bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful in vivo propagation of factor IX-producing hepatocytes in mice: Potential for cell-based therapy in haemophilia B
Authors: Tatsumi Kohei , Kataoka Miho , Shibata Masaru , Naka Hiroyuki , Shima Midori , Hisanaga Michiyoshi , Kanehiro Hiromichi , Okano Teruo , Nakajima Yoshiyuki , Yoshioka Akira , Ohashi Kazuo , Tateno Chise , Yoshizato Katsutoshi 
Published: April 2008

SummaryCell-based therapies using isolated hepatocytes have been proposed to be an attractive application in the treatment of haemophilia B due to the normal production of coagulation factor IX (FIX) in these particular cells. Current cell culture technologies have largely failed to provide adequate isolated hepatocytes, so the present studies were designed to examine a new approach to efficiently proliferate hepatocytes that can retain normal biological function, including the ability to synthesize coagulation factors like FIX. Canine or human primary hepatocytes were transplanted into urokinase-type plasminogen activatorsevere combined immunodeficiency (uPA/SCID) transgenic mice. Both donor hepatocytes from canines and humans were found to progressively proliferate in the recipient mouse livers as evidenced by a sharp increase in the circulating blood levels of species-specific albumin, which was correlated with the production and release of canine and human FIX antigen levels into the plasma. Histological examination confirmed that the transplanted canine and human hepatocytes were able to proliferate and occupy >80% of the host livers. In addition, the transplanted hepatocytes demonstrated strong cytoplasmic staining for human FIX, and the secreted coagulation factor IX was found to be haemostatically competent using specific procoagulant assays. In all, the results from the present study indicated that developments based on this technology could provide sufficient FIX-producing hepatocytes for cell-based therapy for haemophilia B.
Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: Influence of glycosylation, proteolysis and gene mutations
Authors: Riddell Anne F. , Brown Simon A. , Starke Richard , Mackie Ian , Bowen Derrick J. , Jenkins P. Vincent , van Mourik Jan , Millar Carolyn M. 
Published: April 2008

SummaryReduced plasma survival of von Willebrand factor (VWF) may contribute towards the pathogenesis of type 1 von Willebrand disease (VWD). However, little is known about mechanism(s) of VWF clearance and factors that may affect it. The half-life of VWF-related parameters following the administration of DDAVP was measured in 26 patients with type 1 VWD and 10 haemophilia A controls. Binding of lectins Ricinus communis (RCA-I) and Erythina crystagalli (ECA) agglutinins to VWF and VWF susceptibility to ADAMTS-13-mediated proteolysis were investigated. Sequence analysis of targeted regions of the VWF gene was performed to inspect for mutations that have been associated with increased clearance. Post-DDAVP clearance of VWF was increased approximately three-fold in the type 1 VWD cohort overall. However this was not shown to consistently associate with steady-state VWF antigen (VWF:Ag) levels. Furthermore, increased VWF clearance was not consistently associated with increased ratios of VWF propeptide (VWFpp) to VWF:Ag indicating that a normal ratio does not necessarily reflect normal post-DDAVP survival in type 1 VWD patients. RCA-I and ECA binding to VWF were increased in type 1 VWD patients and, although inversely correlated with VWF levels, this was independent of VWF clearance. There was no association between VWF clearance and ADAMTS-13-mediated proteolysis. Three novel candidate mutations with an increased clearance phenotype were identified. The data are consistent with heterogeneity in pathogenic mechanisms in type 1 VWD and are consistent with type 1 VWD representing a complex genetic trait.
Bivalirudin
Authors: Greinacher Andreas , Koster Andreas , Warkentin Theodore 
Published: April 2008

