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| - | <box 35% round left| >{{:chagas1.png?400 |}}</box|Figure 2. Map indicating parts of the world with their respective prevalence of chagas disease> | + | <box 35% round left| >{{:chagas1.png?400 |}}</box|Figure 2. Map indicating parts of the world with their respective prevalence of chagas disease (Bern, 2015)> |
| - | Chagas disease is predominantly in continental part of Latin America (World Health Organization, 2017). It has recently also been detected in the United States, Canada and many European countries due to travelling between these regions. It is estimated that Chagas disease infects 8 million people living in Latin American countries, 30-40% of which develop cardiomyopathy or digestive mega syndromes, or both (Rassi & Marin-Neto, 2010). Chagas disease is getting more attention as it is starting to become a global health concern since WHO recognized it to be the world’s 13th most neglected tropical disease in 2010 (Rassi & Marin-Neto, 2010). It has been estimated that more than 400,000 people have been infected with Chagas disease outside of Latin America with the US being the most affected (Steverding, 2014). //T. cruzi// infection rate is less than 1% per year, with the highest being 4% per year in hyperendemic Bolivian Chaco (Bern, 2015). It is encouraging for the scientific community to know that their efforts to decrease the occurrence rate has paid off since T. cruzi infection rate has decreased from 18 million in 1991 to 5.7 million in 2010(Bern, 2015). | + | Chagas disease is predominantly in continental part of Latin America (World Health Organization, 2017). It has recently also been detected in the United States, Canada and many European countries due to travelling between these regions. It is estimated that Chagas disease infects 8 million people living in Latin American countries, 30-40% of which develop cardiomyopathy or digestive mega syndromes, or both (Rassi & Marin-Neto, 2010). Chagas disease is getting more attention as it is starting to become a global health concern since WHO recognized it to be the world’s 13th most neglected tropical disease in 2010 (Rassi & Marin-Neto, 2010). It has been estimated that more than 400,000 people have been infected with Chagas disease outside of Latin America with the US being the most affected (Steverding, 2014). //T. cruzi// infection rate is less than 1% per year, with the highest being 4% per year in hyperendemic Bolivian Chaco (Bern, 2015). It is encouraging for the scientific community to know that their efforts to decrease the occurrence rate has paid off since T. cruzi infection rate has decreased from 18 million in 1991 to 5.7 million in 2010 (Bern, 2015). |
| ======Symptoms====== | ======Symptoms====== | ||
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| Abnormal ECG: Abnormal Q waves; AV blocks; low QRS voltage; SSS (Sick SInus Syndrome)-malfunctioning sinus node; PVCs (extra heartbeats)(Rassi, 2014)> | Abnormal ECG: Abnormal Q waves; AV blocks; low QRS voltage; SSS (Sick SInus Syndrome)-malfunctioning sinus node; PVCs (extra heartbeats)(Rassi, 2014)> | ||
| - | <box 43% round |>{{:chagas6.png?520|}}</box|Figure 7. Image of Tachycardia ECG> | + | <box 43% round |>{{:chagas6.png?520|}}</box|Figure 7. Image of Tachycardia ECG (Rassi, 2014)> |
| - | <box 43% round |>{{:chagas7.png?520|}}</box|Figure 8. Image of Bradyarrhythmia ECG> | + | <box 43% round |>{{:chagas7.png?520|}}</box|Figure 8. Image of Bradyarrhythmia ECG (Rassi, 2014)> |
| - | <box 50% round |>{{:chagas8.png?600|}}</box|Figure 9. Segmental/Global Dilated Cardiomyopathy> | + | <box 43% round |>{{:chagas8.png?520|}}</box|Figure 9. Segmental/Global Dilated Cardiomyopathy (Rassi, 2014)> |
| - | <box 50% round |>{{:chagas9.png?600|}}</box|Figure 10. Associated megaesophagus and megacolon> | + | <box 43% round |>{{:chagas9.png?520|}}</box|Figure 10. Associated megaesophagus and megacolon (Rassi, 2014)> |
| **In Summary:** | **In Summary:** | ||
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| - | <box 35% round right|>{{ :chagas10.png?420|}}</box|Figure 11. Illustrates the size of potential vectors of //T. cruzi// http://www.wrdw.com/home/headlines/Health-officials-Deadly-kissing-bug-reported-in-Georgia-353134901.html> | + | <box 35% round right|>{{ :chagas10.png?420|}}</box|Figure 11. Illustrates the size of potential vectors of T. cruzi (http://www.wrdw.com/home/headlines/Health-officials-Deadly-kissing-bug-reported-in-Georgia-353134901.html)> |
