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Objectives: To evaluate the quality of life (QoL) of patients with Chagas disease (CD) and the association between QoL domains and several clinical, socioeconomic and lifestyle characteristics of this population.Methods: Cross-sectional observational study conducted from March 2014 to March 2017 including a total of 361 outpatients followed at Evandro Chagas National Institute of Infectious Disease, Brazil. QoL was assessed using the Portuguese shorter version of the original WHO Quality of Life questionnaire (WHOQOL-BREF). Information about clinical CD presentation, presence of comorbidities, functional class, previous benznidazole treatment, socioeconomic profile and lifestyle was also obtained.Results: Environment and physical domains presented the worst QoL scores, while the social relationship domain presented the highest score. Multivariate regression analysis demonstrated that variables independently associated with QoL were functional class, sex, clinical presentation of CD, sleep duration, schooling, physical activity level, smoking, income per capita and residents by domicile.Conclusions: The low socioeconomic status and the physical limitations imposed by the disease presented an important impact on the QoL reduction among CD patients, especially on environment and physical domains. Strategies to improve QoL among CD patients should be tailored and consider many different variables to maximise improvements not only of patients' physical but also of their mental health. [ABSTRACT FROM AUTHOR]

Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug‐resistant strains underscores the need of new drugs. Platinum‐based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1′‐bis(diphenylphosphino)ferrocene pyridine‐2‐thiolate‐1‐oxide Pt(II) hexafluorophosphate, Pt‐dppf‐mpo, was studied on T. cruzi. A promising antitrypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro‐cultured mammal cells. The compound uptake in parasites treated with concentrations of 1× and 10× the IC50 value reached ~75% and 19%, respectively. Pt‐dppf‐mpo induced necrosis after 24 hr of parasite incubation. This event was preceded by depolarization of mitochondrial membrane potential. Cell vitality assays showed high esterase activity in treated parasites. However, despite this increase in metabolic activity, treated epimastigotes showed rounded morphology and loss of flagellum with a reduction in mobility as compound concentration and/or time of incubation was increased. At last, we demonstrate that Pt‐dppf‐mpo incubation also affects the trypomastigote infection process as well as the infection persistence evaluated as the number of amastigotes per cell in a dose‐dependent manner. [ABSTRACT FROM AUTHOR]

Abstract: Chagas disease has spread throughout the world mainly because of the migration of infected individuals. In Brazil, only benznidazole (Bnz) is used; however, it is toxic and not active in the chronic phase, and cases of resistance are described. This work aimed at the synthesis and the trypanocidal evaluation in vitro and in vivo of six new Bnz analogues (3–8). They were designed by exploring the bioisosteric substitution between the amide group contained in Bnz and the 1,2,3‐triazole ring. All the compounds were synthesized in good yields. With the exception of compound 7, the in vitro biological evaluation shows that all Bnz analogues were active against the amastigote form, whereas only compounds 3, 4, 5, and 8 were active against trypomastigote. Compounds 4 and 5 showed the most promising activities in vitro against the form of trypomastigote, being more active than Bnz. In vivo evaluation of compounds, 3–8 showed lower potency and higher toxicity than Bnz. Although the 1,2,3‐triazole ring has been described in the literature as an amide bioisostere, its substitution here has reduced the activity of the compounds and made them more toxic. Thus, further molecular optimization could provide novel therapeutic agents for Chagas’ disease. [ABSTRACT FROM AUTHOR]

In this work, a group of α–keto‐based inhibitors of the cruzain enzyme with anti‐chagas activity was selected for a three‐dimensional quantitative structure–activity relationship study (3D‐QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q2 and r2)for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r2pred = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR‐3D study. [ABSTRACT FROM AUTHOR]

