Cosmic evolution of FRI and FRII sources out to z=2.5

Radio-loud active galactic nuclei (RLAGN) play an important role in the evolution of galaxies through the effects on their environment. The two major morphological classes are core-bright (FRI) and edge-bright (FRII) sources. With the LOw-Frequency ARray (LOFAR) we compare the FRI and FRII evolution down to lower flux densities and with larger samples than before with the aim to examine the cosmic space density evolution for FRIs and FRIIs by analyzing their space density evolution between L_150~10^24.5 W/Hz and L_150~10^28.5 W/Hz and up to z=2.5. We construct radio luminosity functions (RLFs) from FRI and FRII catalogues based on recent data from LOFAR at 150MHz to study the space densities as a function of radio luminosity and redshift. To partly correct for selection biases and completeness, we simulate how sources appear at a range of redshifts. We report a space density enhancement from low to high redshift for FRI and FRII sources brighter than L_150~10^27 W/Hz. This is possibly related to the higher gas availability in the earlier denser universe. The constant FRI/FRII space density ratio evolution as a function of radio luminosity and redshift in our results suggests that the jet-disruption of FRIs might be primarily caused by events occurring on scales within the host galaxy, rather than being driven by changes in the overall large-scale environment. Remaining selection biases in our results also highlight the need to resolve more sources at angular scales below 40 arcsec and therefore strengthens the motivation for the further development and automation of the calibration and imaging pipeline of LOFAR data to produce images at sub-arcsecond resolution

Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Spain and FEDER: "Una manera de hacer Europa"

Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology

To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS).Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula.More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels.Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.Copyright © 2022 Fernández-Velasco, Monreal, Kuhle, Meca-Lallana, Meca-Lallana, Izquierdo, Oreja-Guevara, Gascón-Giménez, Sainz de la Maza, Walo-Delgado, Lapuente-Suanzes, Maceski, Rodríguez-Martín, Roldán, Villarrubia, Saiz, Blanco, Diaz-Pérez, Valero-López, Diaz-Diaz, Aladro, Brieva, Íñiguez, González-Suárez, Rodríguez de Antonio, García-Domínguez, Sabin, Llufriu, Masjuan, Costa-Frossard and Villar

Cosmic evolution of FRI and FRII sources out to <i>z</i> = 2.5

Context. Radio-loud active galactic nuclei (RLAGN) play an important role in the evolution of galaxies through the effects on their environment. The two major morphological classes are core-bright (FRI) and edge-bright (FRII) sources. With the LOw-Frequency ARray (LOFAR), we can now compare the FRI and FRII evolution down to lower flux densities and with larger samples than before. Aims. Our aim is to examine the cosmic space density evolution for FRIs and FRIIs by analyzing their space density evolution between L150 ∼ 1024.5 W Hz−1 and L150 ∼ 1028.5 W Hz−1 and up to z = 2.5. In particular, we look at the space density enhancements and compare the FRI and FRII evolution with the total RLAGN evolution. Methods. We constructed radio luminosity functions (RLFs) from FRI and FRII catalogues based on recent data from LOFAR at 150 MHz to study the space densities as a function of radio luminosity and redshift. These catalogues contain over 100 times the number of FRIs with associated redshifts greater than z = 0.3, compared to the most recent FRI/FRII RLF study. To derive the maximum distance according to which a source can be classified and to correct for detection limits, we conducted simulations of how sources appear across a range of redshifts. Results. Our RLFs do not show any sharp transitions between the space density evolution of FRI and FRII sources as a function of radio luminosity and redshift. We report a space density enhancement from low to high redshift for FRI and FRII sources brighter than L150 ∼ 1027 W Hz−1. Furthermore, while we observe a tentative decrease in the space densities of FRIs with luminosities below L150 ∼ 1026 W Hz−1 and at redshifts beyond z = 0.8, this may be due to residual selection biases. The FRI/FRII space density ratio does not appear to evolve strongly as a function of radio luminosity and redshift. Conclusions. We argue that the measured space density enhancements above L150 ∼ 1027 W Hz−1 are related to the higher gas availability in the earlier, denser universe. The constant FRI/FRII space density ratio evolution as a function of radio luminosity and redshift suggests that the jet-disruption of FRIs might be primarily caused by events occurring on scales within the host galaxy, rather than being driven by changes in the overall large-scale environment. The remaining selection biases in our results also highlight the need to resolve more sources at angular scales below 40″, thereby strengthening the motivation for further developing and automating the calibration and imaging pipeline of LOFAR data to produce images at a sub-arcsecond resolution