| //T. cruzi// is transmitted through contact of faeces of infected insects of the Triatominae (kissing bugs or conenose bugs) subfamily. They are often called “kissing bugs” because they have the tendency to bite individual’s faces. When they bite, they also defecate, leaving their feces free to enter the bite site to transmit the parasite. | //T. cruzi// is transmitted through contact of faeces of infected insects of the Triatominae (kissing bugs or conenose bugs) subfamily. They are often called “kissing bugs” because they have the tendency to bite individual’s faces. When they bite, they also defecate, leaving their feces free to enter the bite site to transmit the parasite. | ||
| Some of the most well known vectors of the disease include //Triatoma infestans// (kissing bugs), as well as //Rhodnius proxlius// and //Panstrongylus megistus// (Steverding, 2014). | Some of the most well known vectors of the disease include //Triatoma infestans// (kissing bugs), as well as //Rhodnius proxlius// and //Panstrongylus megistus// (Steverding, 2014). | ||
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| An infected vector is one that has trypomastigotes in their hindgut. Upon taking a blood meal from humans, they leave their feces on the skin and this is how trypomastigotes enter from kissing bugs to humans. Once they are in the human body, they lose their flagella and transform in the ideal. This is the ideal life cycle for them to reproduce exponentially within the cells. Once they have fully infected the cell, they transform back into trypomastigotes and burst out of the cell and enter the bloodstream. Once in the bloodstream, they can access other organs and once again transform into amastigotes inside the cell to replicate and infect the organ. Keep in mind that if a non-infected T.cruzi takes a blood meal from an infected human, they will become infected as well (Center of Disease Control and Prevention, 2015). | An infected vector is one that has trypomastigotes in their hindgut. Upon taking a blood meal from humans, they leave their feces on the skin and this is how trypomastigotes enter from kissing bugs to humans. Once they are in the human body, they lose their flagella and transform in the ideal. This is the ideal life cycle for them to reproduce exponentially within the cells. Once they have fully infected the cell, they transform back into trypomastigotes and burst out of the cell and enter the bloodstream. Once in the bloodstream, they can access other organs and once again transform into amastigotes inside the cell to replicate and infect the organ. Keep in mind that if a non-infected T.cruzi takes a blood meal from an infected human, they will become infected as well (Center of Disease Control and Prevention, 2015). | ||
| - | <box 65% round |>{{ :chagas_18.png|}}</box|Figure 12. Image of the vector's life cycle (Center of Disease Control and Prevention, 2015)> | + | <box 50% round |>{{ :chagas_18.png?600|}}</box|Figure 12. Image of the vector's life cycle (Center of Disease Control and Prevention, 2015)> |
| ======Mechanism====== | ======Mechanism====== | ||
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| An third way T.Cruzi is internalized is using lipid membrane rafts. The parasitophorous vacuole on T. Cruzi binds strongly to the low density lipoprotein receptor on the cholesterol and sphingolipid areas of the raft, further allowing internalization (Calvet et. al, 2012). | An third way T.Cruzi is internalized is using lipid membrane rafts. The parasitophorous vacuole on T. Cruzi binds strongly to the low density lipoprotein receptor on the cholesterol and sphingolipid areas of the raft, further allowing internalization (Calvet et. al, 2012). | ||
| - | <box 40% round right|> {{:chagas_13.png?400|}}</box|Figure 14. A variety of different adhesion mechanisms that T. cruzi uses to recognize different types of host cells in order to infect and begin internalization. (Calvet et. al, 2012)> | + | <box 40% round right|> {{:chagas_13.png?450|}}</box|Figure 14. A variety of different adhesion mechanisms that T. cruzi uses to recognize different types of host cells in order to infect and begin internalization. (Calvet et. al, 2012)> |
| **Invasion/Internalization** | **Invasion/Internalization** | ||
