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The clinical presentations of COVID-19 may range from an asymptomatic or mild infection to a critical or fatal disease. Several host factors such as elderly age, male gender, and previous comorbidities seem to be involved in the most severe outcomes, but also an impaired immune response that causes a hyperinflammatory state but is unable to clear the infection. In order to get further understanding about this impaired immune response, we aimed to determine the association of specific HLA alleles with different clinical presentations of COVID-19. Therefore, we analyzed HLA Class I and II, as well as KIR gene sequences, in 72 individuals with Spanish Mediterranean Caucasian ethnicity who presented mild, severe, or critical COVID-19, according to their clinical characteristics and management. This cohort was recruited in Madrid (Spain) during the first and second pandemic waves between April and October 2020. There were no significant differences in HLA-A or HLA-B alleles among groups. However, despite the small sample size, we found that HLA-C alleles from group C1 HLA-C*08:02, -C*12:03, or -C*16:01 were more frequently associated in individuals with mild COVID-19 (43.8%) than in individuals with severe (8.3%; p = 0.0030; pc = 0.033) and critical (16.1%; p = 0.0014; pc = 0.0154) disease. C1 alleles are supposed to be highly efficient to present peptides to T cells, and HLA-C*12:03 may present a high number of verified epitopes from abundant SARS-CoV-2 proteins M, N, and S, thereby being allegedly able to trigger an efficient antiviral response. On the contrary, C2 alleles are usually poorly expressed on the cell surface due to low association with β2-microglobulin (β2M) and peptides, which may impede the adequate formation of stable HLA-C/β2M/peptide heterotrimers. Consequently, this pilot study described significant differences in the presence of specific HLA-C1 alleles in individuals with different clinical presentations of COVID-19, thereby suggesting that HLA haplotyping could be valuable to get further understanding in the underlying mechanisms of the impaired immune response during critical COVID-19. This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiologı´a (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM); donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Science and Innovation (PID2019-110275RB-I00); and grant MPY509/19 provided by Instituto de Salud Carlos III. The work of MRLH and SRM is financed by NIH grant R01AI143567. The work of LV is supported by a pre-doctoral contract from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of MT is supported by Instituto de Salud Carlos III (COV20_00679). AJMG is the recipient of a post-doctoral contract“Miguel Servet” supported by the Instituto de Salud Carlos III. Sí

Background FLT3 mutation is present in 25–30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs. Methods We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher’s test. Results A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants. Conclusions We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.

Diarrheic diseases account for the annual death of approximately 1.9 million children under the age of 5 years, and it is a major cause of work absenteeism in developed countries. As diarrheagenic bacteria, enteropathogenic Escherichia coli (EPEC) attach to cells in the small intestine, causing local disappearance of microvilli and inducing the formation of actin-rich pedestals that disrupt the intestinal barrier and help EPEC adhere to and infect intestinal cells. Antibiotics and other bioactive compounds can often be found by analyzing traditional medicines. Here a crude aqueous extract of Hibiscus sabdariffa, which typically grows in subtropical and tropical areas and is a popular medicinal tisane in many countries, was analyzed for antibacterial activity against EPEC. In standard microdilution assays, the extract showed a minimum inhibitory concentration of 6.5 mg/ml against EPEC growth. Time-kill kinetics assays demonstrated significant 24 h bactericidal activity at 25 mg/ml. The extract is able to impede pedestal induction. Not only did the extract inhibit preformed pedestals but it prevented pedestal induction as well. Remarkably, it also promoted the formation of EPEC filaments, as observed with other antibiotics. Our results in vitro support the potential of Hibiscus sabdariffa as an antimicrobial agent against EPEC.

Purpose The objectives of this study were to analyze the characteristics of male and female patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) during 2006–2014 according to the presence or absence of bronchiectasis and to study the factors associated with in-hospital mortality (IHM) in patients hospitalized with AE-COPD and concomitant bronchiectasis. Methods We used the Spanish National Hospital Database to analyze patients admitted with AE-COPD as their primary diagnosis. Patients included in the study were stratified according to the presence or absence of bronchiectasis as their secondary diagnosis. Results We identified 386,646 admissions for AE-COPD, of which 19,679 (5.09%) involved patients with concomitant bronchiectasis. When patients with and without bronchiectasis were compared, we observed that the incidence of infection by Pseudomonas aeruginosa was substantially higher in the former, as were the mean stay, cost, and percentage of readmissions, although IHM and comorbidity were lower. The course of patients with AE-COPD and bronchiectasis was characterized by a gradual increase in prevalence and mean age among men and no differences in prevalence or lower mean age in women. Mortality was 4.24% and 5.02% in patients with and without bronchiectasis, respectively, although significance was lost after a multivariate adjustment (OR 0.94; 95% CI, 0.88–1.01). The factors associated with IHM were older age, higher comorbidity, isolation of P. aeruginosa, mechanical ventilation and readmission. Conclusions The prevalence of admission with AE-COPD and bronchiectasis increased in men but not in women during the study period. In patients hospitalized with AE-COPD, we did not find differences in mortality when comparing the presence and absence of bronchiectasis. The analysis of temporal trends revealed a significant reduction in mortality from 2006 to 2014 in male patients with COPD and concomitant bronchiectasis, but not among women. It is important to consider the factors associated with IHM such as age, comorbidity, isolation of P. aeruginosa, mechanical ventilation and readmission to better identify those patients who are at greater risk of dying during hospitalization.

Purpose We aim to assess if air pollution levels and climatological factors are associated with hospital admissions for exacerbation of chronic obstructive pulmonary disease (COPD) in Spain from 2004 to 2013. Methods We conducted a retrospective study. Information on pollution level and climatological factors were obtained from the Spanish Meteorological Agency and hospitalizations from the Spanish hospital discharge database. A case-crossover design was used to identify factors associated with hospitalizations and in hospital mortality. Postal codes were used to assign climatic and pollutant factors to each patient. Results We detected 162,338 hospital admissions for COPD exacerbation. When seasonal effects were evaluated we observed that hospital admissions and mortality were more frequent in autumn and winter. In addition, we found significant associations of temperature, humidity, ozone (O3), carbon monoxide (CO), particulate matter up to 10 μm in size (PM10) and nitrogen dioxide (NO2) with hospital admissions. Lower temperatures at admission with COPD exacerbation versus 1, 1.5, 2 and 3 weeks prior to hospital admission for COPD exacerbation, were associated with a higher probability of dying in the hospital. Other environmental factors that were related to in-hospital mortality were NO2, O3, PM10 and CO. Conclusions Epidemiology of hospital admissions by COPD exacerbation was negatively affected by colder climatological factors (seasonality and absolute temperature) and short-term exposure to major air pollution (NO2, O3, CO and PM10).

Background The purposes of this study were: firstly, to estimate time trends in the prevalence of prescription antibiotic consumption between 2003 and 2014; secondly, to identify the factors associated with the probability of consuming antibiotics during this period in elderly persons in Spain. Methods We analyzed data collected from the Spanish National Health Survey in 2003 (n = 21,650), 2006 (n = 29,478), and 2012 (n = 20,007) and from the European Health Interview Survey for Spain in 2009 (n = 22,188) and 2014 (n = 22,842). Antibiotic consumption was the dependent variable. We also analyzed sociodemographic features, self-perceived health status, lifestyle habits, comorbid diseases, and disabilities using logistic regression models. Results The prevalence of antibiotic consumption increased from 2003 to 2014 in both sexes. The variables that predicted antibiotic consumption (men; women) were secondary education (OR 1.38; OR 1.31), visits to a general practitioner (OR 2.05; OR 2.15), hospitalization (OR 1.91; OR 1.83), therapy with > 4 non-antibiotic drugs (OR 3.36; OR 5.84), instrumental activities of daily living (OR 1.50; OR 1.24), and activities of daily living (OR 1.39; OR 1.35). In contrast, age > 85 years was associated with low antibiotic consumption in both men (OR 0.81) and women (OR 0.88). Conclusions The prevalence of antibiotic prescription has increased in Spain in the last decade. Our study identified several factors that appear to affect antibiotic consumption in elderly persons, with potential implications for healthcare providers.

