bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombo - cytopenic purpura
Authors: Jilma-Stohlawetz Petra , Gilbert James , Gorczyca Monika , Knöbl Paul , Jilma Bernd 
Published: August 2011

SummaryCongenital thrombotic thrombocytopenic purpura (TTP) is a very rare but potentially life-threatening disorder. This phase I/II trial compared the pharmacokinetics and pharmacodynamics and safety of three different administration modes of the anti-von Willebrand factor (VWF) aptamer ARC1779. This was a prospective clinical trial with a partial cross-over design: three periods comprised subcutaneous injections of 50 mg of ARC1779 on seven subsequent days, a low-dose infusion of ARC1779 (0.002 mg/kg/min) for 24–72 hours and a high-dose infusion (0.004–0.006 mg/kg/min) up to 72 hours. ARC1779 concentrations were determined with high performance liquid chromatography, VWF inhibition was measured with enzyme immunoassay and platelet function was determined with the platelet function analyser (PFA-100) and impedance aggregometry. ARC1779 was well tolerated without any bleeding at concentrations spanning over three orders of magnitude. The daily s.c. injection yielded plasma levels (0.5 μg/ml) of the drug that were too low to sufficiently suppress VWF. The low-dose i.v. infusion increased platelet counts in one patient, whereas the high i.v. dose increased plasma concentrations up to 69 μg/ml, completely blocked free A1 domains, VWF-dependent platelet plug formation and enhanced platelet counts in 2/3 patients. In conclusion, infusion of ARC1779 dosedependently inhibits VWF-dependent platelet function and during infusion ARC1779 increases or stabilises platelet counts in congenital TTP. However, the tested doses, particularly the daily s.c. injections, did not correct all clinical or laboratory features of TTP.
Mutations responsible for MYH9-related thrombocytopenia impair SDF-1-driven migration of megakaryoblastic cells
Authors: Bozzi Valeria , Panza Emanuele , Barozzi Serena , Gruppi Cristian , Seri Marco , Balduini Carlo , Pecci Alessandro 
Published: August 2011

SummaryMYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for the heavy chain of nonmuscle myosin-IIA (NMMHC-IIA). Recent in vitro studies led to the hypothesis that thrombocytopenia of MYH9-RD derives from an ectopic platelet release by megakaryocytes in the osteoblastic areas of bone marrow (BM), which are enriched in type I collagen, rather than in vascular spaces. SDF-1-driven migration of megakaryocytes within BM to reach the vascular spaces is a key mechanism for platelet biogenesis. Since myosin-IIA is implicated in polarised migration of different cell types, we hypothesised that MYH9 mutations could interfere with this mechanism. We therefore investigated the SDF-1-driven migration of a megakaryoblastic cell line, Dami cells, on type I collagen or fibrinogen by a modified transwell assay. Inhibition of myosin-IIA ATPase activity suppressed the SDF-1-driven migration of Dami cells, while over-expression of NMMHC-IIA increased the efficiency of chemotaxis, indicat- ing a role for NMMHC-IIA in this mechanism. Transfection of cells with three MYH9 mutations frequently responsible for MYH9-RD (p.R702C, p.D1424H, or p.R1933X) resulted in a defective SDF-1-driven migration with respect to the wild-type counterpart and in increased cell spreading onto collagen. Analysis of differential localisation of wild-type and mutant proteins suggested that mutant NMMHC-IIAs had an impaired cytoplasmic re-organisation in functional cytoskeletal structures after cell adhesion to collagen. These findings support the hypothesis that a defect of SDF-1-driven migration of megakaryocytes induced by MYH9 mutations contributes to ectopic platelet release in the BM osteoblastic areas, resulting in ineffective platelet production.
Deep-vein thrombosis: A United States cost model for a preventable and costly adverse event
Authors: Holdsworth Mark , Welch Shawn , Borrego Matt , Spyropoulos Alex , Mahan Charles 
Published: August 2011

SummaryPreventable venous thromboembolism (VTE) and “appropriate” type, dose, and duration of prophylaxis are emerging concepts. Contemporary definitions by key quality organisations, including the World Health Organization, have shifted towards “preventable” VTE being considered an adverse event or adverse drug event. A decision tree and cost model were developed to estimate the United States health care costs for total deep-vein thrombosis (DVT), total hospital-acquired DVT, and total “preventable” DVT. Annual cost ranges were obtained in 2010 US dollars for total ($7.5 to $39.5 billion), hospital-acquired ($5 to $26.5billion), and preventable ($2.5 to $19.5 billion) DVT costs. When the sensitivity analysis was applied – taking into consideration higher incidence rates and costs – annual US total, hospital-acquired, and “preventable” DVT costs ranged from $9.8 to $52 billion, $6.8 to $36 billion, and $3.4 to $27 billion, respectively.
Venous thromboembolism in Asia – an unrecognised and under-treated problem?
Authors: Angchaisuksiri Pantep 
Published: August 2011

SummaryVenous thromboembolism (VTE) has been perceived for a long time to be less common in Asian populations, particularly in the Far East, than in Western populations. Generally, thromboprophylaxis is not implemented as frequently as it should be in high-risk patients. However, recent prospective studies undertaken in Asian countries have demonstrated higher rates of VTE after major surgery and in medical wards, approaching those observed in Western populations. Risk factors for VTE are not different in Asian patients from those of Western patients with the exception of thrombophilic mutations. Deficiencies of the natural anticoagulants (protein S, protein C, and antithrombin) are the predominant thrombophilias in Asia whereas factor V Leiden and prothrombin G20210A gene mutation are not found or rarely reported. Further large well-designed clinical studies are needed to evaluate the magnitude of the risk of VTE and the appropriate use of thromboprophylaxis in different clinical situations.
Cardiac troponin testing and the simplified Pulmonary Embolism Severity Index
Authors: Spirk David , Aujesky Drahomir , Husmann Marc , Hayoz Daniel , Baldi Thomas , Frauchiger Beat , Banyai Martin , Baumgartner Iris , Kucher Nils 
Published: August 2011

SummaryA low simplified Pulmonary Embolism Severity Index (sPESI), defined as age ≤80 years and absence of systemic hypotension, tachycardia, hypoxia, cancer, heart failure, and lung disease, identifies low-risk patients with acute pulmonary embolism (PE). It is unknown whether cardiac troponin testing improves the prediction of clinical outcomes if the sPESI is not low. In the prospective Swiss Venous Thromboembolism Registry, 369 patients with acute PE and a troponin test (conventional troponin T or I, highly sensitive troponin T) were enrolled from 18 hospitals. A positive test result was defined as a troponin level above the manufacturers assay threshold. Among the 106 (29%) patients with low sPESI, the rate of mortality or PE recurrence at 30 days was 1.0%. Among the 263 (71%) patients with high sPESI, 177 (67%) were troponin-negative and 86 (33%) troponin-positive; the rate of mortality or PE recurrence at 30 days was 4.6% vs. 12.8% (p=0.015), respectively. Overall, risk assessment with a troponin test (hazard ratio [HR] 3.39, 95% confidence interval [CI] 1.38–8.37; p=0.008) maintained its prognostic value for mortality or PE recurrence when adjusted for sPESI (HR 5.80, 95%CI 0.76–44.10; p=0.09). The combination of sPESI with a troponin test resulted in a greater area under the receiver-operating characteristic curve (HR 0.72, 95% CI 0.63–0.81) than sPESI alone (HR 0.63, 95% CI 0.57–0.68) (p=0.023). In conclusion, although cardiac troponin testing may not be required in patients with a low sPESI, it adds prognostic value for early death and recurrence for patients with a high sPESI.
Inhibition of Nitric Oxide–Stimulated Vasorelaxation by Carbon Monoxide-Releasing Molecules
Authors: Marazioti Antonia , Bucci Mariarosaria , Coletta Ciro , Vellecco Valentina , Baskaran Padmamalini , Szabó Csaba , Cirino Giuseppe , Marques Ana Rita , Guerreiro Bruno , Gonçalves Ana M.L. , Seixas João D. , Beuve Annie , Romão Carlos C. , Papapetropoulos Andreas 
Published: August 2011

Objective—
Carbon monoxide (CO) is a weak soluble guanylyl cyclase stimulator, leading to transient increases in cGMP and vasodilation. The aim of the present work was to measure the effect of CO-releasing molecules (CORMs) on the cGMP/nitric oxide (NO) pathway and to evaluate how selected CORMs affect NO-induced vasorelaxation.

Methods and Results—
Incubation of smooth muscle cells with some but not all of the CORMs caused a minor increase in cGMP levels. Concentration-response curves were bell-shaped, with higher CORMs concentrations producing lower increases in cGMP levels. Although exposure of cells to CORM-2 enhanced cGMP formation, we observed that the compound inhibited NO-stimulated cGMP accumulation in cells and NO-stimulated soluble guanylyl cyclase activity that could be reversed by superoxide anion scavengers. Reactive oxygen species generation from CORMs was confirmed using luminol-induced chemiluminescence and electron spin resonance. Furthermore, we observed that NO is scavenged by CORM-2. When used alone CORM-2 relaxed vessels through a cGMP-mediated pathway but attenuated NO donor-stimulated vasorelaxation.

Conclusion—
We conclude that the CORMs examined have context-dependent effects on vessel tone, as they can directly dilate blood vessels, but also block NO-induced vasorelaxation.
Racial/Ethnic Variation in the Association of Lipid-Related Genetic Variants With Blood Lipids in the US Adult Population
Authors: Chang Man-huei , Ned Renée M. , Hong Yuling , Yesupriya Ajay , Yang Quanhe , Liu Tiebin , Janssens A. Cecile J.W. , Dowling Nicole F. 
Published: August 2011

Background—
Genome-wide association studies (GWAS) have identified a number of single-nucleotide polymorphisms (SNPs) associated with serum lipid level in populations of European descent. The individual and the cumulative effect of these SNPs on blood lipids are largely unclear for the US population.

Methods and Results—

Using data from the second phase (1991–1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative survey of the US population, we examined associations of 57 GWAS-identified or well-established lipid-related genetic loci with plasma concentrations of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, triglycerides, total cholesterol/HDL-C ratio, and non-HDL-C. We used multivariable linear regression to examine single SNP associations and the cumulative effect of multiple SNPs (using a genetic risk score [GRS]) on blood lipid levels. Analyses were conducted in adults from each of the 3 major racial/ethnic groups in the United States: non-Hispanic whites (n=2296), non-Hispanic blacks (n=1699), and Mexican Americans (n=1713). Allele frequencies for all SNPs varied significantly by race/ethnicity, except rs3764261 in
CETP
. Individual SNPs had very small effects on lipid levels, effects that were generally consistent in direction across racial/ethnic groups. More GWAS-validated SNPs were replicated in non-Hispanic whites (<67%) than in non-Hispanic blacks (<44%) or Mexican Americans (<44%). GRSs were strongly associated with increased lipid levels in each racial/ethnic group. The combination of all SNPs into a weighted GRS explained no more than 11% of the total variance in blood lipid levels.

Conclusions—
Our findings show that the combined association of SNPs, based on a GRS, was strongly associated with increased blood lipid measures in all major race/ethnic groups in the United States, which may help in identifying subgroups with a high risk for an unfavorable lipid profile.
Risk of Syncope in Family Members Who Are Genotype-Negative for a Family-Associated Long-QT Syndrome Mutation
Authors: Barsheshet Alon , Moss Arthur J. , McNitt Scott , Polonsky Slava , Lopes Coeli M. , Zareba Wojciech , Robinson Jennifer L. , Ackerman Michael J. , Benhorin Jesaia , Kaufman Elizabeth S. , Towbin Jeffrey A. , Vincent G. Michael , Qi Ming , Goldenberg Ilan 
Published: August 2011

Background—
Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.

Methods and Results—

Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402–442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60;
P
=0.002), prolonged QTc (HR=1.63 per 100 ms increment,
P
=0.02), family history of ACA or SCD (HR=1.89,
P
=0.002), and LQT2 versus LQT1 family mutation (HR=1.41,
P
=0.03). Subgroup analysis showed that the presence of the
K897T
polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (
P
=0.001) increase in the risk of recurrent syncope in genotype-negative subjects.

Conclusions—
Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
Increased Blood–Brain Barrier Permeability and Brain Edema After Focal Cerebral Ischemia Induced by Hyperlipidemia
Authors: ElAli Ayman , Doeppner Thorsten R. , Zechariah Anil , Hermann Dirk M. 
Published: August 2011

Background and Purpose—
Hyperlipidemia is a highly prevalent risk factor for ischemic stroke. Its impact on brain injury and blood–brain barrier permeability, so far, has not been assessed in animal models of ischemic stroke.

Methods—

Wild-type and apolipoprotein E
−/−
mice, fed with normal or cholesterol-rich high-fat food, were subjected to 30 minutes of middle cerebral artery occlusion. Ischemic injury, brain edema, IgG extravasation, lipid peroxidation, calpain-1/2, matrix metalloproteinase-2/9, and RhoA activation, and occludin expression were evaluated 24 hours after reperfusion.

Results—
Cholesterol-rich food, but not apolipoprotein E deficiency, increased IgG extravasation and brain edema without influencing infarct area and the density of DNA fragmented cells. Increased lipid peroxidation and low-density lipoprotein oxidation were noticed in the brain of hyperlipidemic mice and were associated with increased activation of calpain-1/2 and matrix metalloproteinase-2/9, overactivation of RhoA and its guanine exchange factor leukemia-associated guanine exchange factor , and downregulation of the tight junction protein occludin in cerebral microvessels.

Conclusions—
That postischemic blood–brain barrier permeability and brain edema are increased during hyperlipidemia points toward the importance of the recognition and adequate treatment of this highly prevalent condition. Translational studies should more adequately mimic risk factors prevalent in human stroke.
The Prediction of Contralateral Progression in Children and Adolescents With Unilateral Moyamoya Disease
Authors: Yeon Je Young , Shin Hyung Jin , Kong Doo-Sik , Seol Ho Jun , Kim Jong-Soo , Hong Seung-Chyul , Park Kwan 
Published: August 2011

Background and Purpose—
To evaluate the factors predictive of contralateral progression in children and adolescents with unilateral moyamoya disease (MMD), the authors retrospectively analyzed clinicoradiological findings.

Methods—
The records of 394 consecutive patients with MMD aged 0 to17 years were reviewed. Unilateral MMD was defined based on the typical angiographic findings of MMD in 1 hemisphere and no abnormality in the contralateral internal carotid artery and the middle cerebral artery. Of the 394 patients with MMD, 45 (11.4%) had unilateral MMD and the prevalence increased with age. Untreated contralateral hemispheres were followed by serial MR angiography. Follow-up angiography was performed if contralateral progression, defined as any noticeable change in the contralateral internal carotid artery and/or middle cerebral artery, was suggested by MR angiography.

Results—

Eight of the 45 (17.8%) had angiographically documented progression over a mean follow-up of 53.4 months. Mean time to contralateral progression was 27 months (range, 21 to 37 months). An age at diagnosis of <9 years was found to be the only independent predictor of contralateral progression (
P
=0.025), which persisted despite adjustment for sex and ipsilateral Suzuki stage (hazard ratio, 8.26; 95% CI, 1.01 to 67.94). Other factors, including abnormalities in the contralateral anterior cerebral artery, were not found to be predictive of progression to bilateral MMD.

Conclusions—
The incidence of contralateral progression in our cohort of children and adolescents with unilateral MMD appears to be lower than those previously reported. Furthermore, contralateral progression tended to occur in children aged <9 years within 3 years of initial diagnosis (32%).
Concentric Eyewall Formation in Typhoon Sinlaku (2008). Part II: Axisymmetric Dynamical Processes
Authors: Huang Yi-Hsuan , Montgomery Michael T. , Wu Chun-Chieh 
Published: August 2011

Abstract
In Part I of this study, the association between the secondary eyewall formation (SEF) and the broadening of the outer swirling wind in Typhoon Sinlaku (2008) was documented. The findings from Part I help lay the groundwork for the application of a newly proposed intensification paradigm to SEF. Part II presents a new model for SEF that utilizes this new paradigm and its axisymmetric view of the dynamics.
The findings point to a sequence of structure changes that occur in the vortex’s outer-core region, culminating in SEF. The sequence begins with a broadening of the tangential winds, followed by an increase of the corresponding boundary layer (BL) inflow and an enhancement of convergence in the BL where the secondary eyewall forms. The narrow region of strong BL convergence is associated with the generation of supergradient winds in and just above the BL that acts to rapidly decelerate inflow there. The progressive strengthening of BL inflow and the generation of an effective adverse radial force therein leads to an eruption of air from the BL to support convection outside the primary eyewall in a favorable thermodynamic/kinematic environment.
The results suggest that the unbalanced response in the BL serves as an important mechanism for initiating and sustaining a ring of deep convection in a narrow supergradient wind zone outside the primary eyewall. This progressive BL control on SEF suggests that the BL scheme and its coupling to the interior flow need to be adequately represented in numerical models to improve the prediction of SEF timing and preferred location.
Association of the Rainy Season Precipitation with Low-Level Meridional Wind in the Yangtze River Valley and North China
Authors: Zeng Gang , Wang Wei-Chyung , Shen Caiming 
Published: August 2011

Abstract
This study first used measurements to establish the association between the rainy season precipitation in the Yangtze River valley (YRV) and north China (NC) and the 850-hPa meridional wind, and then evaluated the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) models’ simulations of both the associations and precipitation amount. It is shown that there exists a statistically significant positive correlation in the June–July precipitation and wind gradient over the YRV, and in the July–August precipitation and wind over NC. These associations are robust at daily, monthly, and interannual scales. Although many models are found to be capable of simulating the associations, the precipitation amount is still quite inadequate when compared with observations, thus raising the issue of the importance of lower-level wind simulations.
Multidecadal Warming and Shoaling of Antarctic Intermediate Water*
Authors: Schmidtko Sunke , Johnson Gregory C. 
Published: August 2011

Abstract
Antarctic Intermediate Water (AAIW) is a dominant Southern Hemisphere water mass that spreads from its formation regions just north of the Antarctic Circumpolar Current (ACC) to at least 20°S in all oceans. This study uses an isopycnal climatology constructed from Argo conductivity–temperature–depth (CTD) profile data to define the current state of the AAIW salinity minimum (its core) and thence compute anomalies of AAIW core pressure, potential temperature, salinity, and potential density since the mid-1970s from ship-based CTD profiles. The results are used to calculate maps of temporal property trends at the AAIW core, where statistically significant strong circumpolar shoaling (30–50 dbar decade−1), warming (0.05°–0.15°C decade−1), and density reductions [up to −0.03 (kg m−3) decade−1] are found. These trends are strongest just north of the ACC in the southeast Pacific and Atlantic Oceans and decrease equatorward. Salinity trends are generally small, with their sign varying regionally. Bottle data are used to extend the AAIW core potential temperature anomaly analysis back to 1925 in the Atlantic and to ~1960 elsewhere. The modern warm AAIW core conditions appear largely unprecedented in the historical record: biennially and zonally binned median AAIW core potential temperatures within each ocean basin are, with the notable exception of the subtropical South Atlantic in the 1950s–70s, 0.2–1°C colder than modern values. Zonally averaged sea surface temperature anomalies around the AAIW formation latitudes in each ocean and sectoral southern annular mode indices are used to put the AAIW core property trends and variations into context.