bluuebunny/crossref_metadata_2025 huggingface dataset:
Fuzzy neural control for unmanned robot applied to automotive test
Authors: Chen Gang , Zhang Wei‐gong , Zhang Xiao‐na
Published: August 2013

Purpose

The paper aims to overcome the shortcomings that proportional‐integral‐derivative (PID) control for unmanned robot applied to automotive test (URAT) needs a priori manual retuning, has large speed fluctuations and is hard to adjust control parameters. A novel control approach based on fuzzy neural network applied to URAT was proposed.

Design/methodology/approach

According to the target vehicle speed and driving command table, the multiple manipulator coordinated control model was established. After that, the displacement of throttle mechanical leg, clutch mechanical leg, brake mechanical leg and shift mechanical arm for URAT was used as input of fuzzy neural network (FNN) model, and vehicle speed was used as output of FNN model. The number of membership functions was three, and the type of that was generalized bell membership function (gbellmf). The hybrid learning algorithm which combined with back propagation algorithm and least square method was applied to train the model. The Sugeno model was selected as fuzzy reasoning model.

Findings

Experimental results demonstrated that compared with PID control method, the proposed approach can greatly improve the accuracy of vehicle speed tracking. The approach can accurately realize the vehicle speed tracking of given driving test cycle. Therefore, it can ensure the accuracy and effectiveness of automotive test results.

Research limitations/implications

Future work will focus on improving the efficiency of this learning algorithm.

Practical implications

The paper provides effective methods for improving the accuracy of speed tracking and repeatability.

Originality/value

After establishing the multiple manipulator coordinated control model, this paper proposes a novel control approach based on FNN for URAT.
Online measurement based tool path generation toward integrated robotic laser cladding
Authors: Liu Jie
Published: August 2013

Purpose

Refurbishing may be the most practical approach under the low volume production. This effort aims to achieve robotic laser cladding with the main purpose of achieving maximum processing flexibility, predictably high quality, lower maintenance and operating costs. This study aims to focus on online measurement and cladding path generation toward automatic laser cladding.

Design/methodology/approach

Based on the specific requirements of automatic laser cladding, an approach was proposed toward an automatic laser cladding with powder injection for the refurbishment of components with free‐form surfaces. This study assessed the feasibility of integrating a non‐contact free‐form surface measurement system, an industrial robot, and an algorithm for generating cladding tool paths seamlessly.

Findings

3D laser scanning and laser cladding systems can be embedded into an existing robot motion control system. Online measurement based 3D surface reconstruction is a practical approach toward cladding tool path generation for on‐site refurbishment.

Practical implications

Robotic laser cladding may be a potential application by integrating other measurement devices, such as temperature sensor based monitoring system.

Originality/value

Refurbishing worn‐out components could have significant economic benefits. This study indicates that robotic laser cladding may potentially facilitate improved refurbishment of oversized components.
Why I act differently: studying patterns of legitimation among CIOs through motive talk
Authors: Magnusson Johan , Bygstad Bendik
Published: August 2013

Purpose

IT governance has become the recognized norm system for chief information officers. The purpose of this paper is to understand how CIOs relate to these norms, by studying how they legitimate incompliance with the norms.

Design/methodology/approach

The paper uses an interpretive, qualitative, structured interview study with 18 CIOs in large Swedish organizations regarded as having excellent IT governance practice, using motive talk as analytical lens to identify the informants’ relationship to norms.

Findings

The study identifies norm‐specific patterns for how CIOs legitimate incompliance with IT governance, finding that CIOs use a combination of excuse and justifications as strategies of legitimation. The study also finds that CIOs display a tendency of not contesting IT governance‐related norms unless these are in conflict with neighboring professional jurisdictions. This is regarded as an identification of the “margins” of IT governance.

Research limitations/implications

The study illustrates how the theory of motive talk is a viable road ahead for future studies of IT professionals. The generalizability of the identified patterns of legitimation is limited by the selection of large organizations with solely male CIOs, as well as the selection of solely organizations that have succeeded in establishing external legitimacy concerning IT governance and the organizations being Swedish.

Practical implications

CIOs aspiring to increase their legitimacy should avoid direct conflicts with neighboring professions. In addition to this, they should also aspire to be clear in a separation of motive talk and actual practice, since full norm compliance may be detrimental to their factual operations.

Originality/value

The originality of this paper lies in the methodological approach of combining motive talk and speech acts to investigate CIO legitimation practices.
Acquirer's earnings quality and the choice of payment method in mergers and acquisitions
Authors: Yung Kenneth , Sun Qian , Rahman Hamid
Published: August 2013

Purpose

The purpose of this paper is to investigate the role of acquirer's earnings quality on the choice of payment method in mergers and acquisitions (M&A).

