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 ====== Chronic Obstructive Pulmonary Disease (COPD) ======
+{{:4._copd-_presentation.pdf|}}
 ===== Introduction =====
-A Genetically Modified Organism is any organism created by gene splicing techniques and often involves merging DNA from different species (31). Scientists directly manipulate an organism’s genome to isolate traits or characteristics deemed of value. Currently, the safety of GMOs is under research as they are relatively recent developments (22).
 **What is COPD**
-<box width classes round white centre|>{{:timeline_of_the_development_of_gmo_s.png|}}</box| Figure 1: A timeline of the development of GMOs.
+Chronic obstructive pulmonary disease, denoted as COPD is a type of obstructive lung disease (n.d., 2013). It is characterized by long-term poor airflow and displays symptoms including cough with sputum production and shortness of breath. Figure 1 displays a visual representation of a lung tissue of a healthy individual and of an individual with COPD. From the beginning of its diagnosis, these symptoms from individuals with COPD tend to worsen over time. It is the fourth leading cause of death in the world as of 2013.
-Modifed from  http://sitn.hms.harvard.edu/flash/2015/from-corgis-to-corn-a-brief-look-at-the-long-history-of-gmo-technology/>
+<box width classes round white centre|>{{:normal_and_copd_lung.png}}</box| Figure 1: Lung tissues of a normal individual and of an individual with COPD. Retrieved from: http://www.nhlbi.nih.gov/health/health-topics/topics/copd>
-**Prevalence and Epidemiology of the Disease**
-<box width classes round white centre|>{{:procedure_to_make_a_gm_plant.jpeg|}}</box| Figure 2: The procedure to make a GM plant.
+**Epidemiology and Economic Burden of the Disease**
-Modified from: http://sitn.hms.harvard.edu/flash/2015/how-to-make-a-gmo/>
+As of 2010, 329 million people, approximately 4.8% of the population are affected by COPD (n.d. 2010). The primary cause of COPD is due to the rise in tobacco use among both men and women. The increase in the developing world since 1970 is believed to influence the increase in smoking within the region. The global numbers are expected to progressively increase as risk factors remain prevalent and the aging population continues to increase. As expected, COPD is more common in older people; on average, it affects 34-200 out of 1000 people older than 65 years.
+COPD is also considered one of the most expensive conditions to treat in U.S. hospitals in 2011, averaging to approximately $5.7 billion. The global estimated cost of treating COPD is $2.1 trillion; $1.9 trillion goes to direct medical care costs such as patient care and $0.2 trillion goes to indirect medical care costs such as sick pay for medical professionals. Costs are projected to more than double by 2030.
-**Economic Burden of COPD**
 **Mechanism of Disease**
+COPD is an airway inflammation syndrome which consists of structural changes and mucociliary dysfunction.
+**Structural Changes**
-===== Causes and Pathophysiology =====
+The pulmonary system undergoes structural changes as a direct result of the inflammatory response that is associated with COPD. Eventually, this leads to the narrowing of the airways, making it harder for the individual to breathe. Parenchymal destruction is associated with loss of lung tissue elasticity (Takeda, 2012), implicating that the small airways collapse during exhalation and impedes airflow.
-**Environmental Factors - Air Pollution**
+**Mucociliary Dysfunction**
+Chronic smoking and COPD inflammation forces mucous glands that line the airway lung walls to enlarge. This in turn, causes healthy cells to be replaced by excessive mucus-secreting cells. Over time, COPD also causes damage to the mucociliary transport system which is primarily responsible for clearing the mucus from airways. Figure 2 shows a visual representation of the mechanism in how the presence of mucus worsens airflow.
+<box width classes round white centre|>{{:untitled6.png}}</box| Figure 2: Mechanism of Mucociliary effects from COPD. Retrieved from: https://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_disease>
-**The Relationship Between COPD Deaths and Air Pollution**
+===== Causes and Pathophysiology =====
+**Environmental Factors - Air Pollution**
+Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease. Matheson, M.C., et al., performed a cross sectional study of the risk factors of COPD relating to job history of 1200 participants. Those exposed to biological dust had increased risk of chronic bronchitis, emphysema and COPD with incidence being higher in women compared to men even though they reported less exposure to biological dust than men. Biological dust includes microbes such as plant and animal, bacteria, fungi, allergens, endotoxins, peptidoglycans, glucans and pollens. Occupations affected by biological dust are those in the cotton industry, farmers, grain handlers, bakers, saw mill workers, nurses, artists, and cleaners.
+The duration and type of exposure plays a role in increasing risk of COPD. Gas, fumes, and mineral dust do not pose a risk. The only way to reduce risk is to reduce exposure to these in the workplace (Matheson, M., 2005).
-Advances in molecular and reproductive technology have driven the practice of commercial animal pharming over the past twenty years (14). Pharming is a branch of biotechnology which bridges together the contrasting fields of pharmaceuticals and farming. Transgenic plants or animals are utilized for producing pharmaceuticals synthesized for human or animal consumption (7). Animal pharming is promoted as a cost-effective method of biopharmaceutical production (14) and has the potential to become a highly lucrative industry (7).
+**Outdoor Air Pollution**
+Urban areas have the worst air pollution with some countries having more air
+pollution than others. Air pollutants have harmful effects on the airways, they increase oxidative stress, pulmonary and systemic inflammation, amplification of viral infections and reduction in air ciliary activity (Ko, F. & Hui, D., 2012). Higher traffic density is proven to be associated with higher pollution and lower forced expiratory volume (Ko, F. & Hui, D., 2012). Therefore it is biologically possible that air pollutants damage lungs, but it is not determined to be a causative factor due to lack of long-term studies.
-The need for pharmaceutical intervention is evident amongst patients possessing hereditary antithrombin deficiencies. In 2006, an anticoagulant called Antithrombin became the first recombinant protein to be approved for commercialization by the United States’ Food and Drug Administration (FDA) (18). Antithrombin is extracted and purified from the milk of transgenic dairy goats (16). Transgenic animals, such as these goats, are produced via one of two contemporary methods: intra-pronuclear zygotic DNA microinjection (MI) or somatic cell nuclear transfer (NT). As linear DNA enters the nucleus, it is capable of integrating into the genome of cell lines or living organisms (18).
-The most promising site for production of recombinant proteins is the mammary gland due to the large quantities of protein that can be produced (16). Since milk is often produced in abundance, deriving and producing pharmaceuticals in this manner is determined to be cost efficient (14).
+**Indoor Air Pollution**
+Indoor air pollutants include tobacco smoke and biological allergens/ exposure are the
+major indoor pollutants. A cross sectional study in China and the USA proved that tobacco smoke from others is associated with development of COPD (Ko, F. & Hui, D., 2012). Biomass as a fuel source includes burning wood, crop residues, and animals during cooking or heating the home which releases toxins. Toxins are released because these fuels have low combustion efficiency. In rural and developing countries biomass fuel burning happens inside resulting in increased amounts of indoor air pollution (Ko, F. & Hui, D., 2012). Women are also more affected by indoor and outdoor air pollution (Ko, F. & Hui, D., 2012).
+COPD results from the combination of genetic and environmental factors; having more than one risk factor increases odds of getting the disease.
