Experimental study of cerebrospinal fluid tumor necrosis factor-alpha release in penicillin- and cephalosporin-resistant pneumococcal meningitis treated with different antibiotic schedules

Background/Purpose: To measure the inflammatory response in terms of tumor necrosis factor-alpha (TNF-α) levels in cerebrospinal fluid (CSF), using bacteriolytic versus nonbacteriolytic antibiotic therapy and adjunctive treatment with dexamethasone in an experimental rabbit model of pneumococcal meningitis. Methods: In a rabbit model of pneumococcal meningitis, we tested CSF TNF-α levels in several samples from rabbits infected with the HUB 2349 strain and treated with ceftriaxone 100 mg/kg/d, ceftriaxone plus vancomycin 30 mg/kg/d, or daptomycin at 15 mg/kg or 25 mg/kg. Daptomycin schedules were compared with the same doses in combination with dexamethasone at 0.125 mg/kg every 12 hours over a 26-hour period. Results: The ceftriaxone group had the highest levels of TNF-α. TNF-α levels were significantly higher after ceftriaxone administration than in both daptomycin groups. The high-dose daptomycin group presented the lowest inflammatory levels in CSF samples. Adjunctive treatment with dexamethasone in this group modulated the inflammatory response, bringing down CSF TNF-α levels. Conclusion: CSF TNF-α levels were significantly lower in rabbits treated with daptomycin than in rabbits treated with ceftriaxone. Daptomycin avoided the inflammatory peak after administration observed in ceftriaxone-treated rabbits. The use of daptomycin plus dexamethasone achieved a significantly larger reduction in CSF TNF-α levels

Estructura de Financiamiento y su impacto en la Rentabilidad en las Asociaciones Cooperativas de Responsabilidad Limitada del departamento de Sonsonate.

Las asociaciones cooperativas del sector agrícola año tras año buscan la manera más adecuada de estructurar su capital esto con el objetivo de cumplir sus proyectos y mitigar el riesgo de caer en impago, además de buscar la maximización del valor de las aportaciones; sin embargo la actividad agrícola se encuentra en una situación crítica por factores que han dañado directamente sus finanzas, el utilizar herramientas estratégicas les permitirá organizar y analizar la situación económica para tomar decisiones acordes a sus necesidades y a sus objetivos. El utilizar un método de financiamiento surge en la medida que las actividades se desarrollen con normalidad, por lo que se debe tener el capital de trabajo adecuado para cubrir las obligaciones presentes y futuras con proveedores y otras obligaciones con terceros y así al final poder recuperar la inversión con los ingresos. La presente investigación nace por la necesidad de que muchas asociaciones no utilizan o no conocen los beneficios de implementar herramientas financieras que les permita obtener un mejor panorama de la estructura de financiamiento que maximice su rentabilidad. Los objetivos del presente documento es desarrollar un análisis financiero que permita determinar la estructura de financiamiento que genere una mejor rentabilidad a las cooperativas agrícolas, identificar y analizar las fuentes de financiamiento y elaborar un diagnóstico financiero con información histórica en un caso práctico aplicado a la asociación cooperativa XYZ, de R.L. ii El tipo de estudio de este trabajo es de carácter “analítico – descriptivo" e “hipotético-deductivo”; ya que, mediante el análisis interno en las operaciones históricas de las asociaciones, se determinaron los problemas que no utilizan y desconocen los beneficios de una herramienta estratégica para estructurar su financiamiento y la no aplicación eficiente de los recursos que se tienen; es por ello que se propone el utilizar un análisis financiero que ayude a la toma de decisiones en la selección de las fuentes de financiamiento y centrarse en los cultivos que mayor rentabilidad generan como la siembra de una mayor cantidad de manzanas de maíz de semilla y reducir la siembra de caña de azúcar. En conclusión, se determinó que la falta de un análisis financiero al momento de adquirir financiamientos ya sea para operar o proponer nuevos proyectos de inversión impacta en la toma de decisiones y por lo tanto la rentabilidad

