bluuebunny/crossref_metadata_2025_split huggingface dataset:
The appended tail region of heparin cofactor II and additional reactive centre loop mutations combine to increase the reactivity and specificity of α1-proteinase inhibitor M358R for thrombin
Authors: Sutherland Jason , Bhakta Varsha , Sheffield William 
Published: October 2007

SummaryNatural inhibitors of coagulation or inflammation such as the serpins antithrombin (AT), heparin cofactor II (HCII), and 1-proteinase inhibitor (α1-PI) can be overwhelmed in thrombosis and/or sepsis. The reactive centre (P1-P1) variant α1-PI M358R inhibits not only procoagulant thrombin but also anticoagulant activated protein C (APC). We previously described HAPI M358R, comprising a fusion of HCII residues 1–75 to the N-terminus of a1-PI M358R that yielded increased anti-thrombin, but not anti-APC activity. We hypothesized that further alterations to the HAPI M358R reactive centre loop would yield additional refinements in specificity. The reactions with thrombin or APC of recombinant α1-PI M358R variants with or without the HCII extension were characterized electrophoretically and kinetically. Their extension of clotting times and inhibition of fibrin-bound thrombin were measured, and the survival of HAPI M358R in mice was determined. Replacing the P7-P3 and P2’ residues of HAPI M358R with AT residues reduced APC inhibition rates by 140-fold, but those of thrombin less than two-fold;substituting the P16-P2 and P2’-P3’ residues of HAPI M358R with HCII residues reduced APC inhibition rates by 180-fold, but those of thrombin 10.5-fold. Fused variants extended thrombin clotting times more effectively than unfused inhibitors, were at least as effective at inhibiting clot-bound thrombin, and remained intact in the murine circulation. The combination of modifications inside and outside the RCL resulted in a 1,360-fold increase in selectivity of HAPI M358R (AT P7-P3/P2’) for thrombin versus APC relative to α1-PI M358R. Our results predict that this protein may be effective in limiting thrombosis in vivo.
Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery
Authors: Mathew Prasad , Valentino Leonard , Sumner Michael , Seremetis Stephanie , Hoots Keith , Pruthi Rajiv ,   the NovoSeven in Surgery Study Investigators
Published: October 2007

SummaryBolus infusion (BI) recombinant factor VIIa (rFVIIa) administration is safe and effective in the surgical management of haemophilia patients with inhibitors but has not been compared directly with continuous infusion (CI). We conducted an open-label, randomized, multicenter trial comparing the efficacy and safety of rFVIIa administered by BI or CI for the surgical management of haemophilia A or B patients with inhibitors to FVIII or FIX. Safety was compared with that of a control group of noninhibitor patients receiving FVIII or FIX concentrates for major surgery. All inhibitor subjects received an initial bolus dose of 90 μg/kg rFVIIa and were then randomly assigned to BI (n=12) or CI (n=12). The BI group received 90 μg/kg rFVIIa every two hours (h) during surgery through day 5, then every four hours for days 6–10. The CI group received 50 μg/kg/h rFVIIa through day 5, then 25 mg/kg/h for days 6–10. The control group (n=12) received FVIII or FIX per institutional protocols. Twenty-two major surgeries included orthopedic procedures on the knee (n=13), hip (n=3), and abdominal/pelvis procedures (n=4). One patient with an autoimmune FVIII inhibitor randomized to the BI arm was excluded from efficacy analysis. Haemostatic efficacy of rFVIIa in each group was comparable: effective in 8/11 and 9/12 subjects in the BI and CI arms, respectively, and ineffective in three subjects in each arm. Serious adverse events were related to continued or increased bleeding. In conclusion, haemostatic efficacy and safety of BI and CI of rFVIIa are comparable for the surgical management of haemophilia subjects with inhibitors.
Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients
Authors: Federici Marco Orsini , Mourvaki Evangelia , Ferolla Piero , Piroddi Marta , Stabile Anna , Timi Alessandra , Celleno Roberta , Benedetti Massimo Massi , Iorio Alfonso 
Published: October 2007

SummaryReview of literature has shown an increased rate of thrombotic complications in diabetic patients with frequent episodes of hyperketonemia. However, the mechanisms by which ketosis promotes vascular disease in diabetic patients are unclear.It was the aim of this study to investigate early changes in haemostatic parameters and oxidative stress markers during the hyperketonemic status which follows the interruption of continuous subcutaneous insulin infusion (CSII) in type I diabetic patients. Eight CSII-treated type I diabetic patients underwent a 4-hour pump arrest. Blood glucose, insulin and 3-hydroxybutirate were measured to verify the metabolic response. A vein-occlusive (VO) test was performed for the determination of tPA and PAI-1 activities and their antigen levels before and after the CSII arrest. Coagulation factor VII and VIII were evaluated by one-stage PT and PTT method, respectively.TF, vWF, tPA and PAI-1 antigens were determined by ELISA, whereas tPA and PAI-1 activities using chromogenic methods. Plasma malondialdehyde (MDA) and protein carbonyl groups (PCG) levels were determined by HPLC and spectrophotometry, respectively. After the insulin deprivation phase, post-VO tPA antigen level significantly decreased (P=0.0391), whereas TF and post-VO PAI-1 activity and antigen levels significantly increased (P=0.0156 and P=0.0234, respectively). Plasma MDA and PCG levels were 1.88-fold and 1.74-fold higher than baseline values, respectively. In conclusion, the impairment of the fibrinolytic potential and the increases in TF, MDA and PCG levels may enhance the risk of both arterial and venous thrombosis during ketosis.Thus, early detection of hyperketonemia in DM patients could contribute to the prevention of life-threatening vascular events.
A large deletion of the PROS1 gene in a deep vein thrombosis patient with protein S deficiency
Authors: Yin Tong , Takeshita Satoshi , Sato Yukiko , Sakata Toshiyuki , Shin Yongchol , Honda Shigenori , Kawasaki Tomio , Tsuji Hajime , Kojima Tetsuhito , Madoiwa Seiji , Sakata Yoichi , Murata Mitsuru , Ikeda Yasuo , Miyata Toshiyuki 
Published: October 2007

SummaryInherited deficiency of protein S encoded by the PROS1 gene constitutes an important risk factor for deep vein thrombosis (DVT). Nevertheless, although more than 200 deleterious genetic variations in PROS1 have been identified, causative point mutations of PROS1 gene are not detected in approximately half of protein S-deficient families. The present study investigated whether there may exist a large deletion in PROS1 that constitutes a genetic risk factor for Japanese DVT patients. A multiplex ligation-dependent probe amplification analysis was employed to identify the deletions in PROS1 in 163 Japanese patients with DVT. A large gene deletion was identified in one patient who showed 16% protein S activity and did not carry point mutations in PROS1 by DNA sequencing and it was validated by the quantitative PCR method. The deletion spanned at least the whole PROS1 gene (107 kb) and at most from the centromere located downstream of PROS1, to before the D3S3619 marker, the first heterozygous marker in the upstream of PROS1 in chromosome 3. In conclusion, a large deletion in PROS1 was shown to partly account for DVT with protein S deficiency. Screening for large deletions in PROS1 might be warranted in PROS1 causative point mutation-negative DVT patients with protein S deficiency.
Leptin signalling and leptin-mediated activation of human platelets: Importance of JAK2 and the phospholipases Cγ2 and A2
Authors: Dellas Claudia , Schäfer Katrin , Rohm Ilonka , Lankeit Mareike , Leifheit Maren , Hasenfuss Gerd , Loskutoff David , Konstantinides Stavros 
Published: October 2007

SummaryLeptin enhances agonist-induced platelet aggregation, and human platelets have been reported to express the leptin receptor. However, the pathways and mediators lying downstream of leptin binding to platelets remain, with few exceptions, unknown. In the present study, we sought to gain further insight into the possible role of leptin as a platelet agonist. Stimulation of platelets with leptin promoted thromboxane generation and activation of αIIbβ3, as demonstrated by PAC-1 binding. Furthermore, it increased the adhesion to immobilised fibrinogen (p<0.001) and induced cytoskeletal rearrangement of both platelets and Meg01 cells. Leptin time- and dose-dependently phosphorylated the intracellular signalling molecules JAK2 and STAT3, although the importance of STAT3 for leptin-induced platelet activation remains to be determined. Important intracellular mediators and pathways activated by leptin downstream of JAK2 were found to include phosphatidylinositol-3 kinase, phospholipase Cγ2 and protein kinase C, as well as the p38 MAP kinase-phospholipase A2 axis. Accordingly, incubation with the specific inhibitors AG490, Ly294002, U73122, and SB203580 prevented leptin-mediated platelet activation. These results help delineate biologically relevant leptin signalling pathways in platelets and may improve our understanding of the mechanisms linking hyperleptinaemia to the increased thrombosis risk in human obesity.
Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels
Authors: Martínez-Calatrava María José , González-Sánchez José Luis , Martínez-Larrad María Teresa , Pérez-Barba Milagros , Serrano-Ríos Manuel 
Published: October 2007

SummaryC-reactive protein (CRP) is a marker of systemic inflammation significantly associated with an increased risk of cardiovascular disease in the general population. The aim of our current work was to study those clinical and genetic variables potentially associated with interindividual variability in serum CRP levels. A random sample of 844 participants (450 women, mean age 55 years) from a study carried out on the general Spanish population (The Segovia Study) was studied. Our results showed that age, gender, waist circumference, leptin, impaired glucose tolerance and smoking were the clinical variables significantly associated with variations in serum CRP levels. Among those, leptin showed the strongest association, explaining 11% of the interindividual variability in circulating CRP levels (p < 0.001). To study the effect of genetic variants on serum CRP levels, 10 SNPs within the CRP locus were genotyped in 756 participants. Four of these SNPs (rs1417938, rs1800947, rs1130864, rs1205) were significantly associated with CRP levels after adjustment for clinical variables. Among the common haplotypes inferred from eight SNPs, two (CCATGCCT, p = 0.025; CTATCCTT, p = 0.004) explained 2.9% of the total variation in serum CRP. The results here reported show that 2.9% of the total variation in circulating CRP levels seems to be explained by genetics variations within CRP locus. Furthermore, serum leptin levels are strongly associated with serum CRP levels in our Spanish population.
Arteriogenesis: A focus on signal transduction cascades and transcription factors
Authors: Deindl Elisabeth 
Published: October 2007

SummaryIn recent years intensive investigations have been performed to unravel the molecular mechanisms of collateral artery growth (arteriogenesis), a process designed by nature to compensate the devastating consequences of major arterial occlusions. Currently, a variety of gene products as well as signal transduction pathways involved in arteriogenesis have been identified. However, it is still not clear how the progression of cellular signals evoked by an increased blood flow and therefore mechanical stress proceeds. Literature research identified the transcription factors early growth response-1 (Egr-1) as well as serum response factor (SRF) and myocardin-related transcription factors (MRTFs) as liaisons connecting the key pathways of arteriogenesis, i.e.the Rho-kinase pathway and the MEK/ERK pathway, with each other as well as with downstream genes.
Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice
Authors: Turrentine Tiffany , Dawicki McKenna Jennine , Rux Ann , Rader Daniel , Kowalska Anna , Sachais Bruce 
Published: October 2007

SummaryActivated platelets, which release platelet factor 4 (PF4) are present in patients with atherosclerosis. To date, no direct invivo evidence exists for the involvement of PF4 in atherogenesis. In the current study, we tested the hypothesis that PF4 is atherogenic, and that genetic elimination of PF4 would protect mice from atherosclerosis. We have bred PF4-/- mice onto two athero-susceptible backgrounds, WT-C57Bl/6(WT) and apoE-/- to examine the importance of PF4 in atherogenesis. In order to induce atherosclerosis, WT and PF4-/- mice were fed an atherogenic diet for 30 weeks, while apoE-/- and apoE-/- PF4-/- mice were fed a high-fat Western-style diet for 10 weeks. Examination of lesions in the aortic roots of atherogenic diet fed mice demonstrated reduced atherosclerosis in PF4-/- (20% compared to WT). Examination of apoE-/- mice demonstrated similar changes, with apoE-/- PF4-/- mice demonstrating 37% of the aortic atherosclerotic burden compared to apoE-/- mice. Although we found similar levels of total and non-HDL cholesterol inWT and PF4-/- mice, HDL-cholesterol levels were increased in PF4-/- on both backgrounds. These data demonstrate, for the first time, that the platelet specific chemokine PF4 promotes atherosclerotic lesion development in vivo.
Relationship between platelet count and 30-day clinical outcomes after percutaneous coronary interventions
Authors: Ndrepepa Gjin , Mehilli Julinda , Bruskina Olga , Schulz Stefanie , Schömig Albert , Kastrati Adnan , Iijima Raisuke 
Published: October 2007

SummaryPlatelets play an important role in the development of major adverse cardiac events (MACE) following percutaneous coronary intervention (PCI). The impact of platelet count on the outcome of patients undergoing PCI after pre-treatment with clopidogrel is unknown. The study included 5,256 patients enrolled in four randomized trials – ISAR-REACT, ISAR-SMART2, ISAR-SWEET, and ISAR-REACT2 – which assessed the value of abciximab in patients with coronary artery disease (CAD) undergoing PCI after pre-treatment with 600 mg of clopidogrel. Platelet count was measured at baseline before PCI. Primary endpoint was the 30-day incidence of MACE, secondary endpoint was mortality. The tertiles of platelet counts were: lower tertile (<198x109/L; n=1,726), middle tertile (198–244x109/L; n=1,750) and upper tertile (>244x109/L; n=1,780). The 30-day incidence of MACE was 6.7% (n=116) among patients of the lower tertile, 6.3% (n=111) among patients of the middle tertile, and 7.0% (n=124) among patients of the upper tertile (P=0.76). The 30-day mortality was 1.2% (n=22) among patients of the upper tertile, 0.5% (n=9) among patients of middle tertile and 0.6% (n=11) among patients of the lower tertile (P=0.04). Q-wave myocardial infarction occurred in 1.3% of patients (n=23) in the upper tertile, 0.7% of patients (n=13) in the middle tertile and 0.5% of patients (n=8) in the lower tertile (P=0.02). Platelet count was an independent correlate of 30-day mortality (hazard ratio 2.69, 95% confidence interval 1.08–6.67; P=0.033 for the third vs. the first tertile). In conclusion, in patients with CAD undergoing PCI after pre-treatment with 600 mg clopidogrel, baseline platelet count predicts 30-day mortality.
All post-translational modifications except propeptide cleavage are required for optimal secretion of coagulation factor VII
Authors: Steenstrup Thomas , Kristensen Claus , Bolt Gert 
Published: October 2007

SummaryHuman coagulation factor VII (FVII) has two N-glycosylation sites (N145 and N322) and two O-glycosylation sites (S52 and S60). In transiently transfected COS-7 cells, all combinations of N- and O-glycosylation knock-out mutations reduced the release of FVII to the medium. Pulse-chase analysis of CHO-K1 cell lines expressing recombinant FVII demonstrated that virtually all wild-type FVII synthesized was secreted from the cells, whereas both N- and O- glycosylation knock-out mutations induced partial intracellular degradation of the synthesized FVII. Likewise, two thirds of the FVII synthesized in vitamin K-depleted and warfarin-treated CHO cells was degraded intracellularly, demonstrating the importance of gamma-carboxylation for the secretion of FVII. The furin inhibitor decanoyl-R-V-K-R-chloromethylketone inhibited propeptide cleavage, but FVII with propeptide appeared to be secreted equally well as FVII without propeptide. Propeptide cleavage was not inhibited by vitamin K depletion and warfarin treatment, suggesting that for FVII, correct gamma-carboxylation is not required for optimal processing of the propeptide. In conclusion, all post-translational modifications of FVII except propeptide cleavage were important for complete secretion of the synthesized FVII and to avoid intracellular degradation. Thus, the extensive post-translational modification of FVII seems critical for the intracellular stability of the protein and is required for keeping the protein in the secretory pathway.
Landing Mechanics between Noninjured Women and Women with Anterior Cruciate Ligament Reconstruction during 2 Jump Tasks
Authors: Ortiz Alexis , Olson Sharon , Libby Charles L , Trudelle-Jackson Elaine , Kwon Young-Hoo , Etnyre Bruce , Bartlett William 
Published: October 2007

Background Women with anterior cruciate ligament reconstruction have different neuromuscular strategies than noninjured women during functional tasks after ligament reconstruction and rehabilitation. Hypothesis Landing from a jump creates high loads on the knee creating dynamic instability in women with anterior cruciate ligament reconstruction, whereas noninjured women have stable knee landing mechanics. Study Design Controlled laboratory study. Methods Fifteen noninjured women and 13 women with anterior cruciate ligament reconstruction performed 5 trials of a single-legged 40-cm drop jump and 2 trials of a 20-cm up-down hop task. Multivariate analyses of variance were used to compare hip and knee joint kinematics, knee joint moments, ground-reaction forces, and electromyographic findings between the dominant leg in noninjured women and reconstructed leg in women with anterior cruciate ligament reconstruction. Results No statistically significant differences between groups were found for peak hip and knee joint angles for the drop jump task. Statistically significant differences in neuromuscular activity ( P = .001) and anterior-posterior knee shear forces ( P < .001) were seen in women with anterior cruciate ligament reconstruction compared with noninjured women in the drop jump task. However, no statistically significant differences ( P > .05) between groups were found for either peak hip and knee joint angles, peak joint kinetics, or electromyographic findings during the up-down hop task. Conclusion Women with anterior cruciate ligament reconstruction have neuromuscular strategies that allow them to land from a jump similar to healthy women, but they exhibit joint moments that could predispose them to future injury if they participate in sports that require jumping and landing.
Three-Dimensional Analysis of Ankle Instability after Tibiofibular Syndesmosis Injuries
Authors: Teramoto Atsushi , Kura Hideji , Uchiyama Eiichi , Suzuki Daisuke , Yamashita Toshihiko 
Published: October 2007

Background Rupture of the distal tibiofibular syndesmosis commonly occurs with extreme external rotation. Most studies of syndesmosis injuries have concentrated only on external rotation instability of the ankle joint and have not examined other defects. Hypothesis Syndesmosis injuries cause multidirectional ankle instability. Study Design Controlled laboratory study. Methods Ankle instability caused by distal tibiofibular syndesmosis injuries was examined using 7 normal fresh-frozen cadaveric legs. The anterior tibiofibular ligament, interosseous membrane, and posterior tibiofibular ligament, which compose the distal tibiofibular syndesmosis, were sequentially cut. Anterior, posterior, medial, and lateral traction forces, as well as internal and external rotation torque, were applied to the tibia; the diastasis between the tibia and fibula and the angular motion among the tibia, fibula, and talus were measured using a magnetic tracking system. Results A medial traction force with a cut anterior tibiofibular ligament significantly increased the diastasis from 1.1 to 2.0 mm ( P = .001) and talar tilt angles from 9.6° to 15.2° ( P < .001). External rotation torque significantly increased the diastasis from 0.5 to 1.8 mm ( P= .009) with a complete cut; external rotation torque also significantly increased rotational angles from 7.1° to 9.4° ( P = .05) with an anterior tibiofibular ligament cut. Conclusion Syndesmosis injuries caused ankle instability with medial traction force and external rotation torque to the tibia. Clinical Relevance Both physicians and athletes should be aware of inversion instability of the ankle joint caused by tibiofibular syndesmosis injuries.
Meta-analysis of community-based cluster randomization trials with binary outcomes
Authors: Darlington Gerarda A. , Donner Allan 
Published: October 2007

Background Cluster randomization trials are widely used to test the effect of an intervention when individuals are naturally found in groups such as communities. For several separate studies of a similar intervention, it may be of interest to combine their results using meta-analysis procedures. However, this task requires consideration of both the likely dependencies among cluster members (intracluster correlation) and stratification based on the studies considered. Purpose In this article, several possible approaches for meta-analysis are considered for cluster randomization trials having a binary outcome. Methods It is first noted that the standard Mantel—Haenszel test is invalid in this context since it ignores dependencies among cluster members. Two modifications are therefore considered as well as a general inverse variance approach and a procedure based on the Woolf statistic which does not require the availability of trial-specific design effects. Empirical Type I errors and powers for the different procedures considered are evaluated using Monte Carlo simulation. To illustrate the techniques, data are used from trials performed in four countries to compare two antenatal care programs with respect to their effects on the risk of hypertension during pregnancy. Results For the simulation scenarios considered, an adjusted Mantel—Haenszel procedure provides a valid test with the greatest power slightly outperforming the general inverse variance approach. Limitations The potential need to adjust for possible confounding was not considered. However, more detailed information on confounders would not likely be available for most meta-analyses. Conclusion Two procedures performed well. However, the choice of analysis approach also inevitably depends on the nature and extent of the available data. Clinical Trials 2007; 4: 491—498. http://ctj.sagepub.com