bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes
Authors: Senda Asuna , Mukai Yuji , Hayakawa Toru , Kato Yuka , Eliasson Erik , Rane Anders , Toda Takaki , Inotsume Nobuo 
Published: April 2017

AbstractCytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti‐inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC50 indicate that these ARBs might inhibit the AA metabolism in the liver.
Human BJ Fibroblasts is an Alternative to Mouse BALB/c 3T3 Cells in In Vitro Neutral Red Uptake Assay
Authors: Mannerström Marika , Toimela Tarja , Sarkanen Jertta‐Riina , Heinonen Tuula 
Published: April 2017

AbstractThe OECD GD 129 BALB/c 3T3 neutral red uptake (NRU) assay is a standardized test method for estimating starting dose for an acute oral systemic toxicity test in rodents. Mouse BALB/c 3T3 fibroblasts are the most commonly used cells in the NRU assay. We have previously transferred and validated BALB/c 3T3 NRU assay in our GLP laboratory. Subsequently, in order to obtain more human‐relevant cytotoxicity data, we performed an intralaboratory validation using human BJ fibroblasts in the NRU assay instead of mouse BALB/c 3T3 fibroblasts. Here, we present comparative cytotoxicity data of 26 different test chemicals (pharmaceuticals, industrial chemicals, pesticides and food additives) produced with both BALB/c 3T3 NRU and BJ NRU assays.
Mathematical Modelling of Glucose‐Dependent Insulinotropic Polypeptide and Glucagon‐like Peptide‐1 following Ingestion of Glucose
Authors: Røge Rikke M. , Bagger Jonatan I. , Alskär Oskar , Kristensen Niels R. , Klim Søren , Holst Jens J. , Ingwersen Steen H. , Karlsson Mats O. , Knop Filip K. , Vilsbøll Tina , Kjellsson Maria C. 
Published: April 2017

AbstractThe incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), play an important role in glucose homeostasis by potentiating glucose‐induced insulin secretion. Furthermore, GLP‐1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP‐1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP‐1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP‐1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP‐1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.
Nonparametric Bayesian Covariate-Adjusted Estimation of the Youden Index
Authors: Inácio de Carvalho Vanda , de Carvalho Miguel , Branscum Adam J. 
Published: April 2017

Summary
A novel nonparametric regression model is developed for evaluating the covariate-specific accuracy of a continuous biological marker. Accurately screening diseased from nondiseased individuals and correctly diagnosing disease stage are critically important to health care on several fronts, including guiding recommendations about combinations of treatments and their intensities. The accuracy of a continuous medical test or biomarker varies by the cutoff threshold (c) used to infer disease status. Accuracy can be measured by the probability of testing positive for diseased individuals (the true positive probability or sensitivity, Se(c), of the test), and the true negative probability (specificity, Sp(c)) of the test. A commonly used summary measure of test accuracy is the Youden index, , which is popular due in part to its ease of interpretation and relevance to population health research. In addition, clinical practitioners benefit from having an estimate of the optimal cutoff that maximizes sensitivity plus specificity available as a byproduct of estimating YI. We develop a highly flexible nonparametric model to estimate YI and its associated optimal cutoff that can respond to unanticipated skewness, multimodality, and other complexities because data distributions are modeled using dependent Dirichlet process mixtures. Important theoretical results on the support properties of the model are detailed. Inferences are available for the covariate-specific Youden index and its corresponding optimal cutoff threshold. The value of our nonparametric regression model is illustrated using multiple simulation studies and data on the age-specific accuracy of glucose as a biomarker of diabetes.
Measurements of immature platelets with haematology analysers are of limited value to separate immune thrombocytopenia from bone marrow failure
Authors: Cybulska Annalina , Meintker Lisa , Ringwald Jürgen , Krause Stefan W. 
Published: April 2017

SummaryDetection of immature platelets in the circulation may help to dissect thrombocytopenia due to platelet destruction from bone marrow failure (BMF). We prospectively tested the predictive value of immature platelets, measured as immature platelet fraction (IPF) on the XE‐5000 (Sysmex, Kobe, Japan) or percentage of reticulated platelets (rPT) on the CD Sapphire (Abbott Diagnostics, Santa Clara, CA, USA) to separate immune thrombocytopenia (ITP) from BMF (leukaemia, myelodysplastic syndrome, aplastic anaemia). We analysed 58 samples of patients with BMF, 47 samples of patients with ITP and 97 controls. Median rPT (CD Sapphire) was increased to 9·0% in ITP and to 10·9% in BMF, compared to 1·9% in controls. Median IPF (XE‐5000) was 16·2% in ITP, 10·2% in BMF and 2·5% in controls. We found an inverse correlation between high fractions of immature platelets and low platelet counts in thrombocytopenic samples regardless of the diagnosis. In conclusion, we observed a broad overlap of immature platelets between ITP and BMF, which may be caused by an accelerated release of immature platelets in any thrombocytopenic state and decreased production in many patients with ITP. Despite this, IPF (XE‐5000) had some power to discriminate ITP from BMF, whereas rPT (CD Sapphire) was of no predictive value.
‘I call it stinkin’ thinkin’’: A qualitative analysis of metacognition in people with chronic low back pain and elevated catastrophizing
Authors: Schütze Robert , Rees Clare , Slater Helen , Smith Anne , O'Sullivan Peter 
Published: April 2017

ObjectivesPain catastrophizing is widely studied in quantitative pain research because of its strong link with poor pain outcomes, although the exact nature of this construct remains unclear. Focusing on its ruminative dimension, the present qualitative study aimed to explore a nascent aspect of pain catastrophizing – metacognition – by documenting people's attitudes towards rumination and examining how these metacognitions might influence the course it takes.DesignQualitative interview study.MethodsSemi‐structured interviews were conducted in a tertiary care setting with 15 adults experiencing chronic (≥6 months) low back pain who scored highly (≥30) on the Pain Catastrophising Scale. Transcripts were analysed using interpretative phenomenological analysis.ResultsThe first aim of documenting pain metacognitions revealed both positive (e.g., ‘thinking helps me to cope’) and negative (e.g., ‘rumination is uncontrollable’) attitudes towards pain rumination. These were often held simultaneously, creating internal conflict. The second aim of exploring the influence of metacognition on rumination showed that both negative and positive metacognitions could fuel perseverative thinking. However, more nuanced negative metacognitions (e.g., ‘worry is pointless’) could help to end episodes of rumination by motivating the use of concrete problem‐solving or active coping behaviours.ConclusionsWhile most participants described pain rumination as uncontrollable and harmful, dwelling on pain could be helpful when focused on tangible and solvable problems, thereby translating into adaptive coping behaviours that eventually interrupt rumination. Future treatments may be more effective if they are based on individualized formulations of pain catastrophizing that focus on its perseverative nature and implicit function.
Statement of contribution

What is already known on this subject?

Chronic pain affects one in five people, and psychological coping responses are key targets within gold standard biopsychosocial interventions.

People who have elevated pain catastrophizing tend to have worse pain outcomes, including increased pain, disability, and emotional distress.

What people believe about their own thinking (i.e., their metacognitions) influences how much they worry or ruminate.

What does this study add?

This is the first qualitative study exploring metacognitions in people with chronic pain and the first to target a purposive sample of people with elevated pain catastrophizing.

People with elevated pain catastrophizing often see rumination as uncontrollable and harmful but may simultaneously believe it helps them to solve problems or feel prepared for future threats.

Pain catastrophizing is not a stable and enduring trait but fluctuates both within and across individuals in response to pain, context, metacognitive beliefs about rumination, and coping behaviours.
Short Notice, Big Difference? The Effect of Temporary Employment on Firm Competitiveness across Sectors
Authors: Giuliano Romina , Kampelmann Stephan , Mahy Benoît , Rycx François 
Published: April 2017

AbstractThis article is one of the first to examine how the use of fixed‐term employment contracts (FTCs) affects firm competitiveness (i.e. productivity, wages and profits) while controlling for key econometric issues such as time‐invariant unobserved workplace characteristics, endogeneity and state dependence. We apply dynamic panel data estimation techniques to detailed Belgian linked employer–employee data covering all years from 1999 to 2010. Results show that the effects of FTCs on firm competitiveness vary across sectors: while temporary employment is found (at the 10 per cent significance level) to enhance productivity and profits in (labour‐intensive) services, this is not the case in manufacturing and construction.
Characterising subtypes of hippocampal sclerosis and reorganization: correlation with pre and postoperative memory deficit
Authors: Prada Jardim Anaclara , Liu Joan , Baber Jack , Michalak Zuzanna , Reeves Cheryl , Ellis Matthew , Novy Jan , de Tisi Jane , McEvoy Andrew , Miserocchi Anna , Targas Yacubian Elza Marcia , Sisodiya Sanjay , Thompson Pamela , Thom Maria 
Published: April 2017

AbstractNeuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (The 2013 International League Against Epilepsy classification) are based on the qualitative assessment of patterns of neuronal loss with NeuN. In practice, some cases appear indeterminate between type 1 (CA1 and CA4 loss) and type 2 HS (CA1 loss) and we predicted that MAP2 would enable a more stringent classification. HS subtypes, as well as the accompanying alteration of axonal networks, regenerative capacity and neurodegeneration have been previously correlated with outcome and memory deficits and may provide prognostic clinical information. We selected 92 cases: 52 type 1 HS, 15 type 2 HS, 18 indeterminate‐HS and 7 no‐HS. Quantitative analysis was carried out on NeuN and MAP2 stained sections and a labeling index (LI) calculated for six hippocampal subfields. We also evaluated hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated tau) and mossy‐fiber pathway re‐organization (ZnT3). Pathology measures were correlated with clinical epilepsy history, memory and naming test scores and postoperative outcomes, at 1 year following surgery. MAP2 LI in indeterminate‐HS was statistically similar to type 2 HS but this clustering was not shown with NeuN. Moderate verbal and visual memory deficits were noted in all HS types, including 54% and 69% of type 2 HS. Memory deficits correlated with several pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus (DG) and subiculum and poor preservation of the mossy fiber pathway. Decline in memory at 1 year associated with AT8 labeling in the subiculum and DG but not HS type. We conclude that MAP2 is a helpful addition in the classification of HS in some cases. Classification of HS subtype, however, did not significantly correlate with outcome or pre‐ or postoperative memory dysfunction, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis
Authors: Salvage Samantha C , Chandrasekharan Karthik H , Jeevaratnam Kamalan , Dulhunty Angela F , Thompson Andrew J , Jackson Antony P , Huang Christopher L‐H 
Published: April 2017

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)‐Ca2+ channel function. Flecainide accesses its transmembrane Nav1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Nav1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain‐of‐function modifications of Nav1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing [Ca2+]i through a reduced [Na+]i and/or direct open‐state RyR2‐Ca2+ channel antagonism. The consequent [Ca2+]i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.Linked ArticlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
Targeting multiple opioid receptors – improved analgesics with reduced side effects?
Authors: Günther Thomas , Dasgupta Pooja , Mann Anika , Miess Elke , Kliewer Andrea , Fritzwanker Sebastian , Steinborn Ralph , Schulz Stefan 
Published: April 2017

Classical opioid analgesics, including morphine, mediate all of their desired and undesired effects by specific activation of the μ‐opioid receptor (μ receptor). The use of morphine for treating chronic pain, however, is limited by the development of constipation, respiratory depression, tolerance and dependence. Analgesic effects can also be mediated through other members of the opioid receptor family such as the κ‐opioid receptor (κ receptor), δ‐opioid receptor (δ receptor) and the nociceptin/orphanin FQ peptide receptor (NOP receptor). Currently, a new generation of opioid analgesics is being developed that can simultaneously bind with high affinity to multiple opioid receptors. With this new action profile, it is hoped that additional analgesic effects and fewer side effects can be achieved. Recent research is mainly focused on the development of bifunctional μ/NOP receptor agonists, which has already led to novel lead structures such as the spiroindole‐based cebranopadol and a compound class with a piperidin‐4‐yl‐1,3‐dihydroindol‐2‐one backbone (SR16835/AT‐202 and SR14150/AT‐200). In addition, the ornivol BU08028 is an analogue of the clinically well‐established buprenorphine. Moreover, the morphinan‐based nalfurafine exerts its effect with a dominant κ receptor‐component and is therefore utilized in the treatment of pruritus. The very potent dihydroetorphine is a true multi‐receptor opioid ligand in that it binds to μ, κ and δ receptors. The main focus of this review is to assess the paradigm of opioid ligands targeting multiple receptors with a single chemical entity. We reflect on this rationale by discussing the biological actions of particular multi‐opioid receptor ligands, but not on their medicinal chemistry and design.Linked ArticlesThis article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc
Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti‐tubercular agents using a fragment‐based drug design approach
Authors: Ryan Ali , Polycarpou Elena , Lack Nathan A , Evangelopoulos Dimitrios , Sieg Christian , Halman Alice , Bhakta Sanjib , Eleftheriadou Olga , McHugh Timothy D , Keany Sebastian , Lowe Edward D , Ballet Romain , Abuhammad Areej , Jacobs William R , Ciulli Alessio , Sim Edith 
Published: April 2017

Background and PurposeWith the emergence of extensively drug‐resistant tuberculosis, there is a need for new anti‐tubercular drugs that work through novel mechanisms of action. The meta cleavage product hydrolase, HsaD, has been demonstrated to be critical for the survival of Mycobacterium tuberculosis in macrophages and is encoded in an operon involved in cholesterol catabolism, which is identical in M. tuberculosis and M. bovis BCG.Experimental ApproachWe generated a mutant strain of M. bovis BCG with a deletion of hsaD and tested its growth on cholesterol. Using a fragment based approach, over 1000 compounds were screened by a combination of differential scanning fluorimetry, NMR spectroscopy and enzymatic assay with pure recombinant HsaD to identify potential inhibitors. We used enzymological and structural studies to investigate derivatives of the inhibitors identified and to test their effects on growth of M. bovis BCG and M. tuberculosis.Key ResultsThe hsaD deleted strain was unable to grow on cholesterol as sole carbon source but did grow on glucose. Of seven chemically distinct ‘hits’ from the library, two chemical classes of fragments were found to bind in the vicinity of the active site of HsaD by X‐ray crystallography. The compounds also inhibited growth of M. tuberculosis on cholesterol. The most potent inhibitor of HsaD was also found to be the best inhibitor of mycobacterial growth on cholesterol‐supplemented minimal medium.Conclusions and ImplicationsWe propose that HsaD is a novel therapeutic target, which should be fully exploited in order to design and discover new anti‐tubercular drugs.Linked ArticlesThis article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro‐organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc
The battle of living with obsessive compulsive disorder: a qualitative study of young people's experiences
Authors: Keyes Carly , Nolte Lizette , Williams Timothy I. 
Published: April 2017

BackgroundThere has been an abundance of studies that have employed quantitative methods to research obsessive compulsive disorder (OCD) and its neurobiology and neurochemistry. However, there appears to be a paucity of research investigating how OCD is experienced by those living with the diagnosis, particularly young people.MethodA qualitative cross‐sectional semistructured interview design was used to address this lack of research. Ten young people, aged 14–17 years old, with a diagnosis of OCD were recruited from Child and Adolescent Mental Health Services in the United Kingdom. Thematic analysis was used to analyse the data.ResultsFour themes were identified: ‘Traumatic and stressful life events’, ‘Responses to signs of OCD’, ‘The battle of living with OCD’ and ‘Ambivalent relationship to help’. Young people reported experiencing stressful or traumatic life events prior to obsessive and compulsive behaviour. OCD behaviours were misunderstood by the young people and others, leading to delays in finding help. A sense of shame among the young people led them to keep their OCD secret due to feeling ‘crazy’. The all‐encompassing nature of OCD led the young people to withdraw socially. Most of the young people experienced an inner conflict between fighting and giving in to the compulsions.ConclusionsTraumatic experiences may be an important factor in the development of OCD for young people, which might indicate a direction for prevention. The sense of shame and stigma needs addressing if young people are to access help earlier. Education of the public, medical professionals and educators should be a priority.