bluuebunny/crossref_metadata_2025 huggingface dataset:
Auditor Face‐Work at the Annual General Meeting
Authors: Johed Gustav , Catasús Bino
Published: December 2017

This paper examines how auditors prepare for the annual general meeting (AGM) and how they report their work to the shareholders there. Prior literature has suggested—but not explicitly studied—that the endpoint of an audit is a state of comfort between the auditor and the management and audit committee members, but also is potentially fragile. The fragility can arise from a failure to relay trust to the investor community, which may initiate or increase doubts about the financial report and/or the auditor's independence. We build the case that an AGM is an event to study how the endpoint of an audit engagement is both a state of collective comfort and a fragile state. The analysis is based on ten interviews and three workshops with auditors as well as observations at 67 AGMs. To analyze the field material, the paper draws on Goffman's idea of face‐work, which requires backstage preparations, notably with management, and a front stage performance as an independent auditor to relay trust to the shareholders. The paper details how auditors at the AGM perform as independent verifiers of the management's financial report. Although we recorded that auditors were typically successful in preventing the backstage activities from becoming visible to the shareholders, we found incidents that challenged both the auditors' and the managements' face. In analyzing these incidents, we found that auditors reinforced their image as independent to regain both their own face and the management's face. The management did not take a similar collective responsibility for the auditor's face, which implies that auditors were asymmetrically committed to the management. As a take‐away, the paper discusses how governance mechanisms backstage are linked and can surface front stage at the AGM.
Clinical Examination for Acute Aortic Dissection: A Systematic Review and Meta‐analysis
Authors: Ohle Robert , Kareemi Hashim Khaliq , Wells George , Perry Jeffrey J.
Published: December 2017

Objectives

Acute aortic dissection is a life‐threatening condition due to a tear in the aortic wall. It is difficult to diagnose and if missed carries a significant mortality.

Methods

We conducted a librarian‐assisted systematic review of PubMed, MEDLINE, Embase, and the Cochrane database from 1968 to July 2016. Titles and abstracts were reviewed and data were extracted by two independent reviewers (agreement measured by kappa). Studies were combined if low clinical and statistical heterogeneity (I2 < 30%). Study quality was assessed using the QUADAS‐2 tool. Bivariate random effects meta analyses using Revman 5 and SAS 9.3 were performed.

Results

We identified 792 records: 60 were selected for full text review, nine studies with 2,400 participants were included (QUADAS‐2 low risk of bias, κ = 0.89 [for full‐text review]). Prevalence of aortic dissection ranged from 21.9% to 76.1% (mean ± SD = 39.1% ± 17.1%). The clinical findings increasing probability of aortic dissection were 1) neurologic deficit (n = 3, specificity = 95%, positive likelihood ratio [LR+] = 4.4, 95% confidence interval [CI] = 3.3–5.7, I2 = 0%) and 2) hypotension (n = 4, specificity = 95%, LR+ = 2.9 95% CI = 1.8–4.6, I2 = 42%), and decreasing probability were the absence of a widened mediastinum (n = 4, sensitivity = 76%‐95%, negative likelihood ratio [LR–] = 0.14–0.60, I2 = 93%) and an American Heart Association aortic dissection detection (AHA ADD) risk score < 1 (n = 1, sensitivity = 91%, LR– = 0.22, 95% CI = 0.15–0.33).

Conclusions

Suspicion for acute aortic dissection should be raised with hypotension, pulse, or neurologic deficit. Conversely, a low AHA ADD score decreases suspicion. Clinical gestalt informed by high‐ and low‐risk features together with an absence of an alternative diagnosis should drive investigation for acute aortic dissection.
Low levels of anti‐secretory factor in placenta are associated with preterm birth and inflammation
Authors: Gustafsson Anna M. , Fransson Emma , Dubicke Aurelija , Hjelmstedt Anna K. , Ekman‐Ordeberg Gunvor , Silfverdal Sven‐Arne , Lange Stefan , Jennische Eva , Bohlin Kajsa
Published: December 2017

Introduction

Anti‐secretory factor is a protein that regulates secretory and inflammatory processes and preterm birth is associated with inflammation. Therefore, our hypothesis was that anti‐secretory factor might play a role in immune reactivity and homeostasis during pregnancy.

Material and methods

Following spontaneous onset of labor and preterm or term delivery, placenta biopsies were collected. The levels of anti‐secretory factor and markers of inflammation (CD68, CD163) and vascularization (CD34, smooth muscle actin) were analyzed by immunohistochemistry.

Results

The 61 placental biopsies included 31 preterm (<37 weeks of gestation) and 30 term (37–41 weeks) samples. The preterm placentas exhibited lower levels of anti‐secretory factor (p = 0.008) and larger numbers of CD68‐positive cells (p < 0.001) compared to term. Preterm placentas had blood vessel of smaller diameter (p = 0.036) indicative of immaturity. The level of interleukin‐6 in cord blood was higher after very preterm than term birth, suggesting a fetal inflammatory response. The placenta level of anti‐secretory factor was positively correlated to the length of gestation (p = 0.025) and negatively correlated to the levels of the inflammatory markers CD68 (p = 0.015) and CD163 (p = 0.028).

Conclusions

Preterm delivery is associated with low levels of anti‐secretory factor in placenta. Inflammation, a potential trigger of preterm birth, is more pronounced in the preterm placenta and inversely related to the placental level of anti‐secretory factor, suggesting both a link and a potential target for intervention.
Effects of complex probiotic supplementation in growing pig diets with and without palm kernel expellers on growth performance, nutrient digestibility, blood parameters, fecal microbial shedding and noxious gas emission
Authors: Liu Wenchao , Devi Subramaniammohana , Park Jaewon , Kim Inho
Published: December 2017

In Experiment 1, a total of 100 growing pigs (Duroc × [Landrace × Yorkshire]) with an average initial body weight (BW) of 24.88 ± 1.57 kg were randomly allotted to 2 × 2 factorial arrangement with two concentrations of palm kernel expellers (PKE) in diets at 0% or 10%, and two concentrations of supplemental probiotics at 0 or 6.0 × 107 colony‐forming units/kg. There were five replicate pens per treatment with five pigs per pen. In Experiment 2, eight barrows with average initial BW of 25.78 ± 0.19 kg were allotted to a replicated 4 × 4 Latin square design with four diets and four periods per square. Four experimental diets were the same as Experiment 1. In Experiment 1, dietary probiotic supplementation improved (P < 0.05) the average daily gain (ADG), nutrient digestibility and the fecal Lactobacillus counts. Furthermore, interactive effects (P < 0.05) between PKE and probiotics were observed on ADG and growth‐to‐feed ratio. In Experiment 2, an interactive effect (P < 0.05) of PKE and probiotics was observed in apparent ileal digestibility of nitrogen and some amino acids. In conclusion, dietary probiotics did not improve PKE utilization and the use of probiotics in non‐PKE‐containing diet was more favorable than in PKE‐containing diet.
Nilotinib after imatinib first‐line: a real‐life longitudinal cohort of patients with chronic myeloid leukaemia in chronic phase
Authors: Cony‐Makhoul Pascale , Gardembas Martine , Coiteux Valérie , Carpentier Nathalie , Pommier Cécile , Violet Isabelle , Quittet Philippe , Berger Marc G. ,   TARGET‐RMC Investigators
Published: December 2017

This prospective, observational study enrolled 150 adult patients with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with nilotinib as second‐line after imatinib, in a real life setting in France. Two‐thirds of patients switched to nilotinib treatment due to lack of imatinib efficacy. Of 146 evaluable patients, 16 (11·0%) (95% confidence interval: 6·4–17·2%) achieved uMR4, defined as undetectable molecular disease in cDNA with MR4 sensitivity (≥10 000 ABL1 transcripts) at 18 months and confirmed at 24 months (primary endpoint). Among patients without major molecular response (MMR) or deep molecular response (DMR) at study entry, 66·3% achieved MMR and 44·2% DMR within a median of 5·7 and 6·24 months, respectively. Fifty‐three patients (36·3%) have prematurely terminated the study before 24 months of follow‐up, primarily due to nilotinib treatment discontinuation (n = 43; 29·5%), mainly motivated by treatment intolerance (n = 27; 18·5%) and inefficacy (n = 10; 6·8%). The most frequent extra‐haematological adverse events (AEs) reported as related to treatment with nilotinib were pruritus (16·4%), asthenia (13·7%) and dry skin (13·0%). Ischaemic cardiovascular AEs were reported in 18 patients (12·3%). This French nationwide large cohort adds valuable information to the body of evidence on the efficiency and safety of nilotinib in the treatment of patients with CP‐CML.
Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki
Authors: Horai Makiko , Satoh Shinya , Matsuo Masatoshi , Iwanaga Masako , Horio Kensuke , Jo Tatsuro , Takasaki Yumi , Kawaguchi Yasuhisa , Tsushima Hideki , Yoshida Shinichiro , Taguchi Masataka , Itonaga Hidehiro , Sawayama Yasushi , Taguchi Jun , Imaizumi Yoshitaka , Hata Tomoko , Moriuchi Yukiyoshi , Haase Detlef , Yoshiura Koh‐Ichiro , Miyazaki Yasushi
Published: December 2017

The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (<1·5 km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy‐related MDS. Detailed molecular study is warranted.
Haemostasis and innate immunity – a complementary relationship
Authors: Keragala Charithani B. , Draxler Dominik F. , McQuilten Zoe K. , Medcalf Robert L.
Published: December 2017

Coagulation and innate immunity are linked evolutionary processes that orchestrate the host defence against invading pathogens and injury. The complement system is integral to innate immunity and shares numerous interactions with components of the haemostatic pathway, helping to maintain physiological equilibrium. The term ‘immunothrombosis’ was introduced in 2013 to embrace this process, and has become an area of much recent interest. What is less apparent in the literature however is an appreciation of the clinical manifestations of the coagulation‐complement interaction and the consequences of dysregulation of either system, as seen in many inflammatory and thrombotic disease states, such as sepsis, trauma, atherosclerosis, antiphospholipid syndrome (APS), paroxysmal nocturnal haemoglobinuria (PNH) and some thrombotic microangiopathies to name a few. The growing appreciation of this immunothrombotic phenomenon will foster the drive for novel therapies in these disease states, including anticoagulants as immunomodulators and targeted molecular therapies.
Impact of Contact With Grandparents on Children's and Adolescents’ Views on the Elderly
Authors: Flamion Allison , Missotten Pierre , Marquet Manon , Adam Stéphane
Published: December 2017

Stereotypes, prejudice, and discrimination against the elderly (ageism) may manifest themselves in children at an early age. However, the factors influencing this phenomenon are not well known. Using both explicit and open‐ended questions, this study analyzed the influence of personal and familial parameters on the views of 1,151 seven‐ to sixteen‐year‐old Belgian children and adolescents on the elderly. Four factors were found to affect these views: gender (girls had slightly more positive views than boys), age (ageism was lowest in 10‐ to 12‐year‐old, reminiscent of other forms of stereotypes and cognitive developmental theories), grandparents’ health, and most importantly, quality of contact with grandparents (very good and good contacts correlated with more favorable feelings toward the elderly, especially in children with frequent contacts).
Christiansen filter effect with undyed cellulose triacetate fabric as a scattering agent
Authors: Annis Patricia Anne , Campbell Jacqueline Heather , Knopp James Arthur , King Allen Dupree
Published: December 2017

Light transmission through multiple sheets of undyed cellulose triacetate fabric immersed in binary solutions of carbon disulfide and n‐heptane has been measured using ordinary absorption spectroscopy. The optical transmission of light in the visible spectral range is found to be very high at wavelengths corresponding to a match between the index of refraction of cellulose triacetate and that of the surrounding solution. This phenomenon is commonly referred to as the Christiansen colour filter effect. Indices of refraction of cellulose triacetate from 400 to 700 nm were derived from these data.
Lymphocytes in Sweet syndrome: A potential diagnostic pitfall
Authors: Kazlouskaya Viktoryia , Junkins‐Hopkins Jacqueline M.
Published: December 2017

Background

Patients with Sweet syndrome (SS) have acute onset of cutaneous lesions with characteristic histopathology (dense and diffuse neutrophilic infiltrate, dermal edema, leukocytoclasis and no vasculitis) accompanied by systemic symptoms. Sometimes, only skin lesions with classic histopathologic features are seen. Although SS is considered to be a “neutrophilic dermatosis,” lymphocytes are also seen on histological examination.

Methods

We evaluated the cellular infiltrate in 9 biopsies from SS lesions with routine staining and immunohistochemistry.

Results

Lymphocytes were present in all biopsies in variable amounts, often exceeding the number of intact neutrophils. Prominent fragmentation of neutrophils rendered some biopsies “lymphocyte‐rich” on routine histologic evaluation. Myeloperoxidase was helpful in highlighting the inconspicuous neutrophilic fragments in these cases. Lymphocytes were highlighted with immunohistochemistry, and had a CD3+, CD4+, CD20(−) immunophenotype, with rare CD8+ lymphocytes.

Conclusion

Awareness of the lymphocytic component of SS is important to avoid diagnostic errors, especially in subcutaneous lesions of SS, in which the lymphocytic infiltrate predominates in the upper parts of the dermis, while the typical neutrophilic infiltrate may be seen only in the deeper dermis and subcutis. The lymphocytic component may potentially help to differentiate lesions of SS from neutrophilic urticarial dermatosis, which has not been reported to contain a significant lymphocytic population.
Limited dispersal prevents Quercus rubra invasion in a 14‐species common garden experiment
Authors: Jagodziński Andrzej M. , Dyderski Marcin K. , Horodecki Paweł , Rawlik Katarzyna
Published: December 2017

Aim

Information about the importance of propagule pressure and habitat invasibility in invasion success of dispersal‐limited species is scarce. We aimed to assess invasiveness of Quercus rubra within stands of 14 tree species, and the effects of distance from propagule source on invasion success, to highlight limiting factors for further application in nature conservation.

Location

Siemianice Experimental Forest—a common garden forest experiment with 14 tree species, western Poland.

Methods

We investigated aboveground biomass, leaf area index and density of Q. rubra natural regeneration within 53 experimental plots, as well as distance from the seed source. We also analysed light availability changes between 2005 and 2015 on plots of each tree species. We used multiple linear regression and variable importance to quantify the effect of each factor.

Results

All factors tested influenced ecological success of Q. rubra. Invasion success decreased with increasing distance from the seed source and decreasing light availability and was higher within stands of pioneer tree species. Leaf area index depended mostly on tree stand species, density depended on distance from the propagule source and biomass depended on both. Light availability explained 7.2%–30.2% of the variance; tree species—from 36.1% to 57.4%; and distance from the propagule source—from 12.4% to 56.7%.

Main conclusions

Tree stand species, light availability and distance from the propagule source influence ecological success of invasive Q. rubra, displaying their importance for spread of this species. These factors are controllable in forest/conservation management and may be used to prevent Q. rubra invasion. Planting late‐successional tree species that cast dense shade, maintaining canopy closure and removing fruiting trees from surrounding more invasible stands may prevent Q. rubra invasion.
Functional neurochemical imaging of the human striatal cholinergic system during reversal learning
Authors: Bell Tiffany , Lindner Michael , Mullins Paul Gerald , Christakou Anastasia
Published: December 2017

Animal studies have shown that acetylcholine (ACh) levels in the dorsal striatum play a role in reversal learning. However, this has not been studied in humans due to a lack of appropriate non‐invasive techniques. Proton magnetic resonance spectroscopy (1H‐MRS) can be used to measure metabolite levels in humans in vivo. Although it cannot be used to study ACh directly, 1H‐MRS can be used to study choline, an ACh precursor, which is linked to activity‐dependent ACh release. The aim of this study was to use functional‐1H‐MRS (fMRS) to measure changes in choline levels in the human dorsal striatum during performance of a probabilistic reversal learning task. We demonstrate a task‐dependent decrease in choline, specifically during reversal, but not initial, learning. We interpret this to reflect a sustained increase in ACh levels, which is in line with findings from the animal literature. This task‐dependent change was specific to choline and was not observed in control metabolites. These findings provide support for the use of fMRS in the in vivo study of the human cholinergic system.
Survey on basal blood plasma catecholamine concentrations in Martina Franca donkey (Equus asinus)
Authors: De Palo P. , Maggiolino A. , Ceci E. , Calzaretti G. , Centoducati P. , Tateo A.
Published: December 2017

Background

Catecholamines are among the most frequently investigated parameters for studying sympathoadrenal activity in response to stress conditions.

Objectives

To evaluate basal plasma concentrations of catecholamines (adrenaline, noradrenaline and dopamine) in healthy donkeys.

Study design

Cross‐sectional study.

Methods

Catecholamine concentrations from 440 Martina Franca donkeys were determined: 269 females and 171 entire males, aged from 4 months to 24 years. Animals were subdivided into four age categories: under 12 months old (64 males and 54 females), from 13 to 36 months (56 males and 75 females), from 37 to 120 months (49 males and 80 females) and over 120 months (24 males and 38 females). Indwelling jugular catheters were inserted at least 12 h before drawing blood. The data set was subjected to analysis of variance considering age, sex and the two‐way interaction between them as independent variables. Pearson's correlation coefficients between the three catecholamines were evaluated.

Results

Confidence intervals (CI) for noradrenaline concentration ranged between 239.98 and 255.07 ng/L (mean 247.52 ng/L), for adrenaline between 129.27 and 137.90 ng/L (mean 133.59 ng/L), dopamine concentrations between 149.62 and 160.80 ng/L (mean 155.21 ng/L) and noradrenaline/adrenaline ratio between 1.91 and 2.05 (mean 1.98). Catecholamine plasma concentrations were not influenced by sex. Donkeys older than 37 months had lower adrenaline and noradrenaline plasma concentrations (P<0.001) and higher noradrenaline/adrenaline ratios (P<0.01) than younger animals.

Main limitations

Indwelling catheters and blood drawing procedures may have influenced catecholamine levels.

Conclusions

Catecholamine concentrations were established within a large group of healthy Martina Franca donkeys.
Synthesis and characterization of ferrimagnetic glass‐ceramic frit from waste
Authors: González‐Triviño Isabel , Benítez‐Guerrero Mónica , Carda Castelló Juan , Moreno Belén , Pascual‐Cosp José
Published: December 2017

The large amount of generated waste determines the importance of their valorization. Red mud is the residue of the Bayer process, which stored cumulative value raises 2.7 Bt. This paper describes an easy way to produce a ferrimagnetic glass‐ceramic frit, using bauxite residue, fly ash and glass cullet as raw materials. The synthesized frit consists of faceted and dendritic agglomerated crystals of magnetite and titanomagnetite embedded in a glass matrix, which exhibits a saturation magnetization (MS) of 6.3 emu/g, a remanent magnetization (MR) of 2.7 emu/g and a coercive field (HC) of 347 Oe. Furthermore, it presents Vickers hardness value of HV = 5.55 ± 0.16 GPa and fracture toughness value of KIC = 1.64 ± 0.34 MPa·m1/2.
A novel homozygous mutation in PVRL4 causes ectodermal dysplasia‐syndactyly syndrome 1
Authors: Florian Rupert , Gruber Robert , Volc‐Platzer Beatrix
Published: December 2017

Ectodermal dysplasias (EDs) are a group of hereditary disorders defined by alterations in two or more ectodermal structures. One recently described rare entity is the autosomal recessive inherited ectodermal dysplasia‐syndactyly syndrome 1 (EDSS1). Homozygous and compound heterozygous missense and nonsense mutations in the poliovirus receptor related‐4 (PVRL4) gene, encoding cell adhesion molecule nectin‐4, have been identified as causal for EDSS1. We here report a consanguineous family with a 2‐year‐old girl featuring EDSS1, including slowly progressive alopecia on the head, pili torti‐like twisted hairs in trichoscopy, widely spaced, peg‐shaped and conical teeth, proximal syndactyly with fusion of the 2nd to 4th toes, and generalized dry skin. There was no palmoplantar hyperkeratosis and sweating appeared normal to slightly enhanced, especially on the head. Using exome sequencing, we identified the novel homozygous nonsense mutation c.229C>T (p.Gln77Ter) in PVRL4.
Aerobic exercise training rescues protein quality control disruption on white skeletal muscle induced by chronic kidney disease in rats
Authors: De Moraes Wilson Max Almeida Monteiro , de Souza Pamella Ramona Moraes , da Paixão Nathalie Alves , de Sousa Luís Gustavo Oliveira , Ribeiro Daniel Araki , Marshall Andrea G. , Prestes Jonato , Irigoyen Maria Claudia , Brum Patricia Chakur , Medeiros Alessandra
Published: December 2017

We tested whether aerobic exercise training (AET) would modulate the skeletal muscle protein quality control (PQC) in a model of chronic kidney disease (CKD) in rats. Adult Wistar rats were evaluated in four groups: control (CS) or trained (CE), and 5/6 nephrectomy sedentary (5/6NxS) or trained (5/6NxE). Exercised rats were submitted to treadmill exercise (60 min., five times/wk for 2 months). We evaluated motor performance (tolerance to exercise on the treadmill and rotarod), cross‐sectional area (CSA), gene and protein levels related to the unfolded protein response (UPR), protein synthesis/survive and apoptosis signalling, accumulated misfolded proteins, chymotrypsin‐like proteasome activity (UPS activity), redox balance and heat‐shock protein (HSP) levels in the tibialis anterior. 5/6NxS presented a trend towards to atrophy, with a reduction in motor performance, down‐regulation of protein synthesis and up‐regulation of apoptosis signalling; increases in UPS activity, misfolded proteins, GRP78, derlin, HSP27 and HSP70 protein levels, ATF4 and GRP78 genes; and increase in oxidative damage compared to CS group. In 5/6NxE, we observed a restoration in exercise tolerance, accumulated misfolded proteins, UPS activity, protein synthesis/apoptosis signalling, derlin, HSPs protein levels as well as increase in ATF4, GRP78 genes and ATF6α protein levels accompanied by a decrease in oxidative damage and increased catalase and glutathione peroxidase activities. The results suggest a disruption of PQC in white muscle fibres of CKD rats previous to the atrophy. AET can rescue this disruption for the UPR, prevent accumulated misfolded proteins and reduce oxidative damage, HSPs protein levels and exercise tolerance.
Neuregulin‐1 is essential for nerve plexus formation during cardiac maturation
Authors: Brown Daniel , Samsa Leigh Ann , Ito Cade , Ma Hong , Batres Karla , Arnaout Rima , Qian Li , Liu Jiandong
Published: December 2017

The Neuregulin‐1 (Nrg1)/ErbB pathway plays multiple, critical roles in early cardiac and nervous system development and has been implicated in both heart and nerve repair processes. However, the early embryonic lethality of mouse Nrg1 mutants precludes an analysis of Nrg1's function in later cardiac development and homeostasis. In this study, we generated a novel nrg1 null allele targeting all known isoforms of nrg1 in zebrafish and examined cardiac structural and functional parameters throughout development. We found that zebrafish nrg1 mutants instead survived until young adult stages when they exhibited reduced survivorship. This coincided with structural and functional defects in the developing juvenile and young adult hearts, as demonstrated by reduced intracardiac myocardial density, cardiomyocyte cell number, swimming performance and dysregulated heartbeat. Interestingly, nrg1 mutant hearts were missing long axons on the ventricle surface by standard length (SL) 5 mm, which preceded juvenile and adult cardiac defects. Given that the autonomic nervous system normally exerts fine control of cardiac output through this nerve plexus, these data suggest that Nrg1 may play a critical role in establishing the cardiac nerve plexus such that inadequate innervation leads to deficits in cardiac maturation, function and survival.
TPPU enhanced exercise‐induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction
Authors: Guo Yuan , Luo Fei , Zhang Xv , Chen Jingyuan , Shen Li , Zhu Yi , Xu Danyan
Published: December 2017

Exercise training (ET) is a safe and efficacious therapeutic approach for myocardial infarction (MI). Given the numerous benefits of exercise, exercise‐induced mediators may be promising treatment targets for MI. C57BL/6 mice were fed 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidine‐4‐yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHI), to increase epoxyeicosatrienoic acid (EET) levels, for 1 week before undergoing MI surgery. After 1‐week recovery, the mice followed a prescribed exercise programme. Bone marrow‐derived endothelial progenitor cells (EPCs) were isolated from the mice after 4 weeks of exercise and cultured for 7 days. Angiogenesis around the ischaemic area, EPC functions, and the expression of microRNA‐126 (miR‐126) and its target gene Spred1 were measured. The results were confirmed in vitro by adding TPPU to EPC culture medium. ET significantly increased serum EET levels and promoted angiogenesis after MI. TPPU enhanced the effects of ET to reduce the infarct area and improve cardiac function after MI. ET increased EPC function and miR‐126 expression, which were further enhanced by TPPU, while Spred1 expression was significantly down‐regulated. Additionally, the protein kinase B/glycogen synthase kinase 3β (AKT/GSK3β) signalling pathway was activated after the administration of TPPU. EETs are a potential mediator of exercise‐induced cardioprotection in mice after MI. TPPU enhances exercise‐induced cardiac recovery in mice after MI by increasing EET levels and promoting angiogenesis around the ischaemic area.
TAT‐MTS‐MCM fusion proteins reduce MMA levels and improve mitochondrial activity and liver function in MCM‐deficient cells
Authors: Erlich‐Hadad Tal , Hadad Rita , Feldman Anat , Greif Hagar , Lictenstein Michal , Lorberboum‐Galski Haya
Published: December 2017

Methylmalonic aciduria (MMA) is a disorder of organic acid metabolism resulting from a functional defect of the mitochondrial enzyme, methylmalonyl‐CoA mutase (MCM). The main treatments for MMA patients are dietary restriction of propiogenic amino acids and carnitine supplementation. Liver or combined liver/kidney transplantation has been used to treat those with the most severe clinical manifestations. Thus, therapies are necessary to help improve quality of life and prevent liver, renal and neurological complications. Previously, we successfully used the TAT‐MTS‐Protein approach for replacing a number of mitochondrial‐mutated proteins. In this targeted system, TAT, an 11 a.a peptide, which rapidly and efficiently can cross biological membranes, is fused to a mitochondrial targeting sequence (MTS), followed by the mitochondrial mature protein which sends the protein into the mitochondria. In the mitochondria, the TAT‐MTS is cleaved off and the native protein integrates into its natural complexes and is fully functional. In this study, we used heterologous MTSs of human, nuclear‐encoded mitochondrial proteins, to target the human MCM protein into the mitochondria. All fusion proteins reached the mitochondria and successfully underwent processing. Treatment of MMA patient fibroblasts with these fusion proteins restored mitochondrial activity such as ATP production, mitochondrial membrane potential and oxygen consumption, indicating the importance of mitochondrial function in this disease. Treatment with the fusion proteins enhanced cell viability and most importantly reduced MMA levels. Treatment also enhanced albumin and urea secretion in a CRISPR/Cas9‐engineered HepG2 MUT (‐/‐) liver cell line. Therefore, we suggest using this TAT‐MTS‐Protein approach for the treatment of MMA.
Outbreak of mass mortality of yearling groupers of Epinephelus (Perciformes, Serranidae) associated with the infection of a suspected new enteric Sphaerospora (Myxozoa: Myxosporea) species in South China Sea
Authors: Liu X H , Xu L W , Luo D , Zhao Y L , Zhang Q Q , Liu G F , Zhang J Y
Published: December 2017

A suspected new enteric Sphaerospora species was believed to be directly associated with the mass mortality of yearling groupers of Epinephelus spp. in South China. The epizootic generally emerged from late September to late April of the following year. The infection prevalence and mortality rate were significantly negatively correlated with fish size. Clinical signs included anorexia, cachexia and extrusion of white pulp‐like substance from anus after gentle pressure on the abdomen. Upon necropsy, severe intestinal oedema, thin and transparent intestinal wall, swollen spleen, kidney and gall bladder could be observed. Wet preparation of the infected samples showed large amount of typical disporous plasmodia of the genus Sphaerospora, but no mature spores were observed. Epidemiological investigation showed that this parasite exclusively infected Epinephelus groupers. Histopathologically, this species mainly infected the epithelium of intestine and kidney tubules and caused severe epithelia sloughing and the collapse of intestinal villus. Interestingly, this enteric myxosporidiosis did not cause severe emaciation of infected fish for mass mortality usually emerged within 2–3 days after appearance of clinical signs. The species was most genetically related to Sphaerospora fugu (89% sequence identity) and phylogenetically positioned within marine Sphaerospora lineage. This is the first report of enteric sphaerosporosis of groupers.
Purinergic signalling displays an anti‐inflammatory profile in the spleen of fish experimentally infected with Aeromonas caviae: Modulation of the immune response
Authors: Baldissera M D , Souza C F , Bottari N B , Verdi C M , Santos R C V , Vizzotto B S , Baldisserotto B
Published: December 2017

Extracellular adenosine triphosphate (ATP) and its metabolite adenosine (Ado) are recognized as key mediators of immune and inflammatory responses. Depending on its concentration, ATP may act as an immunostimulant or immunodepressant, while Ado levels display an anti‐inflammatory profile. The aim of this study was to evaluate whether splenic purinergic signalling is capable of modulating immune and inflammatory responses in fish experimentally infected with Aeromonas caviae. Triphosphate diphosphohydrolase (NTPDase) and 5′‐nucleotidase activities increased in the spleen of silver catfish (Rhamdia quelen) experimentally infected with A. caviae compared with the uninfected control group. Moreover, splenic Ado levels increased in the infected animals relative to the uninfected control group. Based on these lines of evidence, our findings revealed that adenine nucleotide hydrolysis is modified in the spleen of fish infected with A. caviae attempting to restrict the inflammatory process through the upregulation of NTPDase and 5′‐nucleotidase activities, which occurs in an attempt to hydrolyse the excessive ATP in the extracellular environment and rapidly hydrolyse AMP to form Ado. In summary, purinergic signalling can modulate immune and inflammatory responses during A. caviae infection.
Meta‐analysis of Interventions to Reduce Adverse Drug Reactions in Older Adults
Authors: Gray Shelly L. , Hart Laura A. , Perera Subashan , Semla Todd P. , Schmader Kenneth E. , Hanlon Joseph T.
Published: December 2017

Objectives

To examine the effect of interventions to optimize medication use on adverse drug reactions (ADRs) in older adults.

Design

Systematic review and meta‐analysis. EMBASE, PubMed, OVID, Cochrane Library, Clinicaltrials.gov, and Google Scholar were searched through April 30, 2017.

Setting

Randomized controlled trials.

Participants

Older adults (mean age ≥65) taking medications.

Measurements

Two authors independently extracted relevant information and assessed studies for risk of bias. Discrepancies were resolved in consensus meetings. The outcomes were any and serious ADRs. Random‐effects models were used to combine the results of multiple studies and create summary estimates.

Results

Thirteen randomized controlled trials involving 6,198 older adults were included. The studies employed a number of different interventions that were categorized as pharmacist‐led interventions (8 studies), other health professional‐led interventions (3 studies), a brief educational session (1 study), and a technology intervention (1 study). The intervention group was 21% less likely than the control group to experience any ADR (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.62–0.99). In the six studies that examined serious ADRs, the intervention group was 36% less likely than the control group to experience a serious ADR (OR = 0.64, 95% CI = 0.42–0.98).

Conclusion

Interventions designed to optimize medication use reduced the risk of any and serious ADRs in older adults. Implementation of these successful interventions in healthcare systems may improve medication safety in older adults.
Metamorphic evolution of a newly identified Mesoproterozoic oceanic slice in the Yuka terrane and its implications for a multi‐cyclic orogenic history of the North QaidamUHPMbelt
Authors: Ren Y. F. , Chen D. L. , Kelsey D. E. , Gong X. K. , Liu L. , Zhu X. H. , Yang S. J.
Published: December 2017

The North Qaidam Orogenic Belt (NQOB), lying at the northern margin of the Tibet Plateau, records two orogenic cycles: A Proterozoic cycle related to the amalgamation and breakup of the supercontinent Rodinia, and an Early Palaeozoic cycle including oceanic subduction and continental deep subduction. At present, the only information about the Proterozoic cycle is the concurrentc. 1,000–900 Ma magmatic and metamorphic events, which limited the understanding of the Proterozoic evolution ofNQOBand the relationship between the Qaidam Block and other Rodinia fragments. In this study, a kyanite‐bearing eclogite was identified in Yuka terrane. It has positive‐slope chondrite‐normalized rare earth element distribution patterns, similar to present‐day N‐MORB.LA–ICP–MSzircon U–Pb dating obtained a protolith age of 1,273 Ma and an eclogite facies metamorphic age of 437 Ma, which is similar to the continental deep subduction age of the Yuka terrane. Zircon Lu–Hf analysis show that the magmatic zircon cores have high εHf(t) of 8.36–15.98 andTDM1of 1,450–1,131 Ma (M = 1,303 ± 55 Ma, consistent with its protolith age within error), indicating a juvenile crust protolith of the eclogite. TheMORB‐like whole‐rock composition and zircon U–Pb and Lu–Hf analysis indicate that the protolith of the kyanite‐bearing eclogite was a Mesoproterozoic oceanic slice.P–Tpseudosection analysis shows that the kyanite‐bearing eclogite experienced four metamorphic stages: (1) a prograde stage with the assemblage garnet+omphacite+talc+lawsonite+phengite+quartz at 22.4–23.2 kbar and 585°C; (2) a peak stage with the assemblage garnet+omphacite+lawsonite+phengite+coesite at 32.5 kbar and 670°C; (3) an early retrograde stage with the assemblage garnet+omphacite+kyanite+phengite+coesite/quartz±lawsonite at 27.1–30.0 kbar and 670–690°C; and (4) a late retrograde stage with the assemblage garnet+omphacite+epidote+hornblende+phengite+quartz at <18.0 kbar. The established clockwiseP–Tpath is similar with other continental‐type eclogites in this area. On the basis of the geochemical and geochronological data, as well as theP–Tpath, we suggest that the protolith of the kyanite‐bearing eclogite was emplaced in the active margin of the Qaidam Block during the assembly of Rodinia and underwent continental deep subduction in the Early Palaeozoic. We conclude that (1) the Qaidam Block participated in the assembly of the Rodinia supercontinent. It was situated at or proximal to the margin of the supercontinent and probably close to India, east Antarctica and Tarim; and (2) both Mesoproterozoic and Early Palaeozoic oceanic crust slices occur in the NQOB. Thus, special caution is needed when using the metamorphic ages of oceanic affinity eclogites without protolith ages to constrain the evolution history of the North QaidamUHPMbelt.
Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone
Authors: Taleb O. , Patte‐Mensah C. , Meyer L. , Kemmel V. , Geoffroy P. , Miesch M. , Mensah‐Nyagan A.‐G.
Published: December 2017

The neurosteroid allopregnanolone (AP) modulates neuroendocrine/neurobiological processes, including hypothalamic‐pituitary‐adrenocortical activities, pain, anxiety, neurogenesis and neuroprotection. These observations raised the hope of developing AP‐based therapies against neuroendocrine and/or neurodegenerative disorders. However, the pleiotropic actions of AP, particularly its cell‐proliferation‐promoting effects, hamper the development of selective/targeted therapies. For example, although AP‐induced neurogenesis may serve to compensate neuronal loss in degenerative brains, AP‐evoked cell‐proliferation is contraindicated for steroid‐sensitive cancer patients. To foster progress, we synthesised 4 novel AP analogues of neurosteroids (ANS) designated BR053 (12‐oxo‐epi‐AP), BR297 (O‐allyl‐epi‐AP), BR351 (O‐allyl‐AP) and BR338 (12‐oxo‐AP). First, because AP is well‐known as allosteric modulator of GABAA receptors (GABAA‐R), we used the electrophysiological patch‐clamp technique to determine the structure‐activity relationship of our ANS on GABAA‐activated current in NCB20 cells expressing functional GABAA‐R. We found that the addition of 12‐oxo‐group did not significantly change the respective positive or negative allosteric effects of 3α‐AP or 3β‐(epi)‐AP analogues. Importantly, substitution of the 3α‐hydroxyl‐group by 3α‐O‐allyl highly modified the ANS activities. Unlike AP, BR351 induced a long‐lasting desensitisation/inhibition of GABAA‐R. Interestingly, replacement of the 3β‐hydroxyl by 3β‐O‐allyl (BR297) completely reversed the activity from negative to positive allosteric action. In a second step, we compared the actions of AP and ANS on SH‐SY5Y neuronal cell viability/proliferation using MTT‐reduction assays. Different dose‐response curves were demonstrated for AP and the ANS. By contrast to AP, BR297 was totally devoid of cell‐proliferative effect. Finally, we compared AP and ANS abilities to protect against oxidative stress‐induced neuronal death pivotally involved in neurodegenerative diseases. Both BR351 and BR297 had notable advantages over AP in protecting SH‐SY5Y cells against oxidative stress‐induced death. Thus, BR297 appears to be a potent neuroprotective compound devoid of cell‐proliferative activity. Altogether, our results suggest promising perspectives for the development of neurosteroid‐based selective and effective strategies against neuroendocrine and/or neurodegenerative disorders.
Type 2 diabetes mellitus and bone
Authors: Compston J.
Published: December 2017

Type 2 diabetes (T2DM) is a rapidly growing public health problem. It is associated with an increased risk of fracture, particularly of the hip, despite normal or high bone mineral density. Longer duration of disease and poor glycaemic control are both associated with higher fracture risk. The factors underlying increased fracture risk have not been clearly established, but increased falls risk, obesity, sarcopenia and co‐morbidities are likely to contribute. The basis for reduced bone strength despite higher bone mineral density remains to be fully elucidated. Bone turnover is reduced in individuals with T2DM, with evidence of impaired bone formation. Most studies indicate normal or superior trabecular bone structure although reduced lumbar spine trabecular bone score (TBS) has been reported. Deficits in cortical bone structure have been demonstrated in some, but not all, studies whilst reduced bone material strength index (BMSi), as assessed by microindentation, has been a consistent finding. Accumulation of advanced glycation end products in bone may also contribute to reduced bone strength. The use of FRAX in individuals with T2DM underestimates fracture probability. Clinical management should focus on falls prevention strategies, avoidance of known risk factors, maintenance of good glycaemic control and bone protective intervention in individuals at high risk of fracture. Dietary and surgical strategies to reduce weight have beneficial effects on diabetes but may have adverse effects on skeletal health. Future research priorities include better definition of the mechanisms underlying increased fracture risk in T2DM and optimal strategies for identifying and treating those at high risk.
Exit, Voice, or Loyalty? An Investigation Into Mandated Portability of Front‐Loaded Private Health Plans
Authors: Atal Juan Pablo , Fang Hanming , Karlsson Martin , Ziebarth Nicolas R.
Published: December 2017

We study theoretically and empirically how consumers in an individual private long‐term health insurance market with front‐loaded contracts respond to a newly mandated portability requirement of their old‐age provisions. To foster competition, effective 2009, the German legislature made the portability of standardized old‐age provisions mandatory. Our theoretical model predicts that the portability reform will increase internal plan switching. However, under plausible assumptions, it will not increase external insurer switching. Moreover, the portability reform will enable unhealthier enrollees to reoptimize their plans. We find confirmatory evidence for the theoretical predictions using claims panel data from a big private insurer.
Perspectives on the motivations for phonetic convergence
Authors: Coles‐Harris Evan Hugh
Published: December 2017

The motivations for spontaneous phonetic convergence have implications for theories of memory, speech production and perception, social cognition, contact‐induced language change, and any number of other phenomena. Thus, this paper examines two distinct but related theoretical positions commonly taken on the motivations for spontaneous phonetic convergence: the Automatist stance and the Interventionist stance. Automatists argue that phonetic convergence is the automatic result of the unmediated action of a perception‐production link; of the action of general psychological processes such as priming and simulation effects on linguistic representations in the brain. Interventionists, on the other hand, argue that convergence is the product of the very mediation of the perception‐production link, be it linguistic or social mediation, typically for the purpose of managing the social distance between interlocutors. I argue that these seemingly diametrically opposed stances are in fact complementary, not contradictory—having been developed to describe data at various points along a continuum of sociality—and that it is most productive to understand one's own position on the issue from this standpoint. Topics such as exemplar theory, gestural drift, entrainment, and communication accommodation theory are discussed for their relevance to the question at hand.
Auxin molecular field maps define AUX1 selectivity: many auxin herbicides are not substrates
Authors: Hoyerova Klara , Hosek Petr , Quareshy Mussa , Li Jun , Klima Petr , Kubes Martin , Yemm Antony A. , Neve Paul , Tripathi Ashutosh , Bennett Malcolm J. , Napier Richard M.
Published: December 2017

Developmental responses to auxin are regulated by facilitated uptake and efflux, but detailed molecular understanding of the carrier proteins is incomplete.

We have used pharmacological tools to explore the chemical space that defines substrate preferences for the auxin uptake carrier AUX1. Total and partial loss‐of‐function aux1 mutants were assessed against wild‐type for dose‐dependent resistance to a range of auxins and analogues. We then developed an auxin accumulation assay with associated mathematical modelling to enumerate accurate IC50 values for a small library of auxin analogues. The structure activity relationship data were analysed using molecular field analyses to create a pharmacophoric atlas of AUX1 substrates.

The uptake carrier exhibits a very high level of selectivity towards small substrates including the natural indole‐3‐acetic acid, and the synthetic auxin 2,4‐dichlorophenoxyacetic acid. No AUX1 activity was observed for herbicides based on benzoic acid (dicamba), pyridinyloxyacetic acid (triclopyr) or the 6‐arylpicolinates (halauxifen), and very low affinity was found for picolinic acid‐based auxins (picloram) and quinolinecarboxylic acids (quinclorac).

The atlas demonstrates why some widely used auxin herbicides are not, or are very poor substrates. We list molecular descriptors for AUX1 substrates and discuss our findings in terms of herbicide resistance management.