Perspectivas para nuevas vacunas antituberculosas en la era posgenómica.

Vaccination with attenuated Mycobacterium bovis BCG has been used as the routine procedure to immunize against tuberculosis. Since the efficacy of BCG vaccination is very controversial, the search for new immunoprophylatic tools against tuberculosis is an area of intense interest. Knowledge of the complete sequence of Mycobacterium tuberculosis (Mtb) H37Rv genome and the application of new immunological, biochemical and genetic technologies has led to a detailed understanding of the transcriptome and proteome of this bacterium. Approximately one-third of the human population is infected with Mtb; however, the bacillus is only detected once the symptoms appear and therefore most of the recent efforts have been devoted to the development of a post-infection vaccine. In theory, this vaccine (1) will give rise to an increase in the long-lasting specific immunity against Mtb, (2) will not have significant adverse effects, and (3) will be affordable for the people in third world countries. The main strategies that have been developed include the subunit vaccines, either as a mixture of relevant immunogenic proteins or DNA constructs, recombinant strains of Mycobacterium bovis BCG and Mtb, designed to secrete immunogenic proteins or with attenuated virulence, respectively, and DNA-based vaccines. The subunit vaccines are delivered either as mixtures of immunogenic proteins and adjuvants, or as naked DNA or by viral vectors in order to induce a potent Th1 response. Most of these vaccines have been tested in several kinds of animal models, but they do not fully reproduce the human pathology. However, the results obtained so far are very encouraging and have led to the development of phase I trials in humans.A pesar de que la vacunación con Mycobacterium bovis BCG es el procedimiento más utilizado a nivel mundial para prevenir la tuberculosis, su eficicacia es muy cuestionable, lo cual ha motivado la búsqueda de nuevas opciones inmunoprofilácticas. El conocimiento generado con el secuenciamiento completo de una cepa de Mycobacterium tuberculosis H37Rv y la aplicación de nuevas tecnologías inmunológicas, bioquímicas y genéticas han permitido realizar una disección fina del transcriptoma y el proteoma de M. tuberculosis, lo cual ha generado una gran cantidad de conocimiento sobre la biología de este microorganismo. Dado que alrededor de una tercera parte de la población mundial puede estar infectada con M. tuberculosis y que éste sólo se detecta cuando se inicia la enfermedad, la mayor parte de los esfuerzos se han dedicado al diseño de vacunas posinfección que induzcan un aumento selectivo de la inmunidad celular específica del hospedero a largo plazo, no generen reacciones adversas y sean de bajo costo. Dentro de las nuevas estrategias que están siendo utilizadas para el desarrollo de vacunas, se destaca la utilización de mezclas de proteínas con una alta inmunogenicidad, cepas de M. bovis BCG recombinantes y de M. tuberculosis genéticamente atenuadas o modificadas para inducir una mayor respuesta inmune, y las vacunas de ADN desnudo. Los candidatos con más potencial incluyen las vacunas de subunidades micobacterianas, las cuales expresan moléculas ampliamente reconocidas por el sistema inmune y cuyo reconocimiento resulta en el incremento de la respuesta Th1 y aquéllas que utilizan vectores virales diseñados para expresar moléculas micobacterianas antigénicas. Aunque los modelos animales son de valor limitado, puesto que la patología observada en ellos sólo reproduce parcialmente la observada en humanos, los resultados obtenidos con estas vacunas son muy prometedores y algunas están siendo actualmente evaluadas en ensayos clínicos de fase I

Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants

AbstractCervical cancer, mainly caused by infection with human papillomaviruses (HPVs), is a major public health problem in Mexico. During a study of the prevalence of HPV types in northeastern Mexico, we identified, as expected from worldwide comparisons, HPV-16, 18, 31, and 35 as highly prevalent. It is well known that the genomes of HPV types differ geographically because of evolution linked to ethnic groups separated in prehistoric times. As HPV intra-type variation results in pathogenic differences, we analyzed genomic sequences of Mexican variants of these four HPV types. Among 112 HPV-16 samples, 14 contained European and 98 American Indian (AA) variants. This ratio is unexpected as people of European ethnicity predominate in this part of Mexico. Among 15 HPV-18 samples, 13 contained European and 2 African variants, the latter possibly due to migration of Africans to the Caribbean coast of Mexico. We constructed phylogenetic trees of HPV-31 and 35 variants, which have never been studied. Forty-six HPV-31 isolates from Mexico, Europe, Africa, and the United States (US) contained a total of 35 nucleotide exchanges in a 428-bp segment, with maximal distances between any two variants of 16 bp (3.7%), similar to those between HPV-16 variants. The HPV-31 variants formed two branches, one apparently the European, the other one an African branch. The European branch contained 13 of 29 Mexican isolates, the African branch 16 Mexican isolates. These may represent the HPV-31 variants of American Indians, as a 55% prevalence of African variants in Mexico seems incomprehensible. Twenty-seven HPV-35 samples from Mexico, Europe, Africa, and the US contained 11 mutations in a 893-bp segment with maximal distances between any two variants of only 5 mutations (0.6%), including a characteristic 16-bp insertion/deletion. These HPV-35 variants formed several phylogenetic clusters rather than two- or three-branched trees as HPV-16, 18, and 31. An HPV-35 variant typical for American Indians was not identifiable. Our research suggests type specific patterns of evolution and spread of HPV-16, 18, 31, and 35 both before and after the worldwide migrations of the last four centuries. The high prevalence of highly carcinogenic HPV-16 AA variants, and the extensive diversity of HPV-18, 31, and 35 variants with unknown pathogenic properties raise the possibility that HPV intra-type variation contributes to the high cervical cancer burden in Mexico

Present and potential erosion at Protected Landscape “El Rebollar” (Sierra de Gata – Salamanca)

Este estudio permitirá conocer la importancia de los procesos erosivos actuales y potenciales en estudios del medio físico, en zonas protegidas, lo que ayudará a tomar decisiones más adecuadas en la ordenación del territorio, y a establecer medidas de protección, con el fin de evitar la pé.rdida de suelo. Entre los muchos métodos para estudiar la erosión, se ha elegido el método USLE (Universal Soil Loss Equation) por erosión laminar y en regueros, al no requerir un gran volumen de datos de entrada y por haber sido aplicado a numerosos estudios ofreciendo buenos resultados, sin olvidar sus limitaciones y adaptándolo a la zona. Mediante el uso del SIG se han generado cartografías para cada uno de los parámetros de la USLE, a partir de las cuales se ha obtenido la erosión potencial y actual. Los resultados muestran que los valores potenciales de pérdida de suelo son débiles en la mayor parte, coincidiendo con los dominios geomorfológicos de pedimento y colinas y lomas. Las zonas más erosionables (erosión actual) coinciden con las de mayor altitud, en laderas con escasa vegetación en la vertiente norte de la Sierra de Francia, este de Martiago y en el escarpe e incisiones fluviales; atenuándose sensiblemente en la vertiente norte de la Sierra de Gata.This study will allow knowing the importance of present and potential erosive processes that will help to make adequate decisions in protected areas, and to establish protection measures if it would be necessary in order to avoid soil losses. Among all available methods to study soil erosion, the USLE (Universal Soil Loss Equation) one was chosen, because it is not necessary a huge volume of input data and it has been applied in several studies offering good results (it is important to know its limitations and to adapt it to the study area). Cartographies for each of the parameters in USLE equation were generated with the use of G.I.S, from which was calculated potential and present erosion. Results show that potential values of soil losses are low in the most of the area, coinciding with geomorphologic domains of pediment and hills. The areas more subject to erosion (present erosion) correspond to the ones with higher altitude, in slopes with limited vegetation in the north slope of Sierra de Francia, east of Martiago and in the fall scarp and fluvial incisions; decreasing considerably in the north slope of Sierra de Gata .Depto. de Biodiversidad, Ecología y EvoluciónFac. de Ciencias BiológicasTRUEMinisterio de Ciencia e Innovación (MICINN)Junta de Castilla y Leónpu

