Experimental chemotherapy for Chagas disease: 15 years of research contributions from in vivo and in vitro studies

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.

Why Public Health Agencies Cannot Depend on Good Laboratory Practices as a Criterion for Selecting Data: The Case of Bisphenol A

In their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special prominence to two industry-funded studies that adhered to standards defined by Good Laboratory Practices (GLP). These same agencies have given much less weight in risk assessments to a large number of independently replicated non-GLP studies conducted with government funding by the leading experts in various fields of science from around the world. OBJECTIVES: We reviewed differences between industry-funded GLP studies of BPA conducted by commercial laboratories for regulatory purposes and non-GLP studies conducted in academic and government laboratories to identify hazards and molecular mechanisms mediating adverse effects. We examined the methods and results in the GLP studies that were pivotal in the draft decision of the U.S. FDA declaring BPA safe in relation to findings from studies that were competitive for U.S. National Institutes of Health (NIH) funding, peer-reviewed for publication in leading journals, subject to independent replication, but rejected by the U.S. FDA for regulatory purposes. DISCUSSION: Although the U.S. FDA and EFSA have deemed two industry-funded GLP studies of BPA to be superior to hundreds of studies funded by the U.S. NIH and NIH counterparts in other countries, the GLP studies on which the agencies based their decisions have serious conceptual and methodologic flaws. In addition, the U.S. FDA and EFSA have mistakenly assumed that GLP yields valid and reliable scientific findings (i.e., "good science"). Their rationale for favoring GLP studies over hundreds of publically funded studies ignores the central factor in determining the reliability and validity of scientific findings, namely, independent replication, and use of the most appropriate and sensitive state-of-the-art assays, neither of which is an expectation of industry-funded GLP research. CONCLUSIONS: Public health decisions should be based on studies using appropriate protocols with appropriate controls and the most sensitive assays, not GLP. Relevant NIH-funded research using state-of-the-art techniques should play a prominent role in safety evaluations of chemicals.

The activity of echinocandins, amphotericin B and voriconazole against fluconazole-susceptible and fluconazole-resistant Brazilian Candida glabrata isolates

The extensive use of azole antifungal agents has promoted the resistance of Candida spp to these drugs. Candida glabrata is a problematic yeast because it presents a high degree of primary or secondary resistance to fluconazole. In Brazil, C. glabrata has been less studied than other species. In this paper, we compared the activity of three major classes of antifungal agents (azoles, echinocandins and polyenes) against fluconazole-susceptible (FS) and fluconazole-resistant (FR) C. glabrata strains. Cross-resistance between fluconazole and voriconazole was remarkable. Among the antifungal agents, the echinocandins were the most effective against FS and FR C. glabrata and micafungin showed the lowest minimal inhibitory concentrations.

A comparative cross-sectional study on the prevalence and morbidity of schistosomiasis in a community in northeastern Brazil (1979-2010)

A cross-sectional study on the prevalence and morbidity of schistosomiasis was conducted in the main settlement of the municipality of Alhandra, in the southern coastal region of the state of Paraíba, in 2010. The results of this study were compared with the results of a previous study conducted in the same area in 1979. The systematic sampling per family conglomerate included approximately 10% of the resident population in the urban area of Alhandra. Faecal examinations were performed using the Kato-Katz method. The clinical forms of the disease were classified in accordance with FS Barbosa as Type I - intestinal form, Type II - hepatointestinal form and Type III - hepatosplenic form. The prevalence of the infection in 2010 was 10.05%, whereas in 1979 it was 46.6% among untreated patients. The percentages of the three clinical forms in 2010 were as follows: 95.3% Type I, 4.6% Type II and 0% Type III; in 1979, the percentages were 94.4%, 3% and 2.6% for Types I, II and III, respectively. In 1979, 6.07% of the Biomphalaria glabrata specimens (the intermediate host in this area) excreted cercariae, where in 2010 only 1.27% of the specimens caught excreted the parasite.

