bluuebunny/crossref_metadata_2025 huggingface dataset:
The Percentage of Amplitude Decrease Warning Criteria for Transcranial MEP Monitoring
Authors: Journée Henricus L. , Berends Hanneke I. , Kruyt Moyo C.
Published: December 2016

Muscle motor evoked potentials (MEPs) from transcranial electrical stimulation (TES) became a standard technique for monitoring the motor functions of the brain and spinal cord at risk during spinal and brain surgery. However, a wide range of criteria based on the percentage of amplitude decrease is used in practice. A survey of the current literature on clinical outcome parameters reveals a variety of percentages in a range of 30% to 100% (50% to 100% spinal procedures) with no consensus. The interpretation of muscle MEPs is hampered by their sensitivity to many interfering factors. Trial-to-trial MEP variations may partly be reduced by controllable parameters of which TES parameters are in the hands of the neuromonitorist. We propose an operational model based on basic neurophysiologic knowledge to interpret the characteristics of MEP-TES voltage curves and predict the influences of the location on the sigmoid voltage curve on spontaneous MEP-variations and influences of factors affecting the voltage curve. The model predicts a correlation between the slope, expressed by a gain, and variations of muscle MEP amplitudes. This complies with two case examples. The limited specificity/sensitivity of warning criteria based on the percentage of amplitude reduction can possibly be improved by developing standards for set-up procedures of TES paradigms. These procedures include strategies for desensitizing MEPs for variations of controllable parameters. The TES voltage or current is a feasible controlling parameter and should be related to the motor threshold and the onset of the supramaximal level being landmarks of MEP-voltage functions. These parameters may offer a valuable addition to multicenter outcome studies.
Intraoperative Neuromonitoring and Alarm Criteria for Judging MEP Responses to Transcranial Electric Stimulation: The Threshold-Level Method
Authors: Calancie Blair
Published: December 2016

The motor evoked potential (MEP) is used in the operating room to gauge—and ultimately protect—the functional integrity of the corticospinal tract (CST). However, there is no consensus as to how to best interpret the MEP for maximizing its sensitivity and specificity to CST compromise. The most common way is to use criteria associated with response magnitude (response amplitude; waveform complexity, etc.). With this approach, should an MEP in response to a fixed stimulus intensity diminish below some predetermined cutoff, suggesting CST dysfunction, then the surgical team is warned. An alternative approach is to examine the minimum stimulus energy—the threshold—needed to elicit a minimal response from a given target muscle. Threshold increases could then be used as an alternative basis for evaluating CST functional integrity. As the original proponent of this Threshold-Level alarm criteria for MEP monitoring during surgery, I have been asked to summarize the basis for this method. In so doing, I have included justification for what might seem to be arbitrary recommendations. Special emphasis is placed on anesthetic considerations because these issues are especially important when weak stimulus intensities are called for. Finally, it is important to emphasize that all the alarm criteria currently in use for interpreting intraoperative MEPs have been shown to be effective for protecting CST axons during surgery. Although differences between approaches are more than academic, overall it is much better for patient welfare to be using some form of MEP monitoring than to use none at all, while you wait for consensus about alarm criteria to emerge.
Choreography of budding yeast chromosomes during the cell cycle
Authors: Lazar-Stefanita Luciana , Scolari Vittore F. , Mercy Guillaume , Thierry Agnès , Muller Héloise , Mozziconacci Julien , Koszul Romain
Published: December 2016

To ensure the proper transmission of the genetic information, DNA molecules must be faithfully duplicated and segregated. These processes involve dynamic modifications of chromosomes internal structure to promote their individualization, as well as their global repositioning into daughter cells (Guacci et al., 1994; Kleckner et al., 2014; Mizuguchi et al., 2014). In eukaryotes, these events are regulated by conserved architectural proteins, such as structural maintenance of chromosomes (SMCi.e.cohesin and condensin) complexes (Aragon et al., 2013a; Uhlmann, 2016). Although the roles of these factors have been actively investigated, the genome-wide chromosomal architecture and dynamics both at small and large-scales during cell division remains elusive. Here we report a comprehensive Hi-C (Dekker et al., 2002; Lieberman-Aiden et al., 2009) analysis of the dynamic changes of chromosomes structure over theSaccharomyces cerevisiaecell cycle. We uncover specific SMC-dependent structural transitions between the different phases of the mitotic cycle. During replication, cohesion establishment promotes the increase of long-range intra-chromosomal contacts. This process correlates with the individualization of chromosomes, which culminates at metaphase. Mitotic chromosomes are then abruptly reorganized in anaphase by the mechanical forces exerted by the mitotic spindle on the centromere cluster. The formation of a condensin-dependent loop, that bridges centromere cluster with the cenproximal flanking region of the rDNA, suggests that these forces may directly facilitate nucleolus segregation. This work provides a comprehensive overview of chromosome dynamics during the cell cycle of a unicellular eukaryote that recapitulates and unveils new features of highly conserved stages of the cell division.
grID: A CRISPR-Cas9 guide RNA Database and Resource for Genome-Editing
Authors: Jaskula-Ranga Vinod , Zack Donald J.
Published: December 2016

