

Trypanosoma cruzi, the Causative Agent of Chagas' Disease:

### A Biological, Cultural, and Economic Review

Nicole Searcey

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Copyright 2012 by Nicole Searcey

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Searcey, N. 2012 _Trypanosoma cruzi_ , the Causative Agent of Chagas' Disease:

A Biological, Cultural, and Economic Review. Smashwords Edition.

ISBN: 9781301035359

Table of Contents

Introduction

1. Overview of Trypanosoma cruzi: Classification, Characteristics, and Life Cycle

2. Historical Conceptions and Advancements in Understanding T. cruzi

3. Methodological Research: How Data are Gathered and Examples of Studies

4. The Proliferation of T. cruzi through Populations: a Review of Contributing Factors

5. Pathological Insults of T. cruzi Infection

6. Demographic and Geographic Trends of Infection

7. Doctors' and Chagas' Disease Patients: Historical and Current Treatments

8. The Role of Public Health in Contesting Chagas' Disease

9. Demands of Chagas' Disease Research: Financial, Logistical, Regulatory, and Political

10. Current Research: Who is Doing It, Where, and Why

11. The Cost of Chagas' Disease: How It Affects Economical Systems

12. How Culture Defines Chagas' Disease: Social Aspects of Being Infected

13. Big, Extravagant Ideas: Connecting People to Disconnect Chagas' Disease

Conclusion

Bibliography

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**Introduction**

An unexpected bite from a hematophagous reduviid bug and subsequent inoculation with the parasite _Trypanosoma cruzi_ results in the incurable Chagas' Disease. This debilitating illness has been referred to in the literature as "The new HIV/AIDS of the Americas." Similar to HIV/AIDS, Chagas' Disease is characterized by prolonged and expensive treatment plans and prevalence in economically depressed communities (Hotez et al., 2012). The history of _Trypanosoma_ _cruzi_ is documented in thousands or more of scientific journals, books, online articles, and other mediums. There is a fascinating web of questions raised from one scientist to the next, and from one article to the next. Through searching UNL's online database and checking out journals and books from the library, I found information on the antiquity and evolution of the _T. cruzi_ taxon, the fluctuating beliefs of transmission and distribution, the reforming of experiments, and the development of drugs and control methods.

Reading old and recent texts, those in old-English and ones translated, even a bit incorrectly, from Spanish to English made me realize how quickly information becomes outdated. The data collected and ideas suggested by one scientist gets added to by another scientist, and based on more data something slightly different is believed. Then the paper gets translated to different languages and the same message is represented by different letters. Can you image pre-historic humans using cave drawings to communicate an idea generated by the pathology of _T. cruzi_? Through time and from country to country, what we know about Chagas' Disease is constantly transforming and being updated.

A metaphor for the difficulty in understanding this parasite may be the number of times it has changed names. In 1909, the year _T. cruzi_ was discovered, Carlos Chagas named it _Schizotrypanum cruzi_ because he thought the trypanosome went through schizogony in the lungs of the host (Roberts and Janovy, 2009). I'm unsure why the following names were used to describe this species, yet nonetheless in 1916 Kofoid and McCulloch described the parasite with the name _Trypanosoma_ _triatomoe_ (maybe because it lives in _Triatoma_ bugs) and in 1920 Yorke described it with the name _Trypanosoma_ _escomeli_. It is now most commonly referred to as _Trypanosoma cruzi_.

The objective of this review is to alleviate difficulty in learning about _T. cruzi_ by summarizing numerous articles and connecting main ideas for a fluent and comprehensive understanding of Chagas' Disease. I have written about many fascinating aspects including lifecycle information, a history of its understanding, methods of epidemiological research, environmental factors affecting the proliferation of _T. cruzi_ , associated pathology and disease, demographic and geographic distributions, historical and current treatment methods, public health, associated economic costs, social stigma, and my own far-fetched ideas of how to combat this disease. The following pages are about becoming familiarized with Chagas' Disease and learning about commonly overlooked important aspects of how _Trypanosoma cruzi_ is affecting our lives on Earth.

This book was initially written in the spring of 2012 to fulfill requirements of a University of Nebraska – Lincoln (UNL) undergraduate honors seminar: 395H Tropical Medicine, Infectious Disease, and Global Health. In the fall of 2012, it was further expanded and edited to meet requirements for an undergraduate senior thesis. This book was submitted to the UNL Honors Program and the UNL College of Arts and Sciences, for graduation from the University Honors Program and for graduation with High Distinction with a Bachelor of Science in Biological Sciences, respectively. As a 2013 Fulbright Scholar, I look forward to learning even more about _Trypanosoma cruzi_ from the study of mummies in Arica, Chile.

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**1. Overview of** _Trypanosoma cruzi_ **: Classification, Characteristics, and Life Cycle**

_Trypanosoma cruzi_ is a member of the phylum Excavata, class Kinetoplasta, order Trypanosomatida, and family Trypanosomatidae. Phylum Excavata is composed of various protozoa. Examples include diplomonads, oxymonads, and euglenozoans (Simpson et al., 2006). Species comprising the class Kinetoplasta are characterized by having a kinetoplast, or a body, within a mitochondrion, that contains linked circles of kDNA. The order Trypanosomatida is composed of species having a single flagellum. The flagellum may be long and protruding or short and non-protruding. Trypanosomatids also change body forms during different lifecycle stages. These forms include amastigote, choanomastigote, promastigote, opisthomastigote, epimastigote, and trypomastigote stages. The sequence of stages a trypanosomatid undergoes depends on the species. The Genus _Trypanosoma_ includes species that cause major human diseases such as African sleeping sickness and Chagas' Disease (Roberts and Janovy, 2009).

Chagas' Disease is the sickness in humans caused by _T. cruzi_ , which was discovered many years before it was proven to cause human pathology. _Trypanosoma_ _cruzi_ epimastigotes were discovered in _Triatoma_ spp. bugs in 1909 when Carlos Chagas dissected a number of them in Brazil. He sent several bugs to the Oswaldo Cruz Institute where they experimentally fed on a variety of mammals such as marmosets and guinea pigs. Within 30 days of the experiments, trypomastigote stages of the parasite were discovered in the mammal's blood. Chagas named the parasite _Schizotrypanum cruzi_ because he thought the parasite lifecycle was going through schizogony in the lungs of the mammals. This was proven incorrect and in 1930 it was established that infection resulted from feces of _Triatoma_ spp. bugs entering the body. The genus name of this heteroxenous parasite was changed from _Schizotrypanum_ to _Trypanosoma_ to better represent the organism (Roberts and Janovy, 2009). The Latin prefix "trypano" means auger or screw-like (the parasite's movement resembles a corkscrew) and soma means body.

As noted, _Trypanosoma cruzi_ demonstrates various body forms depending on its lifecycle stage. While in the bloodstream, _T. cruzi_ is morphed into its trypomastigote stage, where its 16-20 micron long body is slender, pointed, and contains a flagella at the posterior end. At the base of the flagella is a kinetosome or basal body, and a central axoneme protrudes from this. An outer sheath, which is a continuation of the cell membrane, surrounds the axoneme. A flagellar pocket is at the base of the flagella, and the flagella wraps along the body surface anteriorly where it freely undulates. This narrow, undulating membrane adheres to the pellicle (the membrane of the cell). The nucleus is centrally located in all lifecycle forms. A large mitochondria with a disk made of kDNA is always in close association with the flagella. All organisms in the class Kinetoplasta are characterized by this organelle (Roberts and Janovy, 2009). The peculiar relationship between these two organelles is not completely understood. Studies show transmembrane filaments physically connect the kDNA and kinetosome. Furthermore, the kinetoplast is metabolically active while in the vector host, and its metabolic processes and morphology are reduced in the trypomastigote stage in the definitive host (Lukeš et al., 2010). Both the kinetosome and kinetoplast are positioned posteriorly in the trypomastigote forms. Amastigote stages occur in the cells and tissues of the human body or other host. These spheroid bodies range from 1.5 to 4 microns wide and they cluster together. Their flagella are very short and just barely project from the flagellar pocket. This small eukaryotic cell still contains a kinetoplast closely associated with the kinetosome. The epimastigote stage occurs in the midgut of the bug vector. In this stage, the kinetoplast and kinetosome are located between the anterior end and nucleus (the nucleus is central in position). The flagellum continues anteriorly and the undulating membrane is shorter in length than the trypomastigote stage (Roberts and Janovy, 2009).

As discovered in 1930, _Trypanosoma cruzi_ is transmitted to humans from a bug of the genus _Triatoma_. These vectors are often called _Triatoma_ bugs, triatomine bugs, assassin bugs, "kissing" bugs, or reduviid bugs (web source 1). Reduviid bugs feed on human blood and defecate while feeding. This typically occurs during the night. The feces of these infected bugs contain metacyclic (or infective) trypanosomes, which deposit on the host's skin. The trypanosomes enter the host's body through a small wound such as where the bug bit, a scratched area of skin, or through mucous membranes. For example, a bug may deposit feces near the eye during the night and then this fecal material, containing flagellates, gets sleepily and unknowingly rubbed into the eye. In about 50% of infections, the trypanosome enters the body through the conjunctiva of the eye, subjecting the person to display signs and symptoms of Romaña's sign, which is characterized by excess fluid under the skin that causes swelling of the eyelid, conjunctiva, and the preauricular lymph node. A localized reaction, called chagoma, comprising inflammation and a small red nodule often occurs where trypanosomes enter the body (Roberts and Janovy, 2009).

Once the trypomastigotes enter the human body they circulate in the blood. Next they enter cells and transform into amastigotes where they reproduce by binary fission. Cells of the liver, spleen, lymphatics and muscle cells in cardiac, smooth, and skeletal muscles are the most commonly invaded. They mode of invasion is still scrutinized, but there are suggestions that trypomastigotes enter through penetration or phagocytosis by host macrophages. During replication numerous amastigotes are produced and pseudocysts or "cystlike pockets of parasites" form in muscle tissue (Roberts and Janovy, 2009). The reproduction capabilities of the amastigotes exceed the cell integrity, the cell lyses, the parasite is released, and it attacks other cells and repeats binary fission. Some transform into trypomastigotes and enter the blood stream once again.

A feeding triatomine bug ingests blood along with circulating trypomastigotes. The parasite remains in the trypomastigote form while occupying the bug's foregut, and transforms into the epimastigote form as it passes posteriorly. In this location and stage, the epimastigotes multiply by longitudinal fission. As the parasite passes into the hindgut, it transforms back into the trypomastigote stage. About eight to ten days after ingesting infected blood from a human, the trypomastigotes enter the bug's rectum and become metacyclic (infective). These are deposited in feces that may infect another person. Figure 1 at the end of this chapter further describes the life cycle.

It is currently estimated that 8-11 million people are infected with _T. cruzi_ , with the most prevalence in Mexico, Central America, and South America (web source 1). In the early 1990s in South and Central America it was estimated that 12 to 19 million persons were infected. Eradication efforts by many countries have reduced the number of infections, yet around 25% of people in Latin America are still considered at risk of being infected. There is a risk of acquiring this disease in the United States, especially in the southern states where the reduviid bug is more prevalent. Fourteen mammal species in the U.S. are known to be reservoir hosts of _Trypanosoma cruzi,_ including raccoons, opossums, striped skunks, bobcats, and coyotes (Roberts and Janovy, 2009; Brown et al., 2010). States where _T. cruzi_ has been found in these mammals include Maryland, Georgia, Florida, Texas, Arizona, New Medico, California, Alabama, and Louisiana. Chagas' Disease is the third largest parasitic disease globally next to malaria and schistosomiasis (Roberts and Janovy, 2009).

**Figure 1.** This type of refuge promotes infection by limiting barriers between the home and the surrounding environment.

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**2. Historical Conceptions and Advancements in Understanding** _T. cruzi_

If you're a biologist, biology student, or in some related field, maybe you have dissected a termite gut. If you're not one of these individuals, your most likely thoughts might be, "Why in the world would I want to even touch a termite; I want them all dead, etc." Luckily there are people who want to explore such things, because insects, bugs, and various other "scary monsters" harbor forms of life that are medically important and in that we actually should be afraid. Termite guts are not one of them. After pinching the head with forceps, pulling the body in the opposite direction with forceps, and then teasing the long, slender gut to make a microscope slide from its contents, you will encounter some of the most intriguing forms of life, which are various forms of obscure-looking protists. Some are elongated, snake-like, and skinny; some are helix-shaped, similar to DNA; others are pear-shaped with stringy flagella; some have spines. See Figure 2 for an image of such organisms, which contains photographs taken from a permanent slide of protists I made in the summer of 2010 at UNL's Cedar Point Biological Station.

Observing these life forms is almost mystical, making you think, "These are the life forms in which I am sharing the Earth, and they must have lived here much before me; I wonder when and how they evolved?" "Why is this organism helical and in what way does this body form help it survive?" and "have these always lived in termite guts and why are they here?" The first time I witnessed these mysterious creatures, I learned they live in termite guts to digest cellulose; without gut protists to metabolize ingested cellulose, the termite could not survive (Watanabe et al., 1998).

Just like students or scientists study bugs/insects/etc. and what is inside of them, in 1907 Carlos Chagas microscopically viewed the gut of a reduviid bug, _Panstrongylus megistus_. What he observed was remarkable. If he would have known how deadly the never-before-seen organism was, he should have been overwhelmed; just like the average person looking at termites. But Carlos Chagas was a scientist, and after being the first person to ever lay eyes on and document these organisms, much of his life was dedicated to studying them. In 1909 he described the new species as _Schizotrypanum_ _cruzi_. At first, Chagas did not suspect this organism to produce pathology in humans, the trypanosome's evolutionary origins were completely unknown, and its geological distribution was in question (Belding, 1952). Little did Chagas or the rest of the world know, what he discovered was afflicting pain and death to a significant percent of the population in South and Central America. For over 100 years now, professionals have been raising questions in an attempt to understand, control, and discover the antiquity of _Trypanosoma cruzi_.

Some of the oldest reports are from 4,000-year-old mummies of northern Chile, discovered with megacolon, tissue pathology, and other clinical indications of Chagas' Disease (Solari, 2011). A study shows even 9,000-year-old mummies may have been infected with _T. cruzi_. Two hundred eighty three desiccated mummy tissue samples of Chile and Southern Peru ranging between around 9,000 and 500 years old were tested with a DNA probe directed toward kDNA and amplified with PCR; 41% were positive. It is believed that Chagas' Disease was established in sylvatic mammal cycles and then began to create lifecycles in which it infected humans as soon as humans began inhabiting sylvatic cycle areas (Aufderheide et al., 2004).

In the triatomine's transition between sylvatic cycles and human cycles, a specific reduviid bug, _Triatoma infestans_ , played a major roll by adapting to live primarily in human dwellings. It is believed this evolution occurred around 500 AD (Solari, 2011). Before this time _T. cruzi_ probably used the wild insect vector, _Mepraia gajardoi,_ to proliferate itself among non-human mammals. This is an all-black species closely related to _Mepraia spinolai_ , a species endemic in Chile (Frias et al., 1998).

The distribution and transmission of _T. cruzi_ extends well beyond Chile and Peru. Although Belding's textbook (1952) states there were no human infections in the U.S. at that time, the CDC website states there have been cases of vector-borne human infection of _T. cruzi_ in the U.S., although they are rare (web source 1). Belding's textbook (1952) also states, "The incidence of South American trypanosomiasis is unknown, but it is probably higher than generally believed, since asymptomatic cases are unrecognized." With advances in communication and technology we can now better estimate this number, and it is believed half a million people in Chile alone were infected in the 1980s (Schofield, 1982).

Along with a better understanding of at-risk populations, treatment of _T. cruzi_ infection has also changed. For example, beginning in 1936 inoculations of Bayer 7602, a 4-aminoquinoline of the surfen group, were used to treat Chagas' Disease (Belding, 1952). Currently the drugs nifurtimox (introduced in 1965) and benznidazole (introduced in 1971) seem moderately effective, but only in acute infections and this drug appears to only clear the parasites from the blood, not the entire body (Bern et al., 2007). A drug or vaccine successful in killing Chagas' Disease parasites has yet to be created (Roberts and Janovy, 2009).

While various drugs and vaccines are being studied to treat Chagas' Disease patients, developing advanced preventative measures are just as important. Transmission can occur congenitally, through blood transfusions, organ donations, laboratory accidents, or even rarely through food and drink (web source 1). It was not even until December of 2006 that the U. S. screened donated blood for _T. cruzi_. By September of 2007, 193 donations tested positive for the trypanosome (Bern et al., 2007). There is now greater awareness in organ donations, and there are methods for donor screening and follow-up treatment and testing for recipients of infected donors (Chin-Hong et al., 2011).

In addition to closely regulating _T. cruzi_ in blood and organ donations, manipulating its insect vector is a productive control method. According to Belding (1952), the most successful reduviid bug elimination methods are fumigation, whitewashing, and insecticides. More recently, scientists in Mexico have implemented ecological-niche modeling in an attempt to understand "vector and parasite-reservoir distributions" throughout the country (Peterson et al., 2002).

Even with advancements in control methods, the development of new drugs, and over two hundred million dollars spent in control attempts, Chagas' Disease will most likely remain in many parts of the Americas for various reasons. For example, people of some Mexican villages believe reduviid bugs are aphrodisiacs and so will eat them, which subsequently infects the person when trypanosomes enter the human body through the oral mucosa (Roberts and Janovy, 2009). In addition, Schofield (1982) explains _, "_ the current status of Chagas' Disease is likely to be maintained through its association with poor quality housing, poverty and ecological degradation." We have many obstacles ahead in attempting to eradicate _T. cruzi_. While efforts in the U.S. have been largely successful, economic and cultural situations in Latin and South America may be too severe to overcome Chagas' Disease.

**Figure 2.** Various species of protists of one termite from western Nebraska.

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**3. Methodological Research: How Data are Gathered and Examples of Studies**

Chagas' Disease epidemiology is exceptionally complex for various reasons. The propagation of _Trypanosoma cruzi_ through reduviid bugs, humans, and other reservoir hosts contributes to the complexity. Different factors at each lifecycle stage affect the public health of a region. The species of reduviid bug acting as the vector, the environment in which the vector lives, the cultural and traditional actions of humans, the type of environment humans have made to live in, and other actions affect the success of this disease-causing parasite. Studies have been conducted in many areas of Central and South America in an attempt to understand how this parasite proliferates and to determine its prevalence; various methods have been used to collect data for these studies.

A study in Ecuador, where an estimated 120,000 to 200,000 people are infected with _T. cruzi_ , assessed household characteristics and their correlation in contracting Chagas' Disease. In 14 rural communities of Manabi, Guayas, and Loja, almost all residents took a survey and donated a blood sample. Mamabi and Guayas are situated near each other in a lowland area, and Loja is a highland region. Infection with _T. cruzi_ was determined serologically. Some residents did not donate a blood sample and some samples were not suitable for testing. Overall, 3,286 subjects from 997 households consented to the study (Black et al., 2007).

Prevalence of infection between highland and lowland (costal) regions was assumed to be different because various regions of Ecuador contain different species of reduviid bugs. These bugs live in specific habitats and have unique behaviors. In addition, people living in separate regions often use different materials to build homes, which affects prevalence of Chagas' Disease. For example, walls made of adobe provide cracks where reduviid bugs take refuge during the day, and then at night come out and infect people as they are sleeping. The accumulation of things outside the home is also a factor. Organic matter, rocks, bricks, trash, or firewood outside the home provide a place for the reduviid bugs to colonize and live, and therefore they do not go inside the home. A risk is posed if firewood containing the bugs is brought inside. The number of palm trees around the home may also affect prevalence of Chagas' Disease in a particular region because specific species of reduviid bugs colonize the trees. In addition, the roofs of homes are often made of palm, which may harbor the bugs (Black et al., 2007). For example, the species _Rhodnius pictipes and Rhodnius neglectus_ are found in frond clefts of palm-trees in the Amazonian regions of Brazil (Teixeira et al., 2001).

The following factors, which are commonly considered in other studies, were assessed in this Ecuador study: type of floor, material used to build walls, type of roof, prevalence of palm trees around the house, and other items surrounding the house including organic matter, firewood, rocks, bricks, trash, and lumber. This study found a positive correlation between cane and adobe walls and _T. cruzi_ infection. Homes with cement walls had fewer cases of Chagas' Disease. It was also found the more accumulation of organic matter outside the house the less likely the residents are to contract Chagas' Disease (Black et al., 2007). There are numerous contributing factors to the proliferation of the disease, indicating various methods of prevention and control are necessary to deal with Chagas' Disease. This requires many research studies and data collections in many countries.

In regions all throughout the Amazon, tribes are susceptible to _T. cruzi_ infection because of various factors including living conditions and healthcare. A paper by Coimbra (1988) describes the differences in Chagas' Disease epidemiology between native South American Amerindians. The epidemiology of Chagas' Disease in tribal communities is based on biological adaptations of host and parasite, while in urban and periurban areas Chagas' Disease epidemiology is "more a result of differential political and socioeconomic considerations" (Coimbra, 1988).

This study explains that Amazonian Indians are mobile for various reasons: depleted soil due to crops, infestation of weeds, availability to animal game, or even anthills surrounding the villages. Because tribes are mobile, vector species are not allowed adequate time to colonize homes, and as a result prevalence of Chagas' Disease is lower. Populations of villages are small, usually under 500 people, reducing the chances of infestation. In addition, fewer animals such as guinea pigs are domesticated, lowering the risk of infection; guinea pigs may serve as reservoir hosts to _T. cruzi_. The type of house and materials used to build it was also recorded. Separate reduviid species prefer different living environments. The genus _Rhodnius_ , for example _R. prolixus_ from Venezuela, prefers thatched roofs or walls; _Triatoma dimidata_ of Costa Rica, is most commonly found in wooden houses or beneath houses build on stilts. In this particular study, the type of palm tree used in building homes and the species of triatomine found on the palms were recorded. Overall, the fact these tribes were mobile, small, and did not domesticate many animals were the main factors that contributed to the low prevalence of Chagas' Disease (Coimbra, 1988).

Many studies collect data by taking serological test from villages in separate regions. For example, scientists described in the paper by Teixeira et al. (2001) obtained blood samples from 15 separate villages in Paço do Lumiar county in Brazil. The villages contained homes with mud walls, thatched roofs, and various animals such as cats, dogs, and chickens running about. There was no clear separation between these peridomestic villages and the surrounding, partly deforested rainforest. This was a major undertaking, as 25,431 residents between the age of 1 and 75 were pricked on the finger and then blood was deposited onto Whatman (Clifton, NJ) 1-mm filter paper to test for seropositivity. The paper dried at room temperature and then sets of 10 papers were organized into separate plastic containers and put into an icebox until they could be frozen. As Teixeira (2001) describes in the paper, "at the laboratory, filter paper blood samples were punched out and eluted in 100μL of phosphate-buffered saline (PBS), pH 7.4. The test was standardized for obtaining 5 μL of blood in 1 cm2 of the filter paper, and serum proteins were eluted in 100 μL of PBS, pH 7.4, yielded a 1:20 final dilution for screening seropositivity. For quality control, 10% of the samples were analyzed by a second examiner."

Reduviid bugs were also trapped in this study. This was done by various methods including by organizing community meetings where a dead and dried reduviid bug was presented and then the capture of the bugs in the home by residents was advocated. The captured bugs kept in a plastic container were then given to scientists for dissection. Residents explained that the bugs often flew from palm trees toward the homes at night because they were attracted to light sources. Homes were most invaded during the rainy season. In addition, 23 palm trees were dissected into segments of stipe, crown shaft, petiole, leaves, and fronds, which were examined for mammals and insects. Three different species of triatomines were discovered, and a precipitin test aided in typing the blood in the intestinal contents of 44 adult male and 44 adult female bugs. As described in the paper by Teixeira et al. (2001), "The test consisted of two-dimensional immunodiffusion of blood in the insects' intestinal fluid against taxon-specific antisera."

Along with the complexity of laboratory tests and dissections, asking people of the villages to cooperate, let their fingers be pricked, and for them to trap bugs must have taken some serious public education and organization. How the researchers got people to assist in the study was not included in the paper, but possibly they used posters, flyers, door-to-door advocates, public speakers, or other methods such as the "scare tactic." Maybe a slogan similar to "We need your help to prevent Chagas' Disease from afflicting your children" was printed onto flyers. A simple web image search can provide examples of outreach posters.

Another important aspect in studying and collecting data is being able to identify _T. cruzi_ subtypes. This species is diverse, and separate zymodemes have been recognized. Zymodemes are defined by the Free Medical Dictionary as "groups of parasites with the same isoenzymes" (web source 2). Isoenzymes are enzymes that catalyze the same reaction but are coded for by different genes and separate amino acid sequences. For example, a study in Bahia state, Brazil discovered that _T. cruzi_ zymodeme II has a domestic lifecycle and that _T. cruzi_ zymodeme I has a sylvatic lifecycle. These two related, zymodeme species live in proximity to each other in Bahia state, and different triatomine species sustain each _T. cruzi_ zymodeme in their respective areas (domestic or sylvatic). However, a study in Venezuela demonstrated that _T. cruzi_ zymodeme I lives in both sylvatic and domestic areas. The _T. cruzi_ vector in this case, _Rhodnius prolixus_ , may have been moving from sylvatic to domestic lifecycles depending on habitat characteristics (Miles et al., 2003). Possibly there are many palm trees surrounding one village and so _R. prolixus_ left the palms to colonize the homes, but in villages with fewer palms, this would not happen.

These types of studies show the importance of _T. cruzi_ molecular typing, which may reveal a link between _T. cruzi_ zymodemes and sylvatic or domestic cycles. _Trypanosoma cruzi_ typing has been performed using various molecular methods to define the two main types mentioned above ( _T. cruzi_ I and _T. cruzi_ II). Within _T. cruzi_ II, five subgroups are recognized. It was speculated that this diversity is due to genetic recombination between different types of _T. cruzi_. Studies have proven that _T. cruzi_ is mainly reproduced asexually (by cloning) but genetic recombination is still possible by fusions, which produce hybrid strains. This hybridization could allow for speciation and evolution of _T. cruzi_ that could live in new hosts and in new geographical environments.

The most profound phenomenon is that _T. cruzi_ I is endemic in northern parts of South America where infection is usually non-life threatening or benign and that _T. cruzi_ II is endemic to southern parts of South America where megasyndromes and chronic infections are severe. It is unknown whether the susceptibly of the human genome or the virulence of the _T. cruzi_ strain is responsible for determining if infected people lead normal lives or succumb to chronic Chagas' Disease (Miles et al., 2003). Being able to molecularly determine the species of _T. cruzi_ is important because "the great hope, as with other pathogens, is that sequencing the _T. cruzi_ genome will identify new drug targets present in the parasite but not in the host" (Miles et al., 2003). If scientists can determine the exact species of _T. cruzi_ in a particular area, they collect more precise epidemiological data. In summary, the most common ways scientists gather data is by taking blood tests and surveys, assessing the environment in and around homes, and accurately recording the species of vector and type of _T. cruzi_.

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**4. The Proliferation of** _T. cruzi_ **through Populations: a Review of Contributing Factors**

As with any parasite, the ecology of _T. cruzi_ is complicated because of many lifecycle stages and hosts the parasite transitions through. As defined by Cain et al. (2008), "ecology is the scientific study of interactions between different species of organisms, one another, and their environment." At every point in the lifecycle of _T. cruzi_ its interactions with other things can be studied. Imagine the interactions of this parasite within its insect and mammal hosts and then the interactions of the hosts with various environments. The populations of zoonoses such as raccoons and skunks, the presence of un-fragmented living habitats such as populations of palms, and appropriate climate are examples of just a few ecological factors that affect the proliferation of _T. cruzi_ through human populations.

_Trypanosoma cruzi_ uses reduviid bugs to propagate itself through communities of people. A reduviid bug finds a human host, usually a person asleep for the night, and takes a blood meal. Simultaneously, the bug defecates on the skin, often near the eye. The feces contain infective trypomastigotes, which may enter the host through a break or wound in the skin. I can imagine there are many factors affecting these synchronized actions. Ecological questions about these initial interactions may include the following: Are reduviid bugs living in close proximity to people or where they participate in activities? How do the bugs gain access into the home? Is the reduviid bug attracted to all ages, sexes, and races of people the same? Are people living with pets or other animals? Would the bug rather bite the animal? Are the animals affecting the humans' chances of becoming infected? Does the person have many cuts in the skin? Would a prickly plant outside the home cause this? What if the person is really hairy where the bug defecates, are chances of becoming infected changed? Even more questions could be raised about the physiological interactions between, for example, trypomastigotes stages in human or other mammalian blood, amastigote stages in muscle tissue, epimastigote stages within insect vectors, or reproduction in different tissues. The following examples describe some of these ecological questions answered or questioned in more detail.

