bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of the catalyst structure in the cycloaddition of isocyanates to oxiranes promoted by tetraarylstibonium cations
Authors: Yang Mengxi , Pati Nilanjana , Bélanger-Chabot Guillaume , Hirai Masato , Gabbaï François P.
Published: March 2018

In the context of our work on electron deficient group 15 cations as Lewis acid catalysts, we have synthesized the triflate salts of a series of tetraarylstibonium cations and evaluated their catalytic activity for the cycloaddition of isocyanates to oxiranes.
Efficient and reversible absorption of ammonia by cobalt ionic liquids through Lewis acid–base and cooperative hydrogen bond interactions
Authors: Zeng Shaojuan , Liu Lei , Shang Dawei , Feng Jianpeng , Dong Haifeng , Xu Qiuxia , Zhang Xiangping , Zhang Suojiang
Published: March 2018

Cobalt ionic liquids with highly efficient and reversible absorption of NH3 through Lewis acid–base and hydrogen bond interactions were designed.
Analysis of halide composition in CsPb(Br/Cl)3 nanocrystals with trace amounts of samples using laser induced breakdown spectroscopy
Authors: Wang Menghan , Zhao Mengjie , Ye Shuai , Zhu Ming , Yi Rongxing , Liu Liwei , Qu Junle
Published: March 2018

LIBS is a superior approach for quantitatively determining the elemental composition in nanocrystals.
Multiple carrier-transfer pathways in a flower-like In2S3/CdIn2S4/In2O3 ternary heterostructure for enhanced photocatalytic hydrogen production
Authors: Ma Dandan , Shi Jian-Wen , Zou Yajun , Fan Zhaoyang , Shi Jinwen , Cheng Linhao , Sun Diankun , Wang Zeyan , Niu Chunming
Published: March 2018

A novel flower-like In2S3/CdIn2S4/In2O3 ternary heterostructure is rationally constructed for the first time, and it shows significantly enhanced photocatalytic H2 production.
A rational microstructure design of SnS2–carbon composites for superior sodium storage performance
Authors: Zhao Yi , Guo Binbin , Yao Qianqian , Li Jiaxin , Zhang Jianshuo , Hou Kun , Guan Lunhui
Published: March 2018

Effects of the SnS2–C microstructure on sodium storage performance have been systematically studied to achieve superior anode materials.
Temperature-modulated diastereoselective transformations of 2-vinylindoles to tetrahydrocarbazoles and tetrahydrocycloheptadiindoles
Authors: Wani Imtiyaz Ahmad , Bhattacharyya Aditya , Sayyad Masthanvali , Ghorai Manas K.
Published: March 2018

The Fe(OTf)3-catalyzed dimerization of 2-vinylindolesviadiastereoselective [4 + 2] or [4 + 3] cyclization gives rise to tetrahydrocarbazoles at low temperature or tetrahydrocycloheptadiindoles at high temperature.
Enantioselective addition of selenosulfonates to α,β-unsaturated ketones
Authors: Luo Shilong , Zhang Nan , Wang Zhen , Yan Hailong
Published: March 2018

An efficient organo-catalyzed enantioselective addition of selenosulfonates to α,β-unsaturated ketones was developed for the first time.
Bimodal probability density characterizes the elastic behavior of a semiflexible polymer in 2D under compression
Authors: Kurzthaler Christina , Franosch Thomas
Published: March 2018

We explore the elastic behavior of a wormlike chain under compression in terms of exact solutions for the associated probability densities.
Correction: Electronic and transport properties of Li-doped NiO epitaxial thin films
Authors: Zhang J. Y. , Li W. W. , Hoye R. L. Z. , MacManus-Driscoll J. L. , Budde M. , Bierwagen O. , Wang L. , Du Y. , Wahila M. J. , Piper L. F. J. , Lee T.-L. , Edwards H. J. , Dhanak V. R. , Zhang K. H. L.
Published: March 2018

Correction for ‘Electronic and transport properties of Li-doped NiO epitaxial thin films’ by J. Y. Zhang et al., J. Mater. Chem. C, 2018, 6, 2275–2282.
Superpixel texture analysis for classification of breast masses in dense background
Authors: Sajeev Shelda , Bajger Mariusz , Lee Gobert
Published: March 2018

Finding masses in dense background is a difficult task for even experienced radiologist. It is due to the similarity of intensity between the masses and the overlapped normal dense tissues. A novel method for classification of masses localised in dense background of breast is proposed. Nine structured superpixel patterns were generated using local binary pattern technique on superpixels. Analysis of these nine structured superpixel patterns revealed the most prominent ones, allowing for successful classification of malignant masses and normal dense breast regions. Two mammographic databases were used to evaluate the proposed approach: the publicly available digital database for screening mammography (DDSM), and a local database of mammograms (BreastScreen SA, BSSA). A total of 525 regions of interest (ROIs) were used (301 extracted from DDSM and 224 from BSSA). All 525 ROIs were localised in dense backgrounds of breasts. The results indicate that features generated from structured superpixel patterns can produce very effective and efficient texture descriptors of breast masses localised in dense background. Using Fisher linear discriminant analysis classifier, an area under the receiver operating characteristic curve score of 0.96 was achieved for DDSM and 0.93 for BSSA with only six features.
Printed log‐periodic trapezoidal dipole array antenna with a balun‐feed for ultra‐wideband applications
Authors: Zengin Fatma , Akkaya Eren , Güneş Filiz , Ecevit Fevzi Necati
Published: March 2018

The authors present design of a printed log‐periodic trapezoidal dipole array (PLPTDA) antenna with a balun‐feed operating throughout the 2–18 GHz frequency range. For this purpose, the antenna is designed and simulated in the CST Microwave Studio environment. Thus, better directivity along the operation bandwidth is achieved via the iterative simulations with a 33.33% reduction in the dipole length at the lowest frequency 2 GHz as compared with the counterpart standard log‐periodic antennas. Furthermore, they fabricated the PLPTDA antenna with and without the balun‐feed. Thus, influence of the balun on the performance is investigated and the average gain of the PLPTDA antenna with the balun‐feed is measured as 8.16 dBi provided voltage standing wave ratio (VSWR) < 2, which agrees with the simulation results. Furthermore, these measured gain/directivity results are compared with the counterpart antennas' measured performances in the literature considering their operation bandwidths and sizes. It can be concluded that their proposed PLPTDA antenna will prove to be useful in both wideband civilian and military applications in the S, C, X, and Ku bands within the 1:9 ultra‐wideband bandwidth which is the largest achieved in this class antenna technology in the literature up to now.
Probabilistic methodology for estimating the optimal photovoltaic capacity in distribution systems to avoid power flow reversals
Authors: Lujano‐Rojas Juan M. , Dufo‐López Rodolfo , Bernal‐Agustín José L. , Domínguez‐Navarro José A. , Catalão João P.S.
Published: March 2018

The large‐scale integration of photovoltaic generation (PVG) on distribution systems (DSs) preserving their technical constraints related to voltage fluctuations and active power (AP) flow is a challenging problem. Solar resources are accompanied by uncertainty regarding their estimation and intrinsically variable nature. This study presents a new probabilistic methodology based on quasi‐static time‐series analysis combined with the golden section search algorithm to integrate low and high levels of PVG into DSs to prevent AP flow in reverse direction. Based on the analysis of two illustrative case studies, it was concluded that the successful integration of PVG is not only related to the photovoltaic‐cell manufacturing prices and conversion efficiency but also with the manufacturing prices of power electronic devices required for reactive power control.
Super lithium-rich K giant with low 12C to 13C ratio
Authors: Zhou Y. T. , Shi J. R. , Yan H. L. , Gao Q. , Zhang J. B. , Zhao G. , Pan K. , Kumar Y. B.
Published: March 2018

Context. The lithium abundances in a few percent of giants exceed the value predicted by the standard stellar evolution models, and the mechanisms of Li enhancement are still under debate. The Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) survey has obtained over six million spectra in the past five years, and thus provides a great opportunity to search these rare objects and to more clearly understand the mechanisms of Li enhancement.

Aims. The aim of this work is to accurately measure the Li abundance and investigate the possible mechanisms of Li enrichment for a newly found super Li-rich giant, TYC 3251-581-1, located near the luminosity function bump with a low carbon isotopic ratio.

Methods. Based on the high-resolution spectrum we obtained the stellar parameters (Teff, logg, [Fe/H]), and determined the elemental abundances of Li, C, N, α, Fe-peak, r-process, s-process elements, and the projected rotational velocity. For a better understanding of the effect of mixing processes, we also derived the 12C to 13C ratio, and constrained the evolutionary status of TYC 3251-581-1 based on the BaSTI stellar isochrones.

Results. The super Li-rich giant TYC 3251-581-1 has A(Li) = 3.51, the average abundance of two lithium lines at λ = 6708 Å and 6104 Å based on the non-local thermodynamic equilibrium analysis. The atmospheric parameters show that our target locates on the luminosity function bump. The low carbon isotopic ratio (12C∕13C = 9.0), a slow rotational velocity vsini = 2.2 km s−1, and no sign of IR excess suggest that additional mixing after first dredge up (FDU) should occur to bring internal synthesized Li to the surface. The low carbon ([C∕Fe] ~−0.34) and enhanced nitrogen ([N∕Fe] ~ 0.33) are also consistent with the sign of mixing.

Conclusions. Given the evolutionary stage of TYC 3251-581-1 with the relatively low 12C∕13C, the internal production which replenishes Li in the outer layer is the most likely origin of Li enhancement for this star.
Multiple traces formulation and semi-implicit scheme for modelling biological cells under electrical stimulation
Authors: Henríquez Fernando , Jerez-Hanckes Carlos
Published: March 2018

We model the electrical behavior of several biological cells under external stimuli by extending and computationally improving the multiple traces formulation introduced in Henríquezet al.[Numer. Math.136(2016) 101–145]. Therein, the electric potential and current for a single cell are retrieved through the coupling of boundary integral operators and non-linear ordinary differential systems of equations. Yet, the low-order discretization scheme presented becomes impractical when accounting for interactions among multiple cells. In this note, we consider multi-cellular systems and show existence and uniqueness of the resulting non-linear evolution problem in finite time. Our main tools are analytic semigroup theory along with mapping properties of boundary integral operators in Sobolev spaces. Thanks to the smoothness of cellular shapes, solutions are highly regular at a given time. Hence, spectral spatial discretization can be employed, thereby largely reducing the number of unknowns. Time-space coupling is achievedviaa semi-implicit time-stepping scheme shown to be stable and second order convergent. Numerical results in two dimensions validate our claims and match observed biological behavior for the Hodgkin–Huxley dynamical model.
Upper-Extremity Functional Performance Tests: Reference Values for Overhead Athletes
Authors: Borms Dorien , Cools Ann
Published: March 2018

This study aimed to provide an age, gender and sport-based normative database for three functional shoulder tests: Y Balance Test – Upper Quarter (YBT-UQ), Closed Kinetic Chain Upper Extremity Stability Test (CKCUEST), and Seated Medicine Ball Throw (SMBT). A second aim was to discuss gender, age and sports differences. Finally, correlation between tests was evaluated. Overhead athletes (106 male, 100 female) between 18 and 50 years old and from three different sports (volleyball, tennis, handball) performed all functional tests. A linear mixed or regression model was applied to determine significant differences in test scores between gender, age and sports. Pearson correlation coefficients were analyzed to determine the relationship between tests. Normative values were established and divided by gender, sports and age. Results showed significant gender and age differences for all tests. For YBT-UQ, also significant side and sports differences were recorded. CKCUEST is moderately correlated with SMBT and YBT-UQ. Weak correlation was found between SMBT and YBT-UQ. In conclusion, this study provides normative data for YBT-UQ, CKCUEST and SMBT, which is clinically relevant for functionally screening overhead athletes and benchmark their performance to others from the same gender, age and sports. A combination of included tests is recommended.
Exercise Training at Maximal Fat Oxidation Intensity for Older Women with Type 2 Diabetes
Authors: Tan Sijie , Du Ping , Zhao Wanting , Pang Jiaqi , Wang Jianxiong
Published: March 2018

The purpose of this study was to investigate the pleiotropic effects of 12 weeks of supervised exercise training at maximal fat oxidation (FATmax) intensity on body composition, lipid profile, glycemic control, insulin sensitivity and serum adipokine levels in older women with type 2 diabetes. Thirty-one women with type 2 diabetes, aged 60 to 69 years, were randomly allocated into exercise and control groups. Body composition, lipid profile, blood glucose, insulin resistance and serum leptin and adiponectin concentrations were measured before and after the intervention. Exercise group (n=16) walked at individualized FATmax intensities for 1 h/day for 3 days/week over 12 weeks. No dietary intervention was introduced during the experimental period. Maximal fat oxidation rate was 0.37±0.10 g/min, and occurred at 37.3±7.3% of the estimated VO2max. Within the exercise group, significant improvements were observed for most of the measured variables compared to non-exercising controls; in particular, the FATmax program reduced body fat% (p<0.001), visceral fat% (p<0.001), and insulin resistance (p<0.001). There was no significant change in daily energy intake for all participants during the intervention period. These results suggest that individualized FATmax training is an effective exercise training intensity for managing type 2 diabetes in older women.
Botryane Sesquiterpenoids, Cyclopentadepsipeptides, Xanthones, and Trichothecenes from Trichoderma oligosporum
Authors: Chen Baosong , Li Erwei , Liu Li , Liao Mingfang , Zhu Zhaoxiang , Zhuang Wenying , Bao Li , Liu Hongwei
Published: March 2018

Five new botryane sesquiterpenes (1–5), one new cyclopentadepsipeptide (9), and two new xanthones (11 – 12), together with 11 known compounds, were isolated from Trichoderma oligosporum. The structures of the new compounds were identified by comprehensive spectroscopic methods including nuclear magnetic resonance and mass spectrometry. The cytotoxicity of 1–19 was evaluated against K562, A549, and ASPC cell lines. Compounds 5, 8, 11, 17, and 18 showed cytotoxicity against the K562 cell line with more than 50% inhibition at 12.5 µM. As to A549 cell line, compound

8 showed the strongest cytotoxicity with approximately 50% inhibition at 25.0 µM. No compounds showed cytotoxicity against the ASPC cell line.
Total Synthesis of Natural Terpenoids: Inspired but Not Limited by Biohypothesis
Authors: Liu Bo , Chen Juan
Published: March 2018

This account describes our studies on the total synthesis of several natural terpenoids based on our modified biosynthetic hypothesis. Compared to the originally proposed biosynthetic hypothesis, the modified ones proved to be more practicable for the formation of hispidanin A, a dimeric diterpenoid, and sarcandrolide J and shizukaol D, two dimeric sesquiterpenoids, from a viewpoint of chemical reactivity. Moreover, a cascade reaction involving intermolecular and intramolecular cycloaddition was facilitated to expeditiously accumulate molecular complexity in the total synthesis of bolivianine, a sesterterpenoid, on the basis of a modified biohypothesis.

1 Introduction

2 Total Synthesis of Hispidanin A

3 Total Syntheses of Bolivianine and Isobolivianine

4 Total Syntheses of Sarcandrolide J and Shizukaol D

5 Conclusion
Functional Analyses of Patient-derived IgG Monoclonal Anticardiolipin Antibodies Using In Vivo Thrombosis and In Vivo Microcirculation Models
Authors: Pierangeli Silvia , Liu Xiaowei , Espinola Ricardo , Olee Tsawei , Zhu Min , Harris Nigel , Chen Pojen
Published: March 2018

Antiphospholipid antibodies (aPL) have been associated with thrombosis and pregnancy losses in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. It has been proposed that aPL may affect endothelial cell (EC) function and/or induce their activation, transforming their anticoagulant surface into procoagulant, thus predisposing to thrombosis. It has been proposed that aPL may affect EC cell function and/or induce their activation, transforming their anticoagulant surface into procoagulant, thus predisposing to thrombosis. This study proposes to test the hypotheses that some IgG anticardiolipins (IgG aCL) with thrombogenic properties in mice, exert their effects through activation of endothelium. We studied seven patient-derived monoclonal aCL for their thrombogenic properties in an in vivo pinch-induced thrombosis model, and their functional activities in activating EC by analyzing in vivo leukocyte adhesion to endothelium in microcirculation in venules in exposed murine cremaster muscle and in vitro adhesion molecule expression in cultured EC. The binding of the monoclonal aCL to EC was also tested. In addition to the previous identified thrombogenic IS2, four of the five new more IgG monoclonal aCL (from two patients) were found to be thrombogenic. Of these five thrombogenic aCL, three caused more in vivo leukocyte adhesion to EC in microcirculation, as compared to that induced by the H2 control human monoclonal IgG, and enhanced expression of adhesion molecules (particularly VCAM-1) on cultured EC. These data show that about 2/3 patientderived IgG monoclonal aCL are thrombogenic and suggest that some thrombogenic IgG aCL exert their effects through activating EC.
Postpartum Bone Mineral Density in Women Treated for Thromboprophylaxis with Unfractionated Heparin or LMW Heparin
Authors: Pettilä Ville , Leinonen Pekka , Markkola Antti , Hiilesmaa Vilho , Kaaja Risto
Published: March 2018

Venous thromboembolism remains an important cause of maternal mortality. In a randomised open study, 44 pregnant women with confirmed previous or current thromboembolism were randomised to receive either low-molecular-weight heparin, dalteparin (N = 21) once daily subcutaneously or unfractionated sodium heparin (UF heparin, N = 23) twice daily subcutaneously for thromboprophylaxis during pregnancy and puerperium. Bone mineral density (BMD) in the lumbosacral spine was measured with dual X-ray absorptiometry (DEXA) 1, 6, 16, 52 weeks and, if possible, 3 years after delivery. BMD values were also compared with those of healthy, delivered women (N =19).

Mean BMD of the lumbar spine was significantly lower in the unfractionated heparin group compared with the dalteparin and with the control groups (repeated measures ANOVA p = 0.02). BMD in the dalteparin group did not differ from BMD of healthy delivered women. Multiple logistic regression analysis revealed that therapy was the only independent factor influencing BMD at weeks 16 and 52. Therefore we recommend use of dalteparin instead of UF heparin for long-term thromboprophylaxis during and after pregnancy.
The Role of αvβ3 Integrins in Vascular Healing
Authors: Sajid Mansoor , Stouffer George
Published: March 2018

αvβ3 integrins play an important role in vascular healing. Vascular injury is a stimulus for expression of αvβ3 by vascular cells and, among other effects, αvβ3 integrins function in the adhesion of activated platelets to endothelium, white cell/endothelium interactions, plateletmediated thrombin generation, fibrin clot retraction by nucleated cells, smooth muscle cell (SMC) migration and proliferation, vascular cell apoptosis, and vascular remodeling. There are ten different animal models in which treatment with αvβ3 antagonists reduced the vascular response, including (neo)intima formation, after mechanical injury. These studies, along with mechanistic data derived from cell culture studies, provide compelling evidence that αvβ3 integrins are involved in vascular repair processes. The challenge is to develop a therapeutic agent that will prove effective in reducing restenosis in humans following percutaneous coronary intervention (PCI).
The Tissue Factor and Plasminogen Activator Inhibitor Type-1 Response in Pediatric Sepsis-induced Multiple Organ Failure
Authors: Green Jerril , Doughty Lesley , Kaplan Sandra , Sasser Howell , Carcillo Joseph
Published: March 2018

Cytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type -1 (PAI-1) expression in vitro. Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators.

Because cytokine release is increased in children with sepsisinduced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients.

One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study. Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis.

Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p <0.05), the development of MOF (p <0.05), and mortality (p <0.05). Increased systemic PAI-1 activity was associated with cardiovascular, renal, and hepatic failure (p <0.05). Increased systemic TF activity was associated with the development of coagulopathy (p <0.05) and tended to be associated with mortality (p =0.06, power .77)

A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality. Children with coagulopathy have a shift to a pro-coagulant phenotype. These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.
Efficacy and Safety of the Factor VIII/von Willebrand Factor Concentrate, Haemate-P/Humate-P: Ristocetin Cofactor Unit Dosing in Patients with von Willebrand Disease
Authors: Poon M.-C. , Walker I. , Xie F. , Schwartz B.A. , Lillicrap D. ,   members of the Association of Hemophilia Clinic Directors of Canada
Published: March 2018

The present study was initiated to evaluate the safety and efficacy of Haemate-P® (Humate-P® in North America) (anti-hemophilic FVIII/VWF complex [human] dried, pasteurized) dosed in ristocetin cofactor units (VWF:RCo) in the treatment of von Willebrand disease (VWD) patients in Canada. This retrospective data collection reviewed the medical records of VWD patients treated under the Canadian Emergency Drug Release Program from November 22, 1991, to April 30, 1996. Data collection was accomplished by on-site retrieval from source data for 97 patients. Dosing was based on the German package insert, which lists only Factor VIII:C (FVIII:C) units, which were converted in the study analysis to VWF:RCo units based on the analysis of the individual manufactured lots of product used in these patients (average ratio of 2.6 IU VWF:RCo per IU FVIII:C). Twenty five different lots of Haemate-P/Humate-P were used to treat 437 different events in the 97 study patients (344 hemorrhagic events, 73 surgical interventions and 20 prophylactic infusion cycles). Overall, the median dose of concentrate per infusion used to treat surgical events was 69.1 IU VWF:RCo/kg (range 11.9-222.8); bleeding events 55.3 IU VWF:RCo/kg (range 17.1-227.5) and prophylaxis 41.6 IU VWF:RCo/kg (range 34.6-81.0). Treatment periods varied, with the majority of events treated for ≤ 10 days (91%). Fifty percent of events that were treated longer than 10 days were given for prophylactic reasons. Efficacy was determined in a standardized manner by the physician, based on dosing in VWF:RCo activity. An overall clinical result of “excellent” or “good” was reported in 97% (424/437) of treatment events. A pediatric sub-population analysis of the patient population reported “excellent/good” efficacy in 100% (17/17) of treatment events in infants, 95% (155/164) in children, and 94% (76/81) in adolescent patients. Related adverse events (AEs) were observed in only 4 (4%) patients and were not deemed to be serious. The findings in this study confirm the safety and efficacy of Haemate-P/Humate-P using VWF:RCo dosing in pediatric and adult patients with various types of VWD.
A Dose-ranging Study of the Oral Direct Thrombin Inhibitor, Ximelagatran, and Its Subcutaneous Form, Melagatran, Compared with Dalteparin in the Prophylaxis of Thromboembolism after Hip or Knee Replacement: METHRO I
Authors: Arfwidsson Ann-Christin , Frison Lars , Eriksson Ulf , Bylock Anders , Kälebo Peter , Fager Gunnar , Gustafsson David , Eriksson Bengt
Published: March 2018

The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (sc). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received sc melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU sc once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received sc melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the sc melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.
Bothrojaracin, a Proexosite I Ligand, Inhibits Factor Va-Accelerated Prothrombin Activation
Authors: Monteiro Robson , Zingali Russolina
Published: March 2018

Bothrojaracin (BJC) is a 27 kDa snake venom protein from Bothrops jararaca that has been characterized as a potent ligand (K
D = 75 nM) of human prothrombin (Monteiro RQ, Bock PE, Bianconi ML, Zingali RB, Protein Sci 2001; 10: 1897-904). BJC binds to the partially exposed anion-binding exosite I (proexosite I) forming a stable 1:1, non-covalent complex with the zymogen whereas no interaction with fragment 1 or 2 domains is observed. In addition, BJC interacts with thrombin through exosites I and II (K
D = 0.7 nM), and influences but does not block the proteinase catalytic site. In the present work we studied the effect of BJC on human prothrombin activation by factor Xa in the absence or in the presence of its cofactors, factor Va and phospholipids. In the absence of phospholipids, BJC strongly inhibited (80%) the zymogen activation by factor Xa in the presence but not in the absence of factor Va, suggesting a specific interference in the cofactor activity. In the presence of phospholipid vesicles (75% phosphatidylcholine, 25% phosphatidylserine), BJC also inhibited (35%) prothrombin activation by factor Xa in the presence but not in the absence of factor Va. BJC showed a higher inhibitory effect (70%) towards thrombin formation by prothrombinase complex assembled on phospholipid vesicles composed by 95% phosphatidylcholine, 5% phosphatidylserine. Activation of prothrombin by platelet-assembled prothrombinase complex (factor Xa, factor Va and thrombin-activated platelets) showed that hirudin54-65(SO3-) and BJC efficiently inhibit the thrombin formation (43% and 84%, respectively). Taken together, our results suggest that proexosite I blockage decreases the productive recognition of prothrombin as substrate by factor Xa-factor Va complex and prothrombinase complex. Furthermore, data obtained with human platelets suggest that proexosite I may play an important role in the physiological activation of prothrombin.
First Molecular Characterization of an Unequal Homologous Alu-mediated Recombination Event Responsible for Hemophilia
Authors: Vidal Francisco , Farssac Elisenda , Tusell Joan , Puig Lluís , Gallardo Dominique
Published: March 2018

The large number of Alu repeats in the human genome provides abundant opportunities for unequal homologous recombination events that are responsible of several human diseases. We here describe a novel large FVIII gene deletion from a severe hemophilia A patient in which Alu-repetitive elements are directly involved in the origin of the mutation. Using a long-fragment PCR method, a ∼23 kb deletion was delimited between introns 24 and 25. The resulting FVIII gene had a hybrid 2317-bp intron and lacked exon 25. Absence of exon 25 was confirmed at the RNA level. Multiple sequence alignment of this hybrid intron and normal introns 24 and 25 provided evidence of an homologous recombination event between two Alu repeats and the exact breakpoints were delimited to a 16 bp region. To our knowledge, this is the first report of hemophilia caused by unequal homologous Alu/Alu recombination. This mechanism, commonly related to genetic human disorders, may be involved in a significant number of hemophilia cases considering that FVIII is coded by an Alu-rich gene.
Evaluation of Two Automated Methods for Measurement of the Ristocetin Cofactor Activity of von Willebrand Factor
Authors: Platt S. , Daniele Christine , Kaczor Daniel , Miller Connie
Published: March 2018

We have evaluated two automated methods for measuring ristocetin cofactor activity (VWF:RCo) on an automated coagulation analyzer (STAR®, Diagnostica Stago Inc., Parsippany, NJ). A modification of the BC von Willebrand Reagent method (Dade Behring Inc., Newark, Delaware) was compared with a standard method using a platelet aggregometer, and an in-house automated method was developed using commercially available components. The STAR® measures the change in optical density (OD) caused by agglutination of platelets. Change in OD was linear for plasma dilutions between .25 and .04 U/mL. Coefficient of variation compared favorably with that of the standard method. In 123 normal women, the correlation coefficient (r) = .905. In menorrhagia cases, r = .901. In 20 VWD patients, r = .93. The CDC in-house method was compared to the BC Reagent method in 79 additional menorrhagia cases, with r = .94. The automated methods produced results equivalent or superior to those of traditional methods of measuring VWF:RCo.
Identification of Potentially Effective Antisense Oligodeoxyribonucleotide (ODN) Sequences for Inhibiting Plasminogen Activator Inhibitor-2 (PAI-2) Production by Monocytes
Authors: Humphries Julia , Burnand Kevin , Cunningham Philip , Brock Adrian , Westwood Nigel , Smith Alberto
Published: March 2018

Monocyte fibrinolytic activity may influence thrombus resolution. The balance between uPA and PAI-2 could determine the fibrinolytic activity of the monocyte. Inhibiting PAI-2 production using specific antisense sequences might alter this balance. Selecting effective sequences is a problem as prediction of the secondary structure of target mRNA is difficult. This study reports the modification of a cell free system for rapid antisense screening.

Five 18-19 mer oligodeoxynucleotides (ODN), sequences A, B, K, T and Q, and their matched scrambled controls were designed and screened using a modified rabbit reticulocyte lysate transcription and translation system (RRL). Intracellular uptake of ODNs was confirmed by fluorescence microscopy, scanning laser confocal microscopy and fluorimetery. Monocytes were transfected with a liposome/ODN complex using sequences A, B, A + B combined, or T and PAI-2 levels measured by ELISA. Inhibition of PAI-2 production was calculated as a percentage of control levels (baseline and scrambled).

(i) RRL System – Sequence A was the most effective inhibitor of PAI-2 production in this system (median 63%) compared with sequences, B median 9%, K median 14%, T median 11% and Q median –8% respectively (n = 3). Sequence A was the only sequence, which always inhibited PAI-2. This was confirmed using fluorescently labelled protein (n = 2). (ii) Monocyte transfection Fluorescence microscopy and fluorimetry showed that intracellular delivery of labelled antisense was only achieved when a liposome was used. Transfection of monocytes extracted from 5 subjects showed that sequence A significantly reduced PAI-2 production (mean % 41.4, sem 9.1) compared with sequences B (mean% 3.4, sem 8.9, p = 0.04), A + B (mean % 0.4, sem 7.8, p = 0.04), and T (mean % 5.4, sem 4.9, p = 0.01). Futher studies using sequence A on cells from 10 subjects showed a significant reduction in monocyte PAI-2 production (27.6 ng/ml, sem 3.9) compared with matched scrambled controls (mean 38.3 ng/ml, sem 4.5, p = 0.0112) and baseline (mean 51.4 ng/ml, sem 6.7, p = 0.0009).

Use of the RRL screening system allowed the selection of a novel antisense sequence, which significantly reduced PAI-2 production in monocytes.
Antipsychotic and Antidepressant Drug Use in the Elderly and the Risk of Venous Thromboembolism
Authors: Mamdani Muhammad , Yeo Erik , Ray Joel
Published: March 2018

Preliminary evidence suggests that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism.

To evaluate the relationship between antipsychotic or antidepressant drug use and venous thromboembolism among adults aged 65 years and older.

Retrospective cohort study using linked health care administrative databases over a nine year period.

The entire province of Ontario, Canada.

Individuals aged 65 years and over exclusively prescribed either antipsychotic drugs (n = 22514), antidepressant drugs (n = 75649) or thyroid replacement hormones (33033), the referent control group. We excluded those with an antecedent history of cardiovascular disease, venous thromboembolism or cancer, as well as those dispensed warfarin before study entry.

Diagnosis of deep vein thrombosis or pulmonary embolism.

Relative to those prescribed thyroid hormones, neither anti-depressant (adjusted hazard ratio 1.02, 95% CI 0.91-1.14) nor anti-psychotic (adjusted hazard ratio 1.13, 95% CI 0.96-1.32) drug use was associated with an increased risk for deep vein thrombosis. Similar risk estimates were found for deep vein thrombosis or pulmonary embolism. In a sub-group analysis, only butyrophenone use was found to be associated with a slightly increased risk of deep vein thrombosis (adjusted HR 1.51, 95% CI 1.23-1.86) as well as deep vein thrombosis or pulmonary embolism (adjusted HR 1.43, 95% CI 1.18-1.74).

In a large cohort of adults aged 65 years and older, neither antipsychotic or antidepressant drug use was associated with an increased risk of venous thromboembolism, with the exception of a slightly increased risk among those prescribed butyrophenones. Further data are required before use of these psychoactive drugs can be considered a risk factor for venous thromboembolism.
Adverse Effect of Heparin on Antithrombin Action during Endotoxemia: Microhemodynamic and Cellular Mechanisms
Authors: Vollmar Brigitte , Laschke Matthias , Inthorn Dietrich , Kaneider Nicole , Dunzendorfer Stefan , Wiedermann Christian , Römisch Jürgen , Schildberg Friedrich , Menger Michael , Hoffmann Johannes
Published: March 2018

A recent clinical sepsis trial reported a significant reduction in 90-day mortality by antithrombin (AT) exclusively in the subgroup of patients without simultaneous heparin prophylaxis. Patients additionally receiving heparin did not benefit from AT treatment. Herein, we studied the microhemodynamic and cellular mechanisms of this adverse effect of heparin on AT actions by the use of intravital microscopy and granulocyte culturing. In Syrian golden hamsters normotensive endotoxemia was induced by 2 mg/kg endotoxin (LPS, E. coli) i.v. In a first group of animals, AT (AT, 250 IU/kg i.v., n = 6) was given 5 min before LPS administration. A second group of animals (Heparin+AT, n = 5) received AT (250 IU/kg i.v.) combined with unfractionated heparin (sodium heparin, 100 IU/kg/24 h, i.v.). Additional animals (LMWH+AT, n = 5) received AT (250 IU/kg i.v.) combined with LMWH (nadroparin 47.5 IU anti-Xa/kg, s.c., 2 h before LPS). LPStreated animals, which received only saline, served as controls (control, n = 6). Using dorsal skinfold fold preparations, LPS-induced microvascular leukocyte-endothelial cell interaction (LE) and alteration of functional capillary density (FCD) were studied by intravital video fluorescence microscopy. In controls, LPS induced a massive increase in LE with a maximum at 8 h and an impressive decrease in FCD over a 24-hour period. Both LPS effects were effectively prevented by AT treatment (p <0.01), whereas Heparin+AT and LMWH+AT animals showed microcirculatory alterations comparable to that in controls. In additional in vitro chemotaxis assays, AT blocked neutrophil chemotaxis, an effect reversed by both unfractionated heparin and LMWH. Thus, our study elucidates a relevant in vivo and in vitro unfractionated heparin and LMWH adverse effect in the microcirculatory actions of AT during endotoxemia. These results indicate that heparin should be avoided to permit AT to modulate LPS-induced inflammatory responses.
A Collaborative Study to Establish the 3rd International Standard for Tissue Plasminogen Activator
Authors: Sands Dawn , Whitton Colin , Merton R. , Longstaff Colin
Published: March 2018

An international collaborative study was organised to replace the 2nd International Standard (IS) for tissue plasminogen activator (tPA). The 2nd IS for tPA (86/670) was used to calibrate the replacement Standard, which was selected from two candidate materials included in the collaborative study. Participants were provided with five sets of four samples (A, B, C, D) and asked to use sample A (2nd IS, 86/670, 850 IU/ml) to determine the activity of B (86/624, approximately 850 IU/ml), C and D (coded duplicates of the same material, 98/714 approximately 11000 IU/ml). A total of 14 laboratories returned results from Europe, USA, Japan and Australia, providing data from 60 independent assays. Four laboratories used a reference method based on a published monograph from the European Pharmacopoeia for Alteplase for Injection, 1998, and the remaining 10 used their own method. Fibrin was used as promoter of tPA activity by 12 out of the 14 laboratories, the remaining two used kits where fibrinogen fragments were the promoter. Data from this collaborative study and the previous study to establish the 2nd IS for tPA show that tPA from melanoma cells and recombinant tPA from CHO cells are both suitable materials as International Standards. It was agreed that sample C, D, recombinant tPA, 98/714, be established as the 3rd International Standard for tPA with a potency of 10000 IU per ampoule, calculated as the mean value from laboratories using fibrin as a promoter of tPA activity. The standard was established by WHO in November 2000.
Metalloproteases Cleave the Urokinase-Type Plasminogen Activator Receptor in the D1-D2 Linker Region and Expose Epitopes not Present in the intact Soluble Receptor
Authors: Andolfo Annapaola , English William , Resnati Massimo , Murphy Gillian , Blasi Francesco , Sidenius Nicolai
Published: March 2018

Proteolytic cleavage of the urokinase plasminogen activator receptor (uPA(R)) prevents the binding of uPA and vitronectin while generating biologically active uPAR fragments. We have recently shown that matrix metalloproteinase-12 (MMP-12) releases cellular uPAR-antigen from stimulated human micro-vascular endothelial cells providing a novel feedback mechanism between the plasminogen activation and MMP systems. We now show that MMP-12 and other MMPs directly and efficiently cleave uPAR at the Thr86||Tyr87 peptide bond located in the linker region connecting uPAR domains 1 and 2, releasing the major ligand binding domain 1 from the rest of the receptor. The possible biological importance of uPAR cleavage by MMPs is supported by the observation that also murine uPAR is cleaved by MMP-12 (at the Pro89||Gln90 peptide bond), despite the limited sequence homology between the linker regions. Using an antibody raised against the human uPAR linker region we show that this region of uPAR, which contains the chemotactic SRSRY epitope, is exposed upon MMP cleavage.
Protease-Activated Receptors Upregulate Cyclooxygenase-2 Expression in Human Endothelial Cells
Authors: Houliston Rebecca , Keogh Rosemary , Sugden David , Dudhia Jayesh , Carter Tom , Wheeler-Jones Caroline
Published: March 2018

We have previously shown that the serine protease thrombin and other G protein-coupled agonists acutely enhance synthesis and release of prostacyclin from human umbilical vein endothelial cells (HUVEC) through activation of cPLA2α. Here, we show that thrombin and other physiological endothelial cell agonists upregulate COX-2 induction in HUVEC. Thrombin treatment caused a rapid and sustained increase in prostacyclin (PGI2) synthesis from HUVEC. Thrombin and a selective protease-activated receptor-1 (PAR-1) peptide (TRAP) evoked doseand time-dependent increases in COX-2 protein expression which were equivalent to that induced by the proinflammatory cytokine IL-1α. Quantitative and real-time PCR analysis showed enhanced COX-2 mRNA expression in thrombinor TRAP-stimulated HUVEC whereas COX-1 expression was unaffected. A PAR-2 agonist peptide also induced COX-2 protein and mRNA expression with kinetics distinct from those of thrombin, and promoted PGI2 release. These results demonstrate that regulation of COX-2 induction is an important functional response of HUVEC to PAR activation and suggest that PARs promote sustained upregulation of prostanoid production in human endothelium.
Modulation of Fibrinolytic and Gelatinolytic Activity during Adipose Tissue Development in a Mouse Model of Nutritionally Induced Obesity
Authors: Maquoi Erik , Demeulemeester Diego , Van Hoef Berthe , Collen Désiré , Lijnen H.
Published: March 2018

A nutritionally induced obesity model was used to investigate the modulation of fibrinolytic and gelatinolytic activity during the development of adipose tissue.

Five week old male mice were fed a standard fat diet (SFD, 13% kcal as fat) or a high fat diet (HFD, 42% kcal as fat) for up to 15 weeks. The HFD resulted in body weights of 31 ± 0.9 g, 38 ± 2.0 g and 47 ± 1.9 g at 5, 10 and 15 weeks, respectively; corresponding values for mice on the SFD were 26 ± 0.6 g, 31 ± 0.9 g and 31 ± 1.2 g (all p < 0.001). The weight of the isolated subcutaneous (SC) or gonadal (GON) fat after 15 weeks of HFD was 1,870 ± 180 mg or 1,470 ± 160 mg, as compared to 250 ± 58 mg or 350 ± 71 mg for the SFD (p < 0.001). The HFD induced marked time-dependent hyperglycemia and elevated levels of triglycerides and total cholesterol. The HFD diet also induced a marked hypertrophy of the adipocytes as compared to the SFD, e.g. diameter of 83 ± 3.0 µm versus 52 ± 4.2 µm for GON adipocytes at 15 weeks (p < 0.005). Plasma plasminogen activator inhibitor-1 (PAI-1) levels were higher in mice on the HFD as compared to the SFD; they were comparable in extracts of SC or GON adipose tissue, whereas at different time points tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator activity was somewhat lower in the adipose tissues of mice on HFD. Gelatinolytic activity (mainly MMP-2) was detected in SC but not in GON adipose tissue of mice on SFD, and decreased on the HFD. In situ zymography on cryosections did not reveal different fibrinolytic activities in SC or GON adipose tissues of the HFD as compared to the SFD groups, whereas significantly lower gelatinolytic and higher caseinolytic activities were detected in SC and GON tissues of mice on the HFD (p ≤ 0.05). The fibrillar collagen content was lower in adipose tissue of mice on HFD. Thus, in this model time-dependent development of adipose tissue appears to be associated with modulation of proteolytic activity.
Platelet Activation and Blood Coagulation
Authors: Bevers Edouard , Lindhout Theo , Heemskerk Johan
Published: March 2018

Platelet activation and blood coagulation are complementary, mutually dependent processes in haemostasis and thrombosis. Platelets interact with several coagulation factors, while the coagulation product thrombin is a potent platelet-activating agonist. Activated platelets come in a procoagulant state after a prolonged elevation in cytosolic [Ca2+]i. Such platelets, e. g. when adhering to collagen via glycoprotein VI, expose phosphatidylserine (PS) at their outer surface and produce (PS-exposing) membrane blebs and microvesicles. Inhibition of aminophospholipid translocase and activation of phospholipid scramblase mediate the exposure of PS, whereas calpain-mediated protein cleavage leads to membrane blebbing and vesiculation. Surface-exposed PS strongly propagates the coagulation process by facilitating the assembly and activation of tenase and prothrombinase complexes. Factor IXa and platelet-bound factor Va support these activities. In addition, platelets can support the initiation phase of coagulation by providing binding sites for prothrombin and factor XI. They thereby take over the initiating role of tissue factor and factor VIIa in coagulation activation.
Enhanced Coagulation Activation in Preeclampsia: the Role of APC Resistance, Microparticles and Other Plasma Constituents
Authors: Boer Kees , Berckmans René , Meijers Joost , van der Post Joris , Sturk Augueste , Van Bavel Ed , Nieuwland Rienk , Van Wijk Marja
Published: March 2018

Coagulation activation in pregnancy is further enhanced in preeclampsia. We investigated whether this results from increased thrombin generation by the plasma itself or its cell-derived microparticles. Plasma samples were obtained from preeclamptic, normal pregnant and nonpregnant women (each n = 10). Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) concentrations were increased in pregnancy and further increased in preeclampsia. In pregnancy and preeclampsia, increased activated protein C resistance occurred (APC sensitivity ratio: 3.3 ± 0.8 and 2.5 ± 0.8, both P < 0.001 vs. nonpregnant). In normal pregnant microparticle-free plasma the thrombin generation correlated with TAT (r = 0.84, P = 0.005) and APC resistance correlated with F1+2 (r = 0.68, P = 0.04). In preeclampsia thrombin generation by plasma was increased (P = 0.005), independent of APC resistance. Thrombin generation by microparticles was similar in all groups, although different coagulation activation pathways were utilized, indicating that circulating microparticles are not directly involved in coagulation activation in pregnancy and preeclampsia. In contrast, APC resistance can explain coagulation activation in pregnancy, while enhanced coagulation activation in preeclampsia results, in part, from an increased thrombin generating capacity of plasma independent of APC resistance.