CRISPR-Cas9 genome-editing is a revolutionary technology that is transforming biological research. The explosive growth and advances in CRISPR research over the last few years, coupled with the potential for clinical applications and therapeutics, is heralding a new era for genome engineering. To further support this technology platform and to provide a universal CRISPR annotation system, we introduce the grID database (http://crispr.technology), an extensive compilation of gRNA properties including sequence and variations, thermodynamic parameters, off-target analyses, and alternative PAM sites, among others. To aid in the design of optimal gRNAs, the website is integrated with other prominent databases, providing a wealth of additional resources to guide users fromin silicoanalysis through experimental CRISPR targeting. Here, we make available all the tools, protocols, and plasmids that are needed for successful CRISPR-based genome targeting.
Bioorthogonal pro-metabolites for profiling short chain fatty acylation
Authors: Sinclair Wilson R. , Zengeya Thomas T. , Garlick Julie M. , Worth Andrew J. , Blair Ian A. , Snyder Nathaniel W. , Meier Jordan L.
Published: December 2016

Short chain fatty acids (SCFAs) play a central role in health and disease. One function of these signaling molecules is to serve as precursors for short chain fatty acylation, a class of metabolically-derived posttranslational modifications (PTMs) that are established by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Via this mechanism, short chain fatty acylation serves as an integrated reporter of metabolism as well as KAT and KDAC activity, and has the potential to illuminate the role of these processes in disease. However, few methods to study short chain fatty acylation exist. Here we report a bioorthogonal pro-metabolite strategy for profiling short chain fatty acylation in living cells. Inspired by the dietary component tributyrin, we synthesized a panel of ester-caged bioorthogonal short chain fatty acids. Cellular evaluation of these agents led to the discovery of an azido-ester that is metabolized to its cognate acyl-coenzyme A (CoA) and affords robust protein labeling profiles. We comprehensively characterize the metabolic dependence, toxicity, and histone deacetylase (HDAC) inhibitory activity of these bioorthogonal pro-metabolites, and apply an optimized probe to identify novel candidate protein targets of short chain fatty acids in cells. Our studies showcase the utility of bioorthogonal pro-metabolites for unbiased profiling of cellular protein acylation, and suggest new approaches for studying the signaling functions of SCFAs in differentiation and disease.
Dopamine Negatively Modulates the NCA Ion Channels inC. elegans
Authors: Topalidou Irini , Cooper Kirsten , Pereira Laura , Ailion Michael
Published: December 2016

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. TheCaenorhabditis elegansorthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gqand the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Gosignaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

Author summary

Dopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematodeC. elegansthat involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a G protein-coupled receptor kinase (GRK-2) that inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this study connects dopamine signaling to activity of the NCA channels through G protein signaling pathways.
Comparison of linear spatial filters for identifying oscillatory activity in multichannel data
Authors: Cohen Michael X
Published: December 2016

Background

Large-scale synchronous neural activity produces electrical fields that can be measured by electrodes outside the head, and volume conduction ensures that neural sources can be measured by many electrodes. However, most data analyses in M/EEG research are univariate, meaning each electrode is considered as a separate measurement. Several multivariate linear spatial filtering techniques have been introduced to the cognitive electrophysiology literature, but these techniques are not commonly used; comparisons across filters would be beneficial to the field.

New method

The purpose of this paper is to evaluate and compare the performance of several linear spatial filtering techniques, with a focus on those that use generalized eigendecomposition to facilitate dimensionality reduction and signal-to-noise ratio maximization.

Results

Simulated and empirical data were used to assess the accuracy, signal-to-noise ratio, and interpretability of the spatial filter results. When the simulated signal is powerful, different spatial filters provide convergent results. However, more subtle signals require carefully selected analysis parameters to obtain optimal results.

Comparison with existing methods

Linear spatial filters can be powerful data analysis tools in cognitive electrophysiology, and should be applied more often; on the other hand, spatial filters can latch onto artifacts or produce uninterpretable results.

Conclusions

Hypothesis-driven analyses, careful data inspection, and appropriate parameter selection are necessary to obtain high-quality results when using spatial filters.
When Attended and Conscious Perception Deactivates Fronto-Parietal Regions
Authors: Farooqui Ausaf Ahmed , Manly Tom
Published: December 2016

Conscious and attended perception is commonly thought to elicit fronto-parietal activity. However, supportive evidence comes largely from studies which involve detecting a target and reporting its visibility. This approach confounds conscious perception with goal completion of either the perceptual task of detection or the metacognitive task of introspective reporting. In contrast, in real life such perceptions are a means of achieving goals and rarely a goal in themselves, and almost never involve explicit metacognitive reports. It therefore remains unclear if fronto-parietal activity is indeed a correlate of conscious perception or is the result of confounds related to goal completion. Here we show that conscious and attended perception when delinked from goals does not increase fronto-parietal activity, and when inconsequential for the goal may even deactivate these regions. In experiments 1 and 2 participants attended to a highly visible stream of letters to detect the occasional targets in their midst. The non-target letters, in spite of being visible and attended to, deactivated fronto-parietal regions. In experiment 3 we looked at the activity elicited by a loud auditory cue that had to be kept in memory for up to 9 s and used to select the correct rule for completing the goal. Even such a salient, attended and remembered event did not elicit prefrontal activity. Across these experiments conscious and attended perception only activated the relevant sensory regions while goal completion events activated fronto-parietal regions.

Significance statement

Consciousness and attended perception has been seen to correlate with fronto-parietal activity. This informs key theories of consciousness and attention, e.g. widespread availability of incoming information or its higher level representation causes perceptual awareness, or that top down attention during perception broadcasts incoming sensations into frontal and parietal regions. However such experiments unwittingly conflate attended and conscious perception with some form of goal completion, whereas such perception in our daily life mostly serves as a means of goal completion and not a goal in itself. Here we show that such perception when delinked from goal completion does not activate fronto-parietal regions, and may even deactivate these regions if the percept is inconsequential for goal completion.
Convergence of dispersed regulatory mutations predicts driver genes in prostate cancer
Authors: Sallari Richard C. , Sinnott-Armstrong Nicholas A. , French Juliet D. , Kron Ken J. , Ho Jason , Moore Jason H. , Stambolic Vuk , Edwards Stacey L. , Lupien Mathieu , Kellis Manolis
Published: December 2016

Cancer sequencing predicts driver genes using recurrent protein-altering mutations, but detecting recurrence for non-coding mutations remains unsolved. Here, we present a convergence framework for recurrence analysis of non-coding mutations using three-dimensional co-localization of epigenomically-identified regions. We define the regulatory plexus of each gene as its cell-type-specific three-dimensional gene-regulatory neighborhood, inferred using Hi-C chromosomal interactions and chromatin state annotations. Using 16 matched tumor-normal prostate transcriptomes, we predict tumor-upregulated genes, and find enriched plexus mutations in distal regulatory regions normally repressed in prostate, suggesting out-of-context de-repression. Using 55 matched tumor-normal prostate genomes, we predict 15 driver genes by convergence of dispersed, low-frequency mutations into high-frequency dysregulation events along prostate-specific plexi, while controlling for mutational heterogeneity across regions, chromatin states, and patients. These putative drivers play roles in growth signaling, immune evasion, mitochondrial function, and vascularization, suggesting higher-order pathway-level convergence. We experimentally validate thePLCB4plexus and its ability to affect the canonical PI3K cancer pathway.
Training Genotype Callers with Neural Networks
Authors: Torracinta Remi , Campagne Fabien
Published: December 2016

We present an open source software toolkit for training deep learning models to call genotypes in high-throughput sequencing data. The software supports SAM, BAM, CRAM and Goby alignments and the training of models for a variety of experimental assays and analysis protocols. We evaluate this software in the Illumina Platinum whole genome datasets and find that a deep learning model trained on 80% of the genome achieves a 0.986% accuracy on variants (genotype concordance) when trained with 10% of the data from a genome. The software is distributed athttps://github.com/CampagneLaboratory/variationanalysis. The software makes it possible to train genotype calling models on consumer hardware with CPUs or GPU(s). It will enable individual investigators and small laboratories to train and evaluate their own models and to make open source contributions. We welcome contributions to extend this early prototype or evaluate its performance on other gold standard datasets.
Contributions of local speech encoding and functional connectivity to audio-visual speech integration
Authors: Giordano Bruno L. , Ince Robin A. A. , Gross Joachim , Panzeri Stefano , Schyns Philippe G. , Kayser Christoph
Published: December 2016

Seeing a speaker’s face enhances speech intelligibility in adverse environments. We investigated the underlying network mechanisms by quantifying local speech representations and directed connectivity in MEG data obtained while human participants listened to speech of varying acoustic SNR and visual context. During high acoustic SNR speech encoding by entrained brain activity was strong in temporal and inferior frontal cortex, while during low SNR strong entrainment emerged in premotor and superior frontal cortex. These changes in local encoding were accompanied by changes in directed connectivity along the ventral stream and the auditory-premotor axis. Importantly, the behavioural benefit arising from seeing the speaker's face was not predicted by changes in local encoding but rather by enhanced functional connectivity between temporal and inferior frontal cortex. Our results demonstrate a role of auditory-motor interactions in visual speech representations and suggest that functional connectivity along the ventral pathway facilitates speech comprehension in multisensory environments.
Interspecific plastome recombination reflects ancient reticulate evolution inPicea(Pinaceae)
Authors: Sullivan Alexis R. , Schiffthaler Bastian , Lee Thompson Stacey , Street Nathaniel R. , Wang Xiao-Ru
Published: December 2016

Plastid sequences are a cornerstone in plant systematic studies and key aspects of their evolution, such as uniparental inheritance and absent recombination, are often treated as axioms. While exceptions to these assumptions can profoundly influence evolutionary inference, detecting them can require extensive sampling, abundant sequence data, and detailed testing. Using advancements in high-throughput sequencing, we analyzed the whole plastomes of 65 accessions ofPicea,a genus of ~35 coniferous forest tree species, to test for deviations from canonical plastome evolution. Using complementary hypothesis and data-driven tests, we found evidence for chimeric plastomes generated by interspecific hybridization and recombination in the clade comprising Norway spruce (P. abies) and ten other species. Support for interspecific recombination remained after controlling for sequence saturation, positive selection, and potential alignment artifacts. These results reconcile previous conflicting plastid-based phylogenies and strengthen the mounting evidence of reticulate evolution inPicea.Given the relatively high frequency of hybridization and biparental plastid inheritance in plants, we suggest interspecific plastome recombination may be more widespread than currently appreciated and could underlie reported cases of discordant plastid phylogenies.
EEG correlates of working memory performance in females
Authors: Pavlov Yuri G. , Kotchoubey Boris
Published: January 2017

Background

The study investigates oscillatory brain activity during working memory (WM) tasks. The tasks employed varied in two dimensions. First, they differed in complexity from average to highly demanding. Second, we used two types of tasks, which required either only retention of stimulus set or retention and manipulation of the content. We expected to reveal EEG correlates of temporary storage and central executive components of WM and to assess their contribution to individual differences.

Results

Generally, as compared with the retention condition, manipulation of stimuli in WM was associated with distributed suppression of alpha1 activity and with the increase of the midline theta activity. Load and task dependent decrement of beta1 power was found during task performance. Beta2 power increased with the increasing WM load and did not significantly depend on the type of the task.

At the level of individual differences, we found that the high performance (HP) group was characterized by higher alpha rhythm power. The HP group demonstrated task-related increment of theta power in the left anterior area and a gradual increase of theta power at midline area. In contrast, the low performance (LP) group exhibited a drop of theta power in the most challenging condition. HP group was also characterized by stronger desynchronization of beta1 rhythm over the left posterior area in the manipulation condition. In this condition, beta2 power increased in the HP group over anterior areas, but in the LP group over posterior areas.

Conclusions

WM performance is accompanied by changes in EEG in a broad frequency range from theta to higher beta bands. The most pronounced differences in oscillatory activity between individuals with high and low WM performance can be observed in the most challenging WM task.
CircularLogo: A lightweight web application to visualize intra-motif dependencies
Authors: Ye Zhenqing , Ma Tao , Kalmbach Michael T. , Dasari Surendra , Kocher Jean-Pierre A. , Wang Liguo
Published: January 2017

Background

The sequence logo has been widely used to represent DNA or RNA motifs for more than three decades. Despite its intelligibility and intuitiveness, the traditional sequence logo is unable to display the intra-motif dependencies and therefore is insufficient to fully characterize nucleotide motifs. Many methods have been developed to quantify the intra-motif dependencies, but fewer tools are available for visualization.

Result

We developedCircularLogo, a web-based interactive application, which is able to not only visualize the position-specific nucleotide consensus and diversity but also display the intra-motif dependencies. ApplyingCircularLogoto HNF6 binding sites and tRNA sequences demonstrated its ability to show intra-motif dependencies and intuitively reveal biomolecular structure.CircularLogois implemented in JavaScript and Python based on the Django web framework. The program’s source code and user’s manual are freely available athttp://circularlogo.sourceforge.net.CircularLogoweb server can be accessed fromhttp://bioinformaticstools.mayo.edu/circularlogo/index.html.

Conclusion

CircularLogois an innovative web application that is specifically designed to visualize and interactively explore intra-motif dependencies.
Reflections and projections
Authors: Guthrie James , Parker Lee D.
Published: January 2017

Purpose

The purpose of this paper is to reflect on 30 years of Accounting, Auditing & Accountability Journal (AAAJ), and contemplates the future. It makes a case for diversity, including a broad range of theories and research methodologies, as a defining feature of AAAJ. As we have done since 1988 in AAAJ’s first editorial, we continue to urge interdisciplinary accounting researchers to undertake innovative research and be both original and creative, avoiding the narrow focus and detachment from society that is characteristic of globally pervasive North American economics-based accounting research.

Design/methodology/approach

The paper employs an analysis and critique of trends in interdisciplinary research, drawing upon the previous 29 editorials/commentaries published in AAAJ. It also elucidates the field of scholarship associated with AAAJ in 2016 as evidence of the patterning of recent research and publishing trends.

Findings

This paper identifies challenges confronting interdisciplinary researchers in the globalised academic community. These include our obsession with theoretical engorgement and our adversarial rather than cooperative approach to knowledge development. Furthermore, the authors argue that researchers must reflect on their motivation, informing theories and values if they intend to contribute to practice, policy and a wider societal good. Accounting researchers have a responsibility to go beyond observation, engaging in and constructing a more equal and fair society.

Originality/value

This commentary reflects on developments in AAAJ and its community over three decades. The authors also address the wider AAAJ community, including the Asia Pacific Interdisciplinary Research in Accounting (APIRA) conference attendees, AAAJ special issue editors, the editorial board, ad hoc reviewers, authors and supporters across AAAJ’s 30 years.
Development and validation of a unidimensional domain-specific entrepreneurial self-efficacy scale
Authors: Schjoedt Leon , Craig Justin B.
Published: January 2017

Purpose

Given the nature of entrepreneurship, a domain-specific self-efficacy scale should pertain to venture creation, be unidimensional, and be developed and validated using nascent entrepreneurs – persons for whom self-efficacy may be most important. Extant measures employed in entrepreneurship research do not meet all these criteria. The purpose of this paper is to develop and validate a unidimensional entrepreneurial self-efficacy (ESE) scale based on samples of nascent entrepreneurs.

Design/methodology/approach

Data from a sample of nascent entrepreneurs and items from PSED I were used to develop and assess the validity of a new ESE scale. To further establish scale validity, a comparison group from PSED I along with a sample of nascent entrepreneurs from PSED II were employed.

Findings

A unidimensional three-item self-efficacy scale for assessing a person’s belief that s/he can create a new business successfully is developed and validated using samples of nascent entrepreneurs and a control group.

Research limitations/implications

The scale offers opportunity to enhance research-based assessment using a parsimonious, reliable, and valid unidimensional measure of ESE. The scale may enhance future research findings, as well as promoting reconsideration of past research findings, on many issues in the entrepreneurship literature.

Originality/value

This research uses a sample of nascent entrepreneurs to provide a new three-item scale for assessment of ESE that is parsimonious, valid, and unidimensional.
Aphasia and literacy—the insider's perspective
Authors: Kjellén Emma , Laakso Katja , Henriksson Ingrid
Published: December 2016

Background

Few studies have investigated how people with aphasia (PWA) experience literacy skills. Taking the insider's perspective is a way to increase understanding of the individual experiences of literacy among PWA, which may have clinical implications.

Aims

To describe how literacy, i.e., reading and writing, is experienced in everyday life by PWA and to gain insight into the part played by literacy skills in their lives.

Methods & Procedures

A qualitative descriptive research approach was taken. In‐depth interviews were conducted with 12 PWA (six women and six men) who had all lived with aphasia for at least 6 months post‐stroke. The interviews were analysed using qualitative content analysis.

Outcomes & Results

One overarching theme emerged from the data: literacy as an ongoing recovery process. Based on this overarching theme, two subthemes were identified: changes in conditions for literacy (experiences of reading and writing initially post‐onset compared with experiences at the time of the interview); and facing expectations about literacy (participants’ own and other people's expectations of them in terms of literacy).

Conclusions & Implications

The findings are important at a general level in that they indicate that PWA are able to articulate their individual experiences and thoughts about literacy, i.e., reading and writing. Specifically, PWA in this study experience literacy as playing an essential part in their lives and the findings imply that personal experiences are important in the design of reading and writing interventions in speech and language therapy.
Outcomes in patients with diabetes 10 years after liver transplantation
Authors: Ramos‐Prol Agustín , Hervás‐Marín David , García‐Castell Alia , Merino‐Torres Juan F.
Published: December 2016

Background

There are discrepancies between studies regarding the effect of diabetes mellitus on morbidity and mortality in patients undergoing liver transplantation. The aim of the present study was to compare mortality, risk of liver graft rejection, and cardiovascular events in patients with and without diabetes undergoing liver transplantation over a 10‐year follow‐up period.

Methods

A retrospective study was performed on 183 patients who underwent liver transplantation in 2005 and 2006. Mortality and morbidity data were collected until 2016, including information on mortality and survival time, graft rejection and graft survival time, coronary heart disease, stroke, and peripheral arterial ischemia.

Results

During the follow‐up, 41.3% and 27.8% of patients in the groups with and without diabetes, respectively, died. A trend for lower survival time was observed in patients with diabetes, although this effect was not confirmed by the Cox regression model. There was an increased risk of graft rejection in the group with diabetes compared with the group without diabetes (
P
 < 0.001). In the survival analysis, diabetes was associated with reduced graft survival time (
P
 = 0.001). Cardiovascular events were also more likely in the group with diabetes (
P
 = 0.005).

Conclusions

In the present study diabetes was associated with a higher risk of liver graft rejection and cardiovascular events. There was also a trend for higher mortality, although the effect was not statistically significant. These findings suggest that patients with diabetes require a more rigorous pretransplant evaluation and closer monitoring after transplantation in order to try to reduce associated complications.
Effective suppression of atrial fibrillation by the antihistaminic agent antazoline: First experimental insights into a novel antiarrhythmic agent
Authors: Frommeyer Gerrit , Sterneberg Magdalena , Dechering Dirk G. , Kaese Sven , Bögeholz Nils , Pott Christian , Fehr Michael , Bogossian Harilaos , Milberg Peter , Eckardt Lars
Published: December 2016

Introduction

The antihistaminic antazoline (ANT) was reported to be highly effective and safe for rapid conversion of atrial fibrillation (AF). We therefore analyzed underlying mechanisms in an experimental whole‐heart model.

Methods and Results

Isolated and retrogradely perfused rabbit hearts underwent a standardized protocol employing atrial burst pacing‐induced AF in five of 20 hearts under baseline conditions (seven episodes). Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Two monophasic action potential recordings on the left‐ and two on the right atrial epicardium showed a decrease in atrial action potential duration (aAPD, −25 msec, P<.05) and atrial effective refractory period (aERP; −52 msec, P<.01) after infusion of acetylcholine (1 μmol/L) and isoproterenol (1 μmol/L). This led to induction of AF in 14 of 20 hearts (145 episodes). Simultaneous infusion of ANT (20 μmol/L) led to a complete suppression of AF in all inducible hearts. Treatment with ANT also led to a significant increase in aAPD (+41 msec, P<.01) and aERP (+74 msec, P<.05), leading to a marked increase in atrial postrepolarization refractoriness (aPRR, +33 msec, P<.01). Results were compared to 13 rabbits treated with flecainide. Flecainide induced a significant increase in aPRR and resulted in induction of AF in seven of 13 hearts (51 episodes) while 11 of 13 hearts were inducible with acetylcholine and isoproterenol (93 episodes).

Conclusion

Administration of ANT was highly effective in suppressing AF. The antiarrhythmic effect could be explained by a significant increase in postrepolarization refractoriness as a result of a more marked increase in aERP as compared with aAPD.
Targeted P2X7R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction
Authors: Gao Hongmei , Yin Jie , Shi Yugen , Hu Hesheng , Li Xiaolu , Xue Mei , Cheng Wenjuan , Wang Ye , Li Xinran , Li Yongkang , Wang Yu , Yan Suhua
Published: December 2016

Background

Inflammation‐dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although P2X7R is a key immune mediator, its role has yet to be explored.

Objective

We investigated whether P2X7R regulates NF‐κB and affects cardiac sympathetic reinnervation in rats undergoing MI.

Methods and Results

An adenoviral vector with a short hairpin RNA (shRNA) sequence inserted was adopted for the inhibition of P2X7R in vivo. Myocardial infarction was induced by left coronary artery ligation, and immediately after that, recombinant P2X7R‐shRNA adenovirus, negative adenovirus (control), or normal saline solution (vehicle) was injected intramyocardially around the MI region and border areas. A high level of P2X7R was activated in the infarcted tissue at an early stage. The administration of P2X7R RNAi resulted in the inhibition of Akt and Erk1/2 phosphorylation and decreased the activation of NF‐κB and macrophage infiltration, as well as attenuated the expression of nerve growth factor (NGF). Eventually, the NGF‐induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth‐associated protein 43 (GAP 43). At 7 days post‐MI, the arrhythmia score of programmed electrical stimulation in the vehicle‐treated infarcted rats was higher than the MI‐shRNA group. Further amelioration of cardiac dysfunction was also detected.

Conclusions

The administration of P2X7R RNAi during the acute inflammatory response phase prevented the process of sympathetic hyperinnervation after MI, which was associated in part with inhibiting the Akt and ERK1/2 pathways and NF‐κB activation.
Hydrochlorothiazide modulates ischemic heart failure‐induced cardiac remodeling via inhibiting angiotensin II type 1 receptor pathway in rats
Authors: Luo Jinghong , Chen Xuanlan , Luo Chufan , Lu Guihua , Peng Longyun , Gao Xiuren , Zuo Zhiyi
Published: December 2016

Aims

Our previous study indicates that hydrochlorothiazide inhibits transforming growth factor (TGF)‐β/Smad signaling pathway, improves cardiac function and reduces fibrosis. We determined whether these effects were common among the diuretics and whether angiotensin II receptor type 1 (AT1) signaling pathway played a role in these effects.

Methods

Heart failure was produced by ligating the left anterior descending coronary artery in adult male Sprague Dawley rats. Two weeks after the ligation, 70 rats were randomly divided into five groups: sham‐operated group, control group, valsartan group (80 mg/kg/d), hydrochlorothiazide group (12.5 mg/kg/d) and furosemide group (20 mg/kg/d). In addition, neonatal rat ventricular fibroblasts were treated with angiotensin II.

Results

After eight‐week drug treatment, hydrochlorothiazide group and valsartan group but not furosemide group had improved cardiac function (ejection fraction was 49.4±2.1%, 49.5±1.8% and 39.9±1.9%, respectively, compared with 40.1±2.2% in control group), reduced cardiac interstitial fibrosis and collagen volume fraction (9.7±1.2%, 10.0±1.3% and 14.1±0.8%, respectively, compared with 15.9±1.1% in control group), and decreased expression of AT1, TGF‐β and Smad2 in the cardiac tissues. In addition, hydrochlorothiazide reduced plasma angiotensin II and aldosterone levels. Furthermore, hydrochlorothiazide inhibited angiotensin II‐induced TGF‐β1 and Smad2 protein expression in the neonatal rat ventricular fibroblasts.

Conclusions

Our study indicates that the cardiac function and remodeling improvement after ischemic heart failure may not be common among the diuretics. Hydrochlorothiazide may reduce the left ventricular wall stress and angiotensin II signaling pathway to provide these beneficial effects.
Comparison of early‐ and new‐generation drug‐eluting stent implantations for ostial right coronary artery lesions
Authors: Watanabe Yusuke , Takagi Kensuke , Naganuma Toru , Nakamura Sunao
Published: December 2016

Background

Percutaneous coronary intervention (PCI) with early‐generation drug‐eluting stent (eDES) implantation for ostial right coronary artery (RCA) lesions is challenging because of the frequent need for repeat revascularization. We compared midterm clinical outcomes following eDES or new‐generation DES (nDES) implantation for ostial RCA lesions.

Methods

The study included 150 patients with ostial RCA lesions, 76 treated with eDES and 74 with nDES between January 2005 and September 2013. Study endpoints were major adverse cardiac events (MACEs), specifically all‐cause death, target lesion revascularization (TLR), or myocardial infarction within 2 years after PCI.

Results

Patient characteristics between the groups were similar. The MACE rate was significantly lower in patients treated with nDES compared with those treated with eDES, mainly driven by the lower rates of TLR in the nDES group. Cox regression analysis identified severe chronic kidney disease (CKD) and the use of nDES as the independent predictors of MACE.

Conclusions

The implantation of nDES for ostial RCA lesions significantly reduced the MACE rate compared with early‐generation DES, mainly driven by a reduction in the TLR rate. However, nDES implantations for ostial RCA lesions may still be challenging in patients with severe CKD.
Epac‐Rap1‐activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction
Authors: Khan Irfan , Ali Anwar , Akhter Muhammad Aleem , Naeem Nadia , Chotani Maqsood Ahmed , Iqbal Hana'a , Kabir Nurul , Atiq Mehnaz , Salim Asmat
Published: December 2016

Introduction

Rap1, a member of Ras superfamily of small GTP‐binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth.

Aims

Our aim was to analyze Rap1‐activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation.

Methods

Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery. MSCs were treated with 8‐pCPT‐2′‐O‐Me‐cAMP (CPT) to activate Rap1. Normal (untreated) and CPT‐treated MSCs were transplanted through intramyocardial injection in respective groups. Cardiac function was assessed by echocardiography at 2 and 4 weeks after cell transplantation. Histological analysis was performed to observe changes at tissue level.

Results

Homing of CPT‐treated MSCs was significantly (***P<.001) higher as compared to normal MSCs in the infarcted hearts. This may be due to increase in the gene expression of some of the cell adhesion molecules as evident by qRT‐PCR analysis. Significant (***P<.001) improvement in the restoration of heart function in terms of left ventricular diastolic and systolic internal diameters (LVIDd, LVIDs), % ejection fraction, % fraction shortening and end‐systolic and end‐diastolic volumes were observed in CPT‐treated MSCs as compared to the MI model. Histological analyses showed significant (***P<.001) reduction in scar formation in the CPT‐treated group. Differentiation of treated MSCs into functional cardiomyocytes was evident through immunohistochemical staining. LV wall thickness was also preserved significantly (***P<.001). Blood vessel formation was more pronounced in CPT‐treated group although both cell therapy groups showed significant increase as compared to MI model.

Conclusion

Our findings showed that pharmacological activation of Epac‐Rap1 improves cardiac function through better survival, adhesion and differentiation of transplanted cells. Transplantation of these MSCs in the infarct area restored functional myocardium.
Association of Hospital Resources and Imaging Choice for Appendicitis in Pediatric Emergency Departments
Authors: Fullerton Katherine , Depinet Holly , Iyer Sujit , Hall Matt , Herr Sandra , Morton Inge , Lee Timothy , Melzer‐Lange Marlene
Published: December 2016

Objective

Abdominal pain and concern for appendicitis are common chief complaints in patients presenting to the pediatric emergency department (PED). Although many professional organizations recommend decreasing use of computed tomography (CT) and choosing ultrasound as first‐line imaging for pediatric appendicitis, significant variability persists in imaging utilization. This study investigated practice variation across children's hospitals in the diagnostic imaging evaluation of appendicitis and determined hospital‐level characteristics associated with the likelihood of ultrasound as the first imaging modality.

Methods

This was a multicenter (seven children's hospitals) retrospective investigation. Data from chart review of 160 consecutive patients aged 3–18 years diagnosed with appendicitis from each site were compared with a survey of site medical directors regarding hospital resource availability, usual practices, and departmental‐level demographics.

Results

In the diagnostic evaluation of 1,090 children with appendicitis, CT scan was performed first for 22.4% of patients, with a range across PEDs of 3.1% to 83.8%. Ultrasound was performed for 54.0% of patients with a range of 2.5% to 96.9%. The only hospital‐level factor significantly associated with ultrasound as the first imaging modality was 24‐hour availability of in‐house ultrasound (odds ratio = 29.2, 95% confidence interval = 1.2–691.8).

Conclusion

Across children's hospitals, significant practice variation exists regarding diagnostic imaging in the evaluation of patients with appendicitis. Variation in hospital‐level resources may impact the diagnostic evaluation of patients with appendicitis. Availability of 24‐hour in‐house ultrasound significantly increases the likelihood of ultrasound as first imaging and decreases CT scans. Hospitals aiming to increase the use of ultrasound should consider adding 24‐hour in‐house coverage.
The presence of vaginal Lactobacillus species does not contribute to a measureable difference in amniotic fluid lactate levels collected from the vaginal tract of laboring women
Authors: Hall Beverley , Wong Diana , Healy Clare , Tracy Mark B. , Tracy Sally K. , Rawlinson William D.
Published: December 2016

Introduction

Amniotic fluid lactate research is based on the hypothesis that a relationship exists between fatigued uterine muscles and raised concentrations of the metabolite lactate, which is excreted into the amniotic fluid during labor. To assess potentially confounding effects of lactate‐producing organisms on amniotic fluid lactate measurements, we aimed to determine if the presence of vaginal Lactobacillus species was associated with elevated levels of amniotic fluid lactate, measured from the vaginal tract of women in labor.

Material and methods

Results from this study contribute to a large prospective longitudinal study of amniotic fluid lactate at a teaching hospital in Sydney, Australia. Amniotic fluid lactate measurement was assessed at the time of routine vaginal examination, after membranes had ruptured, using a hand‐held lactate meter StatStripXPress (Nova Biomedical). Vaginal swab samples were collected at the time of the first amniotic fluid lactate measurement and stored for later detection and quantification of Lactobacillus species using a TaqMan real‐time PCR assay. Swab sample and amniotic fluid lactate results were paired and analyzed.

Results

The PCR assay detected Lactobacillus species in 48 of 388 (12%) vaginal swab specimens (8% positive, 4% low positive) collected from women in labor after membranes had ruptured. There was no significant difference in median and mean (respectively) amniotic fluid lactate levels with (8.35 mmol/L; 8.95 mmol/L) or without (8.5 mmol/L; 9.08 mmol/L) Lactobacillus species detected.

Conclusion

There was no association between the presence or level of vaginal Lactobacillus species and the measurement of amniotic fluid lactate collected from the vaginal tract of women during labor.
Restoration of perivascular adipose tissue function in diet‐induced obese mice without changing bodyweight
Authors: Xia Ning , Weisenburger Sabrina , Koch Egon , Burkart Martin , Reifenberg Gisela , Förstermann Ulrich , Li Huige
Published: January 2017

Background and Purpose

We have recently shown that a reduced function of endothelial nitric oxide synthase (eNOS) in the perivascular adipose tissue (PVAT) contributes crucially to obesity‐induced vascular dysfunction in mice. The current study was conducted to test the hypothesis that vascular dysfunction in obesity can be reversed by in vivo improvement of PVAT eNOS activity.

Experimental Approach

Male C57BL/6J mice were fed a high‐fat diet (HFD) for 22 weeks to induce obesity. During the last 4 weeks of HFD feeding, the obese mice were treated p.o. with the standardized Crataegus extract WS® 1442, which has been shown previously to improve eNOS activity.

Key Results

Diet‐induced obesity in mice markedly reduced the vasodilator response of thoracic aorta to acetylcholine in wire myograph experiments. Strikingly, this vascular dysfunction was only evident in PVAT‐containing aorta but not in PVAT‐free aorta. In vivo treatment of obese mice with WS® 1442 had no effect on body weight or epididymal fat mass, but completely restored the vascular function of PVAT‐containing aorta. Feeding a HFD led to a reduced phosphorylation and an enhanced acetylation of PVAT eNOS, both effects were reversed by WS® 1442 treatment.

Conclusion and Implications

PVAT plays a key role in vascular dysfunction in diet‐induced obese mice. Not obesity itself, but a PVAT dysfunction is responsible for obesity‐induced vascular disorders. Improving PVAT function by pharmacological means (e.g. with WS® 1442) can ameliorate vascular function even without reducing body weight or fat mass.

Linked Articles

This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc