bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with disallowance of compulsory mental healthcare referrals
Authors: Fuglseth N. L. D. , Gjestad R. , Mellesdal L. , Hunskaar S. , Oedegaard K. J. , Johansen I. H.
Published: January 2016

Objective

Norwegian studies report that a substantial amount of referrals for compulsory mental health care are disallowed at specialist assessment, at a rate that varies with referring agent. Knowledge on factors associated with disallowance could improve the practice of compulsory mental health care. This study aims to examine such factors, placing particular emphasis on the impact of referring agents.

Method

This study utilized data from the prospective, longitudinal cohort study ‘Suicidality in Psychiatric Emergency Admissions’ conducted at a Norwegian psychiatric emergency unit which served approximately 400 000 inhabitants. Data on referral, admission and patient characteristics were retrieved on compulsory admissions conducted between 1 May 2005 and 30 April 2008. Bivariate and logistic regression analyses and structural multilevel modelling were performed.

Results

Among 2813 compulsory admissions, 764 were disallowed. Low competence in the referring agent, high GAF S score, observed alcohol or drug intoxication, reported suicide risk, and the presence of neurotic, stress‐related and somatoform disorders, personality disorders and other non‐specified diagnoses were associated with above average disallowance frequency. Non‐Norwegian ethnicity and schizophrenia spectrum disorders were associated with below average disallowance rates.

Conclusion

Among several factors associated with disallowance, low symptom load was the strongest, whilst referring agent competence modestly affected disallowance rate.
Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder
Authors: Zois Evangelos , Kiefer Falk , Lemenager Tagrid , Vollstädt‐Klein Sabine , Mann Karl , Fauth‐Bühler Mira
Published: January 2016

Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non‐comorbid (PGPURE) and two comorbid (PGALCOHOL and PGPOLY) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel‐based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post‐central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects.
No Compromise: Political Consequences of Moralized Attitudes
Authors: Ryan Timothy J.
Published: January 2016

Evolutionary, neuroscientific, and cognitive perspectives in psychology have converged on the idea that some attitudes are moralized—a distinctive characteristic. Moralized attitudes reorient behavior from maximizing gains to adhering to rules. Here, I examine a political consequence of this tendency. In three studies, I measure attitude moralization and examine how it relates to approval of political compromise. I find that moralized attitudes lead citizens to oppose compromises, punish compromising politicians, and forsake material gains. These patterns emerge on economic and noneconomic issues alike and identify a psychological phenomenon that contributes to intractable political disputes.
“I found the truth in Foot Locker”: London 2011, Urban Culture, and the Post‐Political City
Authors: Millington Gareth
Published: January 2016

The article begins with an overview of what is implied in the notion of the “post‐political” before looking closely at post‐political interpretations of the 2011 London riots. It presents a critique of the restricted sense of political subjectivity in such accounts. It demonstrates how participation in the riots and their aftermath may be seen as indicative of an embryonic form of urban politics that works with and against the post‐political city. This discussion is illuminated by an analysis of the discursive space of London hip‐hop which reveals an ironic, complex and reflexive dialogue about identity, justice and politics that is far removed from the caricature offered by “strong” interpretations of the post‐political subject. This is then linked to readings of the post‐political city that place a welcome stress not only on the evacuation of the political dimension from the city, but also on the opportunities for the re‐emergence of the proto‐political.
Reregulating for Freshwater Enclosure: A State of Exception in Canterbury, Aotearoa New Zealand
Authors: Thomas Amanda C. , Bond Sophie
Published: January 2016

In this paper, we argue that democracy is increasingly indistinguishable from authoritarianism, in a process that is entangled with neoliberalisms. To build this argument, we examine a case study of central government intervention in regional environmental decision making in Aotearoa New Zealand through the lens of Agamben's “state of exception”. The intervention—unprecedented and unconstitutional—squeezed democratic spaces for decision making about freshwater and sought to smooth the way for capital accumulation. The audacity of government actions indicate, we argue, an abandonment of efforts to disguise neoliberal encroachments on democracy, known as the double truth tactic. Yet we also argue that in identifying this as a state of exception, we can examine it as part of a process and therefore demonstrate the possibilities for counter‐hegemonic actions to emerge.
What's China Got to Do With It? U.S. Alliances, Partnerships in the Asia‐Pacific
Authors: Tow William T. , Limaye Satu
Published: January 2016

U.S. alliances in the Asia‐Pacific are increasingly viewed as more than just threat‐centric policy instruments. Three core principles for alliance management underscore this reasoning: maintaining consensus about purpose and objectives; generating maximum alliance adaptability; and building capabilities to achieve full‐spectrum deterrence. The interests that compel U.S. regional allies to cooperate with Washington are this special issue's analytical focus. Evolving U.S. security partnerships in the Asia‐Pacific, the emergence of “hybrid” forms of security alignment, and Sino‐U.S. tensions complicate understanding the nature and politics of U.S. security alignments in the region. A Chinese “shadow” is likely to confront U.S. alliances and partnerships in ways which will compound strategic competition and tensions in the region. This reality impels the United States and its regional collaborators to understand and to coordinate each other's motivations for security cooperation as effectively as possible.
U.S.‐Vietnam Security Cooperation: Catalysts and Constraints
Authors: Tuan Hoang Anh , Thuy Do Thi
Published: January 2016

In any bilateral relationship, trust is measured by the depth and scope of defense ties, not by trade volume and investment flows. U.S.‐Vietnam defense cooperation over the past 20 years has not been an exception. Despite falling behind in their economic and political relations, security cooperation between the two has been progressing slowly but firmly, serving as a foundation for overall relations to move forward. This article analyzes the various catalysts and constraints on forging U.S.‐Vietnamese strategic trust. It argues that the degree of bilateral security cooperation has been shaped by a number of structural and agential factors: changes in the Asian balance of power stemming from China's rise and the U.S. pivot to Asia, convergences and divergences in national interests and threat perceptions with regard to China policy and the South China Sea disputes, and the accumulation of historical lessons. These have had a “push and pull” effect on strategic cooperation.
An Unaligned Alliance: Thailand‐U.S. Relations in the Early 21st Century
Authors: Pongsudhirak Thitinan
Published: January 2016

U.S.‐Thai security relations are “underperforming” due to major shifts in Thailand's and the United States' relations at the interactive domestic, regional, and international levels. The recent predominance of the military in Thailand's domestic politics has clashed with Washington's interpretation of the Shinawatra family's prior ascent to power through electoral processes. China's rise and its efforts to court the current Thai government by staying out of Thailand's internal politics has further exacerbated tensions with American policymakers who had already reduced the scope and depth of ties with Bangkok. How Thailand's political polarization is resolved will be most consequential to the future of Thai‐U.S. security relations. However, continued U.S. alliance relations remain essential for Thailand in view of China's intense campaign to woo Thailand's coup leaderships in 2006 and 2014. A lopsided Thai‐Chinese relationship puts at risk Thailand's traditionally masterful and clever foreign policy pragmatism and undercuts the traditional benefits that both the United States and Thailand have derived from their longstanding alliance relationship.
U.S.‐India Ties: Calibrating Collaboration Post‐Non‐Alignment
Authors: Rajagopalan Rajeswari Pillai
Published: January 2016

With the rise of India, China, and Japan, the 21st century is often hailed as the Asian century. Whether these states can collaborate with each other over the long‐term in an effort to avoid regional anarchy in the Asia‐Pacific is an open question. How U.S.‐India ties will evolve constitutes a major determinant of how much stability or strife the Asia‐Pacific will experience over the foreseeable future. Selected aspects of this important bilateral relationship will be assessed here. The nature of U.S. grand strategy in Asia, and where India fits in this strategy will be examined. Understanding U.S. grand strategy provides insight to American strategic concerns and their impact on Washington's important bilateral relationships. U.S. and Indian perspectives on grand strategy will then be compared. Finally, how India's grand strategy plays into that country's foreign policy toward the United States relative to overall regional concerns will be evaluated.
Indonesia‐U.S. Security Collaboration: Still Under the Radar?
Authors: Muhibat Shafiah F.
Published: January 2016

Compared with the United States’ much‐celebrated security collaboration with its more formal Asian allies, it is fair to say that its security cooperation with Indonesia is “still under the radar.” Cooperation is limited not only by domestic pressure in the United States with regard to human rights issues, but also from Indonesia's perspective that U.S. policy consistency is often found wanting. Bilateral security relations appear to be relevant in the contemporary Southeast Asian security environment, given increasing tensions in the South China Sea and emerging challenges relating to counterterrorism. This relevance is qualified, however, by both countries’ policymakers’ tendencies to be intermittently detached—if not actually disinterested—in each other's core national security objectives. This article examines the development of Indonesia‐U.S. defense and security relations, analyzing how Indonesia views U.S. presence in the region, and to what degree its own interests and policies benefit from or are complicated by security cooperation with the United States.
America the Indispensable Power: Singapore's Perspective of America as a Security Partner
Authors: Tan See Seng
Published: January 2016

Security relations between Singapore and the United States have evolved significantly since the former gained independence in 1965. From an unlikely partnership pursued by Singapore by default rather than choice during Singapore's formative years, the United States has since evolved into a vital partner of Singapore because of the indispensable role it has played in ensuring a stable balance of power in the Asia‐Pacific and in facilitating the economic prosperity of the region. Their partnership has endured rough patches due to political differences. In the post‐9/11 period, Singapore's security has also been affected as a result of its close ties with the United States. Moreover, Singapore's reliance on hedging has at times fostered doubts—more so now in the era of U.S. rebalancing—about the congruence of its interests with those of America. However, it is clear Singapore prefers the perceived benign presence of the United States over other powers.
Meeting the Chinese Challenge to the Regional Order
Authors: Roy Denny
Published: January 2016

China has reached such a position of relative strength in the Asia‐Pacific region that anxiety about stimulating anti‐China security cooperation among other states, once a powerful moderating force over Chinese foreign policy making, appears less of a restraint for the nationalism‐indulgent Xi Jinping government. Chinese leaders believe that China's challenges to key aspects of the U.S.‐sponsored regional security order will result in increased regime and national security for China, but these challenges also threaten to unravel the order. If Washington and its partners are unwilling to accept the inevitable harm to their own interests that would accompany increased Chinese influence over regional affairs, they should demonstrate a willingness to pursue policies the Chinese would view as strategic setbacks, thereby causing the Chinese to recalculate the advisability of bullying behavior as opposed to cooperative behavior within the rules and institutions of the current regional order, an approach under which China has made spectacular gains.
U.S.‐Philippines Security Ties: Building New Foundations?
Authors: Misalucha Charmaine G. , Amador Julio S.
Published: January 2016

How are regional actors affected by the decline of the U.S.‐led security network and the increasing role of China in Asia? These nuances surface in the Philippines’ role in the South China Sea. We demonstrate that the Philippines is pursuing order‐building initiatives at the multilateral and bilateral levels. First, we focus on the incidents in the South China Sea and the multilateral attempts at addressing the crisis. Second, we posit that the shortcomings of regional solutions necessitate Manila strengthening its relations with the United States. Hence, reinvigorating the U.S.‐Philippines alliance is a critical hedging strategy for the Philippines to ensure its security and win support for its own visions of regional order. The Philippines may indeed be building new foundations, but their sustainability depends on Manila and its regional neighbors gradually shifting policy debates and behavior from nationalist strategies to the applicability of international law and stability in East Asia.
The New Guidelines for Japan‐U.S. Defense Cooperation and an Expanding Japanese Security Role
Authors: Satake Tomohiko
Published: January 2016

This article examines the changing role of Japan and its alliance with the United States by focusing on the new Guidelines for Japan‐U.S. Defense Cooperation announced in April 2015. The article focuses particularly on the implications of the 2015 guidelines for a greater regional security role for Japan, including its potential cooperation with the United States and Australia. To do so, it first considers the meaning and roles encapsulated in the Defense Guidelines using two key concepts—”reassurance” and “burden‐sharing.” Second, the article discusses how the latest guidelines have increased the U.S. commitment to Japanese defense, while assigning Japan a greater security role in the region. Third, it examines the possibilities and challenges ahead for closer U.S.–Japan–Australia cooperation especially in the South China Sea, and concludes that achieving such a goal depends on how Japan can address its domestic and international issues, including the successful implementation of legal reforms in Japanese security policy.
Malaysia Between the United States and China: What do Weaker States Hedge Against?
Authors: Kuik Cheng‐Chwee
Published: January 2016

This article analyzes Malaysia's alignment behavior vis‐à‐vis America and China, with a focus on explaining how the weaker state's insistence on hedging has both motivated and limited its defense links with the competing powers. Contrary to the conventional wisdom that regional states choose to align militarily with the rebalancing America to hedge against China, the article argues that this characterization is only partially true; a more accurate account is that weaker states do not hedge against any single actor per se; rather, they seek to hedge against a range of risks associated with uncertain power relations. In the case of Malaysia, while Putrajaya aims to mitigate the challenges of an assertive Beijing, its alignment behavior is more a function of a desire to offset several systemic and domestic risks, namely, the shadow of entrapment, abandonment, and alienation, alongside the fear of authority erosion at home.
Asian Strategic Partnerships: New Practices and Regional Security Governance
Authors: Envall H. D. P. , Hall Ian
Published: January 2016

This article examines the use of strategic partnerships by Asian states as a means of enhancing national and regional security, as well as advancing economic and other objectives. It argues that strategic partnerships are best conceived as a new practice that signals the emergence of new forms of “security governance” in the region. It observes, however, that whereas early strategic partnerships were based on substantive shared agreement on “system principles,” contemporary strategic partnerships take different forms, some grounding closer cooperation between like‐minded partners and some intending to facilitate better management of partners with divergent values and interests. The contemporary behavior of the United States and its traditional and new security partners in the region conform to this general pattern. The article concludes that the proliferation of strategic partnerships and the emergence of regional security governance should prompt a reappraisal of traditional approaches to Asian security, which tend to concentrate on architecture and community at the expense of practices.
The U.S.‐South Korea Alliance: Local, Regional, and Global Dimensions
Authors: Bong Youngshik Daniel
Published: January 2016

The U.S.‐South Korea military alliance has helped South Korea cope with key conditions that have threatened its sovereignty and national character. It has evolved into a security alliance that is mature, multidimensional, and comprehensive in terms of its main structure, operational scope, and mission. Domestic political conditions and public opinion in South Korea have been largely supportive of the bilateral security alliance. At the regional level, South Korea's anxiety regarding Japan's growing role in regional security matters has collided with its desire to transform the alliance to play a more effective role in the Asia‐Pacific region. The progressive nature of the threat of North Korea's weapons of mass destruction has introduced global objectives into the U.S.‐South Korea security alliance. Effectively coping with such “hybrid” threats from North Korea will remain the key challenge for the U.S.‐South Korea alliance in the future.
Absence of ethnic differences in the pharmacokinetics of moxifloxacin, simvastatin, and meloxicam among three East Asian populations and Caucasians
Authors: Hasunuma Tomoko , Tohkin Masahiro , Kaniwa Nahoko , Jang In‐Jin , Yimin Cui , Kaneko Masaru , Saito Yoshiro , Takeuchi Masahiro , Watanabe Hiroshi , Yamazoe Yasushi , Uyama Yoshiaki , Kawai Shinichi
Published: January 2016

Aim

To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups.

Methods

Open‐label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined.

Results

AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed.

Conclusions

Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies.
Mechanism of isoniazid‐induced hepatotoxicity: then and now
Authors: Metushi Imir , Uetrecht Jack , Phillips Elizabeth
Published: January 2016

Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. Previous mechanistic hypotheses have classified this type of drug‐induced liver injury (DILI) as ‘metabolic idiosyncrasy’ which was thought not to involve an immune response and was mainly due to the bioactivation of the acetylhydrazine metabolite. However, more recent studies support an alternative hypothesis, specifically, that INH itself is directly bioactivated to a reactive metabolite, which in some patients leads to an immune response and liver injury. Furthermore, there appear to be two phenotypes of INH‐induced liver injury. Most cases involve mild liver injury, which resolves with immune tolerance, while other cases appear to have a more severe phenotype that is associated with the production of anti‐drug/anti‐CYP P450 antibodies and can progress to liver failure.
Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis
Authors: Karasu Alev , Baglin Trevor P. , Luddington Roger , Baglin Caroline A. , van Hylckama Vlieg Astrid
Published: January 2016

The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two‐centre population‐based case‐control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1·8‐fold increased risk of a first VT [95% confidence interval (CI) 1·2–2·7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2·9‐fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4·2, 95% CI 1·3–13·5). In the follow‐up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1·5 (95% CI 0·9–2·6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak.
Hemin induces mitophagy in a leukemic erythroblast cell line
Authors: Fader Claudio Marcelo , Salassa Betiana Nebaí , Grosso Rubén Adrián , Vergara Agustín Nicolás , Colombo María Isabel
Published: January 2016

Background Information

In eukaryotic cells, autophagy is considered a lysosomal catabolic process which participates in the degradation of intracellular components in a vacuolar structure termed autolysosome. This pathway plays a significant role in the erythropoiesis process, contributing to the clearance of some organelles (such as mitochondria) that are not necessary in the mature red blood cells. Nevertheless, the role of autophagy in erythrocyte maturation has not been fully established.

Results

Here, we have demonstrated that hemin (a physiological erythroid maturation stimulator) is able to induce the expression of critical autophagic genes (i.e., Map1a1b (LC3), Beclin‐1 gen, Atg5) in an erythroleukemia cell type. We have also shown that hemin increased the size of autophagic vacuoles which were labelled with LC3 and the degradative lysosomal marker dye quenched‐bovine serum albumin. In addition, we have determined by Western blot a rise in the lipidated form of the autophagic protein LC3 (i.e., LC3‐II) upon hemin treatment. Moreover, we provide evidence that hemin induces mitochondrial membrane depolarisation and that mitochondria sequestration by autophagy requires the active form of the NIX protein.

Conclusions

We have found that the physiological erythroid maturation stimulator hemin is able to induce mitophagy in K562 cells, and that the autophagy adaptor NIX is necessary for mitophagy progression. K562 cells have been used as a relevant model to determine the possible therapeutic role of new differentiating compounds.

Significance

It has been proposed that autophagy induction is a feasible new therapeutic key in fighting cancer. Our results suggest that hemin is favoring erythroid maturation by inducing an autophagic response in K562 cells, being a possible therapeutic candidate that may help in the chronic myelogenous leukemia (CML) treatment.
Effects of new‐generation inhibitors of the calcium‐activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract
Authors: Hwang Sung Jin , Basma Naseer , Sanders Kenton M , Ward Sean M
Published: January 2016

Background and Purpose

High‐throughput screening of compound libraries using genetically encoded fluorescent biosensors has identified several second‐generation. low MW inhibitors of the calcium‐activated chloride channel anoctamin 1 (CaCC/Ano1). Here we have (i) examined the effects of these Ano1 inhibitors on gastric and intestinal pacemaker activity; (ii) compared the effects of these inhibitors with those of the more classical CaCC inhibitor, 5‐nitro‐2‐(3‐phenylpropylalanine) benzoate (NPPB); (ii) examined the mode of action of these compounds on the waveform of pacemaker activity; and (iii) compared differences in the sensitivity between gastric and intestinal pacemaker activity to the Ano1 inhibitors.

Experimental Approach

Using intracellular microelectrode recordings of gastric and intestinal muscle preparations from C57BL/6 mice, the dose‐dependent effects of Ano1 inhibitors were examined on spontaneous electrical slow waves.

Key Results

The efficacy of second‐generation Ano1 inhibitors on gastric and intestinal pacemaker activity differed significantly. Antral slow waves were more sensitive to these inhibitors than intestinal slow waves. CaCCinh‐A01 and benzbromarone were the most potent at inhibiting slow waves in both muscle preparations and more potent than NPPB. Dichlorophene and hexachlorophene were equally potent at inhibiting slow waves. Surprisingly, slow waves were relatively insensitive to T16Ainh‐A01 in both preparations.

Conclusions and Implications

We have identified several second‐generation Ano1 inhibitors, blocking gastric and intestinal pacemaker activity. Different sensitivities to Ano1 inhibitors between stomach and intestine suggest the possibility of different splice variants in these two organs or the involvement of other conductances in the generation and propagation of pacemaker activity in these tissues.
Hippocampal 5‐HT7 receptors signal phosphorylation of the GluA1 subunit to facilitate AMPA receptor mediated‐neurotransmission in vitro and in vivo
Authors: Andreetta Filippo , Carboni Lucia , Grafton Gillian , Jeggo Ross , Whyment Andrew D , van den Top Marco , Hoyer Daniel , Spanswick David , Barnes Nicholas M
Published: January 2016

Background and Purpose

The 5‐HT7 receptor is a GPCR that is the target of a broad range of antidepressant and antipsychotic drugs. Various studies have demonstrated an ability of the 5‐HT7 receptor to modulate glutamatergic neurotransmission and cognitive processes although the potential impact upon AMPA receptors has not been investigated directly. The purposes of the present study were to investigate a direct modulation of the GluA1 AMPA receptor subunit and determine how this might influence AMPA receptor function.

Experimental Approach

The influence of pharmacological manipulation of the 5‐HT7 receptor system upon phosphorylation of GluA1 subunits was assessed by Western blotting of fractionated proteins from hippocampal neurones in culture (or proteins resident at the neurone surface) and the functional impact assessed by electrophysiological recordings in rat hippocampus in vitro and in vivo.

Key Results

5‐HT7 receptor activation increased cAMP and relative pCREB levels in cultures of rat hippocampal neurones along with an increase in phosphorylation (Ser845) of the GluA1 AMPA receptor subunit evident in whole neurone extracts and within the neurone surface compartment. Electrophysiological recordings in rat hippocampus demonstrated a 5‐HT7 receptor‐mediated increase in AMPA receptor‐mediated neurotransmission in vitro and in vivo.

Conclusions and Implications

The 5‐HT7 receptor‐mediated phosphorylation of the GluA1 AMPA receptor provides a molecular mechanism consistent with the 5‐HT7 receptor‐mediated increase in AMPA receptor‐mediated neurotransmission.
Safety, pharmacokinetics and pharmacodynamics of the anti‐hepcidin Spiegelmer lexaptepid pegol in healthy subjects
Authors: Boyce M , Warrington S , Cortezi B , Zöllner S , Vauléon S , Swinkels D W , Summo L , Schwoebel F , Riecke K
Published: January 2016

Background and Purpose

Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l‐oligoribonucleotide, binds and inactivates hepcidin.

Experimental Approach

We conducted a placebo‐controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg·kg−1.

Key Results

After treatment with lexaptepid, serum iron concentration and transferrin increased dose‐dependently. Iron increased from approximately 20 μmol·L−1 at baseline by 67% at 8 h after i.v. infusion of 1.2 mg·kg−1 lexaptepid. The pharmacokinetics showed dose‐proportional increases in peak plasma concentrations and moderately over‐proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti‐drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses ≥2.4 mg·kg−1 and with local injection site reactions after s.c. but not after i.v. administration.

Conclusions and Implications

Lexaptepid pegol inhibited hepcidin and dose‐dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease.
In whose words? Struggles and strategies of service providers working with immigrant clients with limited language abilities in the violence against women sector and child protection services
Authors: Alaggia Ramona , Maiter Sarah , Jenney Angelique
Published: January 2016

Newcomer and immigrant clients with limited language abilities face communication barriers that can compromise their capacity to make informed decisions about themselves and their children with serious implications for their families. These clients most likely had high proficiency of language in their country of origin but are learning the language of the new host country. Using a phenomenological design to elicit descriptions from and interpret experiences of Canadian‐helping professionals, we conducted four focus groups first with child protection workers, and second with violence against women service providers. Analyses of these data uncovered five themes: (1) enhancing client engagement and self‐agency; (2) advantages and drawbacks in use of interpreters; (3) creative and intensive translation strategies; (4) structural challenges and (5) gender and cultural considerations. Results are organized into an ecological framework in putting forward implications for policy and practice. The over‐arching finding supports that important training and preparation are necessary for service providers to deliver language‐sensitive services. As well, funding levels need to be increased to better match service delivery goals. Newcomer and immigrant clients whose language needs are not adequately met potentially face safety issues and/or fragmentation of their families.
Long‐term prospective cohort study on dental implants: clinical and microbiological parameters
Authors: Tenenbaum Henri , Bogen Omer , Séverac François , Elkaim René , Davideau Jean‐Luc , Huck Olivier
Published: January 2016

Objective

The aim of the present prospective cohort study is to evaluate clinical and microbiological data of dental implants after at least 8 years of follow‐up.

Material and methods

A total of 110 patients and 232 implants were included at baseline and followed during 1 year. Fifty‐two patients and 108 implants could be evaluated at the final examination. Clinical and microbiological data were taken at baseline, 1 year and at least 8 years.

Results

The mean follow‐up time was 10.8 ± 1.7 years. Plaque index was, respectively, 0.50 ± 0.50 at baseline, 0.50 ± 0.50 at 1 year and 0.33 ± 0.67 at ≥8 years. Gingival index was, respectively, 1.08 ± 0.19 at baseline, 1.01 ± 0.39 at 1 year and 0.22 ± 0.47 at ≥8 years. Sulcular bleeding index was, respectively, 0.17 ± 0.22 at baseline, 0.11 ± 0.33 at 1 year and 0.17 ± 0.22 at ≥8 years. Probing depth was, respectively, 2.67 ± 0.75 at baseline, 3.00 ± 0.83 at 1 year and 2.74 ± 1.00 at ≥8 years. Clinical attachment level was, respectively, 3.75 ± 1.17 at baseline, 4.00 ± 1.06 at 1 year and 4.00 ± 1.17 at ≥8 years. Peri‐implant mucositis was detected around 60.2% of implants in 73.1% of patients, while peri‐implantitis was affecting 12% of implants in 15.4% of patients. Some bacteria species were associated with worsened clinical parameters.

Conclusions

About 69.4% of implants (75/108) and 67.3% of the patients (35/52) were considered as success in the present prospective cohort study after a mean follow‐up of 10.8 years. Microbial follow‐up may help to identify patients at risk for peri‐implant disease.
Dental implant surgery in patients in treatment by dabigatran
Authors: Gómez‐Moreno Gerardo , Fernández‐Cejas Esther , Aguilar‐Salvatierra Antonio , de Carlos Félix , Delgado‐Ruiz Rafael Arcesio , Calvo‐Guirado José Luis
Published: January 2016

Objectives

The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by the oral anticoagulant dabigatran following a specific protocol.

Material and methods

Seventy‐one patients were divided into two groups: 29 had been taking dabigatran for over 6 months (150 mg orally every 12 h) before implant surgery (dabigatran group) and a control group consisting of 42 healthy subjects. Patients were treated in an outpatient setting. All subjects received dental implants in different positions, dabigatran group patients 12 h after the last dose of dabigatran. Nonabsorbable sutures were used and patients were given gauzes impregnated with tranexamic acid 5% to bite on for 30–60 min. Dabigatran patients resumed medication 8 h after the procedure, resuming usual dosage (every 12 h) the day after surgery.

Results

Two dabigatran patients and two control patients presented slight bleeding the day after surgery. Bleeding was managed with gauzes impregnated with tranexamic acid. No statistically significant differences (P = 0.542) were found in relation to bleeding episodes between the groups, with a relative risk of 0.675 based on the pooled groups and a 95% confidence interval of 0.090–5.088.

Conclusions

Dental implant surgery in patients taking dabigatran can be performed safely providing 12 h have passed since the last dose and local hemostatic measures are applied. Normal dosage can be resumed 8 h after implant surgery.
Social deprivation in patients requiring pelvic exenterative surgery
Authors: Radwan R. W. , Coyne P. E. , Jones H. G. , Evans M. D. , Davies M. , Harris D. A. , Beynon J.
Published: January 2016

Aim

Pelvic exenteration is an aggressive operation for locally advanced rectal cancer. Social deprivation has been shown to reduce life expectancy and has been linked to a poorer outcome in patients with colorectal cancer. The aim of this study was to analyse the effect of social deprivation scores on the outcome in these complex patients.

Method

A retrospective review of all patients undergoing pelvic exenteration for primary rectal cancer between 2006 and 2014 was performed. Deprivation scores were calculated for all patients using the Welsh Index of Multiple Deprivation. Patients were then grouped into quartiles, from Q1 (most deprived) to Q4 (least deprived). The primary outcome measure was 5‐year survival.

Results

In all, 120 patients were included (65 female) with a median age of 64 (31–90) years. No differences between quartiles were identified for neoadjuvant therapy (P = 0.687) or type of exenteration (P = 0.690). The median length of stay was significantly higher in the most deprived groups (Q1–Q2; P = 0.023). There was a significant difference in survival between the groups, with lowest 5‐year survival rates (53%) in the most deprived quartile (Q1) (P = 0.015).

Conclusion

Social deprivation is significantly associated with postoperative length of stay and survival in patients undergoing pelvic exenteration for primary rectal cancer.
Risk factors associated with portomesenteric venous thrombosis in patients undergoing restorative proctocolectomy for medically refractory ulcerative colitis
Authors: Gu J. , Stocchi L. , Gorgun E. , Remzi F. H.
Published: January 2016

Aim

Data on risk factors for portomesenteric venous thrombosis (PMVT) following abdominal surgery for ulcerative colitis (UC) are limited. The aim of this study was to investigate factors associated with PMVT after surgical treatment for UC.

Method

Patients who underwent restorative proctocolectomy (RPC) and ileal pouch‐anal anastomosis (IPAA) including diverting ileostomy closure for medically refractory UC were identified from a prospectively maintained database. Patient‐related, disease‐related and treatment‐related variables were collected. Univariable and multivariable analyses were performed to assess factors associated with PMVT.

Results

Of the 521 patients completing surgical treatment for UC between 2006 and 2012, symptomatic PMVT occurred in 36 (7%), which resulted in a significantly increased hospital stay (P < 0.001). Patients developing PMVT were younger (P = 0.014), had a lower preoperative albumin level (P = 0.037) and were more likely to have been taking steroids within 1 month before surgery (P = 0.006). The combined incidence of PMVT was comparable between patients having a three‐stage and two‐stage management (6% vs 8%, P = 0.43), but the relative incidence of PMVT after RPC + IPAA was 8%, significantly higher than the 4% after total abdominal colectomy (TAC) (P = 0.005) and the 2% after subsequent completion proctectomy (CP) + IPAA (P = 0.038). Multivariate analysis confirmed that RPC + IPAA was associated with a significantly greater risk of PMVT than CP + IPAA (OR = 4.9, P = 0.003) or TAC (OR = 3.5, P = 0.011). Preoperative steroid use was an independent factor for PMVT (OR = 5.8, P = 0.006).

Conclusion

Steroid use 1 month before surgery is associated with an increased risk of PMVT. A staged restorative proctocolectomy does not increase the overall incidence of PMVT.
Intermittent hydrostatic pressure maintains and enhances the chondrogenic differentiation of cartilage progenitor cells cultivated in alginate beads
Authors: Li Yang , Zhou Jianxin , Yang Xiaofei , Jiang Yiqiu , Gui Jianchao
Published: January 2016

The objective of this study was to explore the effects of intermittent hydrostatic pressure (IHP) on the chondrogenic differentiation of cartilage progenitor cells (CPCs) cultivated in alginate beads.CPCs were isolated from the knee joint cartilage of rabbits, and infrapatellar fat pad‐derived stem cells (FPSCs) and chondrocytes (CCs) were included as the control cell types. Cells embedded in alginate beads were treated withIHPat 5 Mpa and 0.5 Hz for 4 h/day for 1, 2, or 4 weeks. The cells' migratory and proliferative capacities were evaluated using the scratch and Live/Dead assays, respectively. Hematoxylin and eosin staining, safranin O staining, and immunohistochemical staining were performed to determine the effects ofIHPon the synthesis of extracellular matrix (ECM) proteins. Real‐time polymerase chain reaction analysis was performed to measure the expression of genes related to chondrogenesis. The scratch and Live/Dead assays revealed thatIHPsignificantly promoted the migration and proliferation ofFPSCs andCPCs to different extents. The staining experiments showed greater production of cartilageECMcomponents (glycosaminoglycans and collagenII) by cells exposed toIHP, and the gene expression analysis demonstrated thatIHPstimulated the expression of chondrocyte‐related genes. Importantly, these effects ofIHPwere more prominent inCPCs than inFPSCs andCCs. Considering all of our experimental results combined, we conclude thatCPCs demonstrated a stronger chondrogenic differentiation capacity than theFPSCs andCCs under stimulation withIHP. Thus, the use ofCPCs, combined with mechanical stimulation, may represent a valuable strategy for cartilage tissue engineering.
Use of standardized outcome measures should be common place in the clinical care of children with cerebral palsy: why isn't it?
Authors: Oeffinger Donna
Published: January 2016

This commentary is on the original article by O'Connor et al. on pages 332–347 of this issue.
Estimating the impact of better management of glycaemic control in adults with Type 1 and Type 2 diabetes on the number of clinical complications and the associated financial benefit
Authors: Baxter M. , Hudson R. , Mahon J. , Bartlett C. , Samyshkin Y. , Alexiou D. , Hex N.
Published: January 2016

Aim

To estimate potential cost avoidance through modest and achievable improvements in glycaemic control in adults with Type 1 or Type 2 diabetes mellitus in the UK healthcare system.

Methods

The IMS Core Diabetes Model was used to examine the impact of improved glycaemic control (indicated by reduction in HbA1c level), in a representative cohort of adults with Type 1 or Type 2 diabetes. The cumulative incidence of microvascular and macrovascular complications was modelled across 5‐year periods to a 25‐year time horizon. Complication costs were applied to the data to estimate potential accrued cost avoidance.

Results

Significant cost avoidance of ~£340 m is apparent in the first 5 years, increasing to ~£5.5bn after 25 years of sustained improvement in control. The overwhelming majority of cost avoidance arises from reductions in microvascular complications. In people with Type 1 diabetes the greatest cost avoidance comes from a reduction in renal disease (74% of cost avoidance), while in people with Type 2 diabetes it is generated by a reduction in foot ulcers, amputations and neuropathy: 57% cost avoidance). Greater cost reduction is accrued more rapidly in people with higher starting HbA1c levels.

Conclusion

Modest improvements in glycaemic control generate significant reductions in the incidence and, therefore, cost of microvascular complications in people with Type 1 or Type 2 diabetes. This study provides clear support for the premise that prioritized and sustained investment in early and better intervention can provide concrete financial benefits in both the short and longer term.
Diabetic ketoacidosis in an adolescent and young adult population in the UK in 2014: a national survey comparison of management in paediatric and adult settings
Authors: Edge J. A. , Nunney I. , Dhatariya K. K.
Published: January 2016

Aims

To assess the management of diabetic ketoacidosis in young people, which differs in the UK between paediatric and adult services, and to evaluate outcomes and extent to which national guidelines are used.

Methods

A standardized questionnaire was sent to all paediatric and adult diabetes services in England, requesting details of all diabetic ketoacidosis admissions in young people aged > 14 years in paediatric services (‘paediatric’ patients), and in young adults up to the age of 22 years in adult services (‘adult’ patients).

Results

A total of 64 adult patients aged ≤ 22 years (mean age 19.2 years) were reported, of whom seven were aged between 10 and 16 years. A total of 71 paediatric patients were reported [mean (range) age 14.9 (11–18) years]. We found that 85% of paediatric and 69% of adult patients were treated according to national guidelines, 99% of paediatric and 89% of adult patients were treated with 0.9% saline and fixed‐rate insulin infusions and 16% of adult patients received an insulin bolus. Insulin treatment was initiated later in paediatric patients than in adult patients (100 vs 39 min; P < 0.001). In 23% of adult patients and 8.8% of paediatric patients, potassium levels were < 3.5 mmol/l (P < 0.005). The lowest mean potassium levels were 3.8 mmol/l in paediatric and 3.5 mmol/l in adult patients (P < 0.005). Hypoglycaemia occurred in 42.3% of paediatric and 36% of adult patients. Time to resolution was similar in paediatric and adult patients (16.0 vs 18.2 h), as was duration of hospital stay (2.35 vs 2.53 days).

Conclusions

Young people were treated according to national guidelines, but the quality of monitoring was variable in both paediatric and adult settings. The incidence of hypoglycaemia and hypokalaemia was unacceptably high.