bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Risk of theAPOBrs11279109 Polymorphism for CHD among the Kuwaiti Population
Authors: Al-Bustan Suzanne A. , Ismael Fatma G. , Al-Serri Ahmad , Al-Rashdan Ibrahim
Published: December 2017

Background. Coronary heart disease (CHD) is among the leading causes of death in Kuwait. This case-control study investigated the genetic association ofAPOBrs11279109 with CHD in Kuwaitis.Methods. The polymorphism was genotyped in 734 Kuwaiti samples by direct amplification. Statistical analysis with genetic modeling was used to assess its association with CHD.Results. A statistically significant association (P<0.001) between the rs11279109DDgenotype (OR: 2.43, CI: 1.34–4.41) with CHD was observed. A codominant genetic model revealed a 2.69 risk increase (CI: 1.57–4.61) for theDDgenotype (P=0.009) independent of age, sex, BMI, smoking, hypercholesterolemia, and ethnicity suggestingAPOBrs11279109 as an indicator for the increased risk of CHD.Conclusion. TheDDgenotype may explain molecular mechanisms that underline increased LDL oxidation leading to arthrosclerosis. The findings emphasize the need to identify genetic markers specific to the CHD patient ethnic group in order to improve prognosis and help in early diagnosis and prevention.
Xylopine Induces Oxidative Stress and Causes G2/M Phase Arrest, Triggering Caspase‐Mediated Apoptosis by p53‐Independent Pathway in HCT116 Cells
Authors: Santos Luciano de Souza , Silva Valdenizia Rodrigues , Menezes Leociley Rocha Alencar , Soares Milena Botelho Pereira , Costa Emmanoel Vilaça , Bezerra Daniel Pereira
Published: December 2017

Xylopine is an aporphine alkaloid that has cytotoxic activity to cancer cells. In this study, the underlying mechanism of xylopine cytotoxicity was assessed in human colon carcinoma HCT116 cells. Xylopine displayed potent cytotoxicity in different cancer cell lines in monolayer cultures and in a 3D model of cancer multicellular spheroids formed from HCT116 cells. Typical morphology of apoptosis, cell cycle arrest in the G2/M phase, increased internucleosomal DNA fragmentation, loss of the mitochondrial transmembrane potential, and increased phosphatidylserine externalization and caspase‐3 activation were observed in xylopine‐treated HCT116 cells. Moreover, pretreatment with a caspase‐3 inhibitor (Z‐DEVD‐FMK), but not with a p53 inhibitor (cyclic pifithrin‐α), reduced xylopine‐induced apoptosis, indicating induction of caspase‐mediated apoptosis by the p53‐independent pathway. Treatment with xylopine also caused an increase in the production of reactive oxygen/nitrogen species (ROS/RNS), including hydrogen peroxide and nitric oxide, but not superoxide anion, and reduced glutathione levels were decreased in xylopine‐treated HCT116 cells. Application of the antioxidant N‐acetylcysteine reduced the ROS levels and xylopine‐induced apoptosis, indicating activation of ROS‐mediated apoptosis pathway. In conclusion, xylopine has potent cytotoxicity to different cancer cell lines and is able to induce oxidative stress and G2/M phase arrest, triggering caspase‐mediated apoptosis by the p53‐independent pathway in HCT116 cells.
Radar Target Classification Using an Evolutionary Extreme Learning Machine Based on Improved Quantum‐Behaved Particle Swarm Optimization
Authors: Zhao Feixiang , Liu Yongxiang , Huo Kai , Zhang Zhongshuai
Published: December 2017

A novel evolutionary extreme learning machine (ELM) based on improved quantum‐behaved particle swarm optimization (IQPSO) for radar target classification is presented in this paper. Quantum‐behaved particle swarm optimization (QPSO) has been used in ELM to solve the problem that ELM needs more hidden nodes than conventional tuning‐based learning algorithms due to the random set of input weights and hidden biases. But the method for calculating the characteristic length of Delta potential well of QPSO may reduce the global search ability of the algorithm. To solve this issue, a new method to calculate the characteristic length of Delta potential well is proposed in this paper. Experimental results based on the benchmark functions validate the better performance of IQPSO against QPSO in most cases. The novel algorithm is also evaluated by using real‐world datasets and radar data; the experimental results indicate that the proposed algorithm is more effective than BP, SVM, ELM, QPSO‐ELM, and so on, in terms of real‐time performance and accuracy.
D2D-Enabled Small Cell Network Control Scheme Based on the Dynamic Stackelberg Game
Authors: Kim Sungwook
Published: December 2017

