ABSTRACT Trypanosoma cruzi is the causative agent of Chagas disease. In Paraguay, it is estimated that 165,000 people are infected and currently the main route of transmission is the congenital one, with a prevalence of 5% and about 400 infected children are born per year. The Department of Cordillera is an endemic area of the Eastern Region of the country, where the Chagas Prenatal Control Program was implemented in 1995. The aim of this study was to infer the potential congenital transmission of Chagas disease towards second generation pregnant women from the Department of Cordillera who attended their prenatal control in the period 2010-2012, 15 years after the implementation of the Prenatal Control Program. Of 9,588 pregnant women; 482 were seropositive (5%); 2.74% in the group aged 12 to 19 years, 4.93% aged 20 to 30 years, 8.03% aged 31 to 40 years, and 16.11% aged 41 to 48 years. To estimate the origin of second generation congenital transmission, the 72 seropositive women aged 12 to 19 years were taken into account and according to the database of their respective mothers, 61 mothers of the 72 were seropositive. With this información, it can be estimated that 85% of the transmission to second generation pregnant women aged 12 to 19 years was congenital showing a very significant congenital transmission in the study population. This information could help the National Chagas Program in strengthening the control of congenital transmission of Chagas disease in the country.

RESUMEN Trypanosoma cruzi es el agente causal de la enfermedad de Chagas. En Paraguay se estima que existen 165.000 personas infectadas y actualmente la principal vía de transmisión es la congénita, con una prevalencia del 5% y con alrededor de 400 niños infectados nacidos por año. El departamento de Cordillera es área endémica de la Región Oriental del país, donde se implementó el Programa de Control Prenatal de Chagas en el año 1995. El objetivo de este estudio fue inferir sobre la potencial transmisión congénita de la enfermedad de Chagas en jóvenes embarazadas de segunda generación de Cordillera que asistieron a su control prenatal en el período 2010-2012, 15 años después de la implementación del Programa de Control Prenatal. De 9.588 embarazadas; 482 fueron seropositivas (5%); 2,74% en el grupo de 12 a 19 años, 4,93% de 20 a 30 años, 8,03% de 31 a 40 años y 16,11% de 41 a 48 años. Para estimar el origen de la transmisión congénita de segunda generación se tuvo en cuenta a las 72 seropositivas de 12 a 19 años y según la base de datos de las respectivas madres 61 eran seropositivas. Con esta información se estima que la transmisión a embarazadas de segunda generación de 12 a 19 años fue congénita en un 85% indicando una transmisión congénita muy significativa en la población de estudio. Esta información ayudaría al Programa Nacional de Chagas en el fortalecimiento del control de la transmisión congénita de la enfermedad de Chagas en el país.

Abstract In recent years, nanocarriers have been studied as promising pharmaceutical tools for controlled drug-delivery, treatment-efficacy follow-up and disease imaging. Among them, X-shaped amphiphilic polymeric micelles (Tetronic®, poloxamines) display great potential due to their biocompatibility and non-toxic effects, among others. In the present work, polymeric micelles based on the T1307 copolymer were initially decorated with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-fluorophore in order to determinate its in vivo biodistribution on 4T1 tumor-bearing mice. However, unfavorable results with this probe led to two different strategies. On the one hand, the BODIPY-micelle-loaded, L-T1307-BODIPY, and on the other hand, the 99mTc-micelle-radiolabeled, L-T1307- 99m Tc, were analyzed separately in vivo. The results indicated that T1307 accumulates mainly in the stomach, the kidneys, the lungs and the tumor, reaching the maximum organ-accumulation 2 hours after intravenous injection. Additionally, and according to the results obtained for L-T1307- 99m Tc, the capture of the polymeric micelles in organs could be observed up to 24 hours after injection. The results obtained in this work were promising towards the development of new radiotracer agents for breast cancer based on X-shaped polymeric micelles.

BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.

Our first Organic chemistry course, where the main functional groups, their physicochemical properties and their syntheses are presented, has a strictly theoretical exposure. For this reason, in many subjects, especially physical properties and acid-base properties of organic compounds and functional groups identification reactions, students fail to pass the barrier of meaningful learning. Thus, as a way to complement and strengthen the students' knowledge acquisition, we proposed to implement a series of simple and attractive experimental seminars. Attendance to them and completion of small experimental individual quizzes were included as a requirement to pass the course. Both the results of experimental and theoretical quizzes indicated an improvement in meaningful learning of the subject compared to previous years. On the other hand, the degree of satisfaction and acceptance of students for this modality was very high.

Nuestro primer curso de Química orgánica, donde se presentan los principales grupos funcionales, sus propiedades fisicoquímicas y sus síntesis, poseía un contenido estrictamente teórico. Por este motivo, en muchas temáticas, especialmente propiedades físicas y propiedades ácido-base de los compuestos orgánicos y reacciones de reconocimientos de grupos funcionales los estudiantes no conseguían traspasar la barrera del aprendizaje significativo. Por eso, como forma de complementar y fortalecer la instancia de adquisición de conocimientos, decidimos implementar una serie de seminarios experimentales sencillos y atractivos. La asistencia a los mismos y la realización de pequeñas pruebas individuales y experimentales fueron incluidas como exigencia para aprobar el curso. Tanto los resultados de las pruebas experimentales como los de las pruebas teóricas indicaron una mejoría en el aprendizaje significativo de la temática respecto a años anteriores. Por otro lado, el grado de satisfacción y aceptación por parte de los estudiantes de este tipo de sistema fue muy alto.

