Perfiles de expresión génica y perfiles de activación de la vía JAK-STAT asociados a la respuesta al tratamiento con IFNβ en pacientes con esclerosis múltiple.

Además, la evaluación de la vía JAK-STAT no muestra diferencias en condiciones basales en función de la respuesta al tratamiento. Sin embargo, tras la estimulación in vitro con IFNß, los monocitos de los pacientes respondedores experimentan una rápida modulación a la baja de IFNAR1 y al alza de IFNAR2 en la superficie celular. Este hecho no se reproduce en los pacientes no respondedores lo que sugiere que, en estos últimos podría tener lugar una desensibilización más acusada de la vía JAK-STAT como consecuencia del tratamiento prolongado con IFNß. El abordaje de este estudio ha permitido asociar un "fenotipo clínico de buena respuesta al tratamiento con IFNß" con un "patrón funcional de la vía de señalización" en monocitos, caracterizado por una disminución en los niveles de IFNAR1 y un aumento en los niveles de IFNAR2, pSTAT1 y pSTAT2 tras la estimulación con IFNß. En consecuencia, la ausencia de respuesta terapéutica al IFNß podría explicarse, al menos parcialmente, por una activación diferencial de la vía JAK-STAT entre los pacientes respondedores y los no respondedores. A nivel clínico, uno de los marcadores mas aceptados para monitorizar la respuesta al tratamiento es la detección de anticuerpos neutralizantes frente a IFNß, aunque existe cierta controversia sobre su uso. Debido a que estos anticuerpos bloquean la unión del IFNß a su receptor, nuestra hipótesis de partida era que la activación de la vía de señalización JAK-STAT debe verse alterada. Al evaluar la reactividad cruzada de los anticuerpos neutralizantes frente a IFNß en pacientes con EM y su implicación en la activación de vía de señalización JAK-STAT. Se constató que existe una relación directa entre la reactividad cruzada que presentan los anticuerpos neutralizantes frente a IFNß y el título de los mismos, de forma que los pacientes con títulos medios-altos tienen un riesgo 77 veces mayor de presentar reactividad cruzada que los pacientes con títulos bajos. Además, la presencia de NAbs inhibe la activación por fosforilación de STAT1 in vitro, siendo ésta inversamente proporcional al título de anticuerpos. Esta correlación negativa entre el porcentaje de células positivas para pSTAT1 y el título de NAbs se evidencia fundamentalmente en monocitos y linfocitos T CD4+. La demostración de que la activación de pSTAT1 es inversamente proporcional al título de anticuerpos, sugiere que su determinación por citometría de flujo podría ser una herramienta alternativa al bioensayo para la detección de NAbs.En la actualidad, aunque existen numerosos fármacos disponibles para el tratamiento de la esclerosis múltiple (EM), el interferón beta (IFNß) continúa siendo un tratamiento ampliamente utilizado por su excelente relación seguridad vs eficacia. Sin embargo, existe un porcentaje elevado de pacientes que no responden adecuadamente al tratamiento con este fármaco y no existe ningún biomarcador claro de respuesta al IFNß que permita identificar aquellos pacientes en los que el tratamiento va a ser eficaz. El funcionamiento correcto de la cascada de señalización intracelular JAK-STAT tras la interacción del IFNß con su receptor es fundamental para iniciar la transcripción de los genes inducibles por IFNß y que se lleve a cabo la actividad biológica del mismo. En este sentido, la heterogeneidad en la respuesta terapéutica al IFNß podría explicarse por diferencias en la activación de la vía de señalización y/o por la inducción de los genes tras la administración del fármaco. Una vez que el IFNß interacciona con su receptor debe producirse la adecuada activación, por fosforilación, de residuos específicos de las proteínas que intervienen en la vía JAK-STAT para que se transmita la señal al núcleo celular. La identificación de perfiles de activación asociados a un fenotipo de buena respuesta podría ayudar a monitorizar la eficacia terapéutica del IFNß. Así, tras evaluar los niveles de receptores de membrana y el estado de activación de las proteínas que intervienen en la vía de señalización JAK-STAT, tras estimulación in vitro con IFNß, se obtuvo que la exposición continuada al tratamiento sistémico con IFNß produce una desensibilización de la vía JAK-STAT, de forma que los pacientes tratados presentan una menor respuesta de los monocitos y células T al estímulo in vitro con IFNß que los no tratados, a pesar de tener mayores niveles de activación basal de IFNAR1 y pSTAT1

Determinación de la capacidad de tráfico de una central prototipo de atención de comunicaciones de emergencia con integración de acceso gsm - wlan y software openbts - asterisk propuesta para la universidad privada Antenor Orrego

La presente investigación desarrolla la determinación de trafico de una central prototipo de atención de emergencia con el fin de determinar el trafico capaz a soportar por la misma, mediante previa implementación de la central se desarrollaron diversas pruebas de llamadas durante un tiempo de observación de una hora, estas pruebas permitieron mediante su análisis la futura determinación de troncales equivalentes, probabilidad de bloqueo e intensidad de tráfico de la central. Con los datos obtenidos de las pruebas y de la investigación correspondiente se pudo determinar la capacidad de usuarios que podrían ser atendidos durante una situación de emergencia en la Universidad Privada Antenor Orrego Campus Trujillo de ser requerido su uso en esta institución privada.This research develops determining traffic of a central prototype emergency care in order to determine traffic able to support, through previous central deployment, various call tests were developed during an observation time of one hour, these tests allowed by analyzing the future determination of equivalent trunks, blocking probability and traffic intensity of the central. With the data obtained from the tests and the corresponding investigation could determine the user’s capacity that could be served during an emergency situation at the Private University Antenor Orrego campus of Trujillo if required to use in this private institution

Soluble Receptor Isoform of IFN-Beta (sIFNAR2) in Multiple Sclerosis Patients and Their Association With the Clinical Response to IFN-Beta Treatment

Alternative splicing; Soluble receptors; IFNAR; Interferon beta; Multiple sclerosisEmpalmament alternatiu; Receptors solubles; IFNAR; Interferó beta; Esclerosi múltipleSplicing alternativo; Receptores solubles; IFNAR; Interferón beta; Esclerosis múltiplePurpose: Interferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients. Methods: Ninety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro. Results: Protein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression. Conclusions: IFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.This research was funded by grants from the Instituto de Salud Carlos III and co-funded by European Regional Development Fund (ERDF), Technological Development Project in health DTS/1800045 to BO-M. BO-M holds a contract from Red Andaluza de Investigacion Clínica y Traslacional en Neurología (Neuro-reca) (RIC-0111-2019). PA-G is supported by Promoción de Empleo Joven e Implantación de la Garantía Juvenil 2018 (PEJ2018-002719-A). JR-B is supported by grants from Red Temática de Investigación Cooperativa, Red Española de Esclerosis Multiple REEM (RD16/0015/0010). LL holds a Nicolás Monardes research contract (RC-002-2019) from the Andalusian Ministry of Health and Family. IB-M holds a pFIS contract (FI19/00139) from the Spanish Science and Innovation Ministry

Cognitive impairment in a murine model of experimental autoimmune encephalomyelitis with relapsing-remitting course

Multiple sclerosis (MS) is a neuroinflammatory disorder characterized by demyelination and progressive axonal loss that affects the central nervous system. In addition of physical disability and the neurodegenerative process, MS associates with co-morbid behavioral, neuropsychiatric and cognitive impairment, including learning and memory deficits. The study of cognitive impairment in the currently most suitable experimental animal model of MS, experimental autoimmune encephalomyelitis (EAE), constitutes a very valuable tool to translate ultimately into clinical a better diagnosis and more effective treatment protocols. In our study, we analyzed the behavioral profile of a murine model of EAE induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) which develops a relapsing-remitting course. In the early neuroinflammatory phase of the disease, i.e. 19-21 days post immunization (dpi), EAE mice exhibited deficits in motor coordination/skill learning (Rotarod test), and spatial working memory (spontaneous alternation in Y-maze), as well as depressive symptoms (tail suspension test) and anxiety-like behavior (elevated plus-maze). EAE mice did not yet show object recognition memory impairments, suggesting that reference memory was not altered in this phase. However, from 33-35 dpi until late phases (49-52 dpi), independently of clinical score, EAE mice exhibited a memory decline showing lower discrimination index in the object recognition test. EAE late phase was also characterized by motor coordination and spatial working memory impairments as well as higher anxiety-like behavior. Overall, these data demonstrates a differential pattern of gradual cognitive dysfunctions during the relapsing-remitting EAE course that could help to understand the development of progressive cognitive decline in MS patients. Funding: Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ-1863; CTS643) and of Health (PI-0234-2013; Nicola´s Monardes Programme).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Antiviral, Immunomodulatory and Antiproliferative Activities of Recombinant Soluble IFNAR2 without IFN-beta Mediation

