Combination antiretroviral therapy -associated lipodystrophy : insights into pathogenesis and treatment

Introduction: Combination antiretroviral therapy (cART) has decreased morbidity and mortality of individuals infected with human immunodeficiency virus type 1 (HIV-1). Its use, however, is associated with adverse effects which increase the patients risk of conditions such as diabetes and coronary heart disease. Perhaps the most stigmatizing side effect is lipodystrophy, i.e., the loss of subcutaneous adipose tissue (SAT) in the face, limbs and trunk while fat accumulates intra-abdominally and dorsocervically. The pathogenesis of cART-associated lipodystrophy is obscure. Nucleoside reverse transcriptase inhibitors (NRTI) have been implicated to cause lipoatrophy via mitochondrial toxicity. There is no known effective treatment for cART-associated lipodystrophy during unchanged antiretroviral regimen in humans, but in vitro data have shown uridine to abrogate NRTI-induced toxicity in adipocytes. Aims: To investigate whether i) cART or lipodystrophy associated with its use affect arterial stiffness; ii) lipoatrophic SAT is inflamed compared to non-lipoatrophic SAT; iii) abdominal SAT from patients with compared to those without cART-associated lipoatrophy differs with respect to mitochondrial DNA (mtDNA) content, adipose tissue inflammation and gene expression, and if NRTIs stavudine and zidovudine are associated with different degree of changes; iv) lipoatrophic abdominal SAT differs from preserved dorsocervical SAT with respect to mtDNA content, adipose tissue inflammation and gene expression in patients with cART-associated lipodystrophy and v) whether uridine can revert lipoatrophy and the associated metabolic disturbances in patients on stavudine or zidovudine based cART. Subjects and methods: 64 cART-treated patients with (n=45) and without lipodystrophy/-atrophy (n=19) were compared cross-sectionally. A marker of arterial stiffness, heart rate corrected augmentation index (AgIHR), was measured by pulse wave analysis. Body composition was measured by magnetic resonance imaging and dual-energy X-ray absorptiometry, and liver fat content by proton magnetic resonance spectroscopy. Gene expression and mtDNA content in SAT were assessed by real-time polymerase chain reaction and microarray. Adipose tissue composition and inflammation were assessed by histology and immunohistochemistry. Dorsocervical and abdominal SAT were studied. The efficacy and safety of uridine for the treatment of cART-associated lipoatrophy were evaluated in a randomized, double-blind, placebo-controlled 3-month trial in 20 lipoatrophic cART-treated patients. Results: Duration of antiretroviral treatment and cumulative exposure to NRTIs and protease inhibitors, but not the presence of cART-associated lipodystrophy, predicted AgIHR independent of age and blood pressure. Gene expression of inflammatory markers was increased in SAT of lipodystrophic as compared to non-lipodystrophic patients. Expression of genes involved in adipogenesis, triglyceride synthesis and glucose disposal was lower and of those involved in mitochondrial biogenesis, apoptosis and oxidative stress higher in SAT of patients with than without cART-associated lipoatrophy. Most changes were more pronounced in stavudine-treated than in zidovudine-treated individuals. Lipoatrophic SAT had lower mtDNA than SAT of non-lipoatrophic patients. Expression of inflammatory genes was lower in dorsocervical than in abdominal SAT. Neither depot had characteristics of brown adipose tissue. Despite being spared from lipoatrophy, dorsocervical SAT of lipodystrophic patients had lower mtDNA than the phenotypically similar corresponding depot of non-lipodystrophic patients. The greatest difference in gene expression between dorsocervical and abdominal SAT, irrespective of lipodystrophy status, was in expression of homeobox genes that regulate transcription and regionalization of organs during embryonal development. Uridine increased limb fat and its proportion of total fat, but had no effect on liver fat content and markers of insulin resistance. Conclusions: Long-term cART is associated with increased arterial stiffness and, thus, with higher cardiovascular risk. Lipoatrophic abdominal SAT is characterized by inflammation, apoptosis and mtDNA depletion. As mtDNA is depleted even in non-lipoatrophic dorsocervical SAT, lipoatrophy is unlikely to be caused directly by mtDNA depletion. Preserved dorsocervical SAT of patients with cART-associated lipodystrophy is less inflamed than their lipoatrophic abdominal SAT, and does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal SAT is in expression of transcriptional regulators, homeobox genes, which might explain the differential susceptibility of these adipose tissue depots to cART-induced toxicity. Uridine is able to increase peripheral SAT in lipoatrophic patients during unchanged cART.

A Amazonia : as provincias do Pará e Amazonas e o governo central do Brazil

O Barão de Marajó relata a situação da Amazônia (Pará e Amazonas) em relação ao governo central.

Estudio de "gar" como marcador del discurso: "Pro corona" de Demóstenes

[ES] En este trabajo se estudia gár como marcador del discurso en un corpus del griego ático, el discurso Pro corona de Demóstenes. Gár introduce secciones informativas tanto en el nivel local como en el global. En el primero añade información complementaria, mientras que en el segundo indica la introducción de un nuevo tema como desarrollo de una información preliminar. La función común de gár en los dos casos es marcar la información que introduce como suplementaria.

Diálogos para el estudio de América Latina en el siglo XXI

El Grupo de Estudios sobre América Latina y el Caribe (GEALC) / Latinoamerika eta Kariberi buruzko Ikerketa Taldea (LAKIT) comenzó su andadura en 2012 con diversos objetivos, entre ellos el destinado a impulsar en el País Vasco los intercambios académicos sobre dicha región del mundo; facilitar un espacio de reflexión con actividades como seminarios, congresos, publicaciones, etc.; establecer lazos con grupos similares y centros de estudio de otros lugares y participar en redes cuya función es seguir los acontecimientos habidos en Latinoamérica. El GEALC / LAKIT está adscrito al Departamento de Derecho Internacional Público, Relaciones Internacionales e Historia del Derecho de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU). En el año 2013 convocamos las I Jornadas del GEALC/LAKIT, cuyos resultados fueron recogidos en el libro digital América Latina en la turbulencia global: oportunidades, amenazas y desafíos1. Abrimos el presente libro con las versiones escritas de las dos conferencias. La primera, dictada por la profesora Ángeles Diez Rodríguez, titulada: “Las aportaciones de los procesos revolucionarios latinoamericanos a la teoría política. Venezuela, Ecuador y Bolivia”. Diez es profesora en la Universidad Complutense de Madrid, Doctora en Ciencias Políticas y Sociología, centrándose algunas de sus investigaciones en América Latina. Su trabajo parte de la pregunta siguiente: “¿Los procesos transformadores que están viviendo algunos países latinoamericanos constituyen meras reformas del sistema político representativo o están en la vía de ser rupturas democráticas, es decir, revolucionarias?”. Para conocer sus conclusiones invitamos a la lectura de la aportación de esta académica que, además, se reclama comprometida con “la liberación de los pueblos”. Y la segunda conferencia fue expuesta por el profesor Luismi Uharte Pozas, Licenciado en Sociología por la Universidad Pública de Navarra, Máster en Historia de América Contemporánea por la Universidad Central de Venezuela, Doctor en Estudios Latinoamericanos por la Universidad Complutense de Madrid y actualmente docente en el Departamento de Antropología Social de la UPV/EHU. Su tema fue: “Venezuela: Gobernu Bolibartarraren 15 urte. Balantzea eta erronkak”. Su exposición trató sobre los quince años de Gobiernos Bolivarianos en Venezuela, un tema tan actual como controvertido tanto en medios académicos como políticos, efectuando un balance de ese periodo, la situación hoy día y las perspectivas inmediatas y de futuro. El grueso de los trabajos de Uharte son sobre temáticas que tienen que ver con América Latina, región que conoce bien por sus largas estancias en Venezuela, Ecuador, Bolivia y Paraguay. En el resto del libro difundimos una treintena comunicaciones. En su mayoría se encuadran en los ejes temáticos que propusimos en la convocatoria: procesos de cooperación e integración en la región; América Latina y el Caribe en la geopolítica global; los movimientos, luchas sociales, resistencias y alternativas; ideología, esfera pública y poder; y el movimiento feminista en América Latina y el Caribe.

Coulomb blockade double-dot Aharonov-Bohm interferometer: Giant fluctuations

Electron transport through two parallel quantum dots is a kind of solid-state realization of double path interference We demonstrate that the inter-clot Coulomb correlation and quantum coherence would result in strong current fluctuations with a divergent Fano factor at zero frequency. We also provide physical interpretation for this surprising result, which displays its generic feature and allows us to recover this phenomenon in more complicated systems. (C) 2009 Elsevier B.V. All rights reserved.

El papel de la tecnología en la demostración matemática

En educación matemática el razonamiento cobra especial importancia, al mismo tiempo que su uso puede conducir a opiniones contrapuestas. Entender y dominar la demostración de un resultado matemático ayuda a su comprensión, facilita su empleo en el estudio de otras proposiciones y contribuye a la consolidación de un lenguaje matemático. Pero ¿puede sacarse partido a una demostración si se desconoce qué es, qué papel juega, y dónde reside su fuerza? ¿Deben frenarse los intentos de los alumnos de justificar a su modo los resultados matemáticos, ó modelarlos y sacarles mejor rendimiento? ¿No es mejor una aproximación medianamente fundada pero entendida, que aseveraciones bien formalizadas pero sin significado? Si además se considera la aportación que las nuevas tecnologías realizan a la enseñanza, es necesario una reflexión acerca de cómo se ve afectada, si es que se altera, la forma de validar el conocimiento matemático en el aula, además de establecer cuál es el rigor y la formalidad de las justificaciones que se desarrollan con estos instrumentos. En este reporte, se realiza un acercamiento teórico a diferentes modos de justificar las proposiciones matemáticas en el aula, y al papel que desempeña la tecnología en esta tarea. También se describe una experimentación llevada a cabo con profesores de matemáticas en formación en la que se analizaron las concepciones que tenían acerca del valor educativo que posee la calculadora TI-92 para, de algún modo, validar dichas proposiciones.