Um estudo de DFT em derivados 5-NI foi realizado em diferentes níveis de teoria, a fim procurar a melhor metodologia para calcular constantes de acoplamento hiperfinas (hfccs), distribuições da densidade da rotação e propriedades eletrônicas, sabendo-se que é difícil obter boa concordância entre os valores de hfccs calculados e experimentais para compostos radicais centrados no nitrogênio. Os híbridos funcionais diferentes B1LYP, B3LYP e PBE0 foram usados conjuntamente com vários meios para aumentar o tamanho da base estudada. O modelo de C-PCM foi considerado para interações do soluto-solvente. As comparações de nossos cálculos com os dados experimentais precedentes obtidos por meio de medidas de EPR e raios-X confirmaram que esta aproximação computacional representa importante avanço. Nossos resultados indicaram que os efeitos solventes e a consideração de funções difusas são os fatores mais importantes no cálculo de constantes hiperfinas de acoplamento para este sistema nitro-heterocíclico. Foi verificado também que algumas propriedades eletrônicas calculadas como orbital de LUMO, funções condensadas de Fukui para ataques nucleofílico e afinidade de elétron não são correlacionadas como esperado com a atividade biológica.

A DFT study on 5-NI derivatives was carried out at different levels of theory, in order to seek for the best methodology that helps us to calculate hyperfine coupling constants (hfccs), spin density distributions and electronic properties, since it is difficult to obtain a good agreement between calculated and experimental hfccs for nitrogen center radical compounds. Different functional hybrids namely B1LYP, B3LYP and PBE0 were used in conjunction with various medium to large size basis sets. C-PCM model was considered for solute-solvent interactions. Comparisons of our calculations with previous experimental data obtained from EPR and X-ray techniques confirmed that this computational approach represents an important aid. Our results indicated that solvent effects and consideration of diffuse functions are the most important factors on the calculation of hyperfine coupling constants for this nitro-heterocyclic system. Also, we found that some electronic properties calculated (LUMO orbital, condensed Fukui functions for nucleophilic attacks and electron affinity) do not correlate as expected with the biological activity.

Os efeitos mesoméricos do substituinte benzofuroxano, na preparação de N5,N10-dióxidos de fenazina são descritos. As características eletrônicas do substituinte na posição 5 dos benzofuroxanos determinam a proporção dos isômeros 7 e 8 dos N5,N10-dióxidos de fenazina, quando fenóis substituídos são usados.

The mesomeric effects of the benzofuroxan substituent in the preparation of phenazine N5,N10-dioxides are described. The electronic characteristics of the substituent in 5-substituted benzofuroxans determine the ratio of the 7- and 8-isomers of phenazine N5,N10-dioxides when substituted phenols are used.

Reportamos neste trabalho o estudo sistemático de fragmentação dos derivados de N-óxidos de 1,2,5-oxadiazóis por espectroscopia de massa, usando análogos marcados com deutério para identificar algumas fragmentações críticas. Foi confirmada a perda neutra de CH2O a partir do N2-óxido de 3-hidroximetil-4-fenil-1,2,5-oxidiazol, usando o análogo mono-deuterado. A perda de OH, a partir do oxigênio do N-óxido, por um rearranjo beta-H e delta-H, foi claramente verificada a partir do N2-óxido de 3-(4-metilpiperazina-1-metil)-4-fenil-1,2,5-oxidiazol, usando-se o analogo tetra-deuterado adequado. O isômero N-óxido e análogos desoxigenados foram também usados para confirmar a participação do fragmento óxido no processo de defragmentação.

This paper reported on the study of fragmentation pattern in mass spectrometry of 1,2,5-oxadiazole N-oxide derivatives involving deuterium-labeled analogues to identify some critical fragmentations. A neutral CH2O loss from 3-hydroxymethyl-N2-oxide-4-phenyl-1,2,5-oxadiazole was confirmed with the corresponding mono-deuterated analogue. An OH loss, involving the oxygen of N-oxide, via beta-H and delta-H rearrangement, was clearly revealed from 3-(4-methylpiperazine-1-ylmethyl)-N2 -oxide-4-phenyl-1,2,5-oxadiazole using the adequate tetra-deuterated analogue. N-oxide isomer and deoxygenated analogues were also used to confirm the participation of the oxide moiety in the fragmentation process.

The Electron Spin Resonance (ESR) spectra of radicals obtained from two new potential antitrypanosomal drugs by Trypanosoma cruzi reduction were analyzed. DMPO Spin Trapping was used to investigate the possible formation of free radicals in the trypanosome microsomal system. The Nitro 2 (4-(n-butyl)-1-(5-nitrofurfurylidene)semicarbazide) analogue of Nifurtimox showed better antiparasitic activity than N-oxide 1 (4-(n-butyl)-1-[(7-bromo-N1-oxidebenzo[1,2-c]1,2,5-oxadiazole-5-yl)methylidene]semicarbazide). Only Nitro 2 could produce oxygen redox cycling in T. cruzi epimastigotes. The ESR signal intensities were consistent with the trapping of hydroxyl radical. These results are in agreement with the biological observation that Nitro 2 showed antichagasic activity by an oxidative stress mechanism