71 research outputs found

    High levels of T lymphocyte activation in Leishmania-HIV-1 co-infected individuals despite low HIV viral load

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    <p>Abstract</p> <p>Background</p> <p>Concomitant infections may influence HIV progression by causing chronic activation leading to decline in T-cell function. In the Americas, visceral (AVL) and tegumentary leishmaniasis (ATL) have emerged as important opportunistic infections in HIV-AIDS patients and both of those diseases have been implicated as potentially important co-factors in disease progression. We investigated whether leishmaniasis increases lymphocyte activation in HIV-1 co-infected patients. This might contribute to impaired cellular immune function.</p> <p>Methods</p> <p>To address this issue we analyzed CD4<sup>+ </sup>T absolute counts and the proportion of CD8<sup>+ </sup>T cells expressing CD38 in <it>Leishmania</it>/HIV co-infected patients that recovered after anti-leishmanial therapy.</p> <p>Results</p> <p>We found that, despite clinical remission of leishmaniasis, AVL co-infected patients presented a more severe immunossupression as suggested by CD4<sup>+ </sup>T cell counts under 200 cells/mm<sup>3</sup>, differing from ATL/HIV-AIDS cases that tends to show higher lymphocytes levels (over 350 cells/mm<sup>3</sup>). Furthermore, five out of nine, AVL/HIV-AIDS presented low CD4<sup>+ </sup>T cell counts in spite of low or undetectable viral load. Expression of CD38 on CD8<sup>+ </sup>T lymphocytes was significantly higher in AVL or ATL/HIV-AIDS cases compared to HIV/AIDS patients without leishmaniasis or healthy subjects.</p> <p>Conclusions</p> <p><it>Leishmania </it>infection can increase the degree of immune system activation in individuals concomitantly infected with HIV. In addition, AVL/HIV-AIDS patients can present low CD4<sup>+ </sup>T cell counts and higher proportion of activated T lymphocytes even when HIV viral load is suppressed under HAART. This fact can cause a misinterpretation of these laboratorial markers in co-infected patients.</p

    Molecular Profiling Reveals Diversity of Stress Signal Transduction Cascades in Highly Penetrant Alzheimer's Disease Human Skin Fibroblasts

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    The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD) as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R) inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival pathway in normal fibroblasts lost in PS-1 M146L fibroblasts. Complex molecular profiles of signaling dysfunction in the most putatively straightforward human cellular models of AD suggest that risk ascertainment and therapeutic interventions in AD as a whole will likely demand complex solutions

    Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

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    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

    Multi-messenger observations of a binary neutron star merger

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    On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

    Prevalencia de la violencia contra la mujer entre diferentes grupos étnicos en Perú

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    Cerca de la mitad de las mujeres peruanas de entre 15 y 49 años han sufrido algún acto de violencia por parte de sus parejas. En este trabajo se explora mediante un análisis cuantitativo de qué manera las tasas de violencia contra la mujer varían por grupo étnico y en el tiempo. A partir de una muestra representativa a nivel nacional de más de 75.000 mujeres encuestadas entre 2003 y 2012 y de una revisión de la literatura sobre la clasificación étnica en Perú, se utilizó una tipología para medir la etnicidad a partir de los antecedentes lingüísticos de las mujeres. Esto permite una caracterización étnica consistente durante todo el periodo de análisis. En esta tipología, un primer grupo lo conforman mujeres que actualmente hablan una lengua indígena en el hogar y que no usan el castellano. Un segundo grupo, denominado castellano antiguo, está compuesto por mujeres para quienes el castellano fue el idioma aprendido en la niñez y el cual sigue siendo usado actualmente, mientras que el tercer grupo, llamado castellano reciente, agrupa a las mujeres que crecieron hablando una lengua indígena pero que ahora hablan castellano. Es en este último grupo donde se encuentran las tasas más altas en todos los tipos de violencia. Esta diferencia es mucho mayor en la violencia física severa y la sexual. Esto es consistente con las predicciones del modelo teórico desarrollado en el documento donde la violencia depende del tipo de emparejamiento y donde las mujeres con un outside option menor que el de sus parejas (por ejemplo, aquellas con castellano reciente) experimentan una mayor violencia. Se muestra además que la brecha en las tasas de violencia contra la mujer entre estos tres grupos se ha mantenido constante en el tiempo a pesar de la reducción global. A partir de estos hallazgos, el documento muestra que las actuales políticas para atender a las víctimas y prevenir la violencia contra la mujer serían insuficientes ya que no están necesariamente dirigidas a los grupos con mayor riesgo de violencia, como los definidos en este documento. Esto difiere de los enfoques aplicados en otras áreas de la salud pública donde las intervenciones apuntan directamente a las poblaciones más vulnerables
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