Estruturas de governança interna e a capacidade de inovação em pequenas firmas brasileiras de torrefação e moagem de café

Na pesquisa relatada neste artigo são investigadas quais as combinações de estruturas de governança interna (mercado, burocrática e comunitária) que possibilitam mais capacidade de inovação de produto nas pequenas firmas. Neste estudo, inspirado nos trabalhos de Grandori e Furnari (2008; 2010), tem-se como hipótese que a capacidade de inovação ocorre de modo mais consistente nas firmas que adotam uma estrutura de governança interna multimodal. Essa hipótese foi testada por meio de um survey com 80 indústrias brasileiras de torrefação e moagem de café(1). Para encontrar as combinações de estruturas, foi utilizada a análise comparativa qualitativa (QCA) no software fs/QCA versão 2.0 (RAGIN, 2008). Como resultado, verificou-se que a estrutura de governança interna multimodal - que combina práticas de incentivos monetários, burocráticas e comunitárias - apresentou resultados mais consistentes para a inovação das pequenas firmas de torrefação. Esses resultados, ao permitirem identificar os requisitos organizacionais que produzem mais possibilidades de inovação, podem ajudar a traçar ações de políticas públicas e privadas para as empresas brasileiras, de modo a melhorar sua taxa de inovação e a competitividade em seus mercados.

Comparison of early cortical networks in efficient and inefficient visual search: an event-related potential study.

Functional magnetic resonance imaging studies have indicated that efficient feature search (FS) and inefficient conjunction search (CS) activate partially distinct frontoparietal cortical networks. However, it remains a matter of debate whether the differences in these networks reflect differences in the early processing during FS and CS. In addition, the relationship between the differences in the networks and spatial shifts of attention also remains unknown. We examined these issues by applying a spatio-temporal analysis method to high-resolution visual event-related potentials (ERPs) and investigated how spatio-temporal activation patterns differ for FS and CS tasks. Within the first 450 msec after stimulus onset, scalp potential distributions (ERP maps) revealed 7 different electric field configurations for each search task. Configuration changes occurred simultaneously in the two tasks, suggesting that contributing processes were not significantly delayed in one task compared to the other. Despite this high spatial and temporal correlation, two ERP maps (120-190 and 250-300 msec) differed between the FS and CS. Lateralized distributions were observed only in the ERP map at 250-300 msec for the FS. This distribution corresponds to that previously described as the N2pc component (a negativity in the time range of the N2 complex over posterior electrodes of the hemisphere contralateral to the target hemifield), which has been associated with the focusing of attention onto potential target items in the search display. Thus, our results indicate that the cortical networks involved in feature and conjunction searching partially differ as early as 120 msec after stimulus onset and that the differences between the networks employed during the early stages of FS and CS are not necessarily caused by spatial attention shifts.

Impaired fast-spiking, suppressed cortical inhibition and increased susceptibility to seizures in mice lacking Kv3.2 K+ channel proteins

Voltage-gated K+ channels of the Kv3 subfamily have unusual electrophysiological properties, including activation at very depolarized voltages (positive to −10 mV) and very fast deactivation rates, suggesting special roles in neuronal excitability. In the brain, Kv3 channels are prominently expressed in select neuronal populations, which include fast-spiking (FS) GABAergic interneurons of the neocortex, hippocampus, and caudate, as well as other high-frequency firing neurons. Although evidence points to a key role in high-frequency firing, a definitive understanding of the function of these channels has been hampered by a lack of selective pharmacological tools. We therefore generated mouse lines in which one of the Kv3 genes, Kv3.2, was disrupted by gene-targeting methods. Whole-cell electrophysiological recording showed that the ability to fire spikes at high frequencies was impaired in immunocytochemically identified FS interneurons of deep cortical layers (5-6) in which Kv3.2 proteins are normally prominent. No such impairment was found for FS neurons of superficial layers (2-4) in which Kv3.2 proteins are normally only weakly expressed. These data directly support the hypothesis that Kv3 channels are necessary for high-frequency firing. Moreover, we found that Kv3.2 −/− mice showed specific alterations in their cortical EEG patterns and an increased susceptibility to epileptic seizures consistent with an impairment of cortical inhibitory mechanisms. This implies that, rather than producing hyperexcitability of the inhibitory interneurons, Kv3.2 channel elimination suppresses their activity. These data suggest that normal cortical operations depend on the ability of inhibitory interneurons to generate high-frequency firing.

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A Knudsen flow reactor has been used to quantify functional groups on the surface of seven different types of combustion particle samples: 3 amorphous carbons (FS 101, Printex 60, FW 2), 2 flame soots (hexane soot generated from a rich and a lean diffusion flame), and 2 Diesel particles (SRM 2975, Diesel soot recovered from a Diesel particulate filter). The technique is based on a heterogeneous titration reaction between a probe gas and a specific functional group on the particle surface. Six probe gases have been selected for the quantification of important functional groups: N(CH3)3 for the titration of acidic sites, NH2OH for carbonyl functions of aldehydes and ketones, CF3COOH and HCl for basic sites of different strength, O3 and NO2 for oxidizable groups. The limit of detection was generally well below 1% of a formal monolayer of adsorbed probe gas. Results obtained with N(CH3)3 were higher for the FW 2 amorphous carbon (post-oxidized sample, according to the manufacturer) and the Diesel particles (between 5.2·10 13 and 5.8·10 13 molecule/cm2), indicating a higher state of oxidation than for the other samples (between 1.3·10 12 and 3.7·10 12 molecule/cm2). The ratio of uptakes of CF3COOH and HCl inferred the presence of basic oxides on the particle surface, owing to the larger stability of the acetate compared to the chloride counter ion in the resulting pyrylium salt. The reactivity of the FS 101 amorphous carbon (3.7·10 15 molecule/cm2) and the hexane flame soot (between 1.9·10 15 and 2.7·10 15 molecule/cm2) towards O3 was very high, indicating the presence of a huge amount of oxidizable or reduced groups on the surface of these samples. Besides the quantification of surface functional groups, the kinetics of reactions between particles and probe gases has also been studied. The uptake coefficient γ0 was roughly correlated with the amount of probe gas taken up by the samples. Indeed, the presence of a high density of functional groups led to fast uptake of the probe gas. These different findings indicate that the particle surface appeared multi-functional, with the simultaneous presence of antagonistic functional groups which do not undergo internal chemical reactions, such as acid-base neutralization. Results also point to important differences in the surface reactivity of the samples, depending on the combustion conditions. The relative distribution of the surface functional groups may be a useful indicator for the state of oxidation and the reactivity of the particle surface.

A Influência do Valor da Marca na Satisfação do Espetador em Eventos de Kickboxing

O objetivo do estudo é analisar a influência dos fatores da associação à marca na satisfação dos espetadores de kickboxing. Para tal, criou-se um questionário de acordo como modelo de Ross, Russell e Bang (2008) considerando-se o estudo de Kim, Andrew, e Greenwell (2009). Recolheram-se 252 questionários em eventos de kickboxing, dos quais214 foram validados. Após uma análise fatorial exploratória dos dados, identificou-se que os fatores organizadores, história, violência, restauração, combates, fãs, interação social, marca, sucesso do evento e apreciação estética são os que melhor explicam a associação à marca. Através da regressão linear verificou-se que os fatores de associação à marca têm um bom impacto na explicação da satisfação dos espetadores. Podemos destacar os fatores organizadores, história, restauração, combate, fãs, a interação social, marca e qualidades estéticas como explicativos da satisfação dos espetadores. Relativamente à análise sociodemográfica, verificou-se que não existem diferenças nos níveis de satisfação entre grupos. Alguns dos fatores de associação à marca que mais influenciaram a satisfação, como os de organizadores, fãs, história, interação social e sucesso do evento, tiveram diferenças de acordo com o género, habilitações literárias e se é ou não praticante da modalidade.

Respuesta selectiva de la red de fondo granton 400/127 en el estudio de recursos demersales. Invierno 1966

Se estudia la respuesta selectiva de la red de la arrastre de fondo Granton 400/127, durante el crucero de evaluación de recursos demersales a bordo del BIC SNP-1 9607-08, empleando el método de copo cubierto, con un tamaño de malla de 90 mm (Poliamida PA-nylon). Se obtuvieron las ojivas de selección mediante los métodos de ojiva natural y curva logística, para la zona de pesca de Paita (03°30 ' S- 06°00 'S), presentando un L50% =35,9 y 35,71 cm respectivamente. Se encontró un factor de selección (FS) = 3,95, factor de perímetro (FP) = 0,46 y un máximo factor de selección igual a 4,34. Los resultados fueron mayores que en el experimento modelo de selectividad con red de arrastre de fondo, realizado en verano de 1996.

Experimento modelo de selectividad con red de arrastre de fondo

Presentan los resultados obtenidos del estudio de selectividad en merluza peruana (Merluccius gayi peruanus) con una red de arrastre de fondo, en el área pesquera de Paita (03° a 05° S), basado en el método de copo cubierto (POPE et al. 1975) con diferentes tamaños de malla (poliamida PA-nylon), 90, 105, 110 y 120 mm. Se observó que la diferencia entre el factor de selección calculado por los distintos análisis para la mallas 105 (106) mm y 110 (114) mm no fue significativa, razón por la cual fueron seleccionadas para aplicar los modelos matemáticos adicionales de GULLAND 1970 y BARANOV 1960, determinándose el tamaño óptimo de malla de 110 mm. El factor de selección (FS) para la malla de 90(90,8)mm fue igual a 3,41; para la malla de 105 (106) mm, igual a 3,03; para la malla de 110 (114) mm fue igual a 2,99; para la malla de 120 (122) mm, fue igual a 2,84.

Comportamiento y eficiencia de la red de arrastre pelágico Engel 988/400 en el estudio de recursos pelágicos. Crucero BIC Humboldt 9803-05 de Tumbes a Tacna

Se presentan los resultados del comportamiento de la red de arrastre pelágico modelo alemán Engel 988/400 utilizada para la evaluación de los recursos pelágicos anchoveta (Engraulis ringens), sardina (Sardinops sagax sagax), jurel (Trachurus picturatus murphyi), caballa (Scomber japonicus peruanus) y samasa (Anchoa nasus) durante el Crucero Hidroacústico 9803-05 a bordo del BIC Humboldt entre Caleta La Cruz, Tumbes y Los Palos, Tacna, del 20 de marzo al 7 de mayo 1998. Se determinó la distancia entre puertas, el área de la boca de la red y el volumen de agua filtrada que tuvo la red en los arrastres efectivos de una milla náutica de distancia durante los 144 lances de comprobación, obteniéndose un buen rendimiento; se capturó un total de 39.912,14 kg, correspondiendo para anchoveta 16.838,15 kg, sardina 6.800,74 kg, jurel 1.384 kg, caballa 1.404,58 kg, samasa 8.071,8 kg y otros recursos hidrobiológicos 5.413,48 kg, con un índice de captura (CPUE) de 788,79 kg/h. Los valores de datos de comportamiento de la red como la abertura horizontal de la boca, abertura vertical, profundidad de la red y distancia entre la relinga inferior al fondo, etc., se obtuvo en forma directa por medio de una net sonda FS 900 SIMRAD, los arrastres tuvieron en promedio una duración de de 20,8 minutos con una velocidad de arrastre promedio de 3 nudos.

Respuesta selectiva de la red de arrastre del fondo tipo 450/120 empleada en el estudio de recursos demersales a inicios del invierno 1998. Crucero BIC José Olaya Balandra 9806-07 de puerto Pizarro a Huarmey

Estudia la respuesta selectiva de la red de arrastre de fondo tipo 450/120, utilizada en la toma de muestras durante el Crucero BIC José Olaya Balandra 9806-07 empleando el método de copo cubierto, con un tamaño de malla de 90 mm. (Polipropileno PP). Se obtuvieron las ojivas de selección mediante el método de la curva logística, para la zona de toda la extensión que abarcó el crucero desde las subáreas A, B, C, D, E, F, G y H (3°30 'S - 11°00 'S), presentando una L50%=23,68 cm. y curvas de selectividad parciales de las subáreas A, B, C y D, E, F, G y H con una L50%=25,45 cm. y L50%=23,68 cm. respectivamente. Se encontró un factor de selección general de (FS)=2,63. Los resultados fueron mayores que en el experimento modelo de selectividad con red de arrastre de fondo, realizado en invierno 1997.

Comportamiento de la red de arrastre pelágica Engel 988/400 para el estudio del Krill (Euphasia superba). Verano Austral 1998. Perú Antar IX

Resultado del comportamiento de la red de arrastre pelágica Engel 988/400 utilizada para la evaluación del recurso krill (Euphausia superba) en el Estrecho de Bransfield durante el Crucero Multidisciplinario 9801 a bordo del BIC Humboldt. Se determinó el área de la boca y el volumen de aguas filtrada por la red en los 29 lances de comprobación, siendo positivos en su totalidad, obteniéndose un buen rendimiento. Se capturó un total de 11.629 kg, correspondiendo para el krill 9.522 kg y para otros recursos 2.107 kg, con un índice de captura por unidad de esfuerzo (CPUE) de 961,9 kg/h. Los valores de otros datos de comportamiento de la red como la abertura horizontal de la boca, abertura vertical, profundidad de la red, distancia entre la relinga inferior al fondo, etc., se obtuvo por medio de una netsonda FS 900 SIMRAD, los arrastres tuvieron en promedio una duración de 20,1 minutos con una velocidad de arrastre promedio de 3,0 nudos.