Infiltrating CD16 +

Our aim was to characterize glomerular monocytes (Mo) infiltration and to correlate them with peripheral circulating Mo subsets and severity of lupus nephritis (LN). Methods. We evaluated 48 LN biopsy samples from a referral hospital. Recognition of Mo cells was done using microscopic view and immunohistochemistry stain with CD14 and CD16. Based on the number of cells, we classified LN samples as low degree of diffuse infiltration (<5 cells) and high degree of diffuse infiltration (≥5 cells). Immunophenotyping of peripheral Mo subsets was done using flow cytometry. Results. Mean age was 34.0±11.7 years and the mean SLEDAI was 17.5±6.9. The most common SLE manifestations were proteinuria (91%) and hypocomplementemia (75%). Severe LN was found in 70% of patients (Class III, 27%; Class IV, 43%). Severe LN patients and patients with higher grade of CD16+ infiltration had lower levels of nonclassical (CD14+CD16++) Mo in peripheral blood. Conclusions. Our results might suggest that those patients with more severe forms of LN had a higher grade of CD14+CD16+ infiltration and lower peripheral levels of nonclassical (CD14+CD16++) Mo and might reflect a recruitment process in renal tissues. However, given the small sample, our results must be interpreted carefully

MEIS1, PREP1, and PBX4 Are Differentially Expressed in Acute Lymphoblastic Leukemia: Association of MEIS1 Expression with Higher Proliferation and Chemotherapy Resistance

<p>Abstract</p> <p>Background</p> <p>The Three-amino acid-loop-extension (<it>TALE</it>) superfamily of homeodomain-containing transcription factors have been implicated in normal hematopoiesis and in leukemogenesis and are important survival, differentiation, and apoptosis pathway modulators. In this work, we determined the expression levels of <it>TALE </it>genes in leukemic-derived cell lines, in blood samples of patients with Acute lymphoblastic leukemia (ALL), and in the blood samples of healthy donors.</p> <p>Results</p> <p>Here we show increased expression of <it>MEIS1, MEIS2, </it>and <it>PREP1 </it>genes in leukemia-derived cell lines compared with blood normal cells. High levels of <it>MEIS1 </it>and <it>PREP1</it>, and low levels of <it>PBX4 </it>expression were also founded in samples of patients with ALL. Importantly, silencing of <it>MEIS1 </it>decreases the proliferation of leukemia-derived cells but increases their survival after etoposide treatment. Etoposide-induced apoptosis induces down-regulation of MEIS1 expression or <it>PREP1 </it>up-regulation in chemotherapy-resistant cells.</p> <p>Conclusions</p> <p>Our results indicate that up-regulation of <it>MEIS1 </it>is important for sustaining proliferation of leukemic cells and that down-regulation of <it>MEIS1 </it>or up-regulation of <it>PREP1 </it>and <it>PBX </it>genes could be implicated in the modulation of the cellular response to chemotherapeutic-induced apoptosis.</p

Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

¿Es razonable el abordaje laparoscópico en patología maligna colo-rectal?

Desde que se efectuó la primera resección de colon por vía laparoscópica en 1990, han sido publicados numerosos artículos, manifestándose diferentes opiniones, algunas de ellas francamente contrapuestas, en cuanto a validez o no de esta vía de abordaje quirúrgico, para el tratamiento del cáncer colo-rectal. El presente estudio de revisión pretende poner en claro cuál es la situación actual de la resección de colon por vía laparoscópica. Se analizan las ventajas e inconvenientes de dicho tratamiento, haciendo especial hincapié en situar la realidad actual de la incidencia de metástasis en el orificio de entrada de los trócares, así como, analizar las posibles causas. Se estudia la importancia de la experiencia del equipo quirúrgico y de la curva de aprendizaje para obtener los mejores resultados. Así como la necesidad de mantener las normas establecidas para una correcta resección de intestino grueso desde el punto de vista oncológico y la importancia de efectuar este tipo de cirugía dentro de ensayos clínicos controlados

IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

OBJECTIVES: Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNgamma produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis development. METHODS: A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case. Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. RESULTS: Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNgamma responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log rank p = 0.007). DISCUSSION: CFP-10-induced IFNgamma production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprophylaxis to child contacts regardless of BCG vaccination

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected