bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractFive 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	Introduction2	Total Synthesis of Hispidanin A3	Total Syntheses of Bolivianine and Isobolivianine4	Total Syntheses of Sarcandrolide J and Shizukaol D5	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

SummaryAntiphospholipid 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

SummaryVenous 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

Summaryαvβ3 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

SummaryCytokines 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

SummaryThe 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

SummaryThe 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

SummaryBothrojaracin (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

SummaryThe 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

SummaryWe 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

SummaryMonocyte 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

SummaryPreliminary 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.