bluuebunny/crossref_metadata_2025 huggingface dataset:
LO023: Association between ED-induced delirium and cognitive & functional decline in seniors
Authors: Giroux M. , Émond M. , Sirois M. , Boucher V. , Daoust R. , Gouin E. , Pelletier M. , Voyer P. , Lemire S. , Berthelot S. , Moore L. , Lee J.S. , Lamontagne M.
Published: June 2016

Introduction: Delirium is a common medical complication among seniors in hospital setting. In the emergency department (ED), its prevalence varies between 7 & 14%. Delirium is associated with increased mortality & longer hospital stay. This condition is also associated with functional & cognitive decline in hospitalized seniors and higher risk of institutionalization up to 2 years after their discharge. However, no data is currently available for ED patients. The aim of this study was to evaluate the association between ED-induced delirium and functional & cognitive decline in seniors at 60 days. Methods: This study is part of the Incidence and Impact measurement of Delirium Induced by ED-Stay (INDEED) study, an ongoing multicenter prospective cohort study in 5 Quebec EDs. Patients were recruited after 8 hours in the ED and followed up to 24h after admission. A 60-day follow-up phone assessment was also conducted. Delirium was measured by the validated Confusion Assessment Method & the Delirium Index. Functional status was measured by the validated OARS. Cognitive status was measured using the validated TICS-M. Functional and cognitive decline were obtained by comparing the baseline and 60-days follow-up scores. Results: 380 seniors were recruited and 280 had 60-day follow-up data available. ED-induced delirium was 8.4% of seniors. There was a difference in mean functional decline among seniors with and without ED-induced delirium 2.95(1.23-4.67) vs 1.55(1.20-1.91, pwlicoxon= 0.05] Proportion of seniors showing a decline ≥2 points on the OARS was significantly higher In those with ED-induced delirium (65,0 % vs 40.18 %, p=0.03). Seniors with ED-induced delirium also showed a significant decline in mean TICS scores [3.31 (0,82-5.84) vs -0.01((-.071-0.75)), pwlicoxon =0.009]. There was no significant difference in the proportions of seniors showing a decline ≥ 3 OARS points between those with or without delirium (p=0.06). Conclusion: ED-induced delirium seems to be associated with poor functional and cognitive outcomes in older patients 60 days after discharge from the hospital. Further studies are required to confirm clinical importance ED-induced delirium delayed complication.
LO038: Evaluation of a midstream urine collection technique for infants in the emergency department
Authors: Crombie T. , Slinger R. , Barrowman N. , McGahern C. , Smith L. , Chu J. , McCoy K. , Akiki S. , Plint A.
Published: June 2016

Introduction: A novel bladder stimulation technique has been described for midstream urine (MSU) collection in well-feeding, inpatient newborns. We sought to determine the performance of this technique amongst infants presenting to the Emergency Department (ED). Methods: Our prospective ED-based study enrolled a convenience cohort of infants aged ≤ 90 days who required urine testing. Infants with significant feeding issues, moderate to severe dehydration, or critical illness were excluded. Bladder stimulation consisted of finger tapping on the lower abdomen with or without lower back massage while holding the child upright. Healthcare providers received standardized training in the technique. Primary outcome was the proportion of infants with successful MSU collection via the technique. Success was defined as adequate sample collection (≥ 1 mL urine) within 5 minutes of initiating stimulation. Secondary outcomes included the proportion of contaminated MSU samples, time required for MSU collection and full protocol completion, and patient discomfort as perceived by parent/guardian using a 100 mm visual analog scale [VAS]. Assuming success a priori in 50% of infants, a sample size of 115 allowed a 95% confidence interval of +/- 9.1% around the point estimate. Results: We enrolled 115 infants. Mean age was 53.0 days old (interquartile range [IQR] 26.7-68.0); 58.3% were male (69.2% uncircumcised). Midstream urine was successfully collected in 61 infants (53.0%; 95% CI 0.44,0.62). Thirty-one MSU samples (50.8%) were contaminated; uncircumcised males held the highest proportion (55.0%). Most contaminated samples (83.9%) were reported as “non-significant growth” or “growth of ≥ 3 organisms” and were easily identifiable as contaminants with minimal impact on clinical care. Only 4 (8.5%) of the 47 patients discharged home after successful MSU collection had a repeat ED visit for urine testing. Median stimulation time for MSU collection was 45 seconds (IQR 20-99 secs). Median time for full protocol completion was 30.83 minutes (IQR 24.42-46.83 mins). Mean VAS for infant discomfort was 20.2 mm (SD +/- 20.4 mm). Conclusion: Our pragmatic, ED-based study found the success rate of this bladder stimulation technique to be significantly lower (53%) than its published rate (86%). The contamination rate was high but most contaminated specimens were easily identifiable as such and had minimal clinical impact.
LO042: Sonography in Hypotension and Cardiac Arrest (SHoC) - Hypotension: derivation of an evidence-based consensus algorithm for the integration of point of care ultrasound into resuscitation of hypotensive patients
Authors: Atkinson P. , Bowra J. , Milne J. , Lambert M. , Jarman B. , Noble V. , Lamprecht H. , Lewis D. , Harris T. , Gangahar R. ,   Advisory panel members, Stander M. , Muhr C. , Connolly J. , Gaspari R. , Kessler R. , Raio C. , Sierzenski P. , Hoffmann B. , Pham C. , Woo M. , Olszynski P. , Henneberry R. , Frenkel O. , Chenkin J. , Hall G. , Rang L. , Valois M. , Wurster C. , Tutschka M. , Arntfield R. , Fischer J. , Tessaro M.
Published: June 2016

Introduction: Point of care ultrasound has become an established tool in the initial management of patients with undifferentiated hypotension. Current established protocols (RUSH, ACES, etc) were developed by expert user opinion, rather than objective, prospective data. We wished to use reported disease incidence to develop an informed approach to PoCUS in hypotension using a “4 F’s” approach: Fluid; Form; Function; Filling. Methods: We summarized the incidence of PoCUS findings from an international multicentre RCT, and using a modified Delphi approach incorporating this data we obtained the input of 24 international experts associated with five professional organizations led by the International Federation of Emergency Medicine. The modified Delphi tool was developed to reach an international consensus on how to integrate PoCUS for hypotensive emergency department patients. Results: Rates of abnormal PoCUS findings from 151 patients with undifferentiated hypotension included left ventricular dynamic changes (43%), IVC abnormalities (27%), pericardial effusion (16%), and pleural fluid (8%). Abdominal pathology was rare (fluid 5%, AAA 2%). After two rounds of the survey, using majority consensus, agreement was reached on a SHoC-hypotension protocol comprising: A. Core: 1. Cardiac views (Sub-xiphoid and parasternal windows for pericardial fluid, cardiac form and ventricular function); 2. Lung views for pleural fluid and B-lines for filling status; and 3. IVC views for filling status; B. Supplementary: Additional cardiac views; and C. Additional views (when indicated) including peritoneal fluid, aorta, pelvic for IUP, and proximal leg veins for DVT. Conclusion: An international consensus process based on prospectively collected disease incidence has led to a proposed SHoC-hypotension PoCUS protocol comprising a stepwise clinical-indication based approach of Core, Supplementary and Additional PoCUS views.
LO045: Sonography in Hypotension and Cardiac Arrest (SHoC) - Cardiac Arrest: A consensus on the integration of point of care ultrasound into advanced cardiac life support during cardiac arrest
Authors: Atkinson P. , Bowra J. , Milne J. , Lambert M. , Jarman B. , Noble V. , Lamprecht H. , Lewis D. , Harris T. , Gangahar R. ,   Advisory panel members, Bomann S. , Goudie A. , Poncia H. , Bystrzycki A. , Blecher G. , Rose M. , Dass S. , Doran O. , Large R. , Salter A. , Sadewasser J. , Murray A. , Rawson M. , Stander M. , Muhr C. , Connolly J. , Gaspari R. , Kessler R. , Raio C. , Sierzenski P. , Hoffmann B. , Pham C. , Woo M. , Olszynski P. , Henneberry R. , Frenkel O. , Chenkin J. , Hall G. , Rang L. , Valois M. , Wurster C. , Tutschka M. , Arntfield R. , Fischer J. , Tessaro M.
Published: June 2016

Introduction: Point of care ultrasound (PoCUS) provides invaluable information during resuscitation efforts in cardiac arrest by determining presence/absence of cardiac activity and identifying reversible causes such as pericardial tamponade. There is no agreed guideline on how to safely and effectively incorporate PoCUS into the advanced cardiac life support (ACLS) algorithm. We consider that a consensus-based priority checklist using a “4 F’s” approach (Fluid; Form; Function; Filling), would provide a better algorithm during ACLS. Methods: The ultrasound subcommittee of the Australasian College for Emergency Medicine (ACEM) drafted a checklist incorporating PoCUS into the ACLS algorithm. This was further developed using the input of 24 international experts associated with five professional organizations led by the International Federation of Emergency Medicine. A modified Delphi tool was developed to reach an international consensus on how to integrate ultrasound into cardiac arrest algorithms for emergency department patients. Results: Consensus was reached following 3 rounds. The agreed protocol focuses on the timing of PoCUS as well as the specific clinical questions. Core cardiac windows performed during the rhythm check pause in chest compressions are the sub-xiphoid and parasternal cardiac views. Either view should be used to detect pericardial fluid, as well as examining ventricular form (e.g. right heart strain) and function, (e.g. asystole versus organized cardiac activity). Supplementary views include lung views (for absent lung sliding in pneumothorax and for pleural fluid), and IVC views for filling. Additional ultrasound applications are for endotracheal tube confirmation, proximal leg veins for DVT, or for sources of blood loss (AAA, peritoneal/pelvic fluid). Conclusion: The authors hope that this process will lead to a consensus-based SHoC-cardiac arrest guideline on incorporating PoCUS into the ACLS algorithm.
LO048: Systematic review of the use of low-dose ketamine for analgesia in the emergency department
Authors: Ghate G. , Clark E. , Vaillancourt C.
Published: June 2016

