bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repurposing the Nonsteroidal Anti-inflammatory Drug Diflunisal as an Osteoprotective, Antivirulence Therapy for Staphylococcus aureus Osteomyelitis
Authors: Hendrix Andrew S. , Spoonmore Thomas J. , Wilde Aimee D. , Putnam Nicole E. , Hammer Neal D. , Snyder Daniel J. , Guelcher Scott A. , Skaar Eric P. , Cassat James E. 
Published: June 2016

ABSTRACT

Staphylococcus aureus
osteomyelitis is a common and debilitating invasive infection of bone. Treatment of osteomyelitis is confounded by widespread antimicrobial resistance and the propensity of bacteria to trigger pathological changes in bone remodeling that limit antimicrobial penetration to the infectious focus. Adjunctive therapies that limit pathogen-induced bone destruction could therefore limit morbidity and enhance traditional antimicrobial therapies. In this study, we evaluate the efficacy of the U.S. Food and Drug Administration-approved, nonsteroidal anti-inflammatory (NSAID) compound diflunisal in limiting
S. aureus
cytotoxicity toward skeletal cells and in preventing bone destruction during staphylococcal osteomyelitis. Diflunisal is known to inhibit
S. aureus
virulence factor production by the accessory gene regulator (
agr
) locus, and we have previously demonstrated that the Agr system plays a substantial role in pathological bone remodeling during staphylococcal osteomyelitis. Consistent with these observations, we find that diflunisal potently inhibits osteoblast cytotoxicity caused by
S. aureus
secreted toxins independently of effects on bacterial growth. Compared to commonly used NSAIDs, diflunisal is uniquely potent in the inhibition of skeletal cell death
in vitro
. Moreover, local delivery of diflunisal by means of a drug-eluting, bioresorbable foam significantly limits bone destruction during
S. aureus
osteomyelitis
in vivo
. Collectively, these data demonstrate that diflunisal potently inhibits skeletal cell death and bone destruction associated with
S. aureus
infection and may therefore be a useful adjunctive therapy for osteomyelitis.
Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment
Authors: Hassan Hozeifa Mohamed , Guo Hongli , Yousef Bashir Alsiddig , Guerram Mounia , Hamdi Aida Mejda , Zhang Luyong , Jiang Zhenzhou 
Published: June 2016

ABSTRACT
Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury.
Full-Length Nucleotide Sequences of
mcr-1
-Harboring Plasmids Isolated from Extended-Spectrum-β-Lactamase-Producing Escherichia coli Isolates of Different Origins
Authors: Zurfluh Katrin , Klumpp Jochen , Nüesch-Inderbinen Magdalena , Stephan Roger 
Published: June 2016

ABSTRACT

Here, we present the full sequences of three
mcr-1
-carrying plasmids isolated from extended-spectrum-β-lactamase (ESBL)-producing
Escherichia coli
. The plasmids belong to three different replicon types and are 34,640 bp, 209,401 bp, and 247,885 bp in size. We describe for the first time a composite transposon containing
mcr-1
localized on a multidrug-resistant (MDR) IncHI2 plasmid harboring additional determinants of resistance to six different classes of antibiotics, including the ESBL gene
bla
CTX-M-1
, and heavy metal resistance.
Meningococcal Two-Partner Secretion Systems and Their Association with Outcome in Patients with Meningitis
Authors: Piet Jurgen R. , van Ulsen Peter , ur Rahman Sadeeq , Bovenkerk Sandra , Bentley Stephen D. , van de Beek Diederik , van der Ende Arie 
Published: June 2016