A study conducted by Vaz et al. (2007) in the state of Rio de Janeiro, Brazil examined the effect of habitat fragmentation on prevalence of _T. cruzi_ in wild mammal populations, which may act as reservoir hosts. The scientists reported a decrease in species richness of mammals in fragmented areas. This phenomenon is known to increase infection prevalence because populations of a suitable host may increase while other species succumb to the effects of habitat loss (Allan et al., 2003). This theory was tested when Vaz and colleagues investigated the localities in Brazil where new cases of Chagas' Disease were documented. All of these locations had three common characteristics: high environmental pressures by humans, low mammal diversity, and population maintenance of the common opossum. The opossum is a reservoir host of _T. cruzi_ and a habitat generalist that fairs well in areas affected by humans. Environmental pressures led to deforestation and habitat fragmentation, which led to extinction of species and a decreased species richness, which led to a population increase of generalists such as opossums, which are suitable hosts to _T. cruzi_ , which led to an increase in prevalence of Chagas' Disease in human populations (Vaz et al., 2007).

Prevalence of Chagas' Disease is also affected by the ecological environment people make in their homes, which are often referred to as refuges in the literature. According to Marsden (1984), the materials used in making a refuge, which may only take a couple weeks, are absolutely subject to reduviid bug infestation. For example, in central Brazil refuges are often constructed by slapping mud onto a frame made of wood. Such walls rapidly crack and become living quarters for reduviid bugs. In Bolivia, the bugs regularly infest roofs because they are made of a porous complex of wood, turf, and tile. In addition to what the house is made of, the things kept inside the house affect Chagas' Disease transmission. If families possess animals such as dogs, chickens, or pigs, the bugs may choose to bite them instead of the people in the same environment. Although, keeping such animals around may promote reduviid bug populations. In addition, people may be preferentially bit because they are large compared to most animals and sleep long hours. If people bring firewood into their homes, this is another ecological factor that allows reduviid bugs entrance to refuges (Marsden, 1984).

Climate and weather are considered ecological factors in the transmission of _T. cruzi_. In an experiment by Asin and Catala (1995), 203 reduviid bugs were kept at twenty and twenty-eight degrees Celsius in an attempt to determine if temperature affected _T. cruzi_ development within their guts. It was discovered that bugs of both temperatures produced similar densities of metacyclic trypomastigotes (Asin and Catala, 1995). Although the actual production of trypomastigotes is not affected by temperature (at least in the range of twenty and twenty-eight degrees Celsius), conditions before a thunderstorm in South and Central America may affect human infection with _T. cruzi_ because under these climatic conditions reduviid bugs tend to actively fly into refuges (Marsden, 1984). Similarly, _Triatoma vitticeps_ displays high flight activity during hot months in Brazil (Goncalves et al., 1998). In another climatic study by Vazquez-Prokopec et al. (2002) in rural northwest Argentina, infestations of reduviid bugs in domestic and peridomestic structures were surveyed according to season. It was found the two most preferred habitats for the bug were storerooms and houses made of adobe. Because most structures provide a refuge for reduviid bugs against the weather, "global climate changes are expected to affect peridomestic populations of _T. infestans_ much more than domestic bug populations, provided other local conditions are held constant" (Vazquez-Prokopec et al., 2002).

As demonstrated by the slew of questions in a previous paragraph, there are additional unaddressed complications in understanding the ecology of _T. cruzi_. Considering the dynamic of our quickly changing environment and climate, it's doubtful we will fully understand all ecological factors contributing to the persistence of Chagas' Disease. Although for now, we understand habitat fragmentation, materials used to build homes, animals kept at the home, firewood, weather, global climate change, and more are all accepted ecological factors contributing to the proliferation of _Trypanosoma cruzi_ through human and other mammal populations in Central and South America.

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**5. Pathological Insults of** _T. cruzi_ **Infection**

As with most parasitic infections, Chagas' Disease pathology is exceptionally complex. There are two principal manifestations of Chagas' Disease, the acute and chronic phase. Some individuals experience a latent phase of the disease, where no clinical symptoms are present (Galvao-Castro et al., 1984). The following describes the devastating effects of _Trypanosoma cruzi_ on individuals infected with this parasite.

Acute Phase

The acute phase of Chagas' Disease is most common in children (Roberts and Janovy, 2006). It begins when the reduviid bug vector defecates and exposes the infective trypomastigote to the skin. A local inflammatory response occurs where _T. cruzi_ enters the body, and a small red bump or sore forms, called chagoma. The local lymph nodes swell and become enlarged. Lymph nodes are part of the body's lymphatic system, and lymph is formed when fluid enters into lymphatic capillaries from interstitial spaces, or the spaces between cells. If there are any pathogens, such as _T. cruzi_ , that enter into the lymph, phagocytic cells within lymph nodes will attempt to remove them (Fox, 2011).

Trypanosomes evade the immune system by various mechanisms, including by mounting a suppressive effect on T cells and invading phagocytic cells such as macrophages and adapting to an intracellular environment, which prevents an antibody response. Entrance of _T. cruzi_ into macrophages is mediated by lysosomes recruited to the entrance site on the plasma membrane (Sacks and Sher, 2002) Fifty percent of the time, the trypomastigote enters the body through the conjunctiva of the eye, which is a delicate, continuous mucous membrane between the inside of the eyelids and the forepart of the eyeball (Tortora and Nielsen, 2012). When _T. cruzi_ uses this mode of entry, a symptom called Romaña's sign develops in the ocular area. The conjunctiva and eyelid succumb to edema; there is a buildup of interstitial fluid in these areas. The periauricular lymph node, a lymph node anterior to the ears, also swells as a characteristic of Romaña's sign. If you do an internet image search for this symptom, you will find the affected eye is usually swollen shut. During this acute phase, _Trypanosoma cruzi_ circulates in the blood and may be transported to almost any organ of the body. Trypomastigotes may be detected by serological tests in the acute phase, but in the latent and chronic phases they are rarely found in the blood (Galvao-Castro, 1984). Trypomastigotes enter cells from the circulatory system, transform into amastigotes and reproduce. It is common for the parasite to enter cells of the spleen, liver, and lymphatic system. They also enter cardiac, smooth, and skeletal muscle cells. In other cases, the parasite enters the skin, gonads, intestinal mucosa, bone marrow, and placenta. In muscle cells only, cyst-like sacs of amastigotes called pseudocysts form. The heart muscle is commonly invaded, and up to 80% of cardiac ganglion cells, or masses of nerve cells, may be destroyed (Roberts and Janovy, 2009). The heart contracts and circulates oxygenated blood to the body because of self-stimulating, autonomic impulses generated and conducted by nervous tissue in the heart. If the nervous tissue, which is incapable of division to reproduce itself if damaged, is destroyed by _T. cruzi_ , the heart muscle will no longer contract, it will become enlarged, and eventually this condition is fatal.

Once the parasite has entered the host cell and transformed into an amastigote, it reproduces by binary fission. During this type of asexual reproduction, DNA is duplicated and the cell divides into half, with each half containing a complete set of DNA (Campbell and Reece, 2009). Binary fission is repeated so many times the host cell lyses and is destroyed while _T. cruzi_ exits. The parasite will invade other cells or transform into intermediate forms, such as promastigotes and epimastigotes, in the interstitial spaces. Some of these intermediate forms will convert into trypomastigotes and enter the blood stream to infect other areas of the body.

Pseudocysts within muscle tissue may also rupture and cause cellular damage. When this happens, the affected area becomes inflamed and the local nerve cells are degenerated and necrose, or undergo cell death. The degeneration of nerve cells is caused indirectly. Amastigotes do not invade the nerve cells; rather they invade the muscle tissue surrounding the nerve cells, which eventually ruptures causing necrosis of both the muscle tissue and nerves. The heart is one of the most common muscles where pseudocysts form, and in the chronic phase of the disease, the heart becomes flabby and enlarged in result of destroyed nerve cells and muscle tone (Roberts and Janovy, 2009).

Chronic Phase

The chronic phase of Chagas' Disease is most common in adults. This phase is characterized by a wide variety of symptoms, which are usually caused by damage of the central and peripheral nervous system. The central nervous system includes the spinal chord and brain while the peripheral nervous system includes the nerves extending from these. The neurons that compose the nervous system are responsible for transmitting electrical and chemical impulses all throughout the body. These impulses allow our bodies to understand sensory information, control motor functions, and perform activities such as learning and memory (Fox, 2011). If neurons of the body are destroyed by this parasite, there are a wide variety of consequences.

As mentioned above, the heart is commonly invaded and becomes functionally inefficient. In endemic regions, Chagas' Disease may be responsible for up to 70% of cardiac deaths (Roberts and Janovy, 2009). Other organs commonly invaded include the esophagus and colon. Similar to the heart, muscle tone and neurons throughout the organ are destroyed while the organ loses properties of its function. The organ becomes flabby and extremely enlarged, and in the case of the colon and esophagus, it becomes very difficult or impossible for materials to pass through it. This pathology can be fatal, especially when the infected person physically cannot eat, swallow, or pass digestive contents. These progressive conditions are called megaesophagus and megacolon.

Tissue tropism, or the response of affected tissue due to _T. cruzi_ presence, in the heart and intestinal organs is not completely understood despite nearly a century of Chagas' Disease research. The indirect process of neuronal destruction may result from the following situations:

•Parasitized, neighboring cells may release a toxic substance when they lyse (Koeberle, 1968).

•Parasites and cell destruction cause a great inflammatory response (Tafuri, 1970).

•Antigens attach to the surface membrane of ganglion cells, causing an autoimmune response (Santos, 1977).

Antigens are associated with foreign molecules and your body's own cells (self antigens), these may elicit an immune response by the attachment of antibodies. An autoimmune disorder is when antibodies bind to self antigens. Ganglion cells are collections of nerve cell bodies in the peripheral nervous system. Even though neurons and ganglion cells are not invaded, they are indirectly destroyed by phenomenon's not yet completely understood.

Latent Phase

The latent phase of Chagas' Disease is another aspect of _T. cruzi_ infection that is only partly understood. This phase is fascinating because the individual infected demonstrates no clinical symptoms, and the person may appear healthy for many years. Although, patients in this phase eventually succumb to symptoms of chronic Chagas' Disease, such as heart failure, megacolon, and megaesophagus (Galvao-Castro, 1984).

With this information, many questions can be raised: why do pseudocysts only form in muscle tissue? It is because muscle cells do not divide, providing a permanent space for epimastigotes to accumulate? Is it because muscle cells are compartmentalized into fascicles by connective tissue, also compartmentalizing epimastigotes? If trypomastigotes enter various organs, why do the heart, esophagus, and colon display the most pathology? Is there a sort of cellular signaling that attracts trypomastigotes to these organs more than others? How exactly do trypomastigotes exit blood vessels, pass interstitial space, serous membranes or other connective tissues, and enter into the cells of organs? What sort of biological signaling or nature is motivating _T. cruzi_ to take such paths throughout the human body?

The invasion of cells by _T. cruzi_ has been studied and we are becoming closer to understanding methods of cellular penetration. For example, digital fluorescence microscopy has shown calcium (Ca2+) concentrations in the cytosol of trypomastigotes increases during association with host cells. When calcium concentrations were experimentally raised within trypomastigote cytosol, infective capacity was significantly raised. When cytosol calcium concentrations were lowered, infective capacity was as well (Moreno et al., 1994). These results suggest there is an association between attachment of _T. cruzi_ trypomastigotes to the surface of a host cell and _T. cruzi_ intracellular calcium concentrations. The source of the calcium and mechanism responsible is still unknown (Ulrich et al., 2010). It is questioned whether Ca2+ signaling is also a factor in the differentiation of epimastigotes into metacyclic trypomastigotes, as changes in concentration have been observed (Lammel et al., 1996).

Clinical Manifestations

Understanding the pathology of _T. cruzi_ is a major step in becoming familiarized with Chagas' Disease. Furthermore, seeing a patient with Chagas' or hearing personal stories about this devastating parasite allow a more personal or heart-wrenching understanding. Here are four descriptions of patients with Chagas' in a hospital ward with only four beds in Mambai, Goias State, Brazil (Marsden, 1989).

Bed on the left, closest to the door

Here lays a 32 year-old man with a clinically enlarged heart and congestive heart failure. He suffers from edema. His breathing seems to be normal. Within two years, this person has a 70% chance of not being alive.

_Man with normal sized heart_

This person, also fewer than 40 years old, is positioned next to the first-described patient. When trying to use the toilet he turns blue and throws a fit; this is because he has Adams-Stokes disease. The cardiac conducting system of this person has been completely destroyed by _T. cruzi_ and his heart is entirely blocked, but it's still a normal size. He has been admitted to receive a pacemaker.

Sexes are not mixed in the ward

A 16 year old girl, whose bed is across the room because she is female, seems by the size of her neck and face to be eating plenty, but actually for every bite of rice she attempts to eat she must take a sip of water. She has grade 3 megaesophagus. She may have megacolon, but because she eats so little it is difficult to assess. She is in the hospital because surgeons will excise a segment of her esophagus. Her electrocardiogram is normal.

_Boy with one eye_

This twelve-year-old boy shows the infamous symptoms of Romaña's sign. One of his eyes is swollen shut. A blood test reveals trypomastigotes active in the blood. _Trypanosoma cruzi_ is already in his heart. Reduviid bugs have been found in his house. Benznidazole is used as a treatment, but good health in the future is not certain. In the rural region where these patients came from, about fifty percent of the population is infected with _T. cruzi_. Furthermore, about a third of the population has serious heart problems characterized by abnormal cardiograms, and a tenth of the population has digestive issues due to megaesophagus and megacolon (Marsden, 1989).

Indefinite Pathological Issues

In summary, the pathology of _Trypanosoma cruzi_ can manifest in most regions of the body. There are two widely accepted phases of Chagas' Disease, the acute and chronic phase. Patients may also exhibit a latent phase. In almost all Chagas' Disease patents, tissues of the heart, esophagus, and colon are infected with amastigotes. Nonetheless, the actual phenomenon of tissue tropism to these amastigotes and other forms are yet to be definitively established (Melo and Brener, 1978). In addition, there are pathological factors that have not been addressed in this review. For example, if fifty percent of a population is infected with Chagas' Disease, how did the other fifty percent resist infection? It's likely the other 50% have been exposed to reduviid bugs. Do they have immunity against _Trypanosoma cruzi_? What determines if a person succumbs to Chagas' Disease or enters into the latent phase? Is the chronic phase most common in adults because a great percentage of children acquire the parasite, and then the infection eventually develops into the chronic phase by adulthood? Why do such a great percentage of Chagas' patients exhibit Romaña's sign? Is there something attractive about the eye or face to reduviid bugs? Do these bugs defecate every time they take a blood meal?

Some of these questions may be addressed in the literature, yet chances are, explanations are not completely understood. Chagas' Disease pathology will provide endless opportunities for people to do research because the human body and physiological interactions with _Trypanosoma cruzi_ are profoundly complex.

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**6. Demographic and Geographic Trends of Infection**

The proliferation of _T. cruzi_ through human populations has caused the largest parasitic disease burden next to malaria and schistosomiasis (Roberts and Janovy, 2009). In order to better understand this major parasitic disease, the geographic and demographic distribution of _T. cruzi_ will be described in the following paragraphs.

Geographic distribution

Chagas' Disease is known as American Trypanosomiasis because it occurs throughout Southern, Central, and North America. Human infections are most common in South and Central America, yet wild animal hosts and Reduviid bugs support sylvatic lifecycles of _Trypanosoma_ spp. all throughout the Americas (Woody and Woody, 1955). Although many remote and rural endemic areas were not surveyed at this time, by 1970 an estimated 12 million people were infected with _T. cruzi_ in the Americas (Marsden, 1984). By the early 1990s, an estimated 12-19 million people in South and Central America were infected (Roberts and Janovy, 2009). By 1999 in South America alone, an estimated 16-18 million people were infected. Eradication efforts in recent years have lowered these numbers, possibly as low as 11 million, yet a quarter of the population in Latin and Southern America remain at risk (Coutinho, 1999; Roberts and Janovy, 2009).

Prevalence

Chagas' Disease is prevalent in most every country in Central and South America, and there have also been a few cases of Chagas' Disease in North America. By 1955, the first human case of Chagas' Disease was reported in the U. S. (Woody and Woody, 1955). By 1965, only two known cases of Chagas' Disease were confirmed and both were in Texas. Although, additional serological tests by many clinically unrecognized people proved positive in vulnerable areas of the United States. This phenomenon may occur because the more virulent strains of _T. cruzi_ in the U.S. have been weeded out through their passage in rodents (Lambrecht, 1965). Chagas' Disease is endemic in wild animals and canines in Texas; some examples include armadillos, opossums, mice, and wood rats. _Triatoma_ species are abundant all through the state (Sarkar, 2010; Woody and Woody, 1955).

Few studies have been conducted in Mexico and information about prevalence of Chagas' Disease is sparse. This has occurred despite the fact Chagas' Disease is endemic in this region and supported by the existence of many reservoir hosts and reduviid bugs, along with humans (Dumonteil, 1999). In fact, there have been no _T. cruzi_ surveys in many Latin American countries, although _T. cruzi_ is endemic in most of them including but not limited to Argentina, Brazil, Bolivia, Chile, Paraguay, Venezuela, and more (Marsden, 1984; Roberts and Janovy, 2009). The following provides some information about the prevalence of _T. cruzi_ in these regions.

In Brazil by 1984, an estimated six million people were infected with _T. cruzi_ , and in Argentina and Venezuela an estimate of over 1 million people were infected (Marsden, 1984). Chagas' Disease is also endemic to Chile in both rural and urban environments. For example in Santiago in the 1990's, 23% of substandard homes were infested with reduviid bugs and 69% of the slums were infested. Of the reduviid bugs sampled, 15% were infected with _T. cruzi._ Additionally, in Tegucigalpa, Honduras samples of _Triatoma infestans_ and _Rhodnius prolixus_ were found to be 45% and 35% infected, respectively. A study in Bolivia surveyed ten cities, including Cochabamba and Sucre which are 800-2500m above the sea level, and 42% of bugs were positive for _T. cruzi_ (see Mott et al., 1990, plus references).

It is difficult to find updated statistics on the prevalence of Chagas' Disease by country; I assume because surveys of entire countries would be expensive and complicated. Nonetheless, there are warnings to U.S. travelers issued by the Center for Disease Control of risks of Chagas' Disease in all of the countries of Central and South America: Mexico, Guatemala, Belize, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Venezuela, Columbia, Ecuador, Peru, Chile, Bolivia, Argentina, Brazil, Uruguay, Paraguay, French Guiana, Suriname, Guyana. There are different risks between countries and regions within countries.

Potential Reservoirs

_Trypanosoma_ spp. use many hosts throughout the Americas, and potential reservoir hosts vary depending on the region. The following paragraphs give examples of reservoirs throughout the Americas.

Dogs are commonly infected with _Trypanosoma_ spp., and since they sleep and breed in homes they may contribute to the population of reduviid bugs. Cats may also be infected, although it is usually from eating infected rodents. Since cats generally sleep outside in some regions they are probably less of a risk. Guinea pigs may contract the parasite. Since these are often breed in homes in Bolivia and Peru, they may pose a great risk to infection. Rats and opossums may also be infected with _T. cruzi_ in domestic and peridomestic areas. Generally, large animals on farms are not infected; these may include goats, cattle, pigs, and horses. Birds, such as chickens, cannot become infected with _T. cruzi_ but they can serve as blood meals for reduviid bugs, posing as a factor that introduces bugs to an area (Marsden, 1984).

Complexities of animal reservoirs are further complicated in certain areas because species diversity (and populations of animal reservoirs) is changing because of habitat destruction. A specific study in Brazil documented this trend by surveying seroprevalences of _T. cruzi_ in small mammal species and marsupials representing sixteen genera. A decrease of small mammals and an increase of marsupials, such as the opossum, was observed in fragmented areas. A higher seroprevalence of _T. cruzi_ was observed in the fragmented areas than in non-fragmented areas. This situation resulted because opossums are habitat generalists, surviving rather well in human-modified habitats, and they are hosts of _T. cruzi_ (see Vaz et al., 2007 plus references). In other cases, as in Mambai, Goias State, Brazil, habitat destruction has eliminated populations of hosts of _T. cruzi_ (such as the opossum or other wild animals) and reduviid bugs have successfully colonized human homes (Marsden, 1989).

Demographic distribution

In general, Chagas' Disease is most prevalent in economically depressed, rural areas of South and Central America. This is mainly because poor living conditions favor the colonization of homes by Reduviid bugs and also because reservoir hosts are present in these areas. Many other factors may contribute to the distribution of Chagas' Disease, such as social and economic status, gender, and age.

Age and Sex

Chagas' Disease may be acquired congenitally, and in this case a baby is born with the disease. As the child gets older, characteristic symptoms will occur in different stages (Freilij and Altcheh, 1995). New infections are most common in children under the age of two years old. In this age group the disease is usually fatal (Roberts and Janovy, 2009). Typically Chagas' Disease is acquired in children before the age of ten (Marsden, 1989). Some children succumb to the disease while others are asymptomatic, although, after many years symptoms of chronic Chagas' Disease usually appear. In one study, chance of infection with both _Leishmania chagasi_ and _T. cruzi_ increased with age in an indigenous Columbian population, and no preference was observed between women and men (Corredor Arjona, 1999). It is notable, though, that cardiomyopathy due to Chagas' Disease is more common in men in their prime ages (Marsden, 1989). Unless otherwise noted in literature I have not read, reasons for this observation are unknown. I have not found any literature describing a reduviid bug preference between women or men, or differences in prevalence of Chagas' Disease between genders or sexual orientations.

Economic and social groups

As briefly described above, Chagas' Disease is primarily a problem of the economically depressed living in remote, rural areas. Because such people cannot afford sufficient housing, homes are made of materials that deteriorate rapidly, providing hiding places for reduviid bugs (Marsden, 1984). More recently, Chagas' Disease has become a problem in urban areas, also in the sector of economically disadvantaged people. For example in Salvador, Bahia, Brazil, records suggest that in the same houses _Trypanosoma_ spp. transmission cycles were present between people and _Panstrongylus megistus_ and also between rats and _Triatoma_ _rubofasciata_. In Ecuador, _Triatoma dimidiata_ is a vector for both humans and rats of urban regions (Marsden, 1984). _Triatoma infestans_ is the most successful reduviid bug in infesting homes and peridomestic structures (Cecere et al., 2003).

Remarks

Chagas' Disease has been studied for over 100 years, yet there are still many things we do not know about this ancient disease. Although many areas, especially in Central and Southern America, are yet to be surveyed for the presence of Chagas' Disease, we know it causes suffering and death from the United States to the southernmost regions of Argentina.

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**7. Doctors' and Chagas' Disease Patients: Historical and Current Treatments**

With advances in medical research, it is difficult to imagine acquiring a disease that has no cure. Such a tragic event must feel devastating and hopeless, yet this is the case when each new person becomes infected with _Trypanosoma cruzi_. As of now, there is no completely effective treatment for Chagas' Disease. The economy, productivity, and livelihood of millions of people and their respective countries need a drug that cures _T. cruzi_ infection. If no treatment is found, these and other aspects of society will continually suffer. Related human trypanosomes respond generally well to treatment, but infection with _Trypanosoma cruzi_ is more resistant. Appropriate drugs mainly kill the extracellular blood trypomastigotes but are less effective in the treatment of the intracellular amastigotes, the critical stage in which the parasite reproduces (Roberts and Janovy, 2009). The following are descriptions of past and present chemotherapies, their administration, and effectiveness.

Bayer 7602

Beginning in 1936, Bayer 7602 was used as a treatment for Chagas' Disease. It is also called British M 3024. This drug removes the trypomastigote forms in the blood, but the tissue amastigotes are unaffected, and resultantly relapse may occur. Bayer 7602 was injected intramuscularly in a three percent solution. This was repeated five times and administered every five to six days. By the fifth dose acute symptoms of Chagas' Disease had typically lessened. This was documented to be locally painful. Intravenous injections proved toxic when patients exhibited distress, precordial pain, and sweating. The main side effect to this drug was albuminuria (Belding, 1952). This is a type of proteinuria (protein in the urine) where the protein albumin is present in high conditions in urine. A typical indication of renal damage is when one has 300 mg or more proteinuria. It may be caused for various reasons including hypertension (Fox, 2011).

Ketoconazole

In 1983, this drug was experimentally used on mice infected with four strains of _T. cruzi_. It protected mice that would have otherwise died, even when the parasite was introduced as early as seven days previous to ketoconazole treatment. The over-arching discovery in treated mice was that tissue sections were clear of amastigote stages, the forms known to be most resistant to treatment. An in vitro experiment was also performed with this drug, and with the low concentration of 0.001 µg/ml the amastigote stage was prevented from replicating (McCabe et al., 1984). In a later study by the same researchers, 78.5% of mice infected with _T. cruzi_ were cured when treated with ketoconazole (McCabe et al., 1987). Thus, this drug shows potential for a human chemotherapy.

Nifurtimox and Benznidazole

Nifurtimox is also known as Lampit and Bayer 2502 and was first introduced in 1965. Benznidazole is also known as Radanil, Rochagan, and Roche 7-1051 and was first introduced in 1971. I grouped these different drugs together because they are the most commonly used and are sometimes used in combination with each other. Neither is approved for treatment in the United States, but they may be used under investigational practices when obtained by the Center for Disease Control. They are most effective when used during acute infections, and are known to treat both the trypomastigote and amastigote forms (Bern et al., 2007).

Benznidazole is more commonly used because it has fewer side effects. Many experts prescribe this as the first line of treatment. If it is not well tolerated, then switching to nifurtimox may be appropriate. Benznidazole has a treatment duration of sixty days. Each day an adult may take 5-7 mg/kg divided into two doses. Nifurtimox has a treatment duration of ninety days. Each day an adult may take 8-10 mg/kg divided into three doses (Bern et al., 2007). Although, searching for a better drug is necessary because there are numerous side effects and the duration of treatment is extensive. (Roberts and Janovy, 2009).

Recent approaches

Both benznidazole and nifurtimox are unsatisfactory because of their limited success in treating the chronic stage of Chagas' Disease. As a result, different approaches to chemotherapy are being investigated. Some examples include, "biochemical routes such as the de novo sterol biosynthesis pathway, pain-mediated proteolysis and pyrophosphate metabolism" (Urbina and Docampo, 2003). Many of these compounds have been used in pre-clinical studies and are on track to be used in clinical trials. In addition, there are different approaches of treatment including, "interference with trypanothione synthesis and redox metabolism, in addition to inhibition of purine salvage, dihydrofolate reductase, phospholipid biosynthesis, and protein prenylation and acylation" (Urbina and Docampo, 2003). The big problem in treating Chagas' Disease is the resistance of the amastigote stages, which often infect macrophages, the hosts' cells responsible for eliminating foreign bodies. Another area of research is determining how to increase the macrophage antiparasitic activity. This may be produced by administering nifurtimox, benznidazole, and aspirin together (López-Muñoz et al., 2010). Other studies have shown that causing damage to the function of certain enzymes may arrest the reproduction of amastigotes. Such a study was performed with mice by targeting cysteine protease inhibitors. This action led to an arrest of the parasitic infection (Engel et. al, 1998).

Remarks

It is evident that there is no widely accepted treatment for Chagas' Disease and the most successful treatment possible has not been discovered. Not only are many specific chemicals, molecules, enzymes, etc. under review as possible avenues for chemotherapy, yet the actual origin of Chagas' Disease pathology is still under question. It was previously believed to be of an autoimmune origin and that treatment should be as such, yet more recent controversies suggest Chagas' Disease should be treated as a parasitic infection, and not an autoimmune disease (Urbina, 2001). The present most common therapies include nifurtimox and benznidazole, yet the investigations into new drugs are active and under way. The future of many counties, especially those in Central and Latin America, depend on such researchers to find an absolute cure. The productivity and livelihoods of millions of at-risk people will be transformed when, or if, a cure is found.

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**8. The Role of Public Health in Contesting Chagas' Disease**

Ever since Carlos Chagas discovered _Trypanosoma_ _cruzi_ in 1909, people have been doing research to understand its complex biology, how it differentially affects communities of people, where it is prevalent and why, and many other questions (Roberts and Janovy, 2009). Thousands of scientists have devoted their professional lives to this parasite. People do these things for important reasons, and one intention is to increase the public health of people living in endemic regions.

Truly understanding the biology of _T. cruzi_ would reveal its life history and its current situation. Knowledge of these things is important for many public health reasons. The prevalence of _T. cruzi_ tells us about the living conditions, social norms, and cultural traditions of numerous communities throughout Central and South America. For example, when reduviid bug fecal smears cover hut walls made of adobe and when firewood is brought into huts without being cleared of reduviid bugs, we know current living conditions may increase prevalence of the disease, but that public outreach and education could prevent some cases (Black et al., 2007). In Mexico, where people in some villages eat reduviid bugs believing they are aphrodisiacal, we know cultural norms contribute to life-threatening actions (Salazar-Schettino, 1983). Professionals working in public health have goals of creating awareness about similar dangerous practices.

