bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic uncertainty in a case of neuroleptic malignant syndrome
Authors: Seitz Dallas P. 
Published: July 2016

ABSTRACTNeuroleptic malignant syndrome (NMS) is a potentially life-threatening condition that has been associated with antipsychotic use. Most diagnostic criteria include fever and muscle rigidity, although NMS may present without either. Diagnostic uncertainty in such cases may result in delays in diagnosis and management, leading to adverse consequences for these patients. The differential diagnosis of NMS is broad and includes a number of neurological, medical and psychiatric conditions as well as substance and medication-induced disorders. A case is described that illustrates an atypical presentation of NMS and demonstrates some of the challenges in its diagnosis. Limitations of current NMS criteria are also examined, and suggestions for future criteria are presented.
Nail embolization to the femoral artery
Authors: Baw Bandar , Al-Salamah Majid A. , Al-Hodaib Abdullah , Wadams Heather 
Published: July 2016

ABSTRACTModern air-nailing tools are known to cause penetrating trauma. We report the unusual case of a pneumatically fired carpenter's nail that penetrated the chest of a 30-year-old man and subsequently embolized from the heart to the left femoral artery without clinical evidence of having entered the heart. The nail was surgically removed, and the patient was discharged from hospital without sequelae after 10 days. This case and the relevant literature are discussed from the perspective of the emergency department investigation and care of such patients.
Brugada syndrome in a young patient with palpitations
Authors: Watrich Deanne G. , Woods Robert A. , Steiner Ivan P. 
Published: July 2016

ABSTRACT
Brugada syndrome is a potentially lethal and eminently treatable entity that may present with palpitations or syncope. This article presents the case of a young patient with Brugada syndrome and reviews key features in the epidemiology, pathophysiology, diagnosis, treatment and prognosis of this condition.
Variations in monetary distribution among Ontario’s Alternative Funding Agreement workload model hospitals
Authors: Whyne Mitchell , Whyne Garrett , Rowe Brian H. 
Published: July 2016

ABSTRACTObjectives:Alternative Funding Agreements (AFAs) were in place in 41 hospital emergency departments (EDs) in Ontario at the time of this survey (May to August 2005). Each of these 41 hospitals works with its own internal administrative model. The primary objective of this paper was to document the administrative models used in these Ontario EDs. The secondary objective was to inform current and future AFA EDs of the potential models.Methods:Telephone surveys were conducted with a member of each of the 41 AFA workload model hospitals.Results:All hospitals provided at least 1 emergency physician to answer the questionnaire. Although most AFA hospitals divide the AFA fund pool on an hourly basis, there is impressive variation on premium values awarded for day, evening, weekend and night shifts. Other variations included holdback of funds for bonuses, distribution of non-OHIP (Ontario Health Insurance Plan) dollars, on-call allowances, and different pay scales for the general practitioners and locums working in some departments.Conclusions:Allowing flexibility in distribution of AFA dollars to physicians in each group has helped make this program more acceptable. Many issues unrelated to funding remain to be resolved in order to stabilize ED recruitment and retention as well as improve work satisfaction. Further research on these latter topics is required to develop a fair and equitable funding arrangement that supports and enhances physician coverage in EDs across Canada.
Poisoning due to raw Gyromitra esculenta (false morels) west of the Rockies
Authors: Leathem Anne M. , Dorran Thomas J. 
Published: July 2016

ABSTRACTVomiting with abdominal pain is a common presentation in the emergency department (ED). Without a careful history, unusual causes, such as toxic ingestion, may evade diagnosis. We report a case of an Asian couple who presented to the ED with vomiting and epigastric distress. They were discharged with no definite diagnosis, but on a return ED visit the following day were diagnosed with toxic ingestion ofGyromitra esculenta, commonly known as the western false morel. The patients were admitted and treated with intravenous hydration and pyridoxine. Both patients developed mild hepatotoxicity but went on to fully recover. This case demonstrates that the western false morel may cause significant toxicity and it highlights the importance of obtaining a complete history in patients who present with non-specific gastrointestinal symptoms.
Necrotizing pneumonia and septic shock: suspecting CA-MRSA in patients presenting to Canadian emergency departments
Authors: Vayalumkal Joseph V. , Whittingham Heather , Vanderkooi Otto , Stewart Thomas E. , Low Donald E. , Mulvey Michael , McGeer Allison 
Published: July 2016

ABSTRACTWe report a case of fatal necrotizing pneumonia and sepsis caused by community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) in an otherwise well, 48-year-old Canadian man with type 2 diabetes mellitus who had travelled to Texas. Despite therapy that included intravenous antibiotics, intravenous immune globulin and other supportive measures, the patient succumbed to his illness. Recently, CA-MRSA pneumonia has been reported in several countries. The virulence of this organism may in part be related to its ability to produce toxins, such as Panton-Valentine leukocidin. As rates of CA-MRSA increase worldwide, physicians should be aware of the potential for MRSA to cause life-threatening infections in patients presenting to Canadian emergency departments (EDs). Necrotizing pneumonia caused by MRSA must be considered in the differential diagnosis of acute, severe respiratory illness. Early recognition of this syndrome in the ED may help physicians initiate appropriate antibiotic therapy in a timely manner.
Key indicators of overcrowding in Canadian emergency departments: a Delphi study
Authors: Ospina Maria B. , Bond Kenneth , Schull Michael , Innes Grant , Blitz Sandra , Rowe Brian H. 
Published: July 2016

ABSTRACTObjective:To identify the level of consensus among a group of Canadian emergency department (ED) experts on the importance of a set of indicators to document ED overcrowding.Methods:A 2-round Delphi survey was conducted from February 2005 to April 2005, with a multi-disciplinary group of 38 Canadian experts in various aspects of ED operations who rated the relevance of 36 measures and ranked their relative importance as indicators of ED overcrowding.Results:The response rates for the first and second rounds were 84% and 87%, respectively. The most important indicator identified by the experts was the percentage of the ED occupied by in-patients (mean on a 7-point Likert-type scale 6.53, standard deviation [SD] 0.80). The other 9 indicators, in order of the importance attributed, were the total number of ED patients (mean 6.35, SD 0.75), the total time in the ED (mean 6.16, SD 1.04), the percentage of time that the ED was at or above capacity (mean 6.16, SD 1.08), the overall bed occupancy (mean 6.19, SD 0.93), the time from bed request to bed assignment (mean 6.06, SD 1.08), the time from triage to care (mean 5.84, SD 1.08) the physician satisfaction (mean 5.84, SD 1.22), the time from bed availability to ward transfer (mean 5.53, SD 1.72) and the number of staffed acute care beds (mean 5.53, SD 1.57).Conclusion:Ten clinically important measures were prioritized by the participants as relevant indicators of ED overcrowding. Indicators derived from consensus techniques have face validity, but their metric properties must be tested to ensure their effectiveness for identifying ED overcrowding in different settings.
Emergency medicine training demographics of physicians working in rural and regional southwestern Ontario emergency departments
Authors: Bhimani Munsif , Dickie Gordon , McLeod Shelley , Kim Daniel 
Published: July 2016

ABSTRACTObjectives:We sought to determine the emergency medicine training demographics of physicians working in rural and regional emergency departments (EDs) in southwestern Ontario.Methods:A confidential 8-item survey was mailed to ED chiefs in 32 community EDs in southwestern Ontario during the month of March 2005. This study was limited to nonacademic centres.Results:Responses were received from 25 (78.1%) of the surveyed EDs, and demographic information on 256 physicians working in those EDs was obtained. Of this total, 181 (70.1%) physicians had no formal emergency medicine (EM) training. Most were members of the College of Family Physicians of Canada (CCFPs). The minimum qualification to work in the surveyed EDs was a CCFP in 8 EDs (32.0%) and a CCFP with Advanced Cardiac and Trauma Resuscitation Courses (ACLS and ATLS) in 17 EDs (68.0%). None of the surveyed EDs required a CCFP(EM) or FRCP(EM) certification, even in population centres larger than 50 000.Conclusion:The majority of physicians working in southwestern Ontario community EDs graduated from family medicine residencies, and most have no formal EM training or certification. This information is of relevance to both family medicine and emergency medicine residency training programs. It should be considered in the determination of curriculum content and the appropriate number of residency positions.
Intracellular glutathione determines bortezomib cytotoxicity in multiple myeloma cells
Authors: Starheim K K , Holien T , Misund K , Johansson I , Baranowska K A , Sponaas A-M , Hella H , Buene G , Waage A , Sundan A , Bjørkøy G 
Published: July 2016

AbstractMultiple myeloma (myeloma in short) is an incurable cancer of antibody-producing plasma cells that comprise 13% of all hematological malignancies. The proteasome inhibitor bortezomib has improved treatment significantly, but inherent and acquired resistance to the drug remains a problem. We here show that bortezomib-induced cytotoxicity was completely dampened when cells were supplemented with cysteine or its derivative, glutathione (GSH) in ANBL-6 and INA-6 myeloma cell lines. GSH is a major component of the antioxidative defense in eukaryotic cells. Increasing intracellular GSH levels fully abolished bortezomib-induced cytotoxicity and transcriptional changes. Elevated intracellular GSH levels blocked bortezomib-induced nuclear factor erythroid 2-related factor 2 (NFE2L2, NRF2)-associated stress responses, including upregulation of the xCT subunit of the Xc- cystine-glutamate antiporter. INA-6 cells conditioned to increasing bortezomib doses displayed reduced bortezomib sensitivity and elevated xCT levels. Inhibiting Xc- activity potentiated bortezomib-induced cytotoxicity in myeloma cell lines and primary cells, and re-established sensitivity to bortezomib in bortezomib-conditioned cells. We propose that intracellular GSH level is the main determinant of bortezomib-induced cytotoxicity in a subset of myeloma cells, and that combined targeting of the proteasome and the Xc- cystine-glutamate antiporter can circumvent bortezomib resistance.
Association mapping reveals novel serpentine adaptation gene clusters in a population of symbiotic Mesorhizobium
Authors: Porter Stephanie S , Chang Peter L , Conow Christopher A , Dunham Joseph P , Friesen Maren L 
Published: July 2016

Abstract
The genetic variants that underlie microbial environmental adaptation are key components of models of microbial diversification. Characterizing adaptive variants and the pangenomic context in which they evolve remains a frontier in understanding how microbial diversity is generated. The genomics of rhizobium adaptation to contrasting soil environments is ecologically and agriculturally important because these bacteria are responsible for half of all current biologically fixed nitrogen, yet they live the majority of their lives in soil. Our study uses whole-genome sequencing to describe the pan-genome of a focal clade of wild mesorhizobia that show contrasting levels of nickel adaptation despite high relatedness (99.8% identity at 16S). We observe ecotypic specialization within an otherwise genomically cohesive population, rather than finding distinct specialized bacterial lineages in contrasting soil types. This finding supports recent reports that heterogeneous environments impose selection that maintains differentiation only at a small fraction of the genome. Our work further uses a genome-wide association study to propose candidate genes for nickel adaptation. Several candidates show homology to genetic systems involved in nickel tolerance and one cluster of candidates correlates perfectly with soil origin, which validates our approach of ascribing genomic variation to adaptive divergence.
The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity
Authors: Xu Yuanming , Zhao Fang , Qiu Quan , Chen Kun , Wei Juncheng , Kong Qingfei , Gao Beixue , Melo-Cardenas Johanna , Zhang Bin , Zhang Jinping , Song Jianxun , Zhang Donna D. , Zhang Jianing , Fan Yunping , Li Huabin , Fang Deyu 
Published: July 2016

AbstractIdentification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27kip1, and deletion of p27kip1 in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4+ T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.
Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia
Authors: Sun Kaiqi , Zhang Yujin , D’Alessandro Angelo , Nemkov Travis , Song Anren , Wu Hongyu , Liu Hong , Adebiyi Morayo , Huang Aji , Wen Yuan E. , Bogdanov Mikhail V. , Vila Alejandro , O’Brien John , Kellems Rodney E. , Dowhan William , Subudhi Andrew W. , Jameson-Van Houten Sonja , Julian Colleen G. , Lovering Andrew T. , Safo Martin , Hansen Kirk C. , Roach Robert C. , Xia Yang 
Published: July 2016

AbstractSphingosine-1-phosphate (S1P) is a bioactive signalling lipid highly enriched in mature erythrocytes, with unknown functions pertaining to erythrocyte physiology. Here by employing nonbiased high-throughput metabolomic profiling, we show that erythrocyte S1P levels rapidly increase in 21 healthy lowland volunteers at 5,260 m altitude on day 1 and continue increasing to 16 days with concurrently elevated erythrocyte sphingonisne kinase 1 (Sphk1) activity and haemoglobin (Hb) oxygen (O2) release capacity. Mouse genetic studies show that elevated erythrocyte Sphk1-induced S1P protects against tissue hypoxia by inducing O2release. Mechanistically, we show that intracellular S1P promotes deoxygenated Hb anchoring to the membrane, enhances the release of membrane-bound glycolytic enzymes to the cytosol, induces glycolysis and thus the production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific glycolytic intermediate, which facilitates O2release. Altogether, we reveal S1P as an intracellular hypoxia-responsive biolipid promoting erythrocyte glycolysis, O2delivery and thus new therapeutic opportunities to counteract tissue hypoxia.
Structural investigation of heteroyohimbine alkaloid synthesis reveals active site elements that control stereoselectivity
Authors: Stavrinides Anna , Tatsis Evangelos C. , Caputi Lorenzo , Foureau Emilien , Stevenson Clare E. M. , Lawson David M. , Courdavault Vincent , O'Connor Sarah E. 
Published: July 2016

AbstractPlants produce an enormous array of biologically active metabolites, often with stereochemical variations on the same molecular scaffold. These changes in stereochemistry dramatically impact biological activity. Notably, the stereoisomers of the heteroyohimbine alkaloids show diverse pharmacological activities. We reported a medium chain dehydrogenase/reductase (MDR) from Catharanthus roseus that catalyses formation of a heteroyohimbine isomer. Here we report the discovery of additional heteroyohimbine synthases (HYSs), one of which produces a mixture of diastereomers. The crystal structures for three HYSs have been solved, providing insight into the mechanism of reactivity and stereoselectivity, with mutation of one loop transforming product specificity. Localization and gene silencing experiments provide a basis for understanding the function of these enzymes in vivo. This work sets the stage to explore how MDRs evolved to generate structural and biological diversity in specialized plant metabolism and opens the possibility for metabolic engineering of new compounds based on this scaffold.
RNA polymerase I–Rrn3 complex at 4.8 Å resolution
Authors: Engel Christoph , Plitzko Jürgen , Cramer Patrick 
Published: July 2016

AbstractTranscription of ribosomal DNA by RNA polymerase I (Pol I) requires the initiation factor Rrn3. Here we report the cryo-EM structure of the Pol I–Rrn3 complex at 4.8 Å resolution. The structure reveals how Rrn3 binding converts an inactive Pol I dimer into an initiation-competent monomeric complex and provides insights into the mechanisms of Pol I-specific initiation and regulation.
Structural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization
Authors: Kato Kazuki , Satouh Yuhkoh , Nishimasu Hiroshi , Kurabayashi Arisa , Morita Junko , Fujihara Yoshitaka , Oji Asami , Ishitani Ryuichiro , Ikawa Masahito , Nureki Osamu 
Published: July 2016