Abstract: The aetiological agent of Chagas disease, Trypanosoma cruzi, is a key human pathogen afflicting most populations of Latin America. This vectorborne parasite is transmitted by haematophageous triatomines, whose control by large‐scale insecticide spraying has been the main strategy to limit the impact of the disease for over 25 years. While those international initiatives have been successful in highly endemic areas, this systematic approach is now challenged by the emergence of insecticide resistance and by its low efficacy in controlling species that are only partially adapted to human habitat. In this contribution, we review evidences that Chagas disease control shall now be entering a second stage that will rely on a better understanding of triatomines adaptive potential, which requires promoting microevolutionary studies and –omic approaches. Concomitantly, we show that our knowledge of the determinants of the evolution of T. cruzi high diversity and low virulence remains too limiting to design evolution‐proof strategies, while such attributes may be part of the future of Chagas disease control after the 2020 WHO's target of regional elimination of intradomiciliary transmission has been reached. We should then aim at developing a theory of T. cruzi virulence evolution that we anticipate to provide an interesting enrichment of the general theory according to the specificities of transmission of this very generalist stercorarian trypanosome. We stress that many ecological data required to better understand selective pressures acting on vector and parasite populations are already available as they have been meticulously accumulated in the last century of field research. Although more specific information will surely be needed, an effective research strategy would be to integrate data into the conceptual and theoretical framework of evolutionary ecology and life‐history evolution that provide the quantitative backgrounds necessary to understand and possibly anticipate adaptive responses to public health interventions. [ABSTRACT FROM AUTHOR]

The improvement of Chagas disease treatment is focused not only on the development of new drugs but also in understanding mechanisms of action and resistance to drugs conventionally used. Thus, some strategies aim to detect specific changes in proteins between sensitive and resistant parasites and to evaluate the role played in these processes by functional genomics. In this work, we used a natural Trypanosoma cruzi population resistant to benznidazole, which has clones with different susceptibilities to this drug without alterations in the NTR I gene. Using 2DE-gel electrophoresis, the aldo-keto reductase and the alcohol dehydrogenase proteins were found up regulated in the natural resistant clone and therefore their possible role in the resistance to benznidazole and glyoxal was investigated. Both genes were overexpressed in a drug sensitive T. cruzi clone and the biological changes in response to these compounds were evaluated. The results showed that the overexpression of these proteins enhances resistance to benznidazole and glyoxal in T. cruzi. Moreover, a decrease in mitochondrial and cell membrane damage was observed, accompanied by a drop in the intracellular concentration of reactive oxygen species after treatment. Our results suggest that these proteins are involved in the mechanism of action of benznidazole. [ABSTRACT FROM AUTHOR]

The enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi ( TcG6PDH) catalyses the first step of the pentose phosphate pathway (PPP) and is considered a promising target for the discovery of a new drug against Chagas diseases. In the present work, we describe the crystal structure of TcG6PDH obtained in a ternary complex with the substrate β- d-glucose-6-phosphate (G6P) and the reduced 'catalytic' cofactor NADPH, which reveals the molecular basis of substrate and cofactor recognition. A comparison with the homologous human protein sheds light on differences in the cofactor-binding site that might be explored towards the design of new NADP+ competitive inhibitors targeting the parasite enzyme. [ABSTRACT FROM AUTHOR]

Objective To develop an extemporaneous 1% benznidazole ( BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days. Methods Six batches of 1% BNZ suspension were prepared using safe excipients currently available in a galenic area of Hospital Pharmacy and then stored at 5 and 25 °C for 90 days. The BNZ content was determined by UV spectrophotometry. Physical stability was defined as the absence of colour, odour and/or flavour changes and the re-suspension of solid phase by a reasonable amount of simple 15-s shaking. The compliance with microbiological attributes of non-sterile pharmaceutical products was also evaluated. Results An oral liquid suspension, containing 1% of BNZ, was developed from commercially available BNZ tablets. The formulations stored for 90 days were easily re-dispersed after a simple 15-s shaking, ensuring the pouring of a liquid volume containing the desired dose of BNZ. All samples were within the acceptable range of BNZ concentration with minimal standard deviations. There were no detectable changes in colour, odour, viscosity, pH and microbial growth, complying with official quality requirements. The quality attributes were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multidose containers. Conclusion Paediatric oral liquid suspension containing 1.0% of BNZ was easily prepared starting from commercial tablets, being an interesting alternative for optimising the paediatric treatment of Chagas disease. [ABSTRACT FROM AUTHOR]