As defined by Web Source number three, "Public Health is the science and art of protecting and improving the health of communities through education, promotion of healthy lifestyles, and research for disease and injury prevention. Public Health works to prevent health problems before they occur." Although this description is clear, the public health realm through time and space of human affairs differs drastically. What humans believed was "improving the health of communities through education" 600 years ago in Europe, for example, was actually harming public health (described shortly). Currently, unorganized governments and limited resources weaken many health practices (Mok et al., 2010)

In France and England during the late 14th century, women were not allowed to become licensed doctors or practice under any conditions, although, women had the greatest knowledge of plant based medicine. Even today, most medicines are organic compounds derived from the natural world. Medical knowledge was based on religious and superstitious sanctions in the Middle Ages. One of the most highly respected surgeons, Guy de Chauliac, based his practices upon potions of mummy dust and dragon's blood, and called "women who gathered herbs idiots" and claimed that they "practiced religious nonsense." Knowledgeable and skillful women healers who secretly cured or relieved pain of patients were considered witches and were killed if religious or authority figures (always men) discovered their actions, which men believed to be from the devil. The religious and superstitious affairs of most humans impeded the development of a healthy general public (Hogan and Peterson, 2001).

Even though medical practices have become more scientifically based since the Middle Ages, there are still many difficulties in creating communities with good public health. This is especially the case in less developed countries. When resources are inadequate and enforcement mechanisms are poorly designed, public health standards are reduced. Fortunately, global health initiatives are developing ways to increase public health without dependence on governmental or legal systems (Mok et al., 2010). A code of ethics in public health is also important because of people's various religious or personal preferences. Bioethics, public health ethics, ethical analysis, and collaboration between bioethicists are growing fields and activities (Levin and Fleischman, 2002). These advances from historical times to present are paving the way for a future free of Chagas' Disease, yet the current situations of inadequate resources and enforcement, particularly in underdeveloped countries, are major road bumps.

One facet of Chagas' Disease prevention is spraying huts and homes in an attempt to kill the vector reduviid bug. Throughout Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay, approximately two hundred million dollars have been used to spray two million houses. This probably had a great impact on public health, but nonetheless a quarter of the people in Latin America are still at risk. (Roberts and Janovy, 2009). This is an example of the problematic nature in addressing any public health issue. Sometimes even enormous amounts of money and seemingly organized activism will not produce a satisfactory result.

Other facets of public health include public education and outreach. For example in the United States, the CDC (Centers for Disease Control and Prevention), private and public health companies provide statistics, information, and prevention tips for about every relevant disease. To my knowledge, an organization as advanced as the CDC does not exist in Latin American countries, although less sophisticated measures have been taken, for example creating posters and flyers, or organizing community meetings about urgent public health issues.

Public health practices implemented to control the spread of Chagas' Disease are a small sliver of the practices applied in treating other global diseases. Every other disease also has a specific infectious organism, modes of propagation, and biological histories; there is no other disease exactly like Chagas' Disease. The realm of infectious diseases is massive, and people spend enormous amounts of time and money in the study and practice of public health because nothing is more important than being healthy. A community or society is unable to advance economically or socially if its members are continuously ill, and creating a strong military would be unlikely. If there is a health issue, people will pass time being sick, being less productive, and the healthy individuals will likely focus their attention on improving the health situation. Chagas' Disease provides an example of the complexities and difficulties of success in public health campaigns.

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**9. Demands of Chagas' Disease Research: Financial, Logistical, Regulatory, and Political**

Thousands of people have contributed their professional lives to studying _Trypanosoma cruzi_. I can imagine they do this for various reasons: they are interested in the evolutionary biology of infectious diseases, a friend or relative is sick with Chagas' Disease, they are fascinated by reduviid bugs and the role of the vector, they are interested in _T. cruzi_ epidemiology in a particular region, and the reasons are endless. In the research articles created by these people, the over-arching purpose and result of doing such work is given, but the cost and approach of doing the research is rarely mentioned. The materials and methods section of a research paper explains how the actual experiment was performed, and other scientists may be able to perform the same methods based on the description. This section is described in every research paper, but the _how_ parts not usually detailed outright are the logistical, financial, political, and regulatory costs of doing research. This chapter will illuminate such possible costs while studying _Trypanosoma cruzi_. These costs are important because every scientist must deal with such issues in order to complete a project, publish, and share their results with the rest of the world.

To explain possible logistical, financial, political or regulatory issues of doing research relating to _T. cruzi_ , I am proposing a kind of mind-experiment in which I will hypothetically travel to Chile and do research. I have a strong interest in climate change and the effects of human activities on the environment. Therefore, my experiment proposal is to determine the effects of habitat fragmentation on the prevalence of reduviid bugs, and indirectly Chagas' Disease in Chile. Ever since around the 1970s, deforestation and fragmentation of Chile's natural temperate forests has been increasing in order to suite commercial plantations, mainly for eucalyptus and radiata pine businesses (Cartwright and Gaston, 2002; Echeverria et al., 2006). Other studies have shown that in environments where there is a high rate of habitat change, species known as specialists do not survive or decrease in population, while generalists fair well. If generalists spread infectious diseases then disease prevalence will probably increase. This was the case in the state of Rio de Janeiro, Brazil, where fragmented areas led the generalist opossum to increase its population. Since the opossum is a reservoir host of _Trypanosoma cruzi_ , the prevalence of disease also increased (Vaz et al., 2007).

My research project will survey prevalence of the reduviid bug vector in regions of fragmented and continuous habitat in Chile. My null hypothesis is there will be no difference between the two landscapes, but my hunch is that fragmented areas will have a higher prevalence of reduviid bugs, and in turn a higher prevalence of Chagas' Disease. Some reduviid bugs are specialists and some are generalists. An example of a specialist is _Cavernicola pilosa_ , which specifically preys on bats. Some examples of generalists are _Triatoma infestans_ , _Triatoma dimidiata_ , and _Rhodnius prolixus_. All three of these have adapted to live in human domestic environments. In addition, most species of reduviid bugs can be opportunistic and feed on any organism they encounter (Stevens et al., 2011). They are polyphagous and can use a wide variety of prey as sustenance (Schaefer and Panizzi, 2000). These are reasons why I think reduviid bug populations could be increasing, and in turn Chagas' Disease prevalence is increasing or remaining steady despite numerous eradication attempts.

As a poor college student living in Nebraska, the first thing I would need to begin this project is funding. I would go on-line to various websites like the National Science Foundation, and I would devotedly look for organizations that want to give me money. Being a senior about to graduate, I would look into the U.S. Student Fulbright Research Grant. Buying a lottery ticket might be also a great idea. In order to do research you have to get funding, and usually research fees exceed what the researcher could contribute. Once I worked extremely hard to secure my funding, I would make connections and associate myself with a University laboratory or research center in Chile. A physical place to carry out the research is necessary. Working with colleagues will not only give me access to an equipped laboratory in which everyone can share a common space, but I will be able to work through ideas, questions, and problems with them and they will have an independent perspective to add.

Once the funding and laboratory were secured, I would need to decide in what areas I could survey reduviid bug populations. This may be a more difficult task than it seems. I have never asked a landowner for permission to drive onto their land, unpack strange looking equipment, and perform activities they might not understand, but I can imagine it would take some rhetorical skills to convince anyone to use something of theirs for no apparent benefit. In this case, commercial plantations probably wouldn't want scientists on their land only to tell everyone what a bad thing they are doing to it. If it was government-owned land, I would imagine you might have to fill out a lot of forms and talk to a lot of people on the phone. In addition to dealing with landowners, you will likely have to deal with politics. Depending on the country you want to conduct research in, there may be significant political constraints. I don't foresee this being a problem in Chile, but the government or political environment in some regions may not foster biological research or may not believe humans are altering our physical world in significant ways.

After the funding, laboratory and field space, government clearance, and political issues are addressed and resolved, the task of actually doing research will require even greater attention and dedication. Depending on the location characteristics and other factors, I would survey the reduviid bug populations in different ways, some examples may be to use vacuum sampling, pitfall traps, intercept traps, or chemical knockdown (Moir and Brennan, 2007). A simple Internet search may present images of the pitfall and intercept traps for visual descriptions, fumigation is involved in chemical knockdown, and vacuum sampling uses a vacuum apparatus to collect specimens. In order to describe the fragmented land, I would need to take into account factors not limited to deforestation, mining, agriculture, road developments, dams, and the expansion of urban environments. All of these land use changes may contribute to an increased prevalence of infectious diseases (Patz et al., 2004).

Needless to say, the project logistics would go into much greater detail, and as you go deeper into detail, the more issues and costs you will encounter. My hypothetical research experiment is just an example of the kinds of things people can do in order to better understand _Trypanosoma cruzi_. I don't know if a similar study to what I have proposed has been done, but I could not find evidence of such a study through the literature available to me through UNL's library access. Here is proof, by the proposal of a research idea by an mere undergraduate student, that a lot of research still needs to be done in order to create a better understanding of _T. cruzi_ and Chagas' Disease. Although there will always be logistical, financial, political, and regulatory costs of doing research on such things, many scientists will continually devote their professional lives to uncovering the vagueness of infectious diseases.

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**10. Current Research: Who is Doing It, Where, and Why**

Chagas' Disease is endemic in Central and South America, although scientists with Ph.D's and M.D.'s and even students are doing research on _T. cruzi_ all around the world. These scientists have educational backgrounds in biology, parasitology, microbiology, immunology, cellular biology, and related fields. In order to investigate whom is doing Chagas' Disease research and where it is being done, I conducted an extensive primary literature search and on-line popular article search. This chapter will further describe who is doing Chagas' Disease research, where they are doing it, and what kinds of questions they are really asking.

I conducted a primary literature search with UNLs library databases and by using Google Scholar. Most papers were from universities and laboratories in Brazil and the United States, Argentina and Chile were also common. In the United States, universities in Maryland, Georgia, California, and Washington are a few examples of states that are producing publications about Chagas' Disease. Even places in Japan, Sweden, and other countries far from the _T. cruzi_ endemic areas are studying this infectious disease.

Searching the Internet revealed organizations and university programs that were formed because of _Trypanosoma cruzi_. Here are some examples of research centers and organizations that have goals of controlling Chagas' Disease: The Infectious Disease Research Institute based out of Seattle, Washington (Web Source 4); Doctors Without Borders based out of London (Web Source 5); The Wellcome Trust Sanger Institute based out of England (Web Source 6); The Center for Tropical and Emerging Global Diseases at the University of Georgia (Web Source 7); The Drugs for Neglected Diseases Initiative, which has offices in various countries all over the world (web Source 8); and The Chagas' Disease Foundation based out of Georgia. The latter website was very informative because it pinned Chagas' research centers on a global map, showing that most are in South America and North America, with a few places in Europe such as London, France, and Belgium (Web Source 9).

I have noticed a general trend about authors of research papers: the number of authors on a single paper is increasing with time. In older articles I found it uncommon to see a paper with over five or ten authors, but in recent articles this is more common. The co-authors are increasingly from various areas of the world too. For example, the genome sequence of _Trypanosoma cruzi_ was described in a 2005 article in _Science_. Over eighty authors from eight countries or regions produced this paper. The regions include the United States, Sweden, Brazil, Argentina, France, the United Kingdom, Venezuela, and Singapore (El-Sayed et al., 2005). Advancements in technology and the Internet have made global communication and collaboration more established. This trend seems beneficial, especially because the research fashion is specialization. When an article is written about a general subject, many specialists within the general subject area can contribute their independent ideas to the paper. With new means of communication allowed by computers and technology, specialists from all over the world may collaborate on their work.

Professor Rick Tarleton of Wake Forest University was one of the over eighty scientists to sequence the genome of _T. cruzi._ It was discovered that over half of the genome is repeated in the form of retrotransposons and surface-molecule encoding genes. There are few genes that code for signaling molecules but the kinome has various phosphatases and protein kinases. This is important because regulatory pathways and interactions are vaccine targets (El-Sayed et al., 2005). Targeted genes may be manipulated by introducing deletions or other gene interruptions that ultimately make some genes necessary for infectivity or viability nonfunctional (Brandan et al., 2011).

Professor Tarleton is a prominent research figure who primarily studies immunology of infection. One of his papers from 2011 describes how the mode and site of infection affect the host immune response. He studied and compared host response in mice after parasite antigen introduction via GI tract and inoculations. He discovered CD8+ T-cell response and skeletal muscle colonization were similar in both modes of infection. Tarleton may identify the most productive targets for vaccines by studying host response to various modes of infection. It was discovered that attenuated metacyclic trypomastigotes administered orally to mice provided some protection to wild-type _T_ _. cruzi_ challenge. A common mode of human infection is from a reduviid bug bite, although feces-contaminated food or drink is a recognized mode as well. Reservoir hosts such as dogs or possums are known to eat reduviid bugs and fomites. Professor Tarleton hypothesized to immunize dogs orally with attenuated metacyclic trypomastigotes (Collins et al., 2011).

All scientists including Professor Tarleton are investigating very specific questions about _Trypanosoma cruzi_ , although we can understand them as addressing more general questions. For example, a study authored by thirteen scientists describes the pyrimidine biosynthesis pathway needed for _T. cruzi_ proliferation in the cytoplasm of mammalian host cells (Hashimoto et al., 2012). This study is really addressing the questions of how to treat infected patients. Another study authored by seven scientists describes reduction of trypomastigotes in blood after riboflavin and ultraviolet light exposure (Tonnetti et al., 2012). This study is really addressing the question of how to eliminate _T. cruzi_ in blood donations. Another study authored by eight scientists describes and records species information about _Triatoma baratai_ in Brazil (Obara et al., 2012). This study is providing as much information about the vector host in order to control or eliminate it. Most publications focus on very specific topics or mechanisms, although the questions everyone is really trying to answer are variations of these: How do we control the vector and keep it away from homes, how do we treat infected people in the acute and chronic stage, and how can we prevent infections from blood and organ transplants?

The TDR website lists major research topics. The TDR is the Special Programme for Research and Training in Tropical Diseases, and it is run by the World Health Organization (WHO) and sponsored by the United Nations Children's Fund (UNICEF), the United Nations Development Program (UNDP), and the World Bank. Some of the main research topics include infection incidence in children, chemotherapy, diagnostic tools, insecticide resistance, vector control, blood transfusion safety, congenital Chagas' Disease, and policy frameworks for future research (Web Source 10). Scientists specializing in their respective fields will continue doing research and combining ideas with colleagues all around the world, with the goal of producing answers about very important questions.

