bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the potential impact of a reformulated version of oxycodone upon tampering, non‐adherence and diversion of opioids: the National Opioid Medications Abuse Deterrence (NOMAD) study protocol
Authors: Degenhardt Louisa , Larance Briony , Bruno Raimondo , Lintzeris Nicholas , Ali Robert , Farrell Michael
Published: October 2014

Aims

A new oxycodone formulation (Reformulated OxyContin®) was released in Australia, early 2014. It was developed as a tamper‐resistant (‘abuse‐deterrent’) formulation of the drug. We summarize methods used in the National Opioid Medication Abuse Deterrence (NOMAD) study, which will examine: (i) whether there is a reduction in extra‐medical use (including via tampering) of OxyContin® following the introduction of Reformulated OxyContin®; (ii) potential changes in extra‐medical use of non‐abuse‐deterrent forms of oxycodone, other pharmaceutical opioids and illicit drugs; (iii) whether methods of tampering with Reformulated OxyContin® become widespread over time; (iv) Reformulated OxyContin®'s attractiveness on the illicit market; and (v) sales, prescriptions and harms related to OxyContin® and other drugs.

Methods

There are three major components. First, analyses of existing routine data sources such as: pharmaceutical sales; prescribing data; data on drug overdose deaths; and survey data on drug use in the general population and among people who inject drugs; secondly, specific data on OxyContin® collected through the Illicit Drug Reporting System; and thirdly, a prospective cohort of n = 606 people who regularly misuse or tamper with pharmaceutical opioids was formed prior to the introduction of Reformulated OxyContin®, followed‐up twice post‐release to examine potential changes after Reformulated OxyContin®'s introduction.

Discussion

The study's strengths lie in varied data collections; interrupted time–series analysis; and prospective cohort. To our knowledge, this is one of the most comprehensive and transparently conducted studies conducted to date of the potential impact of an opioid medication upon use, tampering and diversion. Results have the potential to inform policymakers, clinicians, consumers and researchers alike.
Impact of the early detection of esophageal neoplasms in hypopharyngeal cancer patients treated with concurrent chemoradiotherapy
Authors: Watanabe Shigenobu , Ogino Ichiro , Inayama Yoshiaki , Sugiura Madoka , Sakuma Yasunori , Kokawa Atsushi , Kunisaki Chikara , Inoue Tomio
Published: October 2014

Aims

We examined the risk factors and prognostic factors for synchronous esophageal neoplasia (SEN) by comparing the characteristics of hypopharyngeal cancer (HPC) patients with and without SEN.

Methods

We examined 183 patients who were treated with definitive radiotherapy for HPC. Lugol chromoendoscopy screening of the esophagus was performed in all patients before chemoradiotherapy.

Results

Thirty‐six patients had SEN, 49 patients died of HPC and two died of esophageal cancer. The patients with SEN exhibited significantly higher alcohol consumption than those without SEN (P = 0.018). The 5‐year overall survival (OS) rate of the 36 patients with SEN was lower than that of the other patients (36.2% vs 63.4%, P = 0.006). The SEN patients exhibited significantly shorter HPC cause‐specific survival than the other patients (P = 0.039). Both the OS (P = 0.005) and the HPC cause‐specific survival (P = 0.026) of the patients with SEN were significantly shorter than those of the patients without SEN in multivariate analysis. Category 4/T1 stage esophageal cancer was treated with concurrent chemoradiotherapy (CCRT), endoscopic treatment or chemotherapy. The 5‐year survival rates for esophageal cancer recurrence for CCRT, endoscopic treatment and chemotherapy were 71.5, 43.7 and 0%, respectively. The median (range) survival time (months) of CCRT, endoscopic treatment and chemotherapy was 22.7 (7.5–90.6), 46.44 (17.3–136.7) and 7.98 (3.72–22.8), respectively.

Conclusion

Advanced HPC patients with SEN might have a poorer prognosis than those without SEN even when the esophageal cancer is detected early and managed appropriately.
Interleukin‐6 gene‐174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma
Authors: Chakraborty Baidarbhi , Vishnoi Gaurav , Gowda Srinivas H , Goswami Binita
Published: October 2014

Aim

In multiple myeloma (MM), the growth and survival of myeloma cells is controlled by interleukin‐6 (IL‐6), the plasma levels of which is controlled by a guanine/cytosine substitution occurring in position ‐174 of IL‐6 gene promoter region. We studied the occurrence of IL‐6‐174 G/C polymorphism in patients of MM and correlated the presence of genotypes with serum IL‐6 levels and tumor staging.

Methods

One hundred three patients with MM and 117 age‐ and sex‐matched healthy controls were staged by International Staging System. IL‐6 genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis. Serum levels of IL‐6 were assessed by enzyme‐linked immunosorbent assay.

Results

Frequency of GG, GC and CC genotypes did not differ significantly between cases (GG 52%, GC 40%, CC 9%) and controls. The median serum level of IL‐6 was significantly higher among the GC genotype versus other genotypes (24 ng/mL, P = 0.007) as compared with the GG versus other genotypes (12 ng/mL, P = 0.001). GC was associated more with stage 3 disease (27%) than was GG (11%) or CC (22% P = 0.001).

Conclusions

At position 174 of the IL‐6 promoter, patients with GC genotype had higher serum levels of IL‐6 and presented with more severe disease compared with patients with GG or CC genotype.
Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen‐activated protein kinase (MAPK) inhibitor
Authors: Lea Simon , Harbron Chris , Khan Naimat , Booth George , Armstrong Jane , Singh Dave
Published: October 2014

Aims

Some asthma patients remain symptomatic despite using high doses of inhaled corticosteroids (ICS). We used alveolar macrophages to identify individual patients with insensitivity to corticosteroids and to evaluate the anti‐inflammatory effects of a p38 mitogen‐activated protein kinase (MAPK) inhibitor combined with a corticosteroid on these cells.

Methods

Alveolar macrophages from 27 asthma patients (classified according to the Global Initiative for Asthma (GINA) treatment stage. Six GINA1, 10 GINA2 and 11 GINA3/4) were stimulated with lipoploysaccharide (LPS) (1 μg ml−1). The effects of dexamethasone (dex 1–1000 nm), the p38 MAPK inhibitor 1‐(5‐tert‐butyl‐2‐p‐tolyl‐2Hpyrazol‐3‐yl)‐3(4‐(2‐morpholin‐4‐yl‐ethoxy)naphthalen‐1‐yl)urea (BIRB‐796 1–1000 nm) and both drugs combined at all concentrations on supernatant TNFα, IL‐6 and CXCL‐8 concentrations were analyzed by ELISA. Dose‐sparing and efficacy enhancing effects of combination treatment were determined.

Results

Dexamethasone reduced LPS‐induced TNFα, IL‐6 and CXCL‐8 in all groups, but maximum inhibition was significantly reduced for GINA3/4 compared with GINA2 and GINA1 (P < 0.01). A subgroup of corticosteroid insensitive patients with a reduced effect of dexamethasone on cytokine secretion were identified. BIRB‐796 in combination with dexamethasone significantly increased cytokine inhibition compared with either drug alone (P < 0.001) in all groups. This effect was greater in corticosteroid insensitive compared with sensitive patients. There were significant synergistic dose‐sparing effects (P < 0.05) for the combination treatment on inhibition of TNFα, IL‐6 and CXCL‐8 in all groups. There was also significant efficacy enhancing benefits (P < 0.05) on TNFα and IL‐6.

Conclusions

p38 MAPK inhibitors synergistically enhance efficacy of corticosteroids in macrophages from asthma patients. This effect is greater in corticosteroid insensitive asthma patients, suggesting that this class of drug should be targeted to this patient phenotype.
Neurofunctional effects of quetiapine in patients with bipolar mania
Authors: Davis Andrew K , DelBello Melissa P , Eliassen James , Welge Jeffrey , Blom Thomas J , Fleck David E , Weber Wade A , Jarvis Kelly B , Rummelhoff Emily , Strakowski Stephen M , Adler Caleb M
Published: October 2014

Objectives

Several lines of evidence suggest that abnormalities within portions of the extended limbic network involved in affective regulation and expression contribute to the neuropathophysiology of bipolar disorder. In particular, portions of the prefrontal cortex have been implicated in the appearance of manic symptomatology. The effect of atypical antipsychotics on activation of these regions, however, remains poorly understood.

Methods

Twenty‐two patients diagnosed with bipolar mania and 26 healthy subjects participated in a baseline functional magnetic resonance imaging scan during which they performed a continuous performance task with neutral and emotional distractors. Nineteen patients with bipolar disorder were treated for eight weeks with quetiapine monotherapy and then rescanned. Regional activity in response to emotional stimuli was compared between healthy and manic subjects at baseline; and in the subjects with bipolar disorder between baseline and eight‐week scans.

Results

At baseline, functional activity did not differ between subjects with bipolar disorder and healthy subjects in any region examined. After eight weeks of treatment, subjects with bipolar disorder showed a significant decrease in ratings on the Young Mania Rating Scale (YMRS) (p < 0.001), and increased activation in the right orbitofrontal cortex (OFC) (p = 0.002); there was a significant association between increased right OFC activity and YMRS improvement (p = 0.003).

Conclusions

These findings are consistent with suggestions that mania involves a loss of emotional modulatory activity in the prefrontal cortex—restoration of the relatively greater elevation in prefrontal activity widely observed in euthymic patients is associated with clinical improvement. It is not clear, however, whether changes are related to quetiapine treatment or represent a non‐specific marker of affective change.
A cross‐sectional study of thyroid function in 66 patients with bipolar disorder receiving lithium for 10–44 years
Authors: Kraszewska Agnieszka , Chlopocka‐Wozniak Maria , Abramowicz Maria , Sowinski Jerzy , Rybakowski Janusz K
Published: October 2014

Objectives

An important side effect of lithium therapy is an influence on thyroid function. It is unclear whether there is a significant association between thyroid function and duration of lithium administration. The aim of the present cross‐sectional study was to measure levels of thyroid hormones and antibodies in patients with bipolar disorder receiving lithium for more than ten years.

Methods

The study was performed in 66 patients (21 males, 45 females) with bipolar mood disorder, receiving lithium for 10–44 (21 ± 9; mean ± standard deviation) years. Thyroid‐stimulating hormone (TSH), free thyroxine (fT3), and free triiodothyronine (fT4) were measured by the microparticle enzyme immunoassay. Thyroid peroxidase (TPO) antibodies, thyroglobulin (TG) antibodies, and TSH receptor (TSH‐R) antibodies were measured by the radioimmunoassay.

Results

Some features of hypothyroidism were found in ten (22%) female patients (seven received levothyroxine and three had increased TSH). No abnormality in thyroid hormones was found in male patients. A significant percentage of patients had abnormally high levels of anti‐TPO, and anti‐TG antibodies, which correlated with TSH and fT3 concentrations. There were no differences in thyroid function between patients receiving lithium for 10–20 years and those taking the drug for more than 20 years.

Conclusions

These results confirm the greater susceptibility of female subjects for disturbances of thyroid hormones during lithium therapy, with one‐fifth of them showing some features of hypothyroidism. Abnormally high levels of anti‐TPO and anti‐TG antibodies were shown in a significant proportion of patients. However, in contrast to the effect of lithium on kidney function, our results do not show an association between the duration of lithium therapy and thyroid dysfunction.
Enzymatic Studies of Isoflavonoids as Selective and Potent Inhibitors of Human Leukocyte 5‐Lipo‐Oxygenase
Authors: Mascayano Carolina , Espinosa Victoria , Sepúlveda‐Boza Silvia , Hoobler Eric K. , Perry Steve , Diaz Giovanni , Holman Theodore R.
Published: October 2014

Continuing our search to find more potent and selective 5‐LOX inhibitors, we present now the enzymatic evaluation of seventeen isoflavones (IR) and nine isoflavans (HIR), and their in vitro and in cellulo potency against human leukocyte 5‐LOX. Of the 26 compounds tested, 10 isoflavones and 9 isoflavans possessed micromolar potency, but only three were selective against 5‐LOX (IR‐2, HIR‐303, and HIR‐309), with IC50 values at least 10 times lower than those of 12‐LOX, 15‐LOX‐1, and 15‐LOX‐2. Of these three, IR‐2 (6,7‐dihydroxy‐4‐methoxy‐isoflavone, known as texasin) was the most selective 5‐LOX inhibitor, with over 80‐fold potency difference compared with other isozymes; Steered Molecular Dynamics (SMD) studies supported these findings. The presence of the catechol group on ring A (6,7‐dihydroxy versus 7,8‐dihydroxy) correlated with their biological activity, but the reduction of ring C, converting the isoflavones to isoflavans, and the substituent positions on ring B did not affect their potency against 5‐LOX. Two of the most potent/selective inhibitors (HIR‐303 and HIR‐309) were reductive inhibitors and were potent against 5‐LOX in human whole blood, indicating that isoflavans can be potent and selective inhibitors against human leukocyte 5‐LOX in vitro and in cellulo.
TS‐Chemscore, a Target‐Specific Scoring Function, Significantly Improves the Performance of Scoring in Virtual Screening
Authors: Wang Wen‐Jing , Huang Qi , Zou Jun , Li Lin‐Li , Yang Sheng‐Yong
Published: October 2014

Most of the scoring functions currently used in structure‐based drug design belong to ‘universal’ scoring functions, which often give a poor correlation between the calculated scores and experimental binding affinities. In this investigation, we proposed a simple strategy to construct target‐specific scoring functions based on known ‘universal’ scoring functions. This strategy was applied to Chemscore, a widely used empirical scoring function, which led to a new scoring function, termed TS‐Chemscore. TS‐Chemscore was validated on 14 protein targets, which cover a wide range of biological target categories. The results showed that TS‐Chemscore significantly improved the correlation between the calculated scores and experimental binding affinities compared with the original Chemscore. TS‐Chemscore was then applied in virtual screening to retrieve novel JAK3 and YopH inhibitors. Top 30 compounds for each target were selected for experimental validation. Six active compounds for JAK3 and four for YopH were obtained. These compounds were out of the lists of top 30 compounds sorted by Chemscore. Collectively, TS‐Chemscore established in this study showed a better performance in virtual screening than its counterpart Chemscore.
Design, Synthesis, and Anti‐HIV Evaluation of Novel Triazine Derivatives Targeting the Entrance Channel of the NNRTI Binding Pocket
Authors: Chen Xuwang , Meng Qing , Qiu Liyun , Zhan Peng , Liu Huiqing , De Clercq Erik , Pannecouque Christophe , Liu Xinyong
Published: October 2014

A novel series of triazine derivatives targeting the entrance channel of the HIV‐1 non‐nucleoside reverse transcriptase inhibitor binding pocket (NNIBP) were designed and synthesized on the basis of our previous work. The results of a cell‐based antiviral screening assay indicated that most compounds showed good‐to‐moderate activity against wild‐type HIV‐1 with EC50 values within the concentration range of 0.0078–0.16 μm (compound DCS‐a4, EC50 = 7.8 nm). Some compounds displayed submicromolar activity against the K103N/Y181C resistant mutant strain (such as compound DCS‐a4, EC50 = 0.65 μm). Molecular modeling studies confirmed that the new compounds could bind into the NNIBP similarly as the lead compound, and the newly introduced flexible heterocycles could occupy the entrance channel effectively. In addition, the preliminary structure–activity relationship and the RT inhibitory assay are presented in this study.
Parenting interventions in tic disorders: an exploration of parents' perspectives
Authors: Evans G. , Wittkowski A. , Butler H. , Hedderly T. , Bunton P.
Published: October 2014

Background

Parents of children with tic disorders (e.g.Tourette syndrome) experience multiple challenges and stresses, which can impact on family functioning, children's well‐being and could indirectly affect tic severity. Parenting interventions have been recommended for tic disorder populations; however, little is known about parents' views.

Method

The views of parents of children with tic disorders were sought. UsingQ‐methodology, 23 parents provided their opinions regarding the acceptability, effectiveness, feasibility and utility of parenting interventions.