For current and future cellular networks, small cell structure with licensed and unlicensed bandwidth, caching content provisioning, and device-to-device (D2D) communications is seen as a necessary architecture. Recently, a series of control methods have been developed to address a myriad of challenges in next-generation small cell networks. In this study, we focus on the design of novel D2D-enabled small cell network control scheme by allowing caching and unlicensed D2D communications. Motivated by game theory and learning algorithm, the proposed scheme adaptively selects caching contents and splits the available bandwidth for licensed and unlicensed communications. Under dynamically changing network environments, we capture the dynamics of the network system and design a new dynamic Stackelberg game model. Based on a hierarchical and feedback based control manner, small base stations and users can be leaders or followers dynamically while improving 5G network performance. Simulations and performance analysis verify the efficiency of the proposed scheme, showing that our approach can outperform existing schemes by about 5%~15% in terms of bandwidth utilization, cache hit ratio, and system throughput.
Association between Fluorescent Advanced Glycation End-Products and Vascular Complications in Type 2 Diabetic Patients
Authors: Guerin-Dubourg Alexis , Cournot Maxime , Planesse Cynthia , Debussche Xavier , Meilhac Olivier , Rondeau Philippe , Bourdon Emmanuel
Published: December 2017

Objectives. Diabetes is a major health problem associated with hyperglycemia and chronically increased oxidative stress and enhanced formation of advanced glycation end-products (AGEs). The aim of this study was to determine whether oxidative plasma biomarkers in diabetic patients could be evidenced and associated with vascular complications. Methods. Oxidative stress biomarkers such as thiols, ischemia-modified albumin (IMA), glycated albumin (GA), fructosamine, and AGEs were measured in 75 patients with poorly controlled type 2 diabetes (HbA1c > 7.5%) with (44) or without (31) vascular disease and in 31 nondiabetic controls. Results. Most biomarkers of oxidation and glycation were significantly increased in diabetic patients in comparison with nondiabetics. Fructosamines, GA, IMA, and AGEs were positively correlated and levels of fluorescent AGEs were significantly increased in the plasma from patients presenting vascular complication. Conclusions. These results bring new evidence for the potential interest of glycated albumin, oxidative stress, and glycoxidation parameters in the monitoring of type 2 diabetic patients. Furthermore, it emphasizes fluorescent AGEs as a putative indicator for vascular event prediction in diabetic patients.
Paeoniflorin, the Main Active Ingredient of Shuyu Capsule, Inhibits Cav1.2 and Regulates Calmodulin/Calmodulin-Dependent Protein Kinase II Signalling
Authors: Song Chunhong , Wang Jieqiong , Gao Dongmei , Yu Yanhong , Li Fang , Wei Sheng , Sun Peng , Wang Meiyan , Qiao Mingqi
Published: December 2017

The aim of this study was to explore the mechanism underlying the antidepression activity of paeoniflorin, the main active ingredient of paeony extract and Shuyu capsules, and determine its effect on the calmodulin/calmodulin-dependent protein kinase II (CaM/CaMKII) signalling pathway and on the possible target, the voltage-gated calcium channel (Cav). Rats at the nonacceptance stage were selected for premenstrual syndrome (PMS) depression modelling. Behavioural assays were used for model testing. Rats were given Shuyu capsules, paeony extract, and bupleurum. Western blot analysis was used to assess the expression levels of calcium voltage-gated channel subunit alpha 1 C (CACNA1C), brain-derived neurotrophic factor, and CaM/CaMKII signalling pathway proteins. Intracellular Ca2+ concentration in CHO cell line was measured using Fluo-4-AM and whole-cell patch clamps. The PMS depression model was successfully established and demonstrated that Shuyu can mitigate depressive behaviour in a rat PMS model. Paeony extract did not affect CACNA1C protein expression in rat hippocampi but did affect Cav1.2-mediated CaM/CaMKII signalling pathways. Paeoniflorin significantly inhibited KCl-induced increases in intracellular Ca2+ concentration and Cav1.2 current density. Further, it may function via the CaM/CaMKII pathway and its downstream signalling molecules by regulating Cav1.2, thus playing an important role in the treatment and alleviation of affective disorders.
Vision-Based Fall Detection with Convolutional Neural Networks
Authors: Núñez-Marcos Adrián , Azkune Gorka , Arganda-Carreras Ignacio
Published: December 2017

One of the biggest challenges in modern societies is the improvement of healthy aging and the support to older persons in their daily activities. In particular, given its social and economic impact, the automatic detection of falls has attracted considerable attention in the computer vision and pattern recognition communities. Although the approaches based on wearable sensors have provided high detection rates, some of the potential users are reluctant to wear them and thus their use is not yet normalized. As a consequence, alternative approaches such as vision-based methods have emerged. We firmly believe that the irruption of the Smart Environments and the Internet of Things paradigms, together with the increasing number of cameras in our daily environment, forms an optimal context for vision-based systems. Consequently, here we propose a vision-based solution using Convolutional Neural Networks to decide if a sequence of frames contains a person falling. To model the video motion and make the system scenario independent, we use optical flow images as input to the networks followed by a novel three-step training phase. Furthermore, our method is evaluated in three public datasets achieving the state-of-the-art results in all three of them.
Synthesis of Peripherally Tetrasubstituted Phthalocyanines and Their Applications in Schottky Barrier Diodes
Authors: Gorduk Semih , Koyun Ozge , Avciata Oguzhan , Altindal Ahmet , Avciata Ulvi
Published: December 2017

New metal-free and metallophthalocyanine compounds (Zn, Co, Ni, and Cu) were synthesized using 2-hydroxymethyl-1,4-benzodioxan and 4-nitrophthalonitrile compounds. All newly synthesized compounds were characterized by elemental analysis, FT-IR, UV-Vis, 1H-NMR, MALDI-TOF MS, and GC-MS techniques. The applications of synthesized compounds in Schottky barrier diodes were investigated. Ag/Pc/p–Si structures were fabricated and charge transport mechanism in these devices was investigated using dc technique. It was observed from the analysis of the experimental results that the charge transport can be described by Ohmic conduction at low values of the reverse bias. On the other hand, the voltage dependence of the measured current for high values of the applied reverse bias indicated that space charge limited conduction is the dominant mechanism responsible for dc conduction. From the observed voltage dependence of the current density under forward bias conditions, it has been concluded that the charge transport is dominated by Poole-Frenkel emission.
Obturator Nerve Schwannoma as a Mimic of Ovarian Malignancy
Authors: Gleason Tyler , Le Brian H. , Parthasarathy Kirthik , Robinson-Bennett Bernice
Published: December 2017

The obturator nerve is an extremely rare location for schwannomas to originate, and such diagnosis is typically not considered among the imaging diagnostic possibilities for a cystic-solid pelvic mass. A 63-year-old female with a known pelvic mass presented with increasing pelvic pain. The mass, which had been followed by serial imaging over five years, was described showing mixed solid and cystic components, likely arising from the left ovary. Although the key diagnosis to be excluded was a primary ovarian malignancy, the patient chose to pursue active surveillance. Over the five years of close observation, the lesion increased slowly, while her CA-125 level showed no significant elevation. Increase in size of the mass and worsening pain and concern for a gynecologic malignancy on MRI led her to ultimately consent to a hysterectomy with bilateral salpingooophorectomy. During the surgery, the mass was noted to be contiguous with the left obturator nerve. Pathologic evaluation revealed a schwannoma (WHO grade I). The patient’s postsurgical course was uneventful, without residual weakness in the left adductor muscles.
T-Cell Densities in Brain Metastases Are Associated with Patient Survival Times and Diffusion Tensor MRI Changes
Authors: Zakaria Rasheed , Platt-Higgins Angela , Rathi Nitika , Radon Mark , Das Sumit , Das Kumar , Bhojak Maneesh , Brodbelt Andrew , Chavredakis Emmanuel , Jenkinson Michael D. , Rudland Philip S.
Published: December 2017

Brain metastases are common and are usually detected by MRI. Diffusion tensor imaging (DTI) is a derivative MRI technique that can detect disruption of white matter tracts in the brain. We have matched preoperative DTI with image-guided sampling of the brain–tumor interface in 26 patients during resection of a brain metastasis and assessed mean diffusivity and fractional anisotropy (FA). The tissue samples were analyzed for vascularity, inflammatory cell infiltration, growth pattern, and tumor expression of proteins associated with growth or local invasion such as Ki67, S100A4, and MMP2, 9, and 13. A lower FA in the peritumoral region indicated more white matter tract disruption and independently predicted longer overall survival times (HR for death = 0.21; 95% confidence interval, 0.06–0.82; P = 0.024). Of all the biological markers studied, only increased density of CD3+ lymphocytes in the same region correlated with decreased FA (Mann–Whitney U, P = 0.037) as well as confounding completely the effect of FA on multivariate survival analyses. We conclude that the T-cell response to brain metastases is not a surrogate of local tumor invasion, primary cancer type, or aggressive phenotype and is associated with patient survival time regardless of these biological factors. Furthermore, it can be assayed by DTI, potentially offering a quick, noninvasive, clinically available method to detect an active immune microenvironment and, in principle, to measure susceptibility to immunotherapy.

Significance: These findings show that white matter tract integrity is degraded in areas where T-cell infiltration is highest, providing a noninvasive method to identify immunologically active microenvironments in secondary brain tumors. Cancer Res; 78(3); 610–6. ©2017 AACR.
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors
Authors: Jardim Denis L. , de Melo Gagliato Débora , Giles Francis J. , Kurzrock Razelle
Published: December 2017

Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.
A Serum Protein Signature Associated with Outcome after Anti–PD-1 Therapy in Metastatic Melanoma
Authors: Weber Jeffrey S. , Sznol Mario , Sullivan Ryan J. , Blackmon Shauna , Boland Genevieve , Kluger Harriet M. , Halaban Ruth , Bacchiocchi Antonietta , Ascierto Paolo A. , Capone Mariaelena , Oliveira Carlos , Meyer Krista , Grigorieva Julia , Asmellash Senait G. , Roder Joanna , Roder Heinrich
Published: December 2017

A mass spectrometry analysis was performed using serum from patients receiving checkpoint inhibitors to define baseline protein signatures associated with outcome in metastatic melanoma. Pretreatment serum was obtained from a development set of 119 melanoma patients on a trial of nivolumab with or without a multipeptide vaccine and from patients receiving pembrolizumab, nivolumab, ipilimumab, or both nivolumab and ipilimumab. Spectra were obtained using matrix-assisted laser desorption/ionization time of flight mass spectrometry. These data combined with clinical data identified patients with better or worse outcomes. The test was applied to five independent patient cohorts treated with checkpoint inhibitors and its biology investigated using enrichment analyses. A signature consisting of 209 proteins or peptides was associated with progression-free and overall survival in a multivariate analysis. The test performance across validation cohorts was consistent with the development set results. A pooled analysis, stratified by set, demonstrated a significantly better overall survival for “sensitive” relative to “resistant” patients, HR = 0.15 (95% confidence interval: 0.06–0.40, P < 0.001). The test was also associated with survival in a cohort of ipilimumab-treated patients. Test classification was found to be associated with acute phase reactant, complement, and wound healing pathways. We conclude that a pretreatment signature of proteins, defined by mass spectrometry analysis and machine learning, predicted survival in patients receiving PD-1 blocking antibodies. This signature of proteins was associated with acute phase reactants and elements of wound healing and the complement cascade. This signature merits further study to determine if it identifies patients who would benefit from PD-1 blockade. Cancer Immunol Res; 6(1); 79–86. ©2017 AACR.
Digital Socialization? An Exploratory Sequential Analysis of Anonymous Adolescent Internet-Social Interaction
Authors: Zizek Boris
Published: December 2017

This paper applies “extensive sequential analyses” as described by Oevermann in 1996 to a personal account posted on the MTV website A Thin Line (ATL), to the respective anonymous responses posted by account readers and to the website as the pragmatic framework of this interaction. This analysis shows that interactive websites are understood as social spaces where one can find a counterpart for intimate, socialization-relevant interaction. This means that a large amount of confidence is placed in the Internet and social media to provide new possibilities for the discussion of central personal life issues. Beyond the reconstruction of this transformation of social reality, this analysis enables the quality of this interaction that competes with traditional socialization contexts to be judged. P, a 17-year-old girl, is able to control the communication of her private problems in a new way through the use of digital interaction structures, filtering the interaction. The anonymous counterparts are assured by the character limits that they only have to participate superficially and without any major involvement. In the case of traditional instances of socialization, such an unattached and filtered interaction is already an expression of its failure. The Internet-based interaction analyzed here lacks key qualities of socialization interaction.
Palmar Telangiectasias: A Cutaneous Sign for Smoking
Authors: Levi Assi , Shechter Ronen , Lapidoth Moshe , Enk Claes D.
Published: December 2017

Background: Telangiectasias are permanent dilations of blood capillaries which appear in a variety of medical conditions. Cutaneous palmar telangiectasias have been postulated to be associated with smoking. Objective: To determine whether a significant correlation exists between palmar telangiectasias and smoking habits. Patients and Methods: A total of 124 volunteers participated in this observational study by allowing physical evaluation of their palms and by completing a questionnaire. Results: Palmar telangiectasias were found to be associated with current or past smoking. Neither age nor gender was found to be a co-contributor. Discussion: Palmar telangiectasias were found to constitute highly specific and sensitive markers for prolonged smoking.
Which Nebulizer Position Should Be Avoided? An Extended Study of Aerosol Delivery and Ventilator Performance during Noninvasive Positive Pressure Ventilation
Authors: Peng Yun , Dai Bing , Hu Chun-Xiang , Su Jia , Tan Wei , Zhao Hong-Wen , Kang Jian
Published: December 2017

Background: Research on the effect of nebulizer location on aerosol delivery during noninvasive ventilation has reached inconsistent conclusions. Objective: To investigate the effects of nebulizer position on aerosol delivery efficiency and ventilator performance during noninvasive ventilation. Methods: The Active Servo Lung 5000 respiratory simulation system (ASL5000) was used to simulate a COPD patient. The noninvasive ventilator was set to the spontaneous breathing mode. Six nebulizer positions, 2 exhalation valve types (single-arch exhalation port and whisper swivel), 4 combinations of inspiratory and expiratory pressure, and 2 respiratory rates were used. Results: Significant differences between nebulizer positions existed in aerosol delivery (p < 0.05). Aerosol delivery efficiency was lower for nebulizer locations on either side of the exhalation valve and next to the ventilator outlet. When the nebulizer was located between the exhalation valve and the simulated lung, increased inspiratory pressure increased and increased expiratory pressure decreased delivery efficiency (both p < 0.05). When the nebulization device was located between the exhalation valve and the ventilator, no obvious trend was observed. Compared to baseline, nebulization lowered the air leakage volume displayed on the ventilator. There were no differences in ventilator performance between different nebulizer positions. Conclusions: The closer the nebulizer was to the exhalation valves or ventilator, the lower the aerosol delivery efficiency. Nebulizer position had little clinically significant effect on ventilator performance.
Late-Onset Alopecia Areata: A Retrospective Cohort Study
Authors: Lyakhovitsky Anna , Gilboa Sarit , Eshkol Anna , Barzilai Aviv , Baum Sharon
Published: December 2017

Background: Alopecia areata is an immune-mediated disease presenting with sudden onset of nonscarring hair loss. Onset is more common earlier in life, and little is known regarding late-onset alopecia areata. Objectives: To describe the epidemiology, clinical patterns, disease course, and outcome of late-onset alopecia areata in Israeli patients referred to a tertiary medical center. Materials and Methods: This retrospective cohort study considered patients whose disease onset occurred at age ≥50 years. Patients were recruited from among all alopecia areata patients visiting a tertiary center between January 2009 and April 2015. Results: Of the 29 people included, 25 (86.2%) were female (female-to-male ratio, 6.2:1). There was a family history of alopecia areata in 17.2%, thyroid disease in 31%, atopic background in 6.9%, and 17/29 (58.6%) reported a significant stressful event. The most common disease pattern was patchy, and disease was mild in the majority of participants. Complete hair regrowth was observed in 82.8% of participants, and 37.9% relapsed. Conclusion: Late-onset alopecia areata is characterized by marked female predominance, less extensive disease, and a high incidence of complete hair regrowth.
Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies
Authors: Lu Yong-Ping , Hasan Ahmed Abdallah , Zeng Shufei , Hocher Berthold
Published: December 2017

Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.
Clinical Evaluation of Continuous Renal Replacement Therapy in Combination with Ultrasound-Guided Percutaneous Transhepatic Gallbladder Drainage for Acute Severe Biliary Pancreatitis: a Retrospective Study
Authors: Zhu Qingyun , Pan Xinting , Cao Yongxian , Wang Hongqiao , Yu Ning , Liu Fuguo , Yang Shigang , Wang Yunlong , Sun Yunbo , Wang Zhengbin
Published: December 2017

Background/Aims: This study aimed to report the clinical efficacy of continuous renal replacement therapy (CRRT) in combination with ultrasound-guided percutaneous transhepatic gallbladder drainage (PTGD) (CRRT+PTGD) in the treatment of acute severe biliary pancreatitis (ASBP). Methods: Between January 2010 and January 2016, 40 cases of patients with ASBP who received routine CRRT (CRRT group) and 40 of those who received CRRT+PTGD (CRRT+PTGD group) at the Affiliated Hospital of Qingdao University (Qingdao, China) were retrospectively reviewed. Clinical (including abdominal pain remission time, gastrointestinal decompression time, Intensive Care Unit (ICU) hospital stay, respirator treatment time, and mortality rate), laboratory (white blood cells [WBC], platelet [PLT], procalcitonin [PCT], C-reactive protein [CRP], total bilirubin [TBIL], alanine aminotransferase [ALT], albumin [ALB], and blood lactic acid [Lac]) parameters, various critical disease scores, and incidence of complications after the treatment were compared between the two groups. Results: Compared with those in the routine CRRT group, patients in the CRRT+PTGD group exhibited significant remission of clinical symptoms (i.e. shorter abdominal pain remission time, gastrointestinal decompression time, respirator treatment time and ICU hospital stay) (all P<0.05), change of laboratory parameters (WBC, PLT, PCT, CRP, TBIL, ALT) (P<0.05), and improvement of various critical disease scores (P<0.05). Moreover, the variation of most of the above parameters after versus before the treatment was greater in the CRRT+PTGD group than in the CRRT group (all P<0.05). Conclusion: CRRT in combination with PTGD is more effective in the treatment of ASBP than CRRT alone.
Fstl1 Promotes Glioma Growth Through the BMP4/Smad1/5/8 Signaling Pathway
Authors: Jin Xin , Nie Er , Zhou Xu , Zeng Ailiang , Yu Tianfu , Zhi Tongle , Jiang Kuan , Wang Yingyi , Zhang Junxia , You Yongping
Published: December 2017

Background: Gliomas result in the highest morbidity and mortality rates of intracranial primary central nervous system tumors because of their aggressive growth characteristics and high postoperative recurrence. They are characterized by genetic instability, intratumoral histopathological variability and unpredictable clinical behavior in patients. Proliferation is a key aspect of the clinical progression of malignant gliomas, complicating complete surgical resection and enabling tumor regrowth and further proliferation of the surviving tumor cells. Methods: The expression of Fstl1 was detected by western blotting and qRT-PCR. We used cell proliferation and colony formation assays to measure proliferation. Then, flow cytometry was used to analyze cell cycle progression. The expression of Fstl1, p-Smad1/5/8 and p21 in GBM tissue sections was evaluated using immunohistochemical staining. Furthermore, we used coimmunoprecipitation (Co-IP) and immunoprecipitation to validate the relationship between Fstl1, BMP4 and BMPR2. Finally, we used orthotopic xenograft studies to measure the growth of tumors in vivo. Results: We found that follistatin-like 1 (Fstl1) was upregulated in high-grade glioma specimens and that its levels correlated with poor prognosis. Fstl1 upregulation increased cell proliferation, colony formation and cell cycle progression, while its knockdown inhibited these processes. Moreover, Fstl1 interacted with bone morphogenetic protein (BMP) 4, but not BMP receptor (BMPR) 2, and competitively inhibited their association. Furthermore, Fstl1 overexpression suppressed the activation of the BMP4/Smad1/5/8 signaling pathway, while BMP4 overexpression reversed this effect. Conclusion: Our study demonstrated that Fstl1 promoted glioma growth through the BMP4/Smad1/5/8 signaling pathway, and these findings suggest potential new glioblastoma treatment strategies.
Genetic Testing in Pediatric Left Ventricular Noncompaction
Authors: Miller Erin M. , Hinton Robert B. , Czosek Richard , Lorts Angela , Parrott Ashley , Shikany Amy R. , Ittenbach Richard F. , Ware Stephanie M.
Published: December 2017

Background—

Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield.

Methods and Results—

One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic etiology, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, etiology, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively;
P
<0.01).

Conclusions—

Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy.
Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia
Authors: Bermúdez-Jiménez Francisco José , Carriel Víctor , Brodehl Andreas , Alaminos Miguel , Campos Antonio , Schirmer Ilona , Milting Hendrik , Abril Beatriz Álvarez , Álvarez Miguel , López-Fernández Silvia , García-Giustiniani Diego , Monserrat Lorenzo , Tercedor Luis , Jiménez-Jáimez Juan
Published: December 2017

Background:

Desmin (
DES
) mutations cause severe skeletal and cardiac muscle disease with heterogeneous phenotypes. Recently,
DES
mutations were described in patients with inherited arrhythmogenic right ventricular cardiomyopathy/dysplasia, although their cellular and molecular pathomechanisms are not precisely known. Our aim is to describe clinically and functionally the novel
DES
-p.Glu401Asp mutation as a cause of inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia.

Methods:

We identified the novel
DES
mutation p.Glu401Asp in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia and a high incidence of adverse cardiac events. A full clinical evaluation was performed on all mutation carriers and noncarriers to establish clinical and genetic cosegregation. In addition, desmin, and intercalar disc–related proteins expression were histologically analyzed in explanted cardiac tissue affected by the
DES
mutation. Furthermore, mesenchymal stem cells were isolated and cultured from 2 family members with the
DES
mutation (1 with mild and 1 with severe symptomatology) and a member without the mutation (control) and differentiated ex vivo to cardiomyocytes. Then, important genes related to cardiac differentiation and function were analyzed by real-time quantitative polymerase chain reaction. Finally, the p.Glu401Asp mutated
DES
gene was transfected into cell lines and analyzed by confocal microscopy.

Results:

Of the 66 family members screened for the
DES
-p.Glu401Asp mutation, 23 of them were positive, 6 were obligate carriers, and 2 were likely carriers. One hundred percent of genotype-positive patients presented data consistent with inherited arrhythmogenic cardiomyopathy/dysplasia phenotype with variable disease severity expression, high-incidence of sudden cardiac death, and absence of skeletal myopathy or conduction system disorders. Immunohistochemistry was compatible with inherited arrhythmogenic cardiomyopathy/dysplasia, and the functional study showed an abnormal growth pattern and cellular adhesion, reduced desmin RNA expression, and some other membrane proteins, as well, and desmin aggregates in transfected cells expressing the mutant desmin.

Conclusions:

The
DES
-p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.
Functional Metabolomics Characterizes a Key Role for
N
-Acetylneuraminic Acid in Coronary Artery Diseases
Authors: Zhang Lei , Wei Ting-Ting , Li Yong , Li Jing , Fan Yong , Huang Feng-Qing , Cai Yuan-Yuan , Ma Gaoxiang , Liu Jin-Feng , Chen Qian-Qian , Wang Shi-Lei , Li Honglin , Alolga Raphael N. , Liu Baolin , Zhao Dong-Sheng , Shen Jian-Hua , Wang Xiang-Ming , Zhu Wei , Li Ping , Qi Lian-Wen
Published: December 2017

Background:

As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms.

Methods:

A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker
N
-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models.

Results:

We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (
P
=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury.

Conclusions:

Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
Astrocytic Lrp4 (Low-Density Lipoprotein Receptor–Related Protein 4) Contributes to Ischemia-Induced Brain Injury by Regulating ATP Release and Adenosine-A
2A
R (Adenosine A2A Receptor) Signaling
Authors: Ye Xin-Chun , Hu Jin-Xia , Li Lei , Li Qiang , Tang Fu-Lei , Lin Sen , Sun Dong , Sun Xiang-Dong , Cui Gui-Yun , Mei Lin , Xiong Wen-Cheng
Published: December 2017

Background and Purpose—

Lrp4 (low-density lipoprotein receptor–related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4’s function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis.

Methods—

The brain-specific Lrp4 conditional knockout mice (Lrp4
GFAP-Cre
), astrocytic-specific Lrp4 conditional knockout mice (Lrp4
GFAP-creER
), and their control mice (Lrp4
f/f
) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A
2A
R (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate,
d
-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured.

Results—

Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4
GFAP-Cre
and Lrp4
GFAP-creER
mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P
2
X
7
R or adenosine-A
2A
R signaling diminished Lrp4
GFAP-creER
’s protective effect.

Conclusions—

The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A
2A
R signaling.
Spectral Diversity in Default Mode Network Connectivity Reflects Behavioral State
Authors: Craig Michael M. , Manktelow Anne E. , Sahakian Barbara J. , Menon David K. , Stamatakis Emmanuel A.
Published: December 2017

Default mode network (DMN) functional connectivity is thought to occur primarily in low frequencies (<0.1 Hz), resulting in most studies removing high frequencies during data preprocessing. In contrast, subtractive task analyses include high frequencies, as these are thought to be task relevant. An emerging line of research explores resting fMRI data at higher-frequency bands, examining the possibility that functional connectivity is a multiband phenomenon. Furthermore, recent studies suggest DMN involvement in cognitive processing; however, without a systematic investigation of DMN connectivity during tasks, its functional contribution to cognition cannot be fully understood. We bridged these concurrent lines of research by examining the contribution of high frequencies in the relationship between DMN and dorsal attention network at rest and during task execution. Our findings revealed that the inclusion of high frequencies alters between network connectivity, resulting in reduced anticorrelation and increased positive connectivity between DMN and dorsal attention network. Critically, increased positive connectivity was observed only during tasks, suggesting an important role for high-frequency fluctuations in functional integration. Moreover, within-DMN connectivity during task execution correlated with RT only when high frequencies were included. These results show that DMN does not simply deactivate during task execution and suggest active recruitment while performing cognitively demanding paradigms.
Changes in Frontoparietotemporal Connectivity following Do-As-I-Do Imitation Training in Chimpanzees (Pan troglodytes)
Authors: Pope Sarah M. , Taglialatela Jared P. , Skiba Sara A. , Hopkins William D.
Published: December 2017

Human imitation is supported by an underlying “mirror system” principally composed of inferior frontal, inferior parietal, and superior temporal cortical regions. Across primate species, differences in frontoparietotemporal connectivity have been hypothesized to explain phylogenetic variation in imitative abilities. However, if and to what extent these regions are involved in imitation in nonhuman primates is unknown. We hypothesized that “Do As I Do” (DAID) imitation training would enhance white matter integrity within and between frontoparietotemporal regions. To this end, four captive chimpanzees ( Pan troglodytes) were trained to reproduce 23 demonstrated actions, and four age-/sex-matched controls were trained to produce basic husbandry behaviors in response to manual cues. Diffusion tensor images were acquired before and after 600 min of training over an average of 112 days. Bilateral and asymmetrical changes in frontoparietotemporal white matter integrity were compared between DAID trained subjects and controls. We found that imitation trained subjects exhibited leftward shifts in both mean fractional anisotropy and tract strength asymmetry measures in brain regions within the mirror system. This is the first report of training-induced changes in white matter integrity in chimpanzees and suggests that frontoparietotemporal connectivity, particularly in the left hemisphere, may have facilitated the emergence of increasingly complex imitation learning abilities.
Caring and Carers: Diplomatic Personnel and the Duty of Care
Authors: Leira Halvard
Published: December 2017

This article deals with the duty of care that states hold in relation to their citizens abroad — more specifically, the double role of diplomatic personnel, as both providers and recipients of care. The focus of discussion is states’ duty of care for diplomatic personnel, raising questions of how this care can be balanced with the duty of care for citizens and how far this duty stretches. The article first emphasizes the threats, before focusing on the means of protection: evacuation; physical structures; and psychological care. A tension remains, for as states fulfil their duty of care towards personnel through increasing security, they might at the same time reduce their personnel’s capacity to provide care for citizens. One solution for this tension — outsourcing and local personnel — tests the limits of care.
The Effect of Visual and Auditory Information on the Perception of Pleasantness and Roughness of Virtual Surfaces
Authors: Etzi Roberta , Ferrise Francesco , Bordegoni Monica , Zampini Massimiliano , Gallace Alberto
Published: December 2017

Despite the large number of studies on the multisensory aspects of tactile perception, very little is known regarding the effects of visual and auditory sensory modalities on the tactile hedonic evaluation of textures, especially when the presentation of the stimuli is mediated by a haptic device. In this study, different haptic virtual surfaces were rendered by varying the static and dynamic frictional coefficients of a Geomagic®Touch device. In Experiment 1, the haptic surfaces were paired with pictures representing everyday materials (glass, plastic, rubber and steel); in Experiment 2, the haptic surfaces were paired with sounds resulting from the haptic exploration of paper or sandpaper. In both the experiments, participants were required to rate the pleasantness and the roughness of the virtual surfaces explored. Exploration times were also recorded. Both pleasantness and roughness judgments, as well as the durations of exploration, varied as a function of the combinations of the visuo-tactile and the audio-tactile stimuli presented. Taken together, these results suggest that vision and audition modulate haptic perception and hedonic preferences when tactile sensations are provided through a haptic device. Importantly, these results offer interesting suggestions for designing more pleasant, and even more realistic, multisensory virtual surfaces.