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**11. The Cost of Chagas' Disease: How It Affects Economical Systems**

_Trypanosoma cruzi_ was not discovered until roughly a century ago, although infection by _T. cruzi_ has been afflicting humans for thousands of years. We are yet to combat this deadly disease with successful prevention, diagnosis, and treatment strategies. We have attempted to control and eradicate _T. cruzi_ by spraying homes with insecticides and with other initiatives, yet these efforts have not reached a completely effective level. Major impediments in reaching these goals are the large financial sums it takes to implement many control strategies. Additionally, when people become infected they defectively contribute to their countries economic stability. In this chapter, the importance of economics and wealth in dealing with _T. cruzi_ will be revealed.

Chagas' Disease is most common in lower socio-economic classes in rural or periurban regions. Homes of disadvantaged communities are suitable living habitats for reduviid bugs because they cannot afford to build nicer homes that prevent infestation. Chagas' Disease has become an urban problem ever since the 1970's and 1980's when there was a general trend in Latin America to move into cities (Moncayo, 1999). If enough money is allocated to eradicating this disease, for example by providing millions of people with better living conditions, possibly it could be controlled or eradicated. Monetary issues, although almost always, hinder such progress.

Chagas' Disease pressures the economies of afflicted and endemic countries in various ways. As briefly mentioned, the prophylaxis, diagnosis, treatment, and conduction of research for Chagas' Disease all cost enormous amounts of money in order to be successful. Even more, when citizens are debilitated or pass during their prime and productive years, their countries economies are weakened because money is spent for their medical care, possibly paying out sick days, and by not receiving their contribution to the economy through their work. In fact they may eventually be fired from their job. Chagas' Disease negatively effects both employment and social situations, which may cause depression. For example, death of family members and friends, loss of health, social stigma, and employment loss may all contribute to depressive symptoms (Ozaki et al., 2011). Physical, social, and psychological difficulties all lower the quality of life and economic stability in counties where Chagas' Disease is endemic.

Fortunately, many countries are working together through various organizations to address economic barriers and to create control strategies. The Initiative of the Southern Cone Countries (Argentina, Chile, Paraguay, Uruguay, Peru, Bolivia, and Brazil) began in 1991 and has goals of eradicating _T. cruzi_ by targeting vectoral and lateral transmission, by insecticide house spraying and serological tests respectively. From the countries listed above, a total of $303 million had been allocated to this Initiative by 1999. It was estimated that within ten years the economic loss due to Chagas' Disease would be lessened by $12,000 million, which is a return of $45.2 per $1 spent in prevention. The economic loss calculated was due to disability and early mortality of young, otherwise productive adults. The economic loss of the South American continent was estimated to be $18,000 million in 1995, which was roughly equal to five percent of the external debt of the entire continent. Necessary or required medical care also effects economic stability, the cost per patient per year was estimated in 1999 in various counties: Argentina $406, Brazil $1,250, Bolivia $227, and Uruguay $877. The Southern Cone Initiative countries average is $559/patient/per. Additionally, the total annual amount of money spent per year for medical care in the Initiative countries was $2,238 million and $37 million for vector control by 1999. It was discovered that for every $1 spent on prevention there was a save of $37 in medical expenses annually. Specifically for Brazil, there was a savings of $17.50 in medical costs per $1 invested in prevention. Economic costs of treatment, expensive cardiac pacemakers, and productive years lost totaled $391 million in 1996 in the Andean countries. Transmission control in these countries is $16 million per year, and so per $1 spent in prevention, $16 should be saved in medical costs (Moncayo, 1999). There is also a Central American Initiative in Honduras, where pacemaker implants for chronic Chagas' Disease patients costs an estimated $375 million dollars. Transmission prevention is $11 million in this region, but a return of $34 per $1 spent in transmission prevention is expected because of high medical costs of pacemakers (Moncayo, 1999).

As of 2009, most of the Southern Cone Initiative countries had implemented control strategies and were surveying the results. Between 1991 and 2000, $345 million dollars were spent from these countries national budgets for vector control alone. The program in Brazil proved to be highly cost-effective, because per $1 spent in prevention, a total of $17 was saved in economic loss. The chronic phase of Chagas' Disease is the most demanding monetarily. In Brazil, approximately $750 million per year is spent in pacemaker implants and corrective surgery. This money would have been enough to construct over 700,000 improved rural dwellings (spending $1,000 per dwelling) in Brazil in the year 2000. Furthermore, between 1979-1981 Brazil had 14,022 reported deaths due to Chagas' Disease. This approximately represents 259,152 years of life before retirement that otherwise would have been economically productive, but instead the economic loss was $237 million (Moncayo and Silveira, 2009).

The country of Mexico is also taking an economic hit from Chagas' Disease. In 2005 there were over 530,500 cases of chronic Chagas' Disease. Cardiomyopathy is a serious problem in many regions of Mexico, for example one hospital in Salina Cruz, Oaxaca reported that 85% of cardiac insufficiency cases and 16% of all cardiac consultations resulted because of Chagas' Disease. The economic burden of Chagas' Disease in Mexico was estimated at $3160 million annually in 2005 (Ramsey et al., 2005).

In order to prepare and plan economically for such financial burdens, studies have been conducted with predictive cost models. These studies may aid proposals for grants or other research endeavors involving investments. For example, a study explains how reagents, labor, and confirmatory testing are all costs associated with screening blood in the United States for _T. cruzi_ (Agapova et al., 2010). A different study predicted the economic impact of a Chagas' Disease vaccine taking into consideration factors of vaccine price, infection risk, and efficacy. The development of a vaccine would prove very cost-effective according to the model even when vaccine prices are relatively high and efficacy of the vaccine is minimal. For example, the vaccine would be cost effective under these or better conditions: a $75 vaccine in an area with 5% infection risk and a vaccine efficacy of 50% or greater; or a $200 vaccine in an areas with 20% infection risk and a vaccine efficacy of 75% or greater. These numbers help describe the economic value of a Chagas' Disease vaccine in regions with different characteristics (Lee et al, 2010). As described by a paper on the current challenges of Chagas' Disease, "Evidently, with success will come the economic barriers to produce and deliver the vaccine, a common feature of neglected diseases" (Lannes-Vieira et al., 2010).

Economic challenges continue to burden those countries where Chagas' Disease is endemic. Economic hardship has encouraged migration of _T. cruzi_ infected people to non-endemic areas such as the United States and Europe. Now these non-endemic countries must prevent transmission by blood, organ donations, and congenitally (Yadon and Schmunis, 2009). These actions cost money and place an economic burden on non-endemic countries as well. What was once a problem of Latin America is now a global issue. Hopefully with the resources of more developed countries the prevention and control of Chagas' Disease will lead to eradication. This biological threat has been inflicting populations of humans for thousands of years, and unfortunately the current economic situation is not permissive of eradication. Possibly in time, as organizations, research, and investments become more developed, the power of human action will be enough to overcome this ancient, tragic parasite.

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**12. How Culture Defines Chagas' Disease: Social Aspects of Being Infected**

Imagine a small girl, five years old, waking up from the heat of the sun in a room shared with her siblings. She has curly, shabby hair and dark skin. The room is made of adobe and has a thatched roof made of palm. There is a yellow calendar on the wall, along with streaks of reduviid bug feces. The girl has Romaña's sign, characterized by redness and the complete closure of her right eye. Usually she sleeps in a bed with her two younger sisters, but now they are afraid she will give them a fever or cause swelling of their eyes, so they stay on the other side of the room and avoid contact. On the playground at school she is picked last to play games because everyone knows she isn't healthy, and two older girls close one eye and walk around bumping into things, mimicking the sick girl. At home, her mother is busy preparing a meal and tending to other children. The infected child is not given a hug and no one touches her because they do not want to become infected. As the sun fades the girl sadly lays down for sleep. She doesn't understand what is happening to her body, she only knows that it hurts. She also doesn't understand why no one treats her the same, and wishes her mother would come tell her bedtime stories like she did in the past.

Her younger sisters, parents, and friends do not realize that avoiding interaction with the infected child does not protect them, and that physical contact with others does not spread Chagas' Disease (unless blood is involved). What everyone was displaying towards the poor young girl was a common social stigma for those infected with _Trypanosoma cruzi_. This type of health-related stigma is defined by Weiss and Ramakrishna (2006) as: "a social process or related personal experience characterized by exclusion, rejection, blame, or devaluation that results from experience or reasonable anticipation of an adverse social judgment about a person or group identified with a particular health problem." This type of prejudice is unwarranted, but still affects the health of those infected, public health policy, control strategies, and other related subjects.

Because stigmatization plays a major role in such realms, the effect of it has been an increasingly popular area of research, which began in the 1960s. In 1963, Professor Erving Goffman at the University of Pennsylvania wrote a book that started this type of research revolution, titled _Stigma: Notes on the management of spoiled identity_ (Weiss et al., 2006). Goffman described three types of health related stigma in his book: (1) ''Abominations of the body." These are the physical deformities that characterize infection. An example caused by Chagas' Disease is chagoma or Romaña's sign, megacolon and megaesophagus. (2) ''blemishes of individual character . . . weak will . . . passions, treacherous and rigid beliefs, and dishonesty.'' This refers to mental illness, deviant behaviors, or altered personality and motivations. For one example of many, effects of megacolon and megaesophagus produce great stress on the body's digestive system while essentially starving the body because food and nutrients cannot pass through it. This and various other aspects of the disease could cause altered personality and clinical depression. (3) ''Tribal identities.'' This may describe discrimination due to sex, race, religion, or social status. Chagas' Disease is a malady of the economically depressed. Governments in some regions unfortunately overlook such populations. Goffman's studies did not specifically focus on Chagas' Disease, but they encompassed the stigmatization of health-related issues (Goffman, 1963).

Many researchers and their colleagues are producing publications about the stigmatization of _T. cruzi_ infection, such as Weiss (2008), Walton (Walton et al, 2011), and Briceño-León (Briceño-León and Méndez-Galván, 2007). These and most other publications about this topic describe how social stigma antagonizes control strategies, for example by limiting members in organizations and by discouraging individuals to follow treatment strategies. They also describe how seropositive Chagas' Disease patients are laid off from work or put on a labor restriction due to a lack of production (Briceño-León and Méndez-Galván, 2007). Some employers in Latin America will not hire seropositive applicants, and in Brazil many women have been fired when their infections were discovered (Zajac, 1992). Pregnant women in Bolivia that tested positive for Chagas' Disease had many concerns including the possibility of death, harm to the unborn baby, and their spouse's reaction to the news. Sometimes when men are uninformed, they blame their wife for both the infection and transmission to their child. One Bolivian man stated, "be carful of your mother because she may infect you" (Sotomayer et al., 1994).

Adverse social responses, in addition to physical, psychological, and financial issues, all lessen the quality of life in Chagas' Disease patients. Infected individuals develop depressive symptoms in response to many things such as lowered energy, fatigue, negative feelings, lowered memory and concentration, lessened self-esteem, loss of social relationships and sexual activity, lessened financial resources, and non-participation in leisure activities (Ozaki et al., 2011). Depression may also be caused by physical symptoms of pain and discomfort in both children and adults. Children are affected by the acute stage of the disease in which they may experience chagoma, Romaña's sign, fever, hepatosplenomegaly, lymphadenopathy, and heart failure. By adulthood most individuals have entered the chronic phase of the disease, where they experience cardiomyopathy, complete heart block, megaesophagus, megacolon, and related symptoms (Gilles, 2000).

The infected five-year-old girl will probably face a hostile future. If she is lucky, she will enter the indeterminate phase of the disease, where she and _Trypanosoma cruzi_ would be in a type of equilibrium, and no progressive damage would occur (Andrade et al., 1997). She will appear to lead a healthy and normal life in this phase, but will probably succumb to the effects of chronic Chagas' Disease after some time. If she becomes pregnant, she risks the congenital infection of her child. If she gets married, her husband must accept her as being diseased, or she will hide the symptoms as long as possible. When applying for a job, she will want to keep her infection a secret. The young girl is marked as a socially stigmatized, disease ridden, and underprivileged individual that must fight off ill health, depression, and negative cultural phenomenon, all because of single, momentarily painless bug bite.

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**13. Big, Extravagant Ideas: Connecting People to Disconnect Chagas' Disease**

A scientifically sound understanding of _Trypanosoma cruzi_ is essential for all citizens of at-risk countries. If Chagas' Disease education was commonplace, some Mexicans may not eat reduviid bugs for aphrodisiacal effects, husbands may not warn children to be cautious of infective mothers, villagers may not bring bug-infested firewood into living quarters, and children may immediately ask for care when Romaña's sign develops (Salazar et al., 1988; Sotomayer et al, 1994; Black et al., 2007). Not only would individuals and communities become healthier and less infected, but eradication efforts would also be more effective. Public health organizations are working against a current of uneducated people doing harmful activities. If these people based their actions on scientifically proven facts instead of myths and ideas, the current may not be as strong. In the following paragraphs I will propose ideas on how to clear ignorance about the disease and get communities excited about contributing to public health and research studies.

Educational information about Chagas' Disease must reach both the general public of cities along with homes far off in the country. Supplying isolated people with information counter to their life-long beliefs is particularly an issue. Instead of forcing unwanted information on people who may not listen or believe it by distributing pamphlets, flyers, or other pieces of knowledge that generally get thrown in the garbage, I think a more rhetorical approach is necessary. First, create an ethical image. Make the activities seem trustworthy and honorable. Second, be attractive and appealing. Know people's interests and become associated with popular media. Third, make them emotional. Find a way in which people will connect to your activities through any various emotions of, for example, happiness, pleasure, shock, or fright.

Target populations for such activities are those with any prevalence of Chagas' Disease, which is nearly every country in Latin America. A nationwide approach may be appropriate with some activities, but local events may be more meaningful. As examples, I've imagined local initiatives in four different countries that will be described in the following paragraphs. Music will be the focus in Columbia's events, popular literature in Chile, sports in Argentina, and movies in Brazil. Incorporating popular activities is what would make these initiatives attractive, enjoyable, and successful.

Music is a universal interest. Everyone listens to music, people sing and make music, and this is a multicultural aspect of human life. In fact, the reason we love music is probably an evolutionary phenomenon that we share with other species such as birds and whales (Web Source 11). For these reasons, using music as a focal point for a Chagas' Disease initiative should be popular. I propose Shakira, a Columbian-born singer and songwriter, perform a series of free concerts in Columbia with the theme "Combat Chagas' in Columbia," or rather, "La lucha contra la enfermedad de Chagas'." In fact, she should write a song about it. It could be a heart-wrenching story of a young girl with acute Chagas' Disease. Shakira would gently sing about her losing friends in kindergarten and the received social stigma from her family, and then she would forcefully belt out a chorus about eradication and hope for the future. Shakira would promote Chagas' Disease awareness activities on her website, with posters, and other forms of media. These free and entertaining activities would encourage people living far from the city to come and listen to Shakira, and at the same time they will become educated about Chagas' Disease.

Another form of social media, popular literature, should be used in Chile. Two very popular Chilean Nobel Prize poets, Pablo Neruda and Gabriela Mistral, should use their status and talent to compose a book of poems about Chagas' Disease. They can compose writings about personal accounts, unwarranted social stigmas, persuasive preventative instructions, and various other topics that are both informative and entertaining. Unlimited copies of the book should be freely given away to every one in the cities. Books should be taken to communal centers in the country or, if possible, taken to people's secluded homes. The books will instantly be popular because of the two famous co-authors, and everyone will talk about the proposed ideas and suggestions on the street, in coffee shops, and everywhere they go.

For people who enjoy sporting events, an extensive soccer tournament called "Kicking Chagas' into the Ground," or rather "Pateando la enfermedad de Chagas' dentro de la tierra" should be organized in Argentina. Soccer, or rather called football in this region, is the most popular sport in Latin America. The tournament should include the most successful Argentinian clubs such as the River Platte, Boca Juniors, Estudiantes de La Plata, Independiente, and more. Similar to the Shakira concert, people will attend these free games because of the established popularity and hype of the teams. Before every game there should be an announcer communicating the purpose of the tournament, programs with Chagas' Disease information should be passed out through the stands, and there should be signs surrounding the field promoting Chagas'-fighting websites and organizations. All players should wear a symbolic badge, and everyone will want to buy t-shirts, hats, and jerseys with the same badge on it.

Another example that employs popular media is having famous directors and actors create a movie. César Charlone, a well-known Brazilian cinematographer, should create a movie with admired actors that portray an intricate and enthralling story of a village overrun by reduviid bugs. The infestation could have been caused by an illegal deforestation of the nearby wilderness. The reduviid bugs previously contained in sylvatic cycles are now inhabiting domestic and peridomestic domains. The trees and wild animals they formerly occupied and fed from are now gone. The bugs are evolving to the new environment with ease, and they are madly infecting entire families at a time. This movie would create awareness of damaging deforestation effects too, another serious problem in Brazil.

My proposed ideas are extravagant and far-fetched, but the amount of money already allocated towards house spraying, patent care, and other preventative means is equally outrageous. Hundreds of millions of dollars have been spent in Latin America because of Chagas' Disease (Moncayo and Silveira, 2009). The current of damaging individual and societal actions may be too strong for such expensive ventures to be successful. It may be beneficial to allocate some of the enormous amounts of money towards changing people's minds and actions instead of un-educationally treating them. Change happens at the individual level, and it may do a lot of good to convince people to act in scientifically sound ways, to be cautious of unusual behaviors, and to become as educated as possible. Making such actions "cool and hip" may seem like an unscholarly approach, but the general public and economically depressed, or the people suffering from Chagas' Disease, may be motivated to learn and accept unfamiliar information in this way.

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**Conclusion**

Just as I have generated some unanswered questions throughout these chapters, hopefully you have done the same. Maybe you have even decided to send a personal letter to Shakira begging her for free concerts. No matter the ideas running through your mind, I hope reading this review has at least stimulated some sort of intellectual or curious response. A purpose of this thesis is to provide an extensive, thorough evaluation of Chagas' Disease that may be foundations for writing a paper for class, doing research to contribute to a literature review, or just wanting to know more about this major parasitic infection. You now have a basis of the _T. cruzi_ lifecycle, methods of epidemiological research, environmental factors affecting the proliferation of _T. cruzi_ , associated pathology and disease, demographic and geographic distributions, historical and current treatment methods, associated economic costs, social stigma, and many other important and fascinating complexities of Chagas' Disease. As previously explained, our understanding of Chagas' Disease is constantly changing by the addition of new research. With every study, we become closer to controlling this devastating parasite. For the millions of people suffering from Chagas' Disease today and the millions at-risk, we hope scientists will discover a way to overcome managing the disease and to find a cure. For many reasons, the Americas do not need a new HIV/AIDS.

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**Bibliography**

Agapova, M., M. P. Busch, and B. Custer. 2010. Cost-effectiveness of screening the US blood supply for _Trypanosoma cruzi_. _Transfusion_ , 50:2220-2232.

Allan, B. F., F. Keesing, and R. S. Ostfeld. 2003. Effect of forest fragmentation on Lyme disease risk. _Conservation Biology_ , 17:267-272.

Andrade, Z. A., S. G. Andrade, M. Sadigursky, R. J. Wenthold, S. L. Hilbert, and V. J. Ferrans. 1997. The indeterminate phase of Chagas' Disease: Ultrastructural characterization of cardiac changes in the canine model. _The American Journal of Tropical Medicine and Hygiene_ , 57(3):328-336.

Asin, S. and S. Catala. 1995. Development of _Trypanosoma cruzi_ in Triatoma infestans: Influence of temperature and blood consumption. Journal of Parasitology, 81:1-7.

Aufderheide A. C., W. Salo, M. Madden, J. Streitz, J. Buikstra, F. Guhl, B. Arriaza, C. Renier, L. E. Wittmers, Jr., G. Fornaciari, and M. Allison. 2004. A 9,000-year record of Chagas' Disease. _Proceedings Of The National Academy Of Sciences Of The United States Of America_ , 101(7):2034-2039.

Belding, D. 1952. _Textbook of Clinical Parasitology_ , 2nd Ed. Appleton-Century-Crofts, Inc. New York, p. 194- 200.

Bern, C., S. P. Montogmery, B. L. Herwaldt, A. Rassi, Jr., J. A. Marin-Neto, R. O. Dantas, J. H. Maguire, H. Acquatella, C. Morillo, L. V. Kirchhoff, R. H. Gilman, P. A. Reyes, R. Salvatella, and A. C. Moore. 2007. Evaluation and Treatment of Chagas' Disease in the United States. _The Journal of the American Medial Association_ , 298:2171-2181.

Black, C. L., S. Ocaña, D. Riner, J. A. Costales, M. A. Lascano, S. Davila, L. Arcos-Teran, J. R. Seed, and M. J. Grijaiva. 2007. Household Risk Factors for Trypanosoma cruzi Seropositivity in Two Geographic Regions of Ecuador. _The Journal of Parasitology_ , 93:12-16.

Brandan, C. P., A. M. Padilla, D. Xu, R. L. Tarleton, and M. A. Basombrio. 2011. Knockout of the dhfr-ts Gene in _Trypanosoma cruzi_ Generates Attenuated Parasites Able to Confer Protection against a Virulent Challenge. _Public Library of Science Neglected Tropical Diseases_ , 5(12): e1418. doi:10.1371/journal.pntd.0001418.

Briceño-León, R. and J. Méndez-Galván. 2007. The social determinants of Chagas' Disease and the transformations of Latin America. _Memórias do Instituto Oswaldo Cruz, 102:109-112._

Brown, E. L., D. Roellig, M. E. Gompper, R. J. Monello, K. M. Wenning, M. W. Gabriel, and M. J. Yabsley. 2010. Seroprevalence of _Trypanosoma cruzi_ Among Eleven Potential Reservoir Species from Six States Across the Southern United States. _Vector-Borne and Zoonotic Diseases,_ 10: 757-763.

Cain M. L., W. D. Bowman, and S. D. Hacker. 2008. _Ecology_. Sinauer Associates, Inc. Sunderland, Massachusetts. 8p.

Campbell, N. A., and J. B. Reece. 2009. _Biology_ , 8th Ed. Pearson Benjamin Cummings Publishing Company. San Francisco, CA. Pages 236-237.

Cartwright, D. and C. Gaston. 2002. Chapter 5: Chile's Forest Products Markets– A Plantation Success Story. _UNCE/FAE Forest Products Annual Market Review 2001-2002_ , pp. 53-60.

Cecere, M. C., D. M. Canale, and R. E. Gürtler. 2003. Effects of Refuge Availability on the Population Dynamics of _Triatoma infestans_ in Central Argentina. _Journal of Applied Ecology_ , 40(4):742-756.

Chin-Hong, P. V., B. S. Schwartz, C. Bern, S. P. Montgomery, S. Kontak, B. Kubak, M. I. Morris, M. Nowicki, C. Wright, and M. G. Ison. 2011. Screening and Treatment of Chagas' Disease in Organ Transplant Recipients in the United States: Recommendations from the Chagas in Transplant Working Group. _American Journal of Transplantation_ , 11:672-680.

Coimbra, Carlos E. A. Jr. 1988. Human Settlements, Demographic Pattern, and Epidemiology in Lowland Amazonia: the Case of Chagas's Disease. _American Anthropologist_ , 90:82-97.

Collins, M. H., J. M. Craft, J. M Bustamante, and R. L. Tarleton. 2011. Oral Exposure to _Trypanosoma cruzi_ Elicits a Systemic CD8 + T Cell Response and Protection against Heterotopic Challenge. _Infection and Immunity_ , 79(8):3397. DOI: 10.1128/IAI.01080-10

Corredor Arjona, A., C. A. Alvarez Moreno, C. A. Agudelco, M. Bueno, M. C. Lopez, E. Caceres, P. Reyes, S. Duque Beltran, L. E. Gualdron, and M. M. Santacruz. 1999. Prevalence of _Trypanosoma cruzi_ and _Leishmania chagasi_ infection and risk factors in a Colombian indigenous population. _Revista do Instituto de Medicina Tropical de Sao Paulo_ , 41(4):229-234.

Coutinho, Marilia. 1999. Ninety Years of Chagas' Disease: A Success Story at the Periphery. _Social Studies of Science_ , 29(4):519-549.

Dumonteil, Eric. 1999. Update on Chagas' Disease in Mexico. _Salud pública México_ , 41(4):322-327.

Echeverria, C., D. Coomes, J. Salas, J. M. Rey-Benayas, A. Lara, and A. Newton. 2006. Rapid Deforestation and Fragmentation of Chilean Temperate Forests. _Biological Conservation_ ,130:481–494.

El-Sayed, N. M., P. J Myler, D. C. Bartholomeu, D. Nilsson, G. Aggarwal, A. Tran, E. Ghedin, E. A. Worthey, A. L. Delcher, G. Blandin, S. J. Westenberger, E. Caler, G. C. Cerqueira, C. Branche, B. Haas, A. Anupama, E. Arner, L. Aslund, P. Attipoe, E. Bontempi. F. Bringaud, P. Burton, E. Cadag, D. A. Campbell, M. Carrington, J. Crabtree, H. Darban, J. Franco da Silveira, P. de Jong, K. Edwards, P. T. Englund, G. Fazelina, T. Feldblyum, M. Ferella, A. C. Frasch, K. Gull, D. Horn, L. Hou, Y. Huang, E. Kindlund, M. Klingbeil, S. Kluge, H. Koo, D. Lacerda, M. J. Levin, H. Lorenzi, T. Louie, C. R. Machado, R. McCulloch, A. McKenna, Y. Mizuno, J. C. Mottram, S. Nelson, S. Ochaya, K. Osoegawa, G. Pai, M. Parsons, M. Pentony, U. Pettersson, M. Pop. J. L. Ramirez, J. Rinta, L. Robertson, S. L. Salzberg, D. O. Sanchez, A. Seyler, R. Sharma, J. Shetty, A. J. Simpson, E. Sisk, M. T. Tammi, R. Tarleton, S. Teixeira, S. Van Aken, C. Vogt, P. N. Ward, B. Wickstead, J. Wortman, O. White, C. M. Fraser, K. D. Stuart, and B. Andersson. 2005. The Genome Sequence of _Trypanosoma cruzi_ , Etiologic Agent of Chagas' Disease. _Science_ , 309 (5733): 409-415.

Engel, J. C., P. S. Doyle, I. Hsieh, and J. H. McKerrow. 1998. Cysteine Protease Inhibitors Cure an Experimental _Trypanosoma cruzi_ Infection. _The Journal of Experimental Medicine,_ 188(4):725-734 _._

Fox, Stuart Ira. 2011. _Human Physiology_ , 12th Ed. McGraw-Hill Publishing Company, New York, NY. Pages 438-439.

Freilij, H. and J. Altcheh. 1995. Congenital Chagas' Disease: Diagnostic and Clinical Aspects. _Clinical Infectious Diseases_ , 21(3):551-555.

Frias, D. A., A. A. Hendry, and C. R. Gonzalez. 1998. _Mepraia_ _gajardoi_ : a new species of Triatominae (Hemiptera: Reduviidae) from Chile and its comparison with _Mepraia_ _spinolai_. _Revista Chilena de Historia Natural_ , 71:177-188.

Fox, Stuart Ira. 2011. _Human Physiology_ , 12th Ed. McGraw-Hill Publishing Company, New York, NY. 606p.

Galvao-Castro, B., J. A. Sa-Ferreira, and C. Pirmez. 1984. Immunopathological aspects of American Trypanosomiasis: the role of immune complexes in the pathogenesis of the disease. _Memórias do Instituto Oswaldo Cruz,_ 79:69-76.

Gilles, H. 2000. Parasitic disease affecting the heart in childhood. _Images in Paediatric_ _Cardiology_ , 2(4):28-39.

Goffman, E. 1963 _. Stigma: Notes on the management of spoiled identity._ Englewood Cliffs, NJ: Prentice Hall.

Goncalves, T. C. M., E. Oliveira, L. S. Dias, M. D. Almeida, W. O. Nogueira, and F. D. A. Pires. 1998. An investigation on the ecology of _Triatoma vitticeps_ (Stal, 1859) and its possible role in the transmission of _Trypanosoma cruzi_ , in the locality in Triunfo, Santa Maria Madalena Municipal District, State of the Rio de Janeiro, Brazil. Memorias do Instituto Oswaldo Cruz, 93:711-717.

Hashimoto, M., J. Morales, Y. Fukai, S. Suzuki, S. Takamiva, A. Tsubouchi, S. Inoue, M. Inoue, K. Kita, S. Harada, A. Tanaka, T. Aoki, and T. Nara. 2012. Critical importance of the de novo pyrimidine biosynthesis pathway for _Trypanosoma cruzi_ growth in the mammalian host cell cytoplasm. _Biochemical and Biophysical Research Communications_ , 417(3):1022-1006.