Results

Four factors emerged, representing four groups of parents with similar opinions. Although all factors evidenced support for parenting interventions, subtle differences emerged between factors regarding the endorsed content, barriers and delivery of interventions.

Conclusion

Results indicate a perceived clinical need for parenting interventions and provide guidance to further develop and implement such interventions.
The effect of prolactin levels on MPV in women with PCOS
Authors: Yilmaz Özgür , Calan Mehmet , Kume Tuncay , Temur Muzaffer , Yesil Pınar , Senses Mehmet Y.
Published: October 2014

Objective

Polycystic ovary syndrome (PCOS) is associated with cardiovascular risk factors including hypertension, obesity, hyperlipidaemia and glucose intolerance. Several studies demonstrated the link between PCOS and an increased risk of cardiovascular disease. Platelets play a crucial role in the development of atherothrombotic disease. Mean platelet volume (MPV) is a marker of platelet size that reflects its activity. Research points to a link between prolactin (PRL) and platelet activation. The purpose of this study was to investigate whether prolactin levels are associated with MPV in women with PCOS.

Design

The research was designed as a cross‐sectional study.

Patients

Participants were divided into three groups‐PCOS patients with mildly elevated PRL levels (n = 72), patients with PCOS with normal PRL levels (n = 207) and healthy controls (n = 90). They were body mass index and age‐matched and consecutively recruited.

Measurements

Complete blood counts, serum glucose, prolactin, insulin, lipids, high‐sensitivity C‐reactive protein and free‐testosterone levels were measured.

Results

Among the three groups, MPV levels were higher in women with PCOS having mildly elevated PRL levels (P < 0·001) and MPV was found to be correlated with PRL levels (r = 0·387, P < 0·001). Multiple regression analysis showed that PRL levels were associated with MPV levels (R2 = 0·239, β = 0·354, P < 0·001).

Conclusion

Mean platelet volume levels are significantly increased in women with PCOS having mildly elevated PRL. Our results suggest that there is a link between prolactin and MPV levels. In women with PCOS, elevated PRL levels may increase the risk of developing atherothrombotic events via the activation of platelets.
My 30‐year roadmap for pediatric myasthenia gravis in Hong Kong: Searching for international collaboration
Authors: Wong Virginia Chun‐Nei
Published: October 2014

Pediatric myasthenia gravis (P‐MG) is an autoimmune disease affecting the neuromuscular junction (NMJ), and is rare in children. The roadmap of the research carried out for P‐MG in Hong Kong over the past 30 years was reviewed. Currently, there is a lack of epidemiological studies in comparing clinical data or the outcome for people of different ethnic origins. P‐MG is more common in Asians, especially Chinese and Japanese. Because of the lack of comparison studies for P‐MG worldwide, the author initiated collaboration with international colleagues in 2008, and set up “The International Paediatric Myasthenia Gravis Registry Focus Group (FG)” in 2009. We then established an “International Pediatric Myasthenia Gravis Registry (IPMGR)” to review the current knowledge of P‐MG in children. We designed an e‐MG questionnaire for “Myasthenia Syndromes in Children,” and launched through the website (ICNAPaedia) of the International Child Neurology Association (ICNA) in 2009–2010. As of 2014, we had collected 121 replies from clinicians–researchers in 43 countries. In 2013, we started a Delphi process for obtaining a consensus for diagnosis, management and treatment of P‐MG. Despite the lack of research funding support as a result of the rarity of P‐MG, and the lack of innovative pharmaceutical research and development, we still stress that we set up a foundation as a small step towards consolidating international collaboration to carry out epidemiological studies, genetic studies and randomized controlled trials of all the current available treatments, especially steroids for ocular P‐MG, and indications for thymectomy.
Negotiating motherhood: women with troubled upbringings and their self‐conceptions as mothers
Authors: Herland Mari Dalen , Helgeland Ingeborg Marie
Published: October 2014

This paper examines how women who experienced severe adjustment problems during adolescence, and who had troubled childhoods in families with high levels of conflict, construct their self‐conceptions as mothers. Applying data from a 30‐year‐long follow‐up study, this paper examines how participants with troubled upbringings experience social norms of motherhood. Two overall themes emerged along with their associated subcategories, and these are identified as significant findings. The first theme is the stigmatizing gaze, exemplifying how the intervention of the child welfare service is recognized as essential to the women's self‐conception; its three subcategories are prejudiced motherhood, predestined motherhood and self‐critical motherhood. The second theme is significant relationships, exemplifying the mothers' personal bonds and contributing greatly to their self‐conception; its three subcategories are the other half, next of kin and disturbed relations. The findings reveal that the way these women view themselves as mothers cannot be separated from the way that others view them, and in addition, they must negotiate their positions as mothers through the normative discourses of motherhood. The findings apply to both theoretical and practical social work, addressing the need for an understanding of motherhood within the field of child welfare.
Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family
Authors: Chograni M. , Alkuraya F.S. , Ourteni I. , Maazoul F. , Lariani I. , Chaabouni H.B.
Published: October 2014

The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.
Strontium content and collagen‐I coating of Magnesium–Zirconia–Strontium implants influence osteogenesis and bone resorption
Authors: Mushahary Dolly , Wen Cuie , Kumar Jerald M. , Sravanthi Ragamouni , Hodgson Peter , Pande Gopal , Li Yuncang
Published: October 2014

Objective

Our objective was to study the role of Collagen type‐I (Col‐I) coating on Magnesium–Zirconia (Mg–Zr) alloys, containing different quantities of Strontium (Sr), in enhancing the in vitro bioactivity and in vivo bone‐forming and mineralisation properties of the implants.

