bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing methods for detecting multilocus adaptation with multivariate genotype-environment associations
Authors: Forester Brenna R. , Lasky Jesse R. , Wagner Helene H. , Urban Dean L.
Published: April 2017

Identifying adaptive loci can provide insight into the mechanisms underlying local adaptation. Genotype-environment association (GEA) methods, which identify these loci based on correlations between genetic and environmental data, are particularly promising. Univariate methods have dominated GEA, despite the high dimensional nature of genotype and environment. Multivariate methods, which analyze many loci simultaneously, may be better suited to these data since they consider how sets of markers covary in response to environment. These methods may also be more effective at detecting adaptive processes that result in weak, multilocus signatures. Here, we evaluate four multivariate methods, and five univariate and differentiation-based approaches, using published simulations of multilocus selection. We found that Random Forest performed poorly for GEA. Univariate GEAs performed better, but had low detection rates for loci under weak selection. Constrained ordinations showed a superior combination of low false positive and high true positive rates across all levels of selection. These results were robust across the demographic histories, sampling designs, sample sizes, and levels of population structure tested. The value of combining detections from different methods was variable, and depended on study goals and knowledge of the drivers of selection. Reanalysis of genomic data from gray wolves highlighted the unique, covarying sets of adaptive loci that could be identified using redundancy analysis, a constrained ordination. Although additional testing is needed, this study indicates that constrained ordinations are an effective means of detecting adaptation, including signatures of weak, multilocus selection, providing a powerful tool for investigating the genetic basis of local adaptation.
Transcription factor activities enhance markers of drug response in cancer
Authors: Garcia-Alonso Luz , Iorio Francesco , Matchan Angela , Fonseca Nuno , Jaaks Patricia , Falcone Fiamenta , Bignell Graham , McDade Simon S. , Garnett Mathew J. , Saez-Rodriguez Julio
Published: April 2017

Transcriptional dysregulation is a key feature of cancer. Transcription factors (TFs) are the main link between signalling pathways and the transcriptional regulatory machinery of the cell, positioning them as key oncogenic inductors and therefore potential targets of therapeutic intervention. We implemented a computational pipeline to infer TF regulatory activities from basal gene expression and applied it to publicly available and newly generated RNA-seq data from a collection of 1,010 cancer cell lines and 9,250 primary tumors. We show that the predicted TF activities recapitulate known mechanisms of transcriptional dysregulation in cancer and dissect mutant-specific effects in driver genes. Importantly, we show the potential for predicted TF activities to be used as markers of sensitivity to the inhibition of their upstream regulators. Furthermore, combining these inferred activities with existing pharmacogenomic markers significantly improves the stratification of sensitive and resistant cell lines for several compounds. Our approach provides a framework to link driver genomic alterations with transcriptional dysregulation that helps to predict drug sensitivity in cancer and to dissect its mechanistic determinants.
A chromatin extension model for insulator function based on comparison of high-resolution chromatin conformation capture and polytene banding maps
Authors: Stadler Michael R. , Eisen Michael B.
Published: April 2017

Insulator proteins bind to specific genomic loci and have been shown to play a role in partitioning genomes into independent domains of gene expression and chromatin structure. Despite decades of study, the mechanism by which insulators establish these domains remains elusive. Here, we use genome-wide chromatin conformation capture (Hi-C) to generate a high-resolution map of spatial interactions of chromatin fromDrosophila melanogasterembryos. We show that from the earliest stages of development the genome is divided into distinct topologically associated domains (TADs), that we can map the boundaries between TADs to sub-kilobase resolution, and that these boundaries correspond to 500-2000 bp insulator elements. Comparing this map with a detailed assessment of the banding pattern of a region of a polytene chromosome, we show that these insulator elements correspond to low density polytene interbands that divide compacted bands, which correspond to TADs. It has been previously shown that polytene interbands have low packing ratios allowing the conversion of small genomic distances (in base pairs) into a large physical distances. We therefore suggest a simple mechanism for insulator function whereby insulators increase the physical space between adjacent domains via the unpacking and extension of intervening chromatin. This model provides an intuitive explanation for known features of insulators, including the ability to block enhancer-promoter interactions, limit the spread of heterochromatin, and organize the structural features of interphase chromosomes.
Structure of NADP+-bound 7β-hydroxysteroid dehydrogenase reveals two cofactor-binding modes
Authors: Wang Rui , Wu Jiaquan , Jin David Kin , Chen Yali , Lv Zhijia , Chen Qian , Miao Qiwei , Huo Xiaoyu , Wang Feng
Published: April 2017

In mammals, bile acids/salts and their glycine and taurine conjugates are effectively recycled through enterohepatic circulation. 7β-Hydroxysteroid dehydrogenases (7β-HSDHs; EC 1.1.1.201), including that from the intestinal microbeCollinsella aerofaciens, catalyse the NADPH-dependent reversible oxidation of secondary bile-acid products to avoid potential toxicity. Here, the first structure of NADP+bound to dimeric 7β-HSDH is presented. In one active site, NADP+adopts a conventional binding mode similar to that displayed in related enzyme structures. However, in the other active site a unique binding mode is observed in which the orientation of the nicotinamide is different. Since 7β-HSDH has become an attractive target owing to the wide and important pharmaceutical use of its product ursodeoxycholic acid, this work provides a more detailed template to support rational protein engineering to improve the enzymatic activities of this useful biocatalyst, further improving the yield of ursodeoxycholic acid and its other applications.
Structural insights into the mechanism of the drastic changes in enzymatic activity of the cytochrome P450 vitamin D3hydroxylase (CYP107BR1) caused by a mutation distant from the active site
Authors: Yasutake Yoshiaki , Kameda Tomoshi , Tamura Tomohiro
Published: April 2017

Cytochromes P450 (P450s) are haem-containing enzymes that catalyze medically and industrially important oxidative reactions, and many P450s have been subjected to directed evolution and site-directed mutagenesis to improve their activity and substrate specificity. Nonetheless, in most cases the mechanism that leads to drastic changes in specific activity after the introduction of an amino-acid substitution distant from the active-site pocket is unclear. Here, two crystal structures of inactive mutants of the P450 vitamin D3hydroxylase (Vdh), Vdh-F106V and Vdh-L348M, which were obtained in the course of protein-engineering experiments on Vdh, are reported. The overall structures of these mutants show an open conformation similar to that of wild-type Vdh (Vdh-WT), whereas a rearrangement of the common main-chain hydrogen bonds is observed in the CD-loop (residues 102–106), resulting in a more compactly folded CD-loop relative to that of Vdh-WT. The previously reported structures of Vdh-WT and of the highly active Vdh-T107A and Vdh-K1 mutants have a more stretched CD-loop, with partial formation of 310-helix-type hydrogen bonds, both in the open and closed states. Molecular-dynamics simulations also showed that the frequency of the 310-helix is significantly reduced in Vdh-F106V and Vdh-L348M. The closed conformation is crucial for substrate and ferredoxin binding to initiate the catalytic reaction of Vdh. Therefore, it is implied that the small local structural changes observed in this study might disrupt the conformational transition from the open to the closed state, thereby leading to a complete loss of vitamin D3hydroxylase activity.
Strategic B2B customer experience management: the importance of outcomes-based measures
Authors: Zolkiewski Judy , Story Victoria , Burton Jamie , Chan Paul , Gomes Andre , Hunter-Jones Philippa , O’Malley Lisa , Peters Linda D. , Raddats Chris , Robinson William
Published: April 2017

Purpose

The purpose of this paper is to critique the adequacy of efforts to capture the complexities of customer experience in a business-to-business (B2B) context using input–output measures. The paper introduces a strategic customer experience management framework to capture the complexity of B2B service interactions and discusses the value of outcomes-based measurement.

Design/methodology/approach

This is a theoretical paper that reviews extant literature related to B2B customer experience and asks fresh questions regarding B2B customer experience at a more strategic network level.

Findings

The paper offers a reconceptualisation of B2B customer experience, proposes a strategic customer experience management framework and outlines a future research agenda.

Research limitations/implications

This paper is conceptual and seeks to raise questions surrounding the under-examined area of B2B customer experience. As a consequence, it has inevitable limitations resulting from the lack of empirical evidence to support the reconceptualisation.

Practical implications

Existing measures of customer experience are problematic when applied in a B2B (services) context. Rather than adopting input- and output-based measures, widely used in a business-to-consumer (B2C) context, a B2B context requires a more strategic approach to capturing and managing customer experience. Focussing on strategically important issues should generate opportunities for value co-creation and are more likely to involve outcomes-based measures.

Social implications

Improving the understanding of customer experience in a B2B context should allow organisations to design better services and consequently enhance the experiences of their employees, their customers and other connected actors.

Originality/value

This paper critiques the current approach to measuring customer experience in a B2B context, drawing on contemporary ideas of value-in-use, outcomes-based measures and “Big Data” to offer potential solutions to the measurement problems identified.
Customer engagement in a Big Data world
Authors: Kunz Werner , Aksoy Lerzan , Bart Yakov , Heinonen Kristina , Kabadayi Sertan , Ordenes Francisco Villarroel , Sigala Marianna , Diaz David , Theodoulidis Babis
Published: April 2017

Purpose

This paper aims to propose that the literature on customer engagement has emphasized the benefits of customer engagement to the firm and, to a large extent, ignored the customers’ perspective. By drawing upon co-creation and other literature, this paper attempts to alleviate this gap by proposing a strategic framework that aligns both the customer and firm perspectives in successfully creating engagement that generates value for both the customer and the bottom line.

Design/methodology/approach

A strategic framework is proposed that includes the necessary firm resources, data, process, timeline and goals for engagement, and captures customers’ motives, situational factors and preferred engagement styles.

Findings

The authors argue that sustainability of data-driven customer engagement requires a dynamic and iterative value generation process involving customers recognizing the value of engagement behaviours and firm’s ability to capture and passing value back to customers.

Originality/value

This paper proposes a dynamic strategic value-creation framework that comprehensively captures both the customer and firm perspectives to data-driven customer engagement.
Innovation as a key to strengthen the effect of relationship benefits on loyalty in retailing
Authors: Ruiz-Molina Maria-Eugenia , Gil-Saura Irene , Servera-Francés David
Published: April 2017

Purpose

This work aims to attempt an in-depth study of the link between relationship benefits and store loyalty, examining the moderating role of the retailer’s degree of innovation in these relations.

Design/methodology/approach

An equations model has been contrasted based on 820 valid individual structured questionnaires administered to consumers of 13 trade names in four retail distribution sectors (food, textile, electronics and household goods).

Findings

The results provide evidence of the positive influence of relationship benefits on store loyalty and in particular the benefits stemming from trust. The links between social and special treatment benefits in relation to loyalty are, however, significantly stronger in the less innovative establishments.

Research limitations/implications

This paper provides evidence of the moderating role of innovation on the relationship between social benefits and special treatment benefits and loyalty.

Practical implications

Technology may be used as a differentiation tool. The retailer should concentrate its investments on information and communications technology solutions that contribute to enhance the customer experience at the point of sale without neglecting the social dimension to increase the benefits of trust and ultimately, customer loyalty.

Originality/value

The paper provides an in-depth examination of the retail innovation variable which is scarcely analysed in the literature, offering support for the idea that innovation at the point of sale plays a moderating role in the links between relational benefits and customer loyalty.
The three R’s: reading, (W)Riting, and researching through multi-genre project
Authors: Roberts Kathryn , Brugar Kristy
Published: April 2017

Purpose

The purpose of this paper is to examine how the authors, two teacher educators, planned for and guided 23 students (teacher candidates) through a multi-genre historical inquiry experience, integrating instruction on the Inquiry Arc and writing process, during a co-taught literacy and social studies methods course. The authors describe the ways in which the students demonstrated both active and passive participation and resistance to this process/project, and the related implications.

Design/methodology/approach

Using an action research approach, this paper reports analysis and interpretation of lesson plans, course materials, debriefing notes, field notes, student response notebooks and intermediate and final inquiry project artifacts.

Findings

All students demonstrated gains in content knowledge through their products, oral presentations, group discussions, or conferences with the authors; and all gained experience with the Inquiry Arc and process writing. Many students saw the benefits of collaboration and social construction of knowledge as they moved toward more central participation.

Practical implications

Instructors cannot mandate full participation in any task, but can influence the conditions (i.e. pedagogy, task, scaffolding) to increase the possibility of positive peer interactions and learning.

Originality/value

This paper contributes to the knowledge of teaching and learning innovation in teacher preparation coursework.
Scaffolded lesson study
Authors: Saye John W. , Kohlmeier Jada , Howell James B. , McCormick Theresa M. , Jones Robert C. , Brush Thomas A.
Published: April 2017

Purpose

The purpose of this paper is to investigate the effects of scaffolded lesson study on the content knowledge, conceptions of curriculum, and classroom practice of 22 elementary and secondary history teachers in four school districts.

Design/methodology/approach

Teachers, teacher educators, and historians collaborated to design and test research lessons grounded in a theory-based framework for problem-based historical inquiry (PBHI) practice. The authors sought to support consonance between the reform ideas of the formal, professional development, curriculum, and the curriculum as enacted in participants’ classrooms.

Findings

Project participation was associated with significant gains in content knowledge and the conceptualization and implementation of more challenging instruction consistent with the PBHI model and the standards of authentic intellectual work (AIW). Mean AIW instruction scores for research lessons were more than double the scores for participants’ non-lesson study lessons and indicated noteworthy progress in integrating the formal and enacted curricula. Evidence suggested that many teachers developed more nuanced understandings of historical phenomena, gained greater appreciation for the importance of authentic purpose in motivating student engagement in challenging learning, and began to reconsider what is required to facilitate complex learning and to refine their repertoire of learning strategies.

Originality/value

Evidence from the first year of this project offers hope for the potential of collaborative communities of practice to facilitate a shared professional knowledge base of wise practice that brings the formal, intended, and enacted curriculum into greater alignment. These results also emphasize the evolutionary process of conceptual change.
High rate of systemic corticosteroid prescription among outpatient visits for psoriasis: A population‐based epidemiological study using the Korean National Health Insurance database
Authors: Eun Sang Jun , Jang Sihyeok , Lee Jin Yong , Do Young Kyung , Jo Seong Jin
Published: April 2017

The use of systemic corticosteroids (SC) for the treatment of psoriasis is not recommended according to textbooks and guidelines. In clinical practise, however, many physicians frequently prescribe SC for patients with psoriasis. To determine the magnitude of SC prescription for outpatients with psoriasis in Korea and identify factors associated with the use of SC, we used the 2010–2014 nationwide claims data of the Health Insurance Review and Assessment Service of Korea. In frequency analysis for the full scale of prescribed SC, oral methylprednisolone was the most frequently prescribed SC, followed by dexamethasone and betamethasone injections. The prescription rate of SC was 26.4% in outpatient visit episodes for psoriasis. The prescription rate of SC was higher in older patients, Medical Aid recipients, patients who visited office‐based physician practices and hospitals, and patients living in non‐metropolitan areas. In multiple logistic regression analyses, the older age group and smaller health‐care institutions were more associated with the SC prescription. In conclusion, SC were widely prescribed for patients with psoriasis in Korea despite the current guidelines. Both patients’ individual and institutional characteristics were associated with the SC prescription.
Severe primary autoimmune thrombocytopenia in pregnancy: a national cohort study
Authors: Care A , Pavord S , Knight M , Alfirevic Z
Published: April 2017

Objective

To quantify the incidence of severe autoimmune thrombocytopenia (ITP) in pregnancy in the UK, determine current treatment strategies, and establish maternal and neonatal morbidity and mortality associated with severe ITP in pregnancy.

Design

A prospective national cohort study.

Setting

UK.

Population

Women with severe ITP, defined as platelets <50 × 109/L in pregnancy or antenatal treatment of isolated low platelets.

Methods

Data collected via the UK Obstetric Surveillance System (UKOSS) between 1 June 2013 and 31 January 2015 from all UK consultant‐led obstetric units.

Main outcome measure

Incidence of severe ITP in pregnancy.

Results

The estimated incidence of severe ITP in pregnancy is 0.83 per 10 000 maternities (95% CI 0.68–1.00). A total of 22 pregnant women (21%) did not receive any antenatal therapy, and 85 pregnant women (79%) received therapy. There was no difference between asymptomatic treated and untreated cohorts in severity of disease or outcome. Postpartum haemorrhage (51%) and severe postpartum haemorrhage (21%) was reported more frequently than the rate reported in the general pregnant population (5–10%). No neonates required treatment for thrombocytopenia and there were no cases of neonatal intracranial bleeding.

Conclusions

Current UK management of severe ITP in pregnancy results in an exceptionally low morbidity and mortality for the neonate. Mothers with ITP remain at increased risk of severe postpartum haemorrhage, and should be delivered at units that have the capacity to manage severe PPH effectively. Whilst balancing the risks for pregnancy from prophylactic antenatal treatment in asymptomatic women against observed low disease morbidity, we may be over treating asymptomatic patients.

Tweetable abstract

UKOSS study of severe ITP in pregnancy shows exceptionally low neonatal morbidity with current UK management.
Medical students’ perceptions of the importance of exercise and their perceived competence in prescribing exercise to older people
Authors: Jadczak Agathe Daria , Tam Khai Loon , Yu Solomon , Visvanathan Renuka
Published: April 2017

Objective

To determine the effects of a 4.5‐week geriatric medicine course on fifth year medical students’ perception of the importance of and their competence in prescribing exercise to older people.

Methods

The modified Exercise and Physical Activity Competence Questionnaire was administered to 81 students before and after the course. Scores ranged from 0 to 6. One open‐ended question about perceived barriers to exercise prescription was asked.

Results

Students’ perceptions of the importance of designing an exercise prescription (P= 0.038), determining the training heart rate (P= 0.021), determining the body mass index (P> 0.001), referring an older person to an exercise program (P> 0.001) and identifying age‐related limitations (P= 0.029) improved significantly after the course. Students’ self‐perceived competence improved significantly across all items (P> 0.001). Barriers to exercise prescription included lack of: knowledge (57%), patient compliance (39%) and time (33%).

Conclusion

A geriatric medicine course contributes to improved senior medical students’ perceptions of importance of and their competence in prescribing exercise to older people.
Parenting stress and its association with perceived agreement about the disclosure decision in parents following donor conception
Authors: Gebhardt Anja J. , Sydsjö Gunilla , Skoog Svanberg Agneta , Indekeu Astrid , Lampic Claudia
Published: April 2017

Introduction

For many donor‐conceiving heterosexual parents, the process of deciding whether and what to tell children about their genetic origin is challenging. We hypothesized that incomplete couple agreement about disclosure could be associated with parenting stress. The aim of the study was to investigate: (1) parenting stress levels among heterosexual parents of young children following gamete donation and (2) whether parenting stress is related to perceived agreement about disclosure of the donor conception to the children.

Material and methods

This study is part of the longitudinal multicenter Swedish Study on Gamete Donation and included a total of 213 heterosexual parents with children aged 1–4 years following oocyte donation (n = 103) and sperm donation (n = 110). Parents individually completed a questionnaire that included validated instruments on parenting stress (SPSQ) and relationship quality (ENRICH), as well as a study‐specific measure on disclosure agreement. Multiple regression analysis was applied.

Results

Incomplete couple agreement on disclosure to the children was not statistically significantly associated with increased levels of parenting stress. Relationship satisfaction consistently and significantly accounted for variation in parenting stress levels, indicating that relationship satisfaction had a buffering impact on parenting stress.

Conclusions

Parental stress does not appear to be negatively influenced by incomplete couple agreement about disclosure to children. As children grow up, reaching agreement about what to tell the child about the donor conception might become more relevant for couples' stress related to parenthood.
Inhibitory action of oxytocin on spontaneous contraction of rat distal colon by nitrergic mechanism: involvement of cyclic GMP and apamin‐sensitive K+ channels
Authors: Wang R. , Han M. T. , Lv X. L. , Yu Y. A. , Chai S. Q. , Qu C. M. , Liu C. Y.
Published: April 2017

Aim

The mechanisms underlying the inhibitory effects of oxytocin (OT) on colon tone are not totally understood. We explore the mechanisms of OT on spontaneous contractility in rat distal colon and identify the mediators involved in this action.

Methods

In rat distal colon strips, mechanical activity was analysed and the production of nitric oxide (NO) in tissue loaded with the fluorochrome DAF‐FM was visualized by confocal microscopy. OT receptor (OTR) expression was determined by Western blotting and immunofluorescence.

Results

In rat distal colon, OT produced a concentration‐dependent reduction in the spontaneous contraction, which was abolished by the OTR antagonist atosiban, the neural blocker tetrodotoxin and the inhibitor of neuronal nitric oxide synthase (nNOS) NPLA. The inhibitory effects of OT were not affected by propranolol, atropine, the nicotinic cholinoceptor blocker hexamethonium, the vasoactive intestinal peptide receptor antagonist VIPHyb, the P2 purinoceptor antagonist PPADS, the adenosine A1 receptors antagonist DPCPX and the prostacyclin receptor antagonist Ro1138452. The soluble guanylyl cyclase (sGC) inhibitor ODQ and the small conductance Ca2+‐activated K+ (CaK+) channels blocker apamin significantly reduced the relaxation induced by OT, nicotine, sodium nitroprusside and the sGC activator BAY 41‐2272. The neural release of NO elicited by OT was prevented by NPLA, tetrodotoxin and atosiban. The presence of the OTR and its co‐localization with nNOS was detected by immunohistochemistry and Western blotting experiments.

Conclusion

These results demonstrate the NO release from enteric neurones induced by activation of OTR mediates distal colon relaxation. sGC and small conductance CaK+ channels are involved in this relaxation.
Street‐Level Bureaucrats and Irrigation Policy Reform in Southeast Asia
Authors: Ricks Jacob I.
Published: April 2017

Policy reforms are difficult for developing states, especially when they are meant to improve cooperation and collaboration between private citizens and state officials, such as in the case of education, health care provision, business‐state relations, and policing. A large part of this challenge is that the policy reforms required for coproduction of services necessitate development of state capacity in new directions. Using the substantive issue of irrigation reforms, especially those aimed at improving service provision and farmer participation, I identify three lessons for reformers regarding the implementation of policy for the coproduction of services. Drawing on extensive fieldwork in Thailand and Indonesia, as well as the experience of the National Irrigation Administration in the Philippines, I emphasize the importance of street‐level bureaucrats. The lessons drawn from irrigation policy are comparable to other practice‐intensive state activities.
Protein S‐sulfhydration by hydrogen sulfide in cardiovascular system
Authors: Meng Guoliang , Zhao Shuang , Xie Liping , Han Yi , Ji Yong
Published: April 2017

Hydrogen sulfide (H2S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed mechanism of H2S was not clear. Recently, a novel post‐translational modification induced by H2S, named S‐sulfhydration, has been proposed. S‐sulfhydration is the chemical modification of specific cysteine residues of target proteins by H2S. There are several methods for detecting S‐sulfhydration, such as the modified biotin switch assay, maleimide assay with fluorescent thiol modifying regents, tag‐switch method and mass spectrometry. H2S induces S‐sulfhydration on enzymes or receptors (such as p66Shc, phospholamban, protein tyrosine phosphatase 1B, mitogen‐activated extracellular signal‐regulated kinase 1 and ATP synthase subunit α), transcription factors (such as specific protein‐1, kelch‐like ECH‐associating protein 1, NF‐κB and interferon regulatory factor‐1), and ion channels (such as voltage‐activated Ca2+ channels, transient receptor potential channels and ATP‐sensitive K+ channels) in the cardiovascular system. Although significant progress has been achieved in delineating the role of protein S‐sulfhydration by H2S in the cardiovascular system, more proteins with detailed cysteine sites of S‐sulfhydration as well as physiological function need to be investigated in further studies. This review mainly summarizes the role and possible mechanism of S‐sulfhydration in the cardiovascular system. The S‐sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H2S‐related drugs in the future.

Linked Articles

This 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
Cross‐species studies of cognition relevant to drug discovery: a translational approach
Authors: Robbins T W
Published: April 2017

This review advances the case that bidirectional, cross‐species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross‐species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenaline reuptake blocker atomoxetine. Functional neuroimaging evidence suggests a modulation of circuitry including the inferior prefrontal cortex by this drug. Parallel work in rats had shown that atomoxetine improves stop signal performance by affecting possibly homologous regions of the rodent prefrontal cortex. This parallel effect of atomoxetine in rodents and humans could potentially be exploited in other disorders in which impulsivity plays a role, such as stimulant abuse and Parkinson's disease. A contrasting relative lack of involvement of 5‐HT mechanisms in the stop signal reaction time task will also be described. Research in humans and experimental animals that demonstrate effects of serotoninergic agents such as the selective serotonin (5‐HT) reuptake inhibitor citalopram on probabilistic learning and reversal (upon which atomoxetine has little effect) will also be reviewed, possibly relevant to the treatment of clinical depression, Finally, other promising examples of parallel studies of behavioural effects of CNS‐active drugs in animals and humans will also be described.

Linked Articles

This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc
Targeting on poly(ADP‐ribose) polymerase activity with DNA‐damaging hybrid lactam‐steroid alkylators in wild‐type and BRCA1‐mutated ovarian cancer cells
Authors: Trafalis Dimitrios T. , Polonifi Aikaterini , Dalezis Panayiotis , Nikoleousakos Nikolaos , Katsamakas Sotirios , Sarli Vasiliki
Published: April 2017

Conjugated lactam‐steroid alkylators (LSA) have been shown to exhibit superior activity at controlling cancer models and overlap drug resistance to conventional chemjournalapy. Hybrid LSA combine two active compounds in a single molecule and incorporate modified steroids bearing lactam moiety in one or more steroid rings functioning as vectors for cytotoxic agents. We first describe a novel class of LSA that generate excellent anticancer activity against UWB1.289 and UWB1.289 + BRCA1 human ovarian cancer cell lines. Both UWB1.289 and UWB1.289 + BRCA1 cells carry mutations in the tumor suppressor gene TP53 while UWB1.289 cell line carries a germline BRCA1 mutation. In vitro, in vivo, and in silico, experimental methods were utilized to determine the poly(ADP‐ribose) polymerases (PARPs) activity and mRNA transcription, DNA damage, cytostatic and cytotoxic effects, and virtual molecular interactions, in order to study the molecular mechanisms of activity of the tested LSA. LSA produce anticancer activity through dual action by combining the direct induction of cellular DNA damage with the inhibition of PARP activity and consecutive DNA repair activity. BRCA1‐mutated UWB1.289 ovarian cancer cells with defective PARP‐oriented repair mechanism show significantly higher sensitivity to these agents. Combined drug effect on DNA damage and repair is a novel approach in cancer therapeutics.
Identification of indothiazinone as a natural antiplatelet agent
Authors: Yang Chansik , Kwon Sugyeong , Kim Se‐Jong , Jeong Minseon , Park Ji‐Young , Park Dongeun , Hong Soon Jun , Jung Jong‐Wha , Kim Chungho
Published: April 2017

Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in‐house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbβ3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbβ3. It also restricted thrombin‐ and adenosine diphosphate‐dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin‐induced activation of integrin αIIbβ3 presumably by inhibiting talin–integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action.
Weight loss in obese girls with polycystic ovarian syndrome is associated with a decrease in Anti‐Muellerian Hormone concentrations
Authors: Reinehr Thomas , Kulle Alexandra , Rothermel Juliane , Knop Caroline , Lass Nina , Bosse Christina , Holterhus Paul‐Martin
Published: April 2017

Objective

The Anti‐Muellerian Hormone (AMH) has been reported as surrogate marker of antral follicles, which are the origins of hyperandrogenism in polycystic ovarian syndrome (PCOS). Therefore, AMH may be useful for the diagnosis of PCOS. The objective was to study the longitudinal changes in AMH concentrations in girls with and without PCOS.

Design

This is a longitudinal study of obese girls participating in a 1‐year lifestyle intervention.

Patients

Forty obese girls aged 13‐16 years (50% with PCOS) were included in the study. Girls with and without PCOS were matched to age, BMI and change in weight status.

Measurements

AMH, gonadotropins, androstenedione, testosterone, oestradiol and sex hormone‐binding globulin (SHBG) were determined.

Results

Obese girls with PCOS demonstrated significantly (P<.001) higher AMH concentrations (5.8±3.1 ng/mL) compared to obese girls without PCOS (2.4±1.4 ng/mL). None of the girls without PCOS had AMH concentrations ≥6 ng/mL and none of the PCOS girls showed AMH concentrations ≤3 ng/mL. Weight loss in girls with PCOS was associated with a significant drop in AMH concentrations (−1.4±1.8 ng/mL, P=.045). AMH was significantly related to testosterone (cross‐sectional: b‐coefficient 3.7±1.7, P=.001, longitudinal: b‐coefficient 0.54±0.47, P=.026) and luteinizing hormone (LH) (cross‐sectional: b‐coefficient 0.05±0.04, P=.039, longitudinal: b‐coefficient 0.005±0.004, P=.039), but not to any other analysed parameter in multiple linear regression analyses adjusted to multiple confounders.

Conclusions

AMH was increased in adolescent girls with PCOS and normalized with weight loss. AMH was cross‐sectionally and longitudinally related to hyperandrogenism.
Quantitative evaluation of metal artifacts using different CBCT devices, high‐density materials and field of views
Authors: Codari Marina , de Faria Vasconcelos Karla , Ferreira Pinheiro Nicolielo Laura , Haiter Neto Francisco , Jacobs Reinhilde
Published: April 2017

Objective

To objectively compare the influence of different cone‐beam computed tomography (CBCT) devices, high‐density materials and field of views (FOVs) on metal artifact expression.

Material and methods

For this in vitro study, three customized acrylic resin phantoms containing high‐density materials cylinders: titanium, copper–aluminum alloy and amalgam were scanned on three CBCT devices using high‐resolution protocols, same voxel size (0.2 mm) and different FOVs. After fully automatic segmentation and image registration, the same region of interest was defined for the small and medium FOVs. The difference between the segmented and the real volume of the metal cylinders was assessed. Moreover for each segmented slice, the area difference between the segmented and the real axial section was determined. The artifacts on the background were measured as normalizing standard deviation of voxel values in the vicinity of the cylinder, in three different distances.

Results

Considerable differences were observed in volume measurements for all CBCTs devices and materials for both FOV sizes (up to 67%). The slice per slice area analysis indicated higher artifacts at the edges of the metal cylinder. Within the materials, amalgam and titanium had, respectively, the worst and best artifact expression in all the CBCT devices. Standard deviation values varied differently between the three distances in each device.

Conclusion

Our in vitro study showed that different CBCT devices, high‐density materials and FOV should be considered while evaluating CBCT images. More carefully, diagnosis conclusions should be drawn in images containing amalgam and copper–aluminum alloy.
Subsequent malignancies after allogeneic hematopoietic stem cell transplantation
Authors: Gündüz Mehmet , Özen Mehmet , Şahin Uğur , Toprak Selami Koçak , Civriz Bozdağ Sinem , Kurt Yüksel Meltem , Arslan Önder , Özcan Muhit , Demirer Taner , Beksaç Meral , İlhan Osman , Gürman Günhan , Topçuoğlu Pervin
Published: April 2017

We evaluated 979 patients for the development of post‐transplant lymphoproliferative disease (PTLD) and solid malignancies after allogeneic hematopoietic stem cell transplantations (allo‐HSCT) as a late complication. We found 15 (1.5%) subsequent malignancies; three of these malignancies were PTLD, and twelve were solid tumors. The median time from allo‐HSCT to the development of PTLD was 9 (3‐20) months and that from allo‐HSCT to the development of solid tumors was 93 (6‐316) months. The cumulative incidence of evolving subsequent malignancy in patients was 1.3% (±0.5 SE) at 5 years and 3.9% (±1.2 SE) at 10 years. The cumulative incidence of developing subsequent malignancy in patients with benign hematological diseases as the transplant indication was 7.4%±4.2 SE at 5 years. More subsequent malignancy developed in patients having ≥1 year chronic graft‐vs‐host disease (GVHD; 3.7% in ≥1 year chronic GVHD and 0.7% in <1 year chronic GVHD patient groups, P=.002). Subsequent epithelial tumor risk was higher in ≥1 year chronic GVHD patients than <1 year (3.7% vs 0.1%, P<.001). In multivariate analysis, benign hematological diseases as transplant indication (RR: 5.6, CI 95%: 1.4‐22.3, P=.015) and ≥1 year chronic GVHD (RR: 7.1, 95% CI: 2.3‐22.5, P=.001) were associated with the development of subsequent malignancy.
Impact of caring for patients with severe and complex disabilities on health care workers’ quality of life: determinants and specificities
Authors: Rousseau Marie‐Christine , Baumstarck Karine , Leroy Tanguy , Khaldi‐Cherif Cherazad , Brisse Catherine , Boyer Laurent , Resseguier Noémie , Morando Claire , Billette De Villemeur Thierry , Auquier Pascal
Published: April 2017

Aim

Individuals with severe and complex disabilities, defined by a combination of profound intellectual impairment and serious motor deficit resulting in extreme dependence, often remain in hospital or at residential facilities. The aim of this study was to identify the determinants of quality of life (QoL) of 238 health care workers (HCWs) caring for individuals with severe and complex disabilities.

Method

We conducted a cross‐sectional study. The recruitment of the HCWs was performed in five French centres specializing in patients with severe and complex disabilities. The selection criteria were age above 18 years, being an institutional referent HCW (a resource person coordinating various issues for or about the patient), and agreeing to participate. Sociodemographic, health, professional variables, and psycho‐behavioural (QoL, burn‐out, and coping strategies) data were collected.

Results

Of the 362 eligible HCWs, 65.7% returned the questionnaires. The scores of the physical and social dimensions of QoL were significantly lower, and the score of the psychological dimension significantly higher, than those of a comparison group. The main factors modulating QoL were age, financial difficulties, nature of coping strategy, and burn‐out.

Interpretation

This research provides preliminary evidence that caring for patients with severe and complex disabilities affects the QoL of HCWs. These results support the need for optimization of the work environments for HCWs.
Multimodal neurophysiological monitoring in healthy infants born at term: normative continuous somatosensory evoked potentials data
Authors: Lori Silvia , Gabbanini Simonetta , Bastianelli Maria , Bertini Giovanna , Corsini Iuri , Dani Carlo
Published: April 2017

Aim

To describe accurate, standardized 1h‐multimodal neurophysiological monitoring (1h‐MNM), while simultaneously recording VEEG, aEEG, and SEP‐C bilaterally from median nerves, and to collect neonatal normative SEP‐C data related to behavioural states.

Method

Twenty healthy, term newborn infants (13 males, 7 females; gestational age 37–42wks; mean 39.6wks, standard deviation [SD] 1.3wks) underwent 1h‐MNM within 2 days of life, with focus on recording of the SEP‐C (band‐pass setting 1–100 Hz, rate of stimulation 1.1 Hz, 50 alternate stimuli).

Results

1h‐MNM was easily obtained with identification of cervical (N13) and cortical (N1, P1) SEP‐C responses in all infants. SEP‐C minimal and maximum N1 latencies/N1–P1 amplitudes were identified, bilaterally, during periods of spontaneous sleep active‐quiet‐active (AS‐QS‐AS) and quiet‐wakefulness. Minimal latencies and amplitudes occurred in 60% of active sleep/quiet‐wakefulness, with the maximums in 70% of quiet sleep. The SEP‐C mean values were latencies of N13=13.6ms (SD 1.4ms) and N1=33.6ms (SD 3.9ms) to 34.2ms (SD 4.8ms) in left and right hemisphere respectively; central‐conduction‐time (CCT) (N13–N1), 20.0ms (SD 4.3ms) to 20.6ms (SD 4.8ms); N1–P1 amplitude=4.6ms (SD 2.7ms) to 3.8μV (SD 2.2μV).

Interpretation

1h‐MNM can record simultaneously VEEG/aEEG/SEP‐C in newborn infants, showing the modulation of SEP cortical responses in relation to behavioural states in all infants studied using an appropriate neonatal method. We emphasize the importance of obtaining neonatal SEP‐C normative data to better identify pathological findings in neonatal brain injury.
Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: A GoDarts study
Authors: Connelly Paul J. , Lonergan Mike , Soto‐Pedre Enrique , Donnelly Louise , Zhou Kaixin , Pearson Ewan R.
Published: April 2017

Aims

Metformin is renally excreted and has been associated with the development of lactic acidosis. Although current advice is to omit metformin during illnesses that may increase the risk of acute kidney injury (AKI), the evidence supporting this is lacking. We investigated the relationship between AKI, lactate concentrations and the risk of lactic acidosis in those exposed to metformin.

Materials and Methods

We undertook a population‐based case‐control study of lactic acidosis in 1746 participants with Type 2 diabetes and 846 individuals without diabetes with clinically measured lactates with and without AKI between 1994 and 2014. AKI was stratified by severity according to “Kidney Disease: Improving Global Outcomes” guidelines. Mixed‐effects logistic and linear regression were used to analyse lactic acidosis risk and lactate concentrations, respectively.

Results

Eighty‐two cases of lactic acidosis were identified. In Type 2 diabetes, those treated with metformin had a greater incidence of lactic acidosis [45.7 per 100 000 patient years; 95% confidence interval (CI) 35.9‐58.3] compared to those not exposed to this drug (11.8 per 100 000 patient years; 95% CI 4.9‐28.5). Lactate concentrations were 0.34 mmol/L higher in the metformin‐exposed cohort (P < .001). The risk of lactic acidosis was higher in metformin users [odds ratio (OR) 2.3; P = .002] and increased with AKI severity (stage 1: OR 3.0, P = .002; stage 2: OR 9.4, P < .001; stage 3: OR 16.1, P < .001).

Conclusions

A clear association was found between metformin, lactate accumulation and the development of lactic acidosis. This relationship is strongest in those with AKI. These results provide robust evidence to support current recommendations to omit metformin in any illness that may precipitate AKI.
Intraclass differences in the risk of hospitalization for heart failure among patients with type 2 diabetes initiating a dipeptidyl peptidase‐4 inhibitor or a sulphonylurea: Results from the OsMed Health‐DB registry
Authors: Fadini Gian Paolo , Saragoni Stefania , Russo Pierluigi , Degli Esposti Luca , Vigili de Kreutzenberg Saula , Melazzini Mario , Avogaro Angelo ,   on behalf of the OsMed Health DB Network
Published: April 2017

Aims

To re‐analyse data from a previous retrospective study on 127 555 patients, in which we showed that dipeptidyl peptidase‐4 (DPP‐4) inhibitor therapy was associated with a lower risk of hospitalization for HF (HHF) than sulphonylurea (SU) therapy, in order to evaluate intraclass differences among DPP‐4 inhibitors and SUs.

Methods

We included patients with type 2 diabetes (T2D) initiating DPP‐4 inhibitor or SU therapy, alone or in combination with metformin. Patients undergoing intraclass switch, those with a previous HHF, those receiving insulin treatment, and those with <6 months observation were excluded. We calculated the incidence of first and total HHF events/1000 person‐years. Cox proportional hazard and Poisson multiple regression models, as well as propensity‐score matching, were used to account for baseline confounders.

Results

The analysis included 17 615 DPP‐4 inhibitor users (60.1% sitagliptin; 27.0% vildagliptin; 12.9% saxagliptin) and 86 734 SU users (37.5% glibenclamide; 34.6% glimepiride; 27.9% gliclazide). No intraclass difference in the incidence rate of first and total HHF events was noted among the 3 DPP‐4 inhibitors or among the 3 SUs. Multivariable adjustments for baseline confounders or propensity‐score matching did not change the results. In addition, no intraclass difference in HHF risk was observed in patients at high compared with low cardiovascular risk.

Conclusions

In a cohort of patients with T2D taken from approximately one‐third of the Italian population, no intraclass difference was noted for DPP‐4 inhibitor and SU therapy with regard to HHF risk.