The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.

Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids' unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class.

Effects of Cymatocarpus solearis (Trematoda: Brachycoeliidae) on its second intermediate host, the Caribbean spiny lobster Panulirus argus.

Many digenean trematodes require three hosts to complete their life cycle. For Cymatocarpus solearis (Brachycoeliidae), the first intermediate host is unknown; the Caribbean spiny lobster Panulirus argus is a second intermediate host, and the loggerhead turtle Caretta caretta, a lobster predator, is the definitive host. Trophically-transmitted parasites may alter the behavior or general condition of intermediate hosts in ways that increase the hosts' rates of consumption by definitive hosts. Here, we examined the effects of infection by C. solearis on P. argus by comparing several physiological and behavioral variables among uninfected lobsters (0 cysts) and lobsters with light (1-10 cysts), moderate (11-30 cysts), and heavy (>30 cysts) infections. Physiological variables were hepatosomatic index, growth rate, hemocyte count, concentration in hemolymph of cholesterol, protein, albumin, glucose, dopamine (DA) and serotonin (5-HT). Behavioral variables included seven components of the escape response (delay to escape, duration of swimming bout, distance traveled in a swimming bout, swim velocity, acceleration, force exerted, and work performed while swimming). There was no relationship between lobster size or sex and number of cysts. Significant differences among the four lobster groups occurred only in concentration of glucose (lower in heavily infected lobsters) and 5-HT (higher in heavily and moderately infected lobsters) in plasma. As changes in 5-HT concentration can modify the host's activity patterns or choice of microhabitat, our results suggest that infection with C. solearis may alter the behavior of spiny lobsters, potentially increasing the likelihood of trophic transmission of the parasite to the definitive host.

Remote Activation of Enzyme Nanohybrids for Cancer Prodrug Therapy Controlled by Magnetic Heating.

Herein, we have developed nanohybrids (nHs) to remotely activate a therapeutic enzyme for its use in Directed Enzyme Prodrug Therapy (DEPT). The coencapsulation of magnetic nanoparticles (MNPs) with horseradish peroxidase (HRP) using biomimetic silica as an entrapment matrix was optimized to obtain nanosized hybrids (∼150 nm) for remote activation of the therapeutic enzyme. HRP converts indole-3-acetic acid (3IAA) into peroxylated radicals, whereas MNPs respond to alternating magnetic fields (AMFs) becoming local hotspots. The AMF application triggered an increase in the bioconversion rate of HRP matching the activity displayed at the optimal temperature of the nHs (Topt = 50 °C) without altering the temperature of the reaction media. This showed that enzyme nanoactuation is possible with MNPs even if they are not covalently bound. After an extensive physicochemical/magnetic characterization, the spatial location of each component of the nH was deciphered, and an insulating role of the silica matrix was suggested as critical for introducing remote control over HRP. In vitro assays, using a human pancreatic cancer cell line (MIA PaCa-2), showed that only upon exposure to AMF and in the presence of the prodrug, the enzyme-loaded nHs triggered cell death. Moreover, in vivo experiments showed higher reductions in the tumor volume growth in those animals treated with nHs in the presence of 3IAA when exposed to AMF. Thus, this work demonstrates the feasibility of developing a spatiotemporally controlled DEPT strategy to overcome unwanted off-target effects.

Artificial shelters and marine infectious disease: no detectable effect of the use of casitas to enhance juvenile Panulirus argus in shelter-poor habitats on a viral disease dynamics.

Casitas, low-lying artificial shelters that mimic large crevices, are used in some fisheries for Caribbean spiny lobsters (Panulirus argus). These lobsters are highly gregarious and express communal defense of the shelter. Scaled-down casitas have been shown to increase survival, persistence, and foraging ranges of juveniles. Therefore, the use of casitas has been suggested to help enhance local populations of juvenile P. argus in Caribbean seagrass habitats, poor in natural crevice shelters, in marine protected areas. Following the emergence of Panulirus argus virus 1 (PaV1), which is lethal to juveniles of P. argus, concern was raised about the potential increase in PaV1 transmission with the use of casitas. It was then discovered that lobsters tend to avoid shelters harboring diseased conspecifics, a behavior which, alone or in conjunction with predatory culling of diseased lobsters, has been proposed as a mechanism reducing the spread of PaV1. However, this behavior may depend on the ecological context (i.e., availability of alternative shelter and immediacy of predation risk). We conducted an experiment in a lobster nursery area to examine the effect of the use of casitas on the dynamics of the PaV1 disease. We deployed 10 scaled-down casitas per site on five 1-ha sites over a reef lagoon (casita sites) and left five additional sites with no casitas (control sites). All sites were sampled 10 times every 3-4 months. Within each site, all lobsters found were counted, measured, and examined for clinical signs of the PaV1 disease. Mean density and size of lobsters significantly increased on casita sites relative to control sites, but overall prevalence levels remained similar. There was no relationship between lobster density and disease prevalence. Dispersion parameters (m and k of the negative binomial distribution) revealed that lobsters tended to avoid sharing natural crevices, but not casitas, with diseased conspecifics. These results confirm that casitas provide much needed shelter in seagrass habitats and that their large refuge area may allow distancing between healthy and diseased lobsters. On eight additional sampling times over two years, we culled all diseased lobsters observed on casita sites. During this period, disease prevalence did not decrease but rather increased and varied with site, suggesting that other factors (e.g., environmental) may be influencing the disease dynamics. Using scaled-down casitas in shelter-poor habitats may help efforts to enhance juvenile lobsters for conservation purposes, but monitoring PaV1 prevalence at least once a year during the first few years would be advisable.

Discovery of Antitrypanosomal Indolylacetamides by a Deconstruction-Optimization Strategy Applied to Paullones.

The parasitic kinetoplastid diseases Leishmaniasis, Chagas disease and Human African Trypanosomiasis constitute serious threats for populations throughout the (sub-)tropics. Most available drugs to treat these diseases possess inadequate properties and candidates to fill the drug pipeline are urgently needed. Paullone-N5 -acetamides inhibit trypanothione synthetase (TryS), an essential kinetoplastid enzyme, and exhibit antiparasitic activity in the low micromolar range, but lack the desired selectivity against mammalian cells (selectivity index (SI):<10). With the aim to identify the paullones' moieties responsible for TryS inhibition and bioactivity, we applied molecular simplification and ring disconnection approaches. The new indolylacetamides lost activity against the expected molecular target (TryS) compared to the reference paullone MOL2008 (Leishmania infantum TryS IC50 : 150 nM; Trypanosoma brucei bloodstream form EC50 : 4.3 µM and SI: 2.4). However, several of them retained potency (T. b. brucei EC50 : 2.4-12.0 µM) and improved selectivity (SI: 5 to >25).

Mode of action of p-quinone derivatives with trypanocidal activity studied by experimental and in silico models.

Quinones are attractive pharmacological scaffolds for developing new agents for the treatment of different transmissible and non-transmissible human diseases due to their capacity to alter the cell redox homeostasis. The bioactivity and potential mode of action of 19 p-quinone derivatives fused to different aromatic rings (carbo or heterocycles) and harboring distinct substituents were investigated in infective Trypanosoma brucei brucei. All the compounds, except for a furanequinone (EC50=38 µM), proved to be similarly or even more potent (EC50 = 0.5-5.5 µM) than the clinical drug nifurtimox (EC50 = 5.3 µM). Three furanequinones and one thiazolequinone displayed a higher selectivity than nifurtimox. Two of these selective hits resulted potent inhibitors of T. cruzi proliferation (EC50=0.8-1.1 µM) but proved inactive against Leishmania infantum amastigotes. Most of the p-quinones induced a rapid and marked intracellular oxidation in T. b. brucei. DFT calculations on the oxidized quinone (Q), semiquinone (Q•-) and hydroquinone (QH2) suggest that all quinones have negative ΔG for the formation of Q•-. Qualitative and quantitative structure-activity relationship analyses in two or three dimensions of different electronic and biophysical descriptors of quinones and their corresponding bioactivities (killing potency and oxidative capacity) were performed. Charge distribution over the quinone ring carbons of Q and Q.- and the frontier orbitals energies of SUMO (Q.-) and LUMO (Q) correlate with their oxidative and trypanocidal activity. QSAR analysis also highlighted that both bromine substitution in the p-quinone ring and a bulky phenyl group attached to the furane and thiazole rings (which generates a negative charge due to the π electron system polarized by the nearby heteroatoms) are favorable for activity. By combining experimental and in silico procedures, this study disclosed important information about p-quinones that may help to rationally tune their electronic properties and biological activities.

Cytotoxicity of quercetin is related to mitochondrial respiration impairment in Saccharomyces cerevisiae.

Quercetin is a flavonol ubiquitously present in fruits and vegetables that shows a potential therapeutic use in non-transmissible chronic diseases, such as cancer and diabetes. Although this phytochemical has shown promising health benefits, the molecular mechanism behind this compound is still unclear. Interestingly, quercetin displays toxic properties against phylogenetically distant organisms such as bacteria and eukaryotic cells, suggesting that its molecular target resides on a highly conserved pathway. The cytotoxicity of quercetin could be explained by energy depletion occasioned by mitochondrial respiration impairment and its concomitant pleiotropic effect. Thereby, the molecular basis of quercetin cytotoxicity could shed light on potential molecular mechanisms associated with its health benefits. Nonetheless, the evidence supporting this hypothesis is still lacking. Thus, this study aimed to evaluate whether quercetin supplementation affects mitochondrial respiration and whether this is related to quercetin cytotoxicity. Saccharomyces cerevisiae was used as a study model to assess the effect of quercetin on energetic metabolism. Herein, we provide evidence that quercetin supplementation: (1) decreased the exponential growth of S. cerevisiae in a glucose-dependent manner; (2) affected diauxic growth in a similar way to antimycin A (complex III inhibitor of electron transport chain); (3) suppressed the growth of S. cerevisiae cultures supplemented with non-fermentable carbon sources (glycerol and lactate); (4) promoted a glucose-dependent inhibition of the basal, maximal, and ATP-linked respiration; (5) diminished complex II and IV activities. Altogether, these data indicate that quercetin disturbs mitochondrial respiration between the ubiquinone pool and cytochrome c, and this phenotype is associated with its cytotoxic properties.

Snf1p/Hxk2p/Mig1p pathway regulates hexose transporters transcript levels, affecting the exponential growth and mitochondrial respiration of Saccharomyces cerevisiae.

The Crabtree effect molecular regulation comprehension could help to improve ethanol production with biotechnological purposes and a better understanding of cancer etiology due to its similarity with the Warburg effect. Snf1p/Hxk2p/Mig1p pathway has been linked with the transcriptional regulation of the hexose transporters and phenotypes associated with the Crabtree effect. Nevertheless, direct evidence linking the genetic control of the hexose transporters with modulation of the Crabtree effect phenotypes by the Snf1p/Hxk2p/Mig1p pathway is still lacking. In this sense, we provide evidence that SNF1 and HXK2 genes deletion affects exponential growth, mitochondrial respiration, and transcript levels of hexose transporters in a glucose-dependent manner. The Vmax of the hexose transporters with the high transcript levels was correlated positively with the exponential growth and negatively with the mitochondrial respiration. HXT2 gene transcript levels were the most affected by the deletion of the SNF1/HXK2/MIG1 pathway. Deleting the orthologous genes SNF1 and HXK2 in Kluyveromyces marxianus (Crabtree negative yeast) has an opposite effect compared to Saccharomyces cerevisiae in growth and mitochondrial respiration. Overall, these results indicate that the SNF1/HXK2/MIG1 pathway regulates transcript levels of the hexose transporters, which shows an association with the exponential growth and mitochondrial respiration in a glucose-dependent manner.

Inclusión Educativa de los estudiantes con discapacidad en la Universidad Central del Ecuador / Educational inclusion of students with disabilities at theCentral University of Ecuador

Introducción: La inclusión educativa en la educación superior pública y privada, es un problema que ha sido abordado de diversas maneras por las diferentes instituciones de educación superior ecuatorianas. La Universidad Central del Ecuador, es una institución pública en la que estudian 40.000 estudiantes aproximadamente y esto la obliga a imple-mentar culturas, políticas y prácticas inclusivas, que analicen las barreras y las oportunida-des para el acceso a una educación de calidad y en igualdad de condiciones.Objetivo: Identificar las características personales de los estudiantes con discapacidad, los factores contextuales de la Universidad Central del Ecuador y su relación con el nivel de inclusión educativa. Materiales y métodos: Estudio descriptivo, correlacional de tipo observacional, que inclu-yó a 108 estudiantes de la Universidad Central del Ecuador que presentan al menos una discapacidad, y que respondieron vía on line la encuesta de inclusión educativa. Análisis estadístico. Se usó el SPSS 22.0, para el análisis univarial se aplicó la estadística descrip-tiva apoyados en medidas de proporción, mientras que las pruebas x2 cuadrada y Spear-man fueron usadas para el análisis bivarial. Resultados: El 54% de los investigados registra un bajo nivel de inclusión educativa, 22,52% presenta limitaciones para movilizarse, 17,59% para aprender/estudiar y el 14,81% para las interacciones personales. El 35% requieren ayuda de compañeros y familiares, de servicios universitarios y ayudas técnicas para realizar varias de sus actividades académi-cas y acceder al medio físico universitario. Aquellos con limitaciones graves y moderadas para realizar sus actividades tienen 1,4 a 1,8 veces más probabilidad de tener un bajo nivel de inclusión que aquellos con limitaciones leves; este patrón se repite con otras variables personales y contextuales, y refleja la asociación entre los factores personales-contextua-les y la inclusión educativa.Conclusiones:La inclusión es un proceso sistémico en el cual intervienen e interactúan de manera concurrente variables bio-psico-sociales. Las condiciones para crear la inclusión educativa de los estudiantes con discapacidad en la UCE deben estar sustentadas en un cambio de paradigma, y orientadas a la implementación de políticas y procesos de inclusión educativa, que incorporen las necesidades expresadas por los investigados en este estudio.

Introduction: Educational inclusion in public and private higher education is a problem that has been addressed in various ways by different Ecuadorian higher education institutions. The Central University of Ecuador is a public institution where approximately 40,000 stu-dents study, is committed to implementing inclusive cultures, policies and practices, which analyzes the barriers and opportunities for access to quality education and on equal terms.Aim. Identify the personal characteristics of students with disabilities, the contextual factors of the Central University of Ecuador and their relationship with the level of inclusion.Material and methods. Descriptive, correlational, observational study, which investigated 108 students from the Central University of Ecuador who present at least one disability, and who answered the inclusion survey online. Statistic analysis. SPSS 22.0 was used, for the univariate analysis applied descriptive statistics supported by measures of proportion while x2 squared and Spearman tests were used for the bivariate analysis.Results. 54% of those investigated register a low level of educational inclusion, 22.52% pre-sent limitations to move around, 17.59% to learn/study and 14.81% for personal interactions. 35% require help from classmates and family, university services and technical aids to carry out several of their academic activities and access the university physical environment with severe and moderate limitations to carry out their activities are 1.4 to 1.8 times more likely to have a low level of inclusion than those with mild limitations. This pattern is repeated with other personal and contextual variables and reflects the association between personal-con-textual factors and educational inclusion.Conclusions. Inclusion is a systemic process in which bio-psycho-social variables intervene and interact concurrently. The conditions to create the educational inclusion of students with disabilities in the Central University of Ecuador must be supported by a paradigm shift, and oriented towards the implementation of educational inclusion policies and processes, which incorporate the needs expressed by those investigated in this study.

Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in Bloodstream Trypanosoma brucei.

Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding ß-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit µM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.

Do ecological characteristics drive the prevalence of Panulirus argus virus 1 (PaV1) in juvenile Caribbean spiny lobsters in a tropical reef lagoon?

PaV1 is a pathogenic virus found only to infect Caribbean spiny lobsters Panulirus argus, a major fishing resource. P. argus is a benthic mesopredator and has a complex life history, with several ontogenetic habitat changes. Habitat characteristics and species diversity of surrounding communities may have implications for disease dynamics. This is of more concern for juvenile lobsters, which are more susceptible to PaV1 and are far less mobile than adult lobsters. We targeted a population of juvenile P. argus in a reef lagoon in Mexico, where PaV1 was first observed in 2001. Prevalence has been since irregularly assessed, but in 2016 we began a more systematic assessment, with two sampling periods per year (June and November) in three different zones of the reef lagoon. To examine the relationship between PaV1 prevalence and potential ecological determinants, we assessed habitat complexity, cover of different substrates, and invertebrate community composition in all zones during the first four sampling periods (June and November 2016 and 2017). Habitat complexity and percent cover of some substrates varied with zone and sampling period. This was the case for seagrass and macroalgae, which nevertheless were the dominant substrates. The invertebrate community composition varied with sampling period, but not with zone. Probability of infection decreased with increasing lobster size, consistent with previous studies, but was not affected by zone (i.e., variations in ecological characteristics did not appear to be sufficiently large so as to influence prevalence of PaV1). This result possibly reflects the dominance of marine vegetation and suggests that lobsters can be sampled throughout the reef lagoon to assess PaV1 prevalence. Prevalence was higher in only one of seven sampling periods (November 2017), suggesting that the pathogen has leveled off to an enzootic level.

SNF1 controls the glycolytic flux and mitochondrial respiration.

The switch between mitochondrial respiration and fermentation as the main ATP production pathway through an increase glycolytic flux is known as the Crabtree effect. The elucidation of the molecular mechanism of the Crabtree effect may have important applications in ethanol production and lay the groundwork for the Warburg effect, which is essential in the molecular etiology of cancer. A key piece in this mechanism could be Snf1p, which is a protein that participates in the nutritional response including glucose metabolism. Thus, this work aimed to recognize the role of the SNF1 gene on the glycolytic flux and mitochondrial respiration through the glucose concentration variation to gain insights about its relationship with the Crabtree effect. Herein, we found that SNF1 deletion in Saccharomyces cerevisiae cells grown at 1% glucose, decreased glycolytic flux, increased NAD(P)H concentration, enhanced HXK2 gene transcription, and decreased mitochondrial respiration. Meanwhile, the same deletion increased the mitochondrial respiration of cells grown at 10% glucose. Altogether, these findings indicate that SNF1 is important to respond to glucose concentration variation and is involved in the switch between mitochondrial respiration and fermentation.

Glucose-6-Phosphate Dehydrogenase from the Human Pathogen Trypanosoma cruzi Evolved Unique Structural Features to Support Efficient Product Formation.