Materials and methods

MC3T3‐E1 osteoblast cell line was used to analyse the in vitro properties of Col‐I coated and uncoated alloys. Cell viability analysis was performed by MTT assay; cell attachment on alloy surfaces was studied by scanning electron microscopy (SEM); and gene profiling of bone‐specific markers in cells plated on uncoated alloys was performed by Quantitative RT‐PCR. In vivo studies were performed by implanting 2‐mm‐sized cylindrical pins of uncoated and coated alloys in male New Zealand white rabbits (n = 33). Bone formation and mineralisation was studied by Dual Energy X‐ray Absorptiometry (DXA) and histological analysis at one and three months post‐implantation.

Results

Our results clearly showed that Sr content and Col‐I coating of Mg–Zr–Sr alloys significantly improved their bone inducing activity in vitro and in vivo. Osteoblasts on coated alloys showed better viability and surface binding than those on uncoated alloys. Sr inclusion in the alloys enhanced their bone‐specific gene expression. The in vivo activity of implants with higher Sr and Col‐I coating was superior to uncoated and other coated alloys as they showed faster bone induction and higher mineral content in the newly formed bone.

Conclusion

Our results indicate that bone‐forming and mineralising activity of Mg–Zr–Sr implants can be significantly improved by controlling their Sr content and coating their surface with Col‐I.
The effects of healing abutments of different size and anatomic shape placed immediately in extraction sockets on peri‐implant hard and soft tissues. A pilot study in foxhound dogs
Authors: López‐López Patricia J. , Mareque‐Bueno Javier , Boquete‐Castro Ana , Aguilar‐Salvatierra Raya Antonio , Martínez‐González José M. , Calvo‐Guirado José L.
Published: October 2014

Objectives

The aim of this animal study was to compare the effects of narrow, concave–straight and wide anatomic healing abutments on changes to soft tissues and crestal bone levels around implants immediately placed into extraction sockets in foxhound dogs.

Materials and Methods

Forty‐eight titanium implants (Bredent Medical GMBH, Germany) of the same dimensions were placed in six foxhound dogs. They were divided into two groups (n = 24): test (implants with anatomic abutment) and control (implants with concave–straight abutment). The implants were inserted randomly in the post extraction sockets of P2, P3, P4, and M1 bilaterally in six dogs. After eight and twelve weeks, the animals were sacrificed and samples extracted containing the implants and the surrounding soft and hard tissues. Soft tissue and crestal bone loss (CBL) were evaluated by histology and histomorphometry.

Results

All implants were clinically and histologically osseointegrated. Healing patterns were examined microscopically at eight and twelve weeks. After eight and twelve weeks, for hard tissues, the distance from the implant shoulder to the first bone‐to‐implant contact (IS‐C) was higher for control group in the lingual aspect with statistical significance (P < 0.05). For soft tissues (STL), the distance from the top of the peri‐implant mucosa to the apical portion of the junction epithelium (PM‐Je) was significantly less on the lingual aspect in the test group (with wider abutment) at eight and twelve weeks (P < 0.05). The distance from the top of the apical portion of the junction epithelium to the first bone‐to‐implant contact (Je‐C) was significantly higher in the test group (wider abutment) in the lingual aspect at eight and twelve weeks (P < 0.05). There was no connective tissue contact with any abutment surface.

Conclusions

Within the limitations of this animal study, anatomic healing abutments protect soft and hard tissues and reduce crestal bone resorption compared with concave–straight healing abutments.
Benefits of integrating complementarity into priority threat management
Authors: Chadés Iadine  , Nicol Sam  , van Leeuwen Stephen  , Walters Belinda  , Firn Jennifer  , Reeson Andrew  , Martin Tara G.  , Carwardine Josie 
Published: October 2014

Conservation decision tools based on cost‐effectiveness analysis are used to assess threat management strategies for improving species persistence. These approaches rank alternative strategies by their benefit to cost ratio but may fail to identify the optimal sets of strategies to implement under limited budgets because they do not account for redundancies. We devised a multiobjective optimization approach in which the complementarity principle is applied to identify the sets of threat management strategies that protect the most species for any budget. We used our approach to prioritize threat management strategies for 53 species of conservation concern in the Pilbara, Australia. We followed a structured elicitation approach to collect information on the benefits and costs of implementing 17 different conservation strategies during a 3‐day workshop with 49 stakeholders and experts in the biodiversity, conservation, and management of the Pilbara. We compared the performance of our complementarity priority threat management approach with a current cost‐effectiveness ranking approach. A complementary set of 3 strategies: domestic herbivore management, fire management and research, and sanctuaries provided all species with >50% chance of persistence for $4.7 million/year over 20 years. Achieving the same result cost almost twice as much ($9.71 million/year) when strategies were selected by their cost‐effectiveness ranks alone. Our results show that complementarity of management benefits has the potential to double the impact of priority threat management approaches.
Increasing the Scientific Evidence Base in the “High Conservation Value” (HCV) Approach for Biodiversity Conservation in Managed Tropical Landscapes
Authors: Senior Michael J. M. , Brown Ellen , Villalpando Paulina , Hill Jane K.
Published: October 2014

Land‐use change is a major driver of tropical biodiversity declines. The “High Conservation Value” (HCV) approach aims to protect critical environmental and social values in production landscapes, and is a common feature of many voluntary certification schemes (e.g., Forest Stewardship Council, Roundtable on Sustainable Palm Oil). Despite the popularity of the HCV approach within forestry and agriculture production systems, it is little known in academia and the scientific evidence base supporting it is not well developed. By raising the profile of the HCV approach, we hope to instigate new research to examine the impact of the HCV approach on biodiversity conservation. We argue for better knowledge exchange between scientists, policy makers, and HCV users, sharing of information, and consideration of the practical constraints within which HCV users and commodity producers operate. Given the continuing loss and degradation of tropical rainforests, such strategies are required urgently to reduce biodiversity losses in production landscapes.
Therapeutically interchangeable? A study of real‐world outcomes associated with switching basal insulin analogues among US patients with type 2 diabetes mellitus using electronic medical records data
Authors: Levin P. , Wei W. , Miao R. , Ye F. , Xie L. , Baser O. , Gill J.
Published: October 2014

Aims

To evaluate real‐world clinical outcomes for switching basal insulin analogues [insulin glargine (GLA) and insulin detemir (DET)] among US patients with type 2 diabetes mellitus (T2DM).

Methods

Using the GE Centricity Electronic Medical Records database, this retrospective study examined two cohorts: cohort 1, comprising patients previously on GLA and then either switching to DET (DET‐S) or continuing with GLA (GLA‐C); and cohort 2, comprising patients previously on DET and then either switching to GLA (GLA‐S) or continuing with DET (DET‐C). Within each cohort, treatment groups were propensity‐score‐matched on baseline characteristics. At 1‐year follow‐up, insulin treatment patterns, glycated haemoglobin (HbA1c) levels, hypoglycaemic events, weight and body mass index (BMI) were evaluated.

Results

The analysis included 13 942 patients: cohort 1: n = 10 657 (DET‐S, n = 1797 matched to GLA‐C, n = 8860) and cohort 2: n = 3285 (GLA‐S, n = 858 matched to DET‐C, n = 2427). Baseline characteristics were similar between the treatment groups in each cohort. At 1‐year follow‐up, in cohort 1, patients in the DET‐S subgroup were significantly less persistent with treatment, more likely to use a rapid‐acting insulin analogue, had higher HbA1c values, lower HbA1c reductions and lower proportions of patients achieving HbA1c <7.0 or <8.0% compared with patients in the GLA‐C subgroup, while hypoglycaemia rates and BMI/weight values and change from baseline were similar in the two subgroups. In cohort 2, overall, there were contrasting findings between patients in the GLA‐S and those in the DET‐C subgroup.

Conclusions

This study showed contrasting results when patients with T2DM switched between basal insulin analogues, although these preliminary results may be subject to limitations in the analysis. Nevertheless, this study calls into question the therapeutic interchangeability of GLA and DET, and this merits further investigation.
Fibroblast growth factor 21 analogue LY2405319 lowers blood glucose in streptozotocin‐induced insulin‐deficient diabetic mice by restoring brown adipose tissue function
Authors: Kim J.‐H. , Bae K.‐H. , Choi Y.‐K. , Go Y. , Choe M. , Jeon Y.‐H. , Lee H.‐W. , Koo S.‐H. , Perfield J. W. , Harris R. A. , Lee I.‐K. , Park K.‐G.
Published: October 2014

Aim

To investigate the effects of LY2405319, an analogue of fibroblast growth factor 21 (FGF21), on glucose homeostasis in streptozotocin (STZ)‐induced insulin‐deficient mice (STZ mice).

Methods

Nine‐week‐old male C57BL/6J mice were administered a single intraperitoneal injection of STZ (150 mg/kg). One week later, after confirmation of hyperglycaemia, saline or LY2405319 (5 mg/kg) was injected subcutaneously daily for 4 weeks. Changes in glucose homeostasis, energy metabolism and brown adipose tissue (BAT) function were assessed.

Results

The STZ mice had elevated blood glucose and reduced plasma FGF21 levels, impaired glucose uptake in the BAT, and BAT mitochondria with absent or swollen cristae and fewer lipid vacuoles. LY2405319 significantly reduced blood glucose levels and this was associated with increased BAT glucose uptake and changes in gene expression and morphology, indicating improved mitochondrial lipid metabolism in the BAT. Importantly, the ability of LY2405319 to lower blood glucose in STZ mice was compromised after removing interscapular BAT.

Conclusions

Our results show that LY2405319 reduces blood glucose levels in insulin‐deficient diabetes by improving BAT metabolism. Additional studies investigating the therapeutic potential of FGF21 for the treatment of type 1 diabetes are warranted.
Platinum and high‐dose cytarabine‐based regimens are efficient in ultra high/high‐risk chronic lymphocytic leukemia and Richter's syndrome: results of a French retrospective multicenter study
Authors: Durot Eric , Michallet Anne‐Sophie , Leprêtre Stéphane , Le Quoc‐Hung , Leblond Véronique , Delmer Alain
Published: October 2014

Ultra high‐risk chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS) usually display a poor prognosis. Platinum and cytarabine‐based regimens have not been evaluated in large cohorts of patients with CLL or RS. This retrospective study was aimed to assess the efficacy of these regimens in 75 patients with relapsed/refractory (R/R) CLL or RS. Forty‐seven patients had R/R CLL (including 36 ultra high‐risk CLL) and 28 had RS. Median age was 62 years (range, 18–79 years). Median number of previous therapies was 3 (range, 1–7), including fludarabine‐based regimens (75%) and alemtuzumab (32%), and 61% of patients were refractory to their last treatment. Deletions of chromosomes 17p and 11q were found in 40% and 39% of cases, respectively. The overall response rates were 60% with 24% complete response (CR) in CLL, and 43% with 25% CR in RS. The median progression‐free survival and overall survival were 11 and 14.6 months, respectively. Fludarabine refractoriness and 17p deletion were not associated with a poorer outcome. The only factors predicting shorter survival were performance status ≥2 (P = 0.04) and albumin level <3.5 g/dL (P = 0.0004). Toxicities were mainly myelosuppression and infectious complications. Platinum and high‐dose cytarabine‐based regimens provide high response rates in high‐risk CLL and in RS. However, these results will be challenged by the new arriving agents at least in non‐transformed CLL.
Evidence for a role of corrective eye movements during gaze fixation in saccade planning
Authors: Pérez Zapata Laura , Solé Puig María , Aznar‐Casanova Jose Antonio , Supèr Hans
Published: October 2014

In a three‐dimensional (3D) world most saccades are made towards visual targets that are located at different distances. We previously demonstrated that gaze shifts within 3D space consist of two stages: a target saccade followed by a corrective saccade during gaze fixation that directs the eyes to the physical target location. We proposed that, by accurately positioning the eyes on the visual object, the visual system maintains an orderly representation of the visual world. In this study we used a double saccade experiment to assess the function of corrective saccades in humans. We found that, when a corrective eye movement occurred during fixation on the first target point, the direction of the second saccade towards the next target point was accurate. When a corrective saccade was absent, a directional error of the second target saccade was observed. This finding, which cannot be explained by current models of eye movement control, supports the idea of a two‐step model in saccade programming. We suggest that the motor system sends a corollary discharge when programming a corrective saccade for maintaining an orderly representation of the visual world. In conclusion, our results indicate that corrective saccades have a role in programming target saccades within 3D space.
Historians as rooted cosmopolitans: their potentials and limitations
Authors: SAITO HIRO
Published: October 2014

In the 1990s, the so‐called ‘history problem’ began to escalate in East Asia as the result of mutually reinforcing nationalist commemorations in Japan, South Korea and China. In response, historians from the three countries organized joint historical research and textbook projects. In this article, I examine the extent to which these joint projects succeeded in promoting the cosmopolitan logic of historiography that challenged nationalist commemorations. Specifically, I compare governmental and non‐governmental projects and illustrate structural and dispositional mechanisms that facilitated the cosmopolitan logic of historiography. However, at the same time, I show that the joint projects have had only a limited impact on official and public commemorations because of the absence of any formal institutional links between historians' activities, governments and the public. Thus, while historians have the potential to act as rooted cosmopolitans and to mobilize transnational epistemic networks in East Asia, they have been unable effectively to counteract nationalist commemorations.
Raising cosmopolitans: localized educational strategies of international families in Shanghai
Authors: FARRER JAMES , GREENSPAN ANNA
Published: October 2014

This qualitative research documents the educational strategies of international migrants to Shanghai who are attempting to raise their children as cosmopolitans through immersion in local Chinese schools. We distinguish this localizing educational strategy from the established network of international schools designed to serve the families of corporate expatriates. Instead, our research subjects consist of self‐initiated expatriates, or ‘middling transnationals’, who have chosen to prioritize immersion in the language and culture of China by sending their children to local schools. This localized, or Sinocentric, model exposes non‐Chinese children to a challenging and nationalistic Chinese curriculum. Our analysis of these practices as a form of cosmopolitan education challenges both the goal of teaching a universal and placeless ethical cosmopolitanism and the assumption that a meaningful cosmopolitan education must take place in the idealized setting of a liberal cosmopolitan school system. We also highlight the difficulties families face in this approach, describing this as an ‘entangled cosmopolitanism’, an enriching but uncomfortable engagement with both local and home‐country educational cultures.
Effect of BioAggregate on osteoclast differentiation and inflammatory bone resorption in vivo
Authors: Zhang J. , Zhu L. , Peng B.
Published: October 2014

Aim

To investigate the effect of BioAggregate (Innovative Bioceramix, Vancouver, BC, Canada) on lipopolysaccharide (LPS)‐induced bone destruction in vivo and to compare its performance with that of mineral trioxide aggregate (MTA; Dentsply Tulsa Dental, Tulsa, OK, USA).

Methodology

Mouse bone marrow macrophages (BMMs) were primary cultured and treated with several concentrations of BioAggregate and MTA extracts. Cell viability was measured with a Cell Counting Kit‐8 assay, whilst in vitro osteoclast differentiation was evaluated with tartrate‐resistant acid phosphatase (TRAP) staining. LPS‐induced mouse calvarial bone destruction model was established to assess the effect of BioAggregate and MTA extracts in vivo. Mice were killed on day 7, and calvarial bones were prepared for microcomputed tomography scanning, histologic analysis and double‐immunofluorescence staining. Statistical tests used were one‐way anova followed by Student–Newman–Keuls test.

Results

BioAggregate extracts displayed no obvious cytotoxicity to BMMs and significantly inhibited (P < 0.01) the differentiation of RANKL‐stimulated BMMs. Comparable effects were induced by MTA. BioAggregate and MTA extracts markedly reduced (P < 0.01) osteoclast numbers and attenuated (P < 0.05) bone resorption in LPS‐challenged mouse calvaria. The expression levels of osteoclastogenic cathepsin K and its upstream regulator nuclear factor of activated T‐cell cytoplasmic 1 and c‐Fos were also decreased by BioAggregate and MTA extracts.

Conclusions

BioAggregate and MTA showed comparable inhibitory effect on osteoclast differentiation and inflammatory bone resorption in vivo.
Curing Behavior and Structure of Magnesium Phosphate Chemically Bonded Ceramics with Different MgO to KH2PO4 Ratios
Authors: Wang Ai‐juan , Fan Xiao‐jie , Li Jun‐ming , Chen Ding
Published: October 2014

Magnesium phosphate chemically bonded ceramics attracted much attention because of its good biocompatibility. In this work, curing behavior and microstructure of magnesium phosphate chemically bonded ceramics with different MgO to KH2PO4 ratios were investigated. The results showed that the setting time decreased and the maximum temperature during the solidifying process increased as the increase of MgO to KH2PO4 ratio. Phase compositions were different for those samples fabricated with different MgO to KH2PO4 ratios. KH2PO4, MgO, and hydrated product existed in the sample with lower MgO to KH2PO4 ratio because of the incomplete reaction, and numerous acicular polycrystals were found. There were only MgO and hydrated product existed with the higher MgO to KH2PO4 ratio. Besides, a gelatinous structure with lots of cracks was also found. Clearly, the properties of magnesium potassium phosphate chemically bonded ceramics could be controlled by changing the MgO to KH2PO4 ratio. It is better to fabricate magnesium phosphate chemically bonded ceramics with optimal structure and properties suitable for biomedical applications in range of MgO to KH2PO4 ratio from 3:1 to 4:1 in this preparating conditions.
Pro‐ and anti‐inflammatory cytokine gene single‐nucleotide polymorphisms in inflammatory bowel disease
Authors: López‐Hernández R. , Valdés M. , Campillo J. A. , Martínez‐García P. , Salama H. , Bolarin J. M. , Martínez H. , Moya‐Quiles M. R. , Minguela A. , Sánchez‐Torres A. , Botella C. , Salgado G. , Miras M. , Carballo F. , Muro M.
Published: October 2014

Anti‐inflammatory cytokines have an important role in disease, tumour and transplant processes. Alterations in the regulation of several cytokines have been implicated in a variety of inflammatory disorders, including IBD (inflammatory bowel disease) [Crohn′s disease (CD) and ulcerative colitis (UC)]. Cytokine polymorphisms are also known to affect the level of gene expression. Thus, the aim of this study was to determine the relationship between cytokine polymorphisms and the IBD pathologies in a Spanish population. Polymorphisms analysis was performed using PCR‐SSOP using a microbeads luminex assay. The following polymorphisms were determined: TNFα [−238G/A (rs361525) and −308G/A (rs1800629)], IFNγ [+874A/T (rs62559044)], TGFβ [+869C/T (rs1982073) and +915G/C (rs1800471)], IL10 [−1082A/A (rs1800896), −592A/C (rs1800872), −819C/T (rs1800871)], IL6 [−174C/G (rs1800795)], IL12p40 [3′UTR −1188A/C (rs3212227)], IL1α [−889C/T (rs1800587)], IL1β [−511C/T (rs1143634) and +3962C/T (rs1143633)], IL1R [Pst‐1 1970C/T] and IL1RA [Mspa‐1 11100C/T]. No statistical differences in TNFα, IFNγ, TGFβ, IL10, IL6, IL1α, IL1β, IL1R and IL1Ra genotypes and allele distributions between the IBD groups and healthy controls were found. However, we observed significant differences in the 3′UTR −1188A/C polymorphism of IL12p40. So −1188A allele was increased in patients with UC and the −1188C allele (high IL12p40 production) was increased in patients with CD with respect to controls. These data are in concordance with the fact that CD has been shown to be associated with a Th1 T‐cell‐mediated inflammation model and high IL12/IFNγ production at histological affected sites. These data suggest that cytokine polymorphisms in TNFα, IFNγ, TGFβ, IL10, IL6 and IL1α, IL1β, IL1R and IL1Ra cytokine gene do not seem to be relevant in IBD susceptibility and IL12p40 3′UTR −1188A/C polymorphism seems to be associated with a differential IBD development.
Effectiveness of Performance Appraisal: An Integrated Framework
Authors: Iqbal Muhammad Zahid , Akbar Saeed , Budhwar Pawan
Published: October 2014

Based on a robust analysis of the existing literature on performance appraisal (PA), this paper makes a case for an integrated framework of effectiveness of performance appraisal (EPA). To achieve this, it draws on the expanded view of measurement criteria of EPA, i.e. purposefulness, fairness and accuracy, and identifies their relationships with ratee reactions. The analysis reveals that the expanded view of purposefulness includes more theoretical anchors for the purposes of PA and relates to various aspects of human resource functions, e.g. feedback and goal orientation. The expansion in the PA fairness criterion suggests certain newly established nomological networks, which were ignored in the past, e.g. the relationship between distributive fairness and organization‐referenced outcomes. Further, refinements in PA accuracy reveal a more comprehensive categorization of rating biases. Coherence among measurement criteria has resulted in a ratee reactions‐based integrated framework, which should be useful for both researchers and practitioners.