ABSTRACT
Two-partner secretion (TPS) systems export large TpsA proteins to the surface and extracellular milieu. In meningococci, three different TPS systems exist, and of these, TPS system 2 (TPS2) and TPS3 can be detected by the host's immune system. We evaluated the distribution of TPS systems among clinical isolates from two prospective cohort studies comprising 373 patients with meningococcal meningitis. TPS system 1 was present in 91% of isolates, and system 2 and/or 3 was present in 67%. The TPS system distribution was related to clonal complexes. Infection with strains with TPS2 and/or TPS3 resulted in less severe disease and better outcomes than infection with strains without these systems. Using whole-blood stimulation experiments, we found no differences in the host cytokine response between patients infected with TPS system 2 and 3 knockout strains and patients infected with a wild-type strain. In conclusion, meningococcal TPS system 2 and/or 3 is associated with disease severity and outcome in patients with meningitis.
Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis
Authors: Ko Su Hyuk , Rho Da Jeong , Jeon Jong Ik , Kim Young-Jeon , Woo Hyun Ae , Lee Yun Kyung , Kim Jung Mogg 
Published: June 2016

ABSTRACT

The
Bacteroides fragilis
enterotoxin (BFT), a virulence factor of enterotoxigenic
B. fragilis
(ETBF), interacts with intestinal epithelial cells and can provoke signals that induce mucosal inflammation. Although expression of heme oxygenase-1 (HO-1) is associated with regulation of inflammatory responses, little is known about HO-1 induction in ETBF infection. This study was conducted to investigate the effect of BFT on HO-1 expression in intestinal epithelial cells. Stimulation of intestinal epithelial cells with BFT resulted in upregulated expression of HO-1. BFT activated transcription factors such as NF-κB, AP-1, and Nrf2 in intestinal epithelial cells. Upregulation of HO-1 in intestinal epithelial cells was dependent on activated IκB kinase (IKK)–NF-κB signals. However, suppression of Nrf2 or AP-1 signals in intestinal epithelial cells did not result in significant attenuation of BFT-induced HO-1 expression. HO-1 induction via IKK–NF-κB in intestinal epithelial cells was regulated by p38 mitogen-activated protein kinases (MAPKs). Furthermore, suppression of HO-1 activity led to increased apoptosis in BFT-stimulated epithelial cells. These results suggest that a signaling pathway involving p38 MAPK–IKK–NF-κB in intestinal epithelial cells is required for HO-1 induction during exposure to BFT. Following this induction, increased HO-1 expression may regulate the apoptotic process in responses to BFT stimulation.
The Type IV Secretion System Effector Protein CirA Stimulates the GTPase Activity of RhoA and Is Required for Virulence in a Mouse Model of Coxiella burnetii Infection
Authors: Weber Mary M. , Faris Robert , van Schaik Erin J. , McLachlan Juanita Thrasher , Wright William U. , Tellez Andres , Roman Victor A. , Rowin Kristina , Case Elizabeth Di Russo , Luo Zhao-Qing , Samuel James E. 
Published: June 2016

ABSTRACT

Coxiella burnetii
, the etiological agent of Q fever in humans, is an intracellular pathogen that replicates in an acidified parasitophorous vacuole derived from host lysosomes. Generation of this replicative compartment requires effectors delivered into the host cell by the Dot/Icm type IVb secretion system. Several effectors crucial for
C. burnetii
intracellular replication have been identified, but the host pathways coopted by these essential effectors are poorly defined, and very little is known about how spacious vacuoles are formed and maintained. Here we demonstrate that the essential type IVb effector, CirA, stimulates GTPase activity of RhoA. Overexpression of CirA in mammalian cells results in cell rounding and stress fiber disruption, a phenotype that is rescued by overexpression of wild-type or constitutively active RhoA. Unlike other effector proteins that subvert Rho GTPases to modulate uptake, CirA is the first effector identified that is dispensable for uptake and instead recruits Rho GTPase to promote biogenesis of the bacterial vacuole. Collectively our results highlight the importance of CirA in coopting host Rho GTPases for establishment of
Coxiella burnetii
infection and virulence in mammalian cell culture and mouse models of infection.
A Suppressor Mutation That Creates a Faster and More Robust σE Envelope Stress Response
Authors: Konovalova Anna , Schwalm Jaclyn A. , Silhavy Thomas J. 
Published: June 2016

ABSTRACT

The σE envelope stress response is an essential signal transduction pathway which detects and removes mistargeted outer membrane (OM) β-barrel proteins (OMPs) in the periplasm of
Escherichia coli
. It relies on σE, an alternative sigma factor encoded by the
rpoE
gene. Here we report a novel mutation, a nucleotide change of C to A in the third base of the second codon, which increases levels of σE (
rpoE_S2R
). The
rpoE_S2R
mutation does not lead to the induction of the stress response during normal growth but instead changes the dynamics of induction upon periplasmic stress, resulting in a faster and more robust response. This allows cells to adapt faster to the periplasmic stress, avoiding lethal accumulation of unfolded OMPs in the periplasm caused by severe defects in the OMP assembly pathway.

IMPORTANCE
Survival of bacteria under conditions of external or internal stresses depends on timely induction of stress response signaling pathways to regulate expression of appropriate genes that function to maintain cellular homeostasis. Previous studies have shown that strong preinduction of envelope stress responses can allow bacteria to survive a number of lethal genetic perturbations. In our paper, we describe a unique mutation that enhances kinetics of the σE envelope stress response pathway rather than preinducing the response. This allows bacteria to quickly adapt to sudden and severe periplasmic stress.
Ethanolamine Catabolism in Pseudomonas aeruginosa PAO1 Is Regulated by the Enhancer-Binding Protein EatR (PA4021) and the Alternative Sigma Factor RpoN
Authors: Lundgren Benjamin R. , Sarwar Zaara , Pinto Atahualpa , Ganley Jack G. , Nomura Christopher T. 
Published: June 2016

ABSTRACT

Although genes encoding enzymes and proteins related to ethanolamine catabolism are widely distributed in the genomes of
Pseudomonas
spp., ethanolamine catabolism has received little attention among this metabolically versatile group of bacteria. In an attempt to shed light on this subject, this study focused on defining the key regulatory factors that govern the expression of the central ethanolamine catabolic pathway in
Pseudomonas aeruginosa
PAO1. This pathway is encoded by the
PA4022-eat-eutBC
operon and consists of a transport protein (Eat), an ethanolamine-ammonia lyase (EutBC), and an acetaldehyde dehydrogenase (PA4022). EutBC is an essential enzyme in ethanolamine catabolism because it hydrolyzes this amino alcohol into ammonia and acetaldehyde. The acetaldehyde intermediate is then converted into acetate in a reaction catalyzed by acetaldehyde dehydrogenase. Using a combination of growth analyses and β-galactosidase fusions, the enhancer-binding protein PA4021 and the sigma factor RpoN were shown to be positive regulators of the
PA4022-eat-eutBC
operon in
P. aeruginosa
PAO1. PA4021 and RpoN were required for growth on ethanolamine, and both of these regulatory proteins were essential for induction of the
PA4022-eat-eutBC
operon. Unexpectedly, the results indicate that acetaldehyde (and not ethanolamine) serves as the inducer molecule that is sensed by PA4021 and leads to the transcriptional activation of the
PA4022-eat-eutBC
operon. Due to its regulatory role in ethanolamine catabolism, PA4021 was given the name EatR. Both EatR and its target genes are conserved in several other
Pseudomonas
spp., suggesting that these bacteria share a mechanism for regulating ethanolamine catabolism.

IMPORTANCE
The results of this study provide a basis for understanding ethanolamine catabolism and its regulation in
Pseudomonas aeruginosa
PAO1. Interestingly, expression of the ethanolamine-catabolic genes in this bacterium was found to be under the control of a positive-feedback regulatory loop in a manner dependent on the transcriptional regulator PA4021, the sigma factor RpoN, and the metabolite acetaldehyde. Previously characterized regulators of ethanolamine catabolism are known to sense and respond directly to ethanolamine. In contrast, PA4021 (EatR) appears to monitor the intracellular levels of free acetaldehyde and responds through transcriptional activation of the ethanolamine-catabolic genes. This regulatory mechanism is unique and represents an alternative strategy used by bacteria to govern the acquisition of ethanolamine from their surroundings.
Systematic review of patients' participation in and experiences of technology-based monitoring of mental health symptoms in the community
Authors: Walsh Sophie , Golden Eoin , Priebe Stefan 
Published: June 2016

ObjectivesTo review systematically the literature on patients’ experiences of, and participation in, technology-based monitoring of mental health symptoms. This practice was defined as patients monitoring their mental health symptoms, emotions or behaviours outside of routine clinical appointments by submitting symptom data using technology, with feedback arising from the data (for example, supportive messages or symptom summaries, being sent to the patient, clinician or carer).DesignSystematic review following PRISMA guidelines of studies evaluating technology-based symptom monitoring. Tools from narrative synthesis were used to analyse quantitative findings on participation rates and qualitative findings on patient views.Data sourcesPubMed, EMBASE, PsycINFO, BNI, CINAHL, Cochrane Registers and Web of Science electronic databases were searched using a combination of ‘psychiatry’, ‘symptom monitoring’ and ‘technology’ descriptors. A secondary hand search was performed in grey literature and references.Results57 papers representing 42 studies met the inclusion criteria for the review. Technology-based symptom monitoring was used for a range of mental health conditions, either independently of a specific therapeutic intervention or as an integrated component of therapeutic interventions. The majority of studies reported moderate-to-strong rates of participation, though a third reported lower rates. Qualitative feedback suggests that acceptability of monitoring is related to perceived validity, ease of practice, convenient technology, appropriate frequency and helpfulness of feedback, as well as the impact of monitoring on participants’ ability to manage health and personal relationships.ConclusionsSuch symptom monitoring practices appear to be well accepted and may be a feasible complement to clinical practice. However, there is limited availability of data and heterogeneity of studies. Future research should examine robustly patients’ role in the development and evaluation of technology-based symptom monitoring in order to maximise its clinical utility.
Tranexamic acid in hip fracture patients: a protocol for a randomised, placebo controlled trial on the efficacy of tranexamic acid in reducing blood loss in hip fracture patients
Authors: Gausden Elizabeth Bishop , Garner Matthew R , Warner Stephen J , Levack Ashley , Nellestein Andrew M , Tedore Tiffany , Flores Eva , Lorich Dean G 
Published: June 2016

IntroductionThere is a high incidence of blood transfusion following hip fractures in elderly patients. Tranexamic acid (TXA) has proven efficacy in decreasing blood loss in general trauma patients as well as patients undergoing elective orthopaedic surgery. A randomised controlled trial will measure the effect of TXA in a population of patients undergoing hip fracture surgery.MethodsThis is a double-blinded, randomised placebo-controlled trial. Patients admitted through the emergency room that are diagnosed with an intertrochanteric or femoral neck fracture will be eligible for enrolment and randomised to either treatment with 1 g of intravenous TXA or intravenous saline at the time of skin incision. Patients undergoing percutaneous intervention for non-displaced or minimally displaced femoral neck fractures will not be eligible for enrolment. Postoperative transfusion rates will be recorded and blood loss will be calculated from serial haematocrits.Ethics and disseminationThis protocol was approved by the Institutional Review Board (IRB) and is registered with clinicaltrials.gov. The findings of the trial will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberNCT01940536.
The use of the reverse shock index to identify high-risk trauma patients in addition to the criteria for trauma team activation: a cross-sectional study based on a trauma registry system
Authors: Kuo Spencer C H , Kuo Pao-Jen , Hsu Shiun-Yuan , Rau Cheng-Shyuan , Chen Yi-Chun , Hsieh Hsiao-Yun , Hsieh Ching-Hua 
Published: June 2016