Hogan L. and B. Peterson. 2001. _The Sweet Breathing of Plants. Women Writing on the Green World._ North Point Press, New York, p. 104-108.

Hotez, P, J. Dumonteil, L. Woc-Colburn, J. A. Serpa, S. Bezek, M. S. Edwards, C. J. Hallmark, L. W. Musselwhite, B. J. Flink and M. E. Bottazzi. 2012. Chagas' Disease: ''The New HIV/AIDS of the Americas'." _Public Library of Science_ , 6(5): e1498. doi:10.1371/journal.pntd.0001498

Koeberle, F. 1968. Chagas' Disease and Chagas' syndromes: the pathology of American Trypanosomiasis. _Advances in Parasitology_ , 6:63-110.

Lambrecht, F. L. 1965. Biological variations in trypanosomes and their relation to the epidemiology of Chagas' Disease. _Revista do Instituto de Medicina Tropical de São Paulo_ , 7(6):346-352.

Lammel E. M., M. A. Barbieri, S. E. Wilkowsky, F. Bertini, and E. L. Isola. 1996. _Trypanosoma cruzi_ : involvement of intracellular calcium in multiplication and differentiation. _Experimental Parasitology_ , 32:240-249.

Lannes-Vieira, J., T. C. de Araújo-Jorge, M. de Nazaré Correia Soeiro, P. Gadelha, and R. Corrêa-Oliveira. 2010. The Centennial of the Discovery of Chagas' Disease: Facing the Current Challenges. _Public Library of Science_ , 4(6):e645. doi:10.1371/journal.pntd.0000645

Lee B.Y., K. M. Bacon, D. L. Connor, A. M. Willig, and R. R. Bailey. 2010. The Potential Economic Value of a _Trypanosoma cruzi_ (Chagas' Disease) Vaccine in Latin America. _Public Library of Science_ , 4(12): e916. doi:10.1371/journal.pntd.0000916

Levin, B. W. and A. R. Fleischman. 2002. Public Health and Bioethics: the benefits of collaboration. _American Journal of Public Health_ , 92(2): 165-167.

López-Muñoz, R., M. Faúndez, S. Klein, S. Escanilla, G. Torres, D. Lee-Liu, J. Ferreira, U. Kemmerling, M. Orellana, A. Morello, A. Ferreira, and J. D. Maya. 2010. _Trypanosoma cruzi_ : In vitro effect of aspirin with nifurtimox and benznidazole. _Experimental Parasitology_ , 124(2):167-171.

Lukeš J., H. Hashimi, Z. Verner, and Z. Čičová. 2010. The Remarkable Mitochondrion of Trypanosomes and Related Flagellates in _Microbiology Monographs_ , 17:228-229.

Marsden, Philip Davis. 1984. Selective Primary Health Care: Strategies for Control of Disease in the Developing World. XVI. Chagas' Disease. _Reviews of Infectious Diseases_ , 6:855-865.

Marsden, P. D. 1989. American Trypanosomiasis. _British Medical Journal_ , 299(6705):969-970.

McCabe, R. E. J. S. Remington, and F. G. Araujo.1984. Ketoconazole Inhibition of Intracellular Multiplication of _Trypanosoma cruzi_ and Protection of Mice Against Lethal Infection with the Organism. _Journal of Infectious Diseases_ , 150(4):594-601.

McCabe, R. E. J. S. Remington, and F. G. Araujo. 1987. Ketoconazole promotes parasitological sure of mice infected with _Trypanosoma cruzi. Transactions of the Royal Society of Tropical Medicine and Hygiene_ , 81:613-615.

Melo, R. C., and Z. Brener. 1978. Tissue Tropism of Different _Trypanosoma cruzi_ Strains. _The Journal of Parasitology_ , 64(3):475-482.

Miles, M. A., M. D. Feliciangeli, and A. Rojas de Arias. 2003. Science, Medicine, and the Future: American Trypanosomiasis (Chagas' Disease) And the Role of Molecular Epidemiology In Guiding Control Strategies. _British Medical Journal_ , 326:1444-1448.

Moir, M. L, and K. E. C. Brennan. 2007. Chapter 4: Using Bugs (Hemiptera) as Ecological and Environmental Indicators in Forest Ecosystems. _Ecology Research Progress._ Nova Science Publishers, Inc. pp.79-115.

Mok, E. A., L. O. Gostin, M. D. Gupta, and M. Levin. 2010. Implementing Public Health Regulations in Developing Countries: Lessons from the OECD Countries. _Journal of Law, Medicine & Ethics_, 38(3):508-519.

Moncayo, Álvaro. 1999. Progress Towards Interruption of Transmission of Chagas. _Memórias do Instituto Oswaldo Cruz_ , 94:401-404.

Moncayo, Álvaro, and Antonio Carlos Silveira. 2009. Current epidemiological trends for Chagas' Disease in Latin America and future challenges in epidemiology, surveillance and health policy. _Memórias do Instituto Oswaldo Cruz_ , 104:17-30.

Moreno S. N., J. Silva, A. e. Vercesi, and R. Docampo. 1994. Cytosolic-free calcium elevation in _Trypanosoma cruzi_ is required for cell invasion. _The Journal of Experimental_ Medicine, 180:1535-1540.

Mott, K. E., P. Desjeux, A. Moncayo, P. Ranque, and P. de Raadt. 1990. Parasitic Diseases and Urban Development. _Bull World Health Organization_ , 68(6):691-698.

Obara, M. T., J. M. Soares Barata, J. A. Da Rosa, W. Ceretti Junior, P. S. De Almeida, G. A. Goncalves, C. Dale, and R. Gurgel-Goncalves. 2012. Description of the female and new records of Triatoma baratai Carcavallo & Jurberg, 2000 (Hemiptera: Heteroptera: Reduviidae: Triatominae) from Mato Grosso do Sul, Brazil, with a key to the species of the Triatoma matogrossensis subcomplex. _Zootaxa_ , 3151:63-68.

Ozaki, Y., M. E. Guariento, and E. A. de Almeida. 2011. Quality of life and depressive symptoms in Chagas' Disease patients. _Quality of Life Research_ , 20:133-138.

Patz, J. A., P. Daszak, G. M. Tabor, A. A. Aguirre, M. Pearl, J. Epstein, N. D. Wolfe, A. M. Kilpatrick, J. Foufopoulos, D. Molyneux, and D. J. Bradley. 2004. Unhealthy Landscapes: Policy Recommendations on Land Use Change and Infectious Disease Emergence. _Environmental Health Perspectives_ , 112(10):1092-1098.

Peterson, A. T., V. Sánchez-Cordero, C. B. Beard, and J. M. Ramsey. 2002. Ecologic Niche Modeling and Potential Reservoirs for Chagas' Disease, Mexico. _Emerging Infectious Diseases_ , Vol. 8, Num. 7. Available from http://wwwnc.cdc.gov/eid/article/8/7/01-0454.htm

Ramsey, J. M., A. L. Alvear, R. Ordoñez, G. Muñoz, A. Garcia, R. Lopez, and R. Leyva. 2005. Risk factors associated with house infestation by the Chagas' Disease vector _Triatoma pallidipennis_ in Cuernavaca metropolitan area, Mexico. _Medical and Veterinary Entomology_ , 19:219–228.

Roberts, L. S., and J. Janovy, Jr. 2009. _Foundations of Parasitology_ , 8th Ed. McGraw-Hill Publishing Company, Dubuque, Iowa. Pp. 61-80.

Sacks, David and Alan Sher, 2002. Evasion of innate immunity by parasitic protozoa. _Nature_ , 3(11):1041-1047.

Salazar-Schettino, P. M. 1983. Customs which predispose to Chagas' Disease and cysticercosis in Mexico. _American Journal of Tropical Medicine and Hygiene,_ 32:1179-1180.

Salazar-Schettino, P. M., I. de Haro Arteaga, and T. Uribarren Berrueta. 1988. Chagas diease in Mexico. _Parasitology Today_ , 4(12):348-352.

Santos, R. R. 1977. Imunopatologia da destruigao neuronal na Doenca de Chagas experimental. Thesis. Faculty of Medicine of Ribierao Preto, Brazil. 94p.

Sarkar, S., S. E. Strutz, D. M. Frank, C. Rivaldi, B. Sissel, and V. Sanchez-Cordero, 2010. Chagas' Disease Risk in Texas. _Plos Neglected Tropical Diseases_ , 4(10):article number e836.

Schaefer, C. W. and R. Panizzi. 2000. Chapter 29: Assassin Bugs (Reduviidae excluding Triatominae). _Heteroptera of Economic Importance_ , CRC Press LLC, Boca Raton, Florida. p. 695

Schofield, C. J. 1982. The ecology of Chagas' Disease in Chile. _Ecology of Disease_ , 1(2-3):117-29.

Simpson, Alastair G. B., Y. Inagaki, and A. J. Roger. 2006. Comprehensive Multigene Phylogenies of Excavate Protists Reveal the Evolutionary Positions of "Primitive" Eukaryotes. _Molecular Biology and Evolution_ , 23: 615-625.

Solari, Aldo. 2011. Past and Present of Chagas' Disease in Northern Chile. _Chungara, Revista de Antropología Chilena_ , 43:315-322.

Sotomayer, O., J. J. Davalos, C. F. Pena, R. Urgel, A. Melvy, B. Vargas, and O. Pinto. 1994. Socioeconomic, cultural, and psychosocial factors of congenital Chagas' Disease. In Wijeyaratne, P., J. Hatcher Roberts, J. Kitts, and L. Jones Arsenault. Gender, health, and sustainable development: a Latin American perspective. Proceedings of a workshop help in Montevideo, Uruguay, 26-29 April 1994. International Development Research Centre, Ottawa, ON, Canada. Pp. 115-124.

Stevens, L., P. L. Dorn, J. O. Schmidt, J. H. Klotz, D. Lucero, and S. A. Klotz. 2011. Chapter 8: Kissing Bugs. The Vectors of Chagas'. _Advances in Parasitology_ , 75: 169-185.

Tafuri, W. L. 1970. Pathogenesis of lesions of the autonomic nervous system of the mouse in experimental acute Chagas' Disease: light and electron microscope studies. _American Journal of Tropical Medicine and Hygiene_ , 19:405-417.

Teixeira A. R., P. S. Monteiro, J. M. Rebelo, E. R. Argañaraz, D. Vieira, L. Lauria-Pires, R. Nascimento, C. A. Vexenat, A. R. Silva, S. K. Ault, and J. M. Costa. 2001. _Emerging Infectious Diseases_ , 7(1):100-112.

Tonnetti, L., A. M. Thorp, H. L. Reddy, S. D. Keil, R. P. Goodrich, and D. A. Leiby. 2012. Evaluating pathogen reduction of _Trypanosoma cruzi_ with riboflavin and ultraviolet light for whole blood. _Transfusion_ , 52(2):409-416.

Tortora, G. J. and M. T. Nielsen. 2012. _Principles of Human Anatomy_ , 12th edition, John Wiley & Sons, Inc. Hoboken, New Jersey. Pages 723-724

Ulrich, P., R. Cintrón, and R. Docampo. 2010. Calcium Homeostasis and Acidocalcisomes in _Trypanosoma_ cruzi. _Microbiology Monographs_ , 17:314.

Urbina, J. A. 2001. Specific treatment of Chagas' Disease: current status and new developments. _Current Opinion in Infectious Diseases_ , 14(6):733-741.

Urbina, J. A. and R. Docampo. 2003. Specific chemotherapy of Chagas' Disease: controversies and advances. _Trends in Parasitology_ , 19(11):495-501.

Vaz, V. C., P. S. D'Andrea, and A. M. Jansen. 2007. Effects of habitat fragmentation on wild mammal infection by _Trypanosoma cruzi_. _Parasitology_ , 134:1785-1793.

Vazquez-Prokopec, G. M., L. A. Ceballos, M. C. Cecere, and R. E. Gurtler. 2002. Seasonal variations of microclimate conditions in domestic and peridomestic habitats of Triatoma infestans in rural northwest Argentina. _Acta Tropica_ , 84:229-238.

Walton, David A., Paul E. Farmer, and Rebecca Dillingham. 2011. Social and Cultural Factors in Tropical Medicine: Reframing Our Understanding of Disease. In _Tropical Infectious Diseases: Principles, Pathogens, and Practice_. By R. L. Guerrant, D. H. Walker, and P. F. Weller. Edinburgh: Saunders/Elsevier, p. 26-35.

Watanabe, H., H. Noda, G. Tokuda, and N. Lo. 1998. A Cellulase Gene of Termite Origin. _Nature_ , 394:330-331.

Weiss, M. G. 2008. Stigma and the Social Burden of Neglected Tropical Diseases. _Public Library of Science, Neglected Tropical Diseases_ , 2(5):e237. doi:10.1371/journal.pntd.0000237

Weiss, M. G. and J. Ramakrishna. 2006. Stigma interventions and research for international health. _Lancet_ , 367:536–538.

Weiss, M. G., J. Ramakrishna, and D. Somma. 2006. Health-related stigma: Rethinking concepts and interventions. _Psychology, Health, and Medicine_ , 11(3):277-287.

Woody, N. C. and H. B. Woody. 1955. American Trypanosomiasis (Chagas' Disease). First indigenous case in the United States _. The Journal of the American Medical Association,_ 159(7):676-677.

Yadon, Z. E. and G. A. Schmunis. 2009. Congenital Chagas' Disease: Estimating the Potential Risk in the United States. _The American Journal of Tropical Medicine and Hygiene_ , 81(6):927-93.

Zajac, A. 1992. Clinicopathologic and socioeconomic impact of Chagas' Disease on women: a review. In Wijeyaratne, P., E. M. Rathgeber, and E. St-Onge, _Women and tropical diseases._ International Development Research Centre. Ottawa, ON, Canada. P. 134-148.

Web Sources:

1.<http://www.cdc.gov/parasites/chagas/>

2.<http://medical-dictionary.thefreedictionary.com/zymodemes>

3.<http://www.whatispublichealth.org/>

4.<http://www.idri.org/chagas-disease.html>

5.<http://www.msf.org.uk/chagas.focus>

6.<http://www.sanger.ac.uk/about/press/2005/050714.html>

7.<http://www.ctegd.uga.edu/tarleton.php>

8.<http://www.dndi.org/diseases/chagas.html>

9.<http://www.chagasfound.org/index.php>

10.<http://www.who.int/tdr/diseases/chagas/strat_dir_chagas/en/index3.html>

11.<http://www.economist.com/node/12795510>

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