Design/methodology/approach

The paper applies a simultaneous equations model to address the concern of endogeneity between earnings quality and payment method in corporate acquisitions. In addition, a propensity score matching model is used for robustness purpose.

Findings

Previous studies imply that short‐term accruals have a significant impact on the choice of payment method in M&A. In this study, This paper shows that acquisition financing is not significantly affected by short‐term earnings quality once control variables are considered. Instead, this paper finds that it is the long‐term earnings quality of the acquirer that matters. Acquiring firms with poor (good) long‐term earnings quality prefer lower (higher) cash payment in acquisitions. Their results are robust to different definitions of earnings quality.

Research limitations/implications

Researchers should consider the effect of long‐term earnings quality in their future investigations.

Practical implications

Investors should be aware of this issue when evaluating corporate mergers.

Originality/value

This is the first study to examine the impact of long‐term quality of earnings on the choice of payment method in M&A.
Does information production explain bidder liquidity after takeovers?
Authors: Lei Adam Y.C. , Li Huihua
Published: August 2013

Purpose

The purpose of this paper is to determine whether information produced in the takeover process or changes in firm characteristics after takeovers affect bidder liquidity.

Design/methodology/approach

This paper compares the liquidity changes for bidders that complete their takeovers (successful bidders) and bidders that eventually withdraw their takeover attempts (unsuccessful bidders) to disentangle the information production hypothesis and the firm characteristics hypothesis. The authors use both media mentions and changes in the standard deviation of market model residuals to proxy for the information produced in the takeover process, intraday data to construct the liquidity measures, and regression analyses to examine the determinants of bidder liquidity changes.

Findings

This paper finds that unsuccessful bidders experience no less information production than successful bidders during the takeover process, but only successful bidders enjoy liquidity improvements. Once the authors control for the changes in firm characteristics, whether a takeover is successful or not no longer affects bidder liquidity. Moreover, information production reduces information asymmetry for successful Nasdaq bidders but not NYSE bidders. These findings collectively support the firm characteristics hypothesis but also suggest a role of information production on firms with higher information asymmetry.

Originality/value

This paper provides the direct evidence that the information produced in the takeover process does not lead to liquidity improvements of the bidders. It also supplements existing literature with a more comprehensive sample and sheds light on how acquisition withdrawals affect firms' liquidity.
Community participation and social inclusion in Bristol
Authors: Fieldhouse Jon , Donskoy Anne‐Laure
Published: August 2013

Purpose

This paper reports on action research which explored assertive outreach service users’ experiences of community participation and then fed this learning into a multi‐agency forum – where it was used in joint‐planning between mental health services and community partners, aiming to maximise social inclusion locally.

Design/methodology/approach

Action research methodology was chosen to examine the forum's work because it brings together different perspectives to reveal an issue in its entirety and effect change in practice. Service users’ experiences were explored using semi‐structured qualitative interviews.

Findings

Engagement in mainstream community‐based activities re‐connected service users with cherished life roles and developed feelings of self‐efficacy, belonging, and wellbeing. Effective inter‐sectoral working in the forum was based on a shared agenda and collective action planning.

Research limitations/implications

Whilst every effort was made to ensure an authentic service user voice informed service development, it is unfortunate – in action research terms – that no service user interviewees were able to participate directly in the work of the forum. Community development work can build on micro‐level, person‐centred mental health care and extend outwards to collective community activity, aiming to harness social capital.

Practical implications

Assertive outreach – harnessing mainstream occupations through care‐planning – achieved outcomes that institutional rehab could not, and did so with a minimum of stigmatisation.

Social implications

This inquiry highlights that social inclusion is the responsibility of the community as a whole.

Originality/value

This inquiry appreciated service users as evaluators of the services they used and aimed to bring that knowledge to bear on service development.
Improving social inclusion for young people diagnosed with “first episode psychosis”: employment, education and online support
Authors: Holttum Sue
Published: August 2013

Purpose

This article aims to summarise two papers from Australia on supporting young people in early intervention for psychosis. Both have implications for young people's social inclusion and the design of early intervention services.

Design/methodology/approach

The first paper reports a new analysis of a trial of specialist employment and education support in an early intervention service. It used a statistical method called logistic regression to test whether only employment support predicted 41 participants’ success in getting into employment and education, or whether things like condition severity also mattered. The second paper reports on a new online support package for young people with “first episode psychosis” and how acceptable it was. The authors looked at 20 participants’ use of the package, and examined their well‐being before and after using it.

Findings

The first paper reported that nothing except getting specialist employment and education support predicted young people's entry to work or education. They recommend that young people in early intervention should not be denied vocational support because of things like “psychiatric symptoms”. In the second paper, young people in early intervention who used the online package reacted positively. The authors recommend a full controlled trial of the package. It could help young people when leaving the service to maintain their gains.

Originality/value

These papers advance research on early intervention psychosis services regarding young people's social inclusion needs. Specialist vocational support could prevent life‐long social exclusion. An innovative online support package has not yet been proven, but with fast‐evolving technology, it might help future service users stay well when leaving the service.
Frank Hoy
Authors: Ibarreche Santiago
Published: August 2013

Purpose

This paper aims to be a conversation with Frank Hoy, conducted by Santiago Ibarreche, about his career as an internationally known scholar in the field of entrepreneurship and family business.

Design/methodology/approach

This paper is an interview.

Findings

The interview explores Hoy's career, his achievements and continued search for excellence in terms of research, intertwined with his entrepreneurial ventures.

Originality/value

The interview in this special section, A Life in Research, brings out an individual scholar's experience and history, not only as recognition of scholarly impact, but also as recognition of the person.
Network analysis of user generated content quality in Wikipedia
Authors: Ingawale Myshkin , Dutta Amitava , Roy Rahul , Seetharaman Priya
Published: August 2013

Purpose

Social media platforms allow near‐unfettered creation and exchange of user generated content (UGC). Drawing from network science, the purpose of this paper is to examine whether high and low quality UGC differ in their connectivity structures in Wikipedia (which consists of interconnected user generated articles).

Design/methodology/approach

Using Featured Articles as a proxy for high quality, a network analysis was undertaken of the revision history of six different language Wikipedias, to offer a network‐centric explanation for the emergence of quality in UGC.

Findings

The network structure of interactions between articles and contributors plays an important role in the emergence of quality. Specifically the analysis reveals that high‐quality articles cluster in hubs that span structural holes.

Research limitations/implications

The analysis does not capture the strength of interactions between articles and contributors. The implication of this limitation is that quality is viewed as a binary variable. Extensions to this research will relate strength of interactions to different levels of quality in UGC.

Practical implications

The findings help harness the “wisdom of the crowds” effectively. Organisations should nurture users and articles at the structural hubs from an early stage. This can be done through appropriate design of collaborative knowledge systems and development of organisational policies to empower hubs.

Originality/value

The network centric perspective on quality in UGC and the use of a dynamic modelling tool are novel. The paper is of value to researchers in the area of social computing and to practitioners implementing and maintaining such platforms in organisations.
Sensitivity in topic development and meaning making in a process consultation contract meeting
Authors: Puutio Risto , Kykyri Virpi‐Liisa , Wahlström Jarl
Published: August 2013

Purpose

The purpose of this paper is to explore the discursive practices used when the agenda for a consultation process was negotiated in a contract meeting. The paper illustrates the role of sensitivity in meaning making practices, that is, how displays of sensitivity were intertwined with topic development.

Design/methodology/approach

The paper offers an in‐depth analysis of naturally occurring conversation in a meeting between a consultant and two client managers. The audio‐recorded data is analyzed by utilizing methodology introduced and developed in the traditions of Ethnomethodology and Conversation Analysis (CA).

Findings

The authors show how both the consultant and the clients displayed markers of sensitivity when introducing various meaning potentials relevant to the topics under discussion, and how they eventually ‘negotiated’ meanings through formulations and reformulations of the topics.

Practical implications

The findings suggest that indirect and complex discursive practices were functional in that they afforded the participants the possibility to exhibit prospectively threatening meaning potentials of the issues under discussion, while suspending a more thorough topic penetration. The study sheds light on the importance of the details at the early stages of a consulting relationship and the consultant's specific role at the beginning.

Originality/value

The paper illustrates real life practices in process consultation. This sort of data is seldom used in research.
Silent stories of resistance to doing employment
Authors: Mulhall Sue
Published: August 2013

Purpose

Exploring experiences of participants on an Irish active labour market programme, the purpose of this paper is to examine accounts of everyday forms of resistance to the subject positions offered in the dominant discourse of “doing employment” espoused on such schemes.

Design/methodology/approach

Employing narrative research, the process of individual opposition to established work routines is illustrated at the level of meaning, identity and self‐reflection by using the three‐dimensional narrative inquiry space to chronicle three participants’ stories. Their newly formed subjectivities (created by changes encountered in their past lives and the situations they are experiencing in their present realities) challenge the power of the dominant discourse of ‘doing employment’ on these schemes. The paper illustrates how the individuals respond when confronted with feelings of difference between the subject positions offered within the dominant discourse and their own preferred interest.

Findings

Their stories suggest different forms of micro‐political resistance, from subtle acts and behaviours through to contesting subjectivities and meanings. The article describes how they exercise power in imposing their own meanings through challenge and reinscription, thus rendering the dominant discourse less robust. This creates space for further challenge and reinscription, possibly enabling others to think differently, such as the author, who has moved from unquestioning acceptance of the dominant discourse to an emerging micro‐political resistance to “doing employment”.

Originality/value

These accounts highlight the relevance of using narrative research to reveal, heretofore, silent stories of how individual work routines disrupt prevailing institutional discourse, depicting situations where a story by challenges a story of.
Associations of maternal age with maternity care use and birth outcomes in primiparous women: a comparison of results in 1991 and 2008 in Finland
Authors: Klemetti R , Gissler M , Sainio S , Hemminki E
Published: August 2013

Objective

To compare birth outcomes and maternity care use in 1991 and 2008 by age among primiparous Finnish women.

Design

Register‐based study.

Setting

Nationwide Medical Birth Register.

Population

All primiparous women in 1991 (n = 24 765) and 2008 (n = 23 511).

Methods

Women aged 35–39 and ≥40 years were compared with women aged 20–34 years in 1991 and 2008, using logistic regression to adjust for women's background.

Main outcome measures

Maternity care: prenatal visits, hospitalisation during pregnancy, labour induction, delivery mode, long postpartum hospital stay; and birth outcomes: birthweight, preterm birth, Apgar scores, intensive/observation unit, respiratory care, perinatal death.

Results

In both years, older women's deliveries were more often induced, instrumental, or by caesarean section. In 2008 compared with 1991, hospitalisations were lower and instrumental deliveries and labour induction were higher in older women. A significant decrease in adjusted odds ratios (OR, 95% confidence intervals) between 1991 and 2008 among women aged 35–39 was found for preterm birth (1.47, 1.18–1.84 versus 0.96, 0.86–1.07) and for intensive/observation unit (1.73, 1.47–2.05 versus 1.21, 1.07–1.37) and, among women aged ≥40 years, for intensive/observation unit (3.14, 2.30–4.29 versus 1.64, 1.31–2.07). The risk for perinatal death (1.66, 0.60–4.60 versus 2.69, 1.07–6.79) was higher in 2008 than in 1991 among women aged ≥40.

Conclusions

In 2008, older primiparous women still used more maternity care, had more interventions, and poorer birth outcomes than younger women, regardless of care advances. Additional risks declined among women aged 35–39 but not among aged ≥40.
Skin temperature measured by infrared thermography after ultrasound‐guided blockade of the sciatic nerve
Authors: VAN HAREN F. G. A. M. , KADIC L. , DRIESSEN J. J
Published: August 2013

Background

In the present study, we assessed the relationship between subgluteal sciatic nerve blocking and skin temperature by infrared thermography in the lower extremity. We hypothesized that blocking the sciatic nerve will lead to an increase in temperature, and that this will correlate with existing sensory block tests.

Methods

We studied 18 healthy individuals undergoing orthopaedic surgery of the foot under ultrasound‐guided subgluteal blockade of the sciatic nerve with 30 ml ropivacaine 7.5 mg/ml. Skin temperature was measured on the toes, the dorsal and plantar side of the foot, the malleoli, and the lateral side of the lower leg, just before sciatic nerve blockade and at 10‐min intervals thereafter.

Results

Baseline skin temperatures showed a significant distal‐to‐proximal gradient. After sciatic block, temperatures on the blocked side increased significantly in the toes and foot. When comparing pinprick to skin temperature in a receiver operating curve, there was an AUC of 85.9% (95% confidence interval = 83.7–88.2%, P < 0.001). The medial malleolus (not being innervated by the sciatic nerve) showed no significant difference to the lateral.

Conclusions

After sciatic nerve block, temperatures of the foot increased significantly. There was a good correlation between pinprick testing and infrared temperature measurement. This makes infrared skin temperature measuring a good test in determining block success when sensory testing is impossible.
Maintenance of muscle mass and load‐induced growth in Muscle RING Finger 1 null mice with age
Authors: Hwee Darren T. , Baehr Leslie M. , Philp Andrew , Baar Keith , Bodine Sue C.
Published: August 2013

Age‐related loss of muscle mass occurs to varying degrees in all individuals and has a detrimental effect on morbidity and mortality. Muscle RING Finger 1 (MuRF1), a muscle‐specific E3 ubiquitin ligase, is believed to mediate muscle atrophy through the ubiquitin proteasome system (UPS). Deletion of MuRF1 (KO) in mice attenuates the loss of muscle mass following denervation, disuse, and glucocorticoid treatment; however, its role in age‐related muscle loss is unknown. In this study, skeletal muscle from male wild‐type (WT) and MuRF1 KO mice was studied up to the age of 24 months. Muscle mass and fiber cross‐sectional area decreased significantly with age in WT, but not in KO mice. In aged WT muscle, significant decreases in proteasome activities, especially 20S and 26S β5 (20–40% decrease), were measured and were associated with significant increases in the maladaptive endoplasmic reticulum (ER) stress marker, CHOP. Conversely, in aged MuRF1 KO mice, 20S or 26S β5 proteasome activity was maintained or decreased to a lesser extent than in WT mice, and no increase in CHOP expression was measured. Examination of the growth response of older (18 months) mice to functional overload revealed that old WT mice had significantly less growth relative to young mice (1.37‐ vs. 1.83‐fold), whereas old MuRF1 KO mice had a normal growth response (1.74‐ vs. 1.90‐fold). These data collectively suggest that with age, MuRF1 plays an important role in the control of skeletal muscle mass and growth capacity through the regulation of cellular stress.
Secondary Analysis of Publicly Available Data Reveals Superoxide and Oxygen Radical Pathways are Enriched for Associations Between Type 2 Diabetes and Low‐Frequency Variants
Authors: Yazdanpanah Mojgan , Chen Chuhua , Graham Jinko
Published: August 2013

Genome‐wide association studies explain at most 5%‐10% of the heritable components of type 2 diabetes. Some of the “missing type 2 diabetes heritability” could be explained by low‐frequency variants. We examined the associations between low‐frequency variants and type 2 diabetes, using data from 2538 diabetic and 2977 nondiabetic subjects in the publicly available database of Genotypes and Phenotypes. We applied two approaches. First, we combined information from all low‐frequency (1%‐5%) variants at a locus in a gene‐centric analysis of associations with diabetes. Next, we searched for gene ontology (GO) biological processes that were enriched for gene‐centric associations, after correcting for multiple testing to control the false discovery rate (FDR). We found three GO biological processes that were significantly enriched for associations to diabetes: “response to superoxide” (FDR‐adjusted p = 2.7 × 10−3), “response to oxygen radical” (FDR‐adjusted p = 2.7 × 10−3), and “heart contraction” (FDR‐adjusted p = 2.6 × 10−2). There were three genes that contributed to “response to superoxide” and “oxygen radical” pathways, including the SOD1 gene. Gene‐centric tests of association with low‐frequency variants, followed by analysis to evaluate which biological pathways are enriched for these associations has the potential to recover, at least some proportion of, the “missing heritability” of type 2 diabetes.
TAK‐875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β‐cell dysfunction in Zucker diabetic fatty rats
Authors: Ito R , Tsujihata Y , Matsuda‐Nagasumi K , Mori I , Negoro N , Takeuchi K
Published: August 2013

Background and Purpose

TAK‐875, a selective GPCR40/free fatty acid receptor 1 agonist, improves glycaemic control by increasing glucose‐dependent insulin secretion. Metformin is a first‐line drug for treatment of type 2 diabetes that improves peripheral insulin resistance. Based on complementary mechanism of action, combining these agents is expected to enhance glycaemic control. Here, we evaluated the chronic effects of TAK‐875 monotherapy and combination therapy with metformin in diabetic rats.

Experimental Approach

Long‐term effects on glycaemic control and β‐cell function were evaluated using Zucker diabetic fatty (ZDF) rats, which develop diabetes with hyperlipidaemia and progressive β‐cell dysfunction.

Key Results

Single doses of TAK‐875 (3–10 mg·kg−1) and metformin (50–150 mg·kg−1) significantly improved both postprandial and fasting hyperglycaemia, and additive improvements were observed in their combination. Six‐week treatment with TAK‐875 (10 mg·kg−1, b.i.d.) significantly decreased glycosylated Hb (GHb) by 1.7%, and the effect was additively enhanced by combination with metformin (50 mg·kg−1, q.d.; GHb: −2.4%). This improvement in glycaemic control in the combination group was accompanied by significant 3.2‐fold increase in fasting plasma insulin levels. Pancreatic insulin content was maintained at a level comparable to that in normal rats by combination treatment (vehicle: 26, combination: 67.1; normal lean: 69.1 ng·mg−1 pancreas) without affecting pancreatic glucagon content. Immunohistochemical analyses revealed normal morphology, enhanced pancreas duodenum homeobox‐1 expression and increased PCNA‐positive cells in islets of the combination group.

Conclusion and Implications

Our results indicate that combination therapy with TAK‐875 and metformin could be a valuable strategy for glycaemic control and β‐cell preservation in type 2 diabetes.
In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects
Authors: Ignatowska‐Jankowska B M , Ghosh S , Crowe M S , Kinsey S G , Niphakis M J , Abdullah R A , Tao Q , O' Neal S T , Walentiny D M , Wiley J L , Cravatt B F , Lichtman A H
Published: August 2013

Background and Purpose

Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2‐arachidonoylglycerol (2‐AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3‐hexafluoropropan‐2‐yl 4‐(bis(benzo[d][1,3]dioxol‐5‐yl)(hydroxy)methyl)piperidine‐1‐carboxylate).

Experimental Approach

In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac‐induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.

Key Results

KML29 attenuated carrageenan‐induced paw oedema and completely reversed carrageenan‐induced mechanical allodynia. These effects underwent tolerance after repeated administration of high‐dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2‐AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac‐induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ9‐tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose‐dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (−/−) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC‐like subjective effects.

Conclusions and Implications

These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.

Linked Articles

This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐6
ORM‐10103: a significant advance in sodium‐calcium exchanger pharmacology?
Authors: Terracciano C M , Hancox J C
Published: August 2013

The sodium‐calcium exchanger (NCX) is an electrogenic transporter that is widely expressed in different tissues. In the heart, the NCX plays important roles in calcium ion homeostasis, excitation‐contraction coupling and the electrophysiological properties of cardiac myocytes. Precise determination of the roles of the NCX has somewhat been hampered by a lack of selective small molecule inhibitors. In this issue of the BJP, Jost and colleagues present data on a new NCX inhibitor, ORM‐10103, which has submicromolar EC50 values against cardiac forward and reverse exchange activity. The compound exhibits improved selectivity over existing small molecule NCX inhibitors and, in particular, appears to be without effect on L‐type calcium channels at high concentrations. ORM‐10103 could therefore have significant value for studies of the (patho)physiological roles of the NCX in the heart. Further pharmacological studies are required to investigate the actions of ORM‐10103 on cardiac cells and tissues and to determine its effects on non‐cardiac NCX isoforms.

Linked Article

This article is a commentary on Jost et al., pp. 768–778 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12228
Treatment with resveratrol attenuates sublesional bone loss in spinal cord‐injured rats
Authors: Wang Hua‐Dong , Shi Ya‐Min , Li Li , Guo Ji‐Dong , Zhang Yu‐Peng , Hou Shu‐Xun
Published: August 2013

Background and Purpose

Sublesional osteoporosis predisposes individuals with spinal cord injury (SCI) to an increased risk of low‐trauma fracture. The aim of the present work was to investigate the effect of treatment with resveratrol (RES) on sublesional bone loss in spinal cord‐injured rats.

Experimental Approach

Complete SCI was generated by surgical transaction of the cord at the T10–12 level. Treatment with RES (400 mg·kg−1 body mass per day−1, intragastrically) was initiated 12 h after the surgery for 10 days. Then, blood was collected and femurs and tibiae were removed for evaluation of the effects of RES on bone tissue after SCI.

Key Results

Treatment of SCI rats with RES prevented the reduction of bone mass including bone mineral content and bone mineral density in tibiae, preserved bone structure including trabecular bone volume fraction, trabecular number, and trabecular thickness in tibiae, and preserved mechanical strength including ultimate load, stiffness, and energy in femurs. Treatment of SCI rats with RES enhanced femoral total sulfhydryl content, reduced femoral malondialdehyde and IL‐6 mRNA levels. Treatment of SCI rats with RES suppressed the up‐regulation of mRNA levels of PPARγ, adipose‐specific fatty‐acid‐binding protein and lipoprotein lipase, and restored mRNA levels of Wnt1, low‐density lipoprotein‐related protein 5, Axin2, ctnnb1, insulin‐like growth factor 1 (IGF‐1) and receptor for IGF‐1 in femurs and tibiae.

Conclusions and Implications

Treatment with RES attenuated sublesional bone loss in spinal‐cord‐injured rats, associated with abating oxidative stress, attenuating inflammation, depressing PPARγ signalling, and restoring Wnt/β‐catenin and IGF‐1 signalling.
Levels of heroin and its metabolites in blood and brain extracellular fluid after i.v. heroin administration to freely moving rats
Authors: Gottås A , Øiestad E L , Boix F , Vindenes V , Ripel Å , Thaulow C H , Mørland J
Published: August 2013

Background and Purpose

Heroin, with low affinity for μ‐opioid receptors, has been considered to act as a prodrug. In order to study the pharmacokinetics of heroin and its active metabolites after i.v. administration, we gave a bolus injection of heroin to rats and measured the concentration of heroin and its metabolites in blood and brain extracellular fluid (ECF).

Experimental Approach

After an i.v. bolus injection of heroin to freely moving Sprague–Dawley rats, the concentrations of heroin and metabolites in blood samples from the vena jugularis and in microdialysis samples from striatal brain ECF were measured by ultraperformance LC‐MS/MS.

Key Results

Heroin levels decreased very fast, both in blood and brain ECF, and could not be detected after 18 and 10 min respectively. 6‐Monoacetylmorphine (6‐MAM) increased very rapidly, reaching its maximal concentrations after 2.0 and 4.3 min, respectively, and falling thereafter. Morphine increased very slowly, reaching its maximal levels, which were six times lower than the highest 6‐MAM concentrations, after 12.6 and 21.3 min, with a very slow decline during the rest of the experiment and only surpassing 6‐MAM levels at least 30 min after injection.

Conclusions and Implications

After an i.v. heroin injection, 6‐MAM was the predominant opioid present shortly after injection and during the first 30 min, not only in the blood but also in rat brain ECF. 6‐MAM might therefore mediate most of the effects observed shortly after heroin intake, and this finding questions the general assumption that morphine is the main and most important metabolite of heroin.
A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the EGF receptor signalling cascade in prostate stromal cells
Authors: Oliver V L , Poulios K , Ventura S , Haynes J M
Published: August 2013

Background and Purpose

Human prostate growth and function are tightly controlled by androgens that are generally thought to exert their effects by regulating gene transcription. However, a rapid, non‐genomic steroid action, often involving an elevation of intracellular calcium ([Ca2+]i), has also been described in a number of cell types. In this study we investigate whether androgens acutely regulate [Ca2+]i in stromal cells derived from the human prostate.

Experimental Approach

Human‐cultured prostatic stromal cells (HCPSCs) were loaded with the calcium‐sensitive fluorophore, fura‐2‐acetoxymethyl ester (FURA‐2AM) (10 μM). Changes in [Ca2+]i in response to the androgens, dihydrotestosterone (DHT) and testosterone, as well as EGF were measured by fluorescence microscopy.

Key Results

DHT, but not testosterone (0.03–300 nM), elicited concentration‐dependent elevations of [Ca2+]i within 1 min of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10 μM); the sarcoplasmic reticulum ATPase pump inhibitor, thapsigargin (1 μM); the inositol trisphosphate receptor inhibitor, 2‐aminoethyldiphenyl borate (50 μM) and the PLC inhibitor, U‐73122 (1 μM). Responses were also blocked by the L‐type calcium channel blocker, nifedipine (1 μM), and by removal of extracellular calcium. A similar transient elevation of [Ca2+]i was elicited by EGF (100 ng·mL−1). The EGF receptor inhibitor, AG 1478 (30 nM), and the MMP inhibitor, marimastat (100 nM), blocked the DHT‐induced elevation of [Ca2+]i.

Conclusions and Implications

These studies show that DHT elicits an androgen receptor‐dependent acute elevation of [Ca2+]i in HCPSC, most likely by activating EGF receptor signalling.
Midkine and cytoplasmic maturation of mammalian oocytes in the context of ovarian follicle physiology
Authors: Ikeda Shuntaro , Yamada Masayasu
Published: August 2013

Midkine (MK) was originally characterized as a member of a distinct family of neurotrophic factors functioning in theCNS. However, it was later discovered that MK is abundantly expressed in ovarian follicles. Since then, the physiological roles of this molecule in the ovary have been steadily investigated. During thein vitromaturation (IVM) of oocytesMKwas shown to promote the cytoplasmic maturation of oocytes, as indicated by post‐fertilization development. This effect ofMKcould be mediated via its pro‐survival (anti‐apoptotic) effects on the cumulus‐granulosa cells that surround oocytes. The oocyte competence‐promoting effects ofMKare discussed in the context of the recently discovered involvement ofMKin the full maturation of ovarian follicles.MKwas at the frontline of a new paradigm for neurotrophic factors as oocytetrophic factors.MKmay promote the developmental competence of oocytes via common signalling molecules with the other neurotrophic factor(s). Alternatively or concomitantly,MKmay also interact with various transmembrane molecules on cumulus‐granulosa cells, which are important for ovarian follicle growth, dominance and differentiation, and act as a unique pro‐survival factor in ovarian follicles, such thatMKpromotes oocyte competence.MK, along with other ovarian neurotrophic factors, may contribute to the optimization of theIVMsystem.

Linked Articles

This article is part of a themed section on Midkine. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐4
Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer's disease
Authors: Zhang Luqing , Papadopoulos Panayiota , Hamel Edith
Published: August 2013

Background and Purpose

Transient receptor potential vanilloid type 4 (TRPV4) channels are expressed in brain endothelial cells, but their role in regulating cerebrovascular tone under physiological and pathological conditions is still largely unknown.

Experimental Approach

Wild‐type (WT) mice and mice that overexpress a mutated form of the human amyloid precursor protein (APP mice, model of increased amyloid β), a constitutively active form of TGF‐β1 (TGF mice, model of cerebrovascular fibrosis) or both (APP/TGF mice) were used. Dilations to the selective TRPV4 channel opener GSK1016790A (GSK) or to ACh were measured in posterior cerebral artery segments.

Key Results

Both GSK‐ and ACh‐induced dilations virtually disappeared following endothelium denudation in WT mice. These responses were impaired in vessels from APP, TGF and APP/TGF mice compared with WT. Pre‐incubation of WT vessels with the selective TRPV4 channel blocker HC‐067047, or with small‐conductance (SK channel, apamin) and/or intermediate‐conductance (IK channel, charybdotoxin, ChTx) Ca2+‐sensitive K+ channel blocker abolished GSK‐induced dilations and massively decreased those induced by ACh. These treatments had no or limited effects on ACh‐induced dilation in vessels from APP, TGF or APP/TGF mice, and IK and SK channel function was preserved in transgenic mice. Antioxidant superoxide dismutase or catalase normalized GSK‐ and ACh‐mediated dilations only in APP brain arteries.

Conclusion and Implications

We conclude that endothelial TRPV4 channels mediate ACh‐induced dilation in cerebral arteries, that they are impaired in models of cerebrovascular pathology and that they are sensitive, albeit in the reversible manner, to amyloid β‐induced oxidative stress.
Simvastatin induces a central hypotensive effect via Ras‐mediated signalling to cause eNOS up‐regulation
Authors: Cheng Wen‐Han , Ho Wen‐Yu , Chang Chien‐Feng , Lu Pei‐Jung , Cheng Pei‐Wen , Yeh Tung‐Chen , Hong Ling‐Zong , Sun Gwo‐Ching , Hsiao Michael , Tseng Ching‐Jiunn
Published: August 2013

Background and Purpose

Clinical studies indicate that statins have a BP‐lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up‐regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin‐mediated BP regulation in the nucleus tractus solitarii (NTS).

Experimental Approach

To investigate the involvement of Ras and other signalling pathways in simvastatin‐induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras‐specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI‐2133), a PI3K inhibitor (LY294002) or a MAPK‐ERK kinase (MEK) inhibitor (PD98059).

Key Results

FTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin‐induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS‐positive cells in the NTS.

Conclusions and Implications

Simvastatin modulates central BP control in the NTS of SHRs by increasing Ras‐mediated activation of the PI3K‐Akt and ERK1/2‐RSK signalling pathways, which then up‐regulates eNOS activation.
AVE 0991, a non‐peptide mimic of angiotensin‐(1–7) effects, attenuates pulmonary remodelling in a model of chronic asthma
Authors: Rodrigues‐Machado M G , Magalhães G S , Cardoso J A , Kangussu L M , Murari A , Caliari M V , Oliveira M L , Cara D C , Noviello M L M , Marques F D , Pereira J M , Lautner R Q , Santos R A S , Campagnole‐Santos M J
Published: August 2013

Background and Purpose

AVE 0991 (AVE) is a non‐peptide compound, mimic of the angiotensin (Ang)‐(1–7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)‐induced chronic allergic lung inflammation.

Experimental Approach

We used BALB/c mice (6–8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse−1, i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg−1·per day, s.c.) or saline (100 μL·kg−1·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates.

Key Results

Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL‐5 and increased IL‐10 levels in the BAL, accompanied by decreased Ang II levels in lungs.

Conclusions and Implications

AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang‐(1–7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.
Cannabidivarin‐rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor‐independent mechanism
Authors: Hill T D M , Cascio M‐G , Romano B , Duncan M , Pertwee R G , Williams C M , Whalley B J , Hill A J
Published: August 2013

Background and Purpose

Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis‐derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors.

Experimental Approach

The anticonvulsant profiles of two CBDV BDSs (50–422 mg·kg−1) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays.

Key Results

CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg−1) and audiogenic seizure models (≥87 mg·kg−1), and suppressed pilocarpine‐induced convulsions (≥100 mg·kg−1). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co‐administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ9‐tetrahydrocannabinol and Δ9‐tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV.

Conclusions and Implications

CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.