bluuebunny/crossref_metadata_2025 huggingface dataset:
IDPpi: Protein-Protein Interaction Analyses of Human Intrinsically Disordered Proteins
Authors: Perovic Vladimir , Sumonja Neven , Marsh Lindsey A. , Radovanovic Sandro , Vukicevic Milan , Roberts Stefan G. E. , Veljkovic Nevena
Published: July 2018

Intrinsically disordered proteins (IDPs) are characterized by the lack of a fixed tertiary structure and are involved in the regulation of key biological processes via binding to multiple protein partners. IDPs are malleable, adapting to structurally different partners, and this flexibility stems from features encoded in the primary structure. The assumption that universal sequence information will facilitate coverage of the sparse zones of the human interactome motivated us to explore the possibility of predicting protein-protein interactions (PPIs) that involve IDPs based on sequence characteristics. We developed a method that relies on features of the interacting and non-interacting protein pairs and utilizes machine learning to classify and predict IDP PPIs. Consideration of both sequence determinants specific for conformational organizations and the multiplicity of IDP interactions in the training phase ensured a reliable approach that is superior to current state-of-the-art methods. By applying a strict evaluation procedure, we confirm that our method predicts interactions of the IDP of interest even on the proteome-scale. This service is provided as a web tool to expedite the discovery of new interactions and IDP functions with enhanced efficiency.
Quantum phase transition in a realistic double-quantum-dot system
Authors: Kleeorin Yaakov , Meir Yigal
Published: July 2018

Observing quantum phase transitions in mesoscopic systems is a daunting task, thwarted by the difficulty of experimentally varying the magnetic interactions, the typical driving force behind these phase transitions. Here we demonstrate that in realistic coupled double-dot systems, the level energy difference between the two dots, which can be easily tuned experimentally, can drive the system through a phase transition, when its value crosses the difference between the intra- and inter-dot Coulomb repulsion. Using the numerical renormalization group and the semi-analytic slave-boson mean-field theory, we study the nature of this phase transition, and demonstrate, by mapping the Hamiltonian into an even-odd basis, that indeed the competition between the dot level energy difference and the difference in repulsion energies governs the sign and magnitude of the effective magnetic interaction. The observational consequences of this transition are discussed.
Plant-expressed bacteriophage lysins control pathogenic strains of Clostridium perfringens
Authors: Kazanavičiūtė Vaiva , Misiūnas Audrius , Gleba Yuri , Giritch Anatoli , Ražanskienė Aušra
Published: July 2018

The anaerobic spore-forming bacterium Clostridium perfringens is a source of one of the most common food-borne illnesses in the United States and Europe. The costs associated with disease management are high and interventions are limited; therefore, effective and safe antimicrobials are needed to control food contamination by C. perfringens. A viable solution to this problem could be bacteriophage lysins used as food additives or food processing aids. Such antimicrobials could be produced cost-effectively and in ample supply in green plants. By using edible plant species as production hosts the need for expensive product purification can be reduced or obviated. We describe the first successful expression in plants of C. perfringens-specific bacteriophage lysins. We demonstrate that six lysins belonging to two different families (N-acetylmuramoyl-L-alanine amidase and glycosyl hydrolase 25) are active against a panel of enteropathogenic C. perfringens strains under salinity and acidity conditions relevant to food preparation environments. We also demonstrate that plant-expressed lysins prevent multiplication of C. perfringens on cooked meat matrices far better than nisin, the only currently approved bacteriocin food preservative to control this pathogen.
Incidence, causes and risk factors for 30-day readmission after radical gastrectomy for gastric cancer: a retrospective study of 2,023 patients
Authors: Xiao Hua , Quan Hu , Pan Shuguang , Yin Bin , Luo Wei , Tang Ming , Ouyang Yongzhong , Tang Wei
Published: July 2018

The aim of this retrospective study was to investigate the incidence of, causes and risk factors for readmission to hospital ≤30 days after discharge of patients who underwent radical gastrectomy for gastric cancer. A total of 2,023 patients underwent radical gastrectomy operations from November 2010 to July 2017 in our hospital. Of these, 60 patients (3.0%) were readmitted within 30 days after their original discharge. The median time span between the index discharge and readmission was 14 days and the median time for readmission was 8 days. The main reasons for readmission were intestinal obstruction (n = 10, 16.7%), intra-abdominal fluid collection (n = 9, 15.0%), abdominal pain (n = 7, 11.7%), nutritional difficulty (n = 4, 6.7%) and anastomotic leakage (n = 4, 6.7%). Five patients (8.3%) required intensive care and 4 patients (6.7%) died from sudden cardiac arrest, gastrointestinal bleeding, sepsis or multiple organ dysfunctions. Multivariate analysis revealed that post-operative complications (Odds Ratio = 5.116, 95% confidence interval: 2.885–9.073, P < 0.001) was the only independent risk factor for readmission. Thus, appropriate strategies on discharge and close follow-ups for these high-risk patients should be drawn up in order to enhance significantly their quality of care.
3D surface morphology imaging of opaque microstructures via light-field microscopy
Authors: Da Sie Yong , Lin Chun-Yu , Chen Shean-Jen
Published: July 2018