In Chagas disease, chronically infected individuals may be asymptomatic or may present cardiac or digestive complications, and it is well known that the human immune response is related to different clinical manifestations. Different patterns of cytokine levels have been previously described in different clinical forms of this disease, but contradictory results are reported. Our aim was to evaluate the serum levels of interleukin-10 and tumour necrosis factor-alpha in patients with asymptomatic and cardiac Chagas disease. The serum interleukin-10 levels in patients with cardiomyopathy were higher than those in asymptomatic patients, mainly in those without heart enlargement. Although no significant difference was observed in serum tumour necrosis factor-alpha levels among the patients, we found that cardiac patients also present high levels of this cytokine, largely those with heart dilatation. Therefore, these cytokines play an important role in chronic Chagas disease cardiomyopathy. Follow-up investigations of these and other cytokines in patients with chronic Chagas disease need to be conducted to improve the understanding of the immunopathology of this disease. [ABSTRACT FROM AUTHOR]

Chagas disease constitutes a major public health problem in Latin America. Human breast milk is a biological sample of great importance for the analysis of therapeutic drugs, as unwanted exposure through breast milk could result in pharmacological effects in the nursing infant. Thus, the goal of breast milk drug analysis is to inquire to which extent a neonate may be exposed to a drug during lactation. In this work, we developed an analytical technique to quantify benznidazole and nifurtimox (the two antichagasic drugs currently available for medical treatment) in human breast milk, with a simple sample pretreatment followed by an ionic-liquid-based dispersive liquid-liquid microextraction combined with high-performance liquid chromatography and UV detection. For this technique, the ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate has been used as the "extraction solvent." A central composite design was used to find the optimum values for the significant variables affecting the extraction process: volume of ionic liquid, volume of dispersant solvent, ionic strength, and pH. At the optimum working conditions, the average recoveries were 77.5 and 89.7%, the limits of detection were 0.06 and 0.09 μg/mL and the interday reproducibilities were 6.25 and 5.77% for benznidazole and nifurtimox, respectively. The proposed methodology can be considered sensitive, simple, robust, accurate, and green. [ABSTRACT FROM AUTHOR]

CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi . Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates. [ABSTRACT FROM AUTHOR]

Chagas disease is a lifelong, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi. The main form of disease transmission is vector borne, but vertical transmission, such as by organ transplantation from a chronically infected donor, is also possible. The brain tumor-like form can occur years after infection and has been described in patients with acquired immunodeficiency syndrome, and in a very few cases in transplant recipients. We describe the case of a kidney transplant patient who was human immunodeficiency virus negative and infected with T. cruzi, and developed cerebral trypanosomiasis that was successfully treated with benznidazole at 7 mg/kg/day for 60 days. The risk of Chagas disease transmission should not be underestimated in renal transplant patients, even in non-endemic areas. Chagas disease can present as a tumor-like brain lesion, very difficult to differentiate from other opportunistic infectious or neoplastic processes. Frequent monitoring for T. cruzi infection is essential to promptly implement treatment, which, in our patient, proved to be effective and safe. [ABSTRACT FROM AUTHOR]

Benznidazole (BZ) is the most commonly used drug for the treatment of Chagas disease. Although BZ is known to induce the formation of free radicals and electrophilic metabolites within the parasite Trypanosoma cruzi, its precise mechanisms of action are still elusive. Here, we analyzed the survival of T. cruzi exposed to BZ using genetically modified parasites overexpressing different DNA repair proteins. Our results indicate that BZ induces oxidation mainly in the nucleotide pool, as heterologous expression of the nucleotide pyrophosphohydrolase MutT (but not overexpression of the glycosylase TcOgg1) increased drug resistance in the parasite. In addition, electron microscopy indicated that BZ catalyzes the formation of double-stranded breaks in the parasite, as its genomic DNA undergoes extensive heterochromatin unpacking following exposure to the drug. Furthermore, the overexpression of proteins involved in the recombination-mediated DNA repair increased resistance to BZ, reinforcing the idea that the drug causes double-stranded breaks. Our results also show that the overexpression of mitochondrial DNA repair proteins increase parasite survival upon BZ exposure, indicating that the drug induces lesions in the mitochondrial DNA as well. These findings suggest that BZ preferentially oxidizes the nucleotide pool, and the extensive incorporation of oxidized nucleotides during DNA replication leads to potentially lethal double-stranded DNA breaks in T. cruzi DNA. Environ. Mol. Mutagen. 55:309-321, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This study evaluated the influence of moderate physical exercise on the myenteric neurons in the colonic intestinal wall of mice that had been infected with Trypanosoma cruzi. Parasitology and immunological aspects of the mice were considered. Forty-day-old male Swiss mice were divided into four groups: Trained Infected ( TI), Sedentary Infected ( SI), Trained Control ( TC), and Sedentary Control ( SC). The TC and TI were subjected to a moderate physical exercise program on a treadmill for 8 weeks. Three days after finishing exercise, the TI and SI groups were inoculated with 1,300 blood trypomastigotes of the Y strain- T. cruzi. After 75 days of infection results were obtained. Kruskal-Wallis or Analyze of variance (Tukey post hoc test) at 5% level of significance was performed. Moderate physical exercise reduced both the parasite peak (day 8 of infection) and total parasitemia compared with the sedentary groups ( P < 0.05). This activity also contributed to neuronal survival ( P < 0.05). Exercise caused neuronal hypertrophy ( P < 0.05) and an increase in the total thickness of the intestinal wall ( P < 0.05). The TI group exhibited an increase in the number of intraepithelial lymphocytes ( P > 0.05). In trained animals, the number of goblet cells was reduced compared with sedentary animals ( P < 0.05). Physical exercise prevented the formation of inflammatory foci in the TI group ( P < 0.05) and increased the synthesis of TNF-α ( P < 0.05) and TGF-β ( P > 0.05). The present results demonstrated the benefits of moderate physical exercise, and reaffirmed the possibility of that it may contribute to improving clinical treatment in Chagas' disease patients. [ABSTRACT FROM AUTHOR]

