Search

MotivationWith the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine—supporting that language—that federates semantically integrated knowledge-bases.ResultsWe introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface. ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user’s query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning, and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX’s application and utility in specific disease contexts, we present several use-case examples.Availability and ImplementationThe source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web application programming interface (API) endpoint at arax.rtx.ai/api/arax/v1.3/ui/.Contactdmk333@psu.edu

Background Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API). Results To create a knowledge provider system within the Translator project, we have developed RTX-KG2, an open-source software system for building—and hosting a web API for querying—a biomedical knowledge graph that uses an Extract-Transform-Load approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink. Conclusion RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API at arax.rtx.ai/api/rtxkg2/v1.2/openapi.json. The code to build RTX-KG2 is publicly available at github:RTXteam/RTX-KG2.

Digital, CD8+ T-cells play a crucial role in the control of HIV replication. HIV-specific CD8+ T-cell responses rapidly expand since the acute phase of the infection, and it has been observed that HIV controllers harbor CD8+ T-cells with potent anti-HIV capacity. The development of CD8+ T-cell-based vaccine against HIV-1 has focused on searching for immunodominant epitopes. However, the strong immune pressure of CD8+ T-cells causes the selection of viral variants with mutations in immunodominant epitopes. Since HIV-1 mutations are selected under the context of a specific HLA-I, the circulation of viral variants with these mutations is highly predictable based on the most prevalent HLA-I within a population. We previously demonstrated the adaptation of circulating strains of HIV-1 to the HLA-A*02 molecule by identifying mutations under positive selection located in GC9 and SL9 epitopes derived from the Gag protein. Also, we used an in silico prediction approach and evaluated whether the mutations found had a higher or lower affinity to the HLA-A*02. Although this strategy allowed predicting the interaction between mutated peptides and HLA-I, the functional response of CD8+ T-cells that these peptides induce is unknown. In the present work, peripheral blood mononuclear cells from 12 HIV-1+ HLA-A*02:01+ individuals were stimulated with the mutated and wild-type peptides derived from the GC9 and SL9 epitopes. The functional profile of CD8+ T-cells was evaluated using flow cytometry, and the frequency of subpopulations was determined according to their number of functions and the polyfunctionality index. The results suggest that the quality of the response (polyfunctionality) could be associated with the binding affinity of the peptide to the HLA molecule, and the functional profile of specific CD8+ T-cells to mutated epitopes in individuals under cART is maintained., Ciencias Médicas y de la Salud

CD8

Resumen Leptospirosis es una enfermedad re-emergente de distribución mundial ocasionada por espiroquetas patogénicas del género Leptospira que afectan humanos, animales domésticos o silvestres. Las manifestaciones clínicas de la enfermedad son diversas y son el resultado de la interacción de la respuesta inmune del hospedador y las condiciones de virulencia propias de las especies patógenas. Aunque se desconocen muchos aspectos de la inmunidad en la infección por Leptospira spp, es reconocido que los hospe deros susceptibles presentan diferencias en su respuesta inmune, como la activación/evasión del sistema del complemento, la activación de sub poblaciones celulares, la producción de citoquina y el desarrollo de anti cuerpos. El estudio del perfil inmunológico en pacientes con leptospirosis ha sido documentado y contribuye en la identificación de biomarcadores asociados con severidad. Esta revisión presenta algunos de los eventos relacionados con la respuesta inmune desde el ingreso de la bacteria en la fase inicial de la infección hasta su multiplicación y generación de enfer medad en el humano. Abstract Leptospirosis is a re-emergent disease of worldwide distribution caused by pathogenic spirochetes of the Leptospira genus that affect humans, do mestic and wild animals. The clinical manifestations of the disease are diverse and are the result of the interaction of the immune response of the host and the virulence conditions of the pathogenic species. Although many aspects of immunity in infection with Leptospira spp are unknown, it is recognized that susceptible hosts show differences in their immune res ponse, such as activation / evasion of the complement system, activation of cellular subpopulations, production of cytokines, development of anti bodies. Study of the immunological profile in patients with leptospirosis has been documented and contributes in the identification of bio-markers associated with severity. This review presents updated events related to the immune response from the entry of the bacteria in the initial phase of the infection to its multiplication and generation of human disease.

Background: Suicide and suicidal behaviors were already a global public health problem, producing preventable injuries and deaths. This issue may worsen due to the COVID-19 pandemic and may differentially affect vulnerable groups in the population, including children, adolescents, and young adults. The current study evaluated the association of affective variables (depression, hopelessness, and anxiety), drug use (alcohol, tobacco, and others), emotional intelligence, and attachment with suicidal behaviors. Methods: A state-wide survey included 8033 students (51% female, 49% male, mean age of 16 years) from science and technology high-schools using a standardized questionnaire that was distributed online. Multinomial logistic regression models tested associations between suicidal behaviors and several covariates. The analyses accommodated the complex structure of the sample. Results: Approximately 21% of all students reported a suicidal behavior (11% with a low-lethality suicide attempt, 6% with self-injuries, and 4% with a high-lethality suicide attempt). Variables associated with higher odds of suicidal behavior included: female sex, depression, hopelessness, anxiety, alcohol and tobacco use, childhood trauma, and having to self-rely as issues affecting attachment, and low self-esteem. Security of attachment was associated with lower odds of suicidal behavior. Conclusions: The complexity of suicidal behavior makes it clear that comprehensive programs need to be implemented.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae mainly affecting skin and peripheral nerves. Leprosy has a broad range of clinical manifestations that range from mild (tuberculoid leprosy) to severe (lepromatous leprosy) forms, and are highly dependent on the host's immune response. Among the immune response elements involved in the pathogenesis of leprosy are the Toll-like receptors (TLRs), vitamin D receptor (VDR), natural killer cells (NK), and T cells. These innate and adaptive immune response elements may be related to the Notch signaling pathway, which is involved in immune cell growth, differentiation, and proliferation. We hypothesize that failure in Notch signaling in leprosy patients may be associated to: 1) compromising NK cell maturation, lysing of infected cells, and CD4+ Th1 differentiation. 2) VDR alterations and TLR polymorphisms may affect expression of Notch Delta-like ligands (DLL) in antigen presenting cells (APCs). 3) altered DLL expression by APCs could compromise CD4+ T cell differentiation towards the Th1 and Th17 effector phenotypes; and finally 4) expression of Notch Jagged ligands would induce CD4+ T cell differentiation towards Th2 effector phenotype and alternative activation of macrophages. Altogether, these signaling failures could favor proliferation of M. leprae in the host. Therefore, evidence of the proposed immunologic failures in leprosy patients would be essential for the better understanding of immunopathogenesis of this disease, and would ultimately enable detection of susceptible individuals, providing a valuable tool for prevention of this debilitating disease.

Human immunodeficiency virus type-1 (HIV-1) infection represents one of the biggest public health problems worldwide. The immune response, mainly the effector mechanisms mediated by CD8+ T cells, induces the selection of mutations that allows the virus to escape the immune control. These mutations are generally selected within CD8+ T cell epitopes restricted to human leukocyte antigen class I (HLA-I), leading to a decrease in the presentation and recognition of the epitope, decreasing the activation of CD8+ T cells. However, these mutations may also affect cellular processing of the peptide or recognition by the T cell receptor. Escape mutations often carry a negative impact in viral fitness that is partially or totally compensated by the selection of compensatory mutations. The selection of either escape mutations or compensatory mutations may negatively affect the course of the infection. In addition, these mutations are a major barrier for the development of new therapeutic strategies focused ...

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

La lepra es una enfermedad infecciosa crónica causada por Mycobacterium leprae, la cual tiene una notoria afinidad por la piel y los troncos nerviosos periféricos. Esta enfermedad se caracteriza por tener una clínica polimorfa que depende de la respuesta inmune del hospedero. La inmunopatogénesis de esta enfermedad aún representa un reto para los investigadores, y un eslabón faltante en su comprensión es el estudio de los micronutrientes, los cuales se ha demostrado que tienen la capacidad de modular la respuesta inmune innata y adaptativa. El objetivo de esta revisión es describir y relacionar algunos nutrientes, como las vitaminas A, D, E, C y B6, el folato, el zinc y el hierro, con la respuesta inmune en la lepra. Además, proponemos que algunos micronutrientes (vitaminas A, D y C y zinc) serían importantes para mitigar la aparición de reacciones lepróticas por medio de la modulación de la respuesta inmune en el hospedero infectado por M. leprae, y que micronutrientes como las vitaminas A, D, B6 y D, el folato, el hierro y el zinc serían importantes para reducir la incidencia de la lepra, dado que promoverían una mejor respuesta inmune en convivientes. Por lo tanto, el estudio del estado nutricional y el aporte suplementario con micronutrientes en convivientes y en afectados con lepra sería clave en la eliminación de esta enfermedad que ha deformado cuerpos y ha destruido sueños a lo largo de los siglos. Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which has a marked affinity for the skin and peripheral nerve trunks. This disease is characterized by a polymorphic clinical presentation that depends on the immune response in the host. The immunopathogenesis of this disease still represents a challenge for researchers and a missing link in their understanding of it is the study of micronutrients that have been proved to have the ability to modulate the innate and adaptive immune response. The aim of this review is to describe and to relate certain nutrients, such as vitamins A, D, E, C, and B6, folate, zinc and iron, with the immune response in leprosy. In addition, we suggest that some micronutrients (vitamins A, D and C, and zinc) appear to be important in mitigating the occurrence of leprosy reactions by modulating the immune response in the host infected by M. leprae, and that micronutrients such as vitamins A, D, B6, and D, folate, zinc and iron are important in reducing the incidence of leprosy given that they would promote a better immune response in household contacts. Therefore, the study of the nutritional status and the supplementation with micronutrients in household contacts and patients with leprosy seem to be important in eliminating this disease, which has deformed bodies and destroyed dreams for centuries.

Classically, CD4

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. This disease is characterized by skin and peripheral nerve trunk damage. The mechanisms responsible for the observed nerve damage in leprosy could be directly related to the ability of M. leprae to infect Schwann cells, leading to triggering of signaling events. Therefore, we hypothesize that in response to M. leprae infection, activation of the Notch signaling pathway in Schwann cells could play a crucial role in glial cell dedifferentiation. On the other hand, nerve damage evidenced in this disease may be additionally explained by indirect mechanisms such as the immune response and genetic susceptibility of the host. The understanding of the mechanisms leading to nerve damage induced by M. leprae infection will allow us to generate valuable tools for the early detection of leprosy as well as for the mitigation of the effects of this disabling disease.

The introduction of highly active antiretroviral therapy (HAART) has significantly improved life expectancy of HIV-infected patients; nevertheless, it does not eliminate the virus from hosts, so a cure for this infection is crucial. Some strategies have employed the induction of anti-HIV CD8+ T cells. However, the high genetic variability of HIV-1 represents the biggest obstacle for these strategies, since immune escape mutations within epitopes restricted by Human Leukocyte Antigen class I molecules (HLA-I) abrogate the antiviral activity of these cells. We used a bioinformatics pipeline for the determination of such mutations, based on selection pressure and docking/refinement analyses. Fifty HIV-1 infected patients were recruited; HLA-A and HLA-B alleles were typified using sequence-specific oligonucleotide approach, and viral RNA was extracted for the amplification of HIV-1 gag, which was bulk sequenced and aligned to perform selection pressure analysis, using Single Likelihood Ancestor Counting (SLAC) and Fast Unconstrained Bayesian Approximation (FUBAR) algorithms. Positively selected sites were mapped into HLA-I-specific epitopes, and both mutated and wild type epitopes were modelled using PEP-FOLD. Molecular docking and refinement assays were carried out using AutoDock Vina 4 and FlexPepDock. Five positively selected sites were found: S54 at HLA-A*02 GC9, T84 at HLA-A*02 SL9, S125 at HLA-B*35 HY9, S173 at HLA-A*02/B*57 KS12 and I223 at HLA-B*35 HA9. Although some mutations have been previously described as immune escape mutations, the majority of them have not been reported. Molecular docking/refinement analysis showed that one combination of mutations at GC9, one at SL9, and eight at HY9 epitopes could act as immune escape mutations. Moreover, HLA-A*02-positive patients harbouring mutations at KS12, and HLA-B*35-positive patients with mutations at HY9 have significantly higher plasma viral loads than patients lacking such mutations. Thus, HLA-A and -B alleles could be shaping the genetic diversity of HIV-1 through the selection of potential immune escape mutations.

Considering the transformative potential humor has for minorities who experience exclusion and marginalization, I seek to explore how Spanish gay and lesbian youth construct and communicate gay/lesbian identities using humor as a rhetorical tool. Furthermore, I explore the potential implications of their use of humor for social relations, both within gay and lesbian communities and with the broader society. I approach this discussion though a critical discourse analysis of videos from Spanish Queens—a collaborative YouTube channel, in which LGBTQ youth from diverse parts of the country share their experiences, thoughts, and opinions about being LGBTQ in Spain. Stereotypical humor was the primary form of humor used by SQ vloggers when addressing gay and lesbian issues related to both identification and social relations. Looking at how SQ vloggers most frequently use stereotypical humor, three common functions emerged in all ten videos: (a) affirming identity and separating gay and lesbian experiences from those of other groups, including making a distinction between sexual orientation and gender identity; (b) challenging the conflation of sexual and gender identities (i.e., contesting the notion of gay men and lesbians identifying as members of the opposite sex); and (c) disarming discourses that construct gay and lesbian individuals as threats at both interpersonal and societal levels.

We studied the dynamics of mercury (Hg) transfer in Phaseolus vulgaris plants grown in soil with Hg-doped compost at the maximum levels permitted by Colombian law on organic amendments. Quantitative evaluation of transfer was made in different plant organs: roots, stem, leaves, pods and seeds. Matrix effect was determined in doped soil assays, using soil with and without addition of compost. Results showed that the use of organic matter reduced Hg transfer to the plant and the amount transferred was differentially distributed to the organs. We observed an inverse relationship between concentration and distance from the body to the root. It was evident that transfer was mediated by quantitative factors; the greater the presence of mercury in soil, the larger the amount that will be transferred. Results also indicate the remedial effect of compost and the presence of a barrier, at the root level, against mercury translocation to the plant aerial parts.

Resumen La infeccion por el virus de la inmunodeficiencia humana (VIH) es un problema de salud publica global, con un aumento en la incidencia a pesar de las campanas de prevencion. Aunque se ha avanzado en el desarrollo de antirretrovirales, mejorando la expectativa y la calidad de vida de las personas infectadas, los efectos secundarios y la resistencia que se genera por su uso continuo hacen necesario el desarrollo de una vacuna terapeutica y/o profilactica contra el VIH. En esta revision nos centraremos en describir los diversos disenos evaluados, las ventajas, las desventajas y las respectivas modificaciones que se han implementado con base en estudios previos. Se abarcaran desde las estrategias clasicas para el desarrollo de vacunas, hasta las mas recientes en las cuales se modifican diferentes vectores con el fin de desencadenar una respuesta inmune capaz de prevenir la infeccion o potenciar la respuesta existente que permita controlar la replicacion del virus. Adicionalmente se abordara el esquema de vacunacion denominado prime-boost , el cual se ha aplicado en ensayos clinicos mostrando ser un procedimiento de bajo riesgo, con buenos resultados en la induccion de una respuesta inmune humoral y celular.

Human immunodeficiency virus type-1 (HIV-1) infection represents one of the biggest public health problems worldwide. The immune response, mainly the effector mechanisms mediated by CD8

Resumen Objetivo: Estimar las frecuencias de mutaciones y de polimorfismos adicionales asociados con resistencia a los fármacos inhibidores de la integrasa del virus de inmunodeficiencia humana tipo 1 (VIH-1). Metodología: Estudio descriptivo, de corte transversal, en individuos VIH-1 positivos de la ciudad de Medellín, quienes no habían recibido tratamiento antirretroviral. En ellos se determinó, a través del método de 2-dideoxinucleótidos y el sistema ABI3730XL, la secuencia del gen de la integrasa del VIH-1 a partir del ARN viral circulante, la cual fue analizada en la base de datos de resistencia a medicamentos antirretrovirales de la Universidad de Stanford y según reportes de literatura científica. Resultados: Se encontraron las siguientes mutaciones (con sus respectivas frecuencias): una mutación mayor, E138K (1/46), tres mutaciones accesorias G163E (3/46), L74I (3/50) y E157Q (2/48), una mutación no polimórfica A128T (1/49) y otras dos mutaciones potencialmente asociadas con resistencia a inhibidores de integrasa S230N (9/39) y S119P/R/T (4/47, 2/47 y 14/47, respectivamente). Conclusiones: En las secuencias analizadas, llama la atención la presencia de al menos una mutación asociada a resistencia a inhibidores de integrasa en el 14% de los individuos estudiados, sugiriendo una pobre presión selectiva de este tipo de fármacos en la población viral circulante en la zona. Abstract Aim: To estimate the frequencies of major and accessory mutations, as well as additional polymorphisms associated with resistance to human immunodeficiency virus type 1 (VIH-1) integrase strand transfer inhibitors. Materials and methods: Descriptive cross-sectional study, focused on HIV-1 positive individuals from Medellín, recruited between 2013 and 2015, and that had not received antiretroviral therapy. In these patients, the sequence from HIV-1 integrase was determined from circulating viral RNA through Sanger chain termination method with the ABI3730XL system, and the sequences were analyzed using the HIV Drug Resistance Database from the University of Stanford, together with previous literature reports. Results: The following mutations associated with resistance to integrase strand transfer inhibitors, along with its respective frequencies, were found: one major mutation, E138K (1/46), three accessory mutations, G163E (3/46), L74I (3/50) and E157Q (2/48); one non-polymorphic mutation, A128T (1/49); and two mutations potentially associated with resistance to integrase strand transfer inhibitors, S230N (9/39) and S119P/R/T (4/47, 2/47 and 14/47, respectively). Conclusions: In the sequences analyzed, it is noteworthy the presence of at least one mutation related with resistance to integrase inhibitors in 14% of the studied patients, suggesting a poor selective pressure of this kind of drugs in the circulating viral population in our region.

El análisis genético de fragmentos óseos tomados de un cuerpo en descomposición permitió confirmar la muerte de alias “Édgar Tovar”, comandante y responsable del narcotráfico del frente 48 de las Farc. El perfilgenético obtenido de los restos humanos fue comparado con la información del ADN nuclear y de cromosoma Y, del padre de Ángel Gabriel Lozada García,obteniendo una probabilidad estadística de paternidad de 99.991% y una coincidencia total en la información contenida en los marcadores de cromosomaY analizados, lo que sumado a labores investigativas de la Policía Nacional se consideró suficiente para determinar la identificación del cuerpo.

Esta investigación es un estudio descriptivo, transversal, que tiene como finalidad llegar a conocer de manera objetiva la satisfacción del usuario en cuanto a la prestación de los servicios de fisioterapia en diferentes instituciones de Bogotá. Para esto se utilizó el cuestionario de Romero & Romero (2003 ), el cual se modificó para caracterizar la satisfacción en cuanto a la prestación de servicios Se tomaron muestras de 30 instituciones de Bogotá, y se realizaron 25 encuestas en cada una de éstas. Los datos se analizaron por medio de frecuencia y porcentaje, y se encontró que había un buen nivel de satisfacción de los usuarios que acuden al servicio de fisioterapia en Bogotá.

Objetivos Describir el acceso y la oportunidad de la atencion de las urgencias medicas en Medellin, 2006. Materiales y Metodos Se realizo un estudio descriptivo en 27 servicios de urgencias de Instituciones Prestadoras de Servicios de Salud de tercero, segundo y primer nivel de atencion durante una semana continua. A todas las personas admitidas se les realizo seguimiento hasta el egreso del servicio. Las siguientes variables fueron descritas: cacteristicas de persona, tiempos espera, presencia de trauma, consulta previa a un servicio de urgencias en las ultimas 48 horas por la misma causa, referencia y egreso. En aquellas personas no admitidas se estudiaron las causas de no admision. Resultados De 9 703 pacientes que visitaron los servicios de urgencias, 8 703 (89,4 %) fueron admitidos, 13,8 % habian consultado en las ultimas 48 horas a un servicio de urgencias por la misma causa y el 10,5 % tuvieron remision previa. Fue superior el tiempo espera en los servicios de urgencias de primer nivel (40,2 minutos). De las 1 027 (10,6 %) personas que no fueron admitidas, el 62,6 % fue debido a que la consulta no fue considerada urgente por el personal hospitalario, seguido del 16 % por no pertenecer a la red a la cual cotizaba. Conclusiones En los servicios de urgencias de Medellin existen barreras de acceso. El acceso inadecuado de acuerdo al tipo y gravedad de la urgencia y la deficiente la articulacion de los niveles de atencion, soporta la necesidad una red de urgencias en la ciudad.

Numerous reports have focused on consensus peptides to determine CD8+ T-cell responses; however, few studies evaluated the functional profile using peptides derived from circulating strains of a specific region. We determined the effector profile and maturation phenotype of CD8+ T-cells targeting the consensus APPEESFRS (AS9) epitope and its variant APPEESFRF (AF9), previously identified. The free energy of binding, maturation phenotype, and polyfunctional profile of both peptides were similar. The magnitude of CD8+ T-cell responses to AF9 was greater than the one elicited by AS9, although the difference was not significant. The polyfunctional profile of AF9 was characterized by CD107a/interleukin-2 (IL-2)/macrophage inflammatory protein beta (MIP1β) and by interferon gamma (IFNγ)/MIP1β/tumor necrosis factor alpha (TNFα) in response to AS9. TNFα production was significantly higher in response to AF9 than to AS9, and there was a negative correlation between the absolute number of CD8+ T-cell-producing TNFα and the plasma human immunodeficiency virus (HIV) load, suggesting a role of this cytokine in the control of HIV replication.

One of the main characteristics of the human immunodeficiency virus is its genetic variability and rapid adaptation to changing environmental conditions. This variability, resulting from the lack of proofreading activity of the viral reverse transcriptase, generates mutations that could be fixed either by random genetic drift or by positive selection. Among the forces driving positive selection are antiretroviral therapy and CD8+ T-cells, the most important immune mechanism involved in viral control. Here, we describe mutations induced by these selective forces acting on the pol gene of HIV in a group of infected individuals. We used Maximum Likelihood analyses of the ratio of non-synonymous to synonymous mutations per site (dN/dS) to study the extent of positive selection in the protease and the reverse transcriptase, using 614 viral sequences from Colombian patients. We also performed computational approaches, docking and algorithmic analyses, to assess whether the positively selected mutations affected binding to the HLA molecules. We found 19 positively-selected codons in drug resistance-associated sites and 22 located within CD8+ T-cell epitopes. A high percentage of mutations in these epitopes has not been previously reported. According to the docking analyses only one of those mutations affected HLA binding. However, algorithmic methods predicted a decrease in the affinity for the HLA molecule in seven mutated peptides. The bioinformatics strategies described here are useful to identify putative positively selected mutations associated with immune escape but should be complemented with an experimental approach to define the impact of these mutations on the functional profile of the CD8+ T-cells.

En el presente artículo se muestra la utilización del modelo biológico Drosophila melanogaster para la valoración cuantitativa de extractos de neem (Azadiractha indica). Se determinaron, por HPLC, perfiles cromatográficos, encontrándose diferencias altamente significativas en la calidad y cantidad de metabolitos de los extractos etéreo y etanólico de neem y se evaluó el modelo biológico para extractos de diferentes polaridades, resultando una alta correlación entre la inhibición del paso pupa-adulto y el aumento de aquella. Con el mismo modelo biológico se realizó un estudio cinético para dos extractos, hallándose para uno de ellos una estabilidad superior a los seis meses y con las siguientes condiciones de almacenamiento: 20ºC, 80% de humedad y baja luminosidad. Finalmente, se empleó el mismo modelo biológico para realizar un estudio comparativo de diferentes presentaciones comerciales de extractos de neem en función de su actividad biológica.

Describing access to and availability of emergency medical assistance in Medellín in 2006.This was a descriptive survey-based study conducted in 27 emergency services from institutions providing tertiary, secondary and primary level health care services carried out over one full week. All patients participating in the survey were followed-up from being admitted to the emergency department to being discharged. The following parameters were described: a patient's characteristics, waiting time, presence of trauma, previous emergency department visit during the previous 48 hours for the same condition, transfer and discharge. The reasons for non-admission were studied in the case of patients who were not admitted by the emergency service.8,703 (89.4%) out of the 9,730 patients attending the emergency department were then admitted; 13.8% had visited an emergency department during the previous 48 hours for the same condition and 10.5% were early transfers. The highest mean waiting time observed for primary level was 40.2 minutes. Reasons for non-admission for the 1,027 non-admitted patients (10.6%) included hospital staff classifying a case as not being an emergency (62.6%) and lack of social security service coverage (16%).Barriers were found to emergency service access in Medellín. Inadequate access according to the type of emergency and its seriousness and deficient coordination of attention levels support the need for an emergency network in the city.

Medellín has a population of 2.1 million and has 47 acute care hospitals that provide emergency health care services. Perceived seriousness of a medical condition in addition to accessibility and availability of care may influence the use of health care services in the region.A broad-spectrum survey was conducted to rate the urgency of a health condition as perceived by the patient and how that patient proceeded to make use of health care services.The cross sectional survey was conducted, using door-to-door personal interviews in 1,442 homes from 70 neighborhoods.Of the 612,689 individuals interviewed, 533,718 (87,11%) reported that they have had a medical emergency. Respiratory difficulties were the most frequent reason for visiting a health care facility as reported by 113,153 (21.2%) of the participants. Of the 532,718 visits reported, 501,558 (93.97%) led to a hospital admission. Of the 21,042 visits not leading to an admission, 42.0% were considered as non-urgent by the hospital staff. Visits admissions reports were missing, 11.118 (2.08%).In Medellín, the incidence of medical emergencies leading to a health care facility visit is high. The high prevalence of respiratory emergencies and other conditions that can be managed outside the emergency service indicates the need for a pre-hospital emergency service.

NA

La infección con el virus de la inmunodeficiencia humana (VIH-1) sigue siendo un problema de salud pública. Hasta la fecha, considerando la importancia que tiene los linfocitos T CD8+ (LTCD8+) en el control de la replicación viral, algunas estrategias terapéuticas se han enfocado en la inducción de la respuesta de LTCD8+ específicos de péptidos derivados de la proteí-na de Gag. El desarrollo de estas estrategias requiere la identificación de epítopes inmunodominantes de cepas virales circulantes, su interacción con las molé-culas del HLA-I de alta frecuencia en cada población, y su efecto sobre la calidad de la respuesta de los LTCD8+. Una de las principales dificultades para el desarrollo de estas estrategias es el fenómeno de escape inmunológi-co, donde un cambio en un aminoácido dentro de un epítope puede afectar la unión del péptido a la molé-cula del HLA-I, el reconocimiento por el TCR y la gene-ración de una respuesta efectiva por parte del LTCD8+. En un estudio previo, en una cohorte de pacientes infectados con VIH-1 de la ciudad de Medellín, se evidenció la adaptación de cepas circulantes del VIH-1 a las moléculas HLA-I más prevalentes de la población (HLA-A*02 y HLA-B*35), a través de la identificación de mutaciones bajo selección positiva localizadas en epítopes derivados de la proteína Gag (GC9, SL9 y HY9, HA9, respectivamente); además, a través de una predicción in silico se evaluó si las mutaciones encontradas tenían una mayor o una menor afinidad al HLA-I. Si bien esta estrategia permitió predecir la interacción entre péptidos mutados y HLA-I, se desco-noce cuál es la respuesta funcional de los LTCD8+ que pueden inducir estos péptidos.