bluuebunny/crossref_metadata_2025 huggingface dataset:
G protein-coupled estrogen receptor is not required for sex determination or ovary function in zebrafish
Authors: Crowder Camerron M. , Romano Shannon N. , Gorelick Daniel A.
Published: July 2018

Estrogens regulate vertebrate development and function through binding to nuclear estrogen receptors alpha and beta (ERα, ERβ) and the G protein-coupled estrogen receptor (GPER). Studies in mutant animal models demonstrated that ERα and ERβ are required for normal ovary development and function. However, the degree to which GPER signaling contributes to ovary development and function is less well understood. Previous studies using cultured fish oocytes found that estradiol inhibits oocyte maturation in a GPER-dependent manner, but whether GPER regulates oocyte maturation in vivo is not known. To test the hypothesis that GPER regulates oocyte maturation in vivo, we assayed ovary development and function in gper mutant zebrafish. We found that homozygous mutant gper embryos developed into male and female adults with normal sex ratios and fertility. Adult mutant fish exhibited normal secondary sex characteristics and fertility. Additionally, mutant ovaries were histologically normal. We observed no differences in the number of immature versus mature oocytes in mutant versus wild-type ovaries from both young and aged adults. Furthermore, expression of genes associated with sex determination and ovary function were normal in gper mutant ovaries compared to wild type. Our findings suggest that GPER is not required for sex determination, ovary development or fertility in zebrafish.
Inhibition and excitation shape activity selection: effect of oscillations in a decision-making circuit
Authors: Bose Thomas , Reina Andreagiovanni , Marshall James A.R.
Published: July 2018

Decision-making is a complex task and requires adaptive mechanisms that facilitate efficient behaviour. Here, we consider a neural circuit that guides the behaviour of an animal in ongoing binary choice tasks. We adopt an inhibition motif from neural network theory and propose a dynamical system characterized by nonlinear feedback, which links mechanism (the implementation of the neural circuit) and function (increasing reproductive value). A central inhibitory unit influences evidence-integrating excitatory units, which in our terms correspond to motivations competing for selection. We determine the parameter regime where the animal exhibits improved decision-making behaviour, and explain different behavioural outcomes by making the link between bifurcation analysis of the nonlinear neural circuit model and decision-making performance. We find that the animal performs best if it tunes internal parameters of the neural circuit in accordance with the underlying bifurcation structure. In particular, variation of inhibition strength and excitation-over-inhibition ratio have a crucial effect on the decision outcome, by allowing the animal to break decision deadlock and to enter an oscillatory phase that describes its internal motivational state. Our findings indicate that this oscillatory phase may improve the overall performance of the animal in an ongoing foraging task. Our results underpin the importance of an integrated functional and mechanistic study of animal activity selection.

Author summary

Organisms frequently select activities, which relate to economic, social and perceptual decision-making problems. The choices made may have substantial impact on their lives. In foraging decisions, for example, animals aim at reaching a target intake of nutrients; it is generally believed that a balanced diet improves reproductive success, yet little is known about the underlying mechanisms that integrate nutritional needs within the brain. In our study, we address this coupling between physiological states and a decision-making circuit in the context of foraging decisions. We consider a model animal that has the drive to eat or drink. The motivation to select and perform one of these activities (i.e. eating or drinking), is processed in artificial neuronal units that have access to information on how hungry and thirsty the animal is at the point it makes the decision. We show that inhibitory and excitatory mechanisms in the neural circuit shape ongoing binary decisions, and we reveal under which conditions oscillating motivations may improve the overall performance of the animal. Our results indicate that inefficient or pathological decision-making may originate from suboptimal modulation of excitation and inhibition in the neurobiological network.
Different Effects of Three Types of Water on Developmental Behaviors, Lipid Metabolism and Antioxidant Capacity of Juvenile Zebrafish
Authors: Chang Cheng , Zhu Jiajin
Published: July 2018

Adolescence is an important period when people need adequate nutrition for healthy growth and development, whether from food or water. Tap water, bottled water (bottled purified water, and bottled natural water) are now the three most popular drinking waters consumed by adolescents in China. However, the constituents of them differ, which may cause different long-term health effects. In order to determine which type of water is the most beneficial regarding developmental behaviors, lipid metabolism and antioxidant capacity of juvenile zebrafish, 21 dpf (days post-fertilization) zebrafish were given these three waters separately with the same feed until 90 dpf. Results showed that zebrafish in purified water had the lowest survival rate, body weight and body length, while zebrafish in natural water and tap water had similar developmental behaviors; the highest HDL-C level and the lowest TG level were found in natural water, tap water second; and zebrafish in natural water showed the best antioxidant capacity. Thus, the best outcomes were found in natural water, which had suitable pH and proper amount of minerals, tap water also showed good performance, while purified water seemed not suitable for juvenile zebrafish.
GC content shapes mRNA decay and storage in human cells
Authors: Courel Maïté , Clément Yves , Foretek Dominika , Cruchez Olivia Vidal , Yi Zhou , Benassy Marie-Noëlle , Kress Michel , Vindry Caroline , Bénard Marianne , Bossevain Clémentine , Antoniewski Christophe , Morillon Antonin , Brest Patrick , Hubstenberger Arnaud , Crollius Hugues Roest , Standart Nancy , Weil Dominique
Published: July 2018

Control of protein expression results from the fine tuning of mRNA synthesis, decay and translation. These processes, which are controlled by a large number of RNA-binding proteins and by localization in RNP granules such as P-bodies, appear often intimately linked although the rules of this interplay are not well understood. In this study, we combined our recent P-body transcriptome with various transcriptomes obtained following silencing of broadly acting mRNA decay and repression factors. This analysis revealed the central role of GC content in mRNA fate, in terms of P-body localization, mRNA translation and mRNA decay. It also rationalized why PBs mRNAs have a strikingly low protein yield. We report too the existence of distinct mRNA decay pathways with preference for AU-rich or GC-rich transcripts. Compared to this impact of the GC content, sequence-specific RBPs and miRNAs appeared to have only modest additional effects on their bulk targets. Altogether, these results lead to an integrated view of post-transcriptional control in human cells where most regulation at the level of translation is dedicated to AU-rich mRNAs, which have a limiting protein yield, whereas regulation at the level of 5’ decay applies to GC-rich mRNAs, whose translation is optimal.
Fusion of a functional glutaredoxin to the radical-generating subunit of ribonucleotide reductase
Authors: Grinberg Inna Rozman , Lundin Daniel , Sahlin Margareta , Crona Mikael , Berggren Gustav , Hofer Anders , Sjöberg Britt-Marie
Published: July 2018

Class I ribonucleotide reductase (RNR) consists of a catalytic subunit (NrdA) and a radical-generating subunit (NrdB) that together catalyse reduction of the four ribonucleotides to their corresponding deoxyribonucleotides.Facklamia ignavaNrdB is an unprecedented fusion protein with N-terminal add-ons of a glutaredoxin (Grx) domain followed by an ATP-cone. Grx, which in general is encoded elsewhere in the genome than is the RNR operon, is a known physiological reductant of RNRs. Here we show that the fused Grx domain functions as an efficient reductant of theF. ignavaclass I RNR via the common dithiol mechanism and interestingly also via a monothiol mechanism, although less efficiently. A Grx that utilizes either or of these two reaction mechanisms has to our knowledge not been observed with a native substrate before. The ATP-cone, which is commonly found as an N-terminal domain of the catalytic subunit of RNRs, is an allosteric on/off switch that promotes dNDP reduction in presence of ATP and inhibits the enzyme activity in presence of dATP. Here we show that dATP bound to the ATP-cone ofF. ignavaNrdB promotes formation of tetramers that are unable to form enzymatically competent complexes withF. ignavaNrdA. The ATP-cone binds two molecules of dATP, but only one molecule of the activating nucleotide ATP.F. ignavaNrdB contains the recently identified radical factor Mn2III/IV. We show that NrdA from the firmicuteF. ignavacan form a catalytically competent RNR with the Mn2III/IV-containing NrdB from the flavobacteriumLeeuwenhoekiella blandensis.
A predictive epilepsy index based on probabilistic classification of interictal spike waveforms
Authors: Pfammatter Jesse A. , Bergstrom Rachel A. , Wallace Eli P. , Maganti Rama K. , Jones Mathew V.
Published: July 2018

Quantification of interictal spikes in EEG may provide insight on epilepsy disease burden, but manual quantification of spikes is time-consuming and subject to bias. We present a probability-based, automated method for the classification and quantification of interictal events, using EEG data from kainate- and saline-injected mice (C57BL/6J background) several weeks post-treatment. We first detected high-amplitude events, then projected event waveforms into Principal Components space and identified clusters of spike morphologies using a Gaussian Mixture Model. We calculated the odds-ratio of events from kainate-versus saline-treated mice within each cluster, converted these values to probability scores, P(kainate), and calculated an Hourly Epilepsy Index for each animal by summing the probabilities for events where the cluster P(kainate) > 0.5 and dividing the resultant sum by the record duration. This Index is predictive of whether an animal received an epileptogenic treatment (i.e., kainate), even if a seizure was never observed. We applied this method to an out-of-sample dataset to assess epileptiform spike morphologies in five kainate mice monitored for ~1 month. The magnitude of the Index increased over time in a subset of animals and revealed changes in the prevalence of epileptiform (P(kainate) > 0.5) spike morphologies. Importantly, in both data sets, animals that had electrographic seizures also had a high Index. This analysis is fast, unbiased, and provides information regarding the salience of spike morphologies for disease progression. Future refinement will allow a better understanding of the definition of interictal spikes in quantitative and unambiguous terms.
5-HAYED peptide can protect AD brain by scavenging the redundant iron ions and the catalyzed radicals
Authors: Zou Zhenyou , Shao Shengxi , Li Li , Cheng Xiaoying , Shen Qiqiong
Published: July 2018

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory and cognitive decline. It is incurable currently andplaces a great burden on the caregiversof patients. Iron is rich in the brain of AD suffers. It catalyzes radicals which impairs neurons. Therefore, reducing the redundant brain iron is pressing to ease AD. To scavenge the excessive brain iron catalyzed radical, thus protect the brain and decrease the incidence of AD. We synthesized a soluble iron-pro 5-HAYED peptide. By injecting 5-HAYED to the cerebrospinal fluid (CSF) of the AD mouse, we observed that the 5-HAYED is able to decrease the brain iron and radical level, which behaving neurons protection, and can ameliorate the cognition status for AD mouse. Further, 5-HAYED can decreased the AD incidence and can reverse the AD associated anemia and inflammation without hurt kidney and liver.
Comparative analysis of drape characteristics of actually and virtually draped fabrics
Authors: Buyukaslan Evrim , Jevsnik Simona , Kalaoglu Fatma
Published: July 2018

Purpose

The purpose of this paper is to compare real fabric drape images and virtual fabric drape images created by a commercial software. To achieve an in-depth comparison, actual and virtual drape shape properties were considered under three categories: drape area, number of nodes and shape of folds. The results of this research are expected to be useful to improve the reality and accuracy of fabric and garment.

Design/methodology/approach

Five different fabrics were selected for this study. Fabrics’ mechanical properties were tested by fabric assurance for simple testing method, while drape properties were measured by a Cusick drape meter. A commercial garment simulation was used to generate virtual fabric drapes. Real fabric drape images and virtual fabric drape images were analyzed by an image analysis software and results were used to calculate drape properties. Regression analysis was performed to compare real fabric drape and virtual fabric drape properties.

Findings

Differences between real fabric drape and virtual fabric drape were stated clearly. Simulation software was found to be insufficient to reflect drape area. However, simulations were quite successful corresponding to the number of nodes. Only one simulation had +2 nodes than its actual counterpart. This study showed that area and node shape representations of simulation software should be improved while node numbers are sufficiently represented.

Research limitations/implications

There are alternative 3D garment simulation software available to the fashion business. All these companies are working on to improve their simulation reality and accuracy. Some of them are also offering various equipment to measure the fabric properties. In this study, Optitex 3D Suite was selected as the simulation software due to several reasons as explained in this paper. However, other simulation programs might also be employed to perform virtual fabric drapes. Furthermore, in this study, the drape images of five woven fabrics were compared. The fabric selection was done according to a pre-test and consequently similar fabrics were determined to be the subject of the study. However, the more the number of the fabrics, the better the comparison and eventually the better the assessment of simulation success. Therefore, it is prospected to test more fabrics with versatile fabric properties for further studies.

Originality/value

Drape shape was observed from three perspectives: drape area, node numbers, and node shapes. Dealing the problem from these perspectives provided an in-depth comparison of real and virtual drapes. In this study, standard deviation of peak angles was used to explain node distribution that is new to the literature to the authors’ knowledge.
When a calling is living
Authors: Li Hongxia , Yang Xiugang
Published: July 2018

Purpose

The argument that work engagement enhances job performance has gained wide acceptance among practitioners and human resources management literature. There is consensus in management literature that job crafting can affect work engagement. The concept of callings from theology has been resurrected in job behavior and continues to garner growing attention from practitioners in recent years. However, few studies examine how and why living a calling influence job crafting and work engagement. The purpose of this paper is to examine the relationships between living a calling, job crafting and work engagement for knowledgeable employees through questionnaires.

Design/methodology/approach

The part-time MBA students were asked to reflect on present jobs. In total, 390 effective questionnaires were collected from part-time MBA students of four universities in Chongqing, China for finance, administration, manufacturing, service, technology, medication, education and others. Results were analyzed using SPSS and Amos. The measurement scale is given in Appendix.

Findings

First, the author explicitly proposes and validates the direct relationship between living a calling and job crafting. Second, this study confirms that crafting challenging job demands are significant to vigor subdimension and dedication subdimension of work engagement, whereas crafting challenging job demands not significant to absorption subdimension of work engagement. Third, this study indicates that crafting hindering job demands are nonsignificant to vigor, dedication and absorption about three subdimensions of work engagement. Fourth, this study showed living a calling can enhance work engagement for employees. Fifth, this study finds three groups (eight items) of mediation effect between living a calling, job crafting and work engagement.

Practical implications

These insights may help managers to focus on living a calling and encourage beneficial job crafting behaviors in China. The sample is original and has the potential to contribute to debate on work life balance and particularly the meaning of work/careers in China.

Social implications

This study is an interesting revisit to the old workplace sociology and organizational psychology which has become somewhat neglected these days.

Originality/value

This study has provided insight in the relationships between living a calling, job crafting and work engagement.
Design, modelling and imaging of marine seismic swarm surveys
Authors: Muyzert Everhard
Published: July 2018

Autonomous marine vehicles instrumented with seismic sensors allow for new efficient seismic survey designs. One such design is the swarm survey, where a group, or swarm, of slow moving autonomous marine vehicles record seismic data from shots fired by a source vessel sailing around circles within the swarm. The size of the swarm is dictated by the maximum offset requirement of the survey, and it can be shaped to acquire wide‐ and full‐azimuth data. The swarm survey design equation describes the relationship between the source and receiver positions of the survey and the subsurface coverage or fold. It is used to adapt the swarm to the seismic survey requirements and to calculate survey duration time estimates as function of available equipment. It is shown that a survey conducted by a slowly moving swarm requires six times fewer shots than an equivalent seabed node survey conducted over 85.5 km2. Swarm surveys can also be adapted to efficiently conduct infill surveys and replace multi‐vessel undershoots. The efficiency of the survey can further be increased when the autonomous marine vehicles are towing short streamers with multiple receivers. Synthetic tests show that the seismic images for swarm surveys are comparable to those from streamer surveys, while little variation in image quality is found when reducing the number of autonomous marine vehicles but equipping them with a short streamer with multiple receivers.
Mini‐review: Phytoplankton‐derived polysaccharides in the marine environment and their interactions with heterotrophic bacteria
Authors: Mühlenbruch Marco , Grossart Hans‐Peter , Eigemann Falk , Voss Maren
Published: July 2018

Within the wealth of molecules constituting marine dissolved organic matter, carbohydrates make up the largest coherent and quantifiable fraction. Their main sources are from primary producers, which release large amounts of photosynthetic products – mainly polysaccharides – directly into the surrounding water via passive and active exudation. The organic carbon and other nutrients derived from these photosynthates enrich the ‘phycosphere’ and attract heterotrophic bacteria. The rapid uptake and remineralization of dissolved free monosaccharides by heterotrophic bacteria account for the barely detectable levels of these compounds. By contrast, dissolved combined polysaccharides can reach high concentrations, especially during phytoplankton blooms. Polysaccharides are too large to be taken up directly by heterotrophic bacteria, instead requiring hydrolytic cleavage to smaller oligo‐ or monomers by bacteria with a suitable set of exoenzymes. The release of diverse polysaccharides by various phytoplankton taxa is generally interpreted as the deposition of excess organic material. However, these molecules likely also fulfil distinct, yet not fully understood functions, as inferred from their active modulation in terms of quality and quantity when phytoplankton becomes nutrient limited or is exposed to heterotrophic bacteria. This minireview summarizes current knowledge regarding the exudation and composition of phytoplankton‐derived exopolysaccharides and acquisition of these compounds by heterotrophic bacteria.
Modeling of Effective Moisture Diffusivity in Corn Tortilla Baking
Authors: Iribe‐Salazar Rosalina , Gutiérrez‐Dorado Roberto , Ríos‐Iribe Érika , Carrazco‐Escalante Marco , Vázquez‐López Yessica , Hernández‐Calderón Óscar , Caro‐Corrales José
Published: July 2018

The objective of this work was to model the mass transfer in corn tortilla baking using different approaches for effective diffusivity based on the Fick's law of diffusion and to evaluate the impact of the process on quality parameters. The 1st one assumes constant effective diffusivity (method of slopes by subperiods and method of successive approximations) and the 2nd one considers variable effective diffusivity (quadratic function of time and Weibull distribution). In addition, the Weibull distribution was applied to fracturability. The effective moisture diffusivity inside the tortilla during baking is not constant and the estimations generated when considering variable diffusivity with quadratic time and Weibull distribution showed better fits (both, R2 = 0.999) to the average moisture content. Quality parameter fracturability was affected by the baking process and the Weibull model adequately described (R2 = 0.996) the fracturability behavior. This work will allow an adequate estimation of the concentration profiles and histories for mass transfer operations in products that can be represented as an infinite plate. The obtained analytical solutions with variable diffusivity will help to estimate the optimal conditions of the baking process to achieve the required final moisture content for baked corn tortilla shells.

Practical Application

The analytical solutions of the Fick's law of diffusion for the moisture content in products that can be represented as an infinite plate, considering variable diffusivity, can be useful in studies when accurate estimations of effective diffusivity and concentration are needed.
Microbial diversity and biogeography in Arctic soils
Authors: Malard Lucie A. , Pearce David A.
Published: July 2018

Microorganisms dominate terrestrial environments in the polar regions and Arctic soils are known to harbour significant microbial diversity, far more diverse and numerous in the region than was once thought. Furthermore, the geographic distribution and structure of Arctic microbial communities remains elusive, despite their important roles in both biogeochemical cycling and in the generation and decomposition of climate active gases. Critically, Arctic soils are estimated to store over 1500 Pg of carbon and, thus, have the potential to generate positive feedback within the climate system. As the Arctic region is currently undergoing rapid change, the likelihood of faster release of greenhouse gases such as CO2, CH4 and N2O is increasing. Understanding the microbial communities in the region, in terms of their diversity, abundance and functional activity, is key to producing accurate models of greenhouse gas release. This review brings together existing data to determine what we know about microbial diversity and biogeography in Arctic soils.
Priorities to Overcome Barriers Impacting Data Science Application in Emergency Care Research
Authors: Puskarich Michael A. , Callaway Clif , Silbergleit Robert , Pines Jesse M. , Obermeyer Ziad , Wright David W. , Hsia Renee Y. , Shah Manish N. , Monte Andrew A. , Limkakeng Alexander T. , Meisel Zachary F. , Levy Phillip D.
Published: July 2018

For a variety of reasons including cheap computing, widespread adoption of electronic medical records, digitalization of imaging and biosignals, and rapid development of novel technologies, the amount of health care data being collected, recorded, and stored is increasing at an exponential rate. Yet despite these advances, methods for the valid, efficient, and ethical utilization of these data remain underdeveloped. Emergency care research, in particular, poses several unique challenges in this rapidly evolving field. A group of content experts was recently convened to identify research priorities related to barriers to the application of data science to emergency care research. These recommendations included: 1) developing methods for cross‐platform identification and linkage of patients; 2) creating central, deidentified, open‐access databases; 3) improving methodologies for visualization and analysis of intensively sampled data; 4) developing methods to identify and standardize electronic medical record data quality; 5) improving and utilizing natural language processing; 6) developing and utilizing syndrome or complaint‐based based taxonomies of disease; 7) developing practical and ethical framework to leverage electronic systems for controlled trials; 8) exploring technologies to help enable clinical trials in the emergency setting; and 9) training emergency care clinicians in data science and data scientists in emergency care medicine. The background, rationale, and conclusions of these recommendations are included in the present article.
Temporal longevity of unidirectional and dynamic filters to faunal recolonization in post‐mining forest restoration
Authors: Craig Michael D. , Smith Megan E. , Stokes Vicki L. , Hardy Giles E. STJ. , Hobbs Richard J.
Published: July 2018

Understanding the factors, or filters, that preclude the recolonization of, and population persistence in, restoration areas by fauna is important for maximizing the biodiversity benefits of restoration. We investigated filters through a long‐term study examining reptile and mammal recolonization of, and population persistence in, post‐mining restoration in the northern jarrah forest of southwestern Australia. Neither mammal community composition, nor individual mammal species, differed between unmined forest and restoration but reptile communities did and some reptile species were significantly less abundant in restoration than in unmined forest. We concluded that there were no filters to mammal recolonization and persistence but that there were both unidirectional (decreasing gradually over time) and dynamic (fluctuating over time) filters to reptile recolonization of post‐mining restoration that influenced both recolonization and population persistence of some reptile species. Low volumes of coarse woody debris appeared to be a unidirectional filter that will slow recolonization by some reptile species for decades or even centuries. Canopy cover appeared to be a dynamic filter that fluctuated over a period of >7 years and precluded population persistence of some reptile species that had already recolonized the post‐mining restoration. A dearth of studies made it difficult to generalize how widespread these filters were in restoration areas but studies of thinning and burning in natural forests suggested they were likely to be widespread. Although management techniques to reduce the effect of unidirectional and dynamic filters remain poorly developed, their development and adoption will improve the ability of restoration to facilitate fauna recolonization and persistence and better contribute towards biodiversity conservation.
The influence of tree species and edge effects on pheromone trap catches of oak processionary mothThaumetopoea processionea(L.) in the U.K.
Authors: Williams David T. , Jonusas Gillian
Published: July 2018

Many factors influence the efficiency of insect pheromone trapping systems. In particular, captures of male oak processionary moth (OPM)Thaumetopoea processioneain pheromone traps can be highly variable, hence, two trials were conducted to determine whether the tree species in which traps are positioned or edge effects are influential factors in OPM pheromone trapping.

In a ‘host plant trial’, pheromone traps that were positioned in the canopy of pedunculate oak (Quercus robur) trees captured significantly more male OPM than traps positioned in any of the other six tree species (including other species of oak) used in the trial over two successive years.

In an ‘edge effects trial’, pheromone traps positioned on the edges of oak woodland blocks captured more moths than traps positioned within the oak woodland itself.

Although wind direction influenced the numbers of moths that were captured in pheromone traps on woodland edges, with more moths captured in traps positioned on sheltered north‐facing edges, the differences in trap catches between north, south, east and west edges were not significant.

The results from the present study indicate that a greater emphasis should be taken to deploy pheromone traps for oak processionary moth in the canopies of pedunculate oak trees with an open, sunnier disposition rather than within the interior of the forest or woodland, thereby maximizing their efficiency.
Withdrawal severity and early response to treatment in the outpatient transition from opioid use to extended release naltrexone
Authors: Mannelli Paolo , Swartz Marvin , Wu Li‐Tzy
Published: July 2018

Background and Objectives

Long acting naltrexone has improved the therapy of opioid use disorder (OUD), and safe and effective withdrawal management during naltrexone induction may help advance treatment. Despite the uncertain role of opioid withdrawal in predicting successful outcomes, early symptom control may favor detoxification completion.

Methods

We explored withdrawal severity and early response to treatment, safety, and clinical measures in 35 adult patients with DSM‐5 OUD during a 7‐day office‐based buprenorphine‐naltrexone and ancillary medications transition to extended‐release naltrexone (XR‐NTX).

Results

Subjective and objective measures of withdrawal intensity improved consistently throughout treatment in the whole sample. Participants who went on to receive XR‐NTX (n = 27, 77%) reported a greater attenuation of symptoms by treatment day 2 (r = .595, p = .001), and were less likely to be injection drug users (r = −.501, p = .004). Adverse events (AEs) were recorded in 20% of participants: the majority (n = 6, 85.7%) consisted of single episodes of increased withdrawal which were well controlled using ancillary medications. One serious AE was unrelated to treatment.

Conclusions and Scientific Significance

Early opioid withdrawal changes may be a useful indicator of treatment response, helping adjust the transition protocol to the individual patients’ need and gather valuable information for a better understanding of the relationship between initiating and remaining in treatment. (Am J Addict 2018;27:471–476)
EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity
Authors: Brockow Knut , Ardern‐Jones Michael R. , Mockenhaupt Maja , Aberer Werner , Barbaud Annick , Caubet Jean‐Christoph , Spiewak Radoslaw , Torres María José , Mortz Charlotte G.
Published: July 2018

Drug hypersensitivity reactions (DHRs) are common, and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR.
The health and economic outcomes of early egg introduction strategies
Authors: Shaker Marcus , Verma Kanak , Greenhawt Matthew
Published: July 2018

Background

Studies suggest early egg introduction (EEI) in the first year of life is associated with reduced risk of developing egg allergy. No US recommendations exist regarding optimally implementing EEI.

Methods

Using simulation and Markov modelling over a 20‐year horizon, we explored optimal EEI strategies applied to US, European and Canadian populations, comparing screening of high‐risk infants (skin prick testing [SPT] or serum‐specific IgE[sIgE]) before introducing cooked egg at 6 months of life vs egg introduction at home, without screening, for all infants.

Results

A no‐screen approach dominated egg SPT screening of high‐risk infants with early‐onset eczema. Base model per‐patient incremental costs of SPT were $6865 US dollars (USD), 6801 euros and $10 610 Canadian dollars (CAD). For egg sIgE screening in primary care settings, base model incremental costs were $16 722 USD, 18 072 euros and $28 193 CAD. As the simulation concluded 2.5% were egg allergic without screening vs 9.5%, 12% and 21.4% of children undergoing SPT, delayed introduction or sIgE screening. Incremental societal costs from screening reached $2 009 351 175 USD for SPT and $4 894 445 790 USD for sIgE testing. In sensitivity analyses, if the risk of reaction with initial egg ingestion was ≥22.5%, SPT before EEI became a preferred strategy. A no‐screen approach dominated both EEI of raw pasteurized egg and delayed cooked egg introduction approaches.

Conclusions

Assuming initial reaction rates < 22.5%, a no‐screening EEI cooked egg approach has superior health and economic benefits in terms of number of egg allergy cases prevented and total healthcare costs vs screening testing.
How long is the queuing for public childcare facilities in Korea? An empirical analysis of Korean households' childcare mode choice with the limited availability of public childcare facilities
Authors: Woo Seokjin , Jun Byung‐hill
Published: July 2018

This paper empirically investigates Korean households' choice of childcare mode using the Korean Childcare Users Survey (2012). A multivariate logit model with partial observability (hereafter, PO‐logit model) is employed to address the issue of Korean households' demand for public childcare facilities exceeding capacity limits. Our estimation result rejects the hypothesis of no queueing at conventional significance levels to advocate use of the PO‐logit model in explaining Korean households' childcare choices. We decompose choice probabilities of public childcare facilities to estimate the size of queuing. Our results imply that 31.8% of parents preferring public childcare facility are forced to choose other childcare modes due to capacity limit.
Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1
Authors: Wang David B. , Kinoshita Chizuru , Kinoshita Yoshito , Sopher Bryce L. , Uo Takuma , Lee Rona J. , Kim Joon Kyu , Murphy Sean P. , Dirk Keene C. , Garden Gwenn A. , Morrison Richard S.
Published: July 2018

Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron‐specific splice isoforms of Endophilin‐B1 (Endo‐B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo‐B1 expression. HDAC2 knockdown or knockout enhances expression of Endo‐B1. Conversely, HDAC2 overexpression decreases Endo‐B1 expression. We also demonstrate that neurons exposed to beta‐amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase‐3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo‐B1 shRNA and in Endo‐B1‐null neurons, suggesting that HDAC2‐induced neurotoxicity is mediated through suppression of Endo‐B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo‐B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo‐B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.
Tumstatin fragment selectively inhibits neutrophil infiltration in experimental asthma exacerbation
Authors: Nissen Gyde , Hollaender Henrike , Tang Francesca S. M. , Wegmann Michael , Lunding Lars , Vock Christina , Bachmann Anna , Lemmel Solveig , Bartels Rainer , Oliver Brian G. , Burgess Janette K. , Becker Tim , Kopp Matthias V. , Weckmann Markus
Published: July 2018

Background

Asthma is a chronic inflammatory disease with structural changes present. Burgess and colleagues recently found tumstatin markedly reduced in adult asthmatic lung tissue compared with nonasthmatics. ECM fragments such as tumstatin are named matrikines and act independently of the parent molecule. The role of Col IV matrikines in neutrophil inflammation (eg. exacerbation in asthma) has not been investigated to date. Severe adult asthma phenotypes are dominated by neutrophilic inflammation and show a high frequency of severe exacerbations.

Objective

This study sought to investigate the role of a novel active region within tumstatin (CP17) and its implication in neutrophil inflammatory responses related to asthma exacerbation.

Methods

For reactive oxygen production, isolated neutrophils were preincubated with peptides or vehicle for 1 hour and stimulated (PMA). Luminescence signal was recorded (integration over 10 seconds) for 1.5 hours. Neutrophil migration was performed according to the SiMA protocol. Mice were sensitized to OVA/Alumn by intraperitoneal (i.p.) injections. Mice were then treated with CP17, vehicle (PBS) or scrambled peptide (SP17) after OVA exposure (days 27 and 28, polyI:C stimulation). All animals were killed on day 29 with lung function measurement, histology and lavage.

Results

CP17 decreased total ROS production rate to 52.44% (0.5 μmol/L, P < 0.05 vs SP17), reduced the in vitro directionality (vs SP17, P = 1 × 10−6) and migration speed (5 μmol/L, P = 1 × 10−3). In vivo application of CP17 decreased neutrophil inflammation ~1.8‐fold (P < 0.001 vs SP17) and reduced numbers of mucus‐producing cells (−29%, P < 0.05).

Conclusion

CP17 reduced the ROS production rate, migrational speed and selectively inhibited neutrophil accumulation in the lung interstitium and lumen.

Clinical relevance

CP17 may serve as a potential precursor for drug development to combat overwhelming neutrophil inflammation.
Growing up with parental substance use disorder: The struggle with complex emotions, regulation of contact, and lack of professional support
Authors: Wangensteen Turid , Bramness Jørgen Gustav , Halsa Astrid
Published: July 2018

The aim of the study was to explore young people's perceptions and reflections about growing up with parents who have substance use disorder (SUD). In qualitative interviews with 12 young people (aged 13–26) and in an interpretative phenomenological analysis, we investigated their experiences of everyday life, of the relationships with the parents with SUD, and of conversations about this, both retrospectively and at the present. The findings indicated that the relationships with the parents largely occupied the informants, even when they lived separately from the parent and were protected from the daily exposure of substance use. The informants described their mixed and contradictory emotions towards their parents and the struggle to determine regulation and type of contact. They asked for professional support in order to help them cope with this. Sociocultural discourses concerning family life and substance use were discussed in an attempt to understand the findings. The findings of the study suggest that children and young people should be offered sufficient professional support in order to cope with their mixed and contradictory emotions and to determine the regularity and type of contact with the parents.
Vasoactive intestinal peptide induces proliferation of human hepatocytes
Authors: Khedr M. E. M. S. , Abdelmotelb A. M. , Bedwell T. A. , Shtaya A. , Alzoubi M. N. , Abu Hilal M. , Khakoo S. I.
Published: July 2018

Objectives

Proliferation of hepatocytes in vitro can be stimulated by growth factors such as epidermal growth factor (EGF), but the role of vasoactive intestinal peptide (VIP) remains unclear. We have investigated the effect of VIP on maintenance and proliferation of human hepatocytes.

Materials and methods

Human hepatocytes were isolated from liver specimens obtained from patients undergoing liver surgery. Treatment with VIP or EGF was started 24 h after plating and continued for 3 or 5 d. DNA replication was investigated by Bromodeoxyuridine (BrdU) incorporation and cell viability detected by MTT assay. Cell lysate was analysed by western blotting and RT‐PCR. Urea and albumin secretion into the culture supernatants were measured.

Results

VIP increased DNA replication in hepatocytes in a dose‐dependant manner, with a peak response at day 3 of treatment. VIP treatment was associated with an increase in mRNA expression of antigen identified by monoclonal antibody Ki‐67 (MKI‐67) and Histone Cluster 3 (H3) genes. Western blotting analysis showed that VIP can induce a PKA/B‐Raf dependant phosphorylation of extracellular signal‐regulated kinases (ERK). Although EGF can maintain hepatocyte functions up to day 5, no marked efffect was found with VIP.

Conclusions

VIP induces proliferation of human hepatocytes with little or no effect on hepatocyte differentiation. Further investigation of the role of VIP is required to determine if it may ultimately support therapeutic approaches of liver disease.
Structural brain abnormalities in adolescents and young adults with congenital heart defect: a systematic review
Authors: Bolduc Marie‐Eve , Lambert Heather , Ganeshamoorthy Sylviya , Brossard‐Racine Marie
Published: July 2018

Aim

The primary objective of this systematic review is to define and quantify brain structural abnormalities present in adolescents and young adults with complex congenital heart defect (CHD). We also aim to evaluate the extent to which these structural abnormalities are associated with functional outcomes.

Method

A search of studies examining brain structure by magnetic resonance imaging in adolescents and young adults with complex CHD was performed in Embase, MEDLINE, and Web of Science. A meta‐analysis was conducted to determine the odds of brain abnormalities in young people with CHD. Results not included in the meta‐analysis were collated using descriptive statistics.

Results

Two hundred and fifty‐four studies were identified through the literature search. Among these, 14 original studies were included in the review. The odds of brain abnormalities in young people with CHD were 7.9 times higher (p<0.001) than in typically developing comparison individuals. Focal and multifocal lesions were the most common types of abnormality (odds ratio 41.7 [p<0.001]). Preliminary evidence from volumetric, cortical, and microstructural integrity measurements suggests that brain abnormalities are associated with poorer neurocognitive outcomes.

Interpretation

This review provides strong evidence that adolescents and young adults with CHD are at increased risk of presenting with structural brain abnormalities and highlights the contribution of advanced quantitative magnetic resonance imaging techniques to identify the subtle but frequent brain alterations in this population. However, more studies are needed to clarify how these abnormalities relate to function.

What this paper adds

There is a high prevalence of brain abnormalities in young people with congenital heart defect (CHD).

Brain volumes, cortical measurements, and white matter microstructure are altered in young people with CHD.

Brain abnormalities are associated with poorer function in young people with CHD.
Alzheimer's disease: Only prevention makes sense
Authors: Viña José , Sanz‐Ros Jorge
Published: July 2018

Alzheimer's disease therapeutics is one of the most important endeavours in today's clinical investigation. Over more than 30 years of research, no disease‐modifying treatment has been approved by either the FDA or the EMA to treat Alzheimer's disease. Recently, the evidence of pathological alterations in the brain tissue has been gathered showing that the signs of brain damage appear more than 20 years before the onset of Alzheimer's dementia. The major aim of this review is to underpin the idea that in Alzheimer's therapeutics, only prevention makes sense. It is difficult to visualise that would‐be patients may be treated with endovenous administration of antibodies for several years to delay the onset of dementia. Rather, changes in lifestyle that should be specific, stratified and personalised are a likely alternative to delay the transition from asymptomatic Alzheimer's to minimal cognitive impairment and from there to dementia. These efforts are of the utmost importance. If we could delay the onset of full‐blown dementia by 5 years, the number of demented patients would be almost halved. Thus, emphasis on preventive measures that can be implemented for decades must be supported. This approach, where even mild changes in cognition are of the greatest importance, cannot be underestimated in terms of both the individual and society's viewpoints.
Bortezomib‐based therapy for relapsed/refractory multiple myeloma in real‐world medical practice
Authors: Terpos Evangelos , Katodritou Eirini , de la Rubia Javier , Hungria Vania , Hulin Cyrille , Roussou Maria , Delforge Michel , Bries Greet , Stoppa Anne‐Marie , Aagesen Jesper , Sargin Deniz , Belch Andrew , Ahlberg Lucia , Diels Joris , Olie Robert A. , Robinson Don , Spencer Mike , Potamianou Anna , van de Velde Helgi , Dimopoulos Meletios A.
Published: July 2018

Objective

The efficacy and safety of bortezomib‐based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real‐world medical practice.

Method

Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment‐free interval, progression‐free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization.

Results

In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near‐complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment‐free interval was 7.9 months. After 22.6 months’ median follow‐up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new‐onset any‐grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment.

Conclusion

These prospective real‐world data demonstrate the effectiveness and safety of bortezomib‐based therapy for RRMM and confirm high response rates and long OS for this population.