Search

Histone deacetylase SIRT1 represses gene expression through the deacetylation of histones and transcription factors and is involved in the protective cell response to stress and aging. However, upon endoplasmic reticulum (ER) stress, SIRT1 impairs the IRE1α branch of the unfolded protein response (UPR) through the inhibition of the transcriptional activity of XBP-1 and SIRT1 deficiency is beneficial under these conditions. We hypothesized that SIRT1 deficiency may unlock the blockade of transcription factors unrelated to the UPR promoting the synthesis of chaperones and improving the stability of immature proteins or triggering the clearance of unfolded proteins. SIRT1+/+ and SIRT1-/- fibroblasts were exposed to the ER stress inducer tunicamycin and cell survival and expression of heat shock proteins were analyzed 24 h after the treatment. We observed that SIRT1 loss significantly reduced cell sensitivity to ER stress and showed that SIRT1-/- but not SIRT1+/+ cells constitutively expressed high levels of phospho-STAT3 and heat shock proteins. Hsp70 silencing in SIRT1-/- cells abolished the resistance to ER stress. Furthermore, accumulation of ubiquitinated proteins was lower in SIRT1-/- than in SIRT1+/+ cells. Our data showed that SIRT1 deficiency enabled chaperones upregulation and boosted the proteasome activity, two processes that are beneficial for coping with ER stress.

Background: Different approaches of evaluation by cardiologists using telemedicine have the potential of improving care of patients with ST elevation myocardial infarction (STEMI). Objective: To compare the use of pharmacoinvasive strategy and associated clinical outcomes (heart failure [HF] and mortality) among patients with STEMI before and after a program of telemedicine and also according to the level of support by telemedicine. Methods: A chest pain network with the support of a cardiologist through telemedicine was implemented in 2012 in 22 emergency departments without a local cardiac catheterization laboratory. Initially (phase 1 of telemedicine), the decision to discuss the case with the cardiologist was based on the judgment of the emergency physician. At the end of 2018, the use of telemedicine was modified and a dedicated cardiologist was available continuously to discuss systematically all suspected cases (phase 2 of telemedicine). The use of fibrinolytics and the rates of HF and in-hospital mortality were compared among three different periods: pretelemedicine (2011), and phase 1 and phase 2 of the telemedicine program. Results: We evaluated 1034 STEMI patients and after comparing the three phases, we did not find significant differences regarding age, gender, and comorbidities. The use of fibrinolytics before transferring STEMI patients to a percutaneous coronary intervention center (pharmacoinvasive strategy) increased after telemedicine implementation (38% vs. 65.2%; p  < 0.01), which was associated with a lower rate of HF (23.9% vs. 14.4%; p  = 0.01) and death (7.9% vs. 4.0%; p  = 0.05). The in-hospital mortality was lower in phase 2 with systematic evaluation by telemedicine compared with pretelemedicine (7.9% vs. 3.3%; p  = 0.04). Conclusion: The implementation of a systematic and organized chest pain protocol, including telemedicine support, was associated with a significant increase in the use of pharmacoinvasive strategy and better clinical patient outcomes in patients with STEMI. Our findings provide important insights on how to improve the management of this high-risk population, reducing the gap between evidence and clinical practice., Competing Interests: P.G.M.B.S. reports grants and personal fees from Pfizer, Bayer, and Roche Diagnostics outside the submitted work. R.D.L. reports grants from Amgen; personal fees from Bayer, Boehringer Ingelheim, and Portola; and grants and personal fees from Bristol Myers Squibb, Glaxo Smith Kline, Pfizer, and Sanofi-Aventis outside the submitted work. All other authors have no disclosures to report., (© United Health Group Brazil, 2021; Published by Mary Ann Liebert, Inc.)

Methyl-CpG-binding protein 2 (MeCP2) is an X-linked epigenetic modulator whose dosage is critical for neural development and function. Loss-of-function mutations in MECP2 cause Rett Syndrome (RTT, OMIM #312750) while duplications in the Xq28 locus containing MECP2 and Interleukin-1 receptor-associated kinase 1 ( IRAK1 ) cause MECP2 duplication syndrome (MDS, OMIM #300260). Both are rare neurodevelopmental disorders that share clinical symptoms, including intellectual disability, loss of speech, hand stereotypies, vasomotor deficits and seizures. The main objective of this exploratory study is to identify novel signaling pathways and potential quantitative biomarkers that could aid early diagnosis and/or the monitoring of disease progression in clinical trials. We analyzed by RT-PCR gene expression in whole blood and microRNA (miRNA) expression in plasma, in a cohort of 20 females with Rett syndrome, 2 males with MECP2 duplication syndrome and 28 healthy controls, and correlated RNA expression with disease and clinical parameters. We have identified a set of potential biomarker panels for RTT diagnostic and disease stratification of patients with microcephaly and vasomotor deficits. Our study sets the basis for larger studies leading to the identification of specific miRNA signatures for early RTT detection, stratification, disease progression and segregation from other neurodevelopmental disorders. Nevertheless, these data will require verification and validation in further studies with larger sample size including a whole range of ages.

Objectives: To validate the American fatigue scale HIV-Related Fatigue Scale (HRFS) and present the Spanish version called Integrated Fatigue Assessment Scale to assess fatigue in HCV and co-infected patients., Method: Psychometric study with cross-sectional design was used. The HRFS was translated into Spanish using the back-translation method-later to be validated. Participants completed the questionnaire adapted to a self-report form, as well as a sociodemographic questionnaire. The reliability and validity of the Spanish version was evaluated., Results: A total of 7 public service hospitals and two prisons in Catalonia participated in the evaluation. The sample consisted of 122 subjects selected by consecutive sampling in the fourth week of treatment of hepatitis C with combination therapy or triple therapy. The Cronbach alpha for the total scale was 0.958. Content Validity Index (I-CVI) varied from 0.5 to 1. Validity Scale Content-level (S-CVI) was 0.85. Pearson correlations between the three dimensions were between 0.49 and 0.68., Conclusions: The process followed for the cultural adaptation and validation shows that the Spanish version of the HRFS) is a valid and reliable instrument that can be used in clinical practice and in the investigation of fatigue in patients with hepatitis C., (Copyright © 2015 Elsevier España, S.L.U. All rights reserved.)