-<box width classes round white centre|>{{:producing_transgenic_animals.jpg|}}</box| Figure 3. Producing Transgenic Animals. Modified from: Maksimenko, Deykin, Khodarovich & Georgiev (2013)>
+<box width classes round white centre|>{{:summary_of_pathways_and_candidate_genes_involved_in_copd.png|}}</box| Figure 3: Summary of Pathways and Candidate Genes Involved in COPD. Retrieved from:
+http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.629.4676&rep=rep1&type=pdf>
@@ Line 65: / Line 83: @@
-<box width classes round white centre|>{{:a._normal_small_airway_b._abnormal_small_airway_exhibiting_airway_remodeling_in_copd._berge_et_al._2011_.png|}}</box| Figure : A. Normal Small Airway, B. Abnormal Small Airway Exhibiting Airway Remodeling in COPD. Modified from: Berge et al. (2011)>
+<box width classes round white centre|>{{:a._normal_small_airway_b._abnormal_small_airway_exhibiting_airway_remodeling_in_copd._berge_et_al._2011_.png|}}</box| Figure 5: A. Normal Small Airway, B. Abnormal Small Airway Exhibiting Airway Remodeling in COPD. Modified from: Berge et al. (2011)>
 **Biological Perspectives- Genetics**
+Genes might play a significant role in COPD, and might even explain why some people who smoke develop the disease and others do not. There is a genetic component accounting for a small number of COPD cases associated with alpha1-antitrypsin protein deficiency (AATD). Treatment for this involves increasing amounts of AAT protein in the body through intravenous injection of the protein derived from human plasma, therefore halting further damage to lung (Castalsi., P.J., et al., 2010).  AATD inhibits proteases and protects tissues from enzymes of inflammatory cells, when it is absent neutrophils can break eastin down resulting in pulmonary complications including COPD (Castalsi., P.J., et al., 2010). Many researchers have performed genome-wide association studies (GWAS) which provides an unbiased and complete search of the genome for susceptibility to COPD. Pillai and colleagues studies the association between COPD and the CHRNA3/CHRNA5/IREB2 region on chromosome 15 (Pillai, S., et al., 2009). MeMeo and colleagues performed gene expression studies comparing normal to COPD lung tissue resulting in the discovery of IREB2 region on chromosome 15 as a contributing genetic factor (DeMeo, D., et al., 2009). Large population genome studies have also found that SNPs near HHIP can also be associated with COPD (Hancock, D., et al., 2010). Overall, although many things were found the overall conclusions amongst the COPD community and researchers is that there is strong evidence concluding that IREB2, HHIP, and FAM13A loci are association with COPD susceptibility (Hancock, D., et al., 2010).
+Comparison of monozygotic and dizygotic twins used to assess environmental versus genetic effects (MZ share 100% genes, DZ share 50%) showing heritability ranges from 0.5-0.8 (Hancock, D., et al., 2010). The study discovered genes coding for various proteins can exacerbate COPD. Proteases and antiproteases, such as MMP-12, play a role in tissue repair associated with inflammation on chromosomes 11,14,16,20,22 (Pendas, A., et al, 1996). Presence of MMP-12 polymorphisms increase the risk of developing COPD when smoking; in MMP-12 knockout mice they did not develop emphysema when exposed to cigarette smoke (Hautamaki, R., et al., 1997). It is the Asn357Ser polymorphism associated with decline in lung function (Hautamaki, R., et al., 1997). Xenobiotic Metabolizing Enzymes, such as EPHX, are involved in metabolizing high reactive epoxide intermediates formed from cigarette smoke that cause injury (Joos, L., Pare, P., Sandford, A., 2002). Two polymorphisms in EPHX gene with 2 substitutions at exon 3 and 4 result in slower metabolizing enzymes more commonly found in COPD patients and emphysema patients, (Smith, C & Harrison, D., 1997). Additionally, genes coding for inflammatory mediators, antioxidants, and mucociliary clearance factors can all have mutations causing these proteins not to work perfectly resulting in increased COPD symptoms (Joos, L., Pare, P., Sandford, A., 2002).
@@ Line 84: / Line 105: @@
-<box width classes round white centre|>{{:spirometry_traces_representing_healthy_patients_and_copd_patients.png|}}</box| Figure : Spirometry Traces Representing Healthy Patients and COPD Patients. Retrieved from: http://www.thinkcopdifferently.com/en/About-COPD/Diagnosing-COPD/Spirometric-assessment>
+<box width classes round white centre|>{{:spirometry_traces_representing_healthy_patients_and_copd_patients.png|}}</box| Figure 6: Spirometry Traces Representing Healthy Patients and COPD Patients. Retrieved from: http://www.thinkcopdifferently.com/en/About-COPD/Diagnosing-COPD/Spirometric-assessment>
@@ Line 93: / Line 114: @@
 Across North America, pulmonary rehabilitation has become an extremely popular method for long-term management of COPD (Goldstein et al., 1994). It aims to manage and improve some of the disabilities that are associated with COPD, such as decreased motor function and weight loss (Goldstein et al., 1994). There are three facets of pulmonary rehabilitation are: the multidisciplinary nature of, individualized programs and attention to physical and social function (Ries & Squier, 1996). The collaboration between various kinds health care professionals makes pulmonary rehabilitation very successful because it encompasses a variety of health care fields. Individuals involved include: physicians, nurses, occupational therapists, psychologists, nutritionists and exercise specialists. (Ries & Squier, 1996). Additionally, the emphasis on an individualized rehabilitation plans leads to successful outcomes because patients are able to focus on the areas that they need to develop the most (Ries & Squier, 1996). Finally, by focusing on both the physical and social function of these individuals, pulmonary rehabilitation allows patients to work on emotional issues. This aspect has been correlated with better outcomes in physical symptoms, such as lung function and exercise tolerance (Ries & Squier, 1996).
-<box width classes round white centre|>{{:nutrition.png|}}</box| Retrieved from: http://blog.copdstore.com/the-official-guide-to-copd-nutrition>
+<box width classes round white centre|>{{:nutrition.png|}}</box| Figure 7: Foods Full of Nutrition. Retrieved from: http://blog.copdstore.com/the-official-guide-to-copd-nutrition>
@@ Line 99: / Line 120: @@
-<box width classes round white centre|>{{:pulmonary_rehabilitation_in_action.png|}}</box| Retrieved from: http://drvijaynair.8m.com/ >
+<box width classes round white centre|>{{:pulmonary_rehabilitation_in_action.png|}}</box| Figure 8: Pulmonary Rehabilitation in Action. Retrieved from: http://drvijaynair.8m.com/ >
@@ Line 107: / Line 128: @@
-<box width classes round white centre|>{{:significant_improvement_in_exercise_improvement.png|}}</box| Figure : Significant improvement in exercise endurance, for up to 3 months, in individuals who participated in 6 weeks of pulmonary rehabilitation. Modified from: Berry et al. (1999)>
+<box width classes round white centre|>{{:significant_improvement_in_exercise_improvement.png|}}</box| Figure 9: Significant improvement in exercise endurance, for up to 3 months, in individuals who participated in 6 weeks of pulmonary rehabilitation. Modified from: Berry et al. (1999)>
 Furthermore, a study done by Lacasse et al. (2006), showed significant improvements with the participation in pulmonary rehabilitation in other symptoms common to COPD patients as well. It was proven that pulmonary rehabilitation relieved symptoms of dyspnea (labored breathing) and fatigue, which is common found in COPD patients due to the muscle loss and increased energy expenditure of movement (Lacasse et al. 2006). Additionally, improvements to the emotional state of COPD patients were shown to enhance an individual’s sense of mastery and control over their condition (Lacasee et al., 2006). Results of this study are shown below. After much research, the significant yield of results illustrate why pulmonary rehabilitation is a crucial component in the long-term management of COPD.
-<box width classes round white centre|>{{:improvement_of_symptoms.png|}}</box| Figure : Illustration of the improvement of symptoms, which are common in COPD patients, with the participation in pulmonary rehabilitation. Modified from: Lacasse et al. (2006)>
+<box width classes round white centre|>{{:improvement_of_symptoms.png|}}</box| Figure 10: Illustration of the improvement of symptoms, which are common in COPD patients, with the participation in pulmonary rehabilitation. Modified from: Lacasse et al. (2006)>
@@ Line 131: / Line 152: @@
 <box width classes round white centre|>{{:effect_of_smoking_cessation_on_postbronchodilator_forced_expiratory_volume_in_one_second_fev1_decline._willemse_2004_.jpeg|}}</box| Figure 12: Effect of Smoking Cessation on Postbronchodilator Forced Expiratory Volume in One Second (FEV1) Decline. Modified from: Willemse (2004)>
-==== Medical Treatment ====
+===== Medical Treatment =====
 **Bronchodilators**
@@ Line 137: / Line 158: @@
 Bronchodilators are a class of medications that are widely used to treat COPD and aid in preventing airflow obstruction in COPD patients (Shim, 1989). These drugs provide relief of some symptoms commonly associated with COPD, such as dyspnea or decreased exercise tolerance, through the relaxation of smooth muscle that line airways (Barnes, 1995). Due to the increase build-up of smooth muscle in COPD patients and subsequent impairment of lung function, these bronchodilators are extremely important in the prevention/reduction of airway obstruction (Berge et al., 2011). The two main bronchodilators used in the treatment of COPD are beta-agonist’s and anti-cholinergic’s (Barnes, 1995). Beta-agonist’s are the most widely used bronchodilator typically used to treat COPD patients (Barnes, 1995). Beta-agonist’s act by binding to the adrenergic receptors on smooth muscle cells and cause an increase of cyclic-AMP (cAMP), a secondary messenger, within the smooth muscle cell. The increase in cAMP causes an intra-cellular cascade that ultimately leads to a relaxation of the smooth muscle surrounding the airway and thus causing bronchodilation (Tashkin & Fabbri, 2010). Long-acting beta-agonist’s in specific, such as formoterol or salmeterol, have been proven to more effectively than regular beta-agonist medications, primarily due to their rapid onset and long duration of action (Barnes, 1995).
-<box width classes round white centre|>{{:action_of_beta-agonists.png|}}</box| Figure : Mechanism of Action of Beta-Agonists>
+<box width classes round white centre|>{{:action_of_beta-agonists.png|}}</box| Figure 13: Mechanism of Action of Beta-Agonists>
 The other kind of bronchodilator used are anti-cholinergic’s, also known as muscarinic antagonists. These not used as often as beta-agonist’s but have been shown to aid in improvement of airway flow in COPD patients as well (Barnes, 1995). Anti-cholinergic’s act by blocking the binding of acetylcholine, which is released from the pre-synaptic cleft of a neuron, to the smooth muscle acetylcholine receptor. By blocking the binding, anti-cholinergic’s are able to prevent bronchoconstriction (Tashkin & Fabbri, 2010).
-<box width classes round white centre|>{{:action_of_anti-cholinergics.png|}}</box| Figure : Action of Anti-Cholinergics>
+<box width classes round white centre|>{{:action_of_anti-cholinergics.png|}}</box| Figure 14: Action of Anti-Cholinergics>
-==== Efficacy of Bronchodilators ====
+**Efficacy of Bronchodilators**
 Studies have shown the long-acting beta-agonist’s (LABAs), such as formoterol, are the best course of medical treatments for individuals with COPD (Rossi, Khirani & Cazzola, 2008). These LABAs are more effective due to their rapid onset and prolonged duration (Barnes, 1995). When used, COPD patients saw improvement with common symptoms, such as dyspnea and decreased exercise tolerance, within minutes-hours after ingestion. Additionally, these drugs also helped improved lung function, reduce exacerbations and overall improve the health status of symptomatic patients with moderate-severe COPD (Rossi, Khirani & Cazzola, 2008). In a clinical study done by Van Noord et al. (2005), results showed that the efficacy of LABAs improved with the combined use of anti-cholinergic drugs. These results were only found in patients with severe COPD and only for the first 12-24 hours after ingestion (Van Noord et al., 2005).
