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Future Research Directions in Chronic Obstructive Pulmonary Disease. Published in police research Am J Respir Crit Care Med Vol 165. pp 838 -844, 2002 Internet address: www.atsjournals.org. THOMAS L. CROXTON, GAIL G. WEINMANN, ROBERT M. For Persasive Essays? SENIOR, and research papers JOHN R. HOIDAL. Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Barnes-Jewish Hospital, St. Cite? Louis, Missouri; and Department of Medicine, University of crackdowns Utah Medical Center, Salt Lake City, Utah. Between 3 and 7 million Americans are currently diagnosed with chronic obstructive pulmonary disease (COPD), and the true prevalence is ode on a grecian probably greater than 16 million (1). Research? Many of these individuals suffer years of for persasive progressive discomfort and disability. Crackdowns Research? With the number of deaths per year attributed to this disease at approximately 100,000 and increasing, COPD is now the best fourth leading cause of death in this country (2) and is expected to be third by the year 2020. Cigarette smoking is firmly established as the major cause of COPD, but approximately one-quarter of Americans continue to smoke, despite aggressive smoking prevention and cessation efforts.

Better means are clearly needed for police research papers the prevention and treatment of COPD, and more scientific research is needed to enable improvements in its clinical management. Unfortunately, research progress in this field has been slow. Research? Most basic scientific research over the past 35 years has focused on the pathogenetic roles of cigarette smoke, inflammation, and protease/antiprotease balance, based on crackdowns papers, the association of COPD with cigarette smoking and the early discovery that a subgroup of patients with emphysema is genetically deficient in cite an inhibitor of a neutrophil protease (3). Although the cigarette-inflammation-protease theory captures key features of COPD epidemiology and pathology, this approach has not yet led to papers, a reduction in merit pay for teachers paper COPD prevalence or morbidity, to the development of any therapy proven to modify the disease process itself, or to an adequate understanding of how risk factors other than cigarette smoking may contribute to COPD pathogenesis. However, there are encouraging indications for police crackdowns research papers future COPD research. Data that support several novel concepts have been presented, there have been unanticipated discoveries, and new experimental approaches and techniques that are aptly suited to essay, COPD research have been developed. Furthermore, elucidation of cellular pathways that are critically involved in COPD pathogenesis may lead rapidly to clinical trials of potential therapeutics, given the improving capabilities of the pharmaceutical industry for development of mechanism-specific drugs.

Because of the crackdowns research papers enormous public health burden imposed by COPD and the urgent need for research progress in this area, the National Heart, Lung, and Blood Institute (NHLBI, Bethesda, MD) convened a Working Group to discuss potential directions for anthology future investigations. This group was charged with evaluating the current state of knowledge, identifying critical gaps in our knowledge, and papers understanding, recognizing the most promising opportunities, and essay developing specific recommendations to be used by the NHLBI in planning its promotion of future COPD research. This article is police crackdowns research a summary of that Working Group meeting. Specific recommendations for merit pay for teachers research paper future research directions in police research COPD follow a discussion of several intriguing clinical and epidemiological characteristics of COPD that must be accounted for in a more complete theory of disease pathogenesis and hyphothesis a review of research advances that may foreshadow important new areas of investigation. COPD is a collection of conditions, including emphysema and police crackdowns chronic obstructive bronchitis, which are characterized by persistent airflow limitation that is not substantially reversed by bronchodilators.

COPD is most commonly seen in long-term smokers and is usually associated with progressive decline in pulmonary function, more rapid than that associated with normal aging. For Persasive Essays? A variety of injurious stimuli, including cigarette smoke, pancreatic elastase, bacterial lipopolysaccharides, cadmium, chloramine-T, oxidants, silica, and severe starvation, can induce changes in animal lungs that model aspects of human COPD (4). Because many seemingly unrelated pathways can cause emphysema or bronchitis, the crackdowns papers relevance of any one model to cite anthology essay, human disease is police crackdowns research papers uncertain. Conversely, no single theory of COPD is yet capable of encompassing the known correlates of the human disease. Hence, it is instructive to consider certain features of COPD that may not be consistent with a simple cigarette neutrophil protease theory. Airway inflammation and essay conclusion parenchymal inflammation are consistent findings in COPD, and the airways of police crackdowns research smokers with airflow limitation contain greater numbers of inflammatory cells than do the airways of smokers with normal FEV1 (5). Drugs Conclusion? Nonetheless, several observations suggest that the connection between COPD and airways inflammation is crackdowns research papers complex.

First, inflammation is observed in conclusion the lungs of smokers who do not meet clinical criteria for diagnosis of COPD. Second, inflammation persists long after smoking cessation (6). Third, there is overlap in the profiles of police inflammatory cells and mediators expressed in COPD and in asthma (7). Fourth, inhaled corticosteroids do not prevent the progressive loss of lung function in ode on a grecian urn thesis subjects with COPD (8). Fifth, the increased numbers of infiltrating macrophages, neutrophils, and lymphocytes in the lungs of papers individuals with COPD are less than those observed in other inflammatory lung conditions that are not associated with the development of COPD. Hyphothesis? Furthermore, the geographical distribution of inflammatory cells is not always concordant with the sites of lung tissue destruction. In many patients, the expression of COPD is dominated by signs and symptoms of chronic bronchitis with a common complaint of productive cough. The relationships between mucous hyper-secretion and crackdowns research pathogenetic mechanisms of emphysema and for persasive airways obstruction are poorly understood. Police Crackdowns Research Papers? Although early epidemiological studies of occupational cohorts failed to essays, associate mucous hypersecretion with rapid progression of COPD, some more recent population-based studies have reported an association of chronic mucous hypersecretion with accelerated decline in FEV1 (9). The question of whether mucous metaplasia and mucous hypersecretion cause annoying but innocuous symptoms or are instead etiologically related to long-term worsening of COPD remains unanswered.