SummaryBivalirudin is a direct thrombin inhibitor (DTI) frequently used for anticoagulation in the setting of invasive cardiology, particularly percutaneous coronary intervention (PCI). Bivalirudin has a unique pharmacologic profile: unlike other marketed DTIs, it undergoes predominant non-organ elimination (proteolysis), and has the shortest half-life (~25 min). Its affinity for thrombin is intermediate between that of lepirudin (highest) and argatroban (lowest) — this helps explain why it interferes with functional clotting assays to an extent intermediate between that achieved by these two other DTIs. This effect is best known for the PT (INR) — higher affinity for thrombin corresponds to lower molar DTI requirements to prolong the APTT; in turn, lower concentrations required for APTT prolongation (and, presumably, in-vivo effect) result in reduced PT (INR) prolongation. Bivalirudin is primarily used for its first FDA-approved indication, namely anticoagulation during percutaneous transluminal coronary angioplasty ("balloon angioplasty"), the most frequent type of PCI. Bivalirudin is also indicated for PCI with provisional use of glycoprotein IIb/IIIa antagonist therapy, and for patients with, or at risk of, heparin-induced thrombocytopenia (HIT), or HIT with thrombosis syndrome (HITTS), undergoing PCI. The bivalirudin development program has used a "quadruple" endpoint comprising a "triple" efficacy endpoint plus major bleeding —this approach anticipated the subsequent emphasis on strategies to improve clinical outcomes through bleeding reduction. Besides summarizing the key trials evaluating bivalirudin use for acute coronary syndrome (especially employing PCI), we review also the studies of bivalirudin as anticoagulant for "on-" and "off-pump" cardiac surgery, including both HIT and non-HIT situations.
P-selectin gene haplotypes modulate soluble P-selectin concentrations and contribute to the risk of venous thromboembolism
Authors: Kaider Alexandra , Koder Silvia , Panzer Simon , Pabinger Ingrid , Ay Cihan , Jungbauer Lea , Mannhalter Christine 
Published: April 2008

SummaryThe cell adhesion molecule P-selectin mediates the interaction of activated platelets or endothelial cells with leukocytes. In arterial and venous thromboembolism (VTE) increased soluble P-selectin (sP-selectin) concentrations have been found, and associations of P-selectin genotypes with thrombotic disease have been proposed. We assessed the effect of four single nucleotide polymorphisms (SNPs) [one in the promoter region (c.–2123C>G) and three (S290N, c.1087G>A; D562N, c.1902G>A; T715P, c.2363A>C) in the coding region] and the calculated haplotypes in the P-selectin gene (SELP) on sP-selectin concentrations and VTE risk. The analysis was carried out in 116 high-risk patients with a history of objectively confirmed recurrent VTE and 129 age- and sex-matched healthy individuals. Haplotypes were generated using computer-assisted haplotype reconstruction with Phase 2.1. sP-selectin (μg/l) was measured by ELISA. Frequencies of all four individual SNPs were not statistically significantly different between patients and controls. Tenhaplotypes were obtained for the control population, and nine for the patient group. The most frequent haplotype among controls was CGGA (major allele at all positions) (27.8%; frequency in patients 19.0%), which was used as reference for statistical analyses. Among patients GGAA was most frequent (23.3%; frequency in controls 17.5%). Haplotypes were significantly associated with sP-selectin concentrations in patients and in controls (p<0.001 and p=0.011). Compared to CGGA some but not all haplotypes conferred an increased risk for VTE with odds ratios (ORs) between 5.4 (95% CI: 2.5–12.2) for CAGA, 3.3 (1.2–9.2) for CGAC, and 2.4 (1.3–4.7) for GGAA. All ORs remained statistically significant after adjustment for the factor V Leiden mutation, located in close proximity to SELP on chromosome 1, as well as all other established risk factors for VTE. In conclusion, SELP haplotypes modulate plasma concentrations of sP-selectin and affect the risk of recurrent VTE.
Haematopoietic growth factors and their therapeutic use
Authors: Thorpe Robin , Wadhwa Meenu 
Published: April 2008

SummaryHaematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.
Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation
Authors: McBane Robert , Hodge David , Wysokinski Waldemar 
Published: April 2008

SummaryAlthough infrequent, embolic occlusion to non-cerebral arteries may result in limb loss, organ failure, and death. The aim of this study was to define clinical and echocardiographic characteristics determining thromboembolism destination in non-valvular atrial fibrillation. An inception cohort of individuals (n=72) were identified with incident peripheral embolism in the setting of non-valvular atrial fibrillation (1995–2005). A randomly selected group of atrial fibrillation related stroke patients (n=100) were identified for comparison. Arteries of the extremities were the most common site of embolism (85%); lower extremity involvement was twice as common compared with the upper extremity. Clinical features distinguishing peripheral embolism from stroke included age > 75, heart failure and hypertension. Severe left ventricular dysfunction, spontaneous echo contrast and left atrial thrombus were 2–3 fold more common in peripheral embolism patients. Mean CHADS-2 scores were low and comparable for both groups. By multivariate analysis, age>75 years (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.3–3.9; p=0.05) was predictive of peripheral embolism. After adjustment for age > 75 years, severe left atrial enlargement (HR 1.8, 95% CI 0.99–3.1; p=0.055) and CHADS score (HR 1.2, 95% CI 0.99–1.6; p=0.06) were of borderline significance. In conclusion, several clinical and echocardiographic measures distinguish the clinical presentation of thromboembolism in non-valvular atrial fibrillation. Small emboli are destined to lodge in the cerebral circulation as a result of hydrodynamic, anatomic, and physical factors. Advanced age, atrial enlargement and other comorbidities may increase the propensity for the formation of larger thrombi which may bypass the carotid orifice merely as a function of size.
Radiative Transfer Modeling of a Coniferous Canopy Characterized by Airborne Remote Sensing
Authors: Essery Richard , Bunting Peter , Rowlands Aled , Rutter Nick , Hardy Janet , Melloh Rae , Link Tim , Marks Danny , Pomeroy John 
Published: April 2008

Abstract
Solar radiation beneath a forest canopy can have large spatial variations, but this is frequently neglected in radiative transfer models for large-scale applications. To explicitly model spatial variations in subcanopy radiation, maps of canopy structure are required. Aerial photography and airborne laser scanning are used to map tree locations, heights, and crown diameters for a lodgepole pine forest in Colorado as inputs to a spatially explicit radiative transfer model. Statistics of subcanopy radiation simulated by the model are compared with measurements from radiometer arrays, and scaling of spatial statistics with temporal averaging and array size is discussed. Efficient parameterizations for spatial averages and standard deviations of subcanopy radiation are developed using parameters that can be obtained from the model or hemispherical photography.
Transport across 48°N in the Atlantic Ocean
Authors: Lumpkin Rick , Speer Kevin G. , Koltermann K. Peter 
Published: April 2008

Abstract
Transports across 48°N in the Atlantic Ocean are estimated from five repeat World Ocean Circulation Experiment (WOCE) hydrographic lines collected in this region in 1993–2000, from time-varying air–sea heat and freshwater fluxes north of 48°N, and from a synthesis of these two data sources using inverse box model methods.
Results from hydrography and air–sea fluxes treated separately are analogous to recently published transport variation studies and demonstrate the sensitivity of the results to either the choice of reference level and reference velocities for thermal wind calculations or the specific flux dataset chosen. In addition, flux-based calculations do not include the effects of subsurface mixing on overturning and transports of specific water masses. The inverse model approach was used to find unknown depth-independent velocities, interior diapycnal fluxes, and adjustments to air–sea fluxes subject to various constraints on the system. Various model choices were made to focus on annually averaged results, as opposed to instantaneous values during the occupation of the hydrographic lines. The results reflect the constraints and choices made in the construction of the model.
The inverse model solutions show only marginal, not significantly different temporal changes in the net overturning cell strength and heat transport across 48°N. These small changes are similar to seasonally or annually averaged numerical model simulations of overturning. Significant variability is found for deep transports and air–sea flux quantities in density layers. Put another way, if one ignores the details of layer exchanges, the model can be constrained to produce the same net overturning for each repeat line; however, constraining individual layers to have the same transport for each line fails.
Diapycnal fluxes are found to be important in the mean but are relatively constant from one repeat line to the next. Mean air–sea fluxes are modified slightly but are still essentially consistent with either the NCEP data or the National Oceanography Centre, Southampton (NOC) Comprehensive Ocean–Atmosphere Data Set (COADS) within error. Modest reductions in air–sea flux uncertainties would give these constraints a much greater impact. Direct transport estimates over broader regions than the western boundary North Atlantic Current are needed to help resolve circulation structure that is important for variability in net overturning.
The Influence of Air–Sea Roughness, Sea Spray, and Storm Translation Speed on Waves in North Atlantic Storms
Authors: Zhang Weiqing , Perrie William 
Published: April 2008

Abstract
A coupled atmosphere–wave–sea spray model system is used to evaluate the impact of sea spray and wave drag on storm-generated waves, their height variations, and directional wave spectra in relation to the storm location and translation speed. Results suggest that the decrease or increase of significant wave height due to spray and wave drag is most significant in high-wind regions to the right of the storm track. These processes are modulations on the maximum-wave region and tend to occur several hours after the peak wind events, depending on the storm translation velocity. The translation speed of the storm is important. The directional variation between local winds and wind-generated waves within rapidly moving storms that outrun the waves is notably different from that of trapped waves, when the dominant waves’ group velocity approximates the storm translation speed. While wave drag and spray can increase or reduce the magnitudes of wind and significant wave height, their nondirectional formulations allow them to have little apparent effect on the directional wave spectra.
Instabilities of a Baroclinic, Double Diffusive Frontal Zone
Authors: Smyth W. D. 
Published: April 2008

Abstract
The linear theory of double diffusive interleaving is extended to take account of baroclinic effects. This study goes beyond previous studies by including the possibility of modes with nonzero tilt in the alongfront direction, which allows for advection by the baroclinic frontal flow. This requires that the stability equations be solved numerically. The main example is based on observations of interleaving on the lower flank of Meddy Sharon, but a range of parameter values is covered, leading to conclusions that are relevant in a variety of oceanic regimes. The frontal zone is treated as infinitely wide with uniform gradients of temperature, salinity, and alongfront velocity. The stationary, vertically symmetric interleaving mode is shown to have maximum growth rate when its alongfront wavenumber is zero, providing validation for previous studies in which this property was assumed. Besides this, there exist two additional modes of instability: the ageostrophic Eady mode of baroclinic instability and a mode not previously identified. The new mode is oblique (i.e., it tilts in the alongfront direction), vertically asymmetric, and propagating. It is strongly dependent on boundary conditions, and its relevance in the ocean interior is uncertain as a result. Effects of variable diffusivity and buoyancy flux ratio are also considered.
Inertia–Gravity Waves Emitted from Balanced Flow: Observations, Properties, and Consequences
Authors: Williams Paul D. , Haine Thomas W. N. , Read Peter L. 
Published: April 2008

Abstract
This paper describes laboratory observations of inertia–gravity waves emitted from balanced fluid flow. In a rotating two-layer annulus experiment, the wavelength of the inertia–gravity waves is very close to the deformation radius. Their amplitude varies linearly with Rossby number in the range 0.05–0.14, at constant Burger number (or rotational Froude number). This linear scaling challenges the notion, suggested by several dynamical theories, that inertia–gravity waves generated by balanced motion will be exponentially small. It is estimated that the balanced flow leaks roughly 1% of its energy each rotation period into the inertia–gravity waves at the peak of their generation.
The findings of this study imply an inevitable emission of inertia–gravity waves at Rossby numbers similar to those of the large-scale atmospheric and oceanic flow. Extrapolation of the results suggests that inertia–gravity waves might make a significant contribution to the energy budgets of the atmosphere and ocean. In particular, emission of inertia–gravity waves from mesