bluuebunny/crossref_metadata_2025 huggingface dataset:
From plans to actions in patient and public involvement: qualitative study of documented plans and the accounts of researchers and patients sampled from a cohort of clinical trials
Authors: Buck Deborah , Gamble Carrol , Dudley Louise , Preston Jennifer , Hanley Bec , Williamson Paula R , Young Bridget ,   The EPIC Patient Advisory Group
Published: December 2014

Patient and public involvement (PPI) in research is increasingly required, although evidence to inform its implementation is limited.

Objective

Inform the evidence base by describing how plans for PPI were implemented within clinical trials and identifying the challenges and lessons learnt by research teams.

Methods

We compared PPI plans extracted from clinical trial grant applications (funded by the National Institute for Health Research Health Technology Assessment Programme between 2006 and 2010) with researchers’ and PPI contributors’ interview accounts of PPI implementation. Analysis of PPI plans and transcribed qualitative interviews drew on the Framework technique.

Results

Of 28 trials, 25 documented plans for PPI in funding applications and half described implementing PPI before applying for funding. Plans varied from minimal to extensive, although almost all anticipated multiple modes of PPI. Interview accounts indicated that PPI plans had been fully implemented in 20/25 trials and even expanded in some. Nevertheless, some researchers described PPI within their trials as tokenistic. Researchers and contributors noted that late or minimal PPI engagement diminished its value. Both groups perceived uncertainty about roles in relation to PPI, and noted contributors’ lack of confidence and difficulties attending meetings. PPI contributors experienced problems in interacting with researchers and understanding technical language. Researchers reported difficulties finding ‘the right’ PPI contributors, and advised caution when involving investigators’ current patients.

Conclusions

Engaging PPI contributors early and ensuring ongoing clarity about their activities, roles and goals, is crucial to PPI's success. Funders, reviewers and regulators should recognise the value of preapplication PPI and allocate further resources to it. They should also consider whether PPI plans in grant applications match a trial's distinct needs. Monitoring and reporting PPI before, during and after trials will help the research community to optimise PPI, although the need for ongoing flexibility in implementing PPI should also be recognised.
How safe are our paediatric emergency departments? Protocol for a national prospective cohort study
Authors: Plint Amy C , Newton Amanda , Stang Antonia , Bhatt Maala , Barrowman Nick , Calder Lisa
Published: December 2014

Introduction

Adverse events (AEs), defined as unintended patient harm related to healthcare provided rather than an underlying medical condition, represent a significant threat to patient safety and public health. The emergency department (ED) is a high-risk patient safety setting for many reasons including presentation ‘outside of regular hours’, high patient volumes, and a chaotic work environment. Children have also been identified as particularly vulnerable to AEs. Despite the identification of the ED as a high-risk setting and the vulnerability of the paediatric population, little research has been conducted regarding paediatric patient safety in the ED. The study objective is to generate an estimate of the risk and type of AEs, as well as their preventability and severity, for children seen in Canadian paediatric EDs.

Methods and analysis

This multicentre, prospective cohort study will enrol patients under 18 years of age from nine paediatric EDs across Canada. A stratified cluster random sampling scheme will be used to ensure patients recruited are representative of the overall ED population. A rigorous, standardised two-stage process will be used for AE identification. The primary outcome will be the proportion of children with AEs associated with ED care in the 3 weeks following the ED visit. Secondary outcomes will include the proportion of children with preventable AEs and the types and severity of AEs. We will aim to recruit 5632 patients over 1 year and this will allow us to detect a proportion of patients with an AE of 5% (to within an absolute margin of error of 0.6%).

Ethics and dissemination

Ethics approval has been obtained from participating sites. Results will be disseminated through presentations, peer review publications, linkages with emergency research network and a webinars for key knowledge user groups.

Trial registration number

This study is registered at Clinicaltrials.gov (NCT02162147;https://clinicaltrials.gov/ct2/show/NCT02162147).
Integrative medicine for subacute stroke rehabilitation: a study protocol for a multicentre, randomised, controlled trial
Authors: Fang Jianqiao , Chen Lifang , Chen Luni , Wang Chao , Keeler Crystal Lynn , Ma Ruijie , Xu Shouyu , Shen Laihua , Bao Yehua , Ji Conghua
Published: December 2014

Introduction

Many patients with stroke receive integrative medicine in China, which includes the basic treatment of Western medicine and routine rehabilitation, in conjunction with acupuncture and Chinese medicine. The question of whether integrative medicine is efficacious for stroke rehabilitation is still controversial and very little research currently exists on the integrated approach for this condition. Consequently, we will conduct a multicentre, randomised, controlled, assessor-blinded clinical trial to assess the effectiveness of integrative medicine on stroke rehabilitation.

Methods and analysis

360 participants recruited from three large Chinese medical hospitals in Zhejiang Province will be randomly divided into the integrative medicine rehabilitation (IMR) group and the conventional rehabilitation (CR) group in a 1:1 ratio. Participants in the IMR group will receive acupuncture and Chinese herbs in addition to basic Western medicine and rehabilitation treatment. The CR group will not receive acupuncture and Chinese herbal medicine. The assessment data will be collected at baseline, 4 and 8 weeks postrandomisation, and then at 12 weeks’ follow-up. The primary outcome is measured by the Modified Barthel Index. The secondary outcomes are the National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer Assessment, the mini-mental state examination and Montreal Cognitive, Hamilton's Depression Scale and Self-Rating Depression Scale, and the incidence of adverse events.

Ethics and dissemination

Ethical approval was obtained from ethics committees of three hospitals. The results will be disseminated in a peer-reviewed journal and presented at international congresses. The results will also be disseminated to patients by telephone, during follow-up calls inquiring on patient's post-study health status.

Trial registration number

Chinese Clinical Trial Register: ChiCTR-TRC-12001972,http://www.chictr.org/en/proj/show.aspx?proj=2561
Diagnostic accuracy of hyperbilirubinaemia in anticipating appendicitis and its severity
Authors: Muller Sven , Falch Claudius , Axt Steffen , Wilhelm Peter , Hein Dirk , Königsrainer Alfred , Kirschniak Andreas
Published: December 2014

Background

Hyperbilirubinaemia is reported to be a positive predictor in diagnosing appendicitis and especially appendiceal perforation. We, therefore, analysed the diagnostic accuracy of serum bilirubin in anticipating appendicitis and its severity.

Methods

All consecutive patients undergoing appendectomy for suspected appendicitis from May 2009 to August 2011 were analysed. Patients were classified based on final histopathological findings into the groups: no appendiceal inflammation, non-perforated appendicitis and perforated appendicitis. Primary outcome was the diagnostic accuracy of serum bilirubin levels in discriminating between no appendiceal inflammation and any appendicitis (perforated and non-perforated appendicitis) and non-perforated and perforated appendicitis.

Results

Of 493 analysed patients, 125 (25%) had no appendiceal inflammation, 312 (64%) had non-perforated appendicitis and 56 (11%) had perforated appendicitis. The proportion of patients with bilirubin elevation (>1.1 mg/dL) was different between those with no appendiceal inflammation (14%) and any appendicitis (36%) (p<0.0001), and between non-perforated appendicitis and perforated appendicitis 48% (p=0.04). However, the positive and negative likelihood ratios (LRs) for an elevated bilirubin were poor at discriminating the groups: no appendiceal inflammation versus any appendicitis (LR+ 2.62 (95% CI 1.65 to 4.16) and LR− 0.75 (95% CI 0.67 to 0.83)) and non-perforated appendicitis versus perforated appendicitis (LR+ estimate 1.74 (95% CI 1.28 to 2.38) and LR− 0.72 (95% CI 0.55 to 0.93)).

Conclusions

Hyperbilirubinaemia is present in acute appendicitis but has a low diagnostic accuracy in discriminating between any appendicitis versus no appendiceal inflammation and perforated versus non-perforated appendicitis and is, therefore, of limited value in clinical routine.

Trial registration number

NCT01698099.
Diffuse lung disease of infancy: a pattern-based, algorithmic approach to histological diagnosis
Authors: Armes Jane E , Mifsud William , Ashworth Michael
Published: December 2014

Diffuse lung disease (DLD) of infancy has multiple aetiologies and the spectrum of disease is substantially different from that seen in older children and adults. In many cases, a specific diagnosis renders a dire prognosis for the infant, with profound management implications. Two recently published series of DLD of infancy, collated from the archives of specialist centres, indicate that the majority of their cases were referred, implying that the majority of biopsies taken for DLD of infancy are first received by less experienced pathologists. The current literature describing DLD of infancy takes a predominantly aetiological approach to classification. We present an algorithmic, histological, pattern-based approach to diagnosis of DLD of infancy, which, with the aid of appropriate multidisciplinary input, including clinical and radiological expertise and ancillary diagnostic studies, may lead to an accurate and useful interim report, with timely exclusion of inappropriate diagnoses. Subsequent referral to a specialist centre for confirmatory diagnosis will be dependent on the individual case and the decision of the multidisciplinary team.
Impaired affective and cognitive theory of mind and behavioural change in amyotrophic lateral sclerosis
Authors: van der Hulst Egberdina-Józefa , Bak Thomas H , Abrahams Sharon
Published: December 2014

Objectives

Executive and behavioural changes are well-recognised in classical amyotrophic lateral sclerosis (ALS), indicating a subclinical behavioural-variant frontotemporal dementia (bvFTD) in some patients. Social cognitive deficits in ALS have been recently described and an impairment was identified on a simple Theory of Mind (ToM) test, which assesses the judgement of the preference of another through direction of eye gaze. The present study further delineated this deficit, by distinguishing between Affective and Cognitive subcomponents, and determining the relationship to behavioural change, levels of empathy and self-awareness.

Methods

The Cognitive–Affective Judgement of Preference Test was administered to 33 patients with ALS and 26 controls. Furthermore, a comprehensive neuropsychological battery and detailed behavioural assessment, with measures of empathy and awareness, were included.

Results

Patients with ALS showed a significant impairment in Affective ToM only when compared with healthy controls, with a deficit in 36% of patients; 12% showed an isolated Affective ToM deficit while 24% showed more generic ToM dysfunction. A Cognitive ToM deficit was found in 27% of patients, with 3% showing an isolated Cognitive ToM deficit. The patients with ALS showed reduced empathy (Fantasy scale) and increased behavioural dysfunction with high levels of apathy. In addition, patients with either an Affective and/or Cognitive ToM deficit exhibited poor self-awareness of their performance and abnormalities on verbal fluency, while those with an Affective ToM deficit also displayed higher levels of apathy and a naming deficit.

Conclusions

Dysfunctional ToM is a prominent feature of the cognitive profile of ALS. This specific difficulty in identifying and distinguishing the feelings and thoughts of another from a self-perspective may underpin the social behavioural abnormalities present in some patients with ALS, manifest as apathy and loss of awareness.
Improving the quality of documentation of paediatric post-take ward rounds: the impact of an acrostic
Authors: Newnham Amanda L , Hine Christopher , Rogers Camila , Agwu Juliana Chizo
Published: December 2014

Background

Review of patients’ notes while investigating clinical incidents showed a recurring problem of poor documentation of important aspects of the paediatric post-take ward round.

Purpose of the study

To evaluate the impact of an acrostic (type of mnemonic), created to reflect the aspects of care that should be documented after every ward round, on the completeness of note keeping.

Study design

The acrostic, ‘Please Verify Information For Doctors, Please Note Every Plan, was developed in 2010 to make it easy to remember the important aspects of post-take ward round, which are: Problem; Vital signs; Investigations; Fluids; Drugs; Patient/Parental concerns; Nursing concerns; Examination; Plan. The acrostic was introduced to doctors at a teaching session and included in the mandatory induction programme for all new doctors. Impact of use of the acrostic was evaluated in 2011 by audit of case notes before and after its introduction, with re-audit 2 years later. A survey of junior doctors on their attitude to its use was carried out in 2014.

Results

Introduction of the acrostic led to significant improvement in the documentation of problem (84% vs 94%), investigations (26% vs 72%), fluids (16% vs 74%), drugs (26% vs 76%), patient/parental concerns (16% vs 72%) and nursing concerns (4% vs 48%). Most (95% (19/20)) of the junior doctors agreed that the acrostic provided them with an easy format to document important aspects of post-take ward rounds.

Conclusions

Our patient notes now reflect much more clearly the input of patients and their parents/carers and the involvement of the multiprofessional team.
Generation of a directed mono-energetic neutrino beam and measurement of the neutrino mass
Authors: Folan L. M. , Tsifrinovich V. I.
Published: December 2014

We study generation of a directional mono-energetic neutrino beam in electron capture beta-decay and analyze the recoil force exerted by neutrinos. We consider the influence of the neutrino rest mass on the recoil force and discuss the opportunity for neutrino mass measurement using an atomic force microscopy (AFM). We compute the enhancement of the signal-to-noise ratio due to signal accumulation (averaging), find the optimal time for signal accumulation and formulate conditions for measurement of neutrino mass with AFM.
On the Choquet-Bruhat–York–Friedrich formulation of the Einstein–Euler equations
Authors: Disconzi Marcelo M. , Pingali Vamsi P.
Published: December 2014

Short-time existence for the Einstein–Euler and the vacuum Einstein equations is proven using a Friedrich inspired formulation due to Choquet-Bruhat and York, where the system is cast into a symmetric hyperbolic form and the Riemann tensor is treated as one of the fundamental unknowns of the problem. The reduced system of Choquet-Bruhat and York, along with the preservation of the gauge, is shown to imply the full Einstein equations.
Understanding the Other Through Social Roles
Authors: Kaneko Mamoru , Kline J. Jude
Published: December 2014

Inductive game theory has been developed to explore the origin of beliefs of a person from his accumulated experiences of a game situation. It has been restricted to a person's view of the structure not including another person's thoughts. In this paper, we explore the experiential origin of one's view of the other's beliefs about the game situation, especially about the other's payoffs. We restrict our exploration to a 2-role (strategic) game, which has been recurrently played by two people with occasional role-switching. Each person accumulates experiences of both roles, and these experiences become the source for his transpersonal view about the other. Reciprocity in the sense of role-switching is crucial for deriving his own and the other's beliefs. We also consider how a person can use these views for his behavior revision, and we define an equilibrium called an intrapersonal coordination equilibrium. Based on this, we show that cooperation will emerge as the degree of reciprocity increases.
Coalitional ZP-Equilibrium in Games and its Existence
Authors: Nessah Rabia , Larbani Moussa , Tazdaït Tarik
Published: December 2014

We introduce a solution concept for games in normal form with undetermined parameters, coalitional ZP-equilibrium, based on the notions of Z-equilibrium of [Zhukovskii and Chikrii [1994] Linear quadratic differential games, Kiev, Naoukova Doumka] and ZS-equilibrium of [Larbani and Lebbah [1999] A concept of equilibrium for a game under uncertainity. Europ. J. Oper. Res.117, 145–156]. For each coalition structure, ZP-equilibrium ensures both the stability of the partition and equilibrium of coalitional strategies (in Pareto sense). We show that under some quasiconcavity conditions on payoff functions, the coalitional ZP-equilibrium exists in compact, convex and continuous normal form games involving undetermined parameters.
A Note on Payoff Equivalence of the Volunteer's Dilemma and the Stag Hunt Game and Inferiority of Intermediate Thresholds
Authors: Bolle Friedel
Published: December 2014

The launch of a public project requires "enough" support from a group of 'n' players, i.e., a certain threshold has to be passed. The players may be differently important for passing the threshold; they may have different costs of support and different benefits if the project is launched. If players have only binary decision sets (participate or not, vote approvingly or not) this game is called a Binary Threshold Public Goods game (BTPG). We compare the expected equilibrium payoffs in BTPGs with the same costs and benefits but different thresholds. Applying two principles of equilibrium selection, the least and the most demanding threshold, namely "one supporting player is sufficient" (Volunteer's Dilemma) and "support by all players is necessary" (Stag Hunt game) are payoff equivalent for all players. Compared with the Stag Hunt game, all intermediate thresholds are connected with Pareto-inferior payoffs.
Photocatalytic Degradation Research of p-Xylene Using Doped TiO2 Under Different Conditions
Authors: Liu Chen , Chen Jun-Feng , Chen Rong-Chang , Chen Jia-Wei , Cao Xi
Published: December 2014

As the development of the "golden waterway" for the Yangtze River and the formation of the Three Gorges Reservoir area, the inland river shipping of chemical is increasing in China. At the same time, the risk of chemical leak accident is on the rising. Recent years, photo-catalyst has attracted great interest in environmental pollution treating for its unique properties. In order to improve its ability in pollution degradation, different kinds of doped TiO 2 are made in this work. Since the toxicity and transportation quantity, p-Xylene is researched as the aim chemical in this research. The influence of different catalyst, lighting time and reaction temperature to p-Xylene degradation rate are studied respectively in detail.
A Partitioned Implicit Coupling Strategy for Incompressible Flow Past an Oscillating Cylinder
Authors: He Tao
Published: December 2014

A partitioned implicit coupling strategy is proposed for fluid–structure interaction (FSI) problems in this paper. The incompressible Navier–Stokes equations under arbitrary Lagrangian–Eulerian description are solved by the characteristic-based split scheme while the structural equation is evaluated by the composite implicit time integration method. Moving submesh approach is performed for the mesh deformation and a mass source term (MST) is introduced into the pressure Poisson equation for respecting geometric conservation law. Fluid-structure coupling is achieved by the combined interface boundary condition (CIBC) method. The iterative loops are realized by fixed-point iterations with Aitken's Δ2 method. A structural force predictor is employed within the present algorithm, ensuring that the latest quantities belonging to different subdomains are adopted for the CIBC method. The proposed methodology is validated by flow-induced oscillations of a bluff body. The obtained results agree with the well-documented data. Some well-known flow phenomena have been detected successfully.
Single-File Diffusion of Driven Interacting Colloids
Authors: Euán-Díaz Edith C. , Herrera-Velarde Salvador , Misko Vyacheslav R. , Peeters François M. , Castañeda-Priego Ramón
Published: December 2014

The dynamical properties of interacting colloids spatially restricted to move in one-dimensional channels [J. Chem. Phys. 133, 114902 (2010)] and subjected to external periodic energy landscapes [Phys. Rev. E 86, 081123 (2012)] have been recently reported in terms of the long-time self-diffusion behavior. However, the full description of the mean-square displacement, ranging from short times to long times, is still missing. Thus, by means of Brownian dynamics computer simulations, we revisit the process known as single-file diffusion in driven interacting colloidal systems at all time scales. In particular, we review three different pair potentials, namely, Weeks–Chandler–Andersen, Yukawa and superparamagnetic potentials. We mainly focus on the importance of the correlation between particles via the coupling among hydrodynamic interactions and the external periodic field, resulting in nontrivial particle dynamics along the file in systems composed of repulsively interacting particles.

[Formula: see text] Special Issue Comments: This article reviews results on the dynamical properties of interacting colloids in a single file when they are subjected to external periodic energy landscapes presented before in [J. Chem. Phys. 33, 114902 (2010)] and [ Phys. Rev. E 86, 081123 (2012)]. We analyze different interactions that cover from short to long ranges of the interparticle potentials. We mainly focus on the importance of the correlation between particles via the coupling among the hydrodynamic interactions and the external periodic field.

Note from Publisher: In the captions of Figs. 1 through 4, "??" has appeared where the number 9 should appear.

In table 1, in the WCA section, the variable "φ" shows the values: 0.2,0.3,0.3,0.3,0.3,0.3.

The correct values are: 0.2, 0.3, 0.4, 0.5 , 0.6 , 0.7.
On discontinuity of planar optimal transport maps
Authors: Chodosh Otis , Jain Vishesh , Lindsey Michael , Panchev Lyuboslav , Rubinstein Yanir A.
Published: December 2014

Consider two bounded domains Ω and Λ in ℝ2, and two sufficiently regular probability measures μ and ν supported on them. By Brenier's theorem, there exists a unique transportation map T satisfying T#μ = ν and minimizing the quadratic cost ∫ℝn ∣T(x) - x∣2 dμ(x). Furthermore, by Caffarelli's regularity theory for the real Monge–Ampère equation, if Λ is convex, T is continuous.

We study the reverse problem, namely, when is T discontinuous if Λ fails to be convex? We prove a result guaranteeing the discontinuity of T in terms of the geometries of Λ and Ω in the two-dimensional case. The main idea is to use tools of convex analysis and the extrinsic geometry of ∂Λ to distinguish between Brenier and Alexandrov weak solutions of the Monge–Ampère equation. We also use this approach to give a new proof of a result due to Wolfson and Urbas.

We conclude by revisiting an example of Caffarelli, giving a detailed study of a discontinuous map between two explicit domains, and determining precisely where the discontinuities occur.
Global minimizers for Tonelli Lagrangians on the 2-torus
Authors: Schröder Jan Philipp
Published: December 2014

We study action-minimizing orbits in Tonelli Lagrangian systems on the 2-torus on fixed energy levels above Mañé's strict critical value. Our work generalizes the results of Morse, Hedlund and Bangert on minimal geodesics in Riemannian 2-tori. The techniques in the proofs involve classical variational ones, as well as the theories of Mather, Mañé and Fathi, which allow the step from reversible to non-reversible dynamics.
Redeeming an old foe: protective as well as pathophysiological roles for tumor necrosis factor in inflammatory bowel disease
Authors: Dubé Philip E. , Punit Shivesh , Polk D. Brent
Published: December 2014

Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 are major therapeutic targets for inflammatory bowel disease. Research advances have demonstrated that TNF produces pleiotropic responses in the gastrointestinal (GI) tract. Although in excess TNF can contribute to GI pathology, TNF is also a critical protective factor to promote GI homeostasis following injury and inflammation. Genetic studies using candidate and genome-wide association study approaches have identified variants in TNF or its receptors that are associated with Crohn's disease or ulcerative colitis in multiple populations, although the basis for these associations remains unclear. This review considers the efficacy and mechanism of anti-TNF therapies for inflammatory bowel disease to reconcile the many disparate aspects of TNF research and to consider the potential protective effects of TNF signaling in GI health.
Impaired cholecystokinin-induced gallbladder emptying incriminated in spontaneous “black” pigment gallstone formation in germfree Swiss Webster mice
Authors: Woods Stephanie E. , Leonard Monika R. , Hayden Joshua A. , Brophy Megan Brunjes , Bernert Kara R. , Lavoie Brigitte , Muthupalani Sureshkumar , Whary Mark T. , Mawe Gary M. , Nolan Elizabeth M. , Carey Martin C. , Fox James G.
Published: December 2014

“Black” pigment gallstones form in sterile gallbladder bile in the presence of excess bilirubin conjugates (“hyperbilirubinbilia”) from ineffective erythropoiesis, hemolysis, or induced enterohepatic cycling (EHC) of unconjugated bilirubin. Impaired gallbladder motility is a less well-studied risk factor. We evaluated the spontaneous occurrence of gallstones in adult germfree (GF) and conventionally housed specific pathogen-free (SPF) Swiss Webster (SW) mice. GF SW mice were more likely to have gallstones than SPF SW mice, with 75% and 23% prevalence, respectively. In GF SW mice, gallstones were observed predominately in heavier, older females. Gallbladders of GF SW mice were markedly enlarged, contained sterile black gallstones composed of calcium bilirubinate and <1% cholesterol, and had low-grade inflammation, edema, and epithelial hyperplasia. Hemograms were normal, but serum cholesterol was elevated in GF compared with SPF SW mice, and serum glucose levels were positively related to increasing age. Aged GF and SPF SW mice had deficits in gallbladder smooth muscle activity. In response to cholecystokinin (CCK), gallbladders of fasted GF SW mice showed impaired emptying (females: 29%; males: 1% emptying), whereas SPF SW females and males emptied 89% and 53% of volume, respectively. Bilirubin secretion rates of GF SW mice were not greater than SPF SW mice, repudiating an induced EHC. Gallstones likely developed in GF SW mice because of gallbladder hypomotility, enabled by features of GF physiology, including decreased intestinal CCK concentration and delayed intestinal transit, as well as an apparent genetic predisposition of the SW stock. GF SW mice may provide a valuable model to study gallbladder stasis as a cause of black pigment gallstones.
Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment
Authors: Lebeck Janne , Cheema Muhammad Umar , Skowronski Mariusz T. , Nielsen Søren , Praetorius Jeppe
Published: December 2014

The peroxisome proliferator receptor α (PPARα) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPARα plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPARα agonists to explore the effect of PPARα activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPARα agonist WY 14643 (3 mg·kg−1·day−1) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPARα had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPARα agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPARα activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPARα activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose.
Early right ventricular fibrosis and reduction in biventricular cardiac reserve in the dystrophin-deficient mdx heart
Authors: Meyers Tatyana A. , Townsend DeWayne
Published: December 2014

Duchenne muscular dystrophy (DMD) is a progressive disease of striated muscle deterioration. Respiratory and cardiac muscle dysfunction are particularly clinically relevant because they result in the leading causes of death in DMD patients. Despite the clinical and physiological significance of these systems, little has been done to understand the cardiorespiratory interaction in DMD. We show here that prior to the onset of global cardiac dysfunction, dystrophin-deficient mdx mice have increased cardiac fibrosis with the right ventricle being particularly affected. Using a novel biventricular cardiac catheterization technique coupled with cardiac stress testing, we demonstrate that both the right and left ventricles have significant reductions in both systolic and diastolic function in response to dobutamine. Unstimulated cardiac function is relatively normal except for a significant reduction in the ventricular pressure transient duration compared with controls. These biventricular analyses also reveal the absence of a dobutamine-induced increase in isovolumic relaxation in the right ventricle of control hearts. Simultaneous assessment of biventricular pressure demonstrates a dobutamine-dependent enhancement of coupling between the ventricles in control mice, which is absent in mdx mice. Furthermore, studies probing the passive-extension properties of the left ventricle demonstrate that the mdx heart is significantly more compliant compared with age-matched C57BL/10 hearts, which have an age-dependent stiffening that is completely absent from dystrophic hearts. These new results indicate that right ventricular fibrosis is an early indicator of the development of dystrophic cardiomyopathy, suggesting a mechanism by which respiratory insufficiency may accelerate the development of heart failure in DMD.
Renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake
Authors: Hagos Yohannes , Hundertmark Philip , Shnitsar Volodymyr , Marada Venkata V. V. R. , Wulf Gerald , Burckhardt Gerhard
Published: December 2014

Chronic lymphatic leukemia (CLL) is often associated with nephritic syndrome. Effective treatment of CLL by chlorambucil and bendamustine leads to the restoration of renal function. In this contribution, we sought to elucidate the impact of organic anion transporters (OATs) on the uptake of bendamustine and chlorambucil as a probable reason for the superior efficacy of bendamustine over chlorambucil in the treatment of CLL. We examined the effects of structural analogs of p-aminohippurate (PAH), melphalan, chlorambucil, and bendamustine, on OAT1-mediated [3H]PAH uptake and OAT3- and OAT4-mediated [3H]estrone sulfate (ES) uptake in stably transfected human embryonic kidney-293 cells. Melphalan had no significant inhibitory effect on any OAT, whereas chlorambucil reduced OAT1-, OAT3-, and OAT4-mediated uptake of PAH or ES down to 14.6%, 16.3%, and 66.0% of control, respectively. Bendamustine inhibited only OAT3-mediated ES uptake, which was reduced down to 14.3% of control cells, suggesting that it interacts exclusively with OAT3. The IC50value for OAT3 was calculated to be 0.8 μM. Real-time PCR experiments demonstrated a high expression of OAT3 in lymphoma cell lines as well as primary CLL cells. OAT3-mediated accumulation of bendamustine was associated with reduced cell proliferation and an increased rate of apoptosis. We conclude that the high efficacy of bendamustine in treating CLL might be partly contributed to the expression of OAT3 in lymphoma cells and the high affinity of bendamustine for this transporter.
Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing
Authors: Roy Ankita , Goodman Joshua H. , Begum Gulnaz , Donnelly Bridget F. , Pittman Gabrielle , Weinman Edward J. , Sun Dandan , Subramanya Arohan R.
Published: December 2014

Sodium-coupled SLC12 cation chloride cotransporters play important roles in cell volume and chloride homeostasis, epithelial fluid secretion, and renal tubular salt reabsorption. These cotransporters are phosphorylated and activated indirectly by With-No-Lysine (WNK) kinases through their downstream effector kinases, Ste20- and SPS1-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1). Multiple WNK kinases can coexist within a single cell type, although their relative contributions to SPAK/OSR1 activation and salt transport remain incompletely understood. Deletion of specific WNKs from cells that natively express a functional WNK-SPAK/OSR1 network will help resolve these knowledge gaps. Here, we outline a simple method to selectively knock out full-length WNK1 expression from mammalian cells using RNA-guided clustered regularly interspaced short palindromic repeats/Cas9 endonucleases. Two clonal cell lines were generated by using a single-guide RNA (sgRNA) targeting exon 1 of the WNK1 gene, which produced indels that abolished WNK1 protein expression. Both cell lines exhibited reduced endogenous WNK4 protein abundance, indicating that WNK1 is required for WNK4 stability. Consistent with an on-target effect, the reduced WNK4 abundance was associated with increased expression of the KLHL3/cullin-3 E3 ubiquitin ligase complex and was rescued by exogenous WNK1 overexpression. Although the morphology of the knockout cells was indistinguishable from control, they exhibited low baseline SPAK/OSR1 activity and failed to trigger regulatory volume increase after hypertonic stress, confirming an essential role for WNK1 in cell volume regulation. Collectively, our data show how this new, powerful, and accessible gene-editing technology can be used to dissect and analyze WNK signaling networks.
Quantification of microcirculatory blood flow: a sensitive and clinically relevant prognostic marker in murine models of sepsis
Authors: Sand Claire A. , Starr Anna , Wilder Catherine D. E. , Rudyk Olena , Spina Domenico , Thiemermann Christoph , Treacher David F. , Nandi Manasi
Published: December 2014

Sepsis and sepsis-associated multiorgan failure represent the major cause of mortality in intensive care units worldwide. Cardiovascular dysfunction, a key component of sepsis pathogenesis, has received much research interest, although research translatability remains severely limited. There is a critical need for more comprehensive preclinical sepsis models, with more clinically relevant end points, such as microvascular perfusion. The purpose of this study was to compare microcirculatory blood flow measurements, using a novel application of laser speckle contrast imaging technology, with more traditional hemodynamic end points, as part of a multiparameter monitoring system in preclinical models of sepsis. Our aim, in measuring mesenteric blood flow, was to increase the prognostic sensitivity of preclinical studies. In two commonly used sepsis models (cecal ligation and puncture, and lipopolysaccharide), we demonstrate that blood pressure and cardiac output are compromised postsepsis, but subsequently stabilize over the 24-h recording period. In contrast, mesenteric blood flow continuously declines in a time-dependent manner and in parallel with the development of metabolic acidosis and organ dysfunction. Importantly, these microcirculatory perturbations are reversed by fluid resuscitation, a mainstay intervention associated with improved outcome in patients. These data suggest that global hemodynamics are maintained at the expense of the microcirculation and are, therefore, not sufficiently predictive of outcome. We demonstrate that microcirculatory blood flow is a more sensitive biomarker of sepsis syndrome progression and believe that incorporation of this biomarker into preclinical models will facilitate sophisticated proof-of-concept studies for novel sepsis interventions, providing more robust data on which to base future clinical trials.
H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis
Authors: Wu Pei-Chun , Lu Jeng-Wei , Yang Jer-Yen , Lin I-Hsuan , Ou Da-Liang , Lin Yu-Hsiang , Chou Kuan-Hsien , Huang Wen-Feng , Wang Wan-Ping , Huang Yih-Leh , Hsu Chiun , Lin Liang-In , Lin Yueh-Min , Shen C.-K. James , Tzeng Tsai-Yu
Published: December 2014

Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells. Restoring KMT1E expression in this setting suppressed filopodia formation, migration, and invasive behavior. Conversely, loss of KMT1E in lung cancer cells with limited metastatic potential promoted migration in vitro and restored metastatic prowess in vivo. Mechanistic investigations indicated that KMT1E cooperates with the TGFβ-regulated complex SMAD2/3 to repress metastasis through ANXA2. Together, our findings defined an essential role for the KMT1E/SMAD2/3 repressor complex in TGFβ-mediated lung cancer metastasis. Cancer Res; 74(24); 7333–43. ©2014 AACR.
PD-1 Blockade in Renal Cell Carcinoma: To Equilibrium and Beyond
Authors: Harshman Lauren C. , Drake Charles G. , Choueiri Toni K.
Published: December 2014

The past several years have witnessed a resurgence of interest in cancer immunotherapy. The development of blocking antibodies against the inhibitory programmed death-1 (PD-1) pathway represents a clinical breakthrough in the treatment of solid tumors such as melanoma, and these agents show great promise in renal cell carcinoma (RCC). The early data have been surprising in that they demonstrate that blockade of a single immune checkpoint can elicit objective responses in patients with RCC, despite the recognized complexity of the immunosuppressive tumor microenvironment. Reinvigorating the patient's own immune cells to reactivate and to target the tumor has the potential advantages of more selective killing and thus decreased toxicity. In addition, checkpoint blockade immunotherapy has the advantage of inducing a memory response that is unattainable with our current cytotoxic and targeted therapies. This Crossroads overview will highlight the emerging investigation of PD-1 blockade in RCC and how this T cell–targeted strategy may thwart the tumor's escape mechanisms and shift the immune system/tumor balance back to a state of equilibrium and even to tumor elimination. Cancer Immunol Res; 2(12); 1132–41. ©2014 AACR.
Clinical Outcomes of Prenatally Diagnosed Cases of Isolated and Nonisolated Pericardial Effusion
Authors: Kyeong Kyu-Sang , Won Hye-Sung , Lee Mi-Young , Shim Jae-Yoon , Lee Pil Ryang , Kim Ahm
Published: December 2014

Objective: The purpose of this study was to investigate the clinical outcome of fetal pericardial effusion (PE). Methods: This study involved a retrospective review of prenatally diagnosed PE cases. The criterion for inclusion was pericardial fluid in an area greater than 2 mm in diameter. Results: A total of 276 cases of PE and 252 cases diagnosed with other anomalies were initially reviewed. PE is associated with cardiac malformation, hydrops fetalis, extracardiac abnormalities, infections, anemias, intrauterine growth restriction, and aneuploidy markers in fetuses. Of these reviewed cases, 24 cases of isolated fetal PE were studied. In all cases, pericardial fluid filled an area ranging from 2 to 17 mm in diameter. Four cases of isolated PE had an abnormal postnatal condition, and 3 cases were excluded due to lack of follow-up. The size of the PE was not related to the regression of pericardial fluid, adverse outcomes or mortality rate associated with the isolated PE. All newborns were healthy, and there were no chromosomal abnormalities in the study population. Conclusions: There were no adverse clinical outcomes or chromosomal abnormalities in the fetuses diagnosed with isolated PE. Most cases of isolated PE resolved spontaneously and were associated with a good prognosis.
Uterine Artery Pulsatility Index Assessment at 11-13+6 Weeks' Gestation
Authors: Ridding Gus , Schluter Philip J. , Hyett Jon A. , McLennan Andrew C.
Published: December 2014

Introduction: First-trimester uterine artery pulsatility index (PI) measurements form part of an algorithm used to assess the risk of developing pre-eclampsia. The objective of this study was to construct a population-specific reference range for both the lower and mean maternal uterine artery PI at 11-13+6 weeks' gestation and to assess measurement agreement. Materials and Methods: Reference ranges for mean and lower PI measurements were developed using polynomial regression models following prospective collection of maternal uterine artery PI measurements at 11-13+6 weeks' gestation. Measurement agreement studies were performed by two experienced operators. Results: Measurements from 298 women were included in the primary study. Polynomial regression indicated no change over gestational age for the lower PI (mean 1.44). There was an inverse relationship between the average PI and gestational age (mean [0.8960 + (2.9771 × CRL-1/2)]2). PI measurement agreement was good-strong (intraclass correlation (ICC) 0.50-0.79) between operators, and within-operator agreement was almost perfect (ICC 0.88-0.93). Conclusions: Reference ranges for both the average and lowest PI of the maternal uterine arteries were derived at 11-13+6 weeks' gestation. This will provide a basis for development of auditable standards for first-trimester uterine artery Doppler measurements. The PI measurements are reproducible and reliable.
On the Pleotropic Actions of Mineralocorticoids
Authors: Lang Florian
Published: December 2014

Classical effects of mineralocorticoids include stimulation of Na+ reabsorption and K+ secretion in the kidney and other epithelia including colon and several glands. Moreover, mineralocorticoids enhance the excretion of Mg2+ and renal tubular H+ secretion. The renal salt retention following mineralocorticoid excess leads to extracellular volume expansion and hypertension. The increase of blood pressure following mineralocorticoid excess is, however, not only the result of volume expansion but may result from stiff endothelial cell syndrome impairing the release of vasodilating nitric oxide. Beyond that, mineralocorticoids are involved in the regulation of a wide variety of further functions, including cardiac fibrosis, platelet activation, neuronal function and survival, inflammation as well as vascular and tissue fibrosis and calcification. Those functions are briefly discussed in this short introduction to the special issue. Beyond that, further contributions of this special issue amplify on mineralocorticoid-induced sodium appetite and renal salt retention, the role of mineralocorticoids in the regulation of acid-base balance, the involvement of aldosterone and its receptors in major depression, the mineralocorticoid stimulation of inflammation and tissue fibrosis and the effect of aldosterone on osteoinductive signaling and vascular calcification. Clearly, still much is to be learned about the various ramifications of mineralocorticoid-sensitive physiology and pathophysiology.
Effect of Mineralocorticoids on Acid-Base Balance
Authors: Wagner Carsten A.
Published: December 2014

Aldosterone is classically associated with the regulation of salt and potassium homeostasis but has also profound effects on acid-base balance. During acidosis, circulating aldosterone levels are increased and the hormone acts in concert with angiotensin II and other factors to stimulate renal acid excretion. Pharmacological blockade of aldosterone action as well as inherited or acquired syndromes of impaired aldosterone release or action impair the renal response to acid loading and cause hyperkalemic renal tubular acidosis. The mineralocorticoid receptor (MR) mediating the genomic effects of aldosterone is expressed in all cells of the distal nephron including all subtypes of intercalated cells. In acid-secretory type A intercalated cells, aldosterone stimulates proton secretion into urine, whereas in non-type A intercalated cells, aldosterone increases the activity of the luminal anion exchanger pendrin stimulating bicarbonate secretion and chloride reabsorption. Aldosterone has also stimulatory effects on proton secretion that may be mediated by a non-genomic pathway. In addition, aldosterone indirectly stimulates renal acid excretion by enhancing sodium reabsorption through the epithelial sodium channel ENaC. Increased sodium reabsorption enhances the lumen-negative transepithelial voltage that facilitates proton secretion by neighboring intercalated cells. This indirect coupling of sodium reabsorption and proton secretion is thought to underlie the fludrocortisone-furosemide test for maximal urinary acidification in patients with suspected distal renal tubular acidosis. In patients with CKD, acidosis-induced aldosterone may contribute to progression of kidney disease. In summary, aldosterone is a powerful regulator of renal acid excretion required for normal acid-base balance.