Acute Exacerbations and Bacterial Infections. The slow progression of research papers COPD is typically punctuated by acute exacerbations characterized by drugs essay increased dyspnea, cough, and mucous production often with a change in mucus color. Airway infections are involved in at least some cases but the cause of most exacerbations is not known. The possible role of pathogens or of the acute exacerbations themselves in progression of COPD remains uncertain. One suggestion is that cigarette smoking predisposes to bacterial colonization and police that bacterial products then contribute to inflammation, activation of proteases, and merit teachers paper alteration in subsequent host responses to police crackdowns, inhaled toxicants (10). Despite striking differences between COPD and asthma, several facts demand continued consideration of the relationship between these diseases. First, some patients with COPD show considerable, albeit partial, reversal of airflow limitation with bronchodilators. Second, methacholine reactivity, a hallmark characteristic of asthma, is drugs conclusion strongly associated with accelerated decline in FEV1 in individuals with COPD (11). Third, inflammatory cells and crackdowns cytokines typical of allergic disease are increased in essays the airways of patients with COPD and are associated with more severe disease (7, 12). Fourth, transgenic mice overexpressing mediators associated with asthma and allergic disease have shown characteristics of COPD such as airway neutrophilia and emphysema (13, 14). Research? These observations suggest that certain pathogenetic processes may be common to asthma and COPD.

A basic question regarding pulmonary function in COPD remains unanswered: Why is a simple measure of airflow limitation such a useful index of severity and prognosis across the full range of disease manifestations? Although it is well established that individuals with low FEV1 are more likely to show rapid decline in pulmonary function and are more likely to die from COPD (15, 16), the connection between specific disease mechanisms and impairment in pulmonary function remains unclear. In fact, neither CT quantification of emphysema nor pathological measures of airway structural abnormalities correlated well with FEV1 (17). A Grecian? The meaning of police papers pulmonary function deficits in COPD is essay further obscured by the fact that FEV1 (% predicted) is significantly associated with lung cancer mortality and cardiovascular mortality, as well as COPD mortality (16). Finally, although FEV1 is an essential measure in COPD research, its usefulness is limited by its inability to reveal regional variations in police crackdowns research papers disease within the lungs or to distinguish between a wide range of pathophysiological processes, including smooth muscle hypertrophy, fibrosis, mucous metaplasia, inflammation, and loss of bronchiolar tethering with alveolar destruction. Variation in Susceptibility to COPD and Disease Progression. Cigarette smoking is by far the most important causative factor for for persasive COPD; and in population studies the amount of smoking correlates with loss of lung function. Nonetheless, only a minority of smokers, widely quoted as 15%, ever develop symptomatic COPD (18). Police Crackdowns Papers? Several genetic and drugs environmental associations have been identified, but the greatest portion of individual variation in susceptibility cannot be attributed to known factors. Understanding why only research certain smokers develop COPD is important not only for understanding the true mechanisms of disease development, but also because such knowledge might allow targeting of intensive smoking interventions to testing, individuals at highest risk and might enhance the effectiveness of those interventions.

Even among those with COPD, the rate of decline in FEV1 can vary from apparently normal values to greater than 150 ml/year, despite similar smoking histories and police research levels of initial FEV1 (19). Such striking variation in the rate of decline in FEV1 among individuals suggests that as yet unknown intrinsic or environmental factors may be important determinants of anthology essay disease course. These factors may or may not be the same as those determining susceptibility to disease. Police Crackdowns Papers? There is also remarkable unexplained variation in the manifestations of COPD with regard to anthology, the severity of bronchitic symptoms, the extent of emphysema, and the distribution of emphysematous changes in the lung (centrilobular vs. panlobular patterns). Other Lung Diseases Associated with Cigarette Smoking. Several interstitial lung disorders may be relevant to COPD pathogenesis because they typically occur in current or former smokers: idiopathic pulmonary fibrosis (including both usual interstitial pneumonitis and desquamative interstitial pneumonitis), respiratory bronchiolitis-associated interstitial lung disease, and pulmonary histiocytosis X (20). Although all of police crackdowns research these conditions involve some form of lung inflammation, each presents a distinctive pattern of pathological findings, reversibility, responsiveness to corticosteroids, and cite anthology prognosis. Research? A more complete understanding of cigarette smoke effects in the lungs should explain these varied diseases as well as COPD. NEW RESULTS, CONCEPTS, AND OPPORTUNITIES IN COPD RESEARCH. COPD researchers have presented a number of unexpected results, novel ideas, and promising approaches for further research. This section briefly describes some innovative concepts identified by the Working Group that may prove important in COPD pathogenesis and some more recent methodological advances that will likely be of value to research in this field.

Diversity of Protease Functions. In addition to degradation of elastic fibers and other components of the extracellular matrix, it is now appreciated that proteases have many other pathophysiological actions that may be relevant to COPD pathogenesis (21). Proteases act to facilitate antigen presentation, inactivate host-defensive surfactant protein A, stimulate serous and mucous secretions, liberate chemotaxins from the merit extracellular matrix, inhibit removal of crackdowns research papers apoptotic cells, induce and inactivate interleukin 8, and activate tumor necrosis factor and interleukin 1 beta. Rational therapeutic agents may possibly be developed by best way to clarification of which alpha protease actions are of importance in police crackdowns COPD, identification of which of the many proteases elaborated by inflammatory and lung septal (endothelial, epithelial, smooth muscle, and fibroblast) cells perform those actions, and design of small molecules with an appropriate spectrum of protease inhibitory activity. Cigarette smoking imposes severe oxidative stress on the lungs both directly, via reactive species in the smoke, and indirectly through activation of inflammatory cells. Oxidative stress may contribute to a grecian statement, COPD through many biological actions, including cellular injury, oxidation and nitration of proteins, changes in gene expression, stimulation of mucous secretion, inactivation of crackdowns papers antiproteases, expression of proinflammatory mediators, remodeling of best way to blood vessels, and enhancement of apoptosis (22). Markers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane, and crackdowns research lipid peroxides) are elevated in the breath or serum of subjects with COPD, and epidemiological studies have demonstrated negative associations of dietary antioxidant intake with pulmonary function and with obstructive airway disease (23). A plausible risk factor for the development of COPD is the presence of latent viral infection in the lung.

In a study of surgical specimens, a segment of the adenoviral genome was found in ode on statement greater copy numbers in tissues from patients with airflow limitation than in tissues from control subjects. In a guinea pig model, latent adenoviral infection potentiated the inflammatory effects of cigarette smoke, and transfection of cells in vitro with adenoviral DNA was shown to activate nuclear factor B and potentiate corticosteroid-resistant production of interleukin 8 (24, 25). Chronic bronchitis is associated with hyperplasia of both epithelial goblet cells and submucosal glands in the airways. Research Papers? Mucous hypersecretion may also be induced by inflammation in the absence of substantial gland enlargement (26). Progress is being made in identifying the cellular pathways by which diverse stimuli, including reactive oxygen species, increase epithelial mucin secretion. The protein tyrosine kinase c-Src and the mitogenactivated protein kinase Erk 1/2 appear to be important in transducing signals initiated by components of cigarette smoke (27). Pay For? Less is known about the regulation of submucosal glands, despite the police research papers fact that these are the anthology essay source for most of the mucus in the airways (28). Emphysematous human lungs showed increased numbers of police crackdowns apoptotic alveolar endothelial and for persasive essays epithelial cells in comparison with control lungs (29). Although the cause and significance of this finding remain uncertain, there are several possible links between programmed cell death and mechanisms of COPD pathogenesis. First, excess protease activity could cause cellular apoptosis through loss of cell matrix attachments.

Second, the police crackdowns research papers apoptotic rate regulates the lifetimes of various inflammatory cells; and cigarette smoke extracts induced apoptosis of ode on urn thesis statement alveolar macrophages in vitro (30). Third, neutrophil elastase can inactivate a phosphatidylserine receptor involved in cellular uptake and removal of apoptotic cells (31), possibly enhancing inflammation through diminished release of crackdowns papers transforming growth factor beta or through the release of inflammatory mediators from neutrophils that are not properly removed. Role of best way to Blood Vessels. Treatment of rats with a blocker of the vascular endothelial growth factor (VEGF) type 2 receptor caused emphysema that was associated with endothelial cell apoptosis and with markers of oxidant stress but was not accompanied by inflammation (32). The relevance of this process to research papers, COPD is supported by observations that oxidant stress decreases VEGF levels and ode on urn thesis statement that expression of both VEGF and its receptor are decreased in emphysema (29). Emphysema might result from failure of papers a lung cellular and molecular maintenance program due to a vicious cycle of oxidant stress and protease activation. Little is best way to act essay known regarding chronic regulation of alveolar septal endothelial cells, but studies of larger pulmonary vessels indicate that endothelial injury can lead to increased elastase activity and degradation of extracellular matrix (33).

An attractive therapeutic goal would be reversal of emphysema by increasing the number of alveoli. Police Crackdowns Research Papers? One model for this process is the septation of alveoli that occurs during late fetal and postnatal development. Although it has generally been assumed that adult lungs lack a capability for alveolar plasticity, the emphysema caused by lung instillation of elastase in adult rats was reversed by hyphothesis treatment with all- trans retinoic acid (34). A feasibility study of retinoic acid is underway in subjects with COPD. There has been encouraging progress in the identification of police crackdowns chemical markers of COPD.

Subjects with stable COPD were shown to have elevated markers of oxidant stress in exhaled air (35), of inflammation in serum and sputum (36, 37), and of elastin degradation in urine (38). These results suggest that multifaceted characterization of COPD patients may be possible by pay for teachers research noninvasive means. Pulmonary function is influenced by heredity (39, 40). There is also familial aggregation of COPD, indicating probable heritability of risk factors for the disease (41). Crackdowns? Precisely how genetic factors contribute to the risks of development and progression of COPD remains unknown, but there has been progress toward identification of relevant genes. Case control studies suggested associations between COPD and polymorphisms of the alpha1-antitrypsin, tumor necrosis factor alpha, and surfactant protein B genes (19, 42, 43).

A genome-wide screen of families having a proband with severe, early-onset COPD identified interesting regions on several chromosomes that may yield linkages with phenotypes of airflow obstruction and chronic bronchitis (44). Only modest progress has been made in characterizing the lung inflammation associated with COPD, particularly in comparison with the extensive profiling that has been performed in individuals with asthma. There are increased numbers of for persasive CD8 + T cells in the airways and lung parenchyma of smoking subjects with COPD, and there is a negative correlation between FEV1 (% predicted) and CD8+ T cell number (45). The large airways of smokers with severe COPD show increased numbers of crackdowns neutrophils, macrophages, and a grecian statement natural killer lymphocytes in comparison with smokers without clinically defined COPD; and each of these cell types is negatively associated with FEV1 (5). Neutrophils tend to localize with the airway epithelium, but nodules of B lymphocytes are found in the submucosa and adventitia (46). Research Papers? Substantial progress in immunological research should provide a basis for detailed characterization of the inflammatory process in COPD.

Airspace enlargement has been seen in numerous genetic mouse models, including both inbred strains (e.g., tight skin, pallid, and blotchy mice) and mice designed with constitutive overexpression of particular genes (e.g., collagenase or platelet-derived growth factor B). Pay For Paper? More recently, mouse models with inducible, lung-specific expression of particular cytokines have been shown to manifest lung abnormalities that are clearly not attributable to police crackdowns research papers, aberrant development of the lung. Essays? Overexpression of interleukin 11 in adult mice produced peribronchiolar lymphoid nodules similar to research papers, those observed in human COPD but did not cause emphysema (47). Overexpression in adult mice of either interferon, a major product of CD8+ lymphocytes, or interleukin 13, a mediator associated with CD4+ T cells and asthma, produced emphysema-like changes (14, 48). These models showed distinguishable profiles of increased protease expression and essay only interleukin 13 caused mucous metaplasia. Finally, a gene-targeting approach (loss of function) has proven useful for testing the contributions of various matrix metalloproteinases in the development of cigarette smoke-induced emphysema in the mouse (4).

Developments in three techniques for lung imaging may allow more sensitive detection and better quantification of lung injury in smokers and patients with COPD. High-resolution computed tomography (CT) now provides images of airways as small as 2 mm and indices of parenchymal density that correlate well with diffusing capacity (49). Magnetic resonance imaging (MRI) of crackdowns papers tracer gases in the lungs can demonstrate ventilation in real time (50) and way to write act essay may provide a measure of alveolar size (51). Positron emission tomography (PET) can potentially be used to quantify inflammatory cell activity in crackdowns research the lungs (52). These methods may prove to be of cite essay great value for characterization of the lung in COPD with respect to localization of disease (e.g., pattern of emphysema by police CT), physiological sequelae (e.g., air trapping by MRI), and in vivo biochemical and cellular analyses (by PET).

Molecular Characterization of Diseased Tissues and Cells. The identification of most human genes paves the way for characterization of diseased tissues at essay an unprecedented level of molecular detail. The expression levels of a multitude of genes in papers a tissue can be assayed with microarrays of gene-specific probes, whereas reverse transcription in histological sections can be used to show the distribution of expression of a particular gene at high spatial resolution. Development of antibody-based microarrays may allow characterization of the expression of multiple genes at the protein level. Of particular interest to COPD research, given the multiplicity of drugs essay cell types in crackdowns papers the lung, are methods such as laser capture microdissection for isolation of RNA from single cells (53) and techniques for reverse transcription and cDNA amplification in situ . Coupled with sensitive assays, these developing methods may allow gene expression profiling at cite anthology essay the single-cell level (54). Immunoblot analysis of a protein from a single cell may also be possible by amplification of a double-stranded DNA label on the secondary antibody (55). Classes of pharmaceuticals of potential usefulness in COPD that are either available now or are anticipated in the near future include long-acting M3-selective muscarinic antagonists, leukotriene B4 inhibitors, 5-lipoxygenase inhibitors, phosphodiesterase 4 inhibitors, thromboxane antagonists, endothelin antagonists, adenosine A2a agonists, antioxidants, nuclear factor kappa B inhibitors, adhesion molecule antagonists, p38 mitogen-activated protein kinase inhibitors, interleukin 8 antagonists, tumor necrosis factor antagonists, neutrophil elastase inhibitors, matrix metalloproteinase inhibitors, tachykinin antagonists, mucolytics, antiapoptotic compounds, and crackdowns enhancers of mucociliary clearance. Even when proof of pay for teachers research paper principle is established, the ability of any of these agents to alter outcomes in COPD remains speculative because the critical pathogenetic pathways for this disease have not yet been determined. An important limiting factor in development of drug treatments for COPD is the lack of research efficient and economical means to identify which drugs are most likely to be of value and to test their clinical efficacy.

RECOMMENDATIONS FOR FUTURE RESEARCH. There was consensus among members of the Working Group that the way to following objectives are important to COPD research and are feasible within approximately five years. It was noted that the police research papers accomplishment of these goals will require a substantial increase in COPD research activity, with training and recruitment of additional researchers and merit pay for research paper enhanced cooperation between universities and the pharmaceutical industry. In many cases, the need has long been recognized, but the opportunity to accomplish the research has come about as a result of the development of new experimental tools and police crackdowns research techniques. Description of the Disease Process. Characterization of human lung tissues by best write advanced molecular, biochemical, microbiological, and histopathological methods. Research progress in COPD is hampered by a lack of police research fundamental knowledge regarding the essay conclusion pathology of this disease, particularly with regard to small airways.

Changes with COPD in the structure, cellular composition, inflammatory status, and chemical milieu of the lung are poorly defined, as are the relationships of these changes to clinical manifestations of the police crackdowns research papers disease. There is cite anthology a need for systematic comparison of lung structural, inflammatory, and biochemical characteristics with clinical history, status, and research course. Hyphothesis Testing? Characterization of research papers lung tissues can now be performed with exquisite detail, using advanced methods of immunology, viral and microbial detection, molecular histopathology, microarray profiling of gene expression, and proteomic analysis. An appropriate source of tissues for hyphothesis testing such studies may be surgical specimens from individuals with suspected lung cancer, a population that is at substantial risk for COPD. An appropriate mechanism might be a cooperative research program that combines the efforts of police papers academic and industrial researchers in characterization of a large number of subjects and in the establishment of a repository for DNA, tissues, other biological specimens, and clinical data. Biomarkers and intermediate end points. One limitation in COPD research is the lack of essays readily measurable markers that correlate with disease severity or outcome. Long-term monitoring of declines in police crackdowns research papers FEV1 has been used to identify risk factors and gauge the efficacy of testing putative therapies, but that approach is slow and expensive. Biomarkers of COPD would be of value for investigations of the natural history and epidemiology of COPD, for phenotyping in genetic studies, and for clarifying the relationships of animal models to human disease.

Validated surrogate markers of COPD might also serve as intermediate end points for police crackdowns research evaluations of efficacy and appropriate dosage of potential therapeutic agents in essay relatively short-term studies. Markers involving noninvasive methods would be of particular value. A wide range of possible approaches exists, including ( 1 ) chemicals in breath, sputum, blood, or urine that reflect lung inflammation or injury; ( 2 ) improved noninvasive mechanical tests of lung function; ( 3 ) proteomic and gene expression profiling; and ( 4 ) lung imaging by crackdowns CT, MRI, or PET. Longitudinal and cross-sectional studies of well characterized smokers with and without COPD are needed to evaluate the correlation of a broad array of putative markers with COPD susceptibility, severity, exacerbation, and progression. Inflammation. Despite the failure of inhaled corticosteroids to slow the decline of FEV1 in COPD (8), other anti-inflammatory agents might be highly effective.

Studies are needed to better characterize the cite anthology essay inflammation of COPD, to define what is crackdowns papers appropriate immune function in the lung, and to for persasive essays, discover pharmacological means for police research papers ensuring beneficial, rather than injurious, contributions of lung inflammatory cells. Hyphothesis? Three lines of investigation may be involved. First, extensive characterization of the inflammatory status of smokers with and without COPD is needed to define the crackdowns subtypes of inflammatory cells present, the movement and fate of immune cells recruited to the lung, and the particular cytokines involved. Second, genetic factors governing immune responsiveness should be identified and tested as possible determinants of susceptibility to lung injury. Third, in vitro systems and animal models should be utilized to way to, investigate the effects of tobacco smoke components on inflammatory cells and to study inflammatory cell trafficking and mechanisms of crackdowns research sustained inflammation.

Genetic risk factors. A knowledge of genetic determinants of COPD could lead to recognition of biochemical pathways that contribute to the disease and allow targeting of public health interventions to individuals at greatest risk. A program for identification of testing genes related to COPD should consider several issues: First, simultaneous characterization of multiple phenotypes will be necessary because different genes may be related to different aspects of the disease (e.g., susceptibility, severity, propensity to exacerbation, rate of crackdowns research papers progression, and chronic bronchitis vs. emphysema). For Persasive? Second, family-based studies involving genome-wide screening by linkage analysis of research papers affected sibling pairs or extended pedigrees should be used because there is a high probability that unsuspected genes are involved. Families in isolated populations, rather than outbred populations like the general U.S. population, may be studied more efficiently. Third, animal models are an for persasive, essential component of a human genetics program because they can be used to identify candidate genes and to study the pathophysiological ramifications of papers a defined genotype.

Fourth, case-control association studies of particular candidate genes will eventually be needed to test the paper relevance of results obtained in police research particular families to the disease in the general population. Selection criteria for candidate genes should include probable biological relevance to known pathophysiology, evidence of involvement with disease in animal models, and data from human studies for gene linkage with COPD. Fifth, although not ideal for genetic studies, clinical trials involving large numbers of well-characterized subjects with COPD should obtain and essay conclusion archive DNA samples whenever possible to allow for later analysis of candidate genes. Causes and consequences of exacerbations. Crackdowns Research Papers? Although disease exacerbations are a major concern of both patients with COPD and their physicians, an understanding of the origins and development of these episodes is lacking. Ode On Urn Thesis Statement? There is a need for research directed toward identifying the bases of COPD exacerbations and clarifying the pathophysiological processes that contribute to worsening of crackdowns research papers symptoms.

Of particular interest are the roles of best act essay infectious agents, other environmental insults, and immune responsiveness in crackdowns exacerbations and for persasive essays the relationships between exacerbations and the underlying disease process. Mucous metaplasia and research papers excess mucous secretion. Mucous production is troublesome to many patients with COPD, yet little is for persasive essays known regarding the mechanisms of mucous hypersecretion, the benefits and risks associated with increased mucous production, or the police crackdowns research means whereby mucin secretion, mucus composition, and mucociliary clearance might be therapeutically regulated. Research is needed to a grecian statement, expand our understanding of the crackdowns molecular and cellular mechanisms of mucous metaplasia and excess mucous production. Studies of the submucosal glands of small airways are especially needed because these glands are probably of teachers paper most importance in research papers COPD and have attracted relatively little research interest. Animal models. The development of essays new animal models of COPD is important for hypothesis testing regarding pathogenetic mechanisms of COPD. Police Crackdowns Papers? Topics of special interest include the biochemical basis of lung growth, damage, and repair; the necessity and sufficiency of specific inflammatory and mucous pathways for the development of small airways disease; and the reversibility of lung damage.

Efforts should be made to correlate pulmonary physiological abnormalities, radiographic images, proteomic profiles, and small airway pathology in these animal models. Lung development and alveolar regeneration. Stimulation of alveolar regeneration is an exciting possibility for hyphothesis disease-modifying therapy of COPD. Fundamental advances in this area are likely to derive from animal studies of alveolar development in the late fetal and postnatal periods. Such research might include gene expression and proteomic analyses of the developing lung, studies of the regulation of expression of relevant genes, studies of the coordination of vascularization and police papers lung development and repair, use of transgenic mice to evaluate the role of specific growth factors in the lung, and investigations of the mechanisms whereby toxins (e.g., in utero nicotine) impair lung growth. In addition, studies of alveolar regeneration in adults of essays multiple species are needed to deter-mine the capacity of mature lungs for alveolar regrowth and the conditions under which alveolar regeneration can occur. Clinical studies.

Although not extensively discussed, Working Group participants recommended controlled studies to validate or revise current clinical practices. Potential areas for such research include, but are not limited to, indications for long-term oxygen therapy, management of sleep disturbance in COPD, alleviation of nocturnal hypoxemia, prevention and treatment of exacerbations, and better tools for disease monitoring. Acknowledgment : Participants: Chair John R. Hoidal, M.D. Crackdowns Research Papers? (Salt Lake City, UT); Session Chairs David M. Ode On? Center, M.D. (Boston, MA), Donald J. Massaro, M.D. Police Research Papers? (Washington, DC), Robert M. Senior, M.D. (St. Best Act Essay? Louis, MO), Steven D. Police? Shapiro, M.D. (St. Louis, MO), and Edwin K. Hyphothesis Testing? Silverman, M.D. (Boston, MA); and Carol B. Crackdowns Research Papers? Basbaum, Ph.D. Merit Pay For Paper? (San Francisco, CA), Linda B. Police Crackdowns Research Papers? Clerch, Ph.D. (Washington, DC), Thomas L. Croxton, Ph.D., M.D. (Bethesda, MD), Francis M. Cuss, M.D. (Kenilworth, NJ), James Eberwine, Ph.D. (Philadelphia, PA), Dorothy B. Gail, Ph.D. (Bethesda, MD), Jack A. Elias, M.D. Ode On? (New Haven, CT), Michael D. Goldman, M.D., Sc.D. Police Research? (Los Angeles, CA), Douglas Hay, Ph.D. (King of Prussia, PA), Peter M. Essay? Henson, Ph.D. Crackdowns Research? (Denver, CO), Jonathan Jaffe, M.D. Cite Anthology? (Kenilworth, NJ), James P. Kiley, Ph.D. (Bethesda, MD), Talmadge E. King, M.D. Police Crackdowns Research Papers? (San Francisco, CA), Barbara Knorr, M.D. (Rahway, NJ), Claude Lenfant, M.D. (Bethesda, MD), Gloria D. Massaro, M.D. Essay? (Washington, DC), George T. O'Connor, M.D. (Boston, MA), Marlene Rabinovitch, M.D. (Toronto, Canada), Sri Ram, Ph.D. (Bethesda, MD), Garth Rapaport, M.B.Bch., MRCP, FFPM (Greenford, Middlesex, UK), Anuradha Ray, Ph.D. (New Haven, CT), Stephen I. Rennard, M.D. (Omaha, NE), James R. Snapper, M.D. (Research Triangle Park, NC), Rubin M. Tuder, M.D. (Baltimore, MD), Norbert F. Voelkel, M.D. (Denver, CO), Gail G. Weinmann, M.D. Police Crackdowns Papers? (Bethesda, MD), Scott T. Weiss, M.D., M.S. (Boston, MA), Robert A. Wise, M.D. (Baltimore, MD), Theodore J. Witek, Jr., Dr.P.H. (Ridgefield, CT). 1. Stang P, Lydick E, Silberman C, Kempel A, Keating ET.

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( Received in original form August 8, 2001; accepted in final form November 26, 2001 ) Sponsored by the Division of Lung Diseases, National Heart, Lung, and police crackdowns papers Blood Institute on March 5-6, 2001 in Bethesda, Maryland.

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essays on acting On Actors and Acting 1. PLAYERS are the abstracts and brief chronicles of the time; the motley representatives of human nature. They are the only honest hypocrites. Their life is crackdowns papers, a voluntary dream; a studied madness. The height of their ambition is to essay conclusion be beside themselves. To-day kings, to-morrow beggars, it is only when they are themselves, that they are nothing. Made up of mimic laughter and tears, passing from the extremes of research papers, joy or woe at the prompter's call, they wear the livery of conclusion, other men's fortunes; their very thoughts are not their own. They are, as it were, train-bearers in the pageant of life, and hold a glass up to humanity, frailer than itself.

We see ourselves at crackdowns research, second-hand in them: they show us all that we are, all that we wish to be, and all that we dread to be. The stage is an epitome, a bettered likeness of the world, with the dull part left out: and, indeed, with this omission, it is nearly big enough to drugs essay hold all the rest. What brings the papers resemblance nearer is, that, as they imitate us, we, in our turn, imitate them. Merit Teachers Paper. How many fine gentlemen do we owe to the stage? How many romantic lovers are mere Romeos in crackdowns research papers, masquerade? How many soft bosoms have heaved with Juliet's sighs? They teach us when to laugh and when to weep, when to love and when to hate, upon best way to write act essay principle and with a good grace! Wherever there is a play-house, the world will go on not amiss. The stage not only refines the manners, but it is the best teacher of morals, for it is the truest and most intelligible picture of life. It stamps the image of virtue on the mind by first softening the rude materials of police papers, which it is composed, by a sense of pleasure.

It regulates the conclusion passions by giving a loose to the imagination. Crackdowns. It points out the hyphothesis selfish and depraved to our detestation; the amiable and generous to police papers our admiration; and if it clothes the more seductive vices with the borrowed graces of wit and fancy, even those graces operate as a diversion to the coarser poison of experience and bad example, and often prevent or carry off the infection by inoculating the mind with a certain taste and elegance. To shew how little we agree with the common declamations against the immoral tendency of the stage on this score, we will hazard a conjecture, that the acting of the Beggar's Opera a certain number of nights every year since it was first brought out, has done more towards putting down the practice of highway robbery, than all the gibbets that ever were erected. A person, after seeing this piece, is too deeply imbued with a sense of humanity, is in cite, too good humour with himself and crackdowns papers the rest of the world, to set about cutting throats or rifling pockets. Whatever makes a jest of vice, leaves it too much a matter of indifference for any one in his senses to rush desperately on ode on urn thesis statement his ruin for police crackdowns papers, its sake. We suspect that just the contrary effect must be produced by the representation of George Barnwell, which is cite anthology, too much in the style of the Ordinary's sermon to meet with any better success. The mind, in such cases, instead of being deterred by crackdowns research, the alarming consequences held out to it, revolts against the denunciation of them as an insult offered to its free-will, and, in best way to write act essay, a spirit of defiance, returns a practical answer to them, by daring the worst that can happen. The most striking lesson ever read to levity and licentiousness, is in police crackdowns, the last act of the Inconstant, where young Mirabel is preserved by the fidelity of essays, his mistress, Orinda, in the disguise of a page, from the hands of assassins, into whose power he has been allured by the temptations of vice and beauty. There never was a rake who did not become in imagination a reformed man, during the representation of the last trying scenes of this admirable comedy. If the stage is useful as a school of instruction, it is no less so as a source of amusement.

It is the police crackdowns research source of the greatest enjoyment at the time, and a never-failing fund of agreeable reflection afterwards. The merits of a new play, or of for persasive essays, a new actor, are always among the first topics of polite conversation. One way in which public exhibitions contribute to refine and police crackdowns humanize mankind, is by supplying them with ideas and cite anthology essay subjects of conversation and crackdowns interest in common. The progress of civilization is in proportion to conclusion the number of common-places current in society. Crackdowns Papers. For instance, if we meet with a stranger at an inn or in a stage-coach, who knows nothing but his own affairs, his shop, his customers, his farm, his pigs, his poultry, we can carry on no conversation with him on these local and personal matters: the only way is to let him have all the talk to himself. But if he has fortunately ever seen Mr. Testing. Liston act, this is an immediate topic of police crackdowns research papers, mutual conversation, and we agree together the rest of the essay conclusion evening in discussing the merits of that inimitable actor, with the same satisfaction as in talking over the affairs of the most intimate friend. If the stage thus introduces us familiarly to our contemporaries, it also brings us acquainted with former times. It is an interesting revival of past ages, manners, opinions, dresses, persons, and police research actions,-whether it carries us back to the wars of York and Lancaster, or half-way back to the heroic times of Greece and Rome, in some translation from the French, or quite back to the age of Charles II. in ode on a grecian statement, the scenes of Congreve and of Etherege, (the gay Sir George!) -- happy age, when kings and nobles led purely ornamental lives, when the utmost stretch of a morning's study went no farther than the research choice of a sword-knot, or the adjustment of a side-curl; when the soul spoke out in all the pleasing eloquence of dress; and beaux and ode on a grecian urn thesis belles, enamoured of themselves in one another's follies, fluttered like gilded butterflies in police crackdowns, giddy mazes through the walks of St. James's Park!

A good company of comedians, a Theatre-Royal judiciously managed, is your true Herald's College; the only Antiquarian Society that is worth a rush. It is for this reason that there is such an air of romance about players, and that it is pleasanter to see them, even in their own persons, than any of the merit teachers paper three learned professions. We feel more respect for police crackdowns, John Kemble in a plain coat, than for the Lord Chancellor on the woolsack. He is surrounded, to cite essay our eyes, with a greater number of imposing recollections: he is a more reverend piece of police crackdowns papers, formality; a more complicated tissue of costume. We do not know whether to look upon this accomplished actor as Pierre or King John or Coriolanus or Cato or Leontes or the Stranger. But we see in him a stately hieroglyphic of humanity; a living monument of a grecian urn thesis, departed greatness; a sombre comment on the rise and fall of kings. We look after him till he is out of papers, sight, as we listen to a story of hyphothesis testing, one of Ossian's heroes, to a tale of other times! One of the most affecting things we know is to see a favourite actor take leave of the stage. We were present not long ago when Mr. Police Crackdowns Research. Bannister quitted it.

We do not wonder that his feelings were overpowered on the occasion: ours were nearly so too. We remembered him in the first heyday of our youthful spirits, in the Prize in which he played so delightfully with that fine old croaker Suett, and Madame Storace, -- in the farce of My Grandmother, in best write, the Son-in-Law, in Autolycus, and in Scrub, in which our satisfaction was at research, its height. At that time, King and Parsons, and Dodd, and Quick, and cite anthology essay Edwin were in the full vigour of their reputation, who are now all gone. We still feel the vivid delight with which we used to see their names in the play-bills as we went along to the theatre. Police Papers. Bannister was one of the last of these that remained; and we parted with him as we should with one of our oldest and best friends. The most pleasant feature in ode on statement, the profession of a player, and which, indeed; is peculiar to it, is research, that we not only essays, admire the talents of those who adorn it, but we contract a personal intimacy with them. There is police, no class of society whom so many persons regard with affection as actors. We greet them on research the stage; we like to meet them in crackdowns research, the streets; they almost always recall to us pleasant associations; and we feel our gratitude excited, without the uneasiness of a sense of obligation. The very gaiety and popularity, however, which surround the life of a favourite performer, make the retiring from it a very serious business.

It glances a mortifying reflection on write the shortness of human life, and the vanity of human pleasures. Something reminds us, that all the world's a stage, and all the men and women merely players. It has been considered as the misfortune of first-rate talents for the stage, that they leave no record behind them except that of vague rumour, and that the genius of a great actor perishes with him, leaving the world no copy. This is a misfortune, or at least an unpleasant circumstance, to actors; but it is, perhaps, an advantage to the stage. It leaves an opening to originality. The stage is always beginning anew; -- the candidates for theatrical reputation are always setting out afresh, unencumbered by the affectation of the faults or excellences of their predecessors. In this respect, we should imagine that the average quantity of dramatic talent remains more nearly the same than that in any other walk of art. In no other instance do the complaints of the degeneracy of the moderns seem so unfounded as in this; and Colley Cibber's account of the regular decline of the stage, from the time of Shakespeare to police crackdowns research papers that of testing, Charles II. and from the time of police crackdowns papers, Charles II. to the beginning of George II. appears quite ridiculous.

The stage is a place where genius is sure to come upon write its legs, in a generation or two at crackdowns research papers, farthest. In the other arts (as painting and poetry), it has been contended that what has been well done already, by giving rise to endless vapid imitations, is an obstacle to what might be done well hereafter: that the models or chef d'oeuvres of art, where they are accumulated, choke up the pay for teachers path to excellence; and that the police crackdowns works of genius, where they can be rendered permanent and handed down from age to age, not only prevent, but render superfluous, future productions of the same kind. We have not, neither do we want, two Shakespeares, two Miltons, two Raphaels, any more than we require two suns in the same sphere. Even Miss O'Neill stands a little in the way of our recollections of Mrs. Siddons. But Mr. Kean is an excellent substitute for the memory of Garrick, whom we never saw. When an author dies, it is no matter, for his works remain. When a great actor dies, there is a void produced in essays, society, a gap which requires to be filled up. Who does not go to police see Kean?

Who, if Garrick were alive, would go to see him? At least, one or the other must have quitted the stage.We have seen what a ferment has been excited among our living artists by teachers, the exhibition of the works of the old masters at the British Gallery. Police Papers. What would the actors say to it, if, by any spell or power of necromancy, all the celebrated actors, for the last hundred years, could be made to appear again on the boards of Covent Garden and Drury Lane, for the last time, in all their most brilliant parts? What a rich treat to anthology essay the town, what a feast for the critics, to go and police see Betterton, and Booth, and Wilks, and Sandford, and Nokes, and Leigh, and Penkethman, and Bullock, and Esteourt, and Dogget, and merit pay for research paper Mrs. Research. Barry, and Mrs. Testing. Montfort, and Mrs. Oldfield, and Mrs. Bracegirdle, and Mrs.

Cibber, and Cibber himself, the prince of coxcombs, and Macklin, and Quin, and Rich, and Mrs. Research Papers. Clive, and testing Mrs. Crackdowns. Pritchard, and Mrs. Abington, and a grecian Weston, and crackdowns papers Shuter, and Garrick, and all the rest of those, who gladdened life, and whose deaths eclipsed the gaiety of merit teachers research paper, nations! We should certainly be there. We should buy a ticket for the season.

We should enjoy our hundred days again. We should not miss a single night. We would not, for a great deal, be absent from Betterton's Hamlet or his Brutus, or from Booth's Cato, as it was first acted to the contending applause of Whigs and Tories. We should be in the first row when Mrs. Barry (who was kept by Lord Rochester, and with whom Otway was in love) played Monimia or Belvidera; and we suppose we should go to see Mrs. Bracegirdle (with whom all the world was in love) in all her parts. We should then know exactly whether Penkethman's manner of picking a chicken, and Bullock's mode of devouring asparagus, answered to the ingenious account of them in the Tatler; and research whether Dogget was equal to Dowton -- Whether Mrs. Merit Pay For Research. Montfort2 or Mrs. Abington was the finest lady -- Whether Wilks or Cibber was the best Sir Harry Wildair-Whether Macklin was really the crackdowns research Jew that Shakespeare drew, and whether Garrick was, upon the whole, so great an actor as the world have made him out! Many people have a strong desire to pry into the secrets of act essay, futurity: for our own parts, we should be satisfied if we bad the power to recall the dead, and live the papers past over drugs essay conclusion again, as often as we pleased! -- Players, after all, have little reason to complain of their hard-earned, short-lived popularity.

One thunder of applause from pit, boxes, and gallery, is equal to a whole immortality of posthumous fame: and research papers when we hear an actor, whose modesty is equal to his merit, declare that he would like to see a dog wag his tail in approbation, what must he feel when he sets the for persasive whole house in a roar! Besides, Fame, as if their reputation had been entrusted to her alone, has been particularly careful of the police research renown of her theatrical favourites she forgets one by one, and year by year, those who have been great lawyers, great statesmen, and great warriors in their day; but the name of essays, Garrick still survives with the works of Reynolds and of Johnson. Actors have been accused, as a profession, of being extravagant and dissipated. Research. While they are said to be so as a piece of common cant, they are likely to continue so. But there is a sentence in Shakespeare which should be stuck as a label in the mouths of our beadles and whippers-in of morality. The web of our life is hyphothesis testing, of a mingled yarn, good and ill together: our virtues would be proud if our faults whipped them not: and our vices would despair if they were not cherished by our virtues. With respect to the extravagance of actors, as a traditional character, it is not to be wondered at. They live from research hand to hyphothesis testing mouth: they plunge from want into luxury; they have no means of police research, making money breed, and all professions that do not live by turning money into money, or have not a certainty of accumulating it in the end by parsimony, spend it. Uncertain of the future, they make sure of the present moment.

This is not unwise. Chilled with poverty, steeped in essays, contempt, they sometimes pass into the sunshine of fortune, and are lifted to the very pinnacle of public favour; yet even there cannot calculate on the continuance of success; but are, like the giddy sailor on the mast, ready with every blast to topple down into the fatal bowels of the deep! Besides, if the young enthusiast, who is smitten with the stage, and with the public as a mistress, were naturally a close hunks, he would become or remain a city clerk, instead of turning player. Again, with respect to the habit of convivial indulgence, an actor, to police crackdowns be a good one, must have a great spirit of for persasive essays, enjoyment in himself, strong impulses, strong passions, and a strong sense of crackdowns papers, pleasure: for it is his business to imitate the passions, and to communicate pleasure to others. Essays. A man of genius is not a machine. The neglected actor may be excused if he drinks oblivion of his disappointments; the successful one if he quaffs the applause of the crackdowns papers world, and enjoys the friendship of those who are the friends of the favourites of fortune, in draughts of nectar.

There is merit pay for teachers research, no path so steep as that of fame: no labour so hard as the pursuit of excellence. Research Papers. The intellectual excitement, inseparable from those professions which call forth all our sensibility to pleasure and pain, requires some corresponding physical excitement to hyphothesis support our failure, and not a little to allay the ferment of the spirits attendant on research success. If there is any tendency to dissipation beyond this in the profession of a player, it is owing to the prejudices entertained against them, to for persasive that spirit of bigotry which in a neighbouring country would deny actors Christian burial after their death, and to crackdowns research papers that cant of criticism, which, in our own, slurs over their characters, while living, with a half-witted jest. A London engagement is generally considered by actors as the ne plus ultra of their ambition, as a consummation devoutly to be wished; as the great prize in the lottery of their professional life. But this appears to us, who are not in the secret, to be rather the prose termination of their adventurous career: it is the provincial commencement that is the poetical and truly enviable part of it. After that, they have comparatively little to hope or fear. The wine of life is drunk, and but the lees remain. In London, they become gentle men, and drugs conclusion the King's servants: but it is the romantic mixture of the hero and the vagabond that constitutes the essence of the player's life. It is the transition from their real to their assumed characters, from the contempt of the world to the applause of the multitude, that gives its zest to the latter, and crackdowns research papers raises them as much above common humanity at night, as in the day-time they are depressed below it.

Hurried from fierce extremes, by contrast made more fierce, -- it is rags and a flock-bed which give their splendour to a plume of urn thesis statement, feathers and a throne. We should suppose, that if the most admired actor on the London stage were brought to confession on this point, he would acknowledge that all the applause he had received from brilliant and overflowing audiences, was nothing to the light-headed intoxication of unlooked-for success in a barn. In town, actors are criticised: in country-places, they are wondered at, or hooted at: it is of little consequence which, so that the interval is not too long between. For ourselves, we own that the description of the strolling player in Gil Blas , soaking his dry crusts in police research papers, the well by paper, the road-side, presents to us a perfect picture of human felicity. 1 Hazlitt's On Actors and Acting was first published in the The Examiner , January 5, 1817 and was one of the essays picked to crackdowns research go into hyphothesis, his first book, The Round Table (1815-17). 2 The following lively description of this actress is given by Cibber in his Apology: What found most employment for her whole various excellence at once, was the part of Melantha, in Marriage-a-laMode. Melantha is as finished an impertinent as ever fluttered in a drawing-room, and seems to contain the most complete system of female foppery that could possibly be crowded into the tortured form of a fine lady. Her language, dress, motion, manners, soul, and body, are in a continual hurry to be something more than is necessary or commendable. And, though I doubt it will be a vain labour to offer you a just likeness of Mrs. Montfort's action, yet the fantastic impression is crackdowns research papers, still so strong in my memory, that I cannot help saying something, though fantastically, about it. The first ridiculous airs that break from her are upon a gallant never seen before, who delivers her a letter from her father, recommending him to her good graces, as an honourable lover.

Here now, one would think she might naturally show a little of the for persasive essays sex's decent reserve, though never so slightly covered! No, sir; not a tittle of it; modesty is the virtue of a poor-soul'd country gentlewoman: she is too much a court-lady to be under so vulgar a confusion: she reads the police research letter, therefore, with a careless, dropping lip, and an erected brow, humming it hastily over, as if she were impatient to outgo her father's commands, by making a complete conquest of him at once: and that the letter might riot embarrass her attack, crack! she crumbles it at once into her palm, and pours upon him her whole artillery of airs, eyes, and motion; down goes her dainty, diving body to the ground, as if she were sinking under the conscious load of her own attractions; then launches into a flood of fine language and hyphothesis testing compliment, still playing her chest forward in fifty falls and risings, like a swan upon waving water; and, to complete her impertinence, she is so rapidly fond of her own wit, that she will not give her lover leave to praise it. Silent assenting bows, and vain endeavours to speak, are all the share of the conversation he is admitted to, which at last he is relieved from, by her engagement to half a score visits, which she swims from him to make, with a promise to return in a twinkling. -- The Life of crackdowns research papers, Colley Cibber , p. 138.