Search

From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells and protein aggregates. To prevent garbage buildup, the brain is equipped with efficient phagocytes: the microglia. Microglia are similar, but not identical to other tissue macrophages, and in this review, we will first summarize the differences in the origin, lineage and population maintenance of microglia and macrophages. Then, we will discuss several principles that govern macrophage phagocytosis of apoptotic cells (efferocytosis), including the existence of redundant recognition mechanisms ("find-me" and "eat-me") that lead to a tight coupling between apoptosis and phagocytosis. We will then describe that resulting from engulfment and degradation of apoptotic cargo, phagocytes undergo an epigenetic, transcriptional and metabolic rewiring that leads to trained immunity, and discuss its relevance for microglia and brain function. In summary, we will show that neuroimmunologists can learn many lessons from the well-developed field of macrophage phagocytosis biology., (Copyright © 2020 Márquez-Ropero, Benito, Plaza-Zabala and Sierra.)

Aims: Cryoballoon (CB) ablation has emerged as a reliable modality to isolate pulmonary veins (PVs) in atrial fibrillation. Ablation lesions and the long-term effects of energy delivery can be assessed by delayed-enhancement cardiac magnetic resonance (DE-CMR). The aim of the study was to compare the number, extension, and localization of gaps in CB and radiofrequency (RF) techniques in pulmonary vein isolation (PVI)., Methods and Results: Consecutive patients submitted to PVI with CB in whom DE-CMR images were available (n = 30) were matched (1:1) to patients who underwent PVI with RF (n = 30), considering age, sex, hypertension, and diabetes. Delayed-enhancement cardiac magnetic resonance was obtained at 3 months post-procedure, and images were processed to assess the mean number of gaps around PV ostia, their localization, and the normalized gap length (NGL), calculated as the difference between total gap length and total PV perimeter. Patients were followed up for 12 months. The CB and RF procedures did not differ in the mean number of gaps per patient (4.40 vs. 5.13 gaps, respectively; P = 0.21) nor NGL (0.35 vs. 0.32, P = 0.59). For both techniques, a higher mean number of gaps were detected in right vs. left PVs (3.18 vs. 1.58, respectively; P = 0.01). The incidence of recurrences did not differ between techniques (odds ratio 1.87, 95% confidence interval 0.66-4.97; P = 0.29)., Conclusion: Location and extension of ablation gaps in PVI did not differ between CB and RF groups in DE-CMR image analysis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

The use of cardiovascular magnetic resonance imaging left atrial late gadolinium enhancement (LA LGE) is increasing for fibrosis evaluation though the use is still limited to specialized centres due to complex image acquisition and lack of consensus on image analyses. Analysis of LA LGE with image intensity ratio (IIR) (pixel intensity of atrial wall normalized by blood pool intensity) provides an objective method to obtain quantitative data on atrial fibrosis. A threshold between healthy myocardium and fibrosis of 1.2 has previously been established in 3T scans. The aim of the study was to reaffirm this threshold in 1.5T scans. LA LGE was performed using a 1.5T magnetic resonance scanner on: 11 lone-AF patients, 11 age-matched healthy volunteers (aged 27-44) and 11 elderly patients without known history of AF but varying degrees of comorbidities. Mean values of IIR for all healthy volunteers +2SD were set as upper limit of normality and was reproduced to 1.21 and the original IIR-threshold of 1.20 was maintained. The degree of fibrosis in lone-AF patients [median 9.0% (IQR 3.9-12.0)] was higher than in healthy volunteers [2.8% (1.3-8.3)] and even higher in elderly non-AF [20.1% (10.2-35.8), p = 0.001]. The previously established IIR-threshold of 1.2 was reaffirmed in 1.5T LA LGE scans. Patients with lone AF presented with increased degrees of atrial fibrosis compared to healthy volunteers in the same age-range. Elderly patients with no history of AF showed significantly higher degrees of fibrosis compared to both groups with younger individuals.

Aberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of β-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.

Introduction: Recurrences after atrial fibrillation (AF) ablation are still common. Among the reported clinical and imaging predictors of recurrences, diagnosis-to-ablation time (DAT) has been defined as a predictor of ablation outcome in single-center studies. We aimed to validate DAT in a multicenter real-life cohort., Methods: This was a multicenter study including consecutive patients undergoing first paroxysmal and persistent AF ablation with radiofrequency or cryoballoon catheters during 2013. Cox proportional hazard regression models were performed to identify predictors of recurrence., Results: In total, 309 patients were included across nine centers (71% men, 57 ± 10 years old, 46% with hypertension, and 66% with CHA 2 DS 2 -VASc ≤ 1). Most patients had paroxysmal AF (67%) and underwent radiofrequency ablation (68%) with a median DAT of 51 (43) months. Patients with DAT ≤ 1 year (16.6%) were less likely to have repeat procedures (4% vs 18%; P = .017). The adjusted proportional hazards Cox model identified hypertension (P = .005), heart failure (P = .011), nonparoxysmal AF (P = .038), DAT > 1 year (P = .007), and LA diameter (P = .026) as independent predictors for AF recurrence. DAT > 1 year was the only modifiable factor independently associated with recurrence (HR 4.2 [95% CI, 1.5-11.9]) CONCLUSION: Diagnosis-to-ablation time is a modifiable factor independently associated with recurrent arrhythmia and repeat ablation after first AF ablation. An early intervention strategy during the first year from AF diagnosis might improve outcomes., (© 2019 Canadian Society for Chemical Engineering.)

Background: Metabolic syndrome is associated with low-grade systemic inflammation, which is a key driver of premature atherosclerosis. We characterized immune cell behavior in metabolic syndrome, its consequences, and the potential involvement of the CX 3 CL1/CX 3 CR1 and CCL2/CCR2 chemokine axes., Methods: Whole blood from 18 patients with metabolic syndrome and 21 age-matched controls was analyzed by flow cytometry to determine the leukocyte immunophenotypes, activation, platelet-leukocyte aggregates, and CX 3 CR1 expression. ELISA determined the plasma marker levels. Platelet-leukocyte aggregates adhesion to tumor necrosis factor-α (TNFα)-stimulated arterial endothelium and the role of CX 3 CL1/CX 3 CR1 and CCL2/CCR2 axes was investigated with the parallel-plate flow chamber., Results: When compared with the controls, the metabolic syndrome patients presented greater percentages of eosinophils, CD3 + T lymphocytes, Mon2/Mon3 monocytes, platelet-eosinophil and -lymphocyte aggregates, activated platelets, neutrophils, eosinophils, monocytes, and CD8 + T cells, but lower percentages of Mon1 monocytes. Patients had increased circulating interleukin-8 (IL-8) and TNFα levels and decreased IL-4. CX 3 CR1 up-regulation in platelet-Mon1 monocyte aggregates in metabolic syndrome patients led to increased CX 3 CR1/CCR2-dependent platelet-Mon1 monocyte adhesion to dysfunctional arterial endothelium., Conclusion: We provide evidence of generalized immune activation in metabolic syndrome. Additionally, CX 3 CL1/CX 3 CR1 or CCL2/CCR2 axes are potential candidates for therapeutic intervention in cardiovascular disorders in metabolic syndrome patients, as their blockade impairs the augmented arterial platelet-Mon1 monocyte aggregate adhesiveness, which is a key event in atherogenesis.

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1α (IRE α)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood-brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease. SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease., (Copyright © 2019 the authors.)

Introduction: Specific Scorecards are a key element to improve strategic lines aimed at enhancing intermediate health outcomes. Their implementation, involving professionals, requires identifying indicators linked to the outcomes of healthcare actions that the scientific literature may endorse. In addition, the inclusion of objectives that can be defined by parameterized by indicators of intermediate results in the health centre program contract, conveys the relevance of health actions and their impact on health., Objective: To describe the design, development and outcomes of the specific scorecards of indicators of intermediate health outcomes in the Primary Care information system (eSOAP) in order to promote the involvement of professionals in strategic management from clinical management., Methods: Phase 1: description of the process (preparation and publication of 147 indicators, 46 of them of chronicity). Phase 2: observational descriptive study on the use of professionals and managers and data on the intermediate health outcomes obtained., Results: A total of 268,849 reports were generated in 2017, with 35,835 reports of specific balanced scorecard (20%) being downloaded in just 6 months. One-quarter (25%) of the indicators of the Centre program contract are intermediate results. The percentage of diabetic patients controlled was 39.2%, and has improved significantly (P<.05) in 5 years., Discussion: The specific scorecards with indicators of intermediate outcomes linked to strategic lines and their inclusion in the program contracts enables professionals to become involved in clinical and strategic management and improves the decision making of professionals and managers., (Copyright © 2019 FECA. All rights reserved.)

Context: The coping with death competence is of great importance for palliative care professionals, who face daily exposure to death. It can keep them from suffering compassion fatigue and burnout, thus enhancing the quality of the care provided. Despite its relevance, there are only two measures of professionals' ability to cope with death. Specifically, the Coping with Death Scale (CDS) has repeatedly shown psychometric problems with some of its items., Objective: The aim of this study was to develop and validate a short version of the CDS., Methods: Nine items from the original CDS were chosen for the short version. Two cross-sectional surveys were conducted in Spanish (N = 385) and Argentinian (N = 273) palliative care professionals. The CDS and the Professional Quality of Life Scale were used in this study. Statistical analyses included two confirmatory factor analyses (CFAs), followed by a standard measurement invariance routine. Reliability estimates and evidence of validity based on relations with other measures were also gathered., Results: CFA models had excellent fit in both the Spanish (χ 2 (27) = 107.043, P < 0.001; Comparative Fit Index [CFI] = 0.978; Tucker-Lewis Index [TLI] = 0.970; Root Mean Square Error of Approximation [RMSEA] = 0.093 [0.075, 0.112]; Standardized Root Mean Square Residual = 0.030) and Argentinian (χ 2 (27) = 102.982, P < 0.001; CFI = 0.963; TLI = 0.950; RMSEA = 0.106 [0.085, 0.128]) samples. A standard measurement invariance routine was carried out. The most parsimonious model (χ 2 (117) = 191.738, P < 0.001; CFI = 0.987; TLI = 0.992; RMSEA = 0.046 [0.034, 0.058]; Standardized Root Mean Square Residual = 0.043) offered evidence of invariance across countries, with no latent mean differences. Evidence of reliability and evidence of validity based on relations with other measures were also appropriate., Conclusion: Results indicated the psychometric boundaries of the short version of the CDS., (Copyright © 2018 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

In the present work, we demonstrate the preparation of chitosan-based composites as vehicles of the natural occurring multi-drug resveratrol (RES). Such systems are endowed with potential therapeutic effects on inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis, through the sustained colonic release of RES from long-lasting mucoadhesive drug depots. The loading of RES into nanoparticles (NPs) was optimized regarding two independent variables: RES/polymer ratio, and temperature. Twenty experiments were carried out and a Box⁻Behnken experimental design was used to evaluate the significance of these independent variables related to encapsulation efficiency (EE). The enhanced RES EE values were achieved in 24 h at 39 °C and at RES/polymer ratio of 0.75:1 w / w . Sizes and polydispersities of the optimized NPs were studied by dynamic light scattering (DLS). Chitosan (CTS) dispersions containing the RES-loaded NPs were ionically gelled with tricarballylic acid to yield CTS-NPs composites. Macro- and microscopic features (morphology and porosity studied by SEM and spreadability), thermal stability (studied by TGA), and release kinetics of the RES-loaded CTS-NPs were investigated. Release patterns in simulated colon conditions for 48 h displayed significant differences between the NPs (final cumulative drug release: 79⁻81%), and the CTS-NPs composites (29⁻34%).

Forgetting is important. Without it, the relative importance of acquired memories in a changing environment is lost. We discovered that synaptotagmin-3 (Syt3) localizes to postsynaptic endocytic zones and removes AMPA receptors from synaptic plasma membranes in response to stimulation. AMPA receptor internalization, long-term depression (LTD), and decay of long-term potentiation (LTP) of synaptic strength required calcium-sensing by Syt3 and were abolished through Syt3 knockout. In spatial memory tasks, mice in which Syt3 was knocked out learned normally but exhibited a lack of forgetting. Disrupting Syt3:GluA2 binding in a wild-type background mimicked the lack of LTP decay and lack of forgetting, and these effects were occluded in the Syt3 knockout background. Our findings provide evidence for a molecular mechanism in which Syt3 internalizes AMPA receptors to depress synaptic strength and promote forgetting., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To assess the short and medium-term effects of milking maneuver (MM) compared with early cord clamping for infants born before 37 weeks of pregnancy., Material and Methods: 138 infants between 24+0 and 36+6 weeks of gestation were allocated to MM or early cord clamping. Primary outcomes were the requirement of red blood cell transfusions or phototherapy., Results: Initial hemoglobin was significantly higher in the MM group by 1.675 g/dL (p < 0.05) and initial hematocrit by 5.36% (p < 0.05), but no differences in the need of transfusion during the first 30 days after delivery were found (RR 0.8; 95% CI 0.22-2.85). Peak serum bilirubin was similar in both groups (11,097 ± 3.21 vs. 11,247 ± 3.56 mg/dL, p = 0.837). Phototherapy requirements were higher in the MM group (RR 1.62; 95% CI 1.1-2.38). No differences regarding the need of oral iron supplementation, platelet transfusion, respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, periventricular leukomalacia, meconium aspiration syndrome, use of surfactant, days of oxygen supplementation, need of vasopressors, length of stay in the neonatal intensive care unit, or postpartum hemorrhage were found., Conclusion: MM does not reduce the need for red blood cell transfusions and increases phototherapy requirements in preterm infants., (© 2018 S. Karger AG, Basel.)

The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.

The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).

Aims: Left atrial (LA) remodelling is a key determinant of atrial fibrillation (AF) ablation outcome. Optimal methods to assess this process are scarce. LA sphericity is a shape-based parameter shown to be independently associated to procedural success. In a multicentre study, we aimed to test the feasibility of assessing LA sphericity and evaluate its capability to predict procedural outcomes., Methods and Results: This study included consecutive patients undergoing first AF ablation during 2013. A 3D model of the LA chamber, excluding pulmonary veins and LA appendage, was used to quantify LA volume (LAV) and LA sphericity (≥82.1% was considered spherical LA). In total, 243 patients were included across 9 centres (71% men, aged 56 ± 10 years, 44% with hypertension and 76% CHA2DS2-VASc ≤ 1). Most patients had paroxysmal AF (66%) and underwent radiofrequency ablation (60%). Mean LA diameter (LAD), LAV, and LA sphericity were 42 ± 6 mm, 100 ± 33 mL, and 82.6 ± 3.5%, respectively. Adjusted Cox models identified paroxysmal AF [hazard ratio (HR 0.54, P = 0.032)] and LA sphericity (HR 1.87, P = 0.035) as independent predictors for AF recurrence. A combined clinical-imaging score [Left Atrial Geometry and Outcome (LAGO)] including five items (AF phenotype, structural heart disease, CHA2DS2-VASc ≤ 1, LAD, and LA sphericity) classified patients at low (≤2 points) and high risk (≥3 points) of procedural failure (35% vs. 82% recurrence at 3-year follow-up, respectively; HR 3.10, P < 0.001)., Conclusion: In this multicentre, real-life cohort, LA sphericity and AF phenotype were the strongest predictors of AF ablation outcome after adjustment for covariates. The LAGO score was easy to implement, identified high risk of procedural failure, and could help select optimal candidates., Clinical Trial Registration Information: NCT02373982 (http://clinicaltrials.gov/ct2/show/NCT02373982).

HIV infection is strongly conditioned by social factors. Two of the most significant obstacles in the response to HIV is the stigma and the discrimination that is still associated with it. The stigmatization process occurs through individual drivers and structural facilitators that interweave with overlapping stigmas. These stig-mas manifest in several forms and lead to complex consequences that negatively influence prevention, diagnosis, treatment and quality of life. This article reviews these issues and the evidence of stigma in Spain. The response to HIV requires a strong political commitment. However, the economic crisis and the lack of leadership from institutions have slowed down the progress achieved in Spain. HIV must be placed at the forefront of the political agenda in order to achieve international goals., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

The conductive and diffusional behavior of electrolytes in media with different dielectric and viscoelastic properties is investigated. A revised model to separate the contribution of dissociated and nondissociated species to the diffusion coefficients determined with NMR is proposed. Impedance spectroscopy is used to measure the ionic conductivity of lithium salts in aqueous medium, ionic liquids in aprotic solvents, and hydrogel polyelectrolytes. The diffusion coefficients of the species of interest in those systems are determined with multinuclear pulsed-gradient spin-echo (PGSE) NMR. The results are analyzed using the revised model. It is shown that the degree of ionization could be determined directly from measurements of ionic conductivity and diffusion coefficients in very different types of electrolytes and in a wide range of concentrations. Furthermore, these findings support the original Arrhenius hypothesis about electrolytes and show that the assumption of a complete dissociation is not required to describe their conductive behavior. The reduced conductivity observed in hydrogels, at or near swelling equilibrium, compared to that in solutions could be attributed mainly to the hindered ionic mobility caused by the network structure.

Physical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer's disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Dendritic spines compartmentalize information in the brain, and their morphological characteristics are thought to underly synaptic plasticity. Here we identify copine-6 as a novel modulator of dendritic spine morphology. We found that brain-derived neurotrophic factor (BDNF) - a molecule essential for long-term potentiation of synaptic strength - upregulated and recruited copine-6 to dendritic spines in hippocampal neurons. Overexpression of copine-6 increased mushroom spine number and decreased filopodia number, while copine-6 knockdown had the opposite effect and dramatically increased the number of filopodia, which lacked PSD95. Functionally, manipulation of post-synaptic copine-6 levels affected miniature excitatory post-synaptic current (mEPSC) kinetics and evoked synaptic vesicle recycling in contacting boutons, and post-synaptic knockdown of copine-6 reduced hippocampal LTP and increased LTD. Mechanistically, copine-6 promotes BDNF-TrkB signaling and recycling of activated TrkB receptors back to the plasma membrane surface, and is necessary for BDNF-induced increases in mushroom spines in hippocampal neurons. Thus copine-6 regulates BDNF-dependent changes in dendritic spine morphology to promote synaptic plasticity.

Purpose of Review: The current serotonin-based biological model of suicidal behavior (SB) may be too simplistic. There is emerging evidence that other biomarkers and biological systems may be involved in SB pathophysiology. The literature on the endocannabinoid (EC) systems and SB is limited. The objective of the present article is to review all available information on the relationship between cannabinoid receptors (CB 1 and CB 2 receptors), and SB and/or psychological pain., Recent Findings: Our review is limited by the small number and heterogeneity of studies identified: (1) an autopsy study describing elevated levels of CB 1 receptor activity in the prefrontal cortex and suicide in both depression and alcoholism and (2) studies supporting the involvement of both CB 1 and CB 2 receptors in the regulation of neuropathic pain and stress-induced analgesia. We conclude that cannabinoid receptors, particularly CB 1 receptors, may become promising targets for the development of novel therapeutic tools for the treatment of SB.

Objectives: The aim of this study was to compare patient response to cardiac resynchronization therapy (CRT) using fusion-optimized atrioventricular (AV) and interventricular (VV) intervals versus nominal settings., Background: The additional benefit obtained by AV- and VV-interval optimization in patients undergoing CRT remains controversial. Previous studies show short-term benefit in hemodynamic parameters; however, midterm randomized comparison between electrocardiogram optimization and nominal parameters is lacking., Methods: A group of 180 consecutive patients with left bundle branch block treated with CRT were randomized to fusion-optimized intervals (FOI) or nominal settings. In the FOI group, AV and VV intervals were optimized according to the narrowest QRS, using fusion with intrinsic conduction. Clinical response was defined as an increase >10% in the 6-min walk test or an increment of 1 step in New York Heart Association functional class. The left ventricular (LV) remodeling was defined as >15% decrease in left ventricular end-systolic volume (LVESV) at 12-month follow-up. Additionally, patients with LVESV reduction >30% relative to baseline were considered super-responders; by contrast, negative responders had increased LVESV relative to baseline., Results: Participant characteristics included a mean age of 65 ± 10 years, 68% male, 37% with ischemic cardiomyopathy, LV ejection fraction 26 ± 7%, and QRS 180 ± 22 ms. Baseline QRS was shortened significantly more by FOI, compared with nominal settings (-56.55 ± 17.65 ms vs. -37.81 ± 22.07 ms, respectively; p = 0.025). At 12 months, LV reverse remodeling was achieved in a larger proportion of the FOI group (74% vs. 53% [odds ratio: 2.02 (95% confidence interval: 1.08 to 3.76)], respectively; p = 0.026). No significant differences were observed in clinical response (61% vs. 53% [odds ratio: 1.43 (95% confidence interval: 0.79 to 2.59)], respectively; p = 0.24)., Conclusions: Device optimization based on FOI achieves greater LV remodeling, compared with nominal settings. (ECG Optimization of CRT: Evaluation of Mid-Term Response [BEST]; NCT01439529)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aβ pores without changing the membrane embedded Aβ-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Regular use of marijuana during adolescence enhances the risk of long-lasting neurobiological changes in adulthood. The present study was aimed at assessing the effect of long-term administration of the synthetic cannabinoid WIN55212.2 during adolescence in young adult mice. Adolescent mice aged 5 weeks were subjected daily to the pharmacological action of WIN55212.2 for 3 weeks and were then left undisturbed in their home cage for a 5-week period and finally evaluated by behavioral testing. Mice that received the drug during adolescence showed memory impairment in the Morris water maze, as well as a dose-dependent memory impairment in fear conditioning. In addition, the administration of 3 mg/kg WIN55212.2 in adolescence increased adult hippocampal AEA levels and promoted DNA hypermethylation at the intragenic region of the intracellular signaling modulator Rgs7, which was accompanied by a lower rate of mRNA transcription of this gene, suggesting a potential causal relation. Although the concrete mechanisms underlying the behavioral observations remain to be elucidated, we demonstrate that long-term administration of 3 mg/kg of WIN during adolescence leads to increased endocannabinoid levels and altered Rgs7 expression in adulthood and establish a potential link to epigenetic changes., (© 2016 The Authors.Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c-null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 ( Fmn2) is deregulated in PTSD and in Alzheimer's disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity, while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease. Systemic administration of JQ1 elicited a hippocampal gene expression program that is associated with ion channel activity, transcription and DNA repair. Our findings suggest that JQ1 could be used as a therapy against dementia and should be further tested in the context of learning and memory.

The purpose of this study was to assess reports by psychologists and social workers in lawsuits regarding grandparent visitation rights in Barcelona (Spain). Seventy-three reports written during a five-year period were analysed Sixty-three per cent of cases recommended grandparents being granted visitation rights. A content analysis of the reports revealed that they were more likely to contain negative rather than positive comments about a family member (especially grandparents). Finally, the analysis showed that aspects such as grandparent abilities and a hidden agenda on the part of grandparents were associated with a recommendation that a visitation schedule be denied, whereas the presence of a strong bond between grandparents and the grandchild was related to a favourable recommendation. The article discusses directions for further research and the potential value of drawing up guidelines to assess grandparent rights in the event of family conflict., Competing Interests: The authors report no declarations of interest, (© 2017 The Australian and New Zealand Association of Psychiatry, Psychology and Law.)

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The objective of the Balearic Islands Palliative Care (PC) Program is to improve the quality of PC through a shared model consisting of primary health care professionals, home-based PC teams, and PC units in hospitals. According to the World Health Organization (WHO), patients with advanced cancer and other terminal diseases benefit from early identification and proactive PC. We will evaluate the effectiveness of an intervention in which a PC leader is established in the primary health care center, and assess the effect of this intervention on the early identification of patients in need of PC, the efficient use of health care services, and direct health care costs., Methods: Design: A two-arm cluster randomized clinical trial of 30 Primary Health Care Centers (PHCC) in Mallorca (Spain), in which each center was randomized to an intervention arm or a usual care arm. We expect that the number of patients identified as suitable for PC (including non-oncological PC) is at least 5% greater in the intervention arm., Sample Size: A total of 4640 deceased patients. Outcomes will be assessed by a blinded external review of the electronic records., Interventions: General practitioners (GPs) and nurse leaders in PC for each PHCC will be appointed. These leaders will help promote PC training of colleagues, improve symptom management and psychological support of patients, and evaluate the complexity of individual cases so that these cases receive assistance from PC home-based teams., Measurements: Early identification (>90 days before death), evaluation of case complexity, level of case complexity (with referral to a home-based PC team), use and cost of hospital and primary care services, and quality of life during the last month of life (≥2 emergency room visits, ≥2 hospital admissions, ≥14 days of hospitalization)., Discusion: PC leaders in primary care teams will improve the early identification of patients eligible for PC. This initiative could improve the quality of end-of-life care and utilization of hospital resources., Trial Registration: ISRCTN Registry identifier: ISRCTN92479122 . Retrospectively registered on 28 February 2017.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 ( Hdac1 ) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia., Competing Interests: The authors declare no conflict of interest.

Introduction: Dyspepsia is a common disorder in both Primary (PC) and Specialised Care (SC). Gastroscopy is recommended at the start of the study if there are warning signs, although it is not always available in PC., Objectives and Methods: We developed a pilot project establishing an early gastroscopy programme for patients with dyspepsia and warning signs in PC, subsequently extending it to the entire healthcare area. The aim was to evaluate the requirements, impact and opinion of this service at the PC level. Demographic, symptomatic and endoscopic variables on the patients referred to SC from the pilot centre were recorded. A satisfaction survey was conducted among the PC physicians., Results: The one-year pilot study and the first year of implementation of the programme were evaluated. A total of 355 patients were included (median age 56.4 years; IQR 45.5-64.3); 61.2% (56.1-66.3%) were women. The waiting time for examination was 1.5 weeks (IQR 1.5-2.5). Gastroscopy was correctly indicated in 82.7% (78.4-86.3%) of patients. The median number of requests per month was 1.1 per 10,000 adults (range 0.8-1.6). Monthly referrals to SC clinics from the pilot centre fell by 11 subjects (95% CI 5.9-16) with respect to the previous median of 58 (IQR 48-64.5). Almost all those polled (98.4%) considered the programme useful in routine practice., Conclusions: The availability of an early gastroscopy programme in PC for patients with dyspepsia and warning signs reduced the number of referrals to SC., (Copyright © 2016 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.)

Many threatened species in Europe have been expanding their distributions during recent decades owing to protection measures that overcome historical human activity that has limited their distributions. Range expansion has come about via two processes, natural expansion from existing range and reintroductions to new ranges. Reintroductions may prove to be a better way to establish populations because individuals are less subject to competitive relationships lowering breeding success than individuals expanding from existing populations. Whether this is true, however, remains uncertain. We compared success of breeding pairs of an expanding and a reintroduced population of spanish imperial eagles monitored for over 15 years in the south of Spain. We found significant differences in productivity between breeding pairs of each population. Newly established territories in reintroduction areas were almost three times more productive than new territories established as individuals expanded out from an existing population. We conclude that among these eagle populations reintroduced to new areas may fare as well or better than individuals expanding out form existing populations.

The main objective of the present paper has been the development and study of two new biodegradable polyurethanes, PU(dithiodiethanol-DTDI) and PU[( i Pr)Man-DTDI], to be used as sustained matrix forming excipients. Furthermore, their capacity to act as excipient for colon drug delivery systems has been evaluated. Thus, SeDeM diagrams have been obtained to investigate their suitability to be processed through a direct compression process. Matrices containing 10-30% w/w of the polymers and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using a modified dissolution assay simulating pH and redox conditions for the gastro intestinal tract, including colon. Drug dissolution data have been analyzed according to the main kinetic models and their Excipient Efficiencies for prolonged release have been calculated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index obtained for the polymers are above the values considered as adequate for direct compression even without addition of flow agents. The obtained values for Excipient Efficiency show good ability of the polymer to control the drug release. Finally, in the case of PU(dithiodiethanol-DTDI), a clear increase in the release rate has been observed when the formulation is subjected to colon simulating conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: Palliative care professionals' quality of life has emerged as a growing issue of interest in health care literature, centered on concerns about professionals' compassion within a context of work characterized by pain and death., Objectives: The aim of this study was threefold: 1) to study the psychometric properties of both the Spanish and the Portuguese versions of the ProQOL scale, by means of confirmatory factor analyses; 2) to offer a diagnosis of compassion satisfaction and compassion fatigue levels of Spanish and Brazilian palliative care professionals; and 3) to compare levels in ProQOL between countries., Methods: Two surveys with a cross-sectional design were carried out; 161 Brazilian palliative care professionals and 385 Spanish participated in this study., Results: Confirmatory factor analysis for both the Spanish and the Portuguese versions showed an adequate fit. Reliability estimates were also adequate, with problems with the burnout dimension. Spanish and Brazilian palliative care professionals showed high levels of compassion satisfaction (specially, for the Brazilian samples), medium levels of secondary traumatic stress, and low levels of burnout. Finally, statistically significant differences in Spanish and Brazilian levels of compassion satisfaction and secondary traumatic stress were found, but not in burnout., Conclusion: The ProQOL shows psychometric goodness in its Spanish and Portuguese versions, although some items should be revised. The ProQOL is also useful for diagnosis and is sensitive enough to distinguish nuances as that found between Brazilian and Spanish professionals., (Copyright © 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

This paper presents a review of the different approaches existing in the literature to detect and quantify fibrosis in contrast-enhanced magnetic resonance images of the left atrial wall. The paper provides a critical analysis of the different methods, stating their advantages and limitations, and providing detailed analysis on the possible sources of variability in the final amount of detected fibrosis coming from the use of different techniques.

Objectives: To describe the design, implementation, and monitoring of eSOAP (Primary Health Care Balanced Scorecard) and its role in the deployment of strategic objectives and clinical management, as well as to show the lessons learned during six years of follow-up., Method: Descriptive study areas: methodology (conceptual framework, strategic matrix, strategic map, and processes map), technology and standardisation., Results: As of December 2014, 9,046 (78%) professionals are registered in eSOAP. A total of 381 indicators were measured from 16 data sources, of which 36% were of results (EFQM model), 39.1% of clinical management, and 20% were included in the Program Centre Contract. The Balanced Scorecard has enabled to deploy all strategic lines of Primary Health Care, and has enabled the healthcare professionals to evaluate the evolution of results over time, and at patient level (e.g. 16% increase in control of diabetic patients). A total of 295,779 reports were generated and 13,080 professionals were evaluated by goals., Conclusions: There was an increased use of the eSOAP application by the professionals. The Balanced Scorecard was the key in deploying Primary Health Care strategies. It has helped clinical management and improved relevant indicators (health, patient experience, and costs), such as the management models that we used as references (EFQM Kaplan and Norton), and new emerging scenarios (Triple aim)., (Copyright © 2016 SECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

Background: Catheter contact force (CF) has a strong correlation with lesion formation during radiofrequency ablation. Delayed-enhancement cardiac magnetic resonance (DE-CMR) provides lesion information in patients with prior atrial fibrillation (AF) ablation., Objective: The aim of this study was to determine the CF threshold to create permanent lesions detected by DE-CMR., Methods: A total of 36 patients referred for AF ablation were included. A CF catheter was used during the ablation procedure, and DE-CMR was performed 3 months after the ablation procedure. Eighteen pulmonary vein (PV) segments were defined, and 3-dimensional (3D) reconstructions of the left atrium (LA) derived from the DE-CMR images were obtained. One observer evaluated the presence of any discontinuity of previous ablation lesions (gap) in the 3D reconstructions of the LA, and another observer (blinded to the gap findings) determined the minimum CF value in each PV segment., Results: The PV segments where a gap was observed had a lower maximal CF value than did the segments without gap in the 3D LA reconstructions (6.7 ± 4.4 g vs 12.2 ± 4.7 g; P < .001). In receiver operating characteristic analysis, a CF threshold of >8 g provided 73% sensitivity and 81% specificity in the prediction of a complete PV lesion (positive predictive value [PPV] 84%). A CF threshold of >12 g had a specificity of 94% and increased the PPV to 91% in creating a complete lesion in the LA wall (area under the curve 0.834)., Conclusion: A CF threshold of >12 g H5H20 predicts a complete lesion with high specificity and PPV when a dragging ablation strategy is used in AF ablation., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The stimulus-regulated transcription factor Serum Response Factor (SRF) plays an important role in diverse neurodevelopmental processes related to structural plasticity and motile functions, although its precise mechanism of action has not yet been established. To further define the role of SRF in neural development and distinguish between cell-autonomous and non cell-autonomous effects, we bidirectionally manipulated SRF activity through gene transduction assays that allow the visualization of individual neurons and their comparison with neighboring control cells. In vitro assays showed that SRF promotes survival and filopodia formation and is required for normal asymmetric neurite outgrowth, indicating that its activation favors dendrite enlargement versus branching. In turn, in vivo experiments demonstrated that SRF-dependent regulation of neuronal morphology has important consequences in the developing cortex and retina, affecting neuronal migration, dendritic and axonal arborization and cell positioning in these laminated tissues. Overall, our results show that the controlled and timely activation of SRF is essential for the coordinated growth of neuronal processes, suggesting that this event regulates the switch between neuronal growth and branching during developmental processes.

Purpose of Review: To summarize current evidence on evaluation tools for spiritual care, paying special attention to recent validations and new instruments, systematic reviews, recent consensus on spiritual care and its measurement, plus other emergent topics., Recent Findings: The systematic review resulted in 45 identified studies, 14 of which were considered: five works addressed the need for development and validation of spiritual tools; three studies reviewed tools for spirituality assessment, interventions, or related concepts; three more covered the efforts to define guidelines and priorities for spiritual care and its measurement. Other topics such as pediatric spiritual care, the use of new technologies, or nationwide surveys, also arose., Summary: Recent contributions outline usability traits such as to shorten scales and measurement protocols for maximum respect of patients' quality of life. Other works addressed complicated grief or satisfaction with attention to spiritual care, transcending the patients, family and professionals' focus in on a sort of combined perspective. Further attention to culturally based specific models supporting questionnaires, a deeper understanding of quality of the spiritual care, both for patients and families, or further research on the relation between spiritual care and life span should be welcomed.

Introduction: Atherosclerosis is an inflammatory chronic disease influenced by multiple factors. Different prospective studies have shown that plasmatic levels of inflammatory markers were related to atherosclerosis and cardiovascular disease., Objective: To evaluate whether plasmatic levels of interleukin 18 (IL-18) are modulated by SNPs (single nucleotide polymorphisms) of the IL 18 gene and its possible association with insulin levels and other cardiovascular risk factors., Methods: 746 individuals were studied for a period of two years by opportunistic selection in the metropolitan area of Valencia. Parameters of lipid and glucose metabolism were analyzed by standard methodology. IL-18 was measured by ELISA., Results: Individuals with insulin resistance showed significant higher levels of IL-18. IL 18 was significantly correlated with insulin levels and other cardiovascular risk factors. The CC genotype of the rs1834481 SNP was significantly associated with lower levels of IL-18. However, the GG genotype of the rs7559479 was associated with significant higher levels of IL-18., Conclusion: IL-18 is associated with insulin resistance and other cardiovascular risk factors, being those levels genetically regulated., (Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.)

Self-care is a cornerstone issue for those who deal with stressful events, as it is the case of palliative care professionals. It has been related to awareness, coping with death and quality of life, among others, but no measurement instruments have been used in palliative care professionals. This research presents and validates a brief new measure with clinical and psychometric good properties, called Professional Self-Care Scale (PSCS). The PSCS assesses professionals' self-care in three areas: physical self-care, inner self-care, and social self-care. Data come from a cross-sectional survey in a sample of 385 professionals of palliative care. The Mindful Attention Awareness Scale, the Coping with Death Scale, and the Professional's Quality of Life measure were also used. Results of the CFA showed adequate fit (χ2(24, N = 385) = 140.66, p < .01; CFI = .91; GFI = .93; SRMR = .09; and RMSEA = .10). Evidence pointed better reliability indices for the 3-item physical and inner factors of self-care than for the social dimension (Rho and GLB of .64, .90, and .57, respectively). Evidence regarding validity was consistent with previous literature. When levels of self-care were examined, women showed higher levels of inner and social self-care (F(3, 371) = 3.19, p = .02, η2 = .03, as also did psychologists when compared to doctors and nurses (F(9, 1074) = 2.00, p = .04, η2 = .02. The PSCS has shown adequate psychometric properties, and thus it could be used as diagnostic instrument when studying professionals' health.

Aging and increased amyloid burden are major risk factors for cognitive diseases such as Alzheimer's disease (AD). Effective therapies for these diseases are lacking. Here, we evaluated mouse models of age-associated memory impairment and amyloid deposition to study transcriptome and cell type-specific epigenome plasticity in the brain and peripheral organs. We determined that aging and amyloid pathology are associated with inflammation and impaired synaptic function in the hippocampal CA1 region as the result of epigenetic-dependent alterations in gene expression. In both amyloid and aging models, inflammation was associated with increased gene expression linked to a subset of transcription factors, while plasticity gene deregulation was differentially mediated. Amyloid pathology impaired histone acetylation and decreased expression of plasticity genes, while aging altered H4K12 acetylation-linked differential splicing at the intron-exon junction in neurons, but not nonneuronal cells. Furthermore, oral administration of the clinically approved histone deacetylase inhibitor vorinostat not only restored spatial memory, but also exerted antiinflammatory action and reinstated epigenetic balance and transcriptional homeostasis at the level of gene expression and exon usage. This study provides a systems-level investigation of transcriptome plasticity in the hippocampal CA1 region in aging and AD models and suggests that histone deacetylase inhibitors should be further explored as a cost-effective therapeutic strategy against age-associated cognitive decline.

Context: Professionals working in the landscape of death and dying frequently are exposed to existential issues, psychological challenges, and emotional distress associated with care at the end of life. Identifying factors that help professionals cope with frequent exposure to issues related to mortality could enhance palliative care providers' and patients' quality of life., Objectives: To improve our understanding of the factors associated with professionals' inner life, through the assessment of an adapted version of Kearney and Kearney's awareness model of self-care. The main assumptions of the study were that competence in coping with death and awareness would be positively related to compassion satisfaction and negatively to compassion fatigue and burnout; moreover, participating in a specific training program aimed at facing suffering and death, and self-care would positively predict coping with death., Methods: A cross-sectional online survey of Spanish palliative care professionals was conducted through the member e-mail list of the Spanish Society of Palliative Care. A total of 387 professionals completed the survey, which included demographic data, and personal and professional scales on the mentioned constructs., Results: Data fit reasonably well with the estimated model. Whereas the hypothesis relating spiritual training to coping with death was not supported by the data, all other aspects of the hypotheses were supported, namely self-care and awareness positively predicted professionals' competence in coping with death, and this, together with awareness, positively predicted compassion satisfaction and negatively predict compassion fatigue and burnout., Conclusion: The awareness-based model of self-care was successfully tested in a multidisciplinary sample of Spanish palliative care professionals. This research applies a quantitative evaluation of the model, providing evidence of a constellation of key variables for health professionals' quality of life, such as specific training, self-care, awareness and coping with death competency., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples., Methods: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal., Results: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689)., Conclusions: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.

Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers.

Activity-driven transcription is a key event associated with long-lasting forms of neuronal plasticity. Despite the efforts to investigate the regulatory mechanisms that control this complex process and the important advances in the knowledge of the function of many activity-induced genes in neurons, as well as the specific contribution of activity-regulated transcription factors, our understanding of how activity-driven transcription operates at the systems biology level is still very limited. This review focuses on the research of neuronal activity-driven transcription from an "omics" perspective. We will discuss the different high-throughput approaches undertaken to characterize the gene programs downstream of specific activity-regulated transcription factors, including CREB, SRF, MeCP2, Fos, Npas4, and others, and the interplay between epigenetic and transcriptional mechanisms underlying neuronal plasticity changes. Although basic questions remain unanswered and important challenges still lie ahead, the refinement of genome-wide techniques for investigating the neuronal transcriptome and epigenome promises great advances.