provided a foundation to build on; this is clearly a significant step forward in improving the health of women. TERRY YOUNG Department of Preventive Medicine University of Wisconsin-Madison Madison, Wisconsin References 1. Young T, Evans, L, Finn L, Palta M. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep 1997;20:705–706.
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2. Peppard P, Young T, Palta M, Skatrud J. Prospective study of the association of sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. 3. Gottlieb, DJ, Whitney C, Bonekat WH, Iber C, James GD, Lebowitz M, Nieto FJ, Rosenberg CE. Relation of sleepiness to respiratory disturbance index: the Sleep Heart Health Study. Am J Respir Crit Care Med 1999;159:502–507. 4. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence of sleep disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608–613. 5. Fitzpatrick L, Litin S, Bell M. The Women’s Health Initiative: a heart to HRT conversation. Mayo Clin Proc 2000;75:559–561. 6. Charney P, Walsh J, Nattinger AB. Update in women’s health. Ann Intern Med 1998;129:551–558. 7. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham Study. Ann Intern Med 1976;85:447–452. 8. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485–491. 9. Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of homone-replacement therapy with various cardiovascular risk factors in postmenopausal women. N Engl J Med 1993; 328:1069–1075. 10. Rodstrom K, Bengtsson C, Lissner L, Bjorkelund C. Pre-exisiting risk factor profiles in users and nonusers of hormone replacement therapy: prospective cohort study in Gothenburg, Sweden. Br Med J 1999;319: 890–893.
Detailed Occupational History The Cornerstone in Diagnosis of Asbestos-related Lung Disease The pulmonary response to inorganic dust is thought to be proportional to the amount and duration of exposure that contributes to the retention of dust in the distal airspace. The biologic tissue reaction to retained dust involves alterations in signal transduction and mediator production by target cells that initiate or perpetuate pulmonary inflammation and fibrosis. In exposed populations, the dust burden in the lung cannot be directly measured and is most accurately, but indirectly, assessed by a detailed occupational history. In some cases the occupational history can be verified by personal or static environmental measurement of respirable dust in the workplace. The intensity and duration of exposure are combined with indirect measurements of lung inflammation and fibrosis to develop a crude, but reasonably accurate, exposure–response relationship. Exposure–response relationships are useful for population-based epidemiologic studies and for developing safe “threshold limit values” (TLVs), below which dust levels are unlikely to be associated with disease over a worker’s lifetime. However, a pneumoconiosis cannot be completely excluded because the exposure to dust is considered too remote, too short, or in a safe industrial environment, as less defined individual factors may determine dust retention and disease susceptibility. These considerations have led to a search for objective, independent measurement of dust exposure and disease activity. Among candidates are bronchoalveolar lavage (BAL) in conjunction with mineral dust measurements and high-resolution computed tomography (HRCT). Although BAL measurements of dust in the airspace have a marginal predictive value in silicosis (1), they are less useful in asbestosis (2– 4). Although HRCT is remarkably sensitive in detecting mineral disease compared with conventional radiography (5), it is not yet a “gold standard” because an exposure–response relationship has not yet been clearly established.
Pleural plaques are considered diagnostic of asbestos exposure but it is unclear that there is a relationship between cumulative dust exposure and the extent of pleural disease. In this issue of the Journal (pp. 705–710), Van Cleemput and collegues use computed tomography (CT) scanning to measure the exact surface area of localized pleural plaques and compare this with objective measurements of cumulative dust exposure in a group of asbestos workers (6). Their data confirm previous reports that CT scanning is more sensitive for the measuring pleural plaques than conventional radiography (7). These authors showed that the extent of pleural plaques is related to the best objective measurements of workplace ambient dust concentrations, which were used to calculate cumulative exposure during the work history of the individual subjects. They have shown no correlation between the total surface of localized pleural plaques and lung function values. The original and most interesting finding of this work is the lack of correlation of the size and surface area of localized pleural plaques with the cumulative asbestos exposure index or the cumulative cigarette smoke exposure index. This observation is important because pleural plaques are often used as a surrogate for past asbestos exposure, particularly when bilateral, and this is useful in establishing a relationship with mesothelioma (8). The presence of pleural plaques without asbestosis is associated with an increased risk (1.4-fold) of lung carcinoma (9). Outside the primary asbestos production industry, the cumulated asbestos exposure of workers is often ill defined and one may be tempted to use the extent of pleural plaques as an indicator of past asbestos exposure. This is particularly true in brief, but sometimes intense, exposures in the armed services or in other industries prior to modern dust control measures. The investigation by Van Cleemput and coworkers in this issue of the Journal clearly establishes that the
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size and surface of pleural plaques do not correlate with the cumulative asbestos exposure index or the cumulative cigarette smoke exposure index, and thus should not be used as an indicator of past asbestos exposure. The best indicator of past asbestos exposure (the gold standard) remains the detailed past work history (8). In cases of uncertainty, the mineral fiber content of lungs, which necessitates an open lung biopsy, can give a useful indicator of past asbestos exposure when compared with a reference population and with a population with asbestos-related diseases (10–12). In the evaluation of a probability relationship between dust exposure and lung cancer in an asbestos-exposed worker outside the primary industry, when a detailed past work history is unclear regarding the asbestos exposure, the mineral fiber content of lungs can provide the best available indicator to assess the relative risk of lung cancer associated with the patient’s work and thus permit a sound basis for medical expertise. At this time, the pleural plaques cannot provide an index of cumulative asbestos exposure but remain a useful surrogate for past asbestos exposure. The presence of asbestosis would suggest a cumulated asbestos exposure above the generally accepted threshold limit level of 25 fiber ⭈ yr/cm3 but the absence of asbestosis does not establish an exposure level below 25 fiber ⭈ yr/cm3, as only a small fraction of exposed workers at that cumulated level develop asbestosis and/or lung cancer. Thus, beyond the debate of the last decade on the subject of the necessity of having asbestosis to develop an asbestos-related lung cancer, asbestos causation of lung cancer in an individual should be based on intensity and duration of exposure based on a detailed occupational history (13, 14). RAYMOND BÉGIN University of Sherbrooke Sherbrooke, PQ, Canada JOHN W. CHRISTMAN Vanderbilt University School of Medicine Nashville, Tennessee
References 1. Christman JW, Emerson RJ, Hemenway DR, Graham WG, Davis G. Effects of work exposure, retirement, and smoking on bronchoalveolar lavage measurements of lung dust in Vermont granite workers. Am Rev Respir Dis 1991;144:1307–1313. 2. Sebastien P, Armstrong B, Monchaux G, Bignon J. Asbestos bodies in bronchoalveolar lavage fluid and in lung parenchyma. Am Rev Respir Dis 1988;137:75–78. 3. Schwartz DA, Galvin JR, Burmeister LF, Merchant RK, Dayton CS, Merchant JA, Hunninghake GW. The clinical utility and reliability of asbestos bodies in bronchoalveolar fluid. Am Rev Respir Dis 1991;144: 684–688. 4. Teschler H, Friedrichs KH, Hoheisel GB, Wick G, Soltner U, Thompson AB, Konietzko N, Costabel U. Asbestos fibers in bronchoalveolar lavage and lung tissue of former asbestos workers. Am J Respir Crit Care Med 1994;149:641–645. 5. Bégin R, Ostiguy G, Fillion R, Colman N. Computed tomography scan in the early detection of silicosis. Am Rev Respir Dis 1991;144:697–705. 6. Van Cleemput J, De Raeve H, Verschakelen JA, Rombouts J, Lacquet LM, Nemery B. Surface of localized pleural plaques quantitated by CT scanning: no relation with cummulative asbestos exposure and no effect on lung function. Am J Respir Crit Care Med. 2001;163:705–710. 7. Bégin R, Cantin A, Masse S. Recent advances in the pathogenesis and clinical assessment of mineral dust pneumoconiosis: asbestosis, silicosis, and coal pneumoconiosis. Eur Respir J 1989;2:988–1001. 8. Bégin R. Asbestos related diseases. In: Harber P, Schenker MB, Balmes JR, editors. Occupational and environmental respiratory disease. St. Louis, MO: Mosby-Year Book; 1996. p. 293–321. 9. Hillerdal G. Pleural plaques and the risk for bronchial carcinoma and mesothelioma. Chest 1994;105:144–150. 10. Churg A, Wright JL, Vedal S. Fiber burden and patterns of asbestos related disease in chrysotile miners and millers. Am Rev Respir Dis 1984;148:25–31. 11. Dufresne A, Bégin R, Churg A, Massé. Mineral fiber content of lungs in patients with mesothelioma seeking compensation in Québec. Am J Respir Crit Care Med 1996;153:711–718. 12. Dufresne A, Bégin R, Massé S, Dufresne CM, Looseereewarnich P, Perreault G. Retention of asbestos fibres in lungs of workers with asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos township. Occup Environ Med 1995;53:801–807. 13. Egilman D, Reinert A. Lung cancer and asbestos exposure: asbestosis is not necessary. Am J Ind Med 1996;30:398–406. 14. Bégin R. Asbestos exposure and pleuropulmonary cancer. Rev Mal Respir 1998;15:723–730.
Basic Science in Ventilator-induced Lung Injury Implications for the Bedside Over the past two decades we have realized that mechanical ventilation, the life sustaining therapy that has saved thousands of lives since the polio epidemic, can exacerbate or even cause lung injury. Over the past few years, we have begun to unravel the mechanisms underlying the detrimental effects of mechanical ventilation, and have obtained strong clinical data indicating the importance of iatrogenic lung injury (1). The current study from Held and colleagues, reported in this issue of the Journal (2) (pp. 711–716), significantly advances our understanding of the signal transduction mechanisms involved in one mechanism of injury: the release of mediators due to different ventilatory strategies, so-called biotrauma (3, 4). The study is important because it helps illuminate the mechanotransduction mechanisms, and in so doing suggests novel therapeutic targets to abrogate the mediator release due to mechanical ventilation. The study by Held and colleagues helps elucidate the signal transduction mechanisms in a number of ways. First, it confirms previous studies that have demonstrated that the signaling cascade operates via an NF-B pathway that translates the ventilatory (physical) stimulus into a chemical (mediator) response (5). NF-B is a protein transcription factor that en-
hances transcription of a number of genes, most notably cytokines. Second, it confirms the steroid responsiveness of this release of cytokines (5), a finding that has obvious potential clinical application. Third, and most important, this study demonstrates that although the signal transduction mechanisms responsible for biotrauma act, at least partly, via NF-B (similar to lipopolysaccharide [LPS] signaling), the upstream mechanisms appear to be different. As shown by a number of groups, LPS signaling acts via a Toll-like receptor (TLR) (6). The Toll gene, originally identified in Drosophila melanogaster, encodes a receptor that can bind to surface epitopes/ligands on bacteria to effect signaling to the nucleus from the cell membrane. In humans, there are at least 10 types of TLR; one of these, TLR4, appears to be relatively specific for LPS whereas TLR2 mediates responses to gram-positive organisms. The most convincing data in support of the importance of TLR4 in LPS signaling are provided by experiments in C3H/HeJ mice (7), which have been known for more than 20 years to be endotoxin insensitive. In C3H/HeJ mice, LPS does not cause translocation of NF-B and does not cause an increase in inflammatory cytokines; this defective signaling has been shown to be due to a mutation in the TLR4-encoding gene (7). In the
