Risk for transfusion-transmitted infectious diseases in Central and South America.

We report the potential risk for an infectious disease through tainted transfusion in 10 countries of South and Central America in 1993 and in two countries of South America in 1994, as well as the cost of reagents as partial estimation of screening costs. Of the 12 countries included in the study, nine screened all donors for HIV; three screened all donors for hepatitis B virus (HBV); two screened all donors for Trypanosoma cruzi; none screened all donors for hepatitis C virus (HCV); and six screened some donors for syphilis. Estimates of the risk of acquiring HIV through blood transfusion were much lower than for acquiring HBV, HCV, or T. cruzi because of significantly higher screening and lower prevalence.rates for HIV. An index of infectious disease spread through blood transfusion was calculated for each country. The highest value was obtained for Bolivia (233 infections per 10,000 transfusions); in five other countries, it was 68 to 103 infections per 10,000. The risks were lower in Honduras (nine per 10,000), Ecuador (16 per 10,000), and Paraguay (19 per 10,000). While the real number of potentially infected units or infected persons is probably lower than our estimates because of false positives and already infected recipients, the data reinforce the need for an information system to assess the level of screening for infectious diseases in the blood supply. Since this information was collected, Chile, Colombia, Costa Rica, and Venezuela have made HCV screening mandatory; serologic testing for HCV has increased in those countries, as well as in El Salvador and Honduras. T. cruzi screening is now mandatory in Colombia, and the percentage of screened donors increased not only in Colombia, but also in Ecuador, El Salvador, and Paraguay. Laws to regulate blood transfusion practices have been enacted in Bolivia, Guatemala, and Peru. However, donor screening still needs to improve for one or more diseases in most countries

Rapid assessment of the performance of malaria control strategies implemented by countries in the Amazon subregion using adequacy criteria: case study

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to implement a rapid assessment of the performance of four malaria control strategies (indoor spraying, insecticide-treated bed nets, timely diagnosis, and artemisinin-based combination therapy) using adequacy criteria. The assessment was carried out in five countries of the Amazon subregion (Bolivia, Colombia, Ecuador, Guyana, and Peru).</p> <p>Methods</p> <p>A list of criteria in three areas was created for each of the four strategies: preliminary research that supports the design and adaptation of the control strategies, coverage of the control strategies and quality of the implementation of the strategies. The criteria were selected by the research team and based on the technical guidelines established by the World Health Organization. Each criterion included in the four lists was graded relative to whether evidence exists that the criterion is satisfied (value 1), not satisfied (value 0) or partially satisfied (value 0.5). The values obtained were added and reported according to a scale of three implementation categories: adequate, intermediate and deficient.</p> <p>Results</p> <p>Implementation of residual indoor spraying and timely diagnosis was adequate in one country and intermediate or deficient in the rest. Insecticide-treated bed nets ranged between deficient and intermediate in all the countries, while implementation of artemisinin-based combination therapy (ACT) was adequate in three countries and intermediate in the other two countries evaluated.</p> <p>Conclusions</p> <p>Although ACT is the strategy with the better implementation in all countries, major gaps exist in implementation of the other three malaria control strategies in terms of technical criteria, coverage and quality desiredThe countries must implement action plans to close the gaps in the various criteria and thereby improve the performance of the interventions. The assessment tools developed, based on adequacy criteria, are considered useful for a rapid assessment by malaria control authorities in the different countries.</p

Polyfunctional T cell responses in children in early stages of chronic Trypanosoma cruzi infection contrast with monofunctional responses of long-term infected adults

Background: Adults with chronic Trypanosoma cruzi exhibit a poorly functional T cell compartment, characterized by monofunctional (IFN-γ-only secreting) parasite-specific T cells and increased levels of terminally differentiated T cells. It is possible that persistent infection and/or sustained exposure to parasites antigens may lead to a progressive loss of function of the immune T cells. Methodology/Principal Findings: To test this hypothesis, the quality and magnitude of T. cruzi-specific T cell responses were evaluated in T. cruzi-infected children and compared with long-term T. cruzi-infected adults with no evidence of heart failure. The phenotype of CD4+ T cells was also assessed in T. cruzi-infected children and uninfected controls. Simultaneous secretion of IFN-γ and IL-2 measured by ELISPOT assays in response to T. cruzi antigens was prevalent among T. cruzi-infected children. Flow cytometric analysis of co-expression profiles of CD4+ T cells with the ability to produce IFN-γ, TNF-α, or to express the co-stimulatory molecule CD154 in response to T. cruzi showed polyfunctional T cell responses in most T. cruzi-infected children. Monofunctional T cell responses and an absence of CD4+TNF-α+-secreting T cells were observed in T. cruzi-infected adults. A relatively high degree of activation and differentiation of CD4+ T cells was evident in T. cruzi-infected children. Conclusions/Significance: Our observations are compatible with our initial hypothesis that persistent T. cruzi infection promotes eventual exhaustion of immune system, which might contribute to disease progression in long-term infected subjects.Fil: Albareda, María Cecilia. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: de Rissio, Ana María. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Tomas, Gonzalo. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Serjan, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Juan A. Fernández"; ArgentinaFil: Alvarez, María Gabriela. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Viotti, Rodolfo Jorge. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Fichera, Laura Edith. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Esteva, Mónica Inés. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Potente, Daniel Fernando. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Armenti, Alejandro. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Tarleton, Rick L.. University of Georgia; Estados UnidosFil: Laucella, Susana Adriana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Chagas disease: an impediment in achieving the Millennium Development Goals in Latin America

<p>Abstract</p> <p>Background</p> <p>Achieving sustainable economic and social growth through advances in health is crucial in Latin America within the framework of the United Nations Millennium Development Goals.</p> <p>Discussion</p> <p>Health-related Millennium Development Goals need to incorporate a multidimensional approach addressing the specific epidemiologic profile for each region of the globe. In this regard, addressing the cycle of destitution and suffering associated with infection with <it>Trypanosoma cruzi</it>, the causal agent of Chagas disease of American trypanosomiasis, will play a key role to enable the most impoverished populations in Latin America the opportunity to achieve their full potential. Most cases of Chagas disease occur among forgotten populations because these diseases persist exclusively in the poorest and the most marginalized communities in Latin America.</p> <p>Summary</p> <p>Addressing the cycle of destitution and suffering associated with <it>T. cruzi </it>infection will contribute to improve the health of the most impoverished populations in Latin America and will ultimately grant them with the opportunity to achieve their full economic potential.</p

Inhibitors of trypanosoma cruzi Sir2 related protein 1 as potential drugs against Chagas disease.

Chagas disease remains one of the most neglected diseases in the world despite being the most important parasitic disease in Latin America. The characteristic chronic manifestation of chagasic cardiomyopathy is the region's leading cause of heart-related illness, causing significant mortality and morbidity. Due to the limited available therapeutic options, new drugs are urgently needed to control the disease. Sirtuins, also called Silent information regulator 2 (Sir2) proteins have long been suggested as interesting targets to treat different diseases, including parasitic infections. Recent studies on Trypanosoma cruzi sirtuins have hinted at the possibility to exploit these enzymes as a possible drug targets. In the present work, the T. cruzi Sir2 related protein 1 (TcSir2rp1) is genetically validated as a drug target and biochemically characterized for its NAD+-dependent deacetylase activity and its inhibition by the classic sirtuin inhibitor nicotinamide, as well as by bisnaphthalimidopropyl (BNIP) derivatives, a class of parasite sirtuin inhibitors. BNIPs ability to inhibit TcSir2rp1, and anti-parasitic activity against T. cruzi amastigotes in vitro were investigated. The compound BNIP Spermidine (BNIPSpd) (9), was found to be the most potent inhibitor of TcSir2rp1. Moreover, this compound showed altered trypanocidal activity against TcSir2rp1 overexpressing epimastigotes and anti-parasitic activity similar to the reference drug benznidazole against the medically important amastigotes, while having the highest selectivity index amongst the compounds tested. Unfortunately, BNIPSpd failed to treat a mouse model of Chagas disease, possibly due to its pharmacokinetic profile. Medicinal chemistry modifications of the compound, as well as alternative formulations may improve activity and pharmacokinetics in the future. Additionally, an initial TcSIR2rp1 model in complex with p53 peptide substrate was obtained from low resolution X-ray data (3.5 Å) to gain insight into the potential specificity of the interaction with the BNIP compounds. In conclusion, the search for TcSir2rp1 specific inhibitors may represent a valuable strategy for drug discovery against T. cruzi

Impact of Aetiological Treatment on Conventional and Multiplex Serology in Chronic Chagas Disease

The main criterion for treatment effectiveness in Chagas Disease has been the seronegative conversion of previously reactive serology, generally achieved many years post-treatment. The lack of reliable tests to ensure parasite clearance and to examine the effect of treatment is the main difficulty in evaluating treatment for chronic Chagas disease. Decreases of conventional and non-conventional serological titers can be useful tools to monitor the early impact of treatment. We serially measured changes in antibody levels, including seronegative conversion as well as declines in titers in 53 benznidazole-treated and 89 untreated chronically T. cruzi-infected subjects. Seronegative conversion as well as decreases of titers was significantly higher in treated compared with untreated patients. A strong concordance was found between decreases of titers of conventional and non-conventional serologic tests post-treatment, reaffirming the findings. When seronegative conversion plus decreases of titers were considered altogether, the impact of treatment was higher, in a shorter follow-up period than previously considered. New tools for monitoring the effectiveness of treatment of chronic Chagas disease are necessary, and the results showed in this study is a contribution to researchers and physicians who assist patients suffering from this disease

The <i>N</i>-myristoylome of <i>Trypanosoma cruzi</i>

Protein N-myristoylation is catalysed by N-myristoyltransferase (NMT), an essential and druggable target in Trypanosoma cruzi, the causative agent of Chagas’ disease. Here we have employed whole cell labelling with azidomyristic acid and click chemistry to identify N-myristoylated proteins in different life cycle stages of the parasite. Only minor differences in fluorescent-labelling were observed between the dividing forms (the insect epimastigote and mammalian amastigote stages) and the non-dividing trypomastigote stage. Using a combination of label-free and stable isotope labelling of cells in culture (SILAC) based proteomic strategies in the presence and absence of the NMT inhibitor DDD85646, we identified 56 proteins enriched in at least two out of the three experimental approaches. Of these, 6 were likely to be false positives, with the remaining 50 commencing with amino acids MG at the N-terminus in one or more of the T. cruzi genomes. Most of these are proteins of unknown function (32), with the remainder (18) implicated in a diverse range of critical cellular and metabolic functions such as intracellular transport, cell signalling and protein turnover. In summary, we have established that 0.43–0.46% of the proteome is N-myristoylated in T. cruzi approaching that of other eukaryotic organisms (0.5–1.7%)