Introduction: Ketamine is a popular sedative agent for painful procedures. It is not widely used at sub-dissociative analgesic doses in the emergency department (ED). We sought to determine the performance of low-dose ketamine (LDK) as an analgesic for acute pain management in adult patients in the ED. Methods: We systematically reviewed electronic databases (MEDLINE, EMBASE, AMED, CINAHL, PubMed and Cochrane database of systematic reviews), grey literature, conference proceedings and clinical trials registries. Two independent reviewers identified eligible studies using pre-determined criteria. We included peer-reviewed studies that used LDK (<1 mg/kg IV or <2mg/kg IM) in adult patients (>18 yo) requiring acute pain management for any condition in the ED. Our outcome measures included analgesic effect of LDK compared to any opioids, need for rescue analgesia, and neuropsychological adverse events. We assessed inter-rater agreement using kappa statistics, risk of bias using the Cochrane Collaboration’s Tool, and propose a treatment recommendation using GRADE. Heterogeneity among studies precluded meta-analysis. Results: We reviewed 1,408 studies and selected 44 for full review (kappa = 0.70). Thirty-three were excluded due to wrong patient population and non-analgesic use of ketamine. Eleven studies with 1,249 participants were included - six randomized control trials (RCTs) and five observational studies. All of which had an overall low risk of bias. There was extensive variation in the dose and route of LDK used (0.1 - 0.7 mg/kg SC/IV/IM), administration protocols, and use of adjunct analgesia. There is a lack of high quality data regarding the use of LDK as an analgesic agent in the ED. However, the current moderate quality data demonstrates a significant analgesic effect of LDK with occasional need for rescue analgesia and neuropsychological adverse events. Commonly reported neuropsychological adverse events included dizziness, dysphoria, and confusion, rarely agitation or hallucinations. All adverse events were self-limited or occasionally required benzodiazepines for resolution. Conclusion: Our GRADE evidence table identified moderate quality evidence from six RCTs supporting the analgesic effect of LDK for acute pain management in the ED when compared to using opioids alone.
LO051: Validation of a clinical decision rule to detect patients with adverse drug events in the emergency department
Authors: Hohl C.M. , Badke K. , Wickham M.E. , Zhao A. , Sivilotti M. , Perry J.J.
Published: June 2016

Introduction: Adverse drug events (ADE) are a leading cause of emergency department (ED) visits, yet are missed in up to 50% of presentations. In 2014, Accreditation Canada, a not-for-profit organization that evaluates healthcare institutions based on quality of care, introduced a requirement for EDs to identify patients at high-risk for drug-related morbidity, so that medication management interventions can be targeted to high-risk groups. We derived a clinical decision rule to identify patients at high-risk for ADEs using 4 variables. Our objective was to validate the rule by determining its sensitivity and specificity in a new sample. Methods: We conducted a prospective observational study in two tertiary care and one urban community hospital in British Columbia and Ontario. We used a systematic selection algorithm to generate a representative sample, and enrolled adults who reported taking at least one medication during the prior two weeks. Nurses completed the clinical decision rule and evaluated patients for standardized clinical findings. Each patient was assessed by a research pharmacist and a physician who were blinded to data collected by nurses. Any disagreement was subsequently adjudicated by an independent committee. The primary outcome was an ADE, defined as an unintended and harmful event related to medication use resulting a change in medical management, hospital admission or causing death. We calculated the rule’s sensitivity, specificity, and the proportion of patients screening positive with 95% confidence intervals (CI). Results: Among 1529 enrolled patients, 196 (12.8%, 95% CI 11.2-14.6%) were deemed to have experienced an ADE. The rule, consisting of the variables (i) having a pre-existing medical condition or having taken antibiotics within one week, and (ii) age ≥ 80 or having a medication change within 28 days, had a sensitivity of 92.9% (95%CI 88.3%-96.0%) and a specificity of 35.0% (95%CI 32.5%-37.7%) for ADEs. The proportion of patients screening positive was 41.7%. Conclusion: Among adults presenting to EDs, the rule was sensitive for ADEs while maintaining reasonable specificity. If implemented, the rule may help identify those patients at high-risk for ADEs who may benefit from evaluation by a clinical pharmacist in the ED, and will help institutions meet current Accreditation Canada standards.
LO054: The emergency department usage and utility of ISAR and CAM assessment tools in identifying hip fracture patients at risk for developing delirium
Authors: Thompson C. , Sandre A. , McLeod S.L. , Borgundvaag B.
Published: June 2016

Introduction: Delirium is an acute state of mental confusion that is a frequent complication in older adults with a hip fracture, and is often unrecognized by clinicians in the emergency department (ED). It is associated with prolonged hospitalization, functional decline, hospital readmission, and death. The Identification of Seniors At Risk (ISAR) and Confusion Assessment Method (CAM) are two standardized tools designed to facilitate prompt screening and detection of functional decline and delirium respectively amongst adults 65 and older. The objective of this study was to determine the ED usage and utility of ISAR and CAM assessment tools in identifying hip fracture patients at risk for developing delirium. Methods: This was a retrospective chart review of patients aged 65 and older, presenting to an academic ED (annual census 60,000) with a discharge diagnosis of hip fracture from January 1st 2014 to July 31st 2015. At this institution, both the ISAR and CAM are included in the standard ED nursing documentation and are intended to be completed for all patients over 65 years of age. Results: Of the 243 hip fracture cases included in this study, the ISAR and CAM scores were completed for 131 (53.9%) and 69 (28.4%) patients, respectively. There were 43 (17.7%) cases of recorded in-hospital acute delirium. Of the delirium cases, 20 (46.5%) had an ISAR assessment. Patients with an ISAR score of ≥3 were more likely to experience delirium compared to those with lower ISAR scores (28.3% vs 8.3%; Δ 20.0%, 95% CI: 6.6%, 34.9%). Of the 43 patients with delirium, 11 (25.6%) had a CAM score recorded. Patients with a positive CAM score (meeting 3 of 4 criteria in the diagnostic algorithm) were more likely to experience delirium compared to those with negative CAM scores (66.7% vs 11.1%; Δ 55.6%, 95% CI: 17.5%, 79.9%). Conclusion: Vigilant efforts are needed to ensure these screening tools are applied for all patients over the age of 65 presenting to the ED to improve the recognition and early management of delirium. Future research should focus on initiatives to improve delirium screening compliance by ED personnel.
LO055: Increased utilization of Bier block for pediatric forearm fracture reduction following simulation and web-based training
Authors: Burstein B. , Fauteux-Lamarre E. , Cheng A. , Chalut D. , Bretholz A.
Published: June 2016