Situaciones didácticas en la comprensión del concepto de número racional en alumnos de nivel medio superior

Esta investigación se realizó con alumnos de Nivel Medio Superior (NMS) que habían cursado la asignatura de Matemáticas I y que tenían dificultades con la comprensión del concepto de número racional. El propósito fue poner en escena situaciones didácticas, para explorar sus efectos en la comprensión de este concepto. Para tener información precisa de cuál es el estado que guardaba este conocimiento en los alumnos, se hizo un diagnóstico, por lo que se diseñaron y validaron las situaciones que se utilizarían tanto en el diagnóstico como en la puesta en escena. En su diseño se consideraron los contenidos de aritmética de NMS, diferentes sistemas de representación y el modelo utilizado por Sierpinska sobre los actos de comprensión de conceptos matemáticos. Al comparar los resultados que se obtuvieron en el diagnóstico con los de la puesta en escena de las situaciones didácticas, se encontró que: el permitir que los alumnos conocieran diferentes formas de representar a los números racionales, el significado de cada una de ellas, así como convertir o traducir unas representaciones en otras a través de las situaciones didácticas, propició la construcción de este concepto y mejoraran su comprensión.

Literatura y acto: Aquiles, el regreso a la batalla

Greek literature was used from early times with educational purposes, Greek heroes presented were considered as paradigms to follow. However, human acts burst beyond reason and the stories told have little effect on the decisions of the receptor. The aim of this article is to review the character of Achilles in the Iliad, because for him to no avail gifts, friends, much less a narration by his preceptor Phoenix to depose his anger and return to the battlefield to assist his friends.

Desarraigo y experiencia: Lecturas sobre Paul Ricouer y Philipe Claudel

We often wonder what is the role or the role that intellectuals, academics and artists can play in countries and conflict environments, for this specific case, countries and environments that do not have real protection both its integrity and satisfaction their basic and special needs. Beyond establishing what mode as artists, intellectuals and academics can contribute to meeting these requirements, this article is intended to establish a position on the importance acquired symbolic forms and reflected in the writers regardless whether philosophers or writers, let put the rawness of what happens and there comes the lonely spirits whose loneliness imposed and caused never chosen, appears to them as a lifestyle. For Philippe Claudel and the case of Paul Ricoeur, they are thus chosen for this article as incessant dialogues of the ways in which the rootlessness provides food for thought especially for those we see as different titles you are assigned to experiences of violence.

El idiotismo de la sociedad tradicionalista tecnificada de principios de siglo XX en Colombia: La crítica de Luis Vidales a través de "Suenan timbres"

En este artículo tratamos, por medio de Suenan timbres de Luis Vidales, el idiotismo de la sociedad tradicionalista tecnificada de principios de siglo XX en Colombia. Estudio que realizamos desde el concepto de idiotismo de Vidales, en estrecha relación con el de cultura de viñeta de Rafael Gutiérrez Girardot, para plantear la burla del poeta a la sociedad capitalista, que cuestiona la presencia de la Iglesia católica y la política conservadora en todos los estadios de la vida nacional.

Averroes y las cosas justas por naturaleza

En su comentario a la Ética a Nicómaco, Averroes se ocupó del pasaje donde Aristóteles distingue entre las cosas que son justas por naturaleza y aquéllas que lo son en virtud de la ley (V, 7 1134b18-1135a5). Su comentario es particularmente breve, pero plantea algunas dificultades importantes, como su alusión a un derecho naturale legale, que, según Leo Strauss, vendría a ser simplemente un derecho positivo de aceptación general. En este artículo se busca caracterizar lo justo natural y lo justo positivo en el comentario de Averroes y mostrar el alcance de la variación de los criterios propios de la justicia positiva.

Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study

A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE e4 dosage.

The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS)

Genetics plays a crucial role in human aging with up to 30% of those living to the mid-80s being determined by genetic variation. Survival to older ages likely entails an even greater genetic contribution. There is increasing evidence that genes implicated in age-related diseases, such as cancer and neuronal disease, play a role in affecting human life span. We have selected the 10 most promising late-onset Alzheimer's disease (LOAD) susceptibility genes identified through several recent large genome-wide association studies (GWAS). These 10 LOAD genes (APOE, CLU, PICALM, CR1, BIN1, ABCA7, MS4A6A, CD33, CD2AP, and EPHA1) have been tested for association with human aging in our dataset (1385 samples with documented age at death [AAD], age range: 58-108 years; mean age at death: 80.2) using the most significant single nucleotide polymorphisms (SNPs) found in the previous studies. Apart from the APOE locus (rs2075650) which showed compelling evidence of association with risk on human life span (p = 5.27 × 10(-4)), none of the other LOAD gene loci demonstrated significant evidence of association. In addition to examining the known LOAD genes, we carried out analyses using age at death as a quantitative trait. No genome-wide significant SNPs were discovered. Increasing sample size and statistical power will be imperative to detect genuine aging-associated variants in the future. In this report, we also discuss issues relating to the analysis of genome-wide association studies data from different centers and the bioinformatic approach required to distinguish spurious genome-wide significant signals from real SNP associations.

Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus

Nicastrin (NCSTN) is a component of the ?-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued ?-secretase activity and amyloid beta (Aß) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.