Observing dynamic micro-scale phenomena occurring at millisecond time scales, such as organism activity, micron particle flows, or any opaque object observation, requires volumetric microscopy techniques able to achieve high data acquisition rates while maintaining contrast so that measurement of fine micro-scale features is possible. In realizing this purpose, the light-field (LF) technique has already been used on three-dimensional (3D) scene capturing and even for microscopic visualizations. In studying the ability and feasibility of 3D surface morphology reconstruction via LF microscopy, we adopted a lab-made LF microscope and integrated a four-dimensional Fourier slice algorithm and a Markov random field propagation algorithm. Furthermore, for numerical comparison and quantized analysis, the Tenengrad function was utilized to calculate the average contrast of the region of interest. Reflective US Air Force targets and 3D photolithography-made micro-scaffolds coated with 50 nm nickel thin films were adopted for system alignment and calibration. The experimental results demonstrate that the developed LF microscope with the signal processing algorithms can observe the 3D surface morphology of opaque microstructures with one snapshot, and has been preliminary applied to Brownian motion observation with 30 Hz volumetric image rate.
Identification of Uranotaenia sapphirina as a specialist of annelids broadens known mosquito host use patterns
Authors: Reeves Lawrence E. , Holderman Chris J. , Blosser Erik M. , Gillett-Kaufman Jennifer L. , Kawahara Akito Y. , Kaufman Phillip E. , Burkett-Cadena Nathan D.
Published: July 2018

Feeding upon vertebrate blood by mosquitoes permits transmission of diverse pathogens, including viruses, protozoa, and nematodes. Despite over a century of intensive study, no mosquito species is known to specialize on non-vertebrate hosts. Using molecular analyses and field observations, we provide the first evidence, to our knowledge, that a mosquito,Uranotaenia sapphirina, specializes on annelid hosts (earthworms and leeches) while its sympatric congener,Uranotaenia lowii, feeds only on anurans (frogs and toads). Our results demonstrate thatUr. sapphirinafeeds on annelid hosts (100% of identified blood meals;n = 72; collected throughout Florida), findings that are supported by field observations of these mosquitoes feeding onSparganophilusworms and freshwater leeches. These findings indicate that adult mosquitoes utilize a much broader range of host taxa than previously recognized, with implications for epidemiology and the evolution of host use patterns in mosquitoes.
Secondary nucleation in amyloid formation
Authors: Törnquist Mattias , Michaels Thomas C. T. , Sanagavarapu Kalyani , Yang Xiaoting , Meisl Georg , Cohen Samuel I. A. , Knowles Tuomas P. J. , Linse Sara
Published: July 2018

Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates.
Coincident modulation of lattice and electron thermal transport performance in MXenes via surface functionalization
Authors: Guo Zhonglu , Miao Naihua , Zhou Jian , Pan Yuanchun , Sun Zhimei
Published: July 2018

Efficiently modulating the thermal transport performance of materials including MXenes is highly desired as heat transfer is critical in a wide range of applications.
An extended excited-state intramolecular proton transfer (ESIPT) emitter for random lasing applications
Authors: Massue Julien , Felouat Abdellah , Vérité Pauline M. , Jacquemin Denis , Cyprych Konrad , Durko Martyna , Sznitko Lech , Mysliwiec Jaroslaw , Ulrich Gilles
Published: July 2018

An original ESIPT emitter showing random lasing properties is presented in this article.
Synthesis and thermoelastic properties of Zr(CN2)2and Hf(CN2)2
Authors: Dolabdjian Konstantin , Kobald Arne , Romao Carl P. , Meyer Hans-Jürgen
Published: July 2018

Metal carbodiimides with wine-rack topology exhibiting thermoelastic properties like those of flexible framework materials.
ortho-Phenyl dialkylphosphonium sulfonate compounds: two rotamers in equilibrium
Authors: Martin-Mothes E. , Puig E. , Vendier L. , Bijani C. , Grellier M. , Bontemps S.
Published: July 2018

Two known and two new ortho-phenyl phosphonium–sulfonate compounds have been synthesized and analyzed in solution and in the solid state.
Correction: Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: a randomized controlled trial
Authors: Boix-Castejón Marina , Herranz-López María , Gago Alberto Pérez , Olivares-Vicente Mariló , Caturla Nuria , Roche Enrique , Micol Vicente
Published: July 2018

Correction for ‘Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: a randomized controlled trial’ by Marina Boix-Castejón et al., Food Funct., 2018, 9, 3173–3184.
Synthesis and biological evaluation of novel asymmetric naphthalene diimide derivatives as anticancer agents depending on ROS generation
Authors: Xu Xiaojuan , Wang Senzhen , Chang Yuan , Ge Chaochao , Li Xinna , Feng Yongli , Xie Songqiang , Wang Chaojie , Dai Fujun , Luo Wen
Published: July 2018

Compound 3c induced apoptosis and autophagy and inhibited the migration of hepatoma cells depending on ROS generation.
The verticillenes. Pivotal intermediates in the biosynthesis of the taxanes and the phomactins
Authors: Palframan Matthew J. , Pattenden Gerald
Published: July 2018

Recent enzymatic studies, quantum chemical calculations and biomimetic conversions consolidate the role of verticillenes in the biosynthesis of taxanes and phomactins.
Biocompatible protamine sulfate@silicon nanoparticle-based gene nanocarriers featuring strong and stable fluorescence
Authors: Ji Xiaoyuan , Wang Chenyu , Tang Miaomiao , Guo Daoxia , Peng Fei , Zhong Yiling , Song Bin , Su Yuanyuan , He Yao
Published: July 2018

Biocompatible protamine sulfate-modified fluorescent silicon nanoparticle-based gene carriers allow long-term tracking of gene transport and release in live cells.
Synthesis and evaluation of analogues of the glycinocin family of calcium-dependent antibiotics
Authors: Corcilius Leo , Liu Dennis Y. , Ochoa Jessica L. , Linington Roger G. , Payne Richard J.
Published: July 2018

We describe the synthesis and calcium-dependent antimicrobial activity of a small library of glycinocin analogues that differ by variation in the exocyclic fatty acyl substituent.
Dynamic diselenide-containing polyesters from alcoholysis/oxidation of γ-butyroselenolactone
Authors: Wang Can , An Xiaowei , Pang Minglun , Zhang Zhengbiao , Zhu Xiulin , Zhu Jian , Du Prez Filip E. , Pan Xiangqiang
Published: July 2018

A versatile protocol for the synthesis of a variety of multiresponsive diselenide-containing polyesters was investigated.
Effect of spectrin network elasticity on the shapes of erythrocyte doublets
Authors: Hoore Masoud , Yaya François , Podgorski Thomas , Wagner Christian , Gompper Gerhard , Fedosov Dmitry A.
Published: July 2018

Red blood cells (RBCs) in plasma or polymer solution interact attractively to form various shapes of RBC doublets. A rich variety of doublet shapes is found, depending on membrane shear and bending elasticity, reduced volumes, and adhesion strength.
Correction: Efficient carrier transport in halide perovskites: theoretical perspectives
Authors: Du M. H.
Published: July 2018

Correction for ‘Efficient carrier transport in halide perovskites: theoretical perspectives’ by M. H. Du et al., J. Mater. Chem. A, 2014, 2, 9091–9098.
Coenzyme Q10 deficiencies: pathways in yeast and humans
Authors: Awad Agape M. , Bradley Michelle C. , Fernández-del-Río Lucía , Nag Anish , Tsui Hui S. , Clarke Catherine F.
Published: July 2018

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1–COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1–COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway.
Audiology Faculty Author Impact Metrics as a Function of Institution
Authors: Stuart Andrew
Published: July 2018

Purpose

The purpose of this study was to develop a method for the assessment of audiology author impact as a function of institution and compare these results to a recent college ranking of audiology graduate programs.

Method

Scopus author impact metrics (i.e., number of documents, number of citations, and
h
index) from a previous study (Stuart, Faucette, & Thomas, 2017) were generated for 79 accredited graduate programs in audiology in the United States and Canada. Author impact metrics were summed to represent the total institution output, and median values were calculated to reflect a measure of central tendency of individual faculty performance.

Results

Three hundred and seventy-nine audiology faculty members were identified and of those 86.0% (
n
= 326) were found in Scopus. Database presence increased with increasing rank (
p
= .003). Scopus index values were positively skewed. The total summed number of documents, citations, and
h
indices were positively correlated with the total number of faculty in the institutions and with the summed number of coauthors (
p
< .001). The median number of documents, citations, and
h
indices were not significantly correlated with the total number of faculty in the institutions but were positively correlated with the median number of coauthors (
p
< .001). In general, indices were higher for research/doctoral versus nonresearch universities. Higher college program rankings were statistically related with better Scopus index values.

Conclusion

These institutional metrics may be used to serve as a benchmark for institutional production, attracting students, hiring faculty, and assessing allocation of institutional funding.
Forward and Backward Masking of Consonants in School-Age Children and Adults
Authors: Porter Heather L. , Spitzer Emily R. , Buss Emily , Leibold Lori J. , Grose John H.
Published: July 2018

Purpose

This experiment sought to determine whether children's increased susceptibility to nonsimultaneous masking, particularly backward masking, is evident for speech stimuli.

Method

Five- to 9-year-olds and adults with normal hearing heard nonsense consonant–vowel–consonant targets. In Experiments 1 and 2, those targets were presented between two 250-ms segments of 70-dB-SPL speech-shaped noise, at either −30 dB signal-to-noise ratio (Experiment 1) or at the listener's word recognition threshold (Experiment 2). In Experiment 3, the target was presented in steady speech-shaped noise at listener threshold. For all experiments, percent correct was estimated for initial and final consonants.

Results

In the nonsimultaneous noise conditions, child–adult differences were larger for the final consonant than the initial consonant whether listeners were tested at −30 dB signal-to-noise ratio (Experiment 1) or at their individual word recognition threshold (Experiment 2). Children were not particularly susceptible to backward masking relative to adults when tested in a steady masker (Experiment 3).

Conclusions

Child–adult differences were greater for backward than forward masking for speech in a nonsimultaneous noise masker, as observed in previous psychophysical studies using tonal stimuli. Children's greater susceptibility to nonsimultaneous masking, and backward masking in particular, could play a role in their limited ability to benefit from masker envelope modulation when recognizing masked speech.
Immature Auditory Evoked Potentials in Children With Moderate–Severe Developmental Language Disorder
Authors: Kwok Elaine Y. L. , Joanisse Marc F. , Archibald Lisa M. D. , Cardy Janis Oram
Published: July 2018

Purpose

Immature auditory processing has been proposed to underlie language impairments in children with developmental language disorder (DLD; also known as
specific language impairment
). Using newly available normative auditory evoked potential (AEP) waveforms, we estimated AEP maturity in individual children with DLD and explored whether this maturational index was related to their language abilities.

Method

AEPs were elicited by 225 trials of a 490-Hz pure tone. Using intraclass correlation and our previously established normative AEP waveforms of 7- to 10-year-old children with typical development, we estimated the age equivalent of the AEPs (AEP–age) from 21 children with DLD. The relation between AEP maturity and language was explored through regression analysis.

Results

AEP–age predicted 31% of the variance in the language abilities of children with DLD. The AEP–age of children with mild DLD was similar to their chronological age, whereas children with moderate–severe DLD showed, on average, a 1.3-year delay in their neural responses. AEP–age predicted receptive, but not expressive, language performance.

Conclusion

Maturation in auditory neural responses is a significant predictor of language ability, particularly in children with moderate–severe DLD.
Erfolgreich zurück in den Leistungssport nach Verletzung des oberen Sprunggelenks – Ein Fallbeispiel
Authors: Flore Zacharias , Keller Matthias , Welsch Götz , Kurz Eduard
Published: July 2018

Kriterienbasierte Rehabilitationsmodelle unter Berücksichtigung der Wundheilungsphasen rücken in der Nachbehandlung von Sportlern immer weiter in den
Vordergrund. Dabei orientiert sich die Rehabilitation einerseits an der verletzten Struktur, andererseits an den Anforderungen der entsprechenden Zielsportart.
Die Autoren stellen anhand eines Fallbeispiels aus dem Leistungsfußball einen möglichen Therapiealgorithmus nach Verletzungen des Sprunggelenks vor und zeigen,
wie funktionelle Tests ergänzt durch einen spezifischen Fragebogen in der Rehabilitation eingesetzt werden können.
Gleichgewichtstraining zur Verletzungsprävention und Leistungssteigerung
Authors: Keller Martin
Published: July 2018

Gleichgewicht ist eine essenzielle koordinative Fähigkeit. Es hilft, Verletzungen zu vermeiden, und sollte daher gezielt trainiert werden. Dabei stellt sich die
Frage, ob der Effekt bestimmter Übungen auf andere Situationen übertragbar ist und ob sich mit einer guten Übungsauswahl auch andere Leistungsparameter von
Athleten steigern lassen.
Concussion – Gehirnerschütterungen im Sport
Authors: Sutor Volker
Published: July 2018

Die Gehirnerschütterung ist eine ernst zu nehmende Verletzung, die mit den unterschiedlichsten Symptomen auftritt. Besteht bei einem Sportler im Wettkampf der
Verdacht auf eine Gehirnerschütterung, sollte der Betroffene zu seiner eigenen Sicherheit sofort aus dem Spiel genommen werden. Bei adäquater Behandlung erholen
sich Verletzte vollständig und können schon bald wieder zum Sport zurückkehren.
Berufsbiografische Entwicklungen bei der Betreuung Sterbender
Authors: George Wolfgang M.
Published: July 2018

Etwa die Hälfte aller Menschen beendet das Leben in einem Krankenhaus, ein Drittel davon auf einer Intensivstation. Welche Auswirkungen die Betreuung von Sterbenden außerhalb einer ausgewiesenen Palliativstation hat, untersucht eine Studie von Prof. Wolfgang George, der dazu die Daten von knapp 500 Teilnehmern auswerten konnte. Wir stellen die Ergebnisse vor.
Oral Anticoagulation Therapy in Pediatric Patients: a Prospective Study
Authors: Andrew Maureen , Marzinotto Velma , Brooker Lu Ann , Adams Margaret , Ginsberg Jeff , Freedom Robert , Williams William
Published: July 2018

There are no validated guidelines for administering or monitoring oral anticoagulant therapy in pediatric patients. A pediatric thromboembolism program at the Hospital for Sick Children, Toronto, prospectively monitored consecutive children requiring warfarin over an 18 month period. A uniform protocol was followed and dose adjustments based upon international normalized ratios (INRs). One hundred and fifteen consecutive children; 68 males and 47 females, received warfarin. The age distribution was: <ly (19); 1-5 ys (33); 6-10ys (20); 11-18 ys (43). Warfarin was used for secondary prevention of venous thromboembolism (n = 56) and primary prevention of thromboembolism (n = 59). Underlying disorders included: congenital heart disease (CHD) without mechanical valves (MV) (49); CHD with MV (18); cancer (8); longterm total parenteral nutrition (7); renal disorders (10); other (23). Treatment length was considered as short term (3-6 mths) n = 37 (32%); longterm (> 6 mths) n = 38 (33%); and lifelong n = 40 (35%) of children. While receiving warfarin, 95 children received concurrent longterm treatment with other drugs: 1 drug (28); 2 drugs (27); 3 drugs (21); 4 or more drugs (19).

The amounts of warfarin/kg required to achieve INRs of 2 to 3 decreased with increasing age. Children <1 year of age required 0.32 ± 0.05 mg/kg whereas children 11-18 yrs required 0.09 ± 0.01 mg/kg; P <0.001. Monitoring warfarin required an average of 4.0 measurements per month and 1.5 dose changes per month. Changes in warfarin doses were primarily precipitated by drugs, intermittent illness, and changes in diet. A subgroup of children (n = 21) were treated with low dose warfarin either alone (n = 14) or following a course of full dose therapy (n = 7) to achieve an INR of 1.3 to 1.8. These children had persisting predisposing causes for new or recurrent thromboembolism. After the age of 1, the average dose required was 0.08 ± 0.01 mg/kg.

Complications were rare. Two children had significant bleeding events that resolved without further morbidity. There were no recurrent thrombotic events while children were receiving warfarin. In summary, warfarin therapy is age and weight dependent in children; close monitoring is necessary because of changing requirements; and complications are infrequent when management is coordinated through one service.
Thrombin-Based Antithrombin Assays Show Overestimation of Antithrombin III Activity in Patients on Heparin Therapy due to Heparin Cofactor II Influence
Authors: Bohner Jürgen , von Pape Klaus-Werner , Blaurock Mathias
Published: July 2018

An extensive comparison has been performed on the clinical chemistry automate Hitachi 717 between thrombin-and Factor Xa-based methods for determination of antithrombin III activity. In 460 patients who did not receive any heparin therapy the agreement between assays was in general close although the thrombin-based methods resulted in slightly higher assignments of 0.3—2.6% antithrombin III activity. The discrepancy was, however, substantial in plasmas from patients receiving heparin of >20000 IU/day, resulting in plasma levels of heparin of 0.8-1.2 IU/ml. Thus, analysis of 102 patients showed that the thrombin-based methods resulted in, on average, 7-16% higher assignment of antithrombin III activity as compared to the Factor Xa-based method used.

Addition of antibodies to antithrombin III and heparin cofactor II revealed that the discrepancy was primarily due to contribution of heparin cofactor II activity in the thrombin-based methods. The results thus suggest that the Factor Xa-based antithrombin III activity method provides more valid results in patients on heparin therapy.
Effects of Low Intensity Antithrombotic Regimes on the Haemoglobin Level
Authors: Meade T W , Howarth D J , Brennan P J
Published: July 2018

The effects on the haemoglobin level of low dose aspirin and of low intensity oral anticoagulation with warfarin separately and in combination have been established in men aged between 45 and 69 at high risk of ischaemic heart disease. The findings confirm that combined treatment with warfarin and aspirin (WA) leads to a clear excess of minor bleeding episodes over warfarin alone (W) or aspirin alone (A). Each separate treatment on its own (either W or A) leads to an increase in these episodes compared with those on placebo (P) treatment. However, neither combined treatment (WA) nor the separate treatments (W or A) cause a fall in haemoglobin levels over a period of up to two years.
Effect of Low Molecular Weight Heparin, Dextran and Their Combinations on Experimental Venous Thrombosis in Rabbits
Authors: Matthiasson Stefan E , Lindblad Bengt , Mätzsch Thomas , Holst Jan , Bergqvist David
Published: July 2018

An experimental model based on the combination of endothelial damage and flow reduction was used to induce jugular vein thrombosis in rabbits. The effect on thrombosis of a low molecular weight heparin (LMWH [Fragmin]), dextran 70, placebo and their combination was studied in a double-blind fashion with actual doses used in clinical thromboprophylaxis. Saline and polygeline were used as placebo in the control group. Four groups with 120 isolated vein segments in 60 animals were studied for presence of thrombus formation, occlusive thrombi and thrombus weights. Dextran reduced the thrombus weights (p = 0.048) and the formation of occlusive thrombi (p = 0.01), but not the formation of thrombi when compared with the placebo control group. Similarily, LMWH reduced the thrombus weights (p = 0.046), the formation of thrombi (p = 0.007) and occlusive thrombi (p = 0.0001). Compared with the LMWH group the group treated with the combination of LMWH and dextran was found to reduce the frequency of occlusive thrombi (p = 0.03) and numerically, but not significantly, further reduce the overall frequency of thrombosis (p = 0.18) and thrombus weights (p = 0.11). The results are consistent with an augmentation of the antithrombotic effect of LMWH by dextran 70. The need for further evaluation of the combined efficacy of LMWH and dextran is apparent from this study.
Demonstration of a Functionally Active tPA-Like Plasminogen Activator in Human Platelets
Authors: Wang D L , Pan Y T , Wang J J , Cheng C H , Liu C Y
Published: July 2018

The mechanism of platelet-enhanced fibrinolysis is unclear. We therefore investigated the fibrinolytic activity of human platelets and demonstrated that they contain a tissue plasminogen activator (tPA)- like plasminogen activator, abbreviated as tPA-like-PA. This activator was detected by ELISA in platelet incubation medium and in platelet Triton extracts. Plasminogen activation assays showed that this tPA- like-PA could induce plasminogen activation to form plasmin. Western blots of Triton extracts incubated with anti-tPA antibody demonstrated a major 64-kD protein band, compared to a 70-kD band for standard single chain tPA, plus a minor 118-kD band corresponding to a complex of tPA-like-PA and plasminogen activator inhibitor (PAI-1). Western blots of Triton extracts incubated with anti-PAI-1 antibody produced an approximately similar high-molecular-weight (118 kD) protein band. Fibrin zymographic analysis of affinity-purified tPA-like- PA demonstrated a major and a minor fibrin lysis zone, which approximately corresponded to the tPA-like-PA and its complex with PAI-1 observed by Western blots. Immunogold labelling and electron microscopy demonstrated that platelet activator, either as the free form or co-localized with PAI-1, was present in granules and in channels of the open canalicular system. We conclude that platelets contain a functionally active tPA-like-PA, whose low fibrinolytic activity might be due to its readily forming a complex with PAI-1. This functionally active tPA-like-PA might contribute to the enhanced fibrinolytic activity of platelets observed in platelet-rich thrombi.
Intramuscular Dermatan Sulfate MF701 in Patients with Hip Fracture: Relationship between Pharmacokinetics and Antithrombotic Efficacy
Authors: Imbimbo B P , Sié P , Agnelli G , Saivin S , Dupouy D , Damiani M , Houin G , Gianese F
Published: July 2018

Two groups of 23 and 84 patients with hip fracture received intramuscularly 100 and 300 mg dermatan sulfate (MF701) b. i. d., respectively, for the prophylaxis of deep vein thrombosis. Median duration of treatment was 17 and 16 days, respectively. Four blood samples were collected from each patient while under treatment. Plasma levels of dermatan sulfate were determined by a chromogenic substrate assay. A one-compartment model for multiple doses was employed to estimate the pharmacokinetic parameters. Fitting was applied to mean plasma concentrations calculated for each sampling time and weighted according to the number of samples available at each time. Thrombin clotting time was measured on the same plasma samples. Antithrombotic efficacy was assessed by bilateral venography.

Plasma levels of dermatan sulfate increased gradually throughout the treatment, indicating a marked accumulation process. Time to reach steady-state was 14 or 9 days with 100 or 300 mg b. i. d., respectively. This was due to an apparent prolonged terminal half-life (68 or 43 h), which actually reflected slow absorption from the injection sites. The clinical efficacy of MF701 in preventing DVT was found to be dependent on the plasma concentration of the drug and also, but less significantly, on the prolongation of thrombin clotting time. Dermatan sulfate plasma levels greater than 9 μ/ml are advisable to optimize efficacy in hip fracture patients.
Anti-Glycoprotein Ib/IX and llb/llla Antibodies in Patients with Antiphospholipid Antibodies
Authors: Galli Monica , Daldossi Maria , Barbui Tiziano
Published: July 2018

Antiphospholipid antibodies, namely lupus anticoagulant (LA), anticardiolipin (aCL) type A and type B antibodies, are frequently associated with immune-mediated thrombocytopenia. Antiphospholipid antibodies have been suggested to bind to the phospholipids of the platelet membrane, thus participating to the process of platelet destruction, which leads to thrombocytopenia. However, a clear antiphospholipid (aPL) demonstration of such a role has never been given for antibodies. Conversely, autoantibodies directed against membrane-associated glycoproteins (GP) have been shown to be pathogenet- ically linked to the development of thrombocytopenia in patients with idiopathic thrombocytopenic purpura. For this reason, we have measured anti-GPIb/IX and GPlIb/IIIa IgG in the plasma of 68 patients with aPL antibodies by ELISA. The monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay was used.

Twenty-seven out of 68 patients with antiphospholipid antibodies (40%) had increased plasma levels of anti-GP antibodies. In particular, 7 of them had elevated anti-GPIIb/IIIa levels only, 6 had anti-GPIb/IX antibodies only, whereas in the remaining 14 cases both types of autoantibodies were found elevated. The level of anti-GP antibodies in plasma did not correlate with age, sex, clinical associated conditions, history of thrombosis, IgG aCL titer or the presence of a phospholipid- dependent inhibitor of coagulation. In contrast, a statistically significant association between thrombocytopenia and high anti-GP antibody titer was observed (p = 0.0458).

To establish whether there was cross-reactivity between antiphospholipid and anti-GP antibodies, adsorption experiments were performed using eardiolipin-containing liposomes or washed, normal, resting platelets. When patients’ plasma was mixed with resting washed platelets, only anti-GP antibodies were adsorbed on platelet membrane and subsequently eluted from platelets. Conversely, binding to cardio- lipin-containing liposomes but not to platelet surface was demonstrated for antiphospholipid antibodies.

In conclusion, our data indicate that high levels of anti-platelet glycoprotein antibodies are more frequently found in patients with antiphospholipid antibodies and thrombocytopenia and that they might be responsible, more than LA and/or aCL antibodies, for the development of thrombocytopenia.
Expression and Assembly of Procoagulant Complexes by Human Pleural Mesothelial Cells
Authors: Kumar Anuradha , Koenig Kathleen B , Johnson Alice R , Idell Steven
Published: July 2018

Many pleural diseases involve fibrin deposition within the pleural cavity, an event that necessarily involves the mesothelium. This study of human pleural mesothelial cells (HPMC) was designed to determine how the mesothelium initiates and sustains the coagulation process. We used functional assays for activation of both factor X and prothrombin to examine expression and assembly of procoagulant activity by human pleural mesothelial cells in culture. The rates of factor Xa and thrombin formation were calcium-dependent. The rate of factor Xa formation in the presence of added factor VII increased in a concentration-dependent manner, suggesting that tissue factor is the primary procoagulant associated with HPMC. The fact that direct binding of radioiodinated factor Vila to HPMC was specific, concentration-dependent and saturable confirms that tissue factor is expressed on the cell surface. The rate of thrombin formation increased with factor Xa concentration, and the rate was 5-, 6-fold higher in presence of added factor Va indicating that HPMC support expression of prothrombinase activity. Further, direct binding of radioiodinated factor Xa to HPMC was specific, concentration-dependent and saturable, confirming that the cells support the assembly of the prothrombinase complex.
Platelet Shape Change in Whole Blood: Differential Effects of Endotoxin
Authors: Nystrom M L , Barradas M A , Jeremy J Y , Mikhailidis D P
Published: July 2018

The effect of endotoxic lipopolysaccharide (LPS) on platelet shape change (PSC; a preaggregation event) was investigated. PSC is accompanied by an increase in median platelet volume (MPV), which was measured using a channelyzer. In whole blood, but not in platelet rich plasma (PRP), LPS (final concentration 80 mg/1) caused an increase in MPV that could be detected for 2 h. When PRP (prepared from LPS- and saline-pretreated whole blood) was incubated for 40 min, the LPS-mediated increase in MPV could no longer be detected. Taken together, these data imply that PSC is both initiated and maintained by a labile factor(s) present in whole blood, but not in PRP.

PRP was prepared from LPS-pretreated whole blood and incubated for 40 min to allow reversal of the LPS-induced PSC; further stimulation with LPS caused PSC. Platelets from LPS-pretreated whole blood also showed enhanced PSC with seioloum (J-HT), diminished PSC with platelet activating factor (PAF), and no change of response to ADP and collagen. Hence, LPS pretreatment of whole blood differentially alters responses of platelets to further stimulation with LPS and other agonists. A specific PAF antagonist completely abolished the effect of LPS on MPV. These data may contribute to an understanding of the cascading thrombotic events and thrombocylopeuia assoeialed wiib septicaemia.
Clopidogrel – a Platelet Inhibitor which Inhibits Thrombogenesis in Non-Anticoagulated Human Blood Independently of the Blood Flow Conditions
Authors: Roald Helge E , Marius Barstad R , Kierulf Peter , Skjørten Fredrik , Dickinson John P , Kieffer Gilles , Sakariassen Kjell S
Published: July 2018

The goal of the present study was to investigate the effect of 7 and 14 days of daily oral administration of 75 mg clopidogrel on collagen-induced thrombogenesis in flowing non-anticoagulated human blood. Blood was drawn directly from an antecubital vein over immobilised collagen type III fibrils positioned in a parallel-plate perfusion chamber. The wall shear rates at the collagen surface were those characteristic for veins (100 s−1), and for medium sized (650 s−1) and moderately stenosed (2600 s−1) arteries.

Clopidogrel ingestion reduced the thrombus volume significantly (p <0.05) at 100 and 2600 s−1 (39 and 51% respectively). The β-thromboglobulin plasma levels were reduced concomitantly. However, it was not possible to measure accurately the thrombus volume at 650 s−1, due to loose packing of the platelet thrombi. Transmission electron micros-copy substantiated this observation and showed that clopidogrel profoundly reduced the platelet degranulation process (p <0.005). The inhibitory effect of clopidogrel on platelet consumption by the growing thrombi resulted apparently in higher platelet concentration at the collagen surface, which enhanced the platelet-collagen adhesion at all three shear rates (p <0.05). Despite the low deposition of fibrin on collagen, clopidogrel reduced significantly the fibrinopeptide A plasma levels and the fibrin deposition at shear rates below 650 s−1. This was apparently a consequence of the reduced platelet recruitment and the lower activation of platelets, since activated platelets in thrombi promote deposition of fibrin.

Thus, it appears that clopidogrel inhibits thrombus formation in human blood primarily by interfering with platelet-platelet binding and the inhibition is effective independently of the wall shear rate.
Clinical Course of Factor VIII Inhibitors Developed after Exposure to a Pasteurised Dutch Concentrate Compared to Classic Inhibitors in Hemophilia A
Authors: Mauser-Bunschoten E P , Rosendaal F R , Nieuwenhuis H K , Roosendaal G , Briëf E , van den Berg H M
Published: July 2018

After the introduction of a new pasteurised factor VIII concentrate (Factor VIII CPS-P) in The Netherlands in June 1990, an increase in the occurrence of inhibitors in hemophilia A patients was reported. The clinical course of this group of inhibitors (n = 12) was compared with hemophilia patients in whom an inhibitor developed before June 1990 (classic inhibitors) (n = 32). Striking differences were found between both groups not only in patient age (median 22 years versus 8 years) and number of exposure days (<50 − >1000 versus <50), as described in previous reports, but also in clinical course and response to treatment. In the recent group of inhibitors antibody titers showed a rapid decline when product was changed which was not the case in the group with classic inhibitors. In the group of classic inhibitors immune tolerance therapy with low dose factor VIII succeeded in 83%. Success was to a high degree dependent on the inhibitor level. In the group of recent inhibitors immune tolerance with the same concentrate was only successful in a single patient. However, once the patients were switched to another concentrate, antibody levels dropped to less than 2 BU/ml within 8 months in all patients.

It seems likely that in this group of product associated inhibitors, treatment success was due to elimination of antigen stimulation rather than induction of immune tolerance.
Serological and Virological Markers of Human Parvovirus B19 Infection in Sera of Hemophiliacs
Authors: Große-Bley A , Eis-Hübinger A M , Kaiser R , Oldenburg J , Brackmann H H , Schwarz T F , Schneweis K E
Published: July 2018

It is known that parvovirus B19 (B19) is transmitted to hemophiliacs by clotting factors prepared from human plasma. However, it is not clear whether B19 is also transmitted by the more recently used inactivated clotting factor preparations. Therefore, we investigated 69 hemophiliacs, mostly children, receiving only virus-inactivated clotting factors. 49 of them (71%) were B19 IgG-positive and 18 of the IgG-positive hemophiliacs (37%) were also B19 IgM-positive. In contrast, out of 73 age-matched controls only 10 (14%) were IgG-positive, two of them being also IgM-positive. In hemophiliacs treated before 1984 with noninactivated clotting factors, seroprevalence was very similar: 94/136 (69%) presented B19 IgG antibodies as compared to their age-matched controls with 16/50 (32%). Out of the 94 IgG-positive patients 24 (26%) were IgM-positive, whereas IgM antibodies were never found in 16 sera of 16 IgG-positive controls. In 4 out of 24 IgM positive hemophiliacs, B19 DNA was detected in the sera by using the polymerase chain reaction. However, B19 DNA was also found in 3/69 anti-B19 IgM-negative, HIV-infected hemophiliacs (all three patients in CDC stage IV). Since it seems unlikely that the results only represent passive acquisition of B19 DNA from blood products and induction of antibodies by immunization with inactivated antigen, the observations rather suggest that infection with B19 is transmitted by clotting factors, including those treated for virus inactivation.
Patterns of Immunogenicity of an Inactivated Hepatitis A Vaccine in Anti-HIV Positive and Negative Hemophilic Patients
Authors: Santagostino E , Gringeri A , Rocino A , Zanetti A , de Biasi R , Mannucci P M
Published: July 2018

Hepatitis A vaccination has been recommended to patients with hemophilia since they are exposed to potentially infectious clotting factor concentrates. Aim of this study was to assess the immunogenicity of vaccination in hemophiliacs, infected or not with the human immunodeficiency virus (HIV). A formalin-inactivated hepatitis A vaccine was injected subcutaneously to 113 susceptible adults and children and repeated after 1 and 6 months. 47 vaccinees were anti-HIV positive (28 asymptomatic, 15 with CD4 cell counts of less than 200/pl and 4 with symptomatic disease). The first dose of vaccine induced seroconversion, with antibody titers of at least 20 mlU/ml, in 89% of the 66 anti-HIV negative patients, 100% of them responding after the second injection. In anti-HIV positive hemophiliacs seroconversion rates and antibody titers were significantly lower than in non-infected patients. After 12 months, only 76% of anti-HIV positive vaccinees and 40% of those with signs of HIV disease progression maintained the antibody, whereas all anti-HIV negative patients had titers of 20 mlU/ml or more. Our results indicate that there is an association between defective response to hepatitis A vaccine and stage of progression of HIV disease.
Macroaggregation of Platelets in Plasma, as Distinct from Microaggregation in Whole Blood (and Plasma), as Determined Using Optical Aggregometry and Platelet Counting respectively, is Specifically Impaired following Cardiopulmonary Bypass in Man
Authors: Menys Valentine C , Belcher Philip R , Noble Mark I M , Evans Rhys D , Drossos George E , Pillai Ravi , Westaby Steve
Published: July 2018

We determined changes in platelet aggregability following cardiopulmonary bypass, using optical aggregometry to assess macroaggregation in platelet-rich plasma (PRP), and platelet counting to assess microaggregation both in whole blood and PRP. Hirudin was used as the anticoagulant to maintain normocalcaemia.

Microaggregation (%, median and interquartile range) in blood stirred with collagen (0.6 µg/ml) was only marginally impaired following bypass (91 [88, 93] at 10 min postbypass v 95 (92, 96] prebypass; n = 22), whereas macroaggregation (amplitude of response; cm) in PRP stirred with collagen (1.0µg/ml) was markedly impaired (9.5 [8.0, 10.8], n = 41 v 13.4 [12.7,14.3], n = 10; p <0.0001). However, in PRP, despite impairment of macroaggregation (9.1 [8.5, 10.1], n = 12), microaggregation was near-maximal (93 [91, 94]), as in whole blood stirred with collagen. In contrast, in aspirin-treated patients (n = 14), both collagen-induced microaggregation in whole blood (49 [47, 52]) and macroaggregation in PRP (5.1 [3.8, 6.6]) were more markedly impaired, compared with control (both p <0.001).

Similarly, in PRP, macroaggregation with ristocetin (1.5 mg/ml) was also impaired following bypass (9.4 [7.2, 10.7], n = 38 v 12.4 [10.0, 13.4]; p <0.0002, n = 20), but as found with collagen, despite impairment of macroaggregation (7.2 [3.5,10.9], n = 12), microaggregation was again near-maximal (96 [93,97]). The response to ristocetin was more markedly impared after bypass in succinylated gelatin (Gelo-fusine) treated patients (5.6 [2.8, 8.6], n = 17; p <0.005 v control), whereas the response to collagen was little different (9.3 v 9.5). In contrast to findings with collagen in aspirin-treated patients, the response to ristocetin was little different to that in controls (8.0 v 8.3). Impairment of macroaggregation with collagen or ristocetin did not correlate with the duration of bypass or the platelet count, indicating that haemodilution is not a contributory factor.

In conclusion: (1) Macroaggregation in PRP, as determined using optical aggregometry, is specifically impaired following bypass, and this probably reflects impairment of the build-up of small aggregates into larger aggregates. (2) Impairment of aggregate growth and consolidation could contribute to the haemostatic defect following cardiac surgery.