Coordinated regulation of IFITM1, 2 and 3 genes by an IFN-responsive enhancer through long-range chromatin interactions

Publication date: Available online 13 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ping Li, Ming-Lei Shi, Wen-Long Shen, Zhang Zhang, De-Jian Xie, Xiang-Yuan Zhang, Chao He, Yan Zhang, Zhi-Hu Zhao
Interferon-induced transmembrane protein (IFITM) 1, 2 and 3 are a family of interferon (IFN)-induced transmembrane proteins that block entry of a broad spectrum of pathogens. However, the transcriptional regulation of these genes, especially whether there exists any enhancers and their roles during the IFN induction process remain elusive. Here, combining episomal luciferase reporter assay and in vivo genome editing, we identified an IFNβ-responsive enhancer located 35kb upstream of IFITM3 gene promoter upregulating the IFNβ-induced expression of IFITM1, 2 and 3 genes, thus contributing to IFNβ-mediated resistance to influenza A virus (IAV) infection. The enhancer was first identified and verified by data mining and luciferase reporter assay. Then we showed that signal transducers and activators of transcription (STAT) 1 bound to the enhancer after the treatment of IFNβ and was indispensable for the enhancer activity. Next, CRISPR-Cas9 mediated in vivo truncation of the enhancer considerably decreased both IFNβ and IAV-induced expression of IFTIM1, 2 and 3 in HEK293 cells. Furthermore, chromosome conformation capture revealed that the IFITM1, 2 and 3 genes physically clustered together and constitutively looped to the distal enhancer through long-range interactions in both HEK293 and A549 cells, providing structural basis for coordinated regulation of IFITM1, 2 and 3 by IFNβ. Finally, we showed that in vivo truncation of the enhancer impaired IFNβ-induced resistance to IAV infection. These findings expand our understanding of the mechanisms underlying the transcriptional regulation of IFITM1, 2 and 3 expression and its ability to mediate IFN-β signaling.



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Electrolyte and Acid–Base Disturbances in End-Stage Liver Disease: A Physiopathological Approach

Abstract

Electrolyte and acid–base disturbances are frequent in patients with end-stage liver disease; the underlying physiopathological mechanisms are often complex and represent a diagnostic and therapeutic challenge to the physician. Usually, these disorders do not develop in compensated cirrhotic patients, but with the onset of the classic complications of cirrhosis such as ascites, renal failure, spontaneous bacterial peritonitis and variceal bleeding, multiple electrolyte, and acid–base disturbances emerge. Hyponatremia parallels ascites formation and is a well-known trigger of hepatic encephalopathy; its management in this particular population poses a risky challenge due to the high susceptibility of cirrhotic patients to osmotic demyelination. Hypokalemia is common in the setting of cirrhosis: multiple potassium wasting mechanisms both inherent to the disease and resulting from its management make these patients particularly susceptible to potassium depletion even in the setting of normokalemia. Acid–base disturbances range from classical respiratory alkalosis to high anion gap metabolic acidosis, almost comprising the full acid–base spectrum. Because most electrolyte and acid–base disturbances are managed in terms of their underlying trigger factors, a systematic physiopathological approach to their diagnosis and treatment is required.

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Chronic Pancreatitis: Current Status and Challenges for Prevention and Treatment

Abstract

This paper reviews the current status of our understanding of the epidemiology, diagnosis, and management of the continuum of pancreatic diseases from acute and recurrent acute pancreatitis to chronic pancreatitis and the diseases that are often linked with pancreatitis including diabetes mellitus and pancreatic cancer. In addition to reviewing the current state of the field, we identify gaps in knowledge that are necessary to address to improve patient outcomes in these conditions.

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Cancer Center Volume and Type Impact Stage-Specific Utilization of Neoadjuvant Therapy in Rectal Cancer

Abstract

Background

Neoadjuvant chemoradiation reduces local recurrence in locally advanced rectal cancer, and adherence to national and societal recommendations remains unknown.

Objective

To determine variability in guideline adherence in rectal cancer treatment and investigate whether hospital volume correlated with variability seen.

Design

We performed a retrospective analysis using the National Cancer Database rectal cancer participant user files from 2005 to 2010. Stage-specific predictors of neoadjuvant chemotherapy and radiation use were determined, and variation in use across hospitals analyzed. Hospitals were ranked based on likelihood of preoperative therapy use by stage, and observed-to-expected ratios for neoadjuvant therapy use calculated. Hospital outliers were identified, and their center characteristics compared.

Results

A total of 23,488 patients were identified at 1183 hospitals. There was substantial variability in the use of neoadjuvant chemoradiation across hospitals. Patients managed outside clinical guidelines for both stage 1 and stage 3 disease tended to receive treatment at lower-volume, community cancer centers.

Conclusions

There is substantial variability in adherence to national guidelines in the use of neoadjuvant chemoradiation for rectal cancer across all stages. Both hospital volume and center type are associated with over-treatment of early-stage tumors and under-treatment of more invasive tumors. These findings identify a clear need for national quality improvement efforts in the treatment of rectal cancer.

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Use of Electroencephalography Brain Computer Interface systems as a rehabilitative approach for upper limb function after a stroke. A systematic review

Brain computer interface (BCI) systems have been suggested as a promising tool for neurorehabilitation. However, to date, there is a lack of homogeneous findings. Furthermore, no systematic reviews have analyzed the degree of validation of these interventions for upper limb (UL) motor rehabilitation post-stroke.

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Long-term Functional and Psychosocial Outcomes after Hypoxic-Ischemic Brain Injury:A Case-Controlled Comparison to Traumatic Brain Injury

Despite the increasing rate of survival from Hypoxic-Ischemic Brain Injury (HIBI), there is a paucity of evidence on the long-term functional outcomes after inpatient rehabilitation among these non-traumatic patients compared to patients with Traumatic Brain injury (TBI).

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Pediatric Nurse Practitioners in the Emergency Department: Implications for Education and Research

The use of pediatric nurse practitioners in emergency departments is common in the United States. Defining competencies that are specific to the wide span of urgent and emergent pediatric conditions, along with a recognized practice standard for education and method of certification for pediatric nurse practitioners practicing in emergency care, is needed. Pediatric emergency departments require a team of providers with a skill set that aligns with each patient's needs. The use of qualified pediatric nurse practitioners on these teams, both primary care and acute care certified, to provide care to these children is expanding, with implications for education and research.

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Supervised or unsupervised rehabilitation after total hip replacement provides similar improvements for patients: a randomised controlled trial

Publication date: Available online 12 May 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Corinne Coulter, Diana M. Perriman, Teresa M. Neeman, Paul N. Smith, Jennifer M. Scarvell
ObjectiveTo determine do patients do better with unsupervised home PT or in an outpatient setting Are the outcomes after a supervised (centre-based) and an independent (home-based) physical rehabilitation program delivered in the early post-discharge phase (<8weeks) equivalent in an adult THR population.SettingAcute care public hospital in the region, supporting a population of almost 540,000.DesignSingle blinded randomised controlled trial.ParticipantsAdult patients (n=98) after unilateral elective total hip replacement (THR) were randomly assigned to supervised/centre-based exercise (n=56) or unsupervised/home exercise (n=42) and followed 6 months post-surgery.InterventionThe supervised group attended a 4 week outpatient rehabilitation program supervised by a physiotherapist. The unsupervised group was given written and pictorial instructions to perform rehabilitation independently at home.Outcome measuresThe WOMAC, SF-36 mental and physical component scores(MCS and PCS) questionnaires, the UCLA activity rating and the Timed up and Go test (TUG).ResultsThere were no differences between groups for any measure. Overall differences between the adjusted means were: WOMAC 0.5 [-6.75, 5.73], SF-36 PCS 0.8 [-6.5 - 8.1], SF-36 MCS 1.7 [-4.1 - 7.4], UCLA 0.3 [5.19, 6.10] and TUG 0 secs [-1.4 - 1.3].ConclusionResults demonstrated that outcomes in response to rehabilitation after THR are clinically and statistically similar whether the program was supervised or not. The results suggest that early rehabilitation programs can be effectively delivered unsupervised in the home to low-risk patients discharged home after THR. However, the relative effect of late stage rehabilitation was not tested.



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Mindfulness is Associated with Treatment Response from Non-Pharmacological Exercise Interventions in Knee Osteoarthritis

Publication date: Available online 12 May 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Augustine C. Lee, William F. Harvey, Lori Lyn Price, Xingyi Han, Jeffrey B. Driban, John B. Wong, Mei Chung, Timothy E. McAlindon, Chenchen Wang
ObjectiveTo examine the association between baseline mindfulness and response from exercise interventions in knee osteoarthritis (OA).DesignCohort Study; Responder analysis of a clinical trial subsetSettingUrban tertiary care academic hospitalParticipants86 participants with symptomatic, radiographic knee OA (mean age, 60 years; 74% female; 48% white)Interventions12 weeks (twice per week) of Tai Chi or Physical Therapy exerciseMain Outcome Measure(s)Treatment response was defined using Osteoarthritis Research Society International criteria indicating meaningful improvements in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain, function, or Patient Global Assessment scores. At baseline, participants completed the Five Facet Mindfulness Questionnaire (FFMQ; mean total score ±SD: 142±17) and were grouped into three categories of total mindfulness: higher, medium, or lower. Relative risk (RR) ratios were used to compare treatment response across groups.ResultsParticipants with higher total mindfulness appeared to be 38% (95% CI: 1.05, 1.83) more likely to meet responder criteria than those with lower mindfulness. We found no significant difference between medium and lower mindfulness groups (RR=1.0; 95% CI: 0.69, 1.44). Among the 5 mindfulness facets, medium Acting-with–Awareness was 46% (95% CI: 1.09, 1.96) more likely to respond than lower Acting-with–Awareness, and higher Acting-with–Awareness was 34% more likely to respond, but this did not reach significance (95% CI: 0.97, 1.86).ConclusionsIn this study, higher mindfulness, primarily driven by its Acting-with-Awareness facet, was significantly associated with a greater likelihood of response to non-pharmacological exercise interventions in knee OA. This suggests that mindfulness-cultivating interventions may increase the likelihood of response from exercise.



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The Brachypodium distachyon methionine sulfoxide reductase gene family

Abstract

The methionine sulfoxide reductases (MSRs) are a group of thiol-dependent enzymes able to catalyze the conversion of methionine sulfoxide to methionine. Although some plant MSRs are known to act as protectants against various abiotic stresses, their activity in the model grass species Brachypodium distachyon has not been characterized as yet. Here, six B. distachyon MSR (BdMSR) genes have been isolated; they generate eight distinct cDNAs, since two of them (BdMSRB1 and -B5) produce a pair of alternatively spliced messages. The genes were transcribed in the root, culm, leaf and during various stages of caryopsis development. Those induced by abiotic stress (salinity, drought, low temperature, CdCl₂, H₂O₂ and abscisic acid) harbored known stress-responsive cis elements in their promoter sequences. The heterologous expression of five of the BdMSRs (-A2, -A4, -B1.1, -B3 and -B5.1) in yeast revealed that their products gave a measure of protection against salinity, mannitol and oxidative stress. Substrate specificity analysis revealed that BdMSRB1.1 could reduce free Met-R-SO to Met. The enzymatic activities of BdMSRA4, -B1.1 and -B5.1 in transformed yeast under salt treatment have checked and increased obviously resulting in reducing more Met-SO to Met including the peptide and the free types under salt stress than those in control.

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Patient buys ballistic vests for paramedics who saved him

The man said he hopes his gift plants the seed for others to step up and help equip paramedics

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Less postoperative sore throat after nasotracheal intubation using a fiberoptic bronchoscope than using a Macintosh laryngoscope: A double-blind, randomized, controlled study.

Related Articles

Less postoperative sore throat after nasotracheal intubation using a fiberoptic bronchoscope than using a Macintosh laryngoscope: A double-blind, randomized, controlled study.

J Clin Anesth. 2017 Jun;39:113-117

Authors: Tachibana N, Niiyama Y, Yamakage M

Abstract
STUDY OBJECTIVE: To evaluate whether nasotracheal intubation using a fiberoptic bronchoscope reduces postoperative sore throat.
DESIGN: Prospective, double-blinded, randomized, and controlled study.
SETTING: Postoperative areas and surgical ward of a university hospital.
PATIENTS: Seventy-four patients with American Society of Anesthesiologists physical status I-II who were scheduled for elective general anesthesia requiring nasotracheal intubation.
INTERVENTIONS: Patients were randomized to one of two intubation groups, F (fiberoptic bronchoscope-guided) and M (Macintosh laryngoscope-guided), and after induction of general anesthesia, the patients' tracheas were intubated via the nose.
MEASUREMENTS: The intensity of postoperative sore throat was evaluated using a numerical rating score (0=none, 10=severe) at 24 hours postoperatively, and the incidence of nasal mucosal trauma, time to completion of intubation, and hemodynamic responses were recorded and compared between groups.
MAIN RESULTS: The numerical rating score value was significantly lower in group F than in group M (P=.0047), but the incidence of nasal mucosal trauma was comparable between the two groups. The median time to completion of intubation was shorter for group F than group M (P<.0001). Hemodynamic responses were not significantly different.
CONCLUSIONS: Fiberoptic bronchoscope-guided intubation is associated with less sore throat after nasotracheal intubation than M intubation. The time to completion of intubation was significantly shorter using the fiberoptic bronchoscope than that using the Macintosh laryngoscope.

PMID: 28494884 [PubMed - in process]

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Optimal timing for telescoping endotracheal tube into an introducer during nasotracheal intubation.

Related Articles

Optimal timing for telescoping endotracheal tube into an introducer during nasotracheal intubation.

J Clin Anesth. 2017 Jun;39:112

Authors: Huang NC, Chen YW, Cheng CD, Cherng CH

PMID: 28494883 [PubMed - in process]

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Automated cytological detection of Barrett’s neoplasia with infrared spectroscopy

Abstract

Background

Development of a nonendoscopic test for Barrett's esophagus would revolutionize population screening and surveillance for patients with Barrett's esophagus. Swallowed cell collection devices have recently been developed to obtain cytology brushings from the esophagus: automated detection of neoplasia in such samples would enable large-scale screening and surveillance.

Methods

Fourier transform infrared (FTIR) spectroscopy was used to develop an automated tool for detection of Barrett's esophagus and Barrett's neoplasia in esophageal cell samples. Cytology brushings were collected at endoscopy, cytospun onto slides and FTIR images were measured. An automated cell recognition program was developed to identify individual cells on the slide.

Results

Cytology review and contemporaneous histology was used to inform a training dataset containing 141 cells from 17 patients. A classification model was constructed by principal component analysis fed linear discriminant analysis, then tested by leave-one-sample-out cross validation. With application of this training model to whole slide samples, a threshold voting system was used to classify samples according to their constituent cells. Across the entire dataset of 115 FTIR maps from 66 patients, whole samples were classified with sensitivity and specificity respectively as follows: normal squamous cells 79.0% and 81.1%, nondysplastic Barrett's esophagus cells 31.3% and 100%, and neoplastic Barrett's esophagus cells 83.3% and 62.7%.

Conclusions

Analysis of esophageal cell samples can be performed with FTIR spectroscopy with reasonable sensitivity for Barrett's neoplasia, but with poor specificity with the current technique.

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Dose assessment in environmental radiological protection: State of the art and perspectives

Publication date: September 2017
Source:Journal of Environmental Radioactivity, Volumes 175–176
Author(s): Karolina Stark, José M. Goméz-Ros, Jordi Vives i Batlle, Elisabeth Lindbo Hansen, Karine Beaugelin-Seiller, Lawrence A. Kapustka, Michael D. Wood, Clare Bradshaw, Almudena Real, Corynne McGuire, Thomas G. Hinton
Exposure to radiation is a potential hazard to humans and the environment. The Fukushima accident reminded the world of the importance of a reliable risk management system that incorporates the dose received from radiation exposures. The dose to humans from exposure to radiation can be quantified using a well-defined system; its environmental equivalent, however, is still in a developmental state. Additionally, the results of several papers published over the last decade have been criticized because of poor dosimetry. Therefore, a workshop on environmental dosimetry was organized by the STAR (Strategy for Allied Radioecology) Network of Excellence to review the state of the art in environmental dosimetry and prioritize areas of methodological and guidance development. Herein, we report the key findings from that international workshop, summarise parameters that affect the dose animals and plants receive when exposed to radiation, and identify further research needs. Current dosimetry practices for determining environmental protection are based on simple screening dose assessments using knowledge of fundamental radiation physics, source-target geometry relationships, the influence of organism shape and size, and knowledge of how radionuclide distributions in the body and in the soil profile alter dose. In screening model calculations that estimate whole-body dose to biota the shapes of organisms are simply represented as ellipsoids, while recently developed complex voxel phantom models allow organ-specific dose estimates. We identified several research and guidance development priorities for dosimetry. For external exposures, the uncertainty in dose estimates due to spatially heterogeneous distributions of radionuclide contamination is currently being evaluated. Guidance is needed on the level of dosimetry that is required when screening benchmarks are exceeded and how to report exposure in dose-effect studies, including quantification of uncertainties. Further research is needed to establish whether and how dosimetry should account for differences in tissue physiology, organism life stages, seasonal variability (in ecology, physiology and radiation field), species life span, and the proportion of a population that is actually exposed. We contend that, although major advances have recently been made in environmental radiation protection, substantive improvements are required to reduce uncertainties and increase the reliability of environmental dosimetry.



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