Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir/ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an anti-apoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence

Psychological Distress, Family Support and Employment Status in First-Year University Students in Spain

Mental disorders are consistently and closely related to psychological distress. At the start of the university period, the relationship between a student's psychological distress, family support, and employment status is not well-known. The aims of this study were: To determine the prevalence of psychological distress in first-year university students and to analyze its relationship with family support and the student's employment status. Data from 4166 first-year university students from nine universities across Spain were considered. The prevalence of psychological distress was obtained using the GHQ-12, a valid and reliable screening tool to detect poor mental health. To analyze the relationship between psychological distress, family support, and employment status, logistic regression models were fitted. Regarding the prevalence found, 46.9% of men and 54.2% of women had psychological distress. In both genders, psychological distress levels increased as family support decreased. Among women, psychological distress was associated with their employment status. The prevalence of psychological distress among first-year university students in Spain is high. In addition, family support, and employment status for women, could be factors to take into account when developing psychological distress prevention strategies at the beginning of the university period.This study was funded by the National Drug Plan from the Ministry of Health, Social Services and Equality of Spain (Codes: 2010|145 and 2013|034)

Consumo de drogas ilegales, apoyo familiar y factores relacionadosen estudiantes universitarios. Un estudio transversal basado en datosdel Proyecto uniHcos

Objective: To assess the prevalence of illegal drug use in college students on any previous occasion, duringthe previous year and the previous month, and to analyze the relationship between illegal drug use andfamily support and other factors.Methods: A cross-sectional study using data from students participating in the uniHcos project (n = 3767)was conducted. The prevalence and age of onset of consumption of cannabis, non-prescription sedatives,stimulants and depressants was evaluated. Polyconsumption was also assessed. The independent vari-ables were: family support, age, residence, and employment status. To determine the factors related todrug use multivariate logistic regression models stratified by gender were fitted.Results: Differences between men and women in prevalence of illegal drug use except non-prescriptionsedatives were observed. In both genders, less family support was associated with higher consumptionof all drugs, except depressants, and with polyconsumption. To be studying and looking for work wasrelated to cannabis and stimulant use and to polyconsumption among women, but only to cannabis useamong men.Conclusions: These results support the notion that the start of university studies is a particularly relevantstage in the onset of illegal drug use and its prevention, and that consumption may be especially associatedwith family support.Objetivo: Evaluar la prevalencia del consumo de drogas ilegales en estudiantes universitarios y analizarla relación entre dicho consumo, el apoyo familiar y otros factores.Método: Se realizó un dise?no transversal basado en datos de participantes en el proyecto uniHcos (n =3767). Se evaluaron la prevalencia y la edad de inicio del consumo de cannabis, tranquilizantes sin receta,estimulantes y depresores, y el policonsumo. Como variables independientes se consideraron el apoyofamiliar, la edad, la residencia y la situación laboral. Para la determinación de los factores asociados alconsumo de drogas se ajustaron modelos de regresión logística estratificados por sexo.Resultados: Se observaron diferencias entre hombres y mujeres en la prevalencia del consumo de todaslas drogas ilegales, excepto tranquilizantes sin receta. En ambos sexos, cuanto peor apoyo familiar, mayorconsumo de todas las drogas, excepto depresores y policonsumo. Encontrarse estudiando y buscandotrabajo se relacionó con el consumo de cannabis, estimulantes y policonsumo en las mujeres, y solo concannabis en los hombres.Conclusiones: Los resultados de este estudio aportan nueva evidencia a favor de que el inicio de la etapauniversitaria es un momento de especial relevancia en el inicio del consumo de drogas ilegales y suprevención, pudiendo este consumo estar especialmente relacionado con el apoyo familiar

Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours : results from the COPPADIS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

Falls Predict Acute Hospitalization in Parkinson's Disease

[Background] There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission.[Objective] To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort.[Methods] PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit.[Results] Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH.[Conclusion] Falls is an independent predictor of AH in PD patients.Peer reviewe

Geodivulgar: Geología y Sociedad 2018

Depto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasFALSEsubmitte

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Redefiniendo el papel de los neutrófilos mediante modelos complejos de daño y reparación pulmonar

Tesis con mención internacional. Tesis doctoral por el sistema de compendio de publicacionesLa ventilación mecánica es una terapia de soporte vital rutinaria que, a pesar de los beneficios que aporta, puede tener efectos negativos para el paciente. El empleo de ventilación mecánica con presiones positivas puede desencadenar la aparición de la lesión pulmonar inducida por ventilación (VILI). Dado que las estrategias farmacológicas dirigidas específicamente a eliminar el VILI no han alcanzado los resultados esperados, probablemente debido a la heterogeneidad que caracteriza a esta patología, hemos orientado la presente Tesis Doctoral a profundizar en el estudio de la inflamación asociada al, así como del papel que desempeñan los neutrófilos tanto en la inflamación, como en el remodelado de la matriz. En conjunto, los resultados obtenidos ayudan a comprender mejor la complejidad del VILI, y en particular, la respuesta inflamatoria pulmonar derivada de la ventilación mecánica. Tanto el mecanismo de tolerancia a la ventilación, como el papel dual que desempeñan los neutrófilos durante el VILI pueden ofrecer nuevas oportunidades terapéuticas para minimizar el daño pulmonar, y así mejorar el pronóstico de los pacientes críticos

Security in learning management systems: designing collaborative learning activities in secure information systems

The field of research on information technology applications in the design of computer supported collaborative learning (CSCL) activities generates very complex scenarios which must be studied from different approaches. One approach is to consider information security, but not only from a technological point of view. In this paper we argue that current e-learning systems supporting on-line collaborative learning do not sufficiently meet essential security requirements, and this limitation can have a strong influence in the collaborative learning processes. In order to alleviate these problems we have proposed an approach based on Public Key Infrastructure (PKI) models that offer essential security properties and services in on-line collaborative learning, such as availability, integrity, identification and authentication, access control, confidentiality, non repudiation, time stamping, audit service and failure control

A massive data processing approach for effective trustworthiness in online learning groups

This paper proposes a trustworthiness-based approach for the design of secure learning activities in online learning groups. Although computer-supported collaborative learning has been widely adopted in many educational institutions over the last decade, there exist still drawbacks that limit its potential. Among these limitations, we investigate on information security vulnerabilities in learning activities, which may be developed in online collaborative learning contexts. Although security advanced methodologies and technologies are deployed in learning management systems, many security vulnerabilities are still not satisfactorily solved. To overcome these deficiencies, we first propose the guidelines of a holistic security model in online collaborative learning through an effective trustworthiness approach. However, as learners' trustworthiness analysis involves large amount of data generated along learning activities, processing this information is computationally costly, especially if required in real time. As the main contribution of this paper, we eventually propose a parallel processing approach, which can considerably decrease the time of data processing, thus allowing for building relevant trustworthiness models to support learning activities even in real time