Chagas disease, which is caused by the intracellular parasite Trypanosoma cruzi, is a neglected illness with 12-14 million reported cases in endemic geographic regions of Latin America. While the disease still represents an important public health problem in these affected areas, the available therapy, which was introduced more than four decades ago, is far from ideal due to its substantial toxicity, its limited effects on different parasite stocks, and its poor activity during the chronic phase of the disease. For the past 15 years, our group, in collaboration with research groups focused on medicinal chemistry, has been working on experimental chemotherapies for Chagas disease, investigating the biological activity, toxicity, selectivity and cellular targets of different classes of compounds on T. cruzi. In this report, we present an overview of these in vitro and in vivo studies, focusing on the most promising classes of compounds with the aim of contributing to the current knowledge of the treatment of Chagas disease and aiding in the development of a new arsenal of candidates with anti-T. cruzi efficacy.

OBJECTIVE: To reconstruct the historical changes in force of dengue infection in Singapore, and to better understand the relationship between control of Aedes mosquitoes and incidence of classic dengue fever. METHODS: Seroprevalence data were abstracted from surveys performed in Singapore from 1982 to 2002. These data were used to develop two mathematical models of age seroprevalence. In the first model, force of infection was allowed to vary independently each year, while in the second it was described by a polynomial function. Model-predicted temporal trends were analysed using linear regression. Time series techniques were employed to investigate periodicity in predicted forces of infection, dengue fever incidence and mosquito breeding. FINDINGS: Force of infection estimates showed a significant downward trend from 1966, when vector control was instigated. Force of infection estimates from both models reproduced significant increases in the percentage and average age of the population susceptible to dengue infections. Importantly, the year-on-year model independently predicted a five to six year periodicity that was also displayed by clinical incidence but absent from the Aedes household index. CONCLUSION: We propose that the rise in disease incidence was due in part to a vector-control-driven reduction in herd immunity in older age groups that are more susceptible to developing clinical dengue.

OBJETIVO: Determinar la evolución de la virulencia del dengue en Singapur, y profundizar en la relación entre el control del mosquito Aedes y la incidencia de la fiebre del dengue clásica. MÉTODOS: A partir de estudios realizados en Singapur entre 1982 y 2002, se reunieron datos de seroprevalencia que se utilizaron para desarrollar dos modelos matemáticos de seroprevalencia por edades. En el primer modelo se permitió que la virulencia de la infección variara de forma independiente cada año, mientras que en el segundo se describió mediante una función polinómica. Las tendencias temporales previstas por el modelo se analizaron mediante métodos de regresión lineal. Se emplearon técnicas de series temporales para investigar la periodicidad de la virulencia prevista de la infección, la incidencia de fiebre del dengue y la reproducción de los mosquitos. RESULTADOS: Las estimaciones de la virulencia de la infección mostraron una tendencia descendente considerable desde 1966, año en que se empezó a fomentar la lucha antivectorial. Las estimaciones de la virulencia de la infección obtenidas con los dos modelos reprodujeron aumentos importantes del porcentaje y la edad promedio de la población vulnerable al dengue. Un hallazgo importante es que el modelo de año en año predijo de forma independiente una periodicidad de cinco a seis años observable también en la incidencia clínica, pero no así en el índice de Aedes en los hogares. CONCLUSIÒN: El aumento de la incidencia de la enfermedad puede deberse en parte a una reducción, propiciada por la lucha antivectorial, de la inmunidad colectiva en los grupos de personas de edad avanzada que tienen mayor tendencia a desarrollar dengue clínico.

OBJECTIF: Reconstituer les variations historiques à Singapour de la virulence de l'infection par la dengue et mieux comprendre la relation entre la lutte contre les moustiques Aedes et l'incidence de la dengue classique. MÉTHODES: Des données de séroprévalence ont été extraites des enquêtes réalisées à Singapour entre 1982 et 2002. Ces données ont servi à développer deux modèles mathématiques de la séroprévalence en fonction de l'âge. Dans le premier modèle, on a laissé la virulence de l'infection varier chaque année de manière indépendante, tandis que, dans le second, cette virulence était décrite par une fonction polynomiale. On a analysé par régression linéaire les tendances temporelles prédites par les modèles. On a étudié la périodicité des previsions de la virulence de l'infection, de l'incidence de la dengue et de la reproduction des moustiques par des techniques utilisant des séries temporelles. RÉSULTATS: La virulence estimée de l'infection présente une tendance à la baisse significative depuis 1966, année de lancement de la lutte antivectorielle. Les estimations de cette virulence fournies par les deux modèles reflètent des augmentations importantes du pourcentage et de l'âge moyen de la population susceptible de contracter la dengue. Point important : la modélisation d'année en année a prédit de manière indépendante une périodicité de cinq à six ans, que présente également l'incidence clinique, mais pas l'indice « maison » du moustique Aedes. CONCLUSION: Notre interprétation est que l'augmentation de l'incidence de la maladie est en partie due à une baisse de l'immunité collective induite par la lutte antivectorielle dans les tranches d'âges supérieures, plus sensibles au développement de la dengue clinique.

The way in which vectors distribute themselves amongst their hosts has important epidemiological consequences. While the role played by active host choice is largely unquestioned, current knowledge relates mostly to the innate response of vectors towards stimuli signalling the presence or quality of their hosts. Many of those cues, however, can be unpredictable, and therefore prevent the incorporation of the appropriate response into the vector's behavioural repertoire unless some sort of associative learning is possible. We performed a wide range of laboratory experiments to test the learning abilities of the mosquito, Aedes aegypti. Mosquitoes were exposed to choice procedures in (1) an olfactomenter and (2) a 'visual arena'. Our goal was to determine whether the mosquitoes were able to associate unconditional stimuli (blood feeding, human breath, vibration and electrical shock) with particular odours (citral, carvone, citronella oil and eugenol) and visual patterns (horizontal or vertical black bars) to which they had been previously observed to be responsive. We found no evidence supporting the hypothesis that associative learning abilities are present in adult Ae. aegypti. We discuss the possibilities that the assays employed were either inappropriate or insufficient to detect associative learning, or that associative learning is not possible in this species.