Glucose-6-phosphate dehydrogenase (G6PDH) is the key enzyme supplying reducing power (NADPH) to the cells, by oxidation of glucose-6-phosphate (G6P), and in the process providing a precursor of ribose-5-phosphate. G6PDH is also a virulence factor of pathogenic trypanosomatid parasites. To uncover the biochemical and structural features that distinguish TcG6PDH from its human homolog, we have solved and analyzed the crystal structures of the G6PDH from Trypanosoma cruzi (TcG6PDH), alone and in complex with G6P. TcG6PDH crystallized as a tetramer and enzymatic assays further indicated that the tetramer is the active form in the parasite, in contrast to human G6PDH, which displays higher activity as a dimer. This quaternary structure was shown to be particularly stable. The molecular reasons behind this disparity were unveiled by structural analyses: a TcG6PDH-specific residue, R323, is located at the dimer-dimer interface, critically contributing with two salt bridges per subunit that are absent in the human enzyme. This explains why TcG6PDH dimerization impaired enzyme activity. The parasite protein is also distinct in displaying a 37-amino-acid extension at the N-terminus, which comprises the non-conserved C8 and C34 involved in the covalent linkage of two neighboring protomers. In addition, a cysteine triad (C53, C94 and C135) specific of Kinetoplastid G6PDHs proved critical for stabilization of TcG6PDH active site. Based on the structural and biochemical data, we posit that the N-terminal region and the catalytic site are highly dynamic. The unique structural features of TcG6PDH pave the way toward the design of efficacious and highly specific anti-trypanosomal drugs.

¿Las personas con conductas psicopáticas y delictivas, en el funcionamiento cognitivo, son diferentes de las personas regulares? / Are people with psychopathic and criminal behavior, in cognitive functioning, different from regular people?

Contexto: las funciones neuronales superiores como la atención, memoria y funciones ejecutivas, son necesarios al momento de dirimir, planificar, tomar decisiones y actuar. El perfil neuropsicológico cognitivo de las personas con conductas psicopáticas o delictivas difiere de las personas que no poseen estas conductas. Se postula que existe diferencia en los procesos cognitivos de sujetos psicópatas comparado con individuos que no tienen esta característica. Propósito: analizar si las personas que presentan conductas psicopáticas y/o delictivas, evidencian diferencias en el perfil neuropsicológico de atención y memoria comparativamente con las personas que no presentan dichas conductas Sujetos y métodos: es un estudio neuro-psicológico de atención y memoria, correlacional, transversal, en 60 personas privadas de la libertad, hombres y mujeres, entre 18 y 56 años. Se usa métodos científico, estadístico, analítico-sintético, mediante la aplicación de las escalas Hare, NEUROPSI, Atención y Memoria, MINI entrevista Psiquiátrica Internacional, diferenciados en 3 grupos. Resultados: la muestra del estudio lo conformaron 60 sujetos, 20 con conductas psicopáticas, 20 con conductas delictivas y 20 sin estas conductas. Se encuentra que existen diferencias significativas en el foco atencional y en control inhibitorio, lo cual no incide de modo fundamental en los procesos cognitivos de atención y memoria, siendo significativo en el foco atencional, en el control inhibitorio y en el desarrollo y eficiencia de las funciones ejecutivas. Esto a su vez interfiere en la toma de decisiones socialmente funcionales. Se recomienda diseñar y aplicar estudios transversales que sean indicadores descriptivos y predictivos de conductas psicopáticas y/o delictivas para el peritaje y que posteriormente faciliten su rehabilitación e inclusión social. Conclusión: el rendimiento cognitivo en atención y memoria es similar al de las personas sin conductas delictivas pues están dentro de la clasificación normal siendo su mayor interferente conductual el déficit en funciones ejecutivas las cuales son mayoritariamente las reguladoras conductuales. (AU)

Context: higher neural functions such as attention, memory and executive functions, are necessary when deciding, planning, making decisions and acting. The cognitive neuropsychological profile of people with psychopathic or criminal behavior differs from people who do not have these behaviors. It is postulated that there is a difference in the cognitive processes of psychopathic subjects compared with individuals who do not have this characteristic. Purpose: to analyze whether people who present psychopathic and/or criminal behaviors show differences in the neuropsychological profile of attention and memory compared with people who do not present such behaviors. Subjects and methods: it is a neuro-psychological study of attention and memory, correlational, transversal, in 60 people deprived of liberty, men and women, between 18 and 56 years old. Scientific, statistical, analytical-synthetic methods are used, through the application of the Harescales, NEUROPSI,Attention and Memory, MINIInternational Psychiatric Interview,differentiated into 3 groups. Results: the sample of the study consisted of 60 subjects, 20 with psychopathic behaviors, 20 with criminal behaviors and 20 without these behaviors. It is found that there are significant differences in the attentional focus and in inhibitory control, which does not fundamentally affect the cognitive processes of attention and memory, being significant in the attentional focus, in the inhibitory control and in the development and efficiency of the executive functions. This in turn interferes with making socially functional decisions. It is recommended to design and apply cross-sectional studies that are descriptive and predictive indicators of psychopathic and /or criminal conducts for the expertise and that subsequently facilitate their rehabilitation and social inclusion. Conclusion: the cognitive performance in attention and memory is similar to that of people without delinquent behavior because they are within the normal classification being their major behavioral interferencedeficit in executive functions which are mostly behavioral regulators. (AU)

Potential sexual transmission of Giardia in an endemic region: a case series.

We present four cases in which probable sexual transmission of Giardia lamblia was suspected. Diagnosing this mode of transmission in endemic areas is often difficult and should be considered only as possible, because exposure to poor sanitation and a potentially contaminated environment are always latent. However, as patients reported, there was no history of drinking tap water, exposure to recreational water, eating contaminated food, or other potential sources of infection but anilingus with an infected partner. We consider that in endemic countries, even when other more frequent modes of transmission could be playing the main role, the possibility of (re)infection due to sexual transmission should not be forgotten. Talking openly with patients, strengthening patient-specific preventive measures and counselling appear to be needed to reduce risks of Giardia infection transmission due to this often neglected route.

Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi.

Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3ß-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen's enzyme.

HCV-induced immune responses influence the development of operational tolerance after liver transplantation in humans.

Pathogen-induced immune responses prevent the establishment of transplantation tolerance in experimental animal models. Whether this occurs in humans as well remains unclear. The development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection allows us to address this question. We conducted a clinical trial of immunosuppression withdrawal in HCV-infected adult liver recipients to elucidate (i) the mechanisms through which allograft tolerance can be established in the presence of an ongoing inflammatory response and (ii) whether anti-HCV heterologous immune responses influence this phenomenon. Of 34 enrolled liver recipients, drug withdrawal was successful in 17 patients (50%). Tolerance was associated with intrahepatic overexpression of type I interferon and immunoregulatory genes and with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8(+) T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced proinflammatory gene expression and the breadth of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data suggest that in humans, persistent viral infections exert immunoregulatory effects that could contribute to the restraining of alloimmune responses, and do not necessarily preclude the development of allograft tolerance.

Variability in clinical prevalence of PaV1 in Caribbean spiny lobsters occupying commercial casitas over a large bay in Mexico.

In Bahía de la Ascensión, Mexico, the fishery for spiny lobsters Panulirus argus is based on the extensive use of casitas, large artificial shelters that can harbor the full size range of these highly gregarious lobsters. The discovery of a pathogenic virus in these lobsters (Panulirus argus virus 1, or PaV1) has raised concern about its potential effects on casita-based fisheries. Because in Bahía de la Ascensión visibly infected lobsters represent an immediate loss of revenue, we examined variability in clinical prevalence of PaV1 (percentage of lobsters visibly infected) in thousands of lobsters sampled from the commercial catch at the onset of 3 consecutive fishing years, and from 530 casitas distributed over 3 zones within the bay during 2 fishing and 2 closed seasons. In the commercial catch (lobsters 67 to 147 mm carapace length [CL]), clinical prevalence of PaV1 was low and was not affected by year or sex. In lobsters (9.2 to 115.0 mm CL) that occupied casitas, clinical prevalence of PaV1 varied with sampling season and was always higher in juveniles than in subadults or adults, but was consistently lower in one zone relative to the other 2 zones. The average clinical prevalence of PaV1 in this bay was statistically similar to the average clinical prevalence reported in Cuba, where casitas are also used, and in Florida Bay, USA, where casitas are not used. To date, PaV1 has had no discernible impact on the lobster fishery in Bahía de la Ascensión, suggesting that clinical prevalence is not influenced by the use of casitas per se.

