Evaluation of the equity of access to early detection and timely treatment of cancer de cérvix according to social class, in networks of health care effects of argentine provinces

El cáncer de cuello (CaCU) tiene relevancia sanitaria por su morbimortalidad e impacto económico. En Argentina la tasa de mortalidad bruta es de 8/100.000 habitantes. Ocupa el tercer lugar en incidencia y el cuarto de la mortalidad siguiendo al de mama, colon y pulmón, lo que demuestra su relevancia como problema de salud pública. Los esfuerzos actuales por desarrollar conocimientos y prevención del HPV, no parecen ir acompañados de un interés equivalente en investigar acerca de la influencia de factores sociales y sus posibles soluciones. La interacción entre pacientes e instituciones hospitalarias como determinante del acceso a una detección precoz y tratamiento oportuno resulta clave en ese sentido. Este análisis facilitaría disminuir el daño y mejorar los indicadores que se muestran estables en las últimas décadas

Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers

HIV-1(+) individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+) T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+) individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+) patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory

Elite Suppressors Harbor Low Levels of Integrated HIV DNA and High Levels of 2-LTR Circular HIV DNA Compared to HIV+ Patients On and Off HAART

Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population

Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size

Cytomegalovirus (CMV) infection is one of the most common persistent viral infections in humans worldwide and is epidemiologically associated with many adverse health consequences during aging. Previous studies yielded conflicting results regarding whether large, CMV-specific T-cell expansions maintain their function during human aging. In the current study, we examined the in vitro CMV-pp65-reactive T-cell response by comprehensively studying five effector functions (i.e., interleukin-2, tumor necrosis factor-α, interferon-γ, perforin, and CD107a expression) in 76 seropositive individuals aged 70 years or older. Two data-driven, polyfunctionality panels (IL-2-associated and cytotoxicity-associated) derived from effector function co-expression patterns were used to analyze the results. We found that, CMV-pp65-reactive CD8 + and CD4 + T cells contained similar polyfunctional subsets, and the level of polyfunctionality was related to the size of antigen-specific response. In both CD8 + and CD4 + cells, polyfunctional cells with high cytotoxic potential accounted for a larger proportion of the total response as the total response size increased. Notably, a higher serum CMV-IgG level was positively associated with a larger T-cell response size and a higher level of cytotoxic polyfunctionality. These findings indicate that CMV-pp65-specific CD4 + and CD8 + T cell undergo simultaneous cytotoxic polyfunctionality maturation during aging

