bluuebunny/crossref_metadata_2025 huggingface dataset:
LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling
Authors: Pan Enhui , Zhao Zirun , McNamara James O.
Published: December 2018

Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLINs), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to execution of memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High-frequency stimulation of the mossy fibers induces long-term depression (LTD) of their calcium-permeable AMPA receptor synapses with SLINs; previous work localized the site of induction to be postsynaptic and the site of expression to be presynaptic. Yet, the underlying signaling events and the identity of the retrograde signal are incompletely understood. We used whole cell recordings of SLINs in hippocampal slices from wild-type and mutant mice to explore the mechanisms. Genetic and pharmacologic perturbations revealed a requirement for both the receptor tyrosine kinase TrkB and its agonist, brain-derived neurotrophic factor (BDNF), for induction of LTD. Inclusion of inhibitors of Trk receptor kinase and PLC in the patch pipette prevented LTD. Endocannabinoid receptor antagonists and genetic deletion of the CB1 receptor prevented LTD. We propose a model whereby release of BDNF from mossy fiber filopodia activates TrkB and PLCγ1 signaling postsynaptically within SLINs, triggering synthesis and release of an endocannabinoid that serves as a retrograde signal, culminating in reduced glutamate release. Insights into the signaling pathways by which activity modifies function of these synapses will facilitate an understanding of their contribution to the local circuit and behavioral consequences of hippocampal granule cell activity.

NEW & NOTEWORTHY We investigated signaling mechanisms underlying plasticity of the hippocampal mossy fiber filopodial synapse with interneurons in stratum lucidum. High-frequency stimulation of the mossy fibers induces long-term depression of this synapse. Our findings are consistent with a model in which brain-derived neurotrophic factor released from filopodia activates TrkB of a stratum lucidum interneuron; the ensuing activation of PLCγ1 induces synthesis of an endocannabinoid, which provides a retrograde signal leading to reduced release of glutamate presynaptically.
Structure, Gating, and Regulation of the CFTR Anion Channel
Authors: Csanády László , Vergani Paola , Gadsby David C.
Published: December 2018

The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP–dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR’s ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed.
Bogijetong Decoction and Its Selected Formulation Are Involved in Alleviating Neuropathic Pain in a Rat Model of Chronic Constrictive Injury
Authors: Kim Ki-Joong , Ahn Hye-Jeong , Namgung Uk , Cho Chung Sik
Published: December 2018

Bogijetong decoction (BGJTD) is a formulation that is used for the treatment of neuropathic pain caused by cancer therapy, diabetes, and peripheral nerve injury. In the previous study, we selected four herbal constituents from BGJTD, formulated new decoction (BeD), and demonstrated its efficacy on the neuroprotection of peripheral sciatic nerve in streptozotocin‐induced diabetic animals. Here, we report attenuating effects of BGJTD and BeD on neuropathic pain. Neuropathic pain was induced by ligation of the sciatic nerve to generate chronic constrictive injury (CCI). BeD was more effective than BGJTD in alleviating neuropathic pain lasting 3 – 4 weeks after CCI. In vivo administration of BeD did not alter the levels of brain‐derived neurotrophic factor (BDNF) which were strongly induced by CCI in the sciatic nerve but downregulated TrkB production in the sciatic nerve. Downregulation of TrkB signals by BeD was confirmed in cultured DRG neurons. BGJTD was more effective in attenuating TNF‐α production in the sciatic nerve than BeD, whereas BeD increased IL‐6 more efficiently than BGJTD. Furthermore, phopsho‐Erk1/2 was increased in the sciatic nerve and dorsal root ganglia (DRG) after BeD treatment. Neurite outgrowth of primary DRG neurons prepared from rats which had undergone CCI for 7 days was significantly increased in BeD‐treated group of animals compared to the control and BGJTD‐treated groups. Compositional comparison of BeD revealed that the neurite outgrowth was facilitated by the treatments of Panax ginseng and Paeonia lactiflora. Together, these data suggest that BeD induces unique molecular response at the injury site and may trigger retrograde signaling into the neuronal cell body to modulate pain responses.
Development of New Tools to Detect Colistin-Resistance among Enterobacteriaceae Strains
Authors: Bardet Lucie , Rolain Jean-Marc
Published: December 2018

The recent discovery of the plasmid-mediatedmcr-1gene conferring resistance to colistin is of clinical concern. The worldwide screening of this resistance mechanism among samples of different origins has highlighted the urgent need to improve the detection of colistin-resistant isolates in clinical microbiology laboratories. Currently, phenotypic methods used to detect colistin resistance are not necessarily suitable as the main characteristic of themcrgenes is the low level of resistance that they confer, close to the clinical breakpoint recommended jointly by the CLSI and EUCAST expert systems (S ≤ 2 mg/L andR > 2 mg/L). In this context, susceptibility testing recommendations for polymyxins have evolved and are becoming difficult to implement in routine laboratory work. The large number of mechanisms and genes involved in colistin resistance limits the access to rapid detection by molecular biology. It is therefore necessary to implement well-defined protocols using specific tools to detect all colistin-resistant bacteria. This review aims to summarize the current clinical microbiology diagnosis techniques and their ability to detect all colistin resistance mechanisms and describe new tools specifically developed to assess plasmid-mediated colistin resistance. Phenotyping, susceptibility testing, and genotyping methods are presented, including an update on recent studies related to the development of specific techniques.
The Political Complexity of Regional Electricity Policy Formation
Authors: Yoo Kyungjin , Blumsack Seth
Published: December 2018