Aim Megacolon, chronic dilation of a colonic segment,is accompanied by extensive myenteric neuron loss. However, this fails to explain unequivocally the formation of megacolon. We aimed to study further enteric structures that are directly or indirectly involved in colonic motility. Method From surgically removed megacolon segments of seven Chagasic patients, three sets of cryosections from oral, megacolonic and anal zones were immunohistochemically quadruple-stained for smooth-muscle actin (SMA), synaptophysin (SYN, for nerve fibres), S100 (glia) and c-Kit (interstitial cells of Cajal, ICCs). Values of area measurements were related to the appropriate muscle layer areas and these proportions were compared with those of seven non-Chagasic control patients. Results Whereas nerve and glia profile proportions did not mirror unequivocally the changes of Chagasic colon calibre (nondilation/dilation/nondilation), the proportions of SMA (i.e. muscle tissue density) and c-Kit (i.e. ICC density) did so: they decreased from the oral to the megacolonic segment but increased to the anal zones (muscle tissue density: control 68.3%, oral 54.3%, mega 42.1%, anal 47.6%; ICC-density: control 1.8%, oral 1.1%, mega 0.4, anal 0.8%). Conclusion Of the parameters evaluated, muscle tissue and ICC densities may be involved in the formation of Chagasic megacolon, although the mechanism of destruction cannot be deduced. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) influences the development of myocardiopathy in Chagas disease through regulation of (i) parasite invasion of heart cells, (ii) an intracellular parasite cycle, (iii) inflammation and immune response, (iv) heart fibrosis and remodeling, and (v) gap junction modulation and heart conduction. In this review, we discuss the rationale for developing TGF-β signaling-interfering therapies as adjuvant approaches for the management of the cardiac alterations of Chagas disease-affected patients. [ABSTRACT FROM AUTHOR]

The drugs against tropical neglected diseases, especially Chagas' Disease, were launched more than 30 years ago, and the development of resistance requires the discovery of new and more effective chemotherapeutic agents. Trypanosoma cruzi has a redox enzyme called trypanothione reductase which was successfully inhibited for peptide derivatives (McKie et al., Amino Acids, 2001, 20: 145). This work aims at studying the mechanism of inhibition of this enzyme through molecular dynamics simulations and evaluating the behavior of some derivatives when inhibiting this protein. We should affirm that any particular molecular dynamics analysis tools (Hbond pattern, 3-D root-mean-square deviation, solvent accessible surface area, etc.) cannot be used apart from the others to justify completely these peptides inhibitory patterns. Based on our results, we reproduced the experimental data and, moreover, we discriminated against a new site in enzyme aperture, which can assist the development of powerful inhibitors against trypanothione reductase enzyme. [ABSTRACT FROM AUTHOR]

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease. [ABSTRACT FROM AUTHOR]

Antibiotic resistance in pathogens can be mediated by catabolic enzymes thought to originate from soil bacteria, but the physiological functions and evolutionary origins of the enzymes in natural ecosystems are poorly understood. 2-Nitroimidazole (2NI) is a natural antibiotic and an analogue of the synthetic nitroimidazoles used for treatment of tuberculosis, Chagas' disease and cancer. Mycobacterium sp. JS330 was isolated from soil based on its ability to use 2NI as a sole growth substrate. The initial step in the degradation pathway is the hydrolytic denitration of 2NI to produce imidazol-2-one and nitrite. The amino acid sequence of 2NI nitrohydrolase is highly divergent from those of biochemically characterized enzymes, and it confers drug resistance when it is heterologously expressed in Escherichia coli. The unusual enzymatic reaction seems likely to determine the flux of nitroimidazole in natural ecosystems and also represents the discovery of a previously unreported drug resistance mechanism in soil before its identification in clinical situations. [ABSTRACT FROM AUTHOR]

Background and Purpose: The discovery of the pharmacological functions of nitric oxide has led to the development of NO donor compounds as therapeutic agents. A new generation of ruthenium NO donors, cis-[Ru(NO)(bpy)(2)L]X(n), has been developed, and our aim was to show that these complexes are able to lyse Trypanosoma cruzi in vitro and in vivo.Experimental Approach: NO donors were incubated with T. cruzi and their anti-T. cruzi activities evaluated as the percentage of lysed parasites compared to the negative control. In vivo, trypanocidal activity was evaluated by observing the levels of parasitaemia, survival rate and elimination of amastigotes in mouse myocardial tissue. The inhibition of GAPDH was monitored by the biochemical reduction of NAD(+) to NADH.Key Results: The NO donors cis-[Ru(NO)(bpy)(2)L]X(n) presented inhibitory effects on T. cruzi GAPDH (IC(50) ranging from 89 to 153 microM). The crystal structure of the enzyme shows that the inhibitory mechanism is compatible with S-nitrosylation of the active cysteine (cys166) site. Compounds cis-[Ru(NO)(bpy)(2)imN](PF(6))(3) and cis-[Ru(NO)(bpy)(2)SO(3)]PF(6), at a dose of 385 nmol.kg(-1), yielded survival rates of 80 and 60%, respectively, in infected mice, and eradicated any amastigotes from their myocardial tissue.Conclusions and Implications: The ruthenium compounds exhibited potent in vitro and in vivo trypanocidal activities at doses up to 1000-fold lower than the clinical dose for benznidazole. Furthermore, one mechanism of action of these compounds is via the S-nitrosylation of Cys166 of T. cruzi GAPDH. Thus, these compounds show huge potential as candidates for the development of new drugs for the treatment of Chagas's disease. [ABSTRACT FROM AUTHOR]

Background and Purpose: Benznidazole (Bz) is the therapy currently available for clinical treatment of Chagas' disease. However, many strains of Trypanosoma cruzi parasites are naturally resistant. Nitric oxide (NO) produced by activated macrophages is crucial to the intracellular killing of parasites. Here, we investigate the in vitro and in vivo activities against T. cruzi, of the NO donor, trans-[RuCl([15]aneN(4))NO](2+).Experimental Approach: Trans-[RuCl([15]aneN(4))NO](2+)was incubated with a partially drug-resistant T. cruzi Y strain and the anti-proliferative (epimastigote form) and trypanocidal activities (trypomastigote and amastigote) evaluated. Mice were treated during the acute phase of Chagas' disease. The anti-T. cruzi activity was evaluated by parasitaemia, survival rate, cardiac parasitism, myocarditis and the curative rate.Key Results: Trans-[RuCl([15]aneN(4))NO](2+) was 10- and 100-fold more active than Bz against amastigotes and trypomastigotes respectively. Further, trans-[RuCl([15]aneN(4))NO](2+) (0.1 mM) induced 100% of trypanocidal activity (trypomastigotes forms) in vitro. Trans-[RuCl([15]aneN(4))NO](2+) induced permanent suppression of parasitaemia and 100% survival in a murine model of acute Chagas' disease. When the drugs were given alone, parasitological cures were confirmed in only 30 and 40% of the animals treated with the NO donor (3.33 micromol.kg(-1).day(-1)) and Bz (385 micromol.kg(-1).day(-1)), respectively, but when given together, 80% of the animals were parasitologically cured. The cured animals showed an absence of myocarditis and a normalisation of cytokine production in the sera. In addition, no in vitro toxicity was observed at the tested doses.Conclusions and Implications: These findings indicate that trans-[RuCl([15]aneN(4))NO](2+)is a promising lead compound for the treatment of human Chagas' disease. [ABSTRACT FROM AUTHOR]