The Chemistry of the Trailing arm of the Sagittarius Dwarf Galaxy

We present abundances of C, O, Ti, and Fe for eleven M-giant stars in the trailing tidal arm of the Sagittarius dwarf (Sgr). The abundances were derived by comparing synthetic spectra with high-resolution infrared spectra obtained with the Phoenix spectrograph on the Gemini South telescope. The targeted stars are drawn from two regions of the Sgr trailing arm separated by 66 degrees (5 stars) and 132 degrees (6 stars) from the main body of Sgr. The trailing arm provides a more direct diagnostic of the chemical evolution of Sgr compared to the extensively phase-mixed leading arm. Within our restricted sample of ~2-3 Gyr old stars, we find that the stream material exhibits a significant metallicity gradient of -(2.4\pm0.3)x10^{-3} dex / degree (-(9.4\pm1.1)x10^{-4} dex / kpc) away from the main body of Sgr. The tidal disruption of Sgr is a relatively recently event. We therefore interpret the presence of a metallicity gradient in the debris as indicative of a similar gradient in the progenitor. The fact that such a metallicity gradient survived for almost a Hubble time indicates that the efficiency of radial mixing was very low in the Sgr progenitor. No significant gradient is seen to exist in the [alpha/Fe] abundance ratio along the trailing arm. Our results may be accounted for by a radial decrease in star formation efficiency and/or radial increase in the efficiency of galactic wind-driven metal loss in the chemical evolution of the Sgr progenitor. The [Ti/Fe] and [O/Fe] abundance ratios observed within the stream are distinct from those of the Galactic halo. We conclude that the fraction of the intermediate to metal-rich halo population contributed by the recent dissolution (<3 Gyr) of Sgr-like dwarf galaxies can not be substantial.Comment: 22 pages, 7 figures, ApJ accepte

Otolith microchemistry reveals contrasting intra-stock structuring in two demersal species off the Iberian Peninsula

Trabajo presentado en el 7th International Otolith Symposium, celebrado en Viña del Mar (Chile), entre el 9 y el 13 de octubre de 2023.Peer reviewe

The importance of regional differences in vulnerability to climate change for demersal fisheries

Regional differences in climate vulnerability are particularly important in many countries with socio-ecological gradients or geographical and environmental spatial segregation. Many studies are regularly performed at the national level, but regional assessments can provide more detailed information and important insights into intra-national vulnerabilities. They require detailed information of many socio-ecological components that are often neglected at the regional scale but are meaningful and operational at national and international levels. In this work, we developed a climate vulnerability assessment (CVA) to investigate the vulnerability of demersal fisheries based on 19 indicators covering exposure, fisheries sensitivity, species sensitivity (SS) and adaptive capacity (AC) for nine coastal regions of Spain, contrasting the Mediterranean to Atlantic areas. Exposure was consistently larger in the Mediterranean than Atlantic regions, while AC showed the opposite trend. While fisheries and SS did not display a clear Atlantic-Mediterranean pattern, they were critical for capturing regional differences that have an impact on fisheries vulnerability. Our results highlight the generally higher vulnerability of Mediterranean demersal fisheries, mainly due to the lower AC and higher exposure of Mediterranean regions, while providing key regional elements for guiding national and international actions for adaptation. This study demonstrates that the spatial scale considered in the development of CVAs must recognise the spatial heterogeneity in the socio-ecological system within its unit of analysis in order to be a relevant tool for management and policy makers.Preprint2,27

Toward an internally consistent astronomical distance scale

Accurate astronomical distance determination is crucial for all fields in astrophysics, from Galactic to cosmological scales. Despite, or perhaps because of, significant efforts to determine accurate distances, using a wide range of methods, tracers, and techniques, an internally consistent astronomical distance framework has not yet been established. We review current efforts to homogenize the Local Group's distance framework, with particular emphasis on the potential of RR Lyrae stars as distance indicators, and attempt to extend this in an internally consistent manner to cosmological distances. Calibration based on Type Ia supernovae and distance determinations based on gravitational lensing represent particularly promising approaches. We provide a positive outlook to improvements to the status quo expected from future surveys, missions, and facilities. Astronomical distance determination has clearly reached maturity and near-consistency.Comment: Review article, 59 pages (4 figures); Space Science Reviews, in press (chapter 8 of a special collection resulting from the May 2016 ISSI-BJ workshop on Astronomical Distance Determination in the Space Age

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

6 figures.-- Supplementary material available.Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.Work in the JP laboratory is funded by ASPANOA, CIBER (CB 2021; Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación and Union Europea.NextGenerationEU), Fundacion Inocente, Carrera de la Mujer Monzón, FEDER/Gobierno de Aragón (Group B29_17R), and Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017‐83120‐C2‐1‐R and PID2020-113963RB-I00). Predoctoral grants/contracts from Gobierno de Aragon (IU-M and JP) are supported by ARAID Foundation. EG is funded by Ministerio de Ciencia, Innovación y Universidades (MCNU), and Agencia Estatal de Investigación (PID2020-113963RB-I00). MA and LS are funded by Postdoctoral Juan de la Cierva Contract. SR, LC, SH, and IU-M are funded by predoctoral contracts from Aragon Government. PL is funded by FPU predoctoral grants from Ministerio de Ciencia, Innovación e Universidades. Work at the Catalan Institute of Oncology is funded by the entity, the Instituto de Salud Carlos III and Ministerio de Economia y Competitividad, and co-funded by FEDER funds—a way to build Europe (PI20/00767), CIBERESP (grant CB07/02/2005), H2020 grant MoTriColor, and the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. This work is supported by COST Action CA17118.Peer reviewe