Informe del estado ambiental del Río Negro

Fil: Migueles, Nathalia. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Abrameto, Mariza A. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Macchi, Pablo A. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Solimano, Patricio J. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Arias, Andrés. Universidad Nacional del Sur. Buenos Aires, Argentina.Fil: Guardiola Rivas, Fredy J. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Soricetti, Mariano. Universidad Nacional de Río Negro. Río Negro, Argentina.Fil: Morawicki, Santiago N. Universidad Nacional de Río Negro. Río Negro, Argentina.En el marco del compromiso que la Universidad Nacional de Río Negro asumió des-de sus inicios para con el territorio y la sociedad en la que está inserta, me resul-ta grato presentar, los resultados del proyecto “Estado Ambiental del río Negro”. Es un documento de primordial importancia por su dimensión académica pero, fundamentalmente, porque sus resultados y las eventuales acciones a tomar a partir de dichos resultados, tendrán impacto en la vida de todos los rionegrinos. Sus alcances son inéditos en el estudio de nuestro río, es el primer estudio inte-gral realizado en simultáneo en distintos puntos georreferenciados abarcando toda la cuenca en dos oportunidades, evaluando química de agua (agua y material particulado en solución), peces y macroinvertebrados como indicadores ambien-tales. Constituye, por lo tanto, el primer paso para conocer el estado ambiental del río y poder evaluar a futuro la evolución de los indicadores ambientales más relevantes. No es posible tomar buenas decisiones ni ejercer buenas políticas am-bientales sobre lo que no se conoce. Este proyecto propone iniciar el camino para alcanzar ese conocimiento.En cuanto a su dimensión académica, “Estado Ambiental del río Negro”, es un proyecto liderado por miembros de la comunidad universitaria, integrado por 11 docentes investigadores y 19 estudiantes avanzados de la Universidad Nacional de Río Negro, 2 investigadores de la Universidad Nacional del Sur y 1 investiga-dor de la Universidad Nacional del Comahue. Fue realizado con la colaboración de otras universidades -como la Universidad Nacional del Sur a través del Depar-tamento de Química en el IADO, CCT-CONICET, Bahía Blanca, el Centro Científico Tecnológico (CENPAT)-, y otros organismos como Prefectura Naval Argentina, Mi-nisterio de Agricultura, Ganadería y Pesca a través de la Subsecretaría de Pesca y la Secretaría de Ambiente y Desarrollo Sustentable de la provincia de Río Negro.Es importante destacar que el proyecto fue coordinado por la Jefa del Departa-mento de Consultoría e Ingeniería dependiente de la Secretaría de Investigación, Creación Artística, Desarrollo y Transferencia de Tecnología de la Universidad Na-cional de Río Negro, Lic. Nathalia Migueles; y los subproyectos dirigidos por la Dra. Mariza Abrameto, el Dr. Patricio Solimano y el Dr. Pablo Macchi.Fue un intenso trabajo de dos años, que incluyó desde la selección de los sitios de muestreo más representativos de la cuenca, sobre los ríos Limay, Neuquén y Negro, hasta la toma de muestras, su conservación, su traslado, y el análisis de las mismas en los distintos laboratorios de la Universidad Nacional de Río Negro, CENPAT y la Univer sidad Nacional del Sur, donde fueron procesadas, de acuerdo con protocolos estan darizados (EPA 3540C y IOC Nº 20, UNEP, 1992). Los aná-lisis se hicieron por cromato grafía gaseosa capilar y espectrometría de masas (GC Hewlett-Packard 68906C/MS Hewlett-Packard 5972, adheridos al Sistema Nacional de Espectrometría de Masas, https://www.argentina.gob.ar/ciencia/sistemasnacionales/espectometria-de-masas).Se relevaron 21 sitios en la cuenca, 2 sobre el río Limay, 2 sobre el río Neuquén y 17 sobre el río Negro. Las campañas se realizaron durante el año 2018 en dos etapas, una de invierno y otra de primavera/verano.Para el análisis integral de los resultados, se realizaron cuatro encuentros, de los que participaron la totalidad de los miembros del grupo de trabajo, y en los cuales se evaluaron los datos relacionados a la química del agua (hidrocarburos poliaromáticos, bacteriológicos, microbiológicos, metales pesados y organoclo-rados), macroinvertebrados y peces como indicadores ambientales.El estudio describe el sistema hidrográfico de los ríos Limay, Neuquén y Negro, relacionado a la distribución de la población y la infraestructura de saneamiento cloacal y pluvial.El presente documento es de carácter exhaustivo, elaborado con el mayor ri-gor científico. El valor del mismo constituye un soporte importante para apoyar los esfuerzos de múltiples actores con intereses y responsabilidades en la cuenca hidrográfica del río Negro, desde la formulación de planes de manejo y la toma de decisiones para emprender programas o proyectos, hasta la consulta con fines didácticos, informativos y/o científicos.Es nuestra intención avanzar en la formulación de un proyecto de monitoreo del río, que dé continuidad al trabajo iniciado, a partir del segundo semestre de 2019. Es este un gran reto para la UNRN, que requiere contar con el apoyo y el compromiso de los actores involucrados en el desarrollo de la cuenca, tanto en aspectos sociales y económicos como ambientales. Es este compromiso el que permitirá garantizar el éxito del proyecto.Este estudio no se podría haber realizado sin la colaboración de la Subsecre-taría de Ambiente y Desarrollo Sustentable Ing. Dina MIGANI, al Subsecretario de Pesca de la Provincia de Río Negro, Lic. Jorge BRIDI, quienes colaboraron con la logística necesaria para la toma de muestras, y a los técnicos del área, Lic. Cecilia HERNÁNDEZ y Julio DE FLORIAN, a la Prefectura Naval Argentina, y al resto de los profesionales y estudiantes de la UNRN que participaron de las campañas y del trabajo de laboratorio.Esta presentación es una invitación a todos ellos a sumarse al trabajo de los profesionales de esta universidad y formar parte del equipo estratégico para mo-nitorear los aspectos ambientales más relevantes.Son muchas las tareas necesarias para alcanzar estos objetivos. Cada una de ellas dará respuestas concretas acerca de los cambios de los indicadores evalua-dos en este proyecto y de los que se acuerden en un futuro entre los integrantes que cuenten con la formación académica y profesional adecuada para discutirlos e implementarlos.Las acciones integrales que promuevan la gestión estratégica del recurso hí-drico, son parte de la solución al desarrollo sustentable de nuestro territorio. Es este el inicio de un camino en pos del bienestar social, económico y cultural de nuestra región

Immunodominance of HIV-1 Specific CD8+ T-Cell Responses Is Related to Disease Progression Rate in Vertically Infected Adolescents

BACKGROUND: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. CONCLUSIONS/SIGNIFICANCE: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions

Early and Prolonged Antiretroviral Therapy Is Associated with an HIV-1-Specific T-Cell Profile Comparable to That of Long-Term Non-Progressors

Background: Intervention with antiretroviral treatment (ART) and control of viral replication at the time of HIV-1 seroconversion may curtail cumulative immunological damage. We have therefore hypothesized that ART maintenance over a very prolonged period in HIV-1 seroconverters could induce an immuno-virological status similar to that of HIV-1 long-term non-progressors (LTNPs).Methodology/Principal Findings: We have investigated a cohort of 20 HIV-1 seroconverters on long-term ART (LTTS) and compared it to one of 15 LTNPs. Residual viral replication and reservoirs in peripheral blood, as measured by cell-associated HIV-1 RNA and DNA, respectively, were demonstrated to be similarly low in both cohorts. These two virologically matched cohorts were then comprehensively analysed by polychromatic flow cytometry for HIV-1-specific CD4(+) and CD8(+) T-cell functional profile in terms of cytokine production and cytotoxic capacity using IFN-gamma, IL-2, TNF-alpha production and perforin expression, respectively. Comparable levels of highly polyfunctional HIV-1-specific CD4(+) and CD8(+) T-cells were found in LTTS and LTNPs, with low perforin expression on HIV-1-specific CD8+ T-cells, consistent with a polyfunctional/non-cytotoxic profile in a context of low viral burden.Conclusions: Our results indicate that prolonged ART initiated at the time of HIV-1 seroconversion is associated with immuno-virological features which resemble those of LTNPs, strengthening the recent emphasis on the positive impact of early treatment initiation and paving the way for further interventions to promote virological control after treatment interruption

Timing of immune escape linked to success or failure of vaccination

Successful vaccination against HIV should limit viral replication sufficiently to prevent the emergence of viral immune escape mutations. Broadly directed immunity is likely to be required to limit opportunities for immune escape variants to flourish. We studied the emergence of an SIV Gag cytotoxic T cell immune escape variant in pigtail macaques expressing the Mane-A*10 MHC I allele using a quantitative RT-PCR to measure viral loads of escape and wild type variants. Animals receiving whole Gag expressing vaccines completely controlled an SIVmac251 challenge, had broader CTL responses and exhibited minimal CTL escape. In contrast, animals vaccinated with only a single CTL epitope and challenged with the same SIVmac251 stock had high levels of viral replication and rapid CTL escape. Unvaccinated na&iuml;ve animals exhibited a slower emergence of immune escape variants. Thus narrowly directed vaccination against a single epitope resulted in rapid immune escape and viral levels equivalent to that of na&iuml;ve unvaccinated animals. These results emphasize the importance of inducing broadly directed HIV-specific immunity that effectively quashes early viral replication and limits the generation of immune escape variants. This has important implications for the selection of HIV vaccines for expanded human trials.<br /

Broad and Gag-Biased HIV-1 Epitope Repertoires Are Associated with Lower Viral Loads

Background: HLA class-I alleles differ in their ability to control HIV replication through cell-mediated immune responses. No consistent associations have been found between the breadth of Cytotoxic T Lymphocytes (CTL) responses and the control of HIV-1, and it is unknown whether the size or distribution of the viral proteome-wide epitope repertoire, i.e., the intrinsic ability to present fewer, more or specific viral epitopes, could affect clinical markers of disease progression. Methodology/Principal Findings: We used an epitope prediction model to identify all epitope motifs in a set of 302 HIV-1 full-length proteomes according to each individual's HLA (Human Leukocyte Antigen) genotype. The epitope repertoire, i.e., the number of predicted epitopes per HIV-1 proteome, varied considerably between HLA alleles and thus among individual proteomes. In a subgroup of 270 chronically infected individuals, we found that lower viral loads and higher CD4 counts were associated with a larger predicted epitope repertoire. Additionally, in Gag and Rev only, more epitopes were restricted by alleles associated with low viral loads than by alleles associated with higher viral loads. Conclusions/Significance: This comprehensive analysis puts forth the epitope repertoire as a mechanistic component of the multi-faceted HIV-specific CTL response. The favorable impact on markers of disease status of the propensity to present more HLA binding peptides and specific proteins gives impetus to vaccine design strategies that seek to elicit responses to a broad array of HIV-1 epitopes, and suggest a particular focus on Gag