bluuebunny/crossref_metadata_2025_split huggingface dataset:
Demonstration of heterodimeric fibrinogen molecules partially conjugated with albumin in a novel dysfibrinogen: Fibrinogen Mannheim V
Authors: M.George Peter , Borggrefe Martin , Neumaier Michael , Brennan Stephen O. , Dempfle Carl-Erik 
Published: June 2009

SummaryA 30-year-old female experienced three miscarriages in early pregnancy. Extensive laboratory screening showed a low plasma fibrinogen level of approximately 1 g/l detected by PT-derived fibrinogen assay.The fibrinogen level in the immunological assay was 3 g/l.The functional Clauss assay yielded an intermediate result of 1.78 g/l. During her fourth and fifth pregnancy, the patient received fibrinogen concentrates (Haemocomplettan, CLS Behring, Marburg, Germany), starting with 4 grams of human fibrinogen, followed by 2 grams every second day until the 15th week of pregnancy.The further course of these pregnancies was uneventful. SDS-PAGE and immunoblotting showed doublet bands in the positions of the high-molecular weight (HMW)-and lowmolecular-weight (LMW)-fibrinogen, a single LMW’ fibrinogen band, plus additional bands with higher molecular weight than HMW-fibrinogen, which were also reactive with anti-human serum albumin (HSA) antiserum. These bands correspond to variant fibrinogen conjugated with albumin. Reduced SDS-PAGE and immunoblotting using polyclonal anti-fibrinopeptide A antiserum disclosed one additional Aα-chain band with lower molecular weight. Amplification and sequencing of exon 5 of the α gene indicated heterozygosity for a novel single nucleotide deletion at codon Aα494 (C1537delA). His494 is replaced by Pro and this is followed by 23 (LMKLPSSTLPQLEKHSQ VSSHLC) new amino acids before premature truncation after Cys517, yielding a free C-terminal cysteine, which may link with albumin.This new fibrinogen mutation, leads to a balanced array of homo- and heterodimeric fibrinogen molecules, some of which are conjugated to albumin.
The absence of angiopoietin-2 leads to abnormal vascular maturation and persistent proliferative retinopathy
Authors: Feng Yuxi , Hagen Franziska , Wang Yumei , Beck Susanne , Schreiter Kay , Pfister Frederick , Hoffmann Sigrid , Wagner Patrick , Seeliger Mathias , Molema Grietje , Deutsch Urban , Hammes Hans-Peter 
Published: June 2009

SummaryAngiopoietin-2 (Ang-2) antagonises the maturing effect of angiopoietin-1 (Ang-1) on blood vessels, and cooperates with VEGF to induce neovascularisation. In knockout mice,Ang-2 displayed a specific role in postnatal angiogenic remodelling. Here, we demonstrate that mice deficient in Ang-2 fail to form a proper spatial retinal vascular network. The retinal vasculature was characterised by reduced large vessel numbers and defects forming the superficial periphery mostly on the arteriolar site, and the secondary and tertiary deep capillary network. Hypoxia in the retinal periphery induced a four-fold VEGF upregulation and active endothelial proliferation for up to 60 days. Concomitantly, retinal digest preparations showed increased arteriolar (+33%) and capillary diameters (+90%), and fluorescein angiograms revealed leakiness of neovascular front. At one year of age, persistent preretinal vessels were non-leaky in accordance with a relative increase in the ratio of Ang-1 to VEGF.Taken together, the data suggest that Ang-2 has an important function in the spatial configuration of the three-dimensional retinal vasculature. Secondarily, prolonged VEGF activity results in a model of persistent proliferative retinopathy.
Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery
Authors: Karlsson Martin , Ternström Lisa , Hyllner Monica , Baghaei Fariba , Flinck Agneta , Skrtic Stanko , Jeppsson Anders 
Published: June 2009

SummaryIt has been suggested that preoperative fibrinogen plasma concentration is independently associated to postoperative blood loss after cardiac surgery.Theoretically, prophylactic infusion of fibrinogen concentrate may thus reduce postoperative bleeding, but this has not previously been investigated. Twenty elective coronary artery bypass graft (CABG) patients with preoperative plasma fibrinogen levels <3.8 g/l were included in a prospective randomised pilot study. Patients were randomised to receive an infusion of 2 g fibrinogen concentrate (FIB group) or no infusion before surgery (control group). Primary endpoint was safety with clinical adverse events and graft occlusion assessed by multi-slice computed tomography. Predefined secondary endpoints were postoperative blood loss, blood transfusions, haemoglobin levels 24 hours (h) after surgery, and global haemostasis assessed with thromboelastometry, 2 and 24 hours after surgery. Infusion of 2 g fibrinogen concentrate increased plasma levels of fibrinogen by 0.6 ± 0.2 g/l.There were no clinically detectable adverse events of fibrinogen infusion.Computed tomography revealed one subclinical vein graft occlusion in the FIB group. Fibrinogen concentrate infusion reduced postoperative blood loss by 32% (565 ± 150 vs. 830 ± 268 ml/12 h, p=0.010). Haemoglobin concentration was significantly higher 24 h after surgery in the FIB group (110 ± 12 vs. 98 ± 8 g/l, p=0.018). Prophylactic fibrinogen concentrate infusion did not influence global postoperative haemostasis as assessed by thromboelastometry. In conclusion, in this pilot study preoperative fibrinogen concentrate infusion reduced bleeding after CABG without evidence of postoperative hypercoagulability. Larger studies are necessary to ensure safety and confirm efficacy of prophylactic fibrinogen treatment in cardiac surgery.
Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin
Authors: Gerotziafas Grigoris T. , Dupont Charlotte , Spyropoulos Alex C. , Hatmi Mohamed , Samama Meyer M. , Kiskinis Dimitris , Elalamy Ismail 
Published: June 2009

SummaryVitamin K antagonists (VKA) treatment starts with co-administration of low-molecular-weight heparin (LMWH). The anticoagulation induced by the two drugs is still not well determined. In the present study we used thrombin generation assay to evaluate the hypo-coagulation induced by treatment with VKA and by the combination of VKA with LMWH. Tissue factor triggered thrombin generation in platelet-poor plasma was assessed in samples from 15 healthy volunteers, 97 samples from patients treated with VKA and 41 samples from patients receiving enoxaparin and VKA. Patients were classified according to international normalised ratio (INR) level (<2, 2–3 and >3).In plasma samples from patients treated with VKA having INR 2–3 the inhibition of thrombin generation reached 50% compared to controls. In samples with INR>3 this inhibition was 80%. In samples from patients receiving both LMWH and VKA, thrombin generation was significantly decreased compared to the controls and VKA group. In samples with an INR 2–3 obtained from patients treated with LMWH and VKA, the inhibition of thrombin generation was similar to that observed in samples with an INR>3 obtained from VKA treated patients. Thrombin generation assay is sensitive to detect the global the anticoagulant effect produced by the association of LMWH and VKA. For equal INR dual anticoagulant treatment induces significantly more profound inhibition of thrombin generation compared to treatment with VKA alone. The clinical relevance of this observation merits to be studied in prospective studies in patients with defined indications of anticoagulant therapy.
Reduction of early vein graft thrombosis by tissue plasminogen activator gene transfer
Authors: Wyatt Marcella J. , Newby Andrew C. , Thomas Anita C. 
Published: June 2009

SummaryVein grafts are used to bypass coronary arterial stenosis, but many grafts thrombose soon after surgery. A model was developed in the pig to allow continuous measurement of blood flow and production of flow-restricting thrombi (cyclic flow reductions; CFRs). Saphenous vein lumen was exposed to adenovirus ex vivo, to over-express human tissue plasminogen activator (h-tPA), with β-galactosidase adenovirus as a control. The vein segmen ts were engrafted into carotid arteries and examined 0,1 or 3 days later (4–7 animals/group). Untransduced grafts examined on the day of surgery developed repeated CFRs at both normal and restricted flow, but their frequency declined in grafts examined after 3 days. Adenovirus transduction was evident as β-galactosidase or h-tPA expression 1 day after engraftment. Blood flow was increased 1.4-fold in h-tPA transduced grafts after 1 day [control 390 (280–510), h-tPA 550 (450–660) ml/min; p=0.02 (expressed as mean (95% confidence intervals)]. CFRs were less severe (p=0.002) in the h-tPA transduced grafts than β-galactosidase-transduced grafts. CFRs were also less frequent in unstenosed undamaged h-tPA grafts [control 17 (6.1–29), h-tPA 7.6 (1.7–14) CFR/hr; p=0.02], but this difference was reduced after damage or stenosis. CFRs formed faster in h-tPA than in β-galactosidase-transduced grafts [control 14 (11–17), h-tPA 23 (19–27) ml/min2; p<0.001], and resolved twofold faster [control 25 (22–30), h-tPA 48 (39–60) ml/min2; p<0.001]. Hence, in this model, local gene therapy with h-tPA increased graft blood flow and decreased measures of early graft thrombosis, namely quicker CFR resolution and decreased frequency and severity.
Laboratory criteria of the obstetrical antiphospholipid syndrome
Authors: Boinot Catherine , De Carolis Sara , Rovere-Querini Patrizia , Aurousseau Marie-Hélène , Allegri Flavio , Nicaise-Roland Pascale , Barra Anne , Botta Angela , Ambrozic Ales , Avcin Tadej , Tincani Angela , Boffa Marie-Claire 
Published: June 2009

SummaryA debate on updating the laboratory criteria of antiphospholipid syndrome (APS) was recently opened in view to lower the risk of over diagnosis of the syndrome. Based on data related to thrombotic APS, it proposes the exclusion of anticardiolipin antibodies (aCL) and anti-beta2-glycoprotein 1 (a-β2-GPI) IgM detection. Here, we examine this possibility in a study which focuses on obstetrical APS (OAPS).We report new data on a prospective multicenter European cohort of 109 pregnant women having APS.Among them, 73 had purely obstetrical APS, not associated to autoimmune diseases or thrombosis. Isolated antibodies and isolated aCL positivity were present in 50/109 (46%) and in 34/109 (31%) of the women, respectively. An isolated a-β2-GPI IgM was present in three women.These results suggest that aCL and a-β2-GPI IgM cannot be dropped for the diagnosis and classification of OAPS.The low level of some antibodies associated with severe obstetrical complications raise the issue of keeping or not the same laboratory criteria for OAPS and for thrombotic APS and whether additional criteria after large prospective studies could further improve diagnosis.
Point-of-care monitoring of oral anticoagulation therapy in children
Authors: Greenway Anthea , Summerhayes Robyn , Newall Fiona , Burgess Janet , DeRosa Lydia , Monagle Paul , Ignjatovic Vera 
Published: June 2009

SummaryPoint-of-care (POC) monitoring of oral anticoagulation has been widely adopted in both paediatric and adult patients. A new POC system, the CoaguChek XS® has recently been developed to measure the international normalised ratio (INR) and may offer significant advantages. The CoaguChek XS® utilises a new method of electrochemical clot detection based on thrombin generation. This system has not been previously evaluated in children with reference to the laboratory gold standard, the prothrombin time using reference thromboplastin. It was the objective to compare values obtained by the CoaguChek XS® system with both the venous INR and the gold standard for anticoagulant monitoring, prothrombin time with reference thromboplastin (rTF/95).To evaluate the impact of testing using the Coagu-Chek XS® on clinical anticoagulant dosing decisions. Fifty paired venous INR and capillary CoaguChek XS® results were obtained from 31 children (aged up to 16 years).The laboratory gold standard, a manual prothrombin time with reference thromboplastin (rTF/95) was additionally performed on 26 samples. Correlation between the CoaguChek XS® result and the venous INR was r= 0.810. Agreement between the CoaguChek XS result and the reference INR was shown to be higher (r=0.95), in the subset analysed by this method. Correlation between the venous INR and reference INR was r=0.90. Despite changes to the methodology of testing with the CoaguChek XS® POC monitoring system, the accuracy of this method when compared with both the venous INR and gold standard reference INR was satisfactory. This resulted in infrequent changes to clinical decision making regarding anticoagulation
Megakaryocytes of patients with MYH9-related thrombocytopenia present an altered proplatelet formation
Authors: Malara Alessandro , Badalucco Stefania , Bozzi Valeria , Torti Mauro , Balduini Carlo L. , Balduini Alessandra , Pecci Alessandro 
Published: June 2009

Summary
MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations of MYH9, the gene for the heavy chain of myosin-IIA. Pathogenesis of thrombocytopenia of MYH9-RD is unknown. Recent studies in mice demonstrated that myosin-IIA is an inhibitor of proplatelet formation (PPF), and suggested that it could be involved in the suppression of PPF exerted by megakaryocyte adhesion to type I collagen, which regulates the timing of platelet release within bone marrow. However, the consequences on PPF of the heterozygous mutations causative of the MYH9-RD have never been investigated. We studied the in-vitro PPF by megakaryocytes obtained from four patients carrying the p.D1424N or the p.R1933X mutations. We demonstrated that MYH9-RD megakaryocytes completely lose the physiologic suppression of proplatelet extension exerted by interaction with type I collagen, thus supporting the hypothesis that a premature platelet release within bone marrow contributes to pathogenesis of MYH9-related thrombocytopenia. Moreover, proplatelets extended by MYH9-RD megakaryocytes presented a significant defect in branching in secondary processes (p=0.001) and formed a significantly lower number of proplatelet tips (p=0.005). Since platelets are assembled at the level of proplatelet tips, this defect could further contribute to pathogenesis of thrombocytopenia of MYH9-RD patients.
Clinical and economic outcomes in patients at risk of venous thromboembolism receiving appropriate enoxaparin or unfractionated heparin prophylaxis
Authors: Lin Jay , Lenhart Greg , Schulman Kathy , Amin Alpesh 
Published: June 2009

SummaryClinical and economic outcomes were compared following appropriate prophylaxis with enoxaparin or unfractionated heparin (UFH) in a large, real-world population of US hospitalised medical and surgical patients at risk of venous thromboembolism (VTE). Discharges from the Thomson Reuters MarketScan® Hospital Drug Database (January 2004–March 2007) of patients aged ≥40 years, at risk of VTE according to the 7th American College of Chest Physicians (ACCP) guidelines, who spent ≥6 days in hospital and received appropriate ACCP-recommended enoxaparin or UFH prophylaxis were included. Patients with contraindications to anticoagulation were excluded. Hospital-acquired VTE, adverse events, and hospital costs for enoxaparin versus UFH were compared using univariate and multivariate analyses. Of the 5,136 discharges included, 4,014 (78%) received enoxaparin and 1,122 (22%) received UFH. Compared with UFH, enoxaparin was associated with significantly lower risk of hospital-acquired VTE (adjusted odds ratio [OR] 0.51, 95% confidence interval [CI] 0.30–0.86, p=0.012), pulmonary embolism (adjusted OR 0.33, 95% CI 0.14–0.79, p=0.013) or adverse events (adjusted OR 0.73, 95% CI 0.54–0.98, p=0.034). Total hospital costs per discharge were lower for enoxaparin (US $16,865 ± 10,979) than UFH (US $19,252 ± 14,970), with a mean difference of US $2,388 in favour of enoxaparin (p<0.001) (adjusted difference US $439, 95% CI US $ -39 to 909, p=0.072). In patients at risk of VTE, appropriate enoxaparin prophylaxis was associated with a reduction in hospital-acquired VTE, adverse events, and costs compared with appropriate UFH prophylaxis. Increased appropriate use of enoxaparin in patients at risk of VTE may help to reduce the clinical and economic burden of this condition.
The 4–5 December 2001 IMPROVE-2 Event: Observed Microphysics and Comparisons with the Weather Research and Forecasting Model
Authors: Lin Yanluan , Colle Brian A. 
Published: June 2009

Abstract
This paper highlights the observed and simulated microphysical evolution of a moderate orographic rainfall event over the central Oregon Cascade Range during 4–5 December 2001 of the Second Improvement of Microphysical Parameterization through Observational Verification Experiment (IMPROVE-2). Airborne in situ measurements illustrate the spatial variations in ice crystal distributions and amounts over the windward Cascades and within some convective cells. The in situ microphysical observations, ground radars, and surface observations are compared with four bulk microphysical parameterizations (BMPs) within the Weather Research and Forecasting (WRF) model. Those WRF BMP schemes that overpredict surface precipitation along the Cascade windward slopes are shown to have too rapid graupel (rimed snow) fallout. Most BMP schemes overpredict snow in the maximum snow depositional growth region aloft, which results in excessive precipitation spillover into the immediate lee of the Cascades. Meanwhile, there is underprediction to the east of the Cascades in all BMP schemes. Those BMPs that produce more graupel than snow generate nearly twice as much precipitation over the Oregon Coast Range as the other BMPs given the cellular convection in this region. Sensitivity runs suggest that the graupel accretion of snow generates too much graupel within select WRF BMPs. Those BMPs that generate more graupel than snow have shorter cloud residence times and larger removal of available water vapor. Snow depositional growth may be overestimated by 2 times within the BMPs when a capacitance for spherical particles is used rather than for snow aggregates. Snow mass–diameter relationships also have a large impact on the snow and cloud liquid water generation. The positive definite advection scheme for moisture and hydrometeors in the WRF reduces the surface precipitation by 20%–30% over the Coast Range and improves water conservation, especially where there are convective cells.
Allogeneic hematopoietic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin lymphoma: an analysis of the European Group for Blood and Marrow Transplantation
Authors: Claviez Alexander , Canals Carme , Dierickx Daan , Stein Jerry , Badell Isabel , Pession Andrea , Mackinnon Stephen , Slavin Shimon , Dalle Jean-Hugues , Chacón Manuel Jurado , Sarhan Mahmoud , Wynn Robert Francis , Suttorp Meinolf , Dini Giorgio , Sureda Anna , Schmitz Norbert 
Published: June 2009

Abstract
Ninety-one children and adolescents 18 years or younger after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed or refractory Hodgkin lymphoma (HL) were analyzed. Fifty-one patients received reduced intensity conditioning (RIC); 40 patients received myeloablative conditioning (MAC). Nonrelapse mortality (NRM) at 1 year was 21% (± 4%), with comparable results after RIC or MAC. Probabilities of relapse at 2 and 5 years were 36% (± 5%) and 44% (± 6%), respectively. RIC was associated with an increased relapse risk compared with MAC; most apparent beginning 9 months after HSCT (P = .01). Progression-free survival (PFS) was 40% (± 6%) and 30% (± 6%) and overall survival (OS) was 54% (± 6%) and 45% (± 6%) at 2 and 5 years, respectively. Disease status at HSCT was predictive of PFS in multivariate analysis (P < .001). Beyond 9 months, PFS after RIC was lower compared with MAC (P = .02). Graft-versus-host disease did not affect relapse rate and PFS. In conclusion, children and adolescents with recurring HL show reasonable results with allogeneic HSCT. Especially patients allografted in recent years with good performance status and chemosensitive disease show highly encouraging results (PFS: 60% ± 27%, OS: 83% ± 15% at 3 years). Because relapse remains the major cause of treatment failure, additional efforts to improve disease control are necessary.
The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo
Authors: Gratacap Marie-Pierre , Martin Valérie , Valéra Marie-Cécile , Allart Sophie , Garcia Cédric , Sié Pierre , Recher Christian , Payrastre Bernard 
Published: June 2009

AbstractDasatinib is an oral potent adenosine triphosphate (ATP)–competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcγRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcγRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.
Do studies in humans better depict Th17 cells?
Authors: Annunziato Francesco , Romagnani Sergio 
Published: June 2009

AbstractCD4+ T helper (Th) lymphocytes represent a heterogeneous population of cells. In addition to type 1 (Th1) and type 2 (Th2) cells, another subset of CD4+ effector Th cells has been discovered and named as Th17, because of its unique ability to produce interleukin (IL)–17. Studies in mice initially suggested that Th17 cells are the pathogenic cells in autoimmune disorders, whereas Th1 cells may behave rather as protective. Subsequent studies in humans demonstrated the plasticity of Th17 cells and their possibility to shift to Th1. The plasticity of Th17 to Th1 cells has recently been confirmed in mice, where it was found that Th17 cells seem to be pathogenic only when they shift to Th1 cells. Studies in humans also showed that Th17 cells are different than in mice because all of them express CD161 and exclusively originate from CD161+ precursors present in umbilical cord blood and newborn thymus. While murine Th17 cells develop in response to IL-6, IL-1, and transforming growth factor (TGF)–β, human Th17 cells originate from these CD161+ precursors in response to IL-1β and IL-23, the need for TGF-β being controversial. Thus, we believe that studies in humans have better depicted human Th17 cells than studies in mice.