We present a new multi-analytical approach to the characterization of black pigments in Spanish Levantine rock art. This new protocol seeks to identify the raw materials that were used, as well as reconstruct the different technical gestures and decision-making processes involved in the obtaining of these black pigments. For the first of these goals, the pictorial mat- ter of the black figurative motifs documented at the Les Dogues rock art shelter (Ares del Maestre, Castello ́ n, Spain) was characterized through the combination of physicochemical and archeobotanical analyses. During the first stage of our research protocol, in situ and non- destructive analyses were carried out by means of portable Energy Dispersive X-Ray Fluo- rescence spectrometry (EDXRF); during the second stage, samples were analyzed by Opti- cal Microscopy (OM), Raman spectroscopy, and Scanning Electron Microscopy coupled with Energy Dispersive X-ray spectroscopy (SEM-EDX). Two major conclusions have been drawn from these analyses: first, charred plant matter has been identified as a main compo- nent of these prehistoric black pigments; and second, angiosperm and conifer charcoal was a primary raw material for pigment production, identified by means of the archaeobotanical study of plant cells. For the second goal, black charcoal pigments were replicated in the labo- ratory by using different raw materials and binders and by reproducing two main cha¿ınes ope ́ ratoires. The comparative study of the structure and preservation of plant tissues of both prehistoric and experimental pigments by means of SEM-EDX underlines both a complex preparation process and the use of likely pigment recipes, mixing raw material with fatty or oily binders. Finally, the formal and stylistic analysis of the motifs portrayed at Les Dogues allowed us to explore the relationship between identified stylistic phases and black charcoal pigment use, raising new archaeological questions concerning the acquisition of know-how and the transfer of traditionally learned cha¿ınes ope ́ratoires in Spanish Levantine rock art.

Background One reason for the aggressiveness of the pancreatic cancer is that it is diagnosed late, which often limits both the therapeutic options that are available and patient survival. The long-term survival of pancreatic cancer patients is not possible if the tumor is not resected, even among patients who receive chemotherapy in the earliest stages. The main objective of this study was to create a prediction model for in-hospital mortality after a pancreatectomy in pancreatic cancer patients. Methods We performed a retrospective study of all pancreatic resections in pancreatic cancer patients in Spanish public hospitals (2013). Data were obtained from records in the Minimum Basic Data Set. To develop the prediction model, we used a boosting method. Results The in-hospital mortality of pancreatic resections in pancreatic cancer patients was 8.48% in Spain. Our model showed high predictive accuracy, with an AUC of 0.91 and a Brier score of 0.09, which indicated that the probabilities were well calibrated. In addition, a sensitivity analysis of the information available prior to the surgery revealed that our model has high predictive accuracy, with an AUC of 0.802. Conclusions In this study, we developed a nation-wide system that is capable of generating accurate and reliable predictions of in-hospital mortality after pancreatic resection in patients with pancreatic cancer. Our model could help surgeons understand the importance of the patients’ characteristics prior to surgery and the health effects that may follow resection.

Patched homolog 1 gene (PTCH1) expression and the ratio of PTCH1 to Smoothened (SMO) expression have been proposed as prognostic markers of the response of chronic myeloid leukemia (CML) patients to imatinib. We compared these measurements in a realistic cohort of 101 patients with CML in chronic phase (CP) using a simplified qPCR method, and confirmed the prognostic power of each in a competing risk analysis. Gene expression levels were measured in peripheral blood samples at diagnosis. The PTCH1/SMO ratio did not improve PTCH1 prognostic power (area under the receiver operating characteristic curve 0.71 vs. 0.72). In order to reduce the number of genes to be analyzed, PTCH1 was the selected measurement. High and low PTCH1 expression groups had significantly different cumulative incidences of imatinib failure (IF), which was defined as discontinuation of imatinib due to lack of efficacy (5% vs. 25% at 4 years, P = 0.013), probabilities of achieving a major molecular response (81% vs. 53% at first year, P = 0.02), and proportions of early molecular failure (14% vs. 43%, P = 0.015). Every progression to an advanced phase (n = 3) and CML-related death (n = 2) occurred in the low PTCH1 group (P

Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

PurposeWe examined trends, characteristics and in-hospital outcomes in mechanical and bioprosthetic surgical mitral valve replacement (SMVR) among patients with and without chronic obstructive pulmonary disease (COPD) in Spain from 2001 to 2015. We also identified factors associated with in-hospital mortality (IHM) in both groups of patients according to the implanted valve type.MethodsWe analyzed data from the Spanish National Hospital Discharge Database for patients aged 40 years or over. We selected admissions of patients whose medical procedures included SMVR. We grouped hospitalizations by COPD status.ResultsOver 43,024 patients identified, 83.63% underwent mechanical mitral valve replacement and 16.37% bioprosthetic valve (6.71% and 7.78% with COPD, respectively). The incidence of SMVR decreased for mechanical valves and increased for bioprosthetic valves over time in both groups of patients. The incidence of SMVR admissions was lower among COPD patients than in those without COPD, both for mechanical and bioprosthetic valves. IHM decreased significantly over time, regardless of the type of valve, in both groups of patients. COPD was associated with a significant increase in IHM, but only among patients who underwent bioprosthetic SMVR (OR 1.32, 95% CI 1.01-1.73).ConclusionsThe incidence of mechanical SMVR decreased while that of bioprosthetic SMVR increased over time in both groups of patients. COPD patients were less surgically operated than non-COPD patients for both valve types. In COPD patients, bioprosthetic SMVR was proportionally more used than mechanical SMVR. Mortality decreased over time for both valve types in patients with and without COPD. COPD increased in-hospital mortality among patients undergoing a biological SMVR.

Purpose We analyzed temporal trends, demographic and clinical characteristics and hospital mortality rates of postoperative pneumonia among type 2 diabetes mellitus (T2DM) patients in Spain from 2001 to 2015. We also compared the incidence, comorbidities and mortality between patients with and without T2DM suffering from postoperative pneumonia. Finally, we analyzed the factors involved in the prediction of in-hospital mortality among patients suffering postoperative pneumonia. Methods We used the Spanish National Hospital Discharge Database for the period 2001–2015. We analyzed patients aged 40 years or over who had been hospitalized for a surgical procedure and suffered pneumonia or ventilator-associated pneumonia during their hospital admission. We compared patients with and without T2DM. The main outcome measures were the type of surgical procedure, the presence of a comorbidity, the type of isolated pathogens, admission to the emergency room (ER) and in-hospital mortality (IHM). Results We selected 117,665 hospitalized patients who suffered postoperative pneumonia (16.9% with T2DM). After multivariable adjustment, T2DM patients had a 21% higher incidence of postoperative pneumonia than nondiabetic patients (IRR 1.21, 95% CI 1.03–1.42). The IHM was approximately 31% in both groups. Predictors of IHM included age, the presence of comorbidities, treatment with a pleural drainage tube, dialysis, blood transfusion, mechanical ventilation and admission to the ER. From 2001 to 2015, the IHM decreased significantly in both populations. Suffering from T2DM was not a predictor of IHM (OR 0.99, 95% CI 0.96–1.03) in our investigation. Conclusions T2DM patients have a higher incidence of postoperative pneumonia than those without this disease. The IHM decreased from 2001 to 2015, regardless of T2DM status. T2DM did not predict a higher IHM after suffering from postoperative pneumonia.

Objective To analyze changes in the incidence, diagnostic procedures, comorbidity, length of hospital stay (LOHS), costs and in-hospital mortality (IHM) for patients with bronchiectasis who were hospitalized in Spain over a 10-year period. Methods We included all admissions for patients diagnosed with bronchiectasis as primary or secondary diagnosis during 2004–2013. Results 282,207 patients were admitted to the study. After controlling for possible confounders, we observed a significant increase in the incidence of hospitalizations over the study period when bronchiectasis was a secondary diagnosis. When bronchiectasis was the primary diagnosis we observed a significant decline in the incidence. In all cases, this pathology was more frequent in males, and the average age and comorbidity increased significantly during the study period (p

Purpose The purpose of this study was to determine, i) the reliability of blood lactate and ventilatory-based thresholds, ii) the lactate threshold that corresponds with each ventilatory threshold (VT1 and VT2) and with maximal lactate steady state test (MLSS) as a proxy of cycling performance. Methods Fourteen aerobically-trained male cyclists ([Formula: see text] 62.1±4.6 ml·kg-1·min-1) performed two graded exercise tests (50 W warm-up followed by 25 W·min-1) to exhaustion. Blood lactate, [Formula: see text] and [Formula: see text] data were collected at every stage. Workloads at VT1 (rise in [Formula: see text];) and VT2 (rise in [Formula: see text]) were compared with workloads at lactate thresholds. Several continuous tests were needed to detect the MLSS workload. Agreement and differences among tests were assessed with ANOVA, ICC and Bland-Altman. Reliability of each test was evaluated using ICC, CV and Bland-Altman plots. Results Workloads at lactate threshold (LT) and LT+2.0 mMol·L-1 matched the ones for VT1 and VT2, respectively (p = 0.147 and 0.539; r = 0.72 and 0.80; Bias = -13.6 and 2.8, respectively). Furthermore, workload at LT+0.5 mMol·L-1 coincided with MLSS workload (p = 0.449; r = 0.78; Bias = -4.5). Lactate threshold tests had high reliability (CV = 3.4-3.7%; r = 0.85-0.89; Bias = -2.1-3.0) except for DMAX method (CV = 10.3%; r = 0.57; Bias = 15.4). Ventilatory thresholds show high reliability (CV = 1.6%-3.5%; r = 0.90-0.96; Bias = -1.8-2.9) except for RER = 1 and V-Slope (CV = 5.0-6.4%; r = 0.79; Bias = -5.6-12.4). Conclusions Lactate threshold tests can be a valid and reliable alternative to ventilatory thresholds to identify the workloads at the transition from aerobic to anaerobic metabolism.

In this work we analyze the pigments used in the decoration of red and yellow motifs present in the portable art of the Parpallo Cave (Gandia, Spain), one of the most important Palaeolithic sites in the Spanish Mediterranean region. Energy dispersive X-ray fluorescence spectrometry (EDXRF) and spectrophotometry in the visible region (CIEL*a*b*color coordinates and spectral reflectance curves) were used to perform in situ fast analyses of the red and yellow motifs with portable equipment and to characterize their elemental composition and their colorimetric perception, respectively. According to the elemental composition, the intensity of the fluorescence iron signals in red and yellow motifs are higher than average values in the rock substrates. As expected, red motifs possess high values of the chromatic coordinate a* and yellow motifs possess high values of b*. This characterization was complemented with FT-IR analyses of microsamples detached from the red and yellow colored zones of a small set of plaquettes. Our results show that the artists used red and yellow pigments in the decoration likely derived from natural iron oxides as hematite and goethite.

[EN] The study of the heterogeneity of effect sizes is a key aspect of ecological meta-analyses. Here we propose a meta-analytic methodology to study the influence of moderators in effect sizes by splitting heterogeneity: meta-partition. To introduce this methodology, we performed a meta-partition of published data about the traits that influence species sensitivity to habitat loss, that have been previously analyzed through meta-regression. Thus, here we aim to introduce meta-partition and to make an initial comparison with meta-regression. Meta-partition algorithm consists of three steps. Step 1 is to study the heterogeneity of effect sizes under the assumption of fixed effect model. If heterogeneity is found, we perform step 2, that is, to partition the heterogeneity by the moderator that minimizes heterogeneity within a subset while maximizing heterogeneity between subsets. Then, if effect sizes of the subset are still heterogeneous, we repeat step 1 and 2 until we reach final subsets. Finally, step 3 is to integrate effect sizes of final subsets, with fixed effect model if there is homogeneity, and with random effects model if there is heterogeneity. Results show that meta-partition is valuable to assess the importance of moderators in explaining heterogeneity of effect sizes, as well as to assess the directions of these relations and to detect possible interactions between moderators. With meta-partition we have been able to evaluate the importance of moderators in a more objective way than with meta-regression, and to visualize the complex relations that may exist between them. As ecological issues are often influenced by several factors interacting in complex ways, ranking the importance of possible moderators and detecting possible interactions would make meta-partition a useful exploration tool for ecological meta-analyses.

This study aims to describe trends in the prevalence of depression among hospitalized patients with type 2 diabetes in Spain, 2001-2011.We selected patients with a discharge diagnosis of type 2 diabetes using national hospital discharge data. Discharges were grouped by depression status. Prevalence of depression globally and according to primary diagnoses based on the Charlson comorbidity index (CCI) were analyzed. We calculated length of stay (LOHS) and in-hospital mortality (IHM). Multivariate analysis was adjusted by age, year and comorbidity.From 2001 to 2011, 4,723,338 discharges with type 2 diabetes were identified (4.93% with depression). Prevalence of depression in diabetic patients increased from 3.54% in 2001 to 5.80% in 2011 (p0.05). The prevalence of depression was significantly higher in women than in men in each year studied and increased from 5.22% in 2001 to 9.24% in 2011 (p0.01). The highest prevalence was observed in the youngest age group (35-59 years). The median LOHS decreased significantly over this period. Men with diabetes and depression had higher IHM than women in all the years studied (p0.05). Older age and greater comorbidity were significantly associated with a higher risk of dying, among diabetic patients with concomitant depression.Prevalence of depression increased significantly among hospitalized diabetic patients from 2001 to 2011 even if the health profile and LOHS have improved over this period. Programs targeted at preventing depression among persons with diabetes should be reinforced in Spain.

[This corrects the article DOI: 10.1371/journal.pone.0145535.].

Glioblastomas are the most common malignant primary brain tumours in adults and one of the most aggressive and difficult-to-treat cancers. No effective treatment exits actually for this tumour and new therapeutic approaches are needed for this disease. One possible innovative approach involves the nanoparticle-mediated specific delivery of drugs and/or genetic material to glioblastoma cells where they can provide therapeutic benefits. In the present work, we have synthesised and characterised several second generation amphiphilic polylysine dendrons to be used as siRNA carriers. We have found that, in addition to their siRNA binding properties, these new compounds inhibit the proliferation of two glioblastoma cell lines while being nontoxic for non-tumoural central nervous system cells like neurons and glia, cell types that share the anatomical space with glioblastoma cells during the course of the disease. The selective toxicity of these nanoparticles to glioblastoma cells, as compared to neurons and glial cells, involves mitochondrial depolarisation and reactive oxygen species production. This selective toxicity, together with the ability to complex and release siRNA, suggests that these new polylysine dendrons might offer a scaffold in the development of future nanoparticles designed to restrict the proliferation of glioblastoma cells.

The control of cell death is a biological process essential for proper development, and for preventing devastating pathologies like cancer and neurodegeneration. On the other hand, autophagy regulation is essential for protein and organelle degradation, and its dysfunction is associated with overlapping pathologies like cancer and neurodegeneration, but also for microbial infection and aging. In the present report we show that two evolutionarily unrelated receptors--Neurokinin 1 Receptor (NK(1)R,) a G-protein coupled receptor, and Insulin-like Growth Factor 1 Receptor (IGF1R), a tyrosine kinase receptor--both induce non-apoptotic cell death with autophagic features and requiring the activity of the autophagic core machinery proteins PI3K-III, Beclin-1 and Atg7. Remarkably, this form of cell death occurs in apoptosis-competent cells. The signal transduction pathways engaged by these receptors both converged on the activation of the nuclear receptor NR4A1, which has previously been shown to play a critical role in some paradigms of apoptosis and in NK(1)R-induced cell death. The activity of NR4A1 was necessary for IGF1R-induced cell death, as well as for a canonical model of cell death by autophagy induced by the presence of a pan-caspase inhibitor, suggesting that NR4A1 is a general modulator of this kind of cell death. During cell death by autophagy, NR4A1 was transcriptionally competent, even though a fraction of it was present in the cytoplasm. Interestingly, NR4A1 interacts with the tumor suppressor p53 but not with Beclin-1 complex. Therefore the mechanism to promote cell death by autophagy might involve regulation of gene expression, as well as protein interactions. Understanding the molecular basis of autophagy and cell death mediation by NR4A1, should provide novel insights and targets for therapeutic intervention.

This is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al., Ungulates select diets with high energy, protein, and sodium contents. However, it is scarcely known the influence of essential minerals other than Na in diet preferences. Moreover, almost no information is available about the possible influence of toxic levels of essential minerals on avoidance of certain plant species. The aim of this research was to test the relative importance of mineral content of plants in diet selection by red deer (Cervus elaphus) in an annual basis. We determined mineral, protein and ash content in 35 common Mediterranean plant species (the most common ones in the study area). These plant species were previously classified as preferred and non-preferred. We found that deer preferred plants with low contents of Ca, Mg, K, P, S, Cu, Sr and Zn. The model obtained was greatly accurate identifying the preferred plant species (91.3% of correct assignments). After a detailed analysis of these minerals (considering deficiencies and toxicity levels both in preferred and non-preferred plants) we suggest that the avoidance of excessive sulphur in diet (i.e., selection for plants with low sulphur content) seems to override the maximization for other nutrients. Low sulphur content seems to be a forgotten factor with certain relevance for explaining diet selection in deer. Recent studies in livestock support this conclusion, which is highlighted here for the first time in diet selection by a wild large herbivore. Our results suggest that future studies should also take into account the toxicity levels of minerals as potential drivers of preferences., This paper has been funded by the projects AGL2012-38898 (Ministry of Economy and Competitiveness, Spain), MZERO0714 (Ministry of Agriculture, Czech Republic), CIGA-20145001 (Czech University of Life Sciences, Czech Republic) and IGA-20145026 (Faculty of Tropical AgriSciences, Czech Republic).

Background This study aims to describe trends in the prevalence of depression among hospitalized patients with type 2 diabetes in Spain, 2001–2011. Methods We selected patients with a discharge diagnosis of type 2 diabetes using national hospital discharge data. Discharges were grouped by depression status. Prevalence of depression globally and according to primary diagnoses based on the Charlson comorbidity index (CCI) were analyzed. We calculated length of stay (LOHS) and in-hospital mortality (IHM). Multivariate analysis was adjusted by age, year and comorbidity. Results From 2001 to 2011, 4,723,338 discharges with type 2 diabetes were identified (4.93% with depression). Prevalence of depression in diabetic patients increased from 3.54% in 2001 to 5.80% in 2011 (p

Purpose To assess the effect of type 2 diabetes (T2DM) on hospital outcomes such as in hospital postoperative complications (IHPC), length of hospital stay (LOHS) and in-hospital mortality (IHM) after the revision of total hip arthroplasty (RHA) and total knee arthroplasty (RKA) and to identify factors associated with IHPC among T2DM patients undergoing these procedures. Methods We performed a retrospective study using the Spanish National Hospital Discharge Database, 2005–2014. We included patients who were ≥40 years old that had undergone RHA and RKA. For each T2DM patient, we selected a year-, gender-, age- and Charlson Comorbidity Index-matched non-diabetic patient. Results We identified 44,055 and 39,938 patients who underwent RHA (12.72% with T2DM) and RKA (15.01% with T2DM). We matched 4,700 and 5,394 couples with RHA and RKA, respectively. Any IHPC was more frequent among patients with T2DM than among non-T2DM patients (19% vs. 15.64% in the RHA cohort and 12.94% vs. 11.09% in the RKA cohort, respectively). For patients who underwent RHA, postoperative infection (4.51% vs. 2.94%, p