bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiment and theory at the convergence limit: accurate equilibrium structure of picolinic acid by gas-phase electron diffraction and coupled-cluster computations
Authors: Vogt Natalja , Marochkin Ilya I. , Rykov Anatolii N.
Published: March 2018

High accuracy of structure determination allows observation of fine structural effects, for example, due to formation of the intramolecular hydrogen bond.
Lanthanide atom substitutionally doped blue phosphorene: electronic and magnetic behaviors
Authors: Su Bo , Li Nan
Published: March 2018

Lanthanide-doped blue phosphorene is expected to become a novel dilute magnetic semiconductor material.
Correction: Unravelling the impact of hydrocarbon structure on the fumarate addition mechanism – a gas-phase ab initio study
Authors: Bharadwaj Vivek S. , Vyas Shubham , Villano Stephanie M. , Maupin C. Mark , Dean Anthony M.
Published: March 2018

Correction for ‘Unravelling the impact of hydrocarbon structure on the fumarate addition mechanism – a gas-phase ab initio study’ by Vivek S. Bharadwaj et al., Phys. Chem. Chem. Phys., 2015, 17, 4054–4066.
Localization of transmembrane multiblock amphiphilic molecules in phase-separated vesicles
Authors: Kinbara Kazushi , Umetsu Kaori , Sonobe Hiroki , Muraoka Takahiro , Shimokawa Naofumi , Takagi Masahiro
Published: March 2018

Multiblock-amphiphiles preferentially distribute in the Ld phase and encourage delocalization of cholesterol in both the Ld and Lo phases.
A linear concentration gradient generator based on multi-layered centrifugal microfluidics and its application in antimicrobial susceptibility testing
Authors: Tang Minghui , Huang Xinyu , Chu Qian , Ning Xinghai , Wang Yuye , Kong Siu-Kai , Zhang Xuping , Wang Guanghui , Ho Ho-Pui
Published: March 2018

In almost any branch of chemistry or life sciences, it is often necessary to study the interaction between different components in a system by varying their respective concentrations in a systematic manner.
High crystallization of a multiple cation perovskite absorber for low-temperature stable ZnO solar cells with high-efficiency of over 20%
Authors: Dong Xuemei , Chen Dong , Zhou Junshuai , Zheng Yan-Zhen , Tao Xia
Published: March 2018

A highly crystalline photoactive black phase MA and Cs co-alloying FA triple cation perovskite film on ZnO ETL was prepared via the delicately controlling the MA and Cs compositions and annealing temperature. A high efficiency of 20.44% is achieved.
A luminescent europium-dipicolinic acid nanohybrid for the rapid and selective sensing of pyrophosphate and alkaline phosphatase activity
Authors: Zhao Jiahui , Wang Shuang , Lu Shasha , Sun Jian , Yang Xiurong
Published: March 2018

Aqueous-phase synthesis of the Eu(DPA)3@Lap nanohybrid and its application in the luminescence recognition of Cu2+, PPi, and ALP.
Lewis acid-catalyzed enantiospecific [3 + 2] annulations of γ-butyrolactone fused cyclopropanes with aromatic aldehydes: synthesis of chiral furanolignans
Authors: Shen Yue , Yang Peng-Fei , Yang Gaosheng , Chen Wen-Long , Chai Zhuo
Published: March 2018

An enantiospecific [3 + 2] annulation of γ-butyrolactone fused cyclopropanes with aromatic aldehydes was realized to construct chiral furanolignans.
Correction: Clickable glutathione using tetrazine-alkene bioorthogonal chemistry for detecting protein glutathionylation
Authors: Kekulandara Dilini N. , Samarasinghe Kusal T. G. , Munkanatta Godage Dhanushka N. P. , Ahn Young-Hoon
Published: March 2018

Correction for ‘Clickable glutathione using tetrazine-alkene bioorthogonal chemistry for detecting protein glutathionylation’ by Dilini N. Kekulandara et al., Org. Biomol. Chem., 2016, 14, 10886–10893.
Synthesis, self-assembly and drug release behaviors of reduction-labile multi-responsive block miktobrush quaterpolymers with linear and V-shaped grafts
Authors: Wu Wentao , Dai Wenxue , Zhao Xiaoqi , Zhang Jian , Zhao Youliang
Published: March 2018

Stimuli-tunable topological/morphological transitions and drug release properties based on novel disulfide-functionalized coil–comb–coil quaterpolymers were revealed.
One-step construction of complex polyheterocyclesviaa sequential post-GBB cyclization/spiro ring expansion triggered by a [1,5]-hydride shift
Authors: Balwe Sandip Gangadhar , Jeong Yeon Tae
Published: March 2018

An efficient tandem route to novel amino-indazolo[3′,2′:2,3]imidazo[1,5-c]quinazolin-6(5H)-ones has been explored.
A novel glutathione-triggered theranostic prodrug for anticancer and imaging in living cells
Authors: Zhang Hengrui , Fang Zhijie
Published: March 2018

A novel glutathione-triggered theranostic prodrug was synthesized by conjugating the naphthalimide chromophore and vitamin D2via a disulfide bond.
Solution-processed Cu2ZnSnS4 thin film with mixed solvent and its application in superstrate structure solar cells
Authors: Yan Rongjing , Kang Li , Sun Yuxiu , Zhang Jingbo
Published: March 2018

Solution processed superstrate CZTS solar cells with mixed solvent to adjust CZTS particle size.
Investigation on the structural, morphological, electronic and photovoltaic properties of a perovskite thin film by introducing lithium halide
Authors: Lin Zhenhua , Zhu Hai , Zhou Long , Du Jianhui , Zhang Chunfu , Xu Qing-Hua , Chang Jingjing , Ouyang Jianyong , Hao Yue
Published: March 2018

The effects of lithium dopant on the structural, morphological, electronic and photovoltaic properties of perovskite thin film were discussed.
Dewetting of polymer thin films on modified curved surfaces: preparation of polymer nanoparticles with asymmetric shapes by anodic aluminum oxide templates
Authors: Liu Chih-Ting , Tsai Chia-Chan , Chu Chien-Wei , Chi Mu-Huan , Chung Pei-Yun , Chen Jiun-Tai
Published: March 2018

We study the dewetting behaviors of poly(methyl methacrylate) (PMMA) thin films coated in the cylindrical nanopores of anodic aluminum oxide (AAO) templates by thermal annealing.
Confined co-assembly of AB/BC diblock copolymer blends under 3D soft confinement
Authors: Yan Nan , Liu Xuejie , Zhang Yan , Sun Nan , Jiang Wei , Zhu Yutian
Published: March 2018

A series of novel nanostructures were obtained by co-assembly of AB/BC mixtures under 3D soft confinement.
Synergistic effects of P-doping and a MnO2 cocatalyst on Fe2O3 nanorod photoanodes for efficient solar water splitting
Authors: Rui Qiang , Wang Lei , Zhang Yajun , Feng Chenchen , Zhang Beibei , Fu Shurong , Guo Huilin , Hu Hongyan , Bi Yingpu
Published: March 2018

Herein, we demonstrate that Fe2O3 nanorod photoanodes modified with P-doping and a MnO2 oxygen evolution cocatalyst exhibited a remarkably enhanced PEC water oxidation activity.
Hierarchical nanohoneycomb-like CoMoO4–MnO2 core–shell and Fe2O3 nanosheet arrays on 3D graphene foam with excellent supercapacitive performance
Authors: Kumar Sachin , Saeed Ghuzanfar , Kim Nam Hoon , Lee Joong Hee
Published: March 2018

The hierarchical nanohoneycomb-like CoMoO4–MnO2 core–shell and Fe2O3 nanosheet arrays on 3D graphene foam (GF) are reported and explored their use as a binder-free electrode in supercapacitor applications.
Air-processed mixed-cation Cs0.15FA0.85PbI3 planar perovskite solar cells derived from a PbI2–CsI–FAI intermediate complex
Authors: Xu Xiuwen , Ma Chunqing , Xie Yue-Min , Cheng Yuanhang , Tian Yameng , Li Menglin , Ma Yuhui , Lee Chun-Sing , Tsang Sai-Wing
Published: March 2018

A PbI2–(CsI)0.15–(FAI)x intermediate complex associated with preheating enables air-processed, high-efficiency Cs0.15FA0.85PbI3 PSCs for the first time.
Large scale production of polyacrylonitrile-based porous carbon nanospheres for asymmetric supercapacitors
Authors: Liu Yujing , Cao Jingyi , Jiang Xiaohui , Yang Yange , Yu Liangmin , Yan Xuefeng
Published: March 2018

The increasing demand for a satisfactory combination of energy–power features in supercapacitors has triggered considerable research efforts dedicated to the development of high-efficiency energy storage devices.
Facile synthesis of hierarchical porous manganese nickel cobalt sulfide nanotube arrays with enhanced electrochemical performance for ultrahigh energy density fiber-shaped asymmetric supercapacitors
Authors: Wang Xiaona , Zhang Qichong , Sun Juan , Zhou Zhenyu , Li Qiulong , He Bing , Zhao Jingxin , Lu Weibang , Wong Ching-ping , Yao Yagang
Published: March 2018

Hierarchical porous manganese–nickel–cobalt sulfide multi-tripod nanotube arrays on carbon nanotube fibers are prepared by a simple, cost-effective synthesis process.
Formation of hollow MoS2/carbon microspheres for high capacity and high rate reversible alkali-ion storage
Authors: Yang Tianyu , Liang Ji , Sultana Irin , Rahman Md Mokhlesur , Monteiro Michael J. , Chen Ying (Ian) , Shao Zongping , Silva S. Ravi P. , Liu Jian
Published: March 2018

Inspired by the bird nest, we develop a hydrothermal approach to prepare MoS2/carbon hollow microspheres with a carbon inner shell and a vertically aligned MoS2 outer shell, which show an excellent performance for reversible alkali-metal ion (Li+, Na+ and K+) storage.
Photonic hydrogels for the ultratrace sensing of divalent beryllium in seawater
Authors: Qin Junjie , Dong Bohua , Cao Lixin , Wang Wei
Published: March 2018

Photonic hydrogel sensing materials functionalized with 9-crown-3 are fabricated by a two-step process for the sensitive and selective detection of ultratrace Be2+ ions in seawater.
Highly crystalline new benzodithiophene–benzothiadiazole copolymer for efficient ternary polymer solar cells with an energy conversion efficiency of over 10%
Authors: Tamilavan Vellaiappillai , Liu Yanliang , Lee Jihoon , Jung Yun Kyung , Son Semo , Jeong Junghyun , Park Sung Heum
Published: March 2018

A crystalline medium band-gap polymer is prepared. The binary- and ternary-PSCs made with the polymer offered a PCE of 5% and 10%, respectively.
Efficient triplet harvesting in fluorescence–TADF hybrid warm-white organic light-emitting diodes with a fully non-doped device configuration
Authors: Zhao Juan , Yang Zhan , Chen Xiaojie , Xie Zongliang , Liu Tiantian , Chi Zhihe , Yang Zhiyong , Zhang Yi , Aldred Matthew P. , Chi Zhenguo
Published: March 2018

An efficient triplet harvesting strategy provided for fluorescence–TADF hybrid white OLEDs with a fully non-doped device configuration.
Correlation of the cytotoxic effects of cationic lipids with their headgroups
Authors: Cui Shaohui , Wang Yueying , Gong Yan , Lin Xiao , Zhao Yinan , Zhi Defu , Zhou Quan , Zhang Shubiao
Published: March 2018

As effective non-viral vectors of gene therapy, cationic lipids still have the problem of toxicity, which has become one of the main bottlenecks for their applications.
The subchronic exposure to malathion, an organophosphate pesticide, causes lipid peroxidation, oxidative stress, and tissue damage in rats: the protective role of resveratrol
Authors: Akbel Erten , Arslan-Acaroz Damla , Demirel Hasan Huseyin , Kucukkurt Ismail , Ince Sinan
Published: March 2018

The present study was planned to evaluate the protective role of resveratrol (Res) against subchronic malathion exposure in rats over four weeks.
Knowledge‐aided iterative detection and decoding for multiuser multiple‐antenna systems
Authors: Li Peng , de Lamare Rodrigo C. , Liu Jingjing
Published: March 2018

In this work, the authors assess the performance and latency of a receiver design for multiuser multiple‐antenna systems using low‐density parity‐check (LDPC) codes with iterative detection and decoding (IDD). The proposed knowledge‐aided IDD (KA‐IDD) receiver employs a parallel interference cancellation detector with refined iterative processing and a reweighted belief propagation (BP) decoder. Additionally, two BP‐based decoding algorithms are proposed for improved performance of the decoder. The first cycle knowledge‐aided reweighted‐BP decoder takes advantage of the information about the distribution of cycles in the Tanner graph and the second expansion knowledge‐aided reweighted‐BP decoder expands the original graph into a set of subgraphs, then locally optimises the reweighting parameters of each subgraph. Novel reweighting parameter optimisation strategies are developed for decoding regular or irregular LDPC codes. The developed schemes optimise the parameters off‐line and neither of these proposed algorithms imposes extra computational complexity to the on‐line decoding procedure. Furthermore, the proposed schemes reduce the decoding latency. Simulation results show that the proposed KA‐IDD scheme and algorithms outperform prior art and require a reduced number of decoding iterations.
Wideband microstrip magnetoelectric dipole antenna with stripline aperture‐coupled excitation
Authors: Cui Xuewu , Yang Feng , Gao Min , Liang Zhipeng
Published: March 2018

A novel wideband microstrip magnetoelectric (ME) dipole antenna excited by a stripline aperture‐coupled feeding structure is proposed and demonstrated. An antenna prototype is fabricated with low‐cost standard printed circuit board process on three substrates and tested. Measured results show that an impedance bandwidth for voltage standing wave ratio (VSWR)  < 2 is ∼42% (10.2–15.6 GHz), and a measured boresight gain is ∼7.8 ± 0.7 dBi. Almost stable and symmetrical unidirectional radiation patterns with low in cross‐polarization and backward radiation are obtained over the entire operating frequency band. By employing the proposed radiating element, two types of cavity (one is a square cavity, the other is a circular cavity) are introduced for enhancing the antenna gain and investigated. After analysis, a better one is chosen to be fabricated and measured. A measured impedance bandwidth for VSWR < 2 is ∼45% (10.1–15.9GHz), and a measured boresight gain is ∼8.9 ± 0.5 dBi. The measured average gain is ∼1.1 dBi larger than that of the radiating element. The measured radiation patterns, cross‐polarization levels and half power beam width are almost the same as that of the radiating element except that the measured front‐to‐back ratios are improved several decibels.
Asymptotic theory of gravity modes in rotating stars
Authors: Prat V. , Mathis S. , Augustson K. , Lignières F. , Ballot J. , Alvan L. , Brun A. S.
Published: March 2018

Context. Differential rotation has a strong influence on stellar internal dynamics and evolution, notably by triggering hydrodynamical instabilities, by interacting with the magnetic field, and more generally by inducing transport of angular momentum and chemical elements. Moreover, it modifies the way waves propagate in stellar interiors and thus the frequency spectrum of these waves, the regions they probe, and the transport they generate.

Aims. We investigate the impact of a general differential rotation (both in radius and latitude) on the propagation of axisymmetric gravito-inertial waves.

Methods. We use a small-wavelength approximation to obtain a local dispersion relation for these waves. We then describe the propagation of waves thanks to a ray model that follows a Hamiltonian formalism. Finally, we numerically probe the properties of these gravito-inertial rays for different regimes of radial and latitudinal differential rotation.

Results. We derive a local dispersion relation that includes the effect of a general differential rotation. Subsequently, considering a polytropic stellar model, we observe that differential rotation allows for a large variety of resonant cavities that can be probed by gravito-inertial waves. We identify that for some regimes of frequency and differential rotation, the properties of gravito-inertial rays are similar to those found in the uniformly rotating case. Furthermore, we also find new regimes specific to differential rotation, where the dynamics of rays is chaotic.

Conclusions. As a consequence, we expect modes to follow the same trend. Some parts of oscillation spectra corresponding to regimes similar to those of the uniformly rotating case would exhibit regular patterns, while parts corresponding to the new regimes would be mostly constituted of chaotic modes with a spectrum rather characterised by a generic statistical distribution.
Current paediatric orthopaedic practice in hereditary multiple osteochondromas of the forearm: a systematic review
Authors: EL-Sobky Tamer A. , Samir Shady , Atiyya Ahmed Naeem , Mahmoud Shady , Aly Ahmad S. , Soliman Ramy
Published: March 2018

Introduction: This systematic review aims to answer three research questions concerning the management of hereditary multiple osteochondromas of forearm in children: What is the best available evidence for the currently employed surgical procedures? What patient characteristics are associated with better prognosis? What disease characteristics are associated with better prognosis?

Methods: We searched the literature using three major databases with no publication date restrictions. To enhance search sensitivity and maintain precision we used keywords/subject terms correlating with patient population, problem and interventions. We used strict inclusion/exclusion criteria to improve validity evidence.

Results: The search process yielded 34 eligible studies with a total of 282 patients (315 forearms). We comprehensively analysed study and patient demographics and interventions and outcomes. Eleven studies (32%) had a long-term follow-up and 31 studies (91%) were retrospective. Of the total number of forearms, ulnar lengthening +/− associated procedures was used in 210 forearms (66.7%), isolated osteochondroma excision in 65 forearms (20.6%) and isolated distal radius hemiepiphysiodesis in 15 forearms (4.7%) among others.

Discussion: Ulnar lengthening can restore radiologic anatomy, improve appearance and to a lesser extent objective clinical parameters like joint range of motion on the short/intermediate term. Isolated osteochondroma excision can relief pain and satisfy cosmetic concerns occasionally. There is poor evidence to suggest that surgery improves quality of life or function. Predictors of surgical success in regard to patient and disease characteristics remain elusive. Natural history and prospective randomized control studies where the control group receives no treatment should be rethought. They have the potential for bias control and identification of the ideal surgical candidate. The complex interplay between the confounding variables has undermined the capability of most studies to provide well-grounded evidence to support and generalize their conclusions. Valid quality of life scales should supplement objective outcome measures.
Significance of BRAF V600E Mutation and Cytomorphological Features for the Optimization of Papillary Thyroid Cancer Diagnostics in Cytologically Indeterminate Thyroid Nodules
Authors: Beiša Augustas , Kvietkauskas Mindaugas , Beiša Virgilijus , Stoškus Mindaugas , Ostanevičiūtė Elvyra , Jasiūnas Eugenijus , Griškevičius Laimonas , Šeinin Dmitrij , Šileikytė Auksė , Strupas Kęstutis
Published: March 2018

Background Ultrasound guided fine needle aspiration biopsy with cytologic analysis is an initial step in diagnostic of thyroid nodules. Unfortunately, up to 30% of biopsies are indeterminate and diagnostic surgery is required. The aim of this study was to estimate the diagnostic value of BRAF V600E mutation status combined with cytomorphological features for diagnosis of papillary thyroid cancer (PTC) in cytologically indeterminate thyroid nodules.

Methods A prospective study analyzed patients who had ultrasound suspicious thyroid nodules, underwent fine needle aspiration and cytological examination, and were classified according to the Bethesda system. Patients from indeterminate diagnostic categories were examined for BRAF V600E mutation and 22 cytomorphological features, and underwent thyroid surgery. A binary logistic regression model was used to evaluate the diagnostic utility.

Results A total of 219 patients met study criteria. After histological examination, 77 (35.2%) patients were diagnosed with PTC and 142 (64.8%) with benign nodular thyroid disease. According to logistic regression model, significant features for PTC diagnosis were: liquid colloid consistency, papillary structures, eosinophilic colloid bodies, and BRAF V600E mutation. Risk groups classified by this model have sensitivity of 80.5% (95% CI: 69.9 to 88.7), specificity of 99.3% (95% CI: 96.1 to 100), positive predictive value of 98.4% (95% CI: 89.8 to 99.8), negative predictive value of 90.4% (95% CI: 85.7 to 93.7), and accuracy of 92.7% (95% CI: 88.4 to 95.8) for PTC diagnosis.

Conclusions Evaluation of BRAF V600E mutation status combined with cytomorphological features for diagnosis of PTC in cytologically indeterminate thyroid nodules can significantly improve diagnostic accuracy and reduce the number of diagnostic operations (calculator available at www.ptc-calc.we2host.lt).
Cerebral Salt-Wasting Syndrome in Subarachnoid Hemorrhage: A Primer for Interventional Neuroradiologists
Authors: Rajendran Adhithyan , Kannath Santhosh , Vimala Smitha , Rajan Jayadevan
Published: March 2018

Hyponatremia due to several causes could occur in subarachnoid hemorrhage (SAH), and cerebral salt-wasting syndrome (CSWS) is one of the frequent causes of hyponatremia in this clinical setting. Appropriate clinical diagnosis is important as the treatment is entirely different in various etiologies. In the present report, the authors highlight various clinical and biochemical parameters that help in the recognition of CSWS and discuss its clinical management using a clinical prototype. As neurointerventional radiologists are becoming increasingly involved in the management of intra-cranial aneurysms and SAH, awareness of this entity and its appropriate management is essential in providing optimal care to these patients.
Effects of Second and Third Generation Oral Contraceptives and their Respective Progestagens on the Coagulation System in the Absence or Presence of the Factor V Leiden Mutation
Authors: Kemmeren J. M. , Meijers J. C. M. , Bouma B. N. , Grobbee D. E. , Algra A.
Published: March 2018

Compared to second generation, the use of third generation oral contraceptives has been associated with an increased risk of venous thrombosis especially in women with the factor V Leiden mutation. To find an explanation for these risk differences we investigated the effects of desogestrel- and levonorgestrel-containing oral contraceptives as well as their progestagens separately on the coagulation system in the absence or presence of the factor V Leiden mutation.

In a single center, double blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second generation (30 µg ethinylestradiol/150 µg levonorgestrel) or a third generation (30 µg ethinylestradiol/150 µg desogestrel) oral contraceptive. After two cycles of use and a wash-out period of 2 menstrual cycles, the participants received the corresponding progestagen-only preparation containing 150 µg levonorgestrel or 150 µg desogestrel. In plasmas of the participating women fragment 1+2, factor V, VII, VIII, IX, X and XI were determined.

Both combined oral contraceptives induced a decrease in factor V, whereas the levels of all other coagulant parameters increased. However, in women without the factor V Leiden mutation the effects of desogestrel-containing preparations were significantly different compared to levonorgestrel-containing oral contraceptives for factor V (−8.0; 95% Cl −13.4 to −2.6), factor VIl (26.8; 95% Cl 15.5 to 38.0) and factor IX (−9.6; 95% Cl −16.2 to −3.2). When these women used progestagen-only pills, a differential effect between desogestrel and levonorgestrel was only found for factor IX (−6.5; 95% CI –11.4 to –1.5).

In carriers of the factor V Leiden mutation desogestrel-containing oral contraceptives induced more pronounced changes in factor V (−14.2; 95% CI −22.4 to −6.0) and factor VII (36.1; 95% CI 19.7 to 52.6) compared to levonorgestrel-containing oral contraceptives. Comparing desogestrel- and levonorgestrel-only, only for factor V a differential effect was found in these women (−9.5;95% CI –18.3 to –0.6).

It appears that desogestrel-containing oral contraceptives have a more pronounced effect on the coagulation system than levonorgestrelcontaining oral contraceptives which may be explained by a less effective compensation of the thrombotic effect of ethinylestradiol by desogestrel.
Topically Administered Macromolecular Heparin Proteoglycans Inhibit Thrombus Growth in Microvascular Anastomoses
Authors: Olsson Eija , Asko-Seljavaara Sirpa , Lassila Riitta
Published: March 2018

Previously, during blood perfusion over collagen-coated surfaces; soluble or immobilized heparin proteoglycans (HEP-PG) have been shown to block thrombus growth. Our aim was to study the antithrombotic effect of locally applied unfractionated heparin (UFH, 1 mg/ml), or rat mast cell-derived HEP-PG (MW 750 kD, 10 µg/ml) compared with saline in early (10 min) and late (3 days) thrombus formation upon anastomosis of rat common femoral arteries. In both semiquantitative scanning electron microscopy (SEM) and quantitative platelet Indium 111 -labeling HEP-PG inhibited thrombus growth in comparison with saline. At 10 min, the extent of thrombosis (scale 1-4) in SEM followed the order: saline (3.2+/-0.8) > UFH (2.8+/-1.0) > HEP-PG (1.8+/-0.8), and also Indium111-positive platelets (106) accumulated on the anastomosed vessel in the same order 14.2 +/-7.2, 10.3 +/-5.0, and 7.7 +/-3.1 (saline vs. HEP-PG, p = 0.03 and 0.05, respectively). At 3 days all HEP-PGtreated vessels remained patent with only small mural thrombi, whereas 2/7 saline and 1/7 UFH-treated anastomoses occluded and showed more thrombosis overall. We conclude that locally administered HEPPG inhibit arterial thrombus growth in anastomosed small-sized arteries and could prevent thrombotic complications in (micro)vascular surgery and arteriovenous shunts.
Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses
Authors: Liu Miao-Liang , Nakaya Shelley , Thompson Arthur
Published: March 2018

Heteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.
Influence of t-PA and u-PA on Adipose Tissue Development in a Murine Model of Diet-Induced Obesity
Authors: Morange P.E. , Bastelica D. , Bonzi M.F. , Van Hoef B. , Collen D. , Juhan-Vague I. , Lijnen H.R.
Published: March 2018

To investigate the potential role of tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) in development of adipose tissue, we have used a nutritionally induced obesity model in t-PA (t-PA−/−) and u-PA (u-PA−/−) deficient mice. Five week old male wild-type (WT), t-PA−/− or u-PA−/− mice (n = 9 to 16) were fed a high fat diet (HFD, 42% fat). After 16 weeks of HFD, the body weight of t-PA−/− mice was significantly higher than that of WT mice (48 ± 1.1 g vs. 39 ± 2.2 g, p = 0.004). The total weight of the isolated subcutaneous (sc) fat deposit was higher in t-PA−/− than in WT mice (2.4 ± 0.22 g vs. 1.2 ± 0.29 g, p = 0.002), accompanied with higher adipocyte diameters (80 ± 1.7 µm vs. 61 ± 4.7 µm, p < 0.01). These differences were not observed in the intra-abdominal fat deposit. The number of stroma cells in both adipose tissue territories was increased in t-PA−/− as compared to WT mice (2.0 ± 0.13 vs. 1.5 ± 0.10 p = 0.02 and 3.0 ± 0.17 vs 1.6 ± 0.17, p = 0.0001, stroma cells/ adipocytes in sc and intra-abdominal tissue, respectively), partly as a result of an increased number of endothelial cells (192 ± 9 vs. 154 ± 18 p = 0.06 and 108 ± 13 vs. 69 ± 8 p = 0.04 CD31 stained/adipocyte area). In contrast the weight gain and adipose tissue development in u-PA−/− mice was not different from that in WT mice. These data suggest that t-PA but not u-PA plays a role in adipose tissue development.
Differential Effects of Moderate or Heavy Alcohol Consumption on Circulating Adhesion Molecule Levels
Authors: Badía E. , Nicolás J. M. , Fernández-Solá J. , Antúnez E. , Urbano-Márquez A. , Estruch R. , Sacanella E.
Published: March 2018

Epidemiological studies suggest that moderate but not heavy alcohol consumption provides protection against coronary heart disease. We assessed the relationship between alcohol consumption and serum levels of adhesion molecules involved in the pathogenesis of early atherosclerosis. One-hundred apparently healthy men with similar cardiovascular risk factors were divided into four groups according to ethanol intake. Moderate drinkers (20-40 g/day) showed lower serum intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels than abstainers (p <0.05; both), as well as lower serum ICAM-1, VCAM-1 and E-selectin levels than heavy drinkers (p = 0.01; all). The latter also showed higher serum ICAM-1 and E-selectin levels than abstainers (p <0.001; both). We conclude that moderate drinkers show a significant reduction of soluble endothelial adhesion molecule levels compared to abstainers and heavy drinkers, that may contribute to the protective effect of moderate alcohol consumption against atherosclerosis.
Altering Heparin Cofactor II at VAL439 (P6) either Impairs Inhibition of Thrombin or Confers Elastase Resistance
Authors: Cunningham Michael , Bhakta Varsha , Sheffield William
Published: March 2018

Heparin cofactor II (HCII) is plasma glycoprotein and thrombin inhibitor of the serpin type previously shown to inhibit thrombin in the absence of its N-terminal 74 amino acids, and to be cleaved by neutrophil elastase (NE) at two sites: I66-F67 and V439-G440, the P6-P5 bond of the reactive center loop. We examined the contribution of Val439 to the reaction of HCII with thrombin and NE. Hexahistidine-tagged HCII proteins lacking residues 1-66 (H6Δ66HCII) containing either the wild-type Val 439 or one of six substitutions were expressed in E. coli. The rates of heparin-catalyzed thrombin inhibition of the V439L, C, or R variants were reduced at least 80-fold compared to wild-type H6Δ66HCII, while those of the F, S, or W variants were largely unchanged. Following controlled exposure to NE in the presence of heparin, these latter variants retained 3.5to 4.5-fold more residual anti-thrombin activity than wild-type H6Δ66HCII treated in the same manner. This resistance arose due to deflection of NE attack from V439-G440 to secondary sites. The F, S, or W V439 variants exhibited a similar or greater degree of NE resistance when re-expressed as full-length hexahistidine-tagged HCII proteins, suggesting that the I66-F67 NE site is not well recognized in non-glycosylated HCII. Of these full-length variants, the V439F was the most active, exhibiting only a 2-fold reduction in its heparin-catalyzed rate of thrombin inhibition. HCII can therefore be made NE-resistant without severely compromising its capacity to inhibit thrombin.
Evidence that the Platelet Integrin αIIbβ3 Is Regulated by the Integrin-Linked Kinase, ILK, in a PI3-Kinase Dependent Pathway
Authors: Noury Malia , Nurden Alan , Pasquet Jean-Max
Published: March 2018

Platelet aggregation is mediated by the integrin αIIbβ3 which is activated by intracellular signals during platelet activation. We have attempted to determine if ILK (“Integrin-Linked Kinase”) is involved in the regulation of αIIbβ3 function. ILK co-immunoprecipitated with β3 in stimulated platelets. Using confocal microscopy, ILK was detected in the cytoplasm of resting platelets. ADP or PMA stimulation led to its translocation to the plasma membrane. In parallel, there was a transient increase in ILK kinase activity, association with and phosphorylation of β3. Inhibition of PI3-kinase by two unrelated inhibitors (wortmannin and LY294002) prevented ILK-related functions. However, it did not prevent the conformational change in αIIbβ3 (shown by PAC-1 binding), although integrin affinity for fibrinogen was decreased as measured using FITC-fibrinogen. Furthermore, aggregate formation was reduced. Thus ILK transiently associates with and phosphorylates β3 in a PI3-kinase dependent manner suggesting that it participates at an intermediate stage in a critical mechanism for assuring large stable aggregates.
Adenosine Inhibits Tissue Factor Expression by LPS-stimulated Human Monocytes: Involvement of the A3 Adenosine Receptor
Authors: Broussas Matthieu , Cornillet-Lefèbvre Pascale , Potron Gérard , Nguyên Philippe
Published: March 2018

Tissue Factor (TF), an integral membrane glycoprotein that initiates the extrinsic pathway of blood coagulation, is thought to play a major part in coronary acute events. Adenosine, an endogenous nucleoside produced by the degradation of intracellular adenosine triphosphate, has been shown to exert many cardioprotective effects via an inhibition of platelets and neutrophils. This study was conducted to determine whether adenosine (ADO) could modulate the expression of TF by human monocytes. We found that ADO inhibited TF antigen and activity on endotoxin-stimulated monocytes in a dose-dependent manner. The mechanism was at least pre-translational since ADO caused a change in the TF mRNA level. Using ADO receptor-specific analogs, we showed that highly selective A3 agonist N6-(3-iodobenzyl)-adenosine-5’-N’-methyluronamide (IB-MECA) inhibited LPSinduced TF activity expression more potently than A1 agonist R-phenylisopropyladenosine (R-PIA) and A2 agonist CGS 2180. Furthermore, A1/A3 antagonist, xanthine amine congener (XAC) blocked the effect of ADO whereas A2a, A2b and A1 antagonists were ineffective. In addition, we observed that ADO agonists inhibited monocyte TF expression in LPS-stimulated whole blood. The rank order of agonist potency suggested that A2 and A3 receptors might be involved (2-Cado > CGS = IB-MECA > R-PIA). This was supported by the fact that A2 and A3 antagonists reversed the action of 2-Cado. We conclude that TF inhibition by ADO on human purified monocytes involved A3 receptors.
Ramipril Prior to Thrombolysis Attenuates the Early Increase of PAI-1 in Patients with Acute Myocardial Infarction
Authors: Wagner Andreas , Herkner Harald , Schreiber Wolfgang , Bur Andreas , Woisetschläger Christian , Stix Günther , Laggner Anton , Hirschl Michael
Published: March 2018

In a placebo-controlled, double-blinded, randomized study we evaluated the effect of ramipril prior to thrombolysis on the course of PAI-1 plasma levels and on the frequency of postinfarct ischemic events in patients with acute myocardial infarction. Fifty-one out of 99 patients received 2.5 mg ramipril orally prior to thrombolysis and 12 h later. The blood samples for determination of PAI-1 plasma levels were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis. Postinfarct ischemic events were registered until coronary angiography was performed and defined as recurrent chest pain and/or evidence of ischemic signs on the ECG (ST-depression or ST-segment elevation of 1 mm in one or more inferior or anterior leads). Coronary angiography was performed within 7 days after the onset of myocardial infarction. Patients were classified into two groups: those without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and those with reperfusion of the infarct-related artery (TIMI grade 2,3). On admission, PAI-1 plasma levels were similiar in both groups (ramipril: 47.1 [4.8] ng/ml; placebo: 49.1 [4.8] ng/ml). The PAI-1AUC was 77.2 [6.7] ng/ml/h in the ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013). Significant differences between groups were observed at 4, 8 and 12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p < 0.01; 8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p < 0.01; 12 hrs: 71.3 (9.5) vs. 87.4 (7.7) ng/ml, p < 0.05). The relative frequency of postinfarct ischemic events was significantly lower in the ramipril group (2.5% versus 7.1%, p = 0.001). Additionally, we observed a significant higher rate of TIMI grade 2 and 3 of the infarct-related artery in patients receiving oral ramipril compared to the placebo group (73% versus 54%; p = 0.035).

Our study demonstrates a favorable effect of ramipril on the fibrinolytic system after thrombolysis associated with a lower rate of postinfarct ischemic events within the first days after myocardial infarction. Therefore, the application of ramipril prior to thrombolysis appears to be a reasonable concomitant treatment which may reduce early infarctrelated complications.
Chemotherapy-Induced Activation of Hemostasis: Effect of a Low Molecular Weight Heparin (Dalteparin Sodium) on Plasma Markers of Hemostatic Activation
Authors: Weitz Ilene , Israel Valerie , Waisman James , Presant Cary , Rochanda Leanne , Liebman Howard
Published: March 2018

To evaluate the effect of standard chemotherapeutic regimens on the hemostatic profile of patients with breast and lung carcinoma; and to evaluate the effect of a single dose of a low molecular weight (LMW) heparin, dalteparin sodium, administered prior to the chemotherapy on markers of hemostatic activation.

11 patients with breast cancer and 10 patients with lung cancer receiving systemic chemotherapy were studied. 10 breast cancer patients and 9 lung cancer patients completed at least 1 cycle of treatment and had all hemostatic studies. Patients had a complete hemostatic and prothrombotic profile performed at study initiation. Markers of hemostatic activation consisting of immunoassays for thrombin-antithrombin (TAT) complex and D-dimer were measured in plasma samples obtained prior to chemotherapy and at 1, 24 and 48 h after treatment. A 2500 U dose of dalteparin was given prior to the 2nd cycle of chemotherapy; 5000 U of dalteparin was given prior to the 4th treatment cycle.

Chemotherapy resulted in statistically significant increases in TAT and D-dimer for the 1, 24 and 48 h plasma samples in both the breast and lung cancer patients for all cycles of chemotherapy given without LMW heparin. There were statistically significant increases in basal thrombin generation over the 4 cycles of treatment which was unrelated to active cancer. Both pretreatment doses of dalteparin effectively prevented increases in the markers of hemostatic activation. However, in the lung cancer patients, who had significantly increased basal thrombin generation, the 5000 U dose dalteparin was more effective.

Chemotherapy results in significant hemostatic activation in patients with breast and lung cancer. The effect of treatment appears to be cumulative. A single dose of LMW heparin administered prior to therapy can suppress hemostatic activation.

This project was funded by a grant from the Pharmacia corporation
Inhibition of Thrombin Generation in Plasma by Fibrin Formation (Antithrombin I)
Authors: de Bosch N. B. , Ruiz-Sáez A. , Echenagucia M. , Rodriguez-Lemoin A. , Mosesson M. W.
Published: March 2018

The adsorption of thrombin to fibrin during clotting defines “Antithrombin I” activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (‘γA/’γA), whose fibrin has two “low affinity” non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (‘γ´/’γA), which in addition to low affinity thrombin-binding sites in fibrin, has a “high affinity” non-substrate thrombin binding site in the carboxy-terminal region of its ‘γ´ chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or ‘γ´ 414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.

Presented in part at the XVII Congress of the ISTH, Washington, D. C. (1)
Intracellular Factor XIII Crosslinks Platelet Cytoskeletal Elements upon Platelet Activation
Authors: Serrano Katherine , Devine Dana
Published: March 2018

The platelet cytoplasm contains approximately half of the factor XIII (FXIII) transglutaminase content circulating in blood, yet the function of cytoplasmic FXIII is poorly understood. This study investigated functions of platelet FXIII in internal platelet processes by studying the interactions of FXIII with platelet cytoskeletal proteins. FXIII was present in cytoskeletal fractions of platelet lysate separated by centrifugation. When cytoskeletal fractions were immobilized on nitrocellulose membranes, thrombin-activated rFXIII (rFXIIIa*) or calcium iontreated rFXIII (rFXIIIa°) bound to some of these proteins, whereas untreated rFXIII did not. Utilizing fluorescence microscopy, an actin polymerization-dependent transient translocation of FXIII from a diffuse homogeneous distribution throughout the cytoplasm to the platelet periphery was observed upon platelet activation, suggesting an association with cytoskeletal proteins. Transglutaminase activity increased in cytoskeletal fractions of activated versus non-activated platelets. Immunoblotting analysis of platelet cytoskeletal fractions identified filamin and vinculin as being crosslinked upon platelet activation.
Quenching of Intracellular ROS Generation as a Mechanism for Oleate-Induced Reduction of Endothelial Activation and Early Atherogenesis
Authors: Massaro Marika , Basta Giuseppina , Lazzerini Guido , Carluccio Maria , Bosetti Francesca , Solaini Giancarlo , Visioli Francesco , Paolicchi Aldo , De Caterina Raffaele
Published: March 2018

We previously showed that the exposure of vascular endothelium to oleate results in reduced endothelial activation. We now investigate possible mechanisms for this effect in relation to generation of reactive oxygen species (ROS). We stimulated several types of endothelial cells with cytokines or lipopolysaccharide, with or without preincubation with 10-100 µmol/L oleate. Oleate preincubation reduced VCAM-1 expression in all cell types, as well as macrophage-colony stimulating factor release. We simultaneously measured the concentration of intracellular glutathione (GSH), the activity of GSH-related antioxidant enzymes and the production of intracellular ROS. Stimulation of endothelial cells caused a decrease of GSH and an increase in intracellular ROS. The addition of oleate before stimulation, prevented the depletion of GSH and partially prevented stimuli-induced increase of intracellular ROS. This occurred without any change in the activity of GSH-related antioxidant enzymes, superoxide dismutase and catalase. Furthermore, in a cell-free superoxide anion-generating system, oleate quenched the generation of ROS. These results indicate that oleate may exert direct vascular atheroprotective effects by inhibiting endothelial activation through a quenching of stimuli-induced increase in ROS.
Standardisation of von Willebrand Factor in Therapeutic Concentrates: Calibration of the 1st International Standard for von Willebrand Factor Concentrate (00/514)
Authors: Sands Dawn , Chang Andrew , Mazurier Claudine , Hubbard Anthony
Published: March 2018

An international study involving 26 laboratories assayed two candidate von Willebrand Factor (VWF) concentrates (B and C) for VWF:Antigen (VWF:Ag), VWF:Ristocetin Cofactor (VWF:RCo) and VWF:Collagen binding (VWF:CB) relative to the 4th International Standard Factor VIII/VWF Plasma (4th IS Plasma) (97/586). Estimates of VWF:Ag showed good agreement between different methods, for both candidates, and the overall combined means were 11.01 IU/ml with inter-laboratory variability (GCV) of 10.9% for candidate B and 14.01 IU/ml (GCV 11.8%) for candidate C. Estimates of VWF:RCo showed no significant difference between methods for both candidates and gave overall means of 9.38 IU/ml (GCV 23.7%) for candidate B and 10.19 IU/ml (GCV 24.4%) for candidate C. Prior to the calibration of the candidates for VWF:CB it was necessary to calibrate the 4th IS Plasma relative to local frozen normal plasma pools; there was good agreement between different collagen reagents and an overall mean of 0.83 IU per ampoule (GCV 11.8%) was assigned. In contrast, estimates of VWF:CB in both candidates showed large differences between collagen reagents with inter-laboratory GCV’s of 40%. Candidate B (00/514) was established as the 1st International Standard von Willebrand Factor Concentrate by the WHO Expert Committee on Biological Standardisation in November 2001 with assigned values for VWF:Ag (11.0 IU/ampoule) and VWF:RCo (9.4 IU/ampoule). Large inter-laboratory variability of estimates precluded the assignment of a value for VWF:CB.
Inhibition of ADP-induced P-selectin Expression and Platelet-Leukocyte Conjugate Formation by Clopidogrel and the P2Y12 Receptor Antagonist AR-C69931MX but not Aspirin
Authors: Judge Heather , Wilcox Robert , Heptinstall Stan , Storey Robert
Published: March 2018

Platelet-leukocyte interactions are recognised to have pro-inflammatory effects, which may be important in the pathophysiology of ischaemic heart disease. Clopidogrel and the novel intravenous antithrombotic agent AR-C69931MX act at the level of the platelet P2Y12 receptor, which is known to amplify platelet activation, aggregation and other responses induced by numerous platelet agonists. We studied the effects of clopidogrel and aspirin on ADP-induced platelet-leukocyte conjugate formation and P-selectin expression in healthy volunteers. The effects of clopidogrel and AR-C69931MX administered to patients with ischaemic heart disease were also assessed. AR-C69931MX and aspirin were also studied in vitro. Clopidogrel and AR-C69931MX suppressed ADP-induced platelet aggregation, P-selectin expression and platelet-leukocyte conjugate formation whereas aspirin had no inhibitory effect. These effects of clopidogrel and AR-C69931MX may confer therapeutic benefits in the management of acute coronary syndromes.
Intravascular tissue factor pathway – a model for rapid initiation of coagulation within the blood vessel
Authors: Luther Thomas , Müller Ingrid , Engelmann Bernd
Published: March 2018

The loss of blood through vessel wall ruptures is initially prevented by the rapid adhesion of platelets to the subendothelium, and the formation of a thrombus consisting of platelets and different types of leukocytes. Concomitantly, the coagulation process is thought to be activated by vascular wall tissue factor (TF). Here, a new model for the initiation of coagulation is presented, based on unexpected findings on the presence and functional activation of TF within the blood itself. TF was recently found to be stored in the α-granules of resting platelets under physiological conditions. Activation by collagen exposes TF on the platelet cell membrane and on platelet derived microvesicles. Adhesive interactions of the TF bearing platelets and microvesicles to neutrophils and monocytes support the functional activation of the blood based TF. The intravascular TF pathway is proposed to play a significant role during hemostasis by enabling the generation of fibrin at the site of the developing thrombus.