Transcription regulation of TNF-α-early response genes by poly(ADP-ribose) polymerase-1 in murine heart endothelial cells

The original publication is a available at www.oxfordjournals.org.-- 10 pp.[EN] Poly(ADP-ribose) polymerase-1 (PARP-1) has been involved in endothelial cell dysfunction associated with various pathophysiological conditions. The intrinsic mechanism of PARP-1-mediated endothelial cell dysfunction could be related to PARP-1 overactivation, NAD+ consumption and ATP depletion. An alternative way could involve transcription regulation. By using high-density microarrays, we examined early tumor necrosis factor α(TNF- α)- stimulated gene expression profiles in PARP-1+/+ and PARP-1-/- murine heart endothelial cells. TNF-α modulated a significant number of genes in both cell types. We have identified a set of genes whose expression in response to TNF-a is modulated by PARP-1, whereas the expression of others is PARP- 1-independent. Up-regulation of several genes involved in the inflammatory response is hampered in the absence of PARP-1. Moreover, NF-қB-dependent transcriptional activation is partially inhibited in PARP-1-/- compared to PARP-1+/+ cells. However, we found that PARP-1 might also silence transcription of several NF-қB target genes. Overall, our results show that PARP-1 is regulating the expression of genes by the endothelial cells both in a positive and a negative fashion, with the final effects depending on the gene. Individual studies of these genes are now necessary to clarify the intrinsic mechanism by which PARP-1 is controlling transcription and thereby finding out different therapeutic approaches involving PARP-1.A.C. is a recipient of a fellowship from Fundación Séneca. J.Y. is an Investigator from the Ramón y Cajal Program (Spanish Ministerio de Ciencia y Tecnología). This work was supported by the Instituto de Salud Carlos III Grants PI021138 and C03/02.Peer reviewe

La autogestión de emociones y sentimientos para “ser buenas personas”

Teachers are often in classroom environmentswhere emotions emerge. In this article we present a teaching approach called “self-management of problems”, in which emotions and their management are addressed in class through the assembly. For example, when students are involved in making decisions and self-managing their problems, different points of view, consonances and dissonances emerge that bring out emotions such as empathy, anger orlove. In order to encourage active participation of students in their assemblies, it is essential for the student to manage some emotions such as shame or fear. We show the results of implementing a training proposal for Selfmanagement of problems for PE at a peri-urban school in Huércal de Almería (Spain), during the academic year 2011-2012. The analysis of what happens in the assemblies from an emotional perspective allows describing and identifying what happens in the process.Los docentes a menudo nos encontramos en clase situaciones en que las emociones emergen y su tratamiento se hace indispensable en el aula. En el presente artículo presentamos una propuesta denominada “autogestión de problemas” en clases de Primaria de Educación Física (EF), en la que las emociones y su gestión son abordadas en clase mediante la asamblea. Por ejemplo, cuando se involucra a los estudiantes a tomar de decisiones y a autogestionar sus problemas surgen diferentes puntos de vista, consonancias y disonancias que hacen aflorar emociones como la empatía, la rabia, el amor, pero también emergen otras cuyo tratamiento es imprescindibles para que se pueda favorecer la participación de todos en las asambleas, como son la vergüenza o el miedo. Mostramos los resultados de implementar una propuesta formativa de autogestión de problemas para EF del CEIP Buenavista (Huércal de Almería, curso 11-12) y el análisis de lo sucedido en las asambleas desde una mirada emocional que permita describir e identificar qué sucede en el proceso

Transcriptional regulation by Poly(ADP-ribose) polymerase-1 during T cell activation

<p>Abstract</p> <p>Background</p> <p>Accumulating evidence suggests an important role for the enzyme poly(ADP-ribose) polymerase-1 (PARP-1) as an integral part of the gene expression regulatory machinery during development and in response to specific cellular signals. PARP-1 might modulate gene expression through its catalytic activity leading to poly(ADP-ribosyl)ation of nuclear proteins or by its physical association with relevant proteins. Recently, we have shown that PARP-1 is activated during T cell activation. However, the proposed role of PARP-1 in reprogramming T cell gene expression upon activation remains largely unexplored.</p> <p>Results</p> <p>In the present study we use oligonucleotide microarray analysis to gain more insight into the role played by PARP-1 during the gene expression reprogramming that takes place in T cells upon activation with anti-CD3 stimulation alone, or in combination with anti-CD28 co-stimulation. We have identified several groups of genes with expression modulated by PARP-1. The expression of 129 early-response genes to anti-CD3 seems to be regulated by PARP-1 either in a positive (45 genes) or in a negative manner (84 genes). Likewise, in the presence of co-stimulation (anti-CD3 + anti-CD28 stimulation), the expression of 203 genes is also regulated by PARP-1 either up (173 genes) or down (30 genes). Interestingly, PARP-1 deficiency significantly alters expression of genes associated with the immune response such as chemokines and genes involved in the Th1/Th2 balance.</p> <p>Conclusion</p> <p>This study provides new insights into changes in gene expression mediated by PARP-1 upon T cell activation. Pathway analysis of PARP-1 as a nuclear signalling molecule in T cells would be of relevance for the future development of new therapeutic approaches targeting PARP-1 in the acquired immune response.</p

Effectiveness of Fingolimod versus Natalizumab as Second-Line Therapy for Relapsing-Remitting Multiple Sclerosis in Spain: Second-Line GATE Study

Background: There is a lack of head-to-head studies comparing the efficacy of fingolimod (FIN) and natalizumab (NTZ) as second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Methods: Multicenter, observational study, in which, information of 388 patients randomly selected and treated with FIN or NTZ in routine clinical practice was retrospectively collected with the main objective of comparing the annualized relapse rate (ARR) over the first year, after FIN or NTZ treatment initiation. Results: Mean ARR during the first year of treatment was 0.28 in FIN group and 0.12 in NTZ group (p = 0.0064); nevertheless, the difference between groups lost statistical significance when the propensity score analysis was performed. Time to disability -progression was similar in both treatment groups (12.3 +/- 6.7 months in FIN, and 12.8 +/- 0.1 months in NTZ; p = 0.4654). Treatment persistence after the first year of treatment was higher in patients treated with FIN (95%) than in those treated with NTZ (84%; p = 0.0014). Conclusions: After 12 months of treatment, both FIN and NTZ reduced the ARR, but ARR percent reduction was significantly higher with NTZ. Treatment persistence was higher in patients receiving FIN

Blood test dynamics in hospitalized COVID-19 patients: Potential utility of D-dimer for pulmonary embolism diagnosis

Background: A higher incidence of thrombotic events, mainly pulmonary embolism (PE), has been reported in hospitalized patients with COVID-19. The main objective was to assess clinical and laboratory differences in hospitalized COVID-19 patients according to occurrence of PE. Methods: This retrospective study included all consecutive patients hospitalized with COVID-19 who underwent a computed tomography (CT) angiography for PE clinical suspicion. Clinical data and median blood test results distributed into weekly periods from COVID-19 symptoms onset, were compared between PE and non-PE patients. Results: Ninety-two patients were included, 29 (32%) had PE. PE patients were younger (63.9 (SD 13.7) vs 69.9 (SD 12.5) years). Clinical symptoms and COVID-19 CT features were similar in both groups. PE was diagnosed after a mean of 20.0 (SD 8.6) days from the onset of COVID-19 symptoms. Corticosteroid boluses were more frequently used in PE patients (62% vs. 43%). No patients met ISTH DIC criteria. Any parameter was statistically significant or clinically relevant except for D-Dimer when comparing both groups. Median values [IQR] of D-dimer in PE vs non-PE patients were: week 2 (2010.7 [770.1-11208.9] vs 626.0 [374.0-2382.2]; p = 0.004); week 3 (3893.1 [1388.2-6694.0] vs 1184.4 [461.8-2447.8]; p = 0.003); and week 4 (2736.3 [1202.1-8514.1] vs 1129.1 [542.5-2834.6]; p = 0.01). Median fold-increase of D-dimer between week 1 and 2 differed between groups (6.64 [3.02-23.05] vs 1.57 [0.64-2.71], p = 0.003); ROC curve AUC was 0.879 (p = 0.003) with a sensitivity and specificity for PE of 86% and 80%, respectively. Conclusions: Among hospitalized COVID-19 patients, D-dimer levels are higher at weeks 2, 3 and 4 after COVID-19 symptom onset in patients who develop PE. This difference is more pronounced when the fold increase between weeks 1 and 2 is compared

Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis

Abstract Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sAL

A multicenter case-control study comparing sun exposure habits and use of photoprotection measures in patients diagnosed with different types of skin cancer

Background: While skin cancer awareness programs have significantly furthered public understanding about the harmful effects of the sun, there is a disparity between photoprotection knowledge and protection practices. Objective: To compare sun exposure habits and photoprotection measures in patients diagnosed with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma versus controls. Methods: Multicentre case–control observational study carried out by 13 Spanish dermatologists between April 2020 and August 2022. Patients diagnosed with BCC, SCC, or melanoma were considered cases. The control group consisted of individuals with no history of skin cancer. Results: Of the 254 cases (56.2% female; mean age, 62.67 ± 15.65), 119 (31.2%) had BCC, 62 (16.27%) SCC, and 73 (19.1%) melanoma. The control group consisted of 127 (33.33%) individuals. Avoiding sun exposure between 12:00 and 16:00 was the most commonly used photoprotection measure (habitually/always: 63.1%), followed by the use of sunscreen (habitually/always: 58.9%). Patients with melanoma were less likely to use clothing and shade to avoid sun exposure (p  50. No differences were observed in photoprotection measures between people with and without a previous history of skin cancer. Conclusions: We describe differences in photoprotection measures and sun exposure patterns among patients diagnosed with different skin tumor types. Whether these differences may influence the type of tumor each developed will require further investigation

Intensive care adult patients with severe respiratory failure caused by Influenza A (H1N1)v in Spain

Introduction: Patients with influenza A (H1N1)v infection have developed rapidly progressive lower respiratory tract disease resulting in respiratory failure. We describe the clinical and epidemiologic characteristics of the first 32 persons reported to be admitted to the intensive care unit (ICU) due to influenza A (H1N1)v infection in Spain. Methods: We used medical chart reviews to collect data on ICU adult patients reported in a standardized form. Influenza A (H1N1)v infection was confirmed in specimens using real-time reverse transcriptase-polymerase-chain-reaction (RT PCR) assay. Results: Illness onset of the 32 patients occurred between 23 June and 31 July, 2009. The median age was 36 years (IQR = 31 - 52). Ten (31.2%) were obese, 2 (6.3%) pregnant and 16 (50%) had pre-existing medical complications. Twenty-nine (90.6%) had primary viral pneumonitis, 2 (6.3%) exacerbation of structural respiratory disease and 1 (3.1%) secondary bacterial pneumonia. Twenty-four patients (75.0%) developed multiorgan dysfunction, 7 (21.9%) received renal replacement techniques and 24 (75.0%) required mechanical ventilation. Six patients died within 28 days, with two additional late deaths. Oseltamivir administration delay ranged from 2 to 8 days after illness onset, 31.2% received high-dose (300 mg/day), and treatment duration ranged from 5 to 10 days (mean 8.0 +/- 3.3). Conclusions: Over a 5-week period, influenza A (H1N1)v infection led to ICU admission in 32 adult patients, with frequently observed severe hypoxemia and a relatively high case-fatality rate. Clinicians should be aware of pulmonary complications of influenza A (H1N1)v infection, particularly in pregnant and young obese but previously healthy persons