Soluble receptors of cytokines are able to modify cytokine activities and therefore the immune system, and some have intrinsic biological activities without mediation from their cytokines. The soluble interferon beta (IFN-ss) receptor is generated through alternative splicing of IFNAR2 and has both agonist and antagonist properties for IFN-ss, but its role is unknown. We previously demonstrated that a recombinant human soluble IFN-ss receptor showed intrinsic therapeutic efficacy in a mouse model of multiple sclerosis. Here we evaluate the potential biological activities of recombinant sIFNAR2 without the mediation of IFN-ss in human cells. Recombinant sIFNAR2 down-regulated the production of IL-17 and IFN-? and reduced the cell proliferation rate. Moreover, it showed a strong antiviral activity, fully protecting the cell monolayer after being infected by the virus. Specific inhibitors completely abrogated the antiviral activity of IFN-ss, but not that of the recombinant sIFNAR2, and there was no activation of the JAK-STAT signaling pathway. Consequently, r-sIFNAR2 exerts immunomodulatory, antiproliferative and antiviral activities without IFN-ss mediation, and could be a promising treatment against viral infections and immune-mediated diseases

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study

Background: Histoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions. Methodology: We conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation. Principal findings: Evidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections. Conclusions: The high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon

Natalizumab-immunogenicity evaluation in patients with infusion related events or disease exacerbations

IntroductionNatalizumab is a biologic drug for relapsing-remitting multiple sclerosis that may induce the generation of anti-drug antibodies in some patients. Anti-natalizumab antibodies (ANA) increase the risk of adverse events and reduce efficacy, being useful biomarkers for monitoring treatment response.MethodsRetrospective observational study including MS patients treated with natalizumab that experienced infusion-related events (IRE) or disease exacerbations (DE). ANA were tested by Elisa including a screening and a confirmation assay. Patients were further classified as transient (one positive result) or persistent (two or more positive results) ANA.ResultsA total of 1251 MS patients were included and 153 (12.3%) had ANA with at least one single point determination, which were more frequent among patients with IRE compared to those with DE (21,6% vs.10.8%) during the first six infusions. Two or more determinations ANA were performed in 184 patients, being 31.5% permanently positive and 7.1% transiently positive. Interestingly, 26.1% of patients that experienced DE had persistent ANA, while 2.6% were transient. In contrast, 43% of patients with IRE had persistent ANA, and 9.3% had transient antibodies. Patients with persistent antibodies had more frequently high levels at the first sampling compared to patients with transient ANA.ConclusionReal-world evidence shows that the presence of ANA is behind an important percentage of patients treated with natalizumab that experience IRE, as well as DE but in a lower degree. These findings support the need to systematically evaluate ANA towards a personalized management of these patients to avoid undesired complications

4to. Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad. Memoria académica

Este volumen acoge la memoria académica de la Cuarta edición del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad, CITIS 2017, desarrollado entre el 29 de noviembre y el 1 de diciembre de 2017 y organizado por la Universidad Politécnica Salesiana (UPS) en su sede de Guayaquil. El Congreso ofreció un espacio para la presentación, difusión e intercambio de importantes investigaciones nacionales e internacionales ante la comunidad universitaria que se dio cita en el encuentro. El uso de herramientas tecnológicas para la gestión de los trabajos de investigación como la plataforma Open Conference Systems y la web de presentación del Congreso http://citis.blog.ups.edu.ec/, hicieron de CITIS 2017 un verdadero referente entre los congresos que se desarrollaron en el país. La preocupación de nuestra Universidad, de presentar espacios que ayuden a generar nuevos y mejores cambios en la dimensión humana y social de nuestro entorno, hace que se persiga en cada edición del evento la presentación de trabajos con calidad creciente en cuanto a su producción científica. Quienes estuvimos al frente de la organización, dejamos plasmado en estas memorias académicas el intenso y prolífico trabajo de los días de realización del Congreso Internacional de Ciencia, Tecnología e Innovación para la Sociedad al alcance de todos y todas

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake