bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Modified Functional Assays for Activated Protein C Resistance in Patients with Basally Prolonged aPTT
Authors: Montaruli Barbara , Schinco Piercarla , Pannocchia Antonella , Giorgianni Angelica , Borchiellini Alessandra , Tamponi Giacomo , Pileri Alessandro
Published: July 2018

Inherited resistance to activated protein C (APCr) is currently recognized as the most prevalent cause underlying venous thrombophilia, with an estimated prevalence around 20% in thrombotic patients and around 1.8-7% in the general population. A correct laboratory diagnosis of APCr is therefore essential. Two different diagnostic approaches are at present at our disposal: the semi-quantitative plasma test based on the measurement of two aPTTs (in the presence and absence of activated protein C), and the detection of the factor V Arg506 GIn mutation by DNA analysis.

In this study we firstly evaluated sensitivity, specificity and diagnostic efficiency of an aPTT-based plasma clotting test (Chromogenix, Sweden) versus DNA analysis; then, since the APC resistance test is invalidated by a basally prolonged aPTT (i.e. during warfarin and heparin therapy or in patients with clotting factor deficiencies or in the presence of a lupus anticoagulant), patient plasmas were conveniently diluted in factor V deficient plasma in order to correct clotting factor abnormalities. Nevertheless, patients with a LA and an aPTT ratio range 1.8-3.17 were still all misclassified. We obtained correct diagnoses in LA positive patients by preincubating plasmas with a mixture of phospholipids; therefore we decided to perform a double modified clotting test adding a mixture of platelet derived phospholipids to samples previously diluted in factor V deficient plasma. The performance characteristics of this novel method with a different aPTT reagent (Behring, Germany) were also evaluated. With this double modified test all patients were correctly classified as negative or positive for factor V mutation in agreement with DNA analysis, irrespectfully of the basal aPTT value and the aPTT reagent employed. We propose this modified version of the APCr clotting test as an easily reproducible, reliable, very sensitive and specific screening test which possibly reduces the need for DNA analysis.
Characterization and Targeting of the Murine α2-Antiplasmin Gene
Authors: Okada K , Lijnen H R , Dewerchin M , Belayew A , Matsuo O , Collen D , Bernaerts R
Published: July 2018

α2-Antiplasmin (α2-AP) is the main physiological plasmin inhibitor in mammalian plasma. As a first step toward the generation of α2-AP deficient mice, the murine α2-AP
1 gene was characterized and a targeting vector for homologous recombination in embryonic stem (ES) cells constructed. Alignment of nucleotide sequences obtained from genomic subclones allowed location of exons 2 through 10 of the α2-AP 1gene, but failed to identify the 5’ boundary of exon 1. Compared to the human gene, exons 2 through 9 in the murine gene have identical size and intron-exon boundaries obeying the GT/AG rule. The 5’ boundary of exon 10 is identical in both genes while the 3’ non-coding region is 64 bp longer in the human gene. Introns 2,3,6 and 8 have similar sizes in the mouse and human genes; intron 1 is 6-fold smaller, introns 5, 7 and 9 are 2- to 3-fold smaller, whereas intron 4 is about 2-fold larger in the mouse gene. Compared to the human 5’ flanking sequence, an insertion of a simple repeat region with sequence (TGG)n has occurred. The open reading frame of the mouse α2-AP gene encodes a 491-amino acid protein comprising the experimentally determined NH2-terminus of the mature protein Val-Asp-Leu-Pro-Gly-.

A targeting vector, ppPNT.α2-AP, was constructed by introducing a homologous sequence of 8.3 kb in total in the parental pPNT vector. In pPNT.α2-AP, the neomycin resistance expression cassette replaces a 7 kb genomic fragment comprising exon 2 through part of exon 10 (including the stop codon), which represents the entire sequence encoding the mature protein, including the fibrin-binding domain, the reactive site peptide bond and the plasmin(ogen)-binding region. Electroporation of 129R1 embryonic stem (ES) cells with the linearized vector pPNT.α2-AP yielded three targeted clones with correct homologous recombination at the 5’- and 3’-ends, as confirmed by Southern blot analysis of purified genomic DNA with appropriate restriction enzymes and probes. These targeted clones will be used to generate α2-AP deficient mice.
Selection of S18326 as a New Potent and Selective Boronic Acid Direct Thrombin Inhibitor
Authors: Rupin A , Mennecier P , Lila C , de Nanteuil G , Verbeuren T J
Published: July 2018

Using enzymatic microassays, the potency of a series of new boroarginine tripeptides was determined versus thrombin and a panel of serine-proteases implicated in the coagulation and fibrinolysis pathways. The inhibition of the serine-protease complement factor I was also studied. Factor I regulates the alternate pathway of the complement and its inhibition appears to be responsible for the toxic effects of the orally available thrombin inhibitor Ac-D-Phe-Pro-boro-Arg (DuP-714). The structure of the new boronic acid derivatives tested was modified from that of DuP-714 by replacing the proline in the P2 position by N-cycloalkyl-glycine residues of increasing size (SI8989: cyclopropyl; S18563: cyclobutyl; S18326: cyclopentyl; S18229: cyclohexyl). All compounds were found to be slow-tight binding inhibitors of thrombin versus purified human fibrinogen. Replacement of proline by N-cycloalkyl-glycines did not decrease the anti-thrombin potency of the substances up to the cyclopentyl size and this result was confirmed by classical coagulation assays with human plasma in vitro. In contrast, the inhibitory activities of the four new boronic acids were found to be lower than those of DuP-714 versus plasmin, urokinase (u-PA), plasmatic kallikrein, activated protein C (aPC) and complement factor I. The cyclopentyl derivative SI8326 is a slightly more active inhibitor of thrombin than DuP-714 (initial IC50 values 3.99 ± 0.18 nM versus 4.73 ± 0.27 nM, respectively). Moreover SI8326 was identified as the most selective compound of the series with relative potencies being 2 to 29 fold higher than that of DuP-714 versus the panel of serine-proteases tested; the rank order of potency versus the other serine-proteases for S18326 was t-PA>kallikrein>aPC> factor I>plasmin>fXa>u-PA. These results indicate that the size of the thrombin hydrophobic pocket S2 is sufficient to accept larger residues than proline in the P2 position of Ac-D-Phe-X-boroArg derivatives while this is not the case for other important serine-proteases of the fibrinolysis, coagulation and complement pathways. The N-cyclopentyl glycine containing derivative SI8326, which is the most potent and the most selective anti-thrombin compound of the series, currently undergoes major preclinical testing.
Standardisation of Protein S in Plasma: Calibration of the 1st International Standard
Authors: Hubbard Anthony R
Published: July 2018

An international collaborative study, involving 16 laboratories, was carried out to calibrate the 1st International Standard Protein S, plasma, for total and free Protein S antigen and for Protein S function. Potency estimates were calculated relative to locally collected fresh normal plasma pools. Estimates of total Protein S antigen showed good agreement between laboratories with inter-laboratory geometric coefficient of variation (gcv%) of 8.8% and a mean value of 0.89 IU/ampoule. Estimates of free Protein S antigen calculated relative to total Protein S antigen in the fresh normal pools were more variable (gcv 26.8%) than estimates calculated relative to free Protein S antigen (gcv 15.3%); the latter comparison was used for calibration with a mean value of 0.89 IU/ampoule. Functional Protein S was estimated using commercial kits which gave an overall mean value of 0.92 IU/ampoule (gcv 14.0%). The 1st International Standard Protein S, plasma, (coded 93/590) was established in October 1995 with a single potency of 0.90 IU/ampoule for all three parameters.
von Willebrand Factor Activity Detected in a Monoclonal Antibody-based ELISA: an Alternative to the Ristocetin Cofactor Platelet Agglutination Assay for Diagnostic Use
Authors: Murdock Paul J , Woodhams Barry J , Matthews Kathy B , Pasi K John , Goodall Alison H
Published: July 2018

The monoclonal antibody RFF-VIII:R/1 recognises an epitope on von Willebrand factor involved in its interaction with GPIbα. A two-site, solid phase ELISA has been established using RFF-VIII:R/1 as the solid-phase, capture antibody and an enzyme-conjugated, polyclonal antibody to human VWF, which provides an assay for VWF functional activity with a detection limit of 0.5 U/dl VWF and an interassay %CV<10. Plasma from 192 VWD patients (48 studied retrospectively; 144 prospectively) showed VWF levels of <50 U/dl in type 1 patients (n = 156), <25 U/dl in type 2A (n = 26) and <35 U/dl in type 2B (n = 8) which, in type 1 and 2A patients, correlated with RiCoF activity (r >0.82). In plasma from patients with type 1 VWD values of VWF in the Mab-based ELISA were similar to levels of VWF:Ag measured in a polyclonal antibody-based ELISA (r >0.87) but were significantly lower than VWF:Ag in type 2A and 2B plasmas (p <0.0005), allowing discrimination of variant VWD. The Mab-based ELISA has advantages of sensitivity and reproducibility over the RiCoF assay to measure VWF activity and can be used to analyse stored samples. In conjunction with an ELISA for VWF:Ag and VWF multimer analysis, it provides a reliable method, for the laboratory diagnosis of VWD.
Comparison of Enoxaparin, Hirulog, and Heparin as Adjunctive Antithrombotic Therapy during Thrombolysis with rtPA in the Stenosed Canine Coronary Artery
Authors: Leadley Robert J , Kasiewski Charles J , Bostwick Jeffrey S , Bentley Ross , McVey Matthew J , White Francis J , Perrone Mark H , Dunwiddie Christopher T
Published: July 2018

A canine model of electrolytic injury-induced coronary artery thrombosis and rtPA-induced thrombolysis was used to evaluate the relative antithrombotic efficacy of enoxaparin (a low molecular weight heparin), conventional therapy (heparin or heparin plus aspirin), and hirulog (a direct thrombin inhibitor), when used as adjunctive therapy during thrombolysis. After 60 min of clot aging, adjunctive therapy was begun at doses which elevated APTT approximately 2-fold over baseline. Fifteen minutes after the start of adjunctive therapy, recombinant tissue plasminogen activator (rtPA) was administered (100 μg/kg i.v. bolus + 20 μg/kg/min for 60 min). Adjunctive therapy continued for 1 h after termination of rtPA and blood flow was monitored for two additional hours. Enoxaparin (1 mg/kg i.v. bolus + 30 μg/kg/min, n = 10 for each treatment group) was the only adjunctive treatment that significantly increased the total minutes of flow (143 ± 25 min out of a possible 240 min, vs 54 ± 25 min for vehicle, p <0.05) and decreased thrombus mass (6.0 ± 1.3 mg vs 11.8 ± 3.2 mg for vehicle). Although hirulog (2 mg/kg i.v. bolus + 40 μg/kg/min) did not significantly increase the minutes of flow (120 ± 27 min, p <0.06) or decrease thrombus mass (8.7 ± 1.7 mg) compared to vehicle, these values were not significantly different than those measured in the enoxaparin group. However, the results with hirulog were achieved at the expense of a significantly greater increase in template bleeding time than that measured during enoxaparin treatment. Minutes of flow for heparin (50 U/kg i.v. bolus + 0.6 U/kg/min) and heparin plus aspirin (5 mg/kg i.v. bolus) were 69 ± 20 and 60 ± 23 min, respectively; thrombus masses were 8.2 ±1.3 and 7.3 ±1.0 mg, respectively. In summary, enoxaparin was more effective than conventional therapy in this model in terms of vessel patency and thrombus mass, and was as effective as hirulog, at least at a dose of hirulog that only modestly impaired hemostasis. Therefore, enoxaparin may prove to be a safe and effective alternative agent for adjunctive therapy during thrombolysis with rtPA.
Shunt Dependency Syndrome after Cyst-Peritoneal Shunt Resolved by Keyhole Microsurgical Cyst Resection: Two Case Reports and Literature Review
Authors: Dong Fangyong , Wang Zhen , Li Yakun , Chen Zirong , Zhang Suojun , Wan Feng
Published: July 2018

Objective Shunt dependency syndrome after cyst-peritoneal (CP) shunt is a rare but serious complication which leads to increased intracranial pressure and neurological deficit. The possible mechanism still remains in controversy. We present our experience on the treatment of the complication and attempt to find a better therapy strategy for the complication.

Methods Two children with middle fossa arachnoid cysts underwent CP shunt with fixed pressure catheters at an opening pressure of 7 cmH2O and then developed dependency syndrome. Both patients were effectively treated by mini-invasive cyst wall excision with the shunts reserved. The clinical manifestation, radiological findings, treatment methods, and therapeutic outcomes were reviewed retrospectively.

Results The time from shunt surgery to shunt dependency syndrome occurrence was 4 and 2 years, respectively. Computed tomography/magnetic resonance findings of the brain showed remarkably collapsed cysts with normal or small ventricles. Both patients underwent secondary mini-invasive cyst wall excision and shunt catheters were reserved. After the operations, their symptoms were resolved except one case with marginally improved visual impairment.

Conclusion Shunt dependency syndrome is a rare but dangerous complication of CP shunt and should be treated in time. Collapsed and thickened cyst wall intermittent covering the catheter head end, decreased brain compliance due to chronic fibrosis, as well as regression of cerebrospinal fluid absorption could be the pathogenesis. We suggest keyhole resection of the residual cyst wall as an effective and mini-invasive treatment option.
Factor V Leiden and Thermolabile Methylenetetrahydrofolate Reductase in Extreme Old Age
Authors: Rees D C , Liu Y T , Cox M J , Elliott P , Wainscoat J S
Published: July 2018

Both factor V Leiden and the C677T methylenetetrahydrofolate reductase (MTHFR) gene mutation are associated with premature vascular disease, and yet are found at surprisingly high allele frequencies in European populations, 2.7% and 35% respectively. We have investigated the prevalence of these mutations in 87 UK residents over the age of ninety, to look for any evidence of their association with premature death.

Five factor V Leiden heterozygotes were found, giving an allele frequency of 2.9%, similar to that in the general UK population. The frequency of the thermolabile C677T MTHFR mutation was 36% with 11% homozygotes, again similar to that in the UK population; these genotypes are in Hardy-Weinberg equilibrium, suggesting that there is not strong selection against the homozygous state. One person was both heterozygous for factor V Leiden and homozygous for the C677T mutation. This study suggests that neither factor V Leiden nor thermolabile MTHFR are risk factors for premature death.
Antithrombotic and Hemorrhagic Effects of DX-9065a, a Direct and Selective Factor Xa Inhibitor: Comparison with a Direct Thrombin Inhibitor and Antithrombin Ill-Dependent Anticoagulants
Authors: Morishima Yoshiyuki , Tanabe Kiyoshi , Terada Yasuko , Hara Tsuyoshi , Kunitada Satoshi
Published: July 2018

(+)-2S-2-[4-[[(3S)-l-acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate (DX- 9065a) is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DX-9065a with a direct thrombin inhibitor and AT Ill-dependent anticoagulants in rat models of thrombosis and bleeding.

Rats were administered intravenously DX-9065a (0.1-1 mg/kg/h), argatroban (0.1-1 mg/k/h), low molecular weight heparin (25-100 anti- XaU/kg/h), unfractionated heparin (25-100 anti-XaU/kg/h) or Orgaran (30-300 anti-XaU/kg/h) for 1 h. DX-9065a dose-dependently inhibited both thrombus formation and elevation in plasma thrombin-AT III complex (TAT) level in a copper wire-inserted arteriovenous (AV) shunt model in rats. The dose required for 50% inhibition of thrombus formation was 0.27 mg/kg/h. DX-9065a did not prolong transection bleeding time up to 7.78 mg/kg/h. Argatroban and AT Ill-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose. These results suggest that direct and selective inhibition of factor Xa by DX-9065a is preferable for the treatment of thrombosis in the aspect of lack of compromising primary hemostasis.
Enhancement by Ticlopidine of the Inhibitory Effect on In Vitro Platelet Aggregation of the Glycoprotein IIb/IIIa Inhibitor Tirofiban
Authors: Umemura K , Kondo K , Ikeda Y , Nakashima M
Published: July 2018

We determined the effects of combining the glycoprotein IIb/IIIa inhibitor tirofiban (MK-383, Aggrastat) and ticlopidine on inhibition of ADP-induced platelet aggregation, inhibition of collagen-induced platelet aggregation, and prolongation of bleeding time in 5 healthy male volunteers. The study consisted of 2 periods. In period 1, tirofiban was administered intravenously as a bolus injection at a dose of 5.0 µg/kg for 5 min, then as a continuous infusion at a rate of 0.05 µg/kg/min for 5 h 55 min. In period 2, ticlopidine was given orally at a dose of 200 mg once daily for 4 days, after which tirofiban was administered in the same manner as in period 1, starting 2 h after the last dose of ticlopidine. The percent inhibition of platelet aggregation induced by ADP 5 µM at the end of tirofiban infusion in periods 1 and 2 was 73.6 ± 2.6 and 87.1 ± 5.7% (mean ± SD), respectively. The corresponding values for inhibition of platelet aggregation induced by collagen 2 µg/ml were 45.4 ± 36.1 and 82.8 ± 27.0%, respectively. In contrast, the percent inhibition of platelet aggregation induced by ADP and collagen after treatment with ticlopidine alone was 15.8 ± 20.2 and p ± 4.8%, respectively. Compared with tirofiban alone, the combination of tirofiban and ticlopidine significantly enhanced inhibition of platelet aggregation induced by both ADP and collagen (p <0.02 and p <0.012, respectively). The inhibitory effects of ticlopidine alone were not statistically significant. Tirofiban prolonged bleeding time both in period 1 and in period 2. However, tirofiban and ticlopidine combined did not affect bleeding time. Ticlopidine administration did not alter the pharmacokinetics of tirofiban. In conclusion, at the doses of tirofiban and ticlopidine used in this study, the combination of the two drugs enhanced inhibition of platelet aggregation but did not prolong bleeding time, suggesting that appropriate doses of tirofiban can be used concomitantly with ticlopidine with no further safety concerns but with potential additional clinical effects.
Prothrombin Synthesis in the Adult and Fetal Liver
Authors: Cohen Leon , McKinnell James , Puglisi Vincent , Greco Alba , Nardi Michael , Lee Margaret , Karpatkin Margaret
Published: July 2018

Plasma levels of blood coagulation zymogens are lower in the newborn than in the adult, with the lowest levels being in preterm infants. It is not known if the lower coagulation factor levels reflect differences in synthesis, secretion or catabolism.

Using a rabbit model we have compared prothrombin synthesis in the fetus and adult. In previous studies we attempted to compare transcription in the adult and fetal liver by extraction of mRNA, immobilization on a membrane and hybridization with a labeled cDNA for rabbit prothrombin. Comparison was impaired by the markedly dissimilar composition of fetal and adult rabbit liver; fetal liver is approximately fifty percent hematopoietic tissue even at term (1). In the present study, to obtain a more meaningful comparison we have employed in situ hybridization to compare directly prothrombin expression in adult and fetal liver. We report here that fetal liver contains more prothrombin mRNA than does adult liver. We have further compared prothrombin levels in protein extracts of adult and fetal liver and found that per microgram of extract, fetal liver contains as much prothrombin as does the adult. We conclude that the lower plasma prothrombin levels in the fetus do not reflect a lower rate of synthesis.
Selective Screening for the Factor V Leiden Mutation: Is it Advisable prior to the Prescription of Oral Contraceptives?
Authors: Schambeck Christian M , Schwender Stefan , Haubitz Imme , Geisen Ulrich E , Grossmann Ralf E , Keller Franz
Published: July 2018

The cumulative thrombotic risk of Factor V (FV) Leiden and oral contraceptives (OC) recommends screening for the mutation. Assuming that a family history of thrombosis increases the patient’s likelihood of bearing FV Leiden, a selective rather than universal screening would be performed. We studied the utility of a family history of thrombosis for screening of FV Leiden before prescription of OC and, furthermore, the utility of screening even if oral contraception is favoured. 101 patients who had their first and single thromboembolic event while using OC were interviewed. 609 women without any history of thromboembolism recruited by gynecologists completed a standard questionnaire. 101 of these women, age-matched and currently using OC, were selected for a case-control study. Regarding patients with previous thromboembolism, a family history in a first-degree relative had a positive predictive value (PPV) of only 14% for FV Leiden. A PPV of 12% was calculated by investigating the 609 thrombosis-free women. Inherited FV Leiden (odds ratio = 4.9) and acquired risk factors (odds ratio = 10.1) were both found to be the most prominent, but independent additional risks. Nevertheless, FV Leiden carriers, both heterozygotes and homozygotes, did not suffer earlier from thromboembolism than patients without the mutation. In conclusion, family history is an unreliable criterion to detect FV Leiden carriers. Screening for factor V Leiden can be worthwhile even if the advantages of oral contraception are higher assessed than the thrombotic risk. Affected women knowing about their additional risk could contribute to the prevention of thrombosis in risk situations.
Human Tissue Factor Pathway Inhibitor Fused to CD4 Binds both FXa and TF/FVIIa at the Cell Surface
Authors: Riesbeck Kristian , Dorling Anthony , Kemball-Cook Geoffrey , McVey John H , Jones Mick , Tuddenham Edward G D , Lechler Robert I
Published: July 2018

Tissue factor pathway inhibitor (TFPI) is one of the main regulators of the tissue factor (TF) pathway of coagulation. To tether human TFPI to the cell surface, full length or truncated TFPI lacking the third Kunitz domain were fused with domains three and four and the carboxy-termi- nal sequence of human CD4. Constructs were transfected into a mouse fibroblast cell line and individual clones were checked for expression using monoclonal antibodies directed against the first two TFPI Kunitz domains and against CD4. Specific human FXa binding was detected by flow cytometry using an anti-FX polyclonal antibody, and inhibition of FXa proteolytic activity was verified by chromogenic substrate assay using S-2765. In addition, TFPI-CD4-expressing cells, preincubated with FXa, specifically bound human TF-FVIIa complexes as revealed with an anti-human TF polyclonal antibody. No functional difference was observed between full length or truncated TFPI-CD4. These results demonstrate that functionally intact TFPI can be tethered to the cell surface. Genetic manipulation of, for example, endothelial cells leading to the stable expression of TFPI may inhibit the development of coronary artery heart disease following cardiac allotransplantation, and may inhibit thrombosis in the context of xenotransplantation.
Small, Dense LDL Particle Concentration Correlates with Plasminogen Activator Inhibitor Type-1 (PAI-1) Activity
Authors: Väisänen Sari , Baumstark Manfred W , Penttilä Ilkka , Bouchard Claude , Halonen Pirjo , Rankinen Tuomo , Berg Aloys , Rauramaa Rainer
Published: July 2018

The relation between LDL subtractions and fibrinolytic activity was studied in 150 men aged 53 to 63 years. Apolipoprotein B (apoB) concentration in the most dense LDL-5 (r = 0.39, p <0.001) and LDL-6 (r = 0.43, p <0.001) subtractions associated with plasminogen activator inhibitor type-1 (PAI-1) activity. Subjects in the highest LDL-6 apoB tortile had higher PAI-1 (24.7 vs. 13.1 AU/ml, p <0.001) and lower t-PA (0.26 vs. 0.54 IU/ml, p <0.001) activities than men in the lowest tortile. The difference in PAI-1 remained after adjusting for either triglycerides (p = 0.039) or insulin (p = 0.015) with cardiorespiratory fitness as an additional covariate, and history of cardiovascular disease and smoking as factors. In a regression analysis, plasma insulin and LDL-6 apoB, but not plasma triglycerides and body mass index, entered the model, and explained 30.6 and 3.9 % of the variance in PAI-1 activity, respectively. The novel finding of the present study was the independent association between small, dense LDL particles and PAI-1 activity in middle-aged men.
Up-regulation of Tissue Factor Expression by Platelet-derived Growth Factor in Human Vascular Smooth Muscle Cells in Culture
Authors: Xuereb J M , Sié P , Boneu B , Constans J
Published: July 2018

Human vascular smooth muscle cells (SMCs) isolated from normal adult arteries were investigated for the expression of Tissue Factor (TF) procoagulant activity at their membrane surface and TF antigen in lysed cells. In growing conditions, SMCs expressed high levels of TF activity and antigen. When cells were made quiescent by 72 h of subculture in serum-poor medium, these levels fell to about one third of the initial values. Platelet-derived growth factor BB (PDGF) up-regulated in a dose-dependent manner TF expression with a significant increase (1.8 fold) within five hours. PD 98059, a specific inhibitor of mitogen-activated protein kinase (MAPK) pathway involved in cell response to PDGF, also prevented TF up-regulation. Short-term treatment by Pentoxifylline and dibutyryl cAMP also completely prevented induced TF up-regulation, but remained without effect on baseline levels of quiescent, unstimulated cells. At their effective concentrations, pentoxifylline and dibutyryl cAMP also inhibited the activation of MAPK induced by PDGF. The rapid induction of TF upon growth factor stimulation may be important in circumstances where SMCs proliferate, such as vascular events or vessel development.
Creation and Use of an Electronic Health Record Reporting Database to Improve a Laboratory Test Utilization Program
Authors: Kurant Danielle , Baron Jason , Strazimiri Genti , Lewandrowski Kent , Rudolf Joseph , Dighe Anand
Published: July 2018

Objectives Laboratory-based utilization management programs typically rely primarily on data derived from the laboratory information system to analyze testing volumes for trends and utilization concerns. We wished to examine the ability of an electronic health record (EHR) laboratory orders database to improve a laboratory utilization program.

Methods We obtained a daily file from our EHR containing data related to laboratory test ordering. We then used an automated process to import this file into a database to facilitate self-service queries and analysis.

Results The EHR laboratory orders database has proven to be an important addition to our utilization management program. We provide three representative examples of how the EHR laboratory orders database has been used to address common utilization issues. We demonstrate that analysis of EHR laboratory orders data has been able to provide unique insights that cannot be obtained by review of laboratory information system data alone. Further, we provide recommendations on key EHR data fields of importance to laboratory utilization efforts.

Conclusion We demonstrate that an EHR laboratory orders database may be a useful tool in the monitoring and optimization of laboratory testing. We recommend that health care systems develop and maintain a database of EHR laboratory orders data and integrate this data with their laboratory utilization programs.
Adverse Outcomes due to Aggressive Fluid Resuscitation in Children: A Prospective Observational Study
Authors: Muttath Anand , Annayappa Venkatesh Lalitha , Jose Joe , Vasudevan Anil , Ghosh Santu
Published: July 2018

Fluid management has a major impact on the duration, severity, and outcome of critically ill children. The aim of this study was to examine the relationship between cumulative fluid overload (CFO) with mortality and morbidity in critically ill children. This was a prospective observational study wherein children (1 month–16 years) who were critically ill (with shock requiring inotropes and/or mechanically ventilated) were enrolled. CFO was defined as the sum of daily fluid balances. Daily fluid balance was calculated as a difference between fluid intake (oral and intravenous) and output (urine output, discharge from nasogastric tube) in 24 hours. Percentage of fluid overload (FO) (PFO) was calculated as the ratio of CFO with weight at admission in kilogram. The CFO and PFO at 24, 48, 72 hours and at 7 days or end of PICU stay were calculated. A total of 291 children (244 survivors and 47 non-survivors; 47% males) were included in the final analysis. A higher mortality was observed in children with higher PFO (>20% FO: 45.8% mortality vs. 14.5% < 10% FO, p < 0.01) and CFO (10.97 ± 6.4 mL/kg in survivors vs. 13.95 ± 9.6 mL/kg in non-survivors; p = 0.022) at 72 hours. A 1% increase in fluid overload was associated with 6% and 4% increase in mortality at 72 hours and 7 days, respectively. Similarly, the impact of every 1% increase in fluid overload on both ventilation (yes/no) and acute kidney injury (AKI; yes/no) were found to be significant for both parameters at 72 hours, but only AKI had significant correlation on seventh day. In the multivariate stepwise Cox's proportional hazard model for PICU stay and hospital stay, 3% (p < 0.05) and 2% (p > 0.05) increase were found for every 1% increase in fluid overload, respectively. Oxygenation index is also associated with fluid overload with the adjusted model estimated 0.27 units (95% confidence interval: 0.18–0.36) increase per 1% increase in fluid overload. FO was associated with increased mortality and morbidity in critically ill children.
Detecting causality using symmetry transformations
Authors: Roy Subhradeep , Jantzen Benjamin
Published: July 2018

Detecting causality between variables in a time series is a challenge, particularly when the relationship is nonlinear and the dataset is noisy. Here, we present a novel tool for detecting causality that leverages the properties of symmetry transformations. The aim is to develop an algorithm with the potential to detect both unidirectional and bidirectional coupling for nonlinear systems in the presence of significant sampling noise. Most of the existing tools for detecting causality can make determinations of directionality, but those determinations are relatively fragile in the presence of noise. The novel algorithm developed in the present study is robust and very conservative in that it reliably detects causal structure with a very low rate of error even in the presence of high sampling noise. We demonstrate the performance of our algorithm and compare it with two popular model-free methods, namely transfer entropy and convergent cross map. This first implementation of the method of symmetry transformations is limited in that it applies only to first-order autonomous systems.
Hofstadter point spectrum trace and the almost Mathieu operator
Authors: Ouvry Stéphane , Wagner Stephan , Wu Shuang
Published: July 2018

We consider point spectrum traces in the Hofstadter model. We show how to recover the full quantum Hofstadter trace by integrating these point spectrum traces with the appropriate free density of states on the lattice. This construction is then generalized to the almost Mathieu operator and its nth moments which can be expressed in terms of generalized Kreft coefficients.
Broadband ultrafast terahertz spectroscopy in the 25 T Split Florida-Helix
Authors: Curtis Jeremy A. , Burch Ashlyn D. , Barman Biplob , Linn A. Garrison , McClintock Luke M. , O’Beirne Aidan L. , Stiles Matthew J. , Reno John L. , McGill Stephen A. , Karaiskaj Denis , Hilton David J.
Published: July 2018

We describe the development of a broadband (0.3–10 THz) optical pump-terahertz probe spectrometer with an unprecedented combination of temporal resolution (≤200 fs) operating in external magnetic fields as high as 25 T using the new Split Florida-Helix magnet system. Using this new instrument, we measure the transient dynamics in a gallium arsenide four-quantum well sample after photoexcitation at 800 nm.
Spectroscopy of gold atoms and gold oligomers in helium nanodroplets
Authors: Messner Roman , Schiffmann Alexander , Pototschnig Johann V. , Lasserus Maximilian , Schnedlitz Martin , Lackner Florian , Ernst Wolfgang E.
Published: July 2018

The 6p 2P1/2 ← 6s 2S1/2 and 6p 2P3/2 ← 6s 2S1/2 transitions (D lines) of gold atoms embedded in superfluid helium nanodroplets have been investigated using resonant two-photon ionization spectroscopy. Both transitions are strongly blue-shifted and broadened due to the repulsive interaction between the Au valence electron and the surrounding helium. The in-droplet D lines are superimposed by the spectral signature of Au atoms relaxed into the metastable 2D states. These features are narrower than the in-droplet D lines and exhibit sharp rising edges that coincide with bare atom transitions. It is concluded that they originate from metastable 2D state AuHen exciplexes that have been ejected from the helium droplets during a relaxation process. Interestingly, the mechanism that leads to the formation of these complexes is suppressed for very large helium droplets consisting of about 2 × 106 He atoms, corresponding to a droplet diameter on the order of 50 nm. The assignment of the observed spectral features is supported by ab initio calculations employing a multiconfigurational self-consistent field method and a multi-reference configuration interaction calculation. For large helium droplets doped with Au oligomers, excitation spectra for mass channels corresponding to Aun with n = 2, 3, 4, 5, 7, and 9 are presented. The mass spectrum reveals even-odd oscillations in the number of Au atoms that constitute the oligomer, which is characteristic for coinage metal clusters. Resonances are observed close by the in-droplet D1 and D2 transitions, and the corresponding peak forms are very similar for different oligomer sizes.
Off-resonance intermittent contact mode multi-harmonic scanning force microscopy
Authors: Penedo M. , Hug H. J.
Published: July 2018

A robust off-resonance intermittent contact mode scanning force microscopy technique suitable for operation under different environmental conditions is presented. The technique relies on a multi-channel lock-in amplifier to measure multiple high harmonic magnitudes and phases. For distance control, the fundamental harmonic magnitude is used. With this, high intermittent contact frequencies become feasible even with older atomic force microscope data acquisition systems with limited measurement bandwidths, provided high frequency tip-sample distance actuation techniques are used. Suitable higher harmonic magnitude images provide a qualitative materials' contrast. If a sufficiently high number of high harmonic magnitudes and phases are recorded, force-distance curves at all imaged points can be reconstructed. From fitting models of the contact mechanics to force versus tip-sample penetration data, the elastic modulus of the sample can be obtained.
Modulation in charge ordering structure of ferroelectric YbFe2O4 by magnetic ordering
Authors: Nagata T. , Ikeda N.
Published: July 2018

We report the modulation in charge ordering structure of ferroelectric YbFe2O4 by magnetic ordering from x-ray diffraction experiments and magnetic measurements. The incommensurate modulation was observed on (n n 3m+3/2) type diffraction signal around magnetic ordering temperature where n and m are integer. The modulation was also observed on charge ordering signal, indicating spin-charge coupling. The incommensurate modulation was observed only on (n/3 n/3 3m) type charge ordering signal. This selectivity can be explained by polar charge ordering models.
Linear response time-dependent density functional theory without unoccupied states: The Kohn-Sham-Sternheimer scheme revisited
Authors: Hofmann Fabian , Schelter Ingo , Kümmel Stephan
Published: July 2018

The Sternheimer approach to time-dependent density functional theory in the linear response regime is attractive because of its computational efficiency. The latter results from avoiding the explicit calculation of unoccupied orbitals and from the basic structure of the Sternheimer equations, which naturally lend themselves to far-reaching parallelization. In this article, we take a fresh look at the frequency-dependent Sternheimer equations. We first give a complete, self-contained derivation of the equations that complements previous derivations. We then discuss several aspects of an efficient numerical realization. As a worked example, we compute the photoabsorption spectra of small hydrogenated silicon clusters and confirm that for these the quality of the Kohn-Sham eigenvalues is more important than the effects of the exchange-correlation kernel. Finally, we demonstrate how triplet excitations can readily be computed from the Sternheimer approach.
Improvement of durability and switching speed by incorporating nanocrystals in the HfOx based resistive random access memory devices
Authors: Wu Quantan , Banerjee Writam , Cao Jingchen , Ji Zhuoyu , Li Ling , Liu Ming
Published: July 2018

Resistive random access memory (RRAM) has attracted significant interest for next-generation nonvolatile memory applications. However, it is somehow difficult to design a high speed RRAM device with enhanced data reliability. This paper deals with the improvement of high speed durable switching in nanocrystals based RRAM (NC-RRAM) devices. The high performance RRAM devices were prepared by incorporating the NCs into the HfOx oxide layer. As compared to the without (w/o) NC devices, the NC-RRAM devices are capable to execute uniform switching with higher set speed of 100 ns and reset speed of 150 ns, longer retention time and higher endurance of 108 cycles at 85 °C. The possible switching mechanism is due to the formation and rupture of the conductive filaments (CFs) inside the oxide film. The improvement of the NC-RRAM devices is due to the enhanced electric field intensity on the surface of the NCs, which can effectively facilitate the formation and rupture of the CFs.
Hydrodynamic dispersion in thin channels with micro-structured porous walls
Authors: Ling Bowen , Oostrom Mart , Tartakovsky Alexandre M. , Battiato Ilenia
Published: July 2018

Flow and transport within porous- and microtextured-walled channels is relevant to a number of natural and industrial processes. Designing and optimizing the topology of the pores and/or microstructure to achieve target performance at the system scale (or macroscale) is still an open question. In this work, we study whether hydrodynamic dispersion in microfluidic channels with walls structured by obstacles can be modeled by dispersion in channels with porous walls described as continuous porous media of zero or finite permeability. We perform single phase microfluidic non-reactive flow experiments in channels embedded in micropatterns with different topologies. Specifically, we focus on transverse riblets and arrays of pillars as examples of impermeable and permeable obstructions, respectively. We compare the experimental results with three models: 3D pore-scale simulations which resolve the micropattern geometry explicitly and two upscaled models which treat the micropattern as a continuum of zero or finite permeability. This study demonstrates that polydimethylsiloxane micromodels with appropriately patterned surfaces can be successfully employed to validate various continuum-scale modeling approximations in different physical regimes, identified by the order of magnitude of the Péclet number and the obstruction permeability.
Helium line ratio spectroscopy for high spatiotemporal resolution plasma edge profile measurements at ASDEX Upgrade (invited)
Authors: Griener M. , Wolfrum E. , Cavedon M. , Dux R. , Rohde V. , Sochor M. , Muñoz Burgos J. M. , Schmitz O. , Stroth U. ,   ASDEX Upgrade Team
Published: July 2018

The thermal helium beam edge diagnostic has recently been upgraded at the ASDEX Upgrade (AUG) tokamak experiment. Line ratio spectroscopy on neutral helium is a valuable tool for simultaneous determination of the electron temperature and density of plasmas. The diagnostic now offers a temporal resolution of 900 kHz with a spatial resolution of up to 3 mm at 32 lines of sight (LOS) simultaneously. The LOS covers a radial region of 8.5 cm, starting at the limiter radius and reaching into the confined region beyond the separatrix. Two components are of particular importance for the aforementioned hardware improvements. The first is the optical head, which collects the light from the experiment. Equipped with an innovative clamping system for optical fiber ends, an arbitrary distribution pattern of LOS can be achieved to gain radial and poloidal profiles. The second major development is a new polychromator system that measures the intensity of the 587 nm, 667 nm, 706 nm, and 728 nm helium lines simultaneously for 32 channels with filter-photomultiplier tube arrays. Thus, the thermal helium beam diagnostic supplements the AUG edge diagnostics, offering fast and spatially highly resolved electron temperature and density profile measurements that cover the plasma edge and scrape-off layer region. Plasma fluctuations, edge localized modes, filaments, and other turbulent structures are resolved, allowing analysis of their frequency and localization or their propagation velocity.
Output voltage based adaptive step size MPPT controller with improved dynamics for stand-alone photovoltaic system
Authors: Verma Deepak , Mishra Jyotismita , Pattnaik Monalisa
Published: July 2018

In this paper, an efficient adaptive step size output voltage based maximum power point tracking (MPPT) algorithm is presented for a stand-alone photovoltaic system. The proposed algorithm meets the requirement of faster convergence by choosing larger perturbation steps to improve dynamic response and defining smaller perturbation steps to reduce steady state oscillations. In this technique, the voltage oscillation around the MPP is two level, which reduces the power loss during steady state operation. This adaptive MPPT technique is implemented in an Arduino microcontroller. A comprehensive theoretical analysis and experimental validation of the proposed adaptive MPPT algorithm has been carried out. The performance of the system is also compared with the conventional approach to ensure improved efficiency.
Radially scanning magnetic probes to study local helicity injection dynamics
Authors: Richner N. J. , Bongard M. W. , Fonck R. J. , Reusch J. A. , Schaefer C. E.
Published: July 2018

Two new magnetic probes have been deployed on the Pegasus spherical tokamak to study the dynamics of local helicity injection non-solenoidal plasma start-up and current drive. The magnetic radial array probe consists of 15 pickup coils (∼5 × 8 mm each) that measure Ḃz(R) over a 15 cm linear extent. The coils consist of traces embedded in a printed circuit board. Three coil designs are utilized to balance frequency response and coil sensitivity. Helmholtz coil measurements are used to measure coil and full assembly bandwidths (∼2 MHz and ∼200 kHz, respectively) and sensitivities (0.18/0.35/0.96 mV T−1 s). The magnetic radial scanning probe is an array of Hall effect sensors that measure field strength (|B| ≤ 177 mT) and direction at 8 spatial points (ΔR = 1.5 cm), supporting the studies of equilibrium field structure and low-frequency (≤5 kHz) current dynamics. It uses commercial surface-mount Hall effect sensors with chip-integrated amplifiers and compensators that are mounted in a 3-D printed frame. Helmholtz coil measurements indicate negligible cross-field gain nonlinearity and provide absolute calibration of the diagnostic. Both probes are constructed as an electrostatically shielded insertable air-side assembly that mounts within a radially translatable ultrahigh vacuum assembly from an existing probe.
Electronic response of aluminum-bearing minerals
Authors: Prange Micah P. , Zhang Xin , Ilton Eugene S. , Kovarik Libor , Engelhard Mark H. , Kerisit Sebastien N.
Published: July 2018

Aluminum-bearing minerals show different hydrogen evolution and dissolution properties when subjected to radiation, but the complicated sequence of events following interaction with high-energy radiation is not understood. To gain insight into the possible mechanisms of hydrogen production in nanoparticulate minerals, we study the electronic response and determine the bandgap energies of three common aluminum-bearing minerals with varying hydrogen content: gibbsite (Al(OH)3), boehmite (AlOOH), and alumina (Al2O3) using electron energy loss spectroscopy, X-ray photoelectron spectroscopy, and first-principles electronic structure calculations employing hybrid density functionals. We find that the amount of hydrogen has only a small effect on the number and spectrum of photoexcitations in this class of materials. Electronic structure calculations demonstrate that low energy electrons are isotropically mobile, while holes in the valence band are likely constrained to move in layers. Furthermore, holes in the valence band of boehmite are found to be significantly more mobile than those in gibbsite, suggesting that the differences in radiolytic and dissolution behavior are related to hole transport.
Coherently strained epitaxial YBa2Cu3O7−δ films grown on NdGaO3 (110)
Authors: Khanof Sogol , Mannhart Jochen , Boschker Hans
Published: July 2018

YBa2Cu3O7−δ is a good candidate to systematically study high-temperature superconductivity by nanoengineering using advanced epitaxy. An essential prerequisite for these studies is coherently strained YBa2Cu3O7−δ thin films, which we present here using NdGaO3 (110) as a substrate. The films are coherent up to at least 100 nm thickness and have a critical temperature of 89 ± 1 K. The a and b lattice parameters of YBa2Cu3O7−δ are matched to the in-plane lattice parameters of NdGaO3 (110), resulting in a large reduction of the orthorhombicity of YBa2Cu3O7−δ. These results imply that a large amount of structural disorder in the chain layers of YBa2Cu3O7−δ is not detrimental to superconductivity.
High-efficiency virtual cathode oscillator with photonic crystal
Authors: Frolov Nikita S. , Kurkin Semen A. , Koronovskii Alexey A. , Hramov Alexander E. , Rak Alexey O.
Published: July 2018

We study the properties of microwave generation in a virtual cathode oscillator with a photonic crystal composed of metal grids. Our simulation results show the high efficiency of photonic crystal structure utilization in comparison with the standard scheme of an axial virtual cathode oscillator: operation efficiency reaches 20% at the optimal parameters. The obtained results demonstrate that the virtual cathode oscillator with a photonic crystal can be considered as a prospective high-power microwave source where the vircator operation mechanism and photonic crystal properties complement each other to produce high-power electromagnetic radiation.