Nuclear factor-erythroid 2-related factor 2 (Nrf2/NFE2L2), a redox-sensitive transcription factor plays a critical role in adaptation to cellular stress and affords cellular defense by initiating transcription of antioxidative and detoxification genes. While a protein can be regulated at multiple levels, control of Nrf2 has been largely studied at post-translational regulation points by Keap1. Importantly, post-transcriptional/translational based regulation of Nrf2 is less understood and to date there are no reports on such mechanisms in neuronal systems. In this context, studies involving the role of microRNAs (miRs) which are normally considered as fine tuning regulators of protein production through translation repression and/or post-transcriptional alterations, are in place. In the current study, based on in-silico analysis followed by immunoblotting and real time analysis, we have identified and validated for the first time that human NFE2L2 could be targeted by miR153/miR27a/miR142-5p/miR144 in neuronal, SH-SY5Y cells. Co-transfection studies with individual miR mimics along with either WT 3′ UTR of human Nrf2 or mutated miRNA targeting seed sequence within Nrf2 3′ UTR, demonstrated that Nrf2 is a direct regulatory target of these miRs. In addition, ectopic expression of miR153/miR27a/miR142-5p/miR144 affected Nrf2 mRNA abundance and nucleo-cytoplasmic concentration of Nrf2 in a Keap1 independent manner resulting in inefficient transactivating ability of Nrf2. Furthermore, forced expression of miRs diminished GCLC and GSR expression resulting in alteration of Nrf2 dependent redox homeostasis. Finally, bioinformatics based miRNA-disease network analysis (MDN) along with extended computational network analysis of Nrf2 associated pathologic processes suggests that if in a particular cellular scenario where any of these miR153/miR27a/miR142-5p/miR144 either individually or as a group is altered, it could affect Nrf2 thus triggering and/or determining the fate of wide range of disease outcomes.
The inpatient burden of dysphagia has primarily been evaluated in patients with stroke. It is unclear whether dysphagia, irrespective of cause, is associated with worse clinical outcomes and higher costs compared to inpatients with similar demographic, hospital, and clinical characteristics without dysphagia. The aim of this study is to assess how a dysphagia diagnosis affects length of hospital stay (LOS), costs, discharge disposition, and in-hospital mortality among adult US inpatients. Annual and overall dysphagia prevalence, LOS, hospital charges, inpatient care costs, discharge disposition, and in-hospital mortality were measured using the AHRQ Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (2009-2013). Patients aged 45 years or older with ≤180 days of stay in hospital with and without dysphagia were included. Multivariable survey regression methods with propensity weighting were used to assess associations between dysphagia and different outcomes. Overall, 2.7 of 88 million (3.0%) adult US inpatients had a dysphagia diagnosis (50.2% male, 72.4% white, 74.6% age 65-90 years) and prevalence increased from 408,035 (2.5% of admissions) in 2009 to 656,655 (3.3%) in 2013. After inverse probability of treatment weighting adjustment, mean hospital LOS in patients with dysphagia was 8.8 days (95% CI 8.66-8.90) compared to 5.0 days (95% CI 4.97-5.05) in the non-dysphagia group (P < 0.001). Total inpatient costs were a mean $6,243 higher among those with dysphagia diagnoses ($19,244 vs. 13,001, P < 0.001). Patients with dysphagia were 33.2% more likely to be transferred to post-acute care facility (71.9% vs. 38.7%, P < 0.001) with an adjusted OR of 2.8 (95% CI 2.73-2.81, P < 0.001). Compared to non-cases, adult patients with dysphagia were 1.7 times more likely to die in the hospital (95% CI 1.67-1.74). Dysphagia affects 3.0% of all adult US inpatients (aged 45-90 years) and is associated with a significantly longer hospital length of stay, higher inpatient costs, a higher likelihood of discharge to post-acute care facility, and inpatient mortality when compared to those with similar patient, hospital size, and clinical characteristics without dysphagia. Dysphagia has a substantial health and cost burden on the US healthcare system.
Objective Patient-reported outcome (PRO) measures are commonly used to capture patient experience with dysphagia and to evaluate treatment effectiveness. Inappropriate application can lead to distorted results in clinical studies. A systematic review of the literature on dysphagia-related PRO measures was performed to 1) identify all currently available measures and 2) to evaluate each for the presence of important measurement properties that would affect their applicability. Design MEDLINE via the PubMed interface, the Cumulative Index of Nursing and Allied Health Literature, and the Health and Psychosocial Instrument database were searched using relevant vocabulary terms and key terms related to PRO measures and dysphagia. Three independent investigators performed abstract and full text reviews. Each study meeting criteria was evaluated using an 18-item checklist developed a priori that assessed multiple domains: 1) conceptual model, 2) content validity, 3) reliability, 4) construct validity, 6) scoring and interpretation, and 7) burden and presentation. Results Of 4950 abstracts reviewed, a total of 34 dysphagia-related PRO measures (publication year 1987 – 2014) met criteria for extraction and analysis. Several PRO measures were of high quality (MADS for achalasia, SWAL-QOL and SSQ for oropharyngeal dysphagia, PROMIS-GI for general dysphagia, EORTC-QLQ-OG25 for esophageal cancer, ROMP-swallowing for Parkinson’s disease, DSQ-EoE for eosinophilic esophagitis, and SOAL for total laryngectomy-related dysphagia). In all, 17 met at least one criterion per domain. Thematic deficiencies in current measures were evident including: 1) direct patient involvement in content development, 2) empirically justified dimensionality, 3) demonstrable responsiveness to change, 4) plan for interpreting missing responses, and 5) literacy level assessment. Conclusion This is the first comprehensive systematic review assessing developmental properties of all available dysphagia-related PRO measures. We identified several instruments with robust measurement properties in multiple diseases including achalasia, oropharyngeal dysphagia, post-surgical dysphagia, esophageal cancer, and dysphagia related to neurological diseases. Findings herein can assist clinicians and researchers in making more informed decisions in selecting the most fundamentally sound PRO measure for a given clinical, research, or quality initiative.
Background: Diagnostic testing for chronic esophageal disorders rely on histopathology analysis of biopsies or uncomfortable transnasal catheters or wireless pH monitoring, which capture abnormal intraluminal refluxate. We therefore developed a balloon mucosal impedance (MI) catheter system that instantly detects changes in esophageal mucosal integrity during endoscopy over a long segment of the esophagus. We performed a prospective study to evaluate the ability of a balloon-incorporated MI catheter to detect and evaluate esophageal disorders, including gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). Methods: We performed a prospective study of 69 patients undergoing esophagogastroduodenoscopy with or without wireless pH monitoring. Patients were classified as having GERD (erosive esophagitis or abnormal pH; n = 24), EoE (confirmed with pathology
Background Prenatal exposure to ethanol elicits a range of neuro-developmental abnormalities, microcephaly to behavioral deficits. Impaired protein synthesis has been connected to pathogenesis of ethanol-induced brain damage and abnormal neuron development. However, mechanisms underlying these impairments of protein synthesis are not known. In this study, we illustrate the effects of ethanol on programmed cell death protein 4 (PDCD4), a tumor and translation repressor. Methods Primary cortical neurons (PCNs) were treated with ethanol for 2.5mg/ml and 4mg/ml for different time points (4h to 24h) and PDCD4 expression was detected by Western blotting. Protein synthesis was determined using [35S] methionine incorporation assay. Methyl cap pull down assay was performed to establish the effect of ETOH on association of eIF4A with capped mRNA. Luciferase assay was performed to determine the in vivo translation. A 2-day acute 5-dose binge model with ethanol (4 g/kg body wt, 25% v/v) was performed in Sprague Dawley rats at 12h intervals and analyzed for PDCD4, eukaryotic initiation factor 4A (eIF4A) and eIF4A-methyl cap association. Results Ethanol increased PDCD4 expression in a time- and dose-dependent manner in PCNs which inhibited the association of eIF4A with methyl-cap. Ethanol and ectopic PDCD4 expression suppressed in vivo translation in PCNs and RNAi targeting of PDCD4 blocked the inhibitory effect of ethanol on protein synthesis. In utero exposure of pregnant rats to ethanol resulted in a significant increase of PDCD4 protein in fetal cerebral cortex along with inhibition of methyl-cap associated eIF4A, compared to iso-caloric controls. Increased PDCD4 also occurred in pooled fractions of remaining brain regions. Conclusions Our data for the first time, illustrate that PDCD4 mediates inhibitory effects of ethanol on protein synthesis in PCNs and developing brain.
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