-<box width classes round white centre|>{{:improvement_of_lung_capacity.png|}}</box| Figure : Improvement of lung capacity, within the first 12-24 hours, in individuals with severe COPD after the ingestion of both long-acting beta-agonist’s and anticholingeric medications. Modified from: Van Noord et al. (2005)>
+<box width classes round white centre|>{{:improvement_of_lung_capacity.png|}}</box| Figure 15: Improvement of lung capacity, within the first 12-24 hours, in individuals with severe COPD after the ingestion of both long-acting beta-agonist’s and anticholingeric medications. Modified from: Van Noord et al. (2005)>
@@ Line 158: / Line 179: @@
 ===== References =====
+. Barnes, P. J. (1995). Bronchodilators: basic pharmacology. In Chronic obstructive pulmonary disease (pp. 391-417). Springer US.
+. Bauer, J., Biolo, G., Cederholm, T., Cesari, M., Cruz-Jentoft, A. J., Morley, J. E., ... & Visvanathan, R. (2013). Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE Study Group. Journal of the American Medical Directors Association, 14(8), 542-559.
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+. Berge, M. V., Hacken, N. H., Cohen, J., Douma, W. R., & Postma, D. S. (2011). Small Airway Disease in Asthma and COPD. Chest, 139(2), 412-423. doi:10.1378/chest.10-1210
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+. Bourdin, A., Burgel, P., Chanez, P., Garcia, G., Perez, T., & Roche, N. (2009, September 5). Recent advances in COPD: Pathophysiology, respiratory physiology and clinical aspects, including comorbidities. European Respiratory Review, 18(114), 198-212. Doi: 10.1183/09059180.00005509.
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+. Brug, J., Schols, A., & Mesters, I. (2004). Dietary change, nutrition education and chronic obstructive pulmonary disease. Patient education and counseling, 52(3), 249-257.
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+. Cambach, W., Wagenaar, R. C., Koelman, T. W., van Keimpema, T., & Kemper, H. C. (1999). The long-term effects of pulmonary rehabilitation in patients with asthma and chronic obstructive pulmonary disease: a research synthesis. Archives of physical medicine and rehabilitation, 80(1), 103-111.
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+. Castaldi, P., et al. (2010). The COPD genetic association compendium: a comprehensive online database of COPD genetic associations. Human Molecular Genetis. 19 (3), 526-534. Doi:10.1093/hmg/ddp519
+. Chung, K. F. (2005, June 22). The Role of Airway Smooth Muscle in the Pathogenesis of Airway Wall Remodeling in Chronic Obstructive Pulmonary Disease. Proceedings of the American Thoracic Society, 2(4), 347-354. doi:10.1513/pats.200504-028sr.
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+. Hancock, D., et al. (2010). Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nature genetics. 42 (1), 45-52. Doi:10.1038/ng.500
+. Hautamaki, R., et al. (1997). Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science (New York, N.Y.). 277 (5334), 2002-4. Doi:10.1126/science.277.5334.2002
+. Joos, J., Pare, P., Sandford, A. (2002). Genetic risk factors for chronic obstructive pulmonary disease. Wolters Kluwer Health. 8 (2), 87-97. Doi: 2002/03/smw-09752
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+. Matheson, M., et al. (2005). Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease. Thorax. 60 (8), 645-51. Doi: 10.1136/thx.2004.035170
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+. Pillai, S., et al. (2009). A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS genetics. 5 (3). Doi: 10.1371/journal.pgen.1000421
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+. Ries, A. L., Bauldoff, G. S., Carlin, B. W., Casaburi, R., Emery, C. F., Mahler, D. A., ... & Herrerias, C. (2007). Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical practice guidelines. CHEST Journal,131(5_suppl), 4S-42S.
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