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| A second way is through a lysosome dependent mechanism. The parasite causes an increase in cytosolic calcium that leads to depolymerization of the actin and allows the recruitment of lysosomes to the parasite binding site. The lysosomes allow entry into the cell. These elevated levels of calcium are caused by a sensitivity to leupeptin leading to a release of calcium from the sarcoplasmic reticulum calcium stores, and extracellular calcium influx through cellular membrane calcium channels (Teixeira et. al, 2006). | A second way is through a lysosome dependent mechanism. The parasite causes an increase in cytosolic calcium that leads to depolymerization of the actin and allows the recruitment of lysosomes to the parasite binding site. The lysosomes allow entry into the cell. These elevated levels of calcium are caused by a sensitivity to leupeptin leading to a release of calcium from the sarcoplasmic reticulum calcium stores, and extracellular calcium influx through cellular membrane calcium channels (Teixeira et. al, 2006). | ||
| - | <box 50% round|> {{:chagas_14.png?360|}}</box| Figure 15. An image representing T. Cruzi internalized in a cardiomyocyte via phagocytosis and using the parasitophorus vacuole in order to do so (Calvet et al, 2012).> | + | <box 40% round left|> {{:chagas_14.png?450|}}</box| Figure 15. An image representing T. cruzi internalized in a cardiomyocyte via phagocytosis and using the parasitophorus vacuole in order to do so (Calvet et al, 2012).> |
| ======Pathophysiology====== | ======Pathophysiology====== | ||
| - | <box 50% round right|> {{:chagas15.png?360|}} </box|Figure 16. Image A shows a normal neural population in cardiomyocytes and image B shows a degenerative neural population in cardiomyocytes as T. cruzi infection worsens (Calvet, et. al, 2012).> | + | <box 30% round right|> {{:chagas15.png?360|}} </box|Figure 16. Image A shows a normal neural population in cardiomyocytes and image B shows a degenerative neural population in cardiomyocytes as T. cruzi infection worsens (Calvet, et. al, 2012).> |
| Once the parasite has successfully compromised the host cell, the host’s immune system starts generating a response in order to fight the infection. When the amastigotes start to divide rapidly they accumulate and damage the nerve cells and overall structure of the cell. They do so by causing necrosis of the myofibrils in the cytoskeleton and therefore, a dysfunction in the microtubule filaments, specifically fibronectin. Immune response cells are recruited to the site of damage but also end up accumulating and contributes to the enlargement of the cardiomyocytes. The cell will receive specific responses from cytokines, chemokines, and nitric oxide. Some of the genes involved in the accumulation include nitric oxide synthase 2, matrix metalloproteinase -2 (NMP-2), NMP-9, interleukin-6 (IL-6), and tumour necrosis factor-alpha. Although this is meant to be a defensive response against the parasite, it often results in cardiac fibrosis and hypertrophy due to the accumulation of cells (Chaves et al., 2016). Cardiac hypertrophy is the abnormal enlargement of the heart muscle due to an increase in cardiomyocyte cells and size (Calvet et al., 2012). Specifically, a build up of immune response cells, and the protrusion of the cardiomyocyte plasma membrane will cause the hypertrophy. Similarly, cardiac fibrosis is the abnormal thickening of the hearts valves characterised by a dense accumulation of collagen due to the over proliferation of cardiac fibroblasts that results from the disruption in the extracellular matrix (Calvet et al., 2012). | Once the parasite has successfully compromised the host cell, the host’s immune system starts generating a response in order to fight the infection. When the amastigotes start to divide rapidly they accumulate and damage the nerve cells and overall structure of the cell. They do so by causing necrosis of the myofibrils in the cytoskeleton and therefore, a dysfunction in the microtubule filaments, specifically fibronectin. Immune response cells are recruited to the site of damage but also end up accumulating and contributes to the enlargement of the cardiomyocytes. The cell will receive specific responses from cytokines, chemokines, and nitric oxide. Some of the genes involved in the accumulation include nitric oxide synthase 2, matrix metalloproteinase -2 (NMP-2), NMP-9, interleukin-6 (IL-6), and tumour necrosis factor-alpha. Although this is meant to be a defensive response against the parasite, it often results in cardiac fibrosis and hypertrophy due to the accumulation of cells (Chaves et al., 2016). Cardiac hypertrophy is the abnormal enlargement of the heart muscle due to an increase in cardiomyocyte cells and size (Calvet et al., 2012). Specifically, a build up of immune response cells, and the protrusion of the cardiomyocyte plasma membrane will cause the hypertrophy. Similarly, cardiac fibrosis is the abnormal thickening of the hearts valves characterised by a dense accumulation of collagen due to the over proliferation of cardiac fibroblasts that results from the disruption in the extracellular matrix (Calvet et al., 2012). | ||
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| In summary, the constant destruction of cardiac fibres, the collection of collagen leading to fibrosis to replace destroyed myocytes and the hypertrophy of the remaining cardiomyocytes in order to compensate for the loss of myocytes all lead to heart failure and cardiac arrhythmias (Calvet et al., 2012). | In summary, the constant destruction of cardiac fibres, the collection of collagen leading to fibrosis to replace destroyed myocytes and the hypertrophy of the remaining cardiomyocytes in order to compensate for the loss of myocytes all lead to heart failure and cardiac arrhythmias (Calvet et al., 2012). | ||
| - | <box 50% round left|>{{:chagas16.png?360|}}</box| Figure 17. These images are a comparison between an infected cardiomyocyte with an uninfected one. In image A, it is an uninfected cardiomyocyte. In image B, the arrow points to the T. Cruzi parasite, red represents enlarged cells, and the green represents disorganized fibronectin. Image C is an uninfected cardiomyocyte with the blue being the cell, and the red being organized and normally placed fibronectin. Image D displays enlarged cardiomyocytes in blue, with displaced and decreased amounts of fibronectin in red. The arrows point to the parasite T cruzi. Image E represents the invasion of the T. Cruzi parasite (the light blue circles where the arrow is pointing), and the green represents the disorganized and deteriorating microtubules necessary for heart contraction. (Calvet, et. al, 2012)> | + | <box 43% round left|>{{:chagas16.png?500|}}</box| Figure 17. These images are a comparison between an infected cardiomyocyte with an uninfected one. In image A, it is an uninfected cardiomyocyte. In image B, the arrow points to the T. Cruzi parasite, red represents enlarged cells, and the green represents disorganized fibronectin. Image C is an uninfected cardiomyocyte with the blue being the cell, and the red being organized and normally placed fibronectin. Image D displays enlarged cardiomyocytes in blue, with displaced and decreased amounts of fibronectin in red. The arrows point to the parasite T cruzi. Image E represents the invasion of the T. Cruzi parasite (the light blue circles where the arrow is pointing), and the green represents the disorganized and deteriorating microtubules necessary for heart contraction. (Calvet, et. al, 2012)> |
| ======Treatment====== | ======Treatment====== | ||
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| <box 60% round|>{{ :chagas17.png?300 |}}</box| Figure 18. Chemical structures of compounds used in the treatment and control of Chagas disease (Steverding, 2014)> | <box 60% round|>{{ :chagas17.png?300 |}}</box| Figure 18. Chemical structures of compounds used in the treatment and control of Chagas disease (Steverding, 2014)> | ||
| - | **Benznidazole (Benz-nidah-zol)** | + | **Benznidazole** |
| Benznidazole is a nitroimidazole (O₂NC₃H₂N₂H.) and was developed in 1966 and was officially released in 1972 at La Roche Laboratories. It is the primary treatment for the Chagas disease, and it’s FDA approved to use for children between 2 to 12 years. Nonetheless, patients are recommended to consume lower doses of it for their safety and adverse side effects. Through many clinical trials, it was found that Benznidazole is considered somehow effective in reducing the symptoms and detect the T.cruzi parasite inside the body. It was found that this treatment reduced 60 to 85 % of the acute cases, and in more than 90% of congenitally infected infants, if treated in their first year of life. However, the efficacy of Benznidazole in the chronic stage of the Chagas disease is still questionable. Many clinical types of research have shown that Benznidazole fails to treat Chagas patients in the chronical phase. Partially because the benefits of the drug in preventing cardiac and megacolon and megaesophagus manifestations are not yet clear (Gaspar et al., 2015). | Benznidazole is a nitroimidazole (O₂NC₃H₂N₂H.) and was developed in 1966 and was officially released in 1972 at La Roche Laboratories. It is the primary treatment for the Chagas disease, and it’s FDA approved to use for children between 2 to 12 years. Nonetheless, patients are recommended to consume lower doses of it for their safety and adverse side effects. Through many clinical trials, it was found that Benznidazole is considered somehow effective in reducing the symptoms and detect the T.cruzi parasite inside the body. It was found that this treatment reduced 60 to 85 % of the acute cases, and in more than 90% of congenitally infected infants, if treated in their first year of life. However, the efficacy of Benznidazole in the chronic stage of the Chagas disease is still questionable. Many clinical types of research have shown that Benznidazole fails to treat Chagas patients in the chronical phase. Partially because the benefits of the drug in preventing cardiac and megacolon and megaesophagus manifestations are not yet clear (Gaspar et al., 2015). | ||
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| * Peripheral neuropathy | * Peripheral neuropathy | ||
| - | **Nifurtimox (Ni-fur-ti-mix)** | + | **Nifurtimox** |
| It is a Nitrofuran derivative (C10H13N3O5S) and is the only alternative to Benznidazole for the treatment of Chagas Disease. However it is not approved by the FDA. Moreover, Nifurtimox is used also to treat second stage African trypanosomiasis caused by a different parasite (Gaspar et al., 2015). The efficacy of this drug is similar to Benznidazole. However, Nifurtimox is more critical and causes more adverse effects. The mechanism of this drug is very similar to the mechanism of Benznidazole which is using the process of nitro reduction to produce nitro radicals that will affect the parasite on a cellular level. On the other hand, this drug uses Oxygen to produce oxygen species like superoxide and hydrogen peroxide ion that are also toxic to //T.cruzi//. This parasite is proved to be sensitive to oxidative stress as it has weak detoxification mechanisms due to the absence of catalase of peroxidase activity and reduced superoxide dismutase activity. Nifurtimox is not recommended for pregnant ladies for obvious reasons. | It is a Nitrofuran derivative (C10H13N3O5S) and is the only alternative to Benznidazole for the treatment of Chagas Disease. However it is not approved by the FDA. Moreover, Nifurtimox is used also to treat second stage African trypanosomiasis caused by a different parasite (Gaspar et al., 2015). The efficacy of this drug is similar to Benznidazole. However, Nifurtimox is more critical and causes more adverse effects. The mechanism of this drug is very similar to the mechanism of Benznidazole which is using the process of nitro reduction to produce nitro radicals that will affect the parasite on a cellular level. On the other hand, this drug uses Oxygen to produce oxygen species like superoxide and hydrogen peroxide ion that are also toxic to //T.cruzi//. This parasite is proved to be sensitive to oxidative stress as it has weak detoxification mechanisms due to the absence of catalase of peroxidase activity and reduced superoxide dismutase activity. Nifurtimox is not recommended for pregnant ladies for obvious reasons. | ||
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| ======References====== | ======References====== | ||
| + | Bern, C. (2015). Chagas’ disease. New England Journal of Medicine, 373(5), 456-466. | ||
| - | - Bern, C. (2015). Chagas’ disease. New England Journal of Medicine, 373(5), 456-466. | + | Bonney, K. M., & Engman, D. M. (2008). Chagas heart disease pathogenesis: one mechanism or many?. Current molecular medicine, 8(6), 510-518.* |
| - | - Bonney, K. M., & Engman, D. M. (2008). Chagas heart disease pathogenesis: one mechanism or many?. Current molecular medicine, 8(6), 510-518.* | + | |
| - | - Calvet, C. M., Melo, T. G., Garzoni, L. R., Oliveira Jr, F. O., Neto, D. T. S., NSL, M., ... & Pereira, M. C. (2012). Current understanding of the Trypanosoma cruzi-cardiomyocyte interaction. Frontiers in immunology, 3. | + | Calvet, C. M., Melo, T. G., Garzoni, L. R., Oliveira Jr, F. O., Neto, D. T. S., NSL, M., ... & Pereira, M. C. (2012). Current understanding of the Trypanosoma cruzi-cardiomyocyte interaction. Frontiers in immunology, 3. |
| - | - Center of Disease Control and Prevention (2015). Chagas. Retrieved from https://www.cdc.gov/parasites/chagas/biology.html | + | |
| - | - Chaves, A. T., Estanislau, J. D. A. S. G., Fiuza, J. A., Carvalho, A. T., Ferreira, K. S., Fares, R. C. G., ... & da Costa Rocha, M. O. (2016). Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses. BMC infectious diseases, 16(1), 191. | + | Center of Disease Control and Prevention (2015). Chagas. Retrieved from https://www.cdc.gov/parasites/chagas/biology.html |
| - | - Gaspar, L., B Moraes, C., H Freitas-Junior, L., Ferrari, S., Costantino, L., Paola Costi, M., ... & Cordeiro-da-Silva, A. (2015). Current and future chemotherapy for Chagas disease. Current medicinal chemistry, 22(37), 4293-4312. Retrieved from https://research-repository.standrews.ac.uk/bitstream/handle/10023/9920/Gaspar_2016_Current_CurrMedChem_4293.pdf?sequence=1 | + | |
| - | - Loury, E. (2012). Chagas' disease can cast a silent, lifelong shadow. Los Angeles Times. Retrieved from http://articles.latimes.com/2012/jul/08/local/la-me-chagas-20120708 | + | Chaves, A. T., Estanislau, J. D. A. S. G., Fiuza, J. A., Carvalho, A. T., Ferreira, K. S., Fares, R. C. G., ... & da Costa Rocha, M. O. (2016). Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses. BMC infectious diseases, 16(1), 191. |
| - | - Moncayo, Á. (2010). Carlos Chagas: biographical sketch. Acta tropica, 115(1), 1-4. | + | |
| - | - Montgomery, S. (2017). Heart Failure at Age 46? Centers for Disease Control and Prevention. Retrieved from https://blogs.cdc.gov/global/2017/04/14/heart-failure-at-age-46/ | + | Gaspar, L., B Moraes, C., H Freitas-Junior, L., Ferrari, S., Costantino, L., Paola Costi, M., ... & Cordeiro-da-Silva, A. (2015). Current and future chemotherapy for Chagas disease. Current medicinal chemistry, 22(37), 4293-4312. Retrieved from https://research-repository.standrews.ac.uk/bitstream/handle/10023/9920/Gaspar_2016_Current_CurrMedChem_4293.pdf?sequence=1 |
| - | - Rassi, A., (2014) Chagas’ Heart Disease. World Congress of Cardiology Scientific Sessions. | + | |
| - | - Rassi, A., & Marin-Neto, J. A. (2010). Chagas disease. The Lancet, 375(9723), 1388-1402. | + | Loury, E. (2012). Chagas' disease can cast a silent, lifelong shadow. Los Angeles Times. Retrieved from http://articles.latimes.com/2012/jul/08/local/la-me-chagas-20120708 |
| - | - Rassi Jr, A., Rassi, A., & Marin-Neto, J. A. (2009). Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Memorias do Instituto Oswaldo Cruz, 104, 152-158. | + | |
| - | - Steverding, D. (2014). The history of Chagas disease. Parasites & vectors, 7(1), 317. | + | Moncayo, Á. (2010). Carlos Chagas: biographical sketch. Acta tropica, 115(1), 1-4. |
| - | - Teixeira, D. E., Benchimol, M., Crepaldi, P. H., & de Souza, W. (2012). Interactive multimedia to teach the life cycle of Trypanosoma cruzi, the causative agent of Chagas disease. PLoS neglected tropical diseases, 6(8). | + | |
| - | - Teixeira, A.R.L., Nitz, N., Guimaro, M.C., Gomes, C., & Santos-Buch, C.A. (2006). Chagas disease. Postgrad Med J, 82 (974): 788-798. | + | Montgomery, S. (2017). Heart Failure at Age 46? Centers for Disease Control and Prevention. Retrieved from https://blogs.cdc.gov/global/2017/04/14/heart-failure-at-age-46/ |
| - | - World Health Organization (2017). Chagas Disease. Retrieved from: http://www.who.int/mediacentre/factsheets/fs340/en | + | |
| + | Rassi, A., (2014) Chagas’ Heart Disease. World Congress of Cardiology Scientific Sessions. | ||
| + | |||
| + | Rassi, A., & Marin-Neto, J. A. (2010). Chagas disease. The Lancet, 375(9723), 1388-1402. | ||
| + | |||
| + | Rassi Jr, A., Rassi, A., & Marin-Neto, J. A. (2009). Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Memorias do Instituto Oswaldo Cruz, 104, 152-158. | ||
| + | |||
| + | Steverding, D. (2014). The history of Chagas disease. Parasites & vectors, 7(1), 317. | ||
| + | |||
| + | Teixeira, D. E., Benchimol, M., Crepaldi, P. H., & de Souza, W. (2012). Interactive multimedia to teach the life cycle of Trypanosoma cruzi, the causative agent of Chagas disease. PLoS neglected tropical diseases, 6(8). | ||
| + | |||
| + | Teixeira, A.R.L., Nitz, N., Guimaro, M.C., Gomes, C., & Santos-Buch, C.A. (2006). Chagas disease. Postgrad Med J, 82 (974): 788-798. | ||
| + | |||
| + | World Health Organization (2017). Chagas Disease. Retrieved from: http://www.who.int/mediacentre/factsheets/fs340/en | ||