Influence of local habitat features on disease avoidance by Caribbean spiny lobsters in a casita-enhanced bay.

In Bahía de la Ascensión, Mexico, 'casitas' (large artificial shelters) are extensively used to harvest Caribbean spiny lobsters Panulirus argus. After the discovery of a pathogenic virus, Panulirus argus virus 1 (PaV1), in these lobsters, laboratory experiments revealed that PaV1 could be transmitted by contact and through water, and that lobsters avoided shelters harboring diseased conspecifics. To examine these issues in the context of casitas, which typically harbor multiple lobsters of all sizes, we examined the distribution and aggregation patterns of lobsters in the absence/presence of diseased conspecifics (i.e. visibly infected with PaV1) in 531 casitas distributed over 3 bay zones, 1 poorly vegetated ('Vigía Chico', average depth: 1.5 m) and 2 more extensively vegetated ('Punta Allen': 2.5 m; 'Los Cayos': 2.4 m). All zones had relatively high indices of predation risk. Using several statistical approaches, we found that distribution parameters of lobsters were generally not affected by the presence of diseased conspecifics in casitas. Interestingly, however, in the shallower and less vegetated zone (Vigía Chico), individual casitas harbored more lobsters and lobsters were actually more crowded in casitas containing diseased conspecifics, yet disease prevalence was the lowest in lobsters of all sizes. These results suggest that (1) investment in disease avoidance by lobsters is partially modulated by local habitat features, (2) contact transmission rates of PaV1 may be lower in nature than in the laboratory, and (3) water-borne transmission rates may be lower in shallow, poorly vegetated habitats more exposed to solar ultraviolet radiation, which can damage viral particles.

Comparison of two non-contemporaneous HCV-liver transplant cohorts: strategies to improve the efficacy of antiviral therapy.

BACKGROUND & AIMS: In a previous study, advanced fibrosis was associated with worsening efficacy of antiviral therapy in HCV-transplant patients. We aimed at assessing whether changes in treatment policy, that is starting therapy at lesser stages of fibrosis, have resulted in improved efficacy. METHODS: Efficacy (rapid, early, end-of-treatment, and sustained viral response (SVR)) and tolerability (peginterferon (pIFN)/ribavirin (RBV) doses, premature discontinuation, dose reductions, anemia, growth factors, transfusions) were compared between two non-contemporaneous cohorts of post-LT naïve patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated during the period 2005-2007 and Group 2 (n=70), patients treated more recently (2007-2010), where treatment was started once there was evidence of fibrosis. RESULTS: SVR increased from 25% to 54% (p=0.002) due to a reduction in relapse rate. Comparing both cohorts, a decrease in the number of cirrhotic patients together with an increase in platelet count was observed in recent years. Additional non-intentional changes included: (i) an increase of patients treated under cyclosporine immunosuppression, (ii) treatment-related factors with an increase in patients treated with initial full pIFN and RBV doses, who developed anemia and hence required dose modifications and erythropoietin. Baseline factors associated with SVR were younger donor age, lack of cirrhosis or severe necroinflammation and the use of RBV at full doses at initiation while on-treatment variables were adherence and viral kinetics. CONCLUSIONS: Treatment in the absence of cirrhosis is associated with higher SVR warranting strict disease progression monitoring. A more aggressive approach, particularly regarding RBV dosage, is also associated with improved efficacy. Further studies are required to assess whether switching to cyclosporine will result in improved SVR.