Estudio prospectivo, de seguimiento en pacientes con enfermedad de Gaucher Tipo 1 que reciben tratamiento con CERDELGA®. Proyecto TRAZELGA

Poster [PC-303] Introducción: La enfermedad de Gaucher tipo 1 (EG1), secundaria al déficit en la enzima glucocerebrosidasa lisosomal, provoca el acúmulo de glucocerebrósido principalmente en macrófagos, causando deterioro de los órganos en los que se deposita. El nuevo inhibidor de substrato Eliglustat (ELG), aprobado por la EMEA en 2015 y disponible desde enero 2017, inhibe de forma selectiva y potente la enzima glucosilceramida sintasa, disminuyendo el acúmulo de substrato, está indicado en EG1 metabolizadores rápidos, intermedios o lentos para el citocromo CYP2D6. Los ensayos clínicos de fase 2 y 3 demostraron mejora y estabilización de los parámetros tanto en los pacientes naïve, como en los de tratamiento enzimático sustitutivo. En este trabajo se expone el estudio de trazabilidad del tratamiento con eliglustat en pacientes con GD1 en España (TRAZELGA). Material y Métodos: El estudio nacional, multicéntrico TRAZELGA, ha sido diseñado como herramienta para evaluar de forma uniforme la respuesta al tratamiento durante un año, analizando los cambios en parámetros clínicos y biomarcadores habituales, registro de medicamentos concomitantes y efectos adversos a ELG, estudio de calidad de vida e incorporando un estudio exploratorio de marcadores de activación del sistema inmune (perfil de citoquinas, ferritina, lipocalina, gammaglobulinas, marcadores de estrés oxidativo), así como cambios en la infiltración medular cuantificados por RM y DEXA. Previo al inicio de ELG se realizó una evaluación de función cardíaca, hepática y renal. Resultados: 35 pacientes han iniciado tratamiento oral con Eliglustat. En esta presentación aportamos resultados preliminares de 21 pacientes (mediana de edad: 43, 8 años(23-75), 47% varones), genotipo de EG N370S/N370S: (29, 4%), N370S/L444P (41, 2%), otros dobles heterocigotos con N370S (29, 4%), metabolismo del CYP2D6 (12% metabolizadores lentos, 64, 5% intermedios y 33, 5% rápidos, ningún paciente recibió el tratamiento en prímera línea y sus características basales (tabla1), son de pacientes estabilizados con TES (15 casos) o miglustat (6). Un paciente esplenectomizado. 3 pacientes esplenomegalia palpable al momento de inclusión. 6 pacientes con multimorbilidades y polimedicaciones y 5 pacientes aquejaban astenia como síntoma principal antes de su inclusión en este estudio. El seguimiento medio actual es de 6 meses. Conclusiones: Se espera incluir un total de 30 pacientes en el estudio y analizar la influencia de Eliglustat sobre los biomarcadores, marcadores de inflamación, densidad mineral ósea. Tener información sobre adherencia, efectos adversos en práctica clínica habitual y grado de satisfacción. Aunque escasos, hasta ahora no hay publicada información de la respuesta al tratamiento en pacientes provenientes de tratamiento con miglustat. En caso de aceptación se presentará un análisis exhaustivo, invitando a todos los interesados a unirse al proyecto