AbstractSperm–egg fusion is the critical step in mammalian fertilization, and requires the interaction between IZUMO1 on the sperm surface and JUNO (also known as folate receptor (FR) 4 or IZUMO1R) on the egg surface. Whereas other FRs bind and uptake folates, JUNO binds IZUMO1 and establishes the cell–cell adhesion. However, the mechanism of IZUMO1 recognition by JUNO has remained elusive. Here we report the crystal structure of mouse JUNO, at 2.3 Å resolution. A structural comparison of JUNO with the FRs revealed that JUNO and the FRs have similar overall structures, but JUNO lacks the folate-binding pocket, thereby explaining the inability of JUNO to bind folate. Further complementation of Juno knockout eggs with mutant Juno messenger RNAs revealed that the conserved, surface-exposed tryptophan residue of JUNO is required for sperm binding and fertilization. Our structure-based in vivo functional analyses provide a framework towards a mechanistic understanding of mammalian gamete recognition.
Septin 9 induces lipid droplets growth by a phosphatidylinositol-5-phosphate and microtubule-dependent mechanism hijacked by HCV
Authors: Akil Abdellah , Peng Juan , Omrane Mohyeddine , Gondeau Claire , Desterke Christophe , Marin Mickaël , Tronchère Hélène , Taveneau Cyntia , Sar Sokhavuth , Briolotti Philippe , Benjelloun Soumaya , Benjouad Abdelaziz , Maurel Patrick , Thiers Valérie , Bressanelli Stéphane , Samuel Didier , Bréchot Christian , Gassama-Diagne Ama 
Published: July 2016

AbstractThe accumulation of lipid droplets (LD) is frequently observed in hepatitis C virus (HCV) infection and represents an important risk factor for the development of liver steatosis and cirrhosis. The mechanisms of LD biogenesis and growth remain open questions. Here, transcriptome analysis reveals a significant upregulation of septin 9 in HCV-induced cirrhosis compared with the normal liver. HCV infection increases septin 9 expression and induces its assembly into filaments. Septin 9 regulates LD growth and perinuclear accumulation in a manner dependent on dynamic microtubules. The effects of septin 9 on LDs are also dependent on binding to PtdIns5P, which, in turn, controls the formation of septin 9 filaments and its interaction with microtubules. This previously undescribed cooperation between PtdIns5P and septin 9 regulates oleate-induced accumulation of LDs. Overall, our data offer a novel route for LD growth through the involvement of a septin 9/PtdIns5P signalling pathway.
The F-BAR protein pacsin2 inhibits asymmetric VE-cadherin internalization from tensile adherens junctions
Authors: Dorland Yvonne L. , Malinova Tsveta S. , van Stalborch Anne-Marieke D. , Grieve Adam G. , van Geemen Daphne , Jansen Nicolette S. , de Kreuk Bart-Jan , Nawaz Kalim , Kole Jeroen , Geerts Dirk , Musters René J. P. , de Rooij Johan , Hordijk Peter L. , Huveneers Stephan 
Published: July 2016

AbstractVascular homoeostasis, development and disease critically depend on the regulation of endothelial cell–cell junctions. Here we uncover a new role for the F-BAR protein pacsin2 in the control of VE-cadherin-based endothelial adhesion. Pacsin2 concentrates at focal adherens junctions (FAJs) that are experiencing unbalanced actomyosin-based pulling. FAJs move in response to differences in local cytoskeletal geometry and pacsin2 is recruited consistently to the trailing end of fast-moving FAJs via a mechanism that requires an intact F-BAR domain. Photoconversion, photobleaching, immunofluorescence and super-resolution microscopy reveal polarized dynamics, and organization of junctional proteins between the front of FAJs and their trailing ends. Interestingly, pacsin2 recruitment inhibits internalization of the VE-cadherin complex from FAJ trailing ends and is important for endothelial monolayer integrity. Together, these findings reveal a novel junction protective mechanism during polarized trafficking of VE-cadherin, which supports barrier maintenance within dynamic endothelial tissue.
Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors
Authors: Hsieh Tung-Ju , Lin Hsien-Ya , Tu Zhijay , Lin Ting-Chien , Wu Shang-Chuen , Tseng Yu-Yao , Liu Fu-Tong , Hsu Shang-Te Danny , Lin Chun-Hung 
Published: July 2016

AbstractHuman galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3’-deoxy-3,3’-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis) and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A–E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.