Chagas disease (American Trypanosomyasis) is endemic in South America. It has been associated with autonomic dysfunction and increased stroke risk. OBJECTIVE To correlate findings in neurological examination, autonomic nervous system function, and brain magnetic resonance imaging (MRI), in patients with chronic Chagas disease. METHODS Neurological findings of 64 patients from a hospital cohort were correlated with disease stage (according to Los Andes classification) and with signs of autonomic nervous system function (respiratory sinus arrhythmia test). Also, 27 subjects with no cardiac dysfunction (phase IA) had MRI evaluation. Results were correlated with autonomic nervous system variables using Spearman correlation coefficient and Mann-Whitney test. RESULTS There was a significant correlation between the presence and number of white matter hyperintensities in MRI and the respiratory sinus arrhythmia test. There was no correlation between disease stage and autonomic nervous system dysfunction. CONCLUSION There is a significant correlation between parasympathetic nervous system dysfunction and the presence of white matter lesions in patients with chronic Chagas disease without cardiac dysfunction. The pathogenesis of such lesions is unknown, but cardiac arrhythmias could be involved. As hypertension was frequent in our sample and also correlated to MRI hyperintensities, studies excluding hypertensive patients are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Triatoma guasayana (Wygodzinsky & Abalos), a sylvatic vector of Chagas’ disease, occurs in natural and peridomestic habitats of the dry Chaco region of Argentina, Bolivia and Paraguay. Ten-year retrospective spatial analyses of peridomestic T. guasayana abundance in the rural community of Amamá were expanded to the neighbouring community of Trinidad in northwestern Argentina. The distribution of T. guasayana in domiciles, peridomiciles (storerooms, chicken coops and corrals) and natural habitats (bromeliads, dry cacti and logs) around houses (i.e. ‘semi-sylvatic’ habitats) was analysed. The distribution of the 316 T. guasayana specimens collected in domestic and peridomestic sites during 1993–2002 was significantly clustered in both communities. Searches confirmed that the spatial distribution of semi-sylvatic and peridomestic T. guasayana was determined by the joint effects of the local abundance of goats and the density of semi-sylvatic habitats. The integration of detailed entomological and demographic longitudinal data with geographic information system data, high-resolution satellite imagery, appropriate spatial and temporal analyses and field observations allowed us to infer the underlying processes determining the distribution of T. guasayana in rural communities. This approach may be applied to other sylvatic and peridomestic vectors of Chagas’ disease in order to identify high-risk areas for targeted control or environmental management. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi-infected children was treated with benznidazole (Bz) during the early-indeterminate disease (E-IND) and the cytokine pattern of innate and adaptive immune compartments were evaluated prior to the treatment and 1 year after it. At first, we observed that the ex vivo cytokine profile of circulating leukocytes from E-IND ( n = 6) resembled the one observed for healthy schoolchildren ( n = 7). Additionally, in vitro stimulation with T. cruzi antigens drove the E-IND cytokine pattern toward a mixed immune profile with higher levels of IFN- γ+, TNF- α+ and IL-4+ NK cells, increased numbers of IFN- γ+, TNF- α+ and IL-10+ CD4+ T cells in addition to enhanced frequency of TNF- α+/IL-4+ CD19+ lymphocytes. Interestingly, upon T. cruzi antigen in vitro stimulation, E-IND CD8+ lymphocytes displayed a selective enhancement of IFN- γ expression, accounting for a global type 1-modulated cytokine microenvironment. A shift toward a type 1-modulated profile was also the hallmark of Bz-treated children (E-INDT). In this context, despite the mixed overall ex vivo cytokine profile observed for NK and CD8+ T cells, increased ability of these leukocytes to produce IFN- γ in response to T. cruzi antigens was reported. Most noteworthy was the IL-10 production evidenced at T lymphocytes, mainly CD4+ cells, as well as B lymphocytes, both ex vivo and upon antigen stimulation. Together, these findings gave evidence that NK cells and CD8+ T lymphocytes are the major sources of IFN- γ, a pivotal cytokine for successful therapeutic response in human Chagas’ disease. Moreover, our data have also brought additional information, pointing out IL-10 production by CD4+ cells and B lymphocytes, as the putative key element for parasite clearance in the absence of deleterious tissue damage. [ABSTRACT FROM AUTHOR]

Radiolabelling studies using tritiated ornithine, arginine and lysine, together with the relevant amino acid decarboxylase enzyme assays, indicate that the epimastigote stage of Trypanosoma cruzi is unable to synthesize significant amounts of putrescine and cadaverine de novo, compared to the amounts of these diamines scavenged from the growth medium. Radiolabelled putrescine is readily incorporated into spermidine, spermine and the trypanosomatid-specific polyamine-glutathione conjugate trypanothione (N[sup1],N[sup9]-bis(glutathionyl)spermidine). Likewise, radiolabelled cadaverine is incorporated into the analogous polyamines aminopropylcadaverine, bis(aminopropyl)cadaverine and another major unidentified component. Subsequent studies showed this major component to be a novel polyamine-thiol conjugate whose structure was confirmed by chemical synthesis to be N[sup1],N[sup9]-bis(glutathionyl)aminopropylcadaverine (homotrypanothione). Kinetic analyses using recombinant T. cruzi trypanothione reductase demonstrated that homotrypanothione disulphide is readily reduced by this enzyme with kinetic parameters similar to trypanothione disulphide, suggesting that it is a physiological substrate in vivo. Thus the epimastigote form of T. cruzi differs significantly from the African trypanosomes and Leishmania in (a) being unable to synthesize significant amounts of diamines de novo, (b) converting significant amounts of putrescine and cadaverine to spermine and bis(aminopropyl)cadaverine, respectively and (c) the ability to synthesize homotrypanothione as well as trypanothione. The implications of these findings with respect to the prospective chemotherapy of Chagas' disease are discussed. [ABSTRACT FROM AUTHOR]

The antitrypanosomal agent K777•HCl was labeled with carbon-14 to support absorption, distribution, metabolism, and excretion studies of this potential new drug for the treatment of Chagas disease. The radiolabeled compound was prepared in eight steps from [14C(U)]-( l)-phenylalanine with a specific activity of 54.4 mCi/mmol and an overall radiochemical yield of 4.1%. [ABSTRACT FROM AUTHOR]

This report shows the early detection of reactivation of chronic Chagas' disease (CCd) in a 27-year-old man with chronic myelogenous leukemia undergoing allogeneic bone marrow transplantation (ABMT). Preemptive therapy with benznidazole during a period of 7 weeks led to a rapid recovery of the patient, who remains free of parasitemia 2 years after the bone marrow transplantation. [ABSTRACT FROM AUTHOR]

Chagas' disease (CD) is caused by the protozoan Trypanosoma cruzi (Tc) and remains an important cause of morbidity and mortality. Most researchers in the field now agree that chronic low grade parasite persistence in tissue drives tissue damage and the autoimmune component of CD. Current therapy relies on two compounds: benznidazole and nifurtimox. Despite their long history in the treatment of CD, both compounds induce significant side-effects. In the current issue of the BJP, two contributions demonstrate that NO-donors are active, especially in combination with benznidazole, against Tc in vitro and in experimental models in vivo. The basic concept used by the authors to develop novel anti-Tc compounds relied on the demonstrated ability of nitric oxide to kill the parasite. There are several issues still to be resolved but the reported studies are a clear advance to the field and should be considered for further pre-clinical development. [ABSTRACT FROM AUTHOR]

The majority of new compounds (III) and (V) are potent cruzain inhibitors and show similar or greater trypanocidal efficacy than standard drug benznidazole, used for treatment of Chagas disease. [ABSTRACT FROM AUTHOR]

Chronic chagasic cardiomyopathy affects 20% of Chagas' disease patients. At present, Chagas' disease chemotherapy uses nitrofurans, benznidazole (Rochagan®, Rodanil®, Roche) or nifurtimox (Lampit®, Bayer). Treatment during acute and recent chronic phases in childhood effects 71.5% and 57.6%, respectively, of parasitological cure. However, in clinical trials during the late chronic phase, only 5.9% of parasitological cure were achieved. This review focuses on the benefit from aetiological treatment to avoid, stop or revert myocarditis. Divergent data gathered from clinical practice are not convincing to support prescription of aetiological treatment as routine for indeterminate and cardiac chronic patients. [ABSTRACT FROM AUTHOR]