The integration of renewable power supplies into existing electrical grids, or other major technology transitions in electric power, is a complex sociotechnical process. While the technical challenges are well‐understood, the process of adapting electricity policy and market rules to these new technologies is understudied. Planning and market rules are a critical determinant of the technical success of renewable energy integration efforts and the financial viability of renewable energy investments. Organizational adaptation can be particularly complex in electric power, where transmission grids cross multiple political boundaries and decisions are made not by central authorities or governments, but in cooperative regional frameworks that must accommodate many divergent interests. We add to a recently emerging literature on the governance of regional organizations that plan and operate electric power grids by developing and illustrating a novel approach to the study of political power in multistakeholder electricity organizations. We use semistructured interviews with participants in a specific regional electric grid authority, the PJM Regional Transmission Operator in the Mid‐Atlantic United States, to elicit perceptions of where tensions arise in stakeholder‐driven processes for changing PJM’s rules and perceptions of those groups of stakeholders that possess political power. We treat these perceptions as hypotheses that can be evaluated empirically using five years of data from PJM on how stakeholders voted on a wide variety of regional electricity policy issues. Representing voting behavior as a network, we use a community detection method to identify strong coalitions of stakeholders in PJM that provide support for some stakeholder perceptions of political power and refute other perceptions. The degree distribution of the voting network exhibits a fat tail relative to those in other canonical graph models. We show, using relatively simple network metrics including degree, betweenness, and the mixing parameter, that the reason for this fat tail in the degree distribution is the existence of “swing” voters in RTO stakeholder networks. These voters are identifiable in the tail of the degree distribution of the voting network and are influential in pushing highly contentious rule change proposals towards passage or failure. The method we develop is generalizable to other contexts and provides a new framework for the study of regional electricity policy formation.
Dynamic Evolution of Traveler’s Bounded-Rational Route Choice Behavior
Authors: Long Xueqin , Zhang Liancai , Wang Yuejiao , Guan Hongzhi
Published: December 2018

Travelers’ route choice shows bounded-rationality because of different perceptions of route attributes. Based on the bounded-rationality, the paper proposes the dynamic evolution rules and route choice model, and simulation method is applied to study the evolution process and results. The model includes three parameters reflecting the bounded-rationality of travelers. First, simulation results show that the bounded-rationality affects the evolution process. The switching threshold or the perception deviance is larger, convergence rate is faster, and shorter time is needed to reach equilibrium state. Also, fewer perfect rational travelers will lead to similar results. Second, the system can reach equilibrium and the final equilibrium volume of every route is almost unaffected by bounded-rationality. The equilibrium volume of every route is an approximately fixed value under all simulation scenes. At last, it is found that equilibrium volume of every route obeys normal distribution. That is, bounded-rationality affects the equilibrium convergence rate, but volume equilibrium results will not be influenced.
Bone Loss around Dental Implants 5 Years after Implantation of Biphasic Calcium Phosphate (HAp/βTCP) Granules
Authors: Klimecs Vadims , Grishulonoks Alexanders , Salma Ilze , Neimane Laura , Locs Janis , Saurina Eva , Skagers Andrejs
Published: December 2018

Biphasic calcium phosphate ceramic granules (0.5–1.0 mm) with a hydroxyapatite and β-tricalcium phosphate ratio of 90/10 were used. Biphasic calcium phosphate ceramic granules produced in the Riga Technical University, Riga Rudolph Cimdins Biomaterials Innovation and Development Centre, were used for filling the bone loss on 18 patients with peri-implantitis. After 5 years at the minimum, clinical and 3D cone-beam computed tomography control was done. Clinical situation confirmed good stability of implants without any signs of inflammation around. Radiodensity of the previous gap and alveolar bone horizontally from middle point of dental implants showed similar radiodensity as in normal alveolar bone. This trial is registered with ISRCTN13514478.
Evaluation of Roundabout Safety Performance through Surrogate Safety Measures from Microsimulation
Authors: Giuffrè Orazio , Granà Anna , Tumminello Maria Luisa , Giuffrè Tullio , Trubia Salvatore , Sferlazza Antonino , Rencelj Marko
Published: December 2018

The paper presents a microsimulation-based approach for roundabout safety performance evaluation. Based on a sample of Slovenian roundabouts, the vehicle trajectories exported from AIMSUN and VISSIM were used to estimate traffic conflicts using the Surrogate Safety Assessment Model (SSAM). AIMSUN and VISSIM were calibrated for single-lane, double-lane and turbo roundabouts using the corresponding empirical capacity function which included critical and follow-up headways estimated through meta-analysis. Based on calibration of the microsimulation models, a crash prediction model from simulated peak hour conflicts for a sample of Slovenian roundabouts was developed. A generalized linear model framework was used to estimate the prediction model based on field collected crash data for 26 existing roundabouts across the country. Peak hour traffic distribution was simulated with AIMSUN, and peak hour conflicts were then estimated with the SSAM applying the filters identified by calibrating AIMSUN and VISSIM. The crash prediction model was based on the assumption that the crashes per year are a function of peak hour conflicts, the ratio of peak hour traffic volume to average daily traffic volume and the roundabout outer diameter. Goodness-of-fit criteria highlighted how well the model fitted the set of observations also better than the SSAM predictive model. The results highlighted that the safety assessment of any road unit may rely on surrogate safety measures, but it strongly depends on microscopic traffic simulation model used.
Evaluation of MAV/UAV Collaborative Combat Capability Based on Network Structure
Authors: Fan Jieru , Li Dongguang , Li Rupeng
Published: December 2018

The collaborative combat of manned/unmanned aerial vehicles (MAVs/UAVs) is a popular topic in combat application research. It maximizes the autonomous combat capability of UAVs and the control capability of MAVs. Furthermore, it improves the comprehensive combat effectiveness. The quantitative description of intercommunication in different aircrafts along with the evaluation of the collaborative combat capability is an emphasis in military research. This paper analyzes the collaborative combat process. Node and edge models are established in the MAV/UAV collaborative network. The intercommunication and combat behaviors among combat entities are analyzed. Based on the information entropy, the effect of capability uncertainties on the collaborative combat is described quantitatively. An evaluation method of the MAV/UAV collaborative combat capability is proposed. Finally, an example is given to demonstrate the proposed model and evaluation method that prove its feasibility and effectiveness.
An Approximate Analytical Solution of the Nonlinear Schrödinger Equation with Harmonic Oscillator Using Homotopy Perturbation Method and Laplace-Adomian Decomposition Method
Authors: Jaradat Emad K. , Alomari Omar , Abudayah Mohammad , Al-Faqih Ala’a M.
Published: December 2018

The Laplace-Adomian Decomposition Method (LADM) and Homotopy Perturbation Method (HPM) are both utilized in this research in order to obtain an approximate analytical solution to the nonlinear Schrödinger equation with harmonic oscillator. Accordingly, nonlinear Schrödinger equation in both one and two dimensions is provided to illustrate the effects of harmonic oscillator on the behavior of the wave function. The available literature does not provide an exact solution to the problem presented in this paper. Nevertheless, approximate analytical solutions are provided in this paper using LADM and HPM methods, in addition to comparing and analyzing both solutions.
Key-Skeleton-Pattern Mining on 3D Skeletons Represented by Lie Group for Action Recognition
Authors: Li Guang , Liu Kai , Ding Wenwen , Cheng Fei , Chen Boyang
Published: December 2018

The human skeleton can be considered as a tree system of rigid bodies connected by bone joints. In recent researches, substantial progress has been made in both theories and experiments on skeleton-based action recognition. However, it is challenging to accurately represent the skeleton and precisely eliminate noisy skeletons from the action sequence. This paper proposes a novel skeletal representation, which is composed of two subfeatures to recognize human action: static features and dynamic features. First, to avoid scale variations from subject to subject, the orientations of the rigid bodies in a skeleton are employed to capture the scale-invariant spatial information of the skeleton. The static feature of the skeleton is defined as a combination of the orientations. Unlike previous orientation-based representations, the orientation of a rigid body in the skeleton is defined as the rotations between the rigid body and the coordinate axes in three-dimensional space. Each rotation is mapped to the special orthogonal group SO(3). Next, the rigid-body motions between the skeleton and its previous skeletons are utilized to capture the temporal information of the skeleton. The dynamic feature of the skeleton is defined as a combination of the motions. Similarly, the motions are represented as points in the special Euclidean group SE(3). Therefore, the proposed skeleton representation lies in the Lie group (SE(3)×⋯×SE(3), SO(3)×⋯×SO(3)), which is a manifold. Using the proposed representation, an action can be considered as a series of points in this Lie group. Then, to recognize human action more accurately, a new pattern-growth algorithm named MinP-PrefixSpan is proposed to mine the key-skeleton-patterns from the training dataset. Because the algorithm reduces the number of new patterns in each growth step, it is more efficient than the PrefixSpan algorithm. Finally, the key-skeleton-patterns are used to discover the most informative skeleton sequences of each action (skeleton sequence). Our approach achieves accuracies of 94.70%, 98.87%, and 95.01% on three action datasets, outperforming other relative action recognition approaches, including LieNet, Lie group, Grassmann manifold, and Graph-based model.
Crosstalk between MicroRNAs and Peroxisome Proliferator-Activated Receptors and Their Emerging Regulatory Roles in Cardiovascular Pathophysiology
Authors: Zhang Yin-Feng , Xu Hai-Ming , Yu Fei , Wang Man , Li Meng-Yang , Xu Tao , Gao Yan-Yan , Wang Jian-Xun , Li Pei-Feng
Published: December 2018

Peroxisome proliferator-activated receptors (PPARs) play vital roles in cardiovascular pathophysiology, such as energy balance, cell proliferation/apoptosis, inflammatory response, and adipocyte differentiation. These vital roles make PPARs potential targets for therapeutic prevention of cardiovascular diseases (CVDs). Emerging evidence indicates that the crosstalk of microRNAs (miRNAs) and PPARs contributes greatly to CVD pathogenesis. PPARs are inhibited by miRNAs at posttranscriptional mechanisms in the progress of pulmonary hypertension and vascular dysfunction involving cell proliferation/apoptosis, communication, and normal function of endothelial cells and vascular smooth muscle cells. In the development of atherosclerosis and stroke, the activation of PPARs could change the transcripts of target miRNA through miRNA signalling. Furthermore, the mutual regulation of PPARs and miRNAs involves cell proliferation/apoptosis, cardiac remodeling, and dysfunction in heart diseases. In addition, obesity, an important cardiovascular risk, is modulated by the regulatory axis of PPARs/miRNAs, including adipogenesis, adipocyte dysfunction, insulin resistance, and macrophage polarization in adipose tissue. In this review, the crosstalk of PPARs and miRNAs and their emerging regulatory roles are summarized in the context of CVDs and risks. This provides an understanding of the underlying mechanism of the biological process related to CVD pathophysiology involving the interaction of PPARs and miRNAs and will lead to the development of PPARs/miRNAs as effective anti-CVD medications.
Remark on Remnant and Residue Entropy with GUP
Authors: Li Hui-Ling , Li Wei , Han Yi-Wen
Published: December 2018

In this article, close to the Planck scale, we discuss the remnant and residue entropy from a Rutz-Schwarzschild black hole in the frame of Finsler geometry. Employing the corrected Hamilton-Jacobi equation, the tunneling radiation of a scalar particle is presented, and the revised tunneling temperature and revised entropy are also found. Taking into account generalized uncertainty principle (GUP), we analyze the remnant stability and residue entropy based on thermodynamic phase transition. In addition, the effects of the Finsler perturbation parameter, GUP parameter, and angular momentum parameter on remnant and residual entropy are also discussed.
Blockchain Technology: Is It a Good Candidate for Securing IoT Sensitive Medical Data?
Authors: Rifi Nabil , Agoulmine Nazim , Chendeb Taher Nada , Rachkidi Elie
Published: December 2018

In the past few years, the number of wireless devices connected to the Internet has increased to a number that could reach billions in the next few years. While cloud computing is being seen as the solution to process this data, security challenges could not be addressed solely with this technology. Security problems will continue to increase with such a model, especially for private and sensitive data such as personal data and medical data collected with more and more smarter connected devices constituting the so called Internet of Things. As a consequence, there is an urgent need for a fully decentralized peer‐to‐peer and secure technology solution to overcome these problems. The blockchain technology is a promising just‐in‐time solution that brings the required properties to the field. However, there are still challenges to address before using it in the context of IoT. This paper discusses these challenges and proposes a secure IoT architecture for medical data based on blockchain technology. The solution introduces a protocol for data access, smart contracts and a publisher‐subscriber mechanism for notification. A simple analytical model is also presented to highlight the performance of the system. An implementation of the solution as a proof of concept is also presented.
Autologous Dendritic Cell-Cytokine Induced Killer Cell Immunotherapy Combined with S-1 Plus Cisplatin in Patients with Advanced Gastric Cancer: A Prospective Study
Authors: Qiao Guoliang , Wang Xiaoli , Zhou Lei , Zhou Xinna , Song Yuguang , Wang Shuo , Zhao Lei , Morse Michael A. , Hobeika Amy , Song Jin , Yi Xin , Xia Xuefeng , Ren Jun , Lyerly Herbert Kim
Published: December 2018

Purpose:

We have assessed the combination of DC–CIK with S-1 plus cisplatin chemotherapy in advanced gastric cancer (AGC) and the role of mutational analysis of circulating tumor DNA (ctDNA) and T-cell receptor (TCR) repertoire in predicting clinical outcomes.

Patients and Methods:

Consecutive patients (n = 63) with AGC were allocated to treatment with S-1 alone, S-1 plus cisplatin, DC–CIK combined with S-1 or DC–CIK combined with S-1 plus cisplatin. The primary endpoints were progression-free survival (PFS) and overall survival (OS) at 1 year; the secondary endpoints were disease control rate and analysis of ctDNA and TCR repertoire.

Results:

The DC–CIK infusions were well tolerated with no serious adverse events. The disease control rates (CR+PR+SD) were 5.6%, 33.3%, 47.1%, and 76.9% in the S-1 alone, the S-1 plus cisplatin, DC–CIK combined with S-1 and DC–CIK combined with the S-1 plus cisplatin groups, respectively (P = 0.001). After adjusting for competing risk factors, treatment with DC-CIK combined with S-1 plus cisplatin was confirmed to be an independent predictor of PFS and OS (P = 0.001). A decrease in the frequency and number of mutations in ctDNA was observed in 19 patients (63.3%) following the DC–CIK infusions. Decreased ctDNA mutational frequency and restored TCR repertoire were associated with improved PFS and OS (P = 0.001).

Conclusions:

DC–CIK combined with S-1 plus cisplatin provided a favorable PFS and OS in patients with AGC and the combination therapy was safe with tolerable toxicities. Clinical efficacy correlated with decreases in ctDNA mutational profiles and restored TCR repertoire.
A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus–associated Epithelial Cancers
Authors: Stevanović Sanja , Helman Sarah R. , Wunderlich John R. , Langhan Michelle M. , Doran Stacey L. , Kwong Mei Li M. , Somerville Robert P.T. , Klebanoff Christopher A. , Kammula Udai S. , Sherry Richard M. , Yang James C. , Rosenberg Steven A. , Hinrichs Christian S.
Published: December 2018

Purpose:

Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas.

Patients and Methods:

The trial was a phase II design with two cohorts, cervical cancers and noncervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin.

Results:

Objective tumor responses occurred in 5 of 18 (28%) patients in the cervical cancer cohort and 2 of 11 (18%) patients in the noncervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the noncervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response.

Conclusions:

These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies.
Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma
Authors: Davis Lara E. , Nusser Kevin D. , Przybyl Joanna , Pittsenbarger Janét , Hofmann Nicolle E. , Varma Sushama , Vennam Sujay , Debiec-Rychter Maria , van de Rijn Matt , Davare Monika A.
Published: December 2018

Soft-tissue sarcomas such as leiomyosarcoma pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from leiomyosarcoma clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and FISH. We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3, and murine smooth muscle cell) and in vivo tumor modeling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) patients with leiomyosarcoma, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft-tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer.

Implications:

A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors.
National Trends and Procedural Complications from Endomyocardial Biopsy: Results from the National Inpatient Sample, 2007–2014
Authors: Shah Zubair , Vuddanda Venkat , Rali Aniket S. , Pamulapati Hema , Masoomi Reza , Gupta Kamal
Published: December 2018

Aim: The aim of this study is to report recent trends in the performance of endomyocardial biopsy (EMB) and its in-hospital complications (and their predictors) in the United States (US). Method: We analyzed Nationwide Inpatient Sample (NIS) database from years 2007 through 2014 to identify patients who underwent EMB. Once identified, the patients were subdivided into those with no history of heart transplant (HT) (cohort 1) and those with history of HT (cohort 2). We then studied the major complication of pericardial effusion, hemopericardium or/and cardiac tamponade that required a pericardiocentesis or a pericardial window (CTRPD) following the EMB procedure. Results: We observed a steady increase in the in-patient EMB procedures, with more EMB procedures being performed in males and in Caucasians. In cohort 1, the CTRPD was higher (0.70%) as compared to cohort 2 (0.19; p = 0.01). CTRPD in women was higher compared to men (0.94 vs. 0.53% p = 0.022). Most of the EMB procedures are performed in teaching hospitals. The CTRPD rate was significantly higher in the nonteaching hospitals when compared to teaching hospitals in both cohort 1 and cohort 2 (3.4 vs. 0.53% and 1 vs.0.18%, respectively; p = 0.01 and < 0.001, respectively). The overall mortality in cohort 1 was 4.3% as compared to 2.5% in cohort 2; p = 0.01. In cohort 1, the mortality was significantly higher in the group that had EMB-related complications versus the group without the complications (20 vs. 2.5%; p < 0.001). Conclusion: There has been an increase in the number of EMB procedures in the US in recent years. Though the overall risk of CTRPD is very low, the risk is significantly higher in cohort 1, women, and in nonteaching hospitals. The study results provide data benchmarks for assessing EMB outcomes in the US.
An Animal Model for Wheat Allergy Skin Sensitisation: A Comparative Study in Naive versus Tolerant Brown Norway Rats
Authors: Ballegaard Anne-Sofie Ravn , Madsen Charlotte Bernhard , Bøgh Katrine Lindholm
Published: December 2018

Background: Allergic sensitisation to foods may occur in infancy without prior oral exposure to the offending food, leading to the assumption that food allergy sensitisation may occur through the skin. Concerns have been raised regarding the safety of use of personal care products containing hydrolysed wheat proteins, since these products have been shown to induce allergy through the skin, and even cause an abrogation of an already established oral tolerance. Objective: To establish an animal model for food allergy skin sensitisation and compare the sensitising capacity of an unmodified and an acid-hydrolysed gluten product via slightly damaged skin in naïve versus tolerant rats. Methods: Gluten products were applied on the slightly damaged skin of naïve or tolerant Brown Norway (BN) rats without adjuvant 3 times per week for 3 or 5 consecutive weeks. The effect of the skin applications was evaluated by means of different ELISAs and immunoblotting. Results: A robust animal model was developed for food allergy skin sensitisation. In naïve rats, both gluten products were able to induce a statistically significant level of specific antibodies and sensitise through the skin, but in the wheat-tolerant rats, only the acid-hydrolysed gluten was able to sensitise through the skin, albeit at a level much lower than in the naïve rats. Results showed that new epitopes had been developed as a result of acid hydrolysis but original epitopes were maintained. This may explain why only the acid-hydrolysed gluten could induce specific antibody responses in the tolerant animals. Conclusions: This study showed that it is possible to sensitise BN rats through slightly damaged skin, and that the sensitising capacity is heavily influenced by the tolerance status of their immune system and the degree of modification of the wheat products.
End-Stage Kidney Patients Require Hemodialysis Therapy Full Start
Authors: Chazot Charles , Jean Guillaume
Published: December 2018

Recently the concept that prescription of chronic hemodialysis (HD) start should be tailored based on residual renal function (RRF) and urine output (UO) has been revived from the past and called infrequent or incremental dialysis. It mainly consists in prescribing 1 or 2 HD sessions per week instead of what has become the standard thrice-weekly HD. It is both surprising and fascinating that almost 60 years after the first end-stage kidney disease patient was treated by Scribner et al. [Trans Am Soc Artif Intern Organs 1960; 6: 114–122], the nephrology community still questions the best way to start HD therapy. This comforting process is the result of pieces of evidence accumulated with time such as that RRF is associated with better outcomes that starting HD therapy favors the loss of RRF and/or UO and also results in a high rate of deaths in the first weeks of HD therapy. Through this review, we support the idea that when the decision to start HD therapy is made, ideally with the full collaboration of the patient, it is necessary to be efficient to alleviate uremic symptoms, to correct the fluid overload and to allow a full recovery from the uremic state associated with the late stages of non-dialysis chronic kidney disease.
Body Fluids in End-Stage Renal Disease: Statics and Dynamics
Authors: Kooman Jeroen P. , van der Sande Frank M.
Published: December 2018

Background: Abnormalities in fluid status in hemodialysis (HD) patients are highly prevalent and are related to adverse outcomes. Summary: The inherent discontinuity of the HD procedure in combination with an often compromised cardiovascular response is a major contributor to this phenomenon. In addition, systemic inflammation and endothelial dysfunction are related to extracellular fluid overload (FO). Underlying this relation may be factors such as hypoalbuminemia and an increased capillary permeability, leading to an altered fluid distribution between the blood volume (BV) and the interstitial fluid compartments, compromising fluid removal during dialysis. Indeed, whereas estimates of extracellular volume by bioimpedance spectroscopy are highly predictive of mortality, absolute BV assessed by the saline dilution technique was predictive of intra-dialytic morbidity. Changes in relative BV during HD are positively related to ultrafiltration rate (UFR) and, at least in some studies, negatively to FO. High UFR is also related to changes in central venous oxygen saturation (ScvO2), a marker for tissue perfusion. On the one hand, high UFR and more pronounced declines in ScvO2, but on the other hand, flat relative BV curves are also predictive of mortality; the relation between outcome which statics and dynamics of fluid status appears to be complex. Key Message: While technological developments enable the clinician to monitor statics and dynamics of fluid status and hemodynamics during HD in an accessible way, the role of technology-based interventions needs further study.
Dialysate Calcium Levels: Do They Matter?
Authors: van der Sande Frank M. , ter Meulen Karlien J.A. , Kotanko Peter , Kooman Jeroen P.
Published: December 2018

Background: Calcium (Ca) is an essential element that plays a critical role in many biological processes. In dialysis patients, the regulation of Ca balance is highly complex, given the absence of kidney function, endocrine disturbances and the use of drugs such as phosphate binders, vitamin D analogues, and calcimimetics. Also, the use of different dialysate Ca (DCa) baths has profound effect on Ca balance, which depends both on the difference between the Ca concentration in the bath and the serum of the patients, as on the ultrafiltration volume. Summary: The choice of DCa may have important short- and long-term consequences. While lower DCa (especially < 2.5 mEq/L) concentrations have been associated with an increased risk of sudden cardiac death in observational studies, DCa in the higher ranges (3.0 mEq/L and above) may contribute to vascular pathology. Intra-dialytic hemodynamics may also be affected by the choice of DCa. In general, lower DCa concentrations are associated with an increase, and higher DCa concentrations with a decrease in parathyroid hormone (PTH) levels. Preliminary data has suggested that a DCa of 2.75 mEq/L may help in obtaining a net zero intradialytic Ca balance in individual patients, but clinical experience is still limited. Key Message: The optimal Ca balance depends on multiple parameters including blood Ca levels, PTH and the use of phosphate binders and vitamin D analogues, as well as on the risk of hemodynamic stability and cardiac arrhythmias. Therefore, DCa prescription should be individualised. A DCa of 2.75 mEq/L may be useful adjunct for dialysis providers.
The Vermian-Crest Angle: A New Method to Assess Fetal Vermis Position within the Posterior Fossa Using 3-Dimensional Multiplanar Sonography
Authors: Spinelli Marialuigia , Di Meglio Lavinia , Mosimann Beatrice , Di Naro Edoardo , Surbek Daniel , Raio Luigi
Published: December 2018

Background: Normal morphometry of the vermis and its relation to the posterior fossa (PF) rule out most major anomalies of the cerebellum. However, accurate categorization of the position and size of the fetal vermis remains a challenge. Objective: Our aim was to test a new method to assess the position and size of fetal vermis on 3-dimensional ultrasound (3D-US). Methods: We measured the vermian-crest angle (VCA) in normal fetuses using multiplanar 3D-US. We also assessed the diameters (superoinferior, anteroposterior, and horizontal) and volume of the vermis. The Spearman rank test and linear and polynomial regression analyses were used for statistical purposes. Results: We included 126 fetuses. Mean ± SD gestational age (GA) was 26.3 ± 4.6 (range 17–35.5) weeks. Mean ± SD superoinferior, anteroposterior, and horizontal diameters were 16.2 ± 4.9, 11.2 ± 3.6, and 5.6 ± 1.6 mm, respectively. Median (range) vermian volume was 0.50 (0.05–2.9) cm3. The VCA was 64.49° ± 11.45. We found no correlation between GA and VCA (r = 0.15; p = 0.13), a linear correlation between GA and vermian diameters, and a quadratic correlation between GA and vermian volume. Conclusions: We provide a new method to assess vermian position and size within the PF using 3D-US. The combined information may be of value for screening purposes, particularly to differentiate between the various pathological situations encountered within the PF.
The Chick Caudolateral Epiblast Acts as a Permissive Niche for Generating Neuromesodermal Progenitor Behaviours
Authors: Baillie-Johnson Peter , Voiculescu Octavian , Hayward Penny , Steventon Benjamin
Published: December 2018

Neuromesodermal progenitors (NMps) are a population of bipotent progenitors that maintain competence to generate both spinal cord and paraxial mesoderm throughout the elongation of the posterior body axis. Recent studies have generated populations of NMp-like cells in culture, which have been shown to differentiate to both neural and mesodermal cell fates when transplanted into either mouse or chick embryos. Here, we aim to compare the potential of mouse embryonic stem (ES) cell-derived progenitor populations to generate NMp behaviour against both undifferentiated and differentiated populations. We define NMp behaviour as the ability of cells to: (i) contribute to a significant proportion of the anterior-posterior body axis, (ii) enter into both posterior neural and somitic compartments, and (iii) retain a proportion of the progenitor population within the posterior growth zone. We compare previously identified ES cell-derived NMp-like populations to undifferentiated mouse ES cells and find that they all display similar potentials to generate NMp behaviour in vivo. To assess whether this competence is lost upon further differentiation, we generated anterior and posterior embryonic cell types through the generation of 3D gastruloids and show that NMp competence is lost within the anterior (Brachyury-negative) portion of the gastruloid. Together this suggests that in vitro-derived NMp-like cells maintain an ability to contribute to multiple germ layers that is also present within pluripotent ES cells, rather than acquiring a neuromesodermal competent state through differentiation.
Involvement of the cAMP-Dependent Pathway in Dextromethorphan-Induced Inhibition of Spontaneous Glutamate Transmission in the Nucleus Tractus Solitarius Neurons of Guinea Pigs
Authors: Ohi Yoshiaki , Kodama Daisuke , Haji Akira
Published: December 2018

Dextromethorphan (DEX) presynaptically decreases glutamatergic transmission in second-order neurons of the nucleus tractus solitarius (TS). To clarify the inhibitory mechanism of DEX, the present study examined the interaction of DEX with cAMP. The effects of DEX on miniature and TS-evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) were recorded under activation of the cAMP-dependent pathway using the brainstem slices. An increase in cAMP by forskolin counteracted the inhibitory effect of DEX on mEPSCs. Eight-Bromo-cAMP and N-ethylmaleimide also attenuated the DEX effect. However, forskolin had negligible effects on the DEX-induced inhibition of eEPSCs. This suggests that DEX decreases spontaneous glutamate release by inhibiting the cAMP-dependent pathway and synchronous release by another unknown mechanism.
Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine
Authors: Jalali Mashayekhi Farideh , Rasti Mozhgan , Khoshdel Zahra , Owji Ali Akbar
Published: December 2018

Background: Epigenetic mechanisms such as histone modifications may be involved in the structural and behavioral changes associated with addiction. We studied whether morphine-induced changes in mRNA levels of the catecholamine biosynthesis enzyme, tyrosine hydroxylase (TH), are associated with histone modifications around the promoter of this gene in the locus coeruleus (LC) and ventral tegmental area (VTA) of rats. Methods: Dependence was induced in rats by intraperitoneal injections of morphine for 11 days. The animals were killed 2 h (chronic morphine), 24 h and 7 days (spontaneous withdrawal) after the last injection of morphine. Results: Analysis of our real-time quantitative reverse transcription PCR results by 1-way ANOVA showed significant upregulation (5.13 ± 0.39 folds) of LC levels of the TH transcript 24 h after the last injection of morphine to rats, when compared with 2 h and 7 days time points. Chronic morphine and morphine abstinence failed to cause any significant changes in the levels of TH mRNA in the VTA after cessation of morphine. Consistently, chromatin immunoprecipitation real-time quantitative PCR assays revealed that 24 h after the last injection of morphine, levels of H3 acetylation were significantly increased (4.12 ± 0.38 folds) at the promoter of the TH gene in the LC but not in the VTA. Our data also showed that histone H3 trimethylation failed to change around the TH gene promoter either in the VTA or in the LC after morphine abstinence. Conclusions: Results of the present study, for the first time, demonstrate the involvement of histone H3 acetylation in the regulation of TH gene expression in the LC of rats during forced abstinence from morphine.
Serum Neuroendocrine Markers Predict Therapy Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis
Authors: Liu Yangzhou , Zhao Shankun , Wang Jiamin , Zhu Zhiguo , Luo Lianmin , Li Ermao , Tang Fucai , Zhao Zhigang
Published: December 2018

Purpose: To evaluate whether serum neuroendocrine markers could effectively predict treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: The PubMed, Cochrane Library and Embase databases were sought to identify eligible studies concerning serum neuroendocrine markers and the prognosis of post-treatment mCRPC from inception to April 2018. The association between serum neuroendocrine markers, that is, chromogranin A (CgA) and neurone-specific enolase (NSE), levels and the prognosis of post-treatment mCRPC were summarized using a random-effects model and hazard ratio (HR) with 95% CI Sensitivity analyses were conducted to assess potential bias. Results: A total of 234 participants are included in this meta-analysis (mean age = 71.3 years) from 6 studies. The pooled results show that higher markers’ levels at baseline in patients were associated with unfavorable overall survival (OS; univariate analysis: HR 3.775, 95% CI 1.469–9.698, p = 0.006; multivariate analysis: HR 3.838, 95% CI 1.774–8.304, p = 0.001), and a similar situation was observed in progression-free survival (PFS; univariate analysis: HR 2.785, 95% CI 1.315–5.898, p = 0.007; multivariate analysis: HR 1.266, 95% CI 1.017–1.577, p = 0.035). Estimates of the total effects were generally consistent in the sensitivity analysis. Publication bias was observed when performing the univariate analysis of PFS, and we have the explanation accordingly. Conclusions: The results of this pooled analysis confirm serum neuroendocrine markers could be the effective predictor of treatment outcome in patients with mCRPC. In addition, a combination of CgA and NSE is more valuable to predict worse OS. Further randomized case-control trials are required to validate this relationship.
Corpus, texto e gênero em interação em Semântica estrutural
Authors: Ablali Driss
Published: December 2018

Esta contribuição foca exclusivamente sobre a especificidade do projeto semiótico desenvolvido e Semântica Estrutural de Greimas, projeto que é preciso distinguir do restante da obra do semioticista. Trata-se, resumidamente, de estabelecer que o gesto fundador dessa obra, tanto do ponto de vista epistemológico como heurístico, repousa sobre três categorias descritivas (texto, gênero e corpus) que abrem as linhas não de uma semiótica do texto ou do discurso, mas de uma semântica de corpus.
O corpo do líder carismático: uma perspectiva semiótica
Authors: Pozzato Maria Pia
Published: December 2018

Para retomar a questão da relação carismática sob a chave semiótica, o presente estudo possui três ambições modestas: a primeira, introduzir um ponto de vista especificamente semiótico sobre a questão; a segunda, operar algumas distinções entre conceitos que podem ser facilmente confundidos pela sua contiguidade semântica; a terceira, demonstrar que disciplinas diferentes podem dialogar de maneira profícua. A partir da contraposição entre um corpo-texto e um corpo-dispositivo de semiose em ato, a ideia é apresentar e discutir os vários modelos de inscrição de um significado no corpo do líder carismático, que pode se fazer de tempos em tempos ou suporte estável de uma memória social, ou, ao invés disso, elemento de uma presença inovadora e destruidora da tradição. Nossa proposta se concluirá com o exame da liderança carismática contemporânea, caracterizada por uma notável dependência dos meios de comunicação de massa e para a qual ainda é difícil dar um contorno e uma avaliação.