Introduction: Bier block (BB) regional intravenous anesthesia is a safe and effective alternative to procedural sedation for analgesia during forearm fracture reductions, yet BB remains infrequently utilized in the Pediatric Emergency Department (PED). No standardized methods of BB training have previously been described. The objectives of this study were to evaluate comfort and level of experience with BB in the PED, and to determine if a multimodal instructional course increases these from baseline and translates to increased utilization of this technique. Methods: A novel interdisciplinary simulation and web-based training course was developed to teach the use of BB for forearm fracture reduction at a tertiary PED. Participants were surveyed pre/post training, and at 2- and 6-months regarding their comfort with and willingness to use BB. In parallel, we prospectively assessed the clinical utilization of BB in the PED during the 24-month period immediately following course completion. Results: Course participation included 38 members of the PED (N = 26 physicians, 12 nurses), and survey response rate was 100% at all time points. Respondents reported that course participation increased both their comfort (10% pre vs. 89% post-training, p<0.001) and willingness (51% pre vs. 95% post-training, p<0.001) to use BB for forearm fracture reduction, an effect that was sustained at 6-months following course completion (66% and 92%, respectively, p<0.001 for both). Before course attendance, only 6% of respondents indicated that they had ever used BB in a PED setting, and all participants indicated that the course addressed their learning objectives. In clinical practice, there were no BB performed prior to course administration. We observed a consistent and sustained increase in the clinical utilization of BB, with 39% of all PED forearm reductions performed using BB at 24-months post-course completion (114 BB, 17 unique physicians). Conclusion: A combined simulation and web-based training course increased comfort and willingness to use BB and was associated with increased utilization of this technique for forearm fracture reduction in the PED.
LO059: CT head scans yield no relevant findings in patients presenting to the emergency department with bizarre behavior
Authors: Ng P. , McGowan M. , Steinhart B.
Published: June 2016

Introduction: The standard approach between Emergency Departments (EDs) and Psychiatric Emergency Services is to medically “clear” a stable patient of organic pathology prior to psychiatric consultation. Medical clearance involves neuroimaging, typically in the form of a computed tomography (CT) head scan. This study examines the clinical impact of ordering CT head scans for patients presenting with bizarre behaviour. Methods: A 5-year retrospective chart review was conducted at 3 academic, urban ED sites. Inclusion criteria were patients ≥18 years of age triaged as “mental health - bizarre behavior” (defined as deviating from normal cognitive behaviour with no obvious cause) with a CT head scan ordered while under the care of the ED. Exclusion criteria were focal neurologic deficits on exam, alternative medical etiology (i.e. delirium, trauma) and/or pre-existing CNS disease. Demographic, administrative, and neuroimaging data were extracted with 10% of charts independently reviewed by a staff Emergency Physician for inter-rater reliability. Results: 270 cases met study criteria. CT results were unavailable in 3, leaving 267 cases studied. The population demographics were: 49% percent female, average age 51 years old, 28% homeless, 59% arrived by police and/or ambulance. CT head results demonstrated 1 (0.4%) case with possible acute findings on CT. 108 (40%) had incidental findings (i.e. cerebral atrophy, small hypodensities), none of which impacted clinical management. Average time to physician assessment was 1 hour 58 minutes (sd 1:17) and time to CT head completion was 6 hours 50 minutes (sd 7:20) leaving an average of 4 hours 52 minutes awaiting these results. Ultimately 86% of patients were referred to a consultant of which 92% were to Psychiatry. Conclusion: This study of CT head scans for bizarre behavior ED presentations showed that the CT results did not change the clinical management of the patient. Furthermore, awaiting these results prolonged ED length of stay and delayed patient disposition. A prospective trial of a clinical decision tool for ordering CT head scans in these patients is warranted.
Museum Representations of Roman Britain and Roman London: A Post-colonial Perspective
Authors: Polm Martijn
Published: June 2016

This paper offers a post-colonial analysis of past and present representations of the archaeological remains of Roman Britain and Roman London in the British Museum and Museum of London respectively. Since post-colonial criticism of Romano-British archaeology is highly relevant to such an analysis, a brief description is provided at the outset. Thereafter follows a series of six case studies — three for each museum. The first four focus on the history of the Romano-British collections at both museums and sometimes draw on post-colonial insights to explain the development of these collections and the ways in which they were exhibited. The last two case studies investigate how British post-colonial criticism of Roman archaeology has (or has not) impacted on the current displays of the Romano-British collections at both museums. Finally, some recommendations will be offered based on the outcomes of these two case studies. Recurring themes are the representation of: the Roman military; Roman imperialism; the (material) culture of Roman Britain and Roman London.
TRANSITIVITY IN THE PROCESSING OF INTRANSITIVE CLAUSES
Authors: Dekydtspotter Laurent , Seo Hyun-Kyoung
Published: June 2016

We document weak garden paths after intransitive verbs, modulated by intransitivity type, in the treatment of DP1VintransitiveDP2V2sequences as inAs the journalist arrived the editor postponed the meetingin first language (L1) and second language (L2) sentence processing. In a noncumulative moving-window experiment, 25 English native speakers and 22 low-intermediate Korean learners of English with no naturalistic exposure read critical items in which a subordinate clause was either headed by an intransitive verb (unaccusative vs. unergative) or by a copular predicate. A linear mixed model revealed greater processing loads evidenced in longer reading times on V2after intransitive verbs than after copular predicates. This finding echoes post hoc observations in Juffs (2004). These asymmetries were driven by significantly greater loads after unaccusative verbs than after copular predicates and unergative verbs. These asymmetries, found in both L1 and L2, are unexpected on the basis of valence information only, as one-place predicates should rule out a second argument. However, we argue that they receive an explanation if parsing involves the interaction of lexically encoded intransitivity information with a transitivity prediction.
Children's use of evaluative devices in spoken and written narratives
Authors: DRIJBOOMS ELISE , GROEN MARGRIET A. , VERHOEVEN LUDO
Published: June 2016

This study investigated the development of evaluation in narratives from middle to late childhood, within the context of differentiating between spoken and written modalities. Two parallel forms of a picture story were used to elicit spoken and written narratives from fourth- and sixth-graders. It was expected that, in addition to an increase of evaluative devices with age, written narratives would exhibit a higher frequency and diversity as a result of the intrinsic differences between the two modalities. From a developmental perspective, the results showed that only few categories exhibited the expected increase with age. Qualitative analyses provided a fruitful method to illustrate developmental changes. The results further indicated that modality had the expected impact on the diversity, and on the frequency, of most categories of evaluative language. Specifically, markers of decontextualized language and categories with a high degree of syntactic complexity were prone to modality differences.
How Tropical Cyclones Influence Photosynthesis
Authors: Shultz David
Published: June 2016

A new modeling study gives insight into how tropical cyclones affected ecosystems in the southeastern United States between 2002 and 2012.
Transglutaminase 2 has opposing roles in the regulation of cellular functions as well as cell growth and death
Authors: Tatsukawa H , Furutani Y , Hitomi K , Kojima S
Published: June 2016

Transglutaminase 2 (TG2) is primarily known as the most ubiquitously expressed member of the transglutaminase family with Ca2+-dependent protein crosslinking activity; however, this enzyme exhibits multiple additional functions through GTPase, cell adhesion, protein disulfide isomerase, kinase, and scaffold activities and is associated with cell growth, differentiation, and apoptosis. TG2 is found in the extracellular matrix, plasma membrane, cytosol, mitochondria, recycling endosomes, and nucleus, and its subcellular localization is an important determinant of its function. Depending upon the cell type and stimuli, TG2 changes its subcellular localization and biological activities, playing both anti- and pro-apoptotic roles. Increasing evidence indicates that the GTP-bound form of the enzyme (in its closed form) protects cells from apoptosis but that the transamidation activity of TG2 (in its open form) participates in both facilitating and inhibiting apoptosis. A difficulty in the study and understanding of this enigmatic protein is that opposing effects have been reported regarding its roles in the same physiological and/or pathological systems. These include neuroprotective or neurodegenerative effects, hepatic cell growth-promoting or hepatic cell death-inducing effects, exacerbating or having no effect on liver fibrosis, and anti- and pro-apoptotic effects on cancer cells. The reasons for these discrepancies have been ascribed to TG2’s multifunctional activities, genetic variants, conformational changes induced by the immediate environment, and differences in the genetic background of the mice used in each of the experiments. In this article, we first report that TG2 has opposing roles like the protagonist in the novel Dr. Jekyll and Mr. Hyde, followed by a summary of the controversies reported, and finally discuss the possible reasons for these discrepancies.
A20 prevents chronic liver inflammation and cancer by protecting hepatocytes from death
Authors: Catrysse L , Farhang Ghahremani M , Vereecke L , Youssef S A , Mc Guire C , Sze M , Weber A , Heikenwalder M , de Bruin A , Beyaert R , van Loo G
Published: June 2016

An important regulator of inflammatory signalling is the ubiquitin-editing protein A20 that acts as a break on nuclear factor-κB (NF-κB) activation, but also exerts important cytoprotective functions. A20 knockout mice are cachectic and die prematurely due to excessive multi-organ inflammation. To establish the importance of A20 in liver homeostasis and pathology, we developed a novel mouse line lacking A20 specifically in liver parenchymal cells. These mice spontaneously develop chronic liver inflammation but no fibrosis or hepatocellular carcinomas, illustrating an important role for A20 in normal liver tissue homeostasis. Hepatocyte-specific A20 knockout mice show sustained NF-κB-dependent gene expression in the liver upon tumor necrosis factor (TNF) or lipopolysaccharide injection, as well as hepatocyte apoptosis and lethality upon challenge with sublethal doses of TNF, demonstrating an essential role for A20 in the protection of mice against acute liver failure. Finally, chronic liver inflammation and enhanced hepatocyte apoptosis in hepatocyte-specific A20 knockout mice was associated with increased susceptibility to chemically or high fat-diet-induced hepatocellular carcinoma development. Together, these studies establish A20 as a crucial hepatoprotective factor.
Continuous exposure of pancreatic cancer cells to dietary bioactive agents does not induce drug resistance unlike chemotherapy
Authors: Fan P , Zhang Y , Liu L , Zhao Z , Yin Y , Xiao X , Bauer N , Gladkich J , Mattern J , Gao C , Schemmer P , Gross W , Herr I
Published: June 2016

The repeated treatment of cancer cells with chemo- or radiotherapy induces therapy resistance, but it was previously unknown whether the same effect occurs upon continuous exposure of cancer cells to diet-derived chemopreventive agents. We elucidated this interesting question in pancreatic ductal adenocarcinoma, which is a highly aggressive cancer entity with a marked resistance toward gemcitabine and other cytotoxic drugs. The isothiocyanate sulforaphane, present in cruciferous vegetables, and the polyphenol quercetin, present in many fruits and vegetables induced apoptosis and reduced viability in gemcitabine-sensitive BxPC-3 cells but not in non-malignant ductal pancreas cells and mesenchymal stromal cells. In turn, BxPC-3 cells were treated with increasing concentrations of gemcitabine, sulforaphane or quercetin for more than 1 year and the surviving subclones Bx-GEM, Bx-SF and Bx-Q were selected, respectively. While Bx-GEM cells acquired a total resistance, Bx-SF or Bx-Q cells largely kept their sensitivity as proved by MTT assay, annexin staining and FACS analysis. The evaluation of the self-renewal-, differentiation- and migration-potential by colony formation, differentiation or migration assays demonstrated that cancer stem cell features were enriched in gemcitabine-resistant cells, but decreased in sulforaphane- and quercetin-long time-treated cells. These results were confirmed by orthotopic xenotransplantation of cancer cells to the mouse pancreas, where Bx-GEM formed large, Bx-Q small and Bx-SF cells almost undetectable tumors. An mRNA expression profiling array and subsequent gene set enrichment analysis and qRT-PCR confirmed that tumor progression markers were enriched in Bx-GEM, but reduced in Bx-SF and Bx-Q cells. This study demonstrates that the continuous exposure of pancreatic cancer cells to sulforaphane or quercetin does not induce resistance in surviving cells but reduces tumorigenicity by inhibition of tumor progression markers. These results highlight that cancer cells may not adapt to the preventive and therapeutic effects of a regular fruit- and vegetable-based diet.
Initialized decadal prediction for transition to positive phase of the Interdecadal Pacific Oscillation
Authors: Meehl Gerald A. , Hu Aixue , Teng Haiyan
Published: June 2016

The negative phase of the Interdecadal Pacific Oscillation (IPO), a dominant mode of multi-decadal variability of sea surface temperatures (SSTs) in the Pacific, contributed to the reduced rate of global surface temperature warming in the early 2000s. A proposed mechanism for IPO multidecadal variability indicates that the presence of decadal timescale upper ocean heat content in the off-equatorial western tropical Pacific can provide conditions for an interannual El Niño/Southern Oscillation event to trigger a transition of tropical Pacific SSTs to the opposite IPO phase. Here we show that a decadal prediction initialized in 2013 simulates predicted Niño3.4 SSTs that have qualitatively tracked the observations through 2015. The year three to seven average prediction (2015–2019) from the 2013 initial state shows a transition to the positive phase of the IPO from the previous negative phase and a resumption of larger rates of global warming over the 2013–2022 period consistent with a positive IPO phase.
Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations
Authors: Varela Elisa , Muñoz-Lorente Miguel A. , Tejera Agueda M. , Ortega Sagrario , Blasco Maria A.
Published: June 2016

Although telomere length is genetically determined, mouse embryonic stem (ES) cells with telomeres of twice the normal size have been generated. Here, we use such ES cells with ‘hyper-long’ telomeres, which also express green fluorescent protein (GFP), to generate chimaeric mice containing cells with both hyper-long and normal telomeres. We show that chimaeric mice contain GFP-positive cells in all mouse tissues, display normal tissue histology and normal survival. Both hyper-long and normal telomeres shorten with age, but GFP-positive cells retain longer telomeres as mice age. Chimaeric mice with hyper-long telomeres also accumulate fewer cells with short telomeres and less DNA damage with age, and express lower levels of p53. In highly renewing compartments, such as the blood, cells with hyper-long telomeres are longitudinally maintained or enriched with age. We further show that wound-healing rates in the skin are increased in chimaeric mice. Our work demonstrates that mice with functional, longer and better preserved telomeres can be generated without the need for genetic manipulations, such as TERT overexpression.
Pre-40S ribosome biogenesis factor Tsr1 is an inactive structural mimic of translational GTPases
Authors: McCaughan Urszula M. , Jayachandran Uma , Shchepachev Vadim , Chen Zhuo Angel , Rappsilber Juri , Tollervey David , Cook Atlanta G.
Published: June 2016

Budding yeast Tsr1 is a ribosome biogenesis factor with sequence similarity to GTPases, which is essential for cytoplasmic steps in 40S subunit maturation. Here we present the crystal structure of Tsr1 at 3.6 Å. Tsr1 has a similar domain architecture to translational GTPases such as EF-Tu and the selenocysteine incorporation factor SelB. However, active site residues required for GTP binding and hydrolysis are absent, explaining the lack of enzymatic activity in previous analyses. Modelling of Tsr1 into cryo-electron microscopy maps of pre-40S particles shows that a highly acidic surface of Tsr1 is presented on the outside of pre-40S particles, potentially preventing premature binding to 60S subunits. Late pre-40S maturation also requires the GTPase eIF5B and the ATPase Rio1. The location of Tsr1 is predicted to block binding by both factors, strongly indicating that removal of Tsr1 is an essential step during cytoplasmic maturation of 40S ribosomal subunits.
Fluorescence microscopy as an alternative to electron microscopy for microscale dispersion evaluation of organic–inorganic composites
Authors: Guan Weijiang , Wang Si , Lu Chao , Tang Ben Zhong
Published: June 2016

Inorganic dispersion is of great importance for actual implementation of advanced properties of organic–inorganic composites. Currently, electron microscopy is the most conventional approach for observing dispersion of inorganic fillers from ultrathin sections of organic–inorganic composites at the nanoscale by professional technicians. However, direct visualization of macrodispersion of inorganic fillers in organic–inorganic composites using high-contrast fluorescent imaging method is hampered. Here we design and synthesize a unique fluorescent surfactant, which combines the properties of the aggregation-induced emission (AIE) and amphiphilicity, to image macrodispersion of montmorillonite and layered double hydroxide fillers in polymer matrix. The proposed fluorescence imaging provides a number of important advantages over electron microscope imaging, and opens a new avenue in the development of direct three-dimensional observation of inorganic filler macrodispersion in organic–inorganic composites.
14-3-3γ Prevents Centrosome Amplification and Neoplastic Progression
Authors: Mukhopadhyay Amitabha , Sehgal Lalit , Bose Arunabha , Gulvady Anushree , Senapati Parijat , Thorat Rahul , Basu Srikanta , Bhatt Khyati , Hosing Amol S. , Balyan Renu , Borde Lalit , Kundu Tapas K. , Dalal Sorab N.
Published: June 2016

More than 80% of malignant tumors show centrosome amplification and clustering. Centrosome amplification results from aberrations in the centrosome duplication cycle, which is strictly coordinated with DNA-replication-cycle. However, the relationship between cell-cycle regulators and centrosome duplicating factors is not well understood. This report demonstrates that 14-3-3γ localizes to the centrosome and 14-3-3γ loss leads to centrosome amplification. Loss of 14-3-3γ results in the phosphorylation of NPM1 at Thr-199, causing early centriole disjunction and centrosome hyper-duplication. The centrosome amplification led to aneuploidy and increased tumor formation in mice. Importantly, an increase in passage of the 14-3-3γ-knockdown cells led to an increase in the number of cells containing clustered centrosomes leading to the generation of pseudo-bipolar spindles. The increase in pseudo-bipolar spindles was reversed and an increase in the number of multi-polar spindles was observed upon expression of a constitutively active 14-3-3-binding-defective-mutant of cdc25C (S216A) in the 14-3-3γ knockdown cells. The increase in multi-polar spindle formation was associated with decreased cell viability and a decrease in tumor growth. Our findings uncover the molecular basis of regulation of centrosome duplication by 14-3-3γ and inhibition of tumor growth by premature activation of the mitotic program and the disruption of centrosome clustering.
Anomalous uptake and circulatory characteristics of the plant-based small RNA MIR2911
Authors: Yang Jian , Hotz Tremearne , Broadnax LaCassidy , Yarmarkovich Mark , Elbaz-Younes Ismail , Hirschi Kendal D.
Published: June 2016

Inconsistent detection of plant-based dietary small RNAs in circulation has thwarted the use of dietary RNA therapeutics. Here we demonstrate mice consuming diets rich in vegetables displayed enhanced serum levels of the plant specific small RNA MIR2911. Differential centrifugation, size-exclusion chromatography and proteinase K treatment of plant extracts suggest this RNA resides within a proteinase K-sensitive complex. Plant derived MIR2911 was more bioavailable than the synthetic RNA. Furthermore, MIR2911 exhibited unusual digestive stability compared with other synthetic plant microRNAs. The characteristics of circulating MIR2911 were also unusual as it was not associated with exosomes and fractionated as a soluble complex that was insensitive to proteinase K treatment, consistent with MIR2911 being stabilized by modifications conferred by the host. These results indicate that intrinsic stability and plant-based modifications orchestrate consumer uptake of this anomalous plant based small RNA and invite revisiting plant-based microRNA therapeutic approaches.
Erythrocyte intracellular Mg2+ concentration as an index of recognition and memory
Authors: Xiong Wenxiang , Liang Yaru , Li Xue , Liu Guosong , Wang Zhao
Published: June 2016

Magnesium (Mg2+) plays an important role in the neural system, and yet scarcely any research has quantitatively analyzed the link between endogenous Mg2+ level and memory. Using our original technique, we measured erythrocyte intracellular ionized Mg2+ concentration (RBC [Mg2+]i), which linearly correlated to recognition and spatial memory in normal aging rats. In the brain, RBC [Mg2+]i significantly correlated to hippocampus extracellular fluid Mg2+ concentration, and further correlated to hippocampal synapse density. Elevation of Mg2+ intake in aged rats demonstrated an association between RBC [Mg2+]i increase and memory recovery. The therapeutic effect of Mg2+ administration was inversely correlated to individual basal RBC [Mg2+]i. In summary, we provide a method to measure RBC [Mg2+]i, an ideal indicator of body Mg2+ level. RBC [Mg2+]i represents rodent memory performance in our study, and might further serve as a potential biomarker for clinical differential diagnosis and precise treatment of Mg2+-deficiency-associated memory decline during aging.
Carbon isotope fractionation reveals distinct process of CH4 emission from different compartments of paddy ecosystem
Authors: Zhang Guangbin , Yu Haiyang , Fan Xianfang , Ma Jing , Xu Hua
Published: June 2016

Carbon isotopic fractionations in the processes of CH4 emission from paddy field remain poorly understood. The δ13C-values of CH4 in association with production, oxidation and transport of CH4 in different pools of a paddy field were determined, and the stable carbon isotope fractionations were calibrated to assess relative contribution of acetate to CH4 production (fac) and fraction of CH4 oxidized (fox) by different pathways. The apparent isotope fractionation for CO2 conversion to CH4 (αapp) was 1.041–1.056 in the soil and 1.046–1.080 on the roots, indicating that fac was 10–60% and 0–50%, respectively. Isotope fractionation associated with CH4 oxidation (αox) was 1.021 ± 0.007 in the soil and 1.013 ± 0.005 on the roots, and the transport fractionation (εtransport) by rice plants was estimated to be −16.7‰ ~ −11.1‰. Rhizospheric fox was about 30–100%, and it was more important at the beginning but decreased fast towards the end of season. Large value of fox was also observed at the soil-water interface and soil and roots surfaces, respectively. The results demonstrate that carbon isotopic fractionations which might be different in different conditions were sensitive to the estimations of fac and fox in paddy field.
Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway
Authors: Song Eun Ju , Lee Sei-Jung , Lim Hyeon Su , Kim Jun Sung , Jang Kyung Ku , Choi Sang Ho , Han Ho Jae
Published: June 2016

VvhA, a virulent factor of Vibrio (V.) vulnificus, induces acute cell death in a destructive manner. Autophagy plays an important role in cell death, but the functional role of VvhA in autophagy-related cell death has not been elucidated yet. We found that rVvhA significantly increased LC3 puncta formation and autophagic flux in promoting the cell death of human intestinal epithelial Caco-2 cells. The cell death induced by rVvhA was independent of lysosomal permeabilizaton and caspase activation. rVvhA induced rapid phosphorylation of c-Src in the membrane lipid raft, which resulted in an increased interaction between lipid raft molecule caveolin-1 and NADPH oxidase (NOX) complex Rac1 for ROS production. NOX-mediated ROS signaling induced by rVvhA increased the phosphorylation of extracellular signal-regulated kinase (ERK) and eukaryotic translation initiation factor 2α (eIF2α) which are required for mRNA expression of Atg5 and Atg16L1 involved in autophagosome formation. In an in vivo model, VvhA increased autophagy activation and paracellular permeabilization in intestinal epithelium. Collectively, the results here show that VvhA plays a pivotal role in the pathogenesis and dissemination of V. vulnificus by autophagy upregulation, through the lipid raft-mediated c-Src/NOX signaling pathway and ERK/eIF2α activation.
Estrogen/ERR-α signaling axis is associated with fiber-type conversion of upper airway muscles in patients with obstructive sleep apnea hypopnea syndrome
Authors: Chen H. H. , Lu J. , Guan Y. F. , Li S. J. , Hu T. T. , Xie Z. S. , Wang F. , Peng X. H. , Liu X. , Xu X. , Zhao F. P. , Yu B. L. , Li X. P.
Published: June 2016

Estrogen is related with the low morbidity associated with obstructive sleep apnea hypopnea syndrome (OSAS) in women, but the underlying mechanisms remain largely unknown. In this study, we examined the relationship between OSAS and estrogen related receptor-α (ERR-α). We found that the expression levels of ERR-α and Myh7 were both downregulated in palatopharyngeal tissues from OSAS patients. In addition, we report that ERR-α is dynamically expressed during differentiation of C2C12 myoblasts. Knockdown of ERR-α via instant siRNA resulted in reduced expression of Myh7, but not Myh4. Furthermore, differentiation of C2C12 cells under 3% chronic intermittent hypoxia, a model resembling human OSAS, was impaired and accompanied by a obvious reduction in Myh7 expression levels. Moreover, activation of ERR-α with 17β-estradiol (E2) increased the expression of Myh7, whereas pretreatment with the ERR-α antagonist XCT790 reversed the E2-induced slow fiber-type switch. A rat ovariectomy model also demonstrated the switch to fast fiber type. Collectively, our findings suggest that ERR-α is involved in estrogen-mediated OSAS by regulating Myhc-slow expression. The present study illustrates an important role of the estrogen/ERR-α axis in the pathogenesis of OSAS, and may represent an attractive therapeutic target, especially in postmenopausal women.
miR-200 family promotes podocyte differentiation through repression of RSAD2
Authors: Li Zhigui , Yin Hongqiang , Hao Shuang , Wang Lifeng , Gao Jing , Tan Xiaoyue , Yang Zhuo
Published: June 2016

Mature podocytes are highly differentiated cells with several characteristic phenotypic features that are involved in the glomerular filtration function. During kidney development, a series of changes of the morphological characteristics and cellular functions may happen in podocytes. The miR-200 family functions in various biological and pathological processes. But the underlying molecular mechanisms of miR-200 family that functions in podocyte differentiation remain poorly understood. Herein is shown that miR-200a, miR-200b and miR-429 are significantly upregulated during the differentiation of podocytes, with highest upregulation of miR-200a. In these cells, restraint of miR-200 family by RNA interference assay revealed a prominent inhibition of cell differentiation. More intriguingly, miR-200 family directly inhibited the radical S-adenosyl methionine domain-containing protein 2 (RASD2) expression. Moreover, further upregulation of RSAD2 combining with restraint of miR-200 family revealed a promotion of podocyte dedifferentiation and proliferation. In addition, the expression of RSAD2 is consistent with that of in vitro podocyte differentiation in prenatal and postnatal mouse kidney and significantly down-regulated during the kidney development. Together, these findings indicate that miR-200 family may potentially promote podocyte differentiation through repression of RSAD2 expression. Our data also demonstrate a novel role of the antiviral protein RSAD2 as a regulator in cell differentiation.