ObjectivesThe presentation of decrease blood pressure with tachycardia is usually an indicator of significant blood loss. In this study, we used the reverse shock index (RSI), a ratio of systolic blood pressure (SBP) to heart rate (HR), to evaluate the haemodynamic status of trauma patients. As an SBP lower than the HR (RSI<1) may indicate haemodynamic instability, the objective of this study was to assess whether RSI<1 can help to identify high-risk patients with potential shock and poor outcome, even though these patients do not yet meet the criteria for multidisciplinary trauma team activation (TTA).DesignCross-sectional study.SettingTaiwan.ParticipantsWe retrospectively reviewed the data of 20 106 patients obtained from the trauma registry system of a level I trauma centre for trauma admissions from January 2009 through December 2014. Patients for whom a trauma team was not activated (regular patients) and who had RSI<1 were compared with regular patients with RSI≥1. The ORs of the associated conditions and injuries were calculated with 95% CIs.Main outcome measuresIn-hospital mortality.ResultsAmong regular patients with RSI<1, significantly more patients had an Injury Severity Score (ISS) ≥25 (OR 2.4, 95% CI 1.58 to 3.62; p<0.001) and the mortality rate was also higher (2.1% vs 0.5%; OR 3.9, 95% CI 2.10 to 7.08; p<0.001) than in regular patients with RSI≥1. The intensive care unit length of stay was longer in regular patients with RSI<1 than in regular patients with RSI≥1.ConclusionsAmong patients who did not reach the criteria for TTA, RSI<1 indicates a potentially worse outcome and a requirement for more attention and aggressive care in the emergency department.
Predictors of seeking emergency medical help during overdose events in a provincial naloxone distribution programme: a retrospective analysis
Authors: Ambrose Graham , Amlani Ashraf , Buxton Jane A 
Published: June 2016

ObjectivesThis study sought to identify factors that may be associated with help-seeking by witnesses during overdoses where naloxone is administered.SettingOverdose events occurred in and were reported from the five regional health authorities across British Columbia, Canada. Naloxone administration forms completed following overdose events were submitted to the British Columbia Take Home Naloxone programme.ParticipantsAll 182 reported naloxone administration events, reported by adult men and women and occurring between 31 August 2012 and 31 March 2015, were considered for inclusion in the analysis. Of these, 18 were excluded: 10 events which were reported by the person who overdosed, and 8 events for which completed forms did not indicate whether or not emergency medical help was sought.Primary and secondary outcome measuresSeeking emergency medical help (calling 911), as reported by participants, was the sole outcome measure of this analysis.ResultsMedical help was sought (emergency services—911 called) in 89 (54.3%) of 164 overdoses where naloxone was administered. The majority of administration events occurred in private residences (50.6%) and on the street (23.4%), where reported rates of calling 911 were 27.5% and 81.1%, respectively. Overdoses occurring on the street (compared to private residence) were significantly associated with higher odds of calling 911 in multivariate analysis (OR=10.68; 95% CI 2.83 to 51.87; p<0.01), after adjusting for other variables.ConclusionsOverdoses occurring on the street were associated with higher odds of seeking emergency medical help by responders. Further research is needed to determine if sex and stimulant use by the person who overdosed are associated with seeking emergency medical help. The results of this study will inform interventions within the British Columbia Take Home Naloxone programme and other jurisdictions to encourage seeking emergency medical help.
Unit-based incident reporting and root cause analysis: variation at three hospital unit types
Authors: Wagner Cordula , Merten Hanneke , Zwaan Laura , Lubberding Sanne , Timmermans Danielle , Smits Marleen 
Published: June 2016

ObjectivesTo minimise adverse events in healthcare, various large-scale incident reporting and learning systems have been developed worldwide. Nevertheless, learning from patient safety incidents is going slowly. Local, unit-based reporting systems can help to get faster and more detailed insight into unit-specific safety issues. The aim of our study was to gain insight into types and causes of patient safety incidents in hospital units and to explore differences between unit types.DesignProspective observational study.Setting10 emergency medicine units, 10 internal medicine units and 10 general surgery units in 20 hospitals in the Netherlands participated. Patient safety incidents were reported by healthcare providers. Reports were analysed with root cause analysis. The results were compared between the 3 unit types.ResultsA total of 2028 incidents were reported in an average reporting period of 8 weeks per unit. More than half had some consequences for patients, such as a prolonged hospital stay or longer waiting time, and a small number resulted in patient harm. Significant differences in incident types and causes were found between unit types. Emergency units reported more incidents related to collaboration, whereas surgical and internal medicine units reported more incidents related to medication use. The distribution of root causes of surgical and emergency medicine units showed more mutual similarities than those of internal medicine units.ConclusionsComparable incidents and causes have been found in all units, but there were also differences between units and unit types. Unit-based incident reporting gives specific information and therefore makes improvements easier. We conclude that unit-based incident reporting has an added value besides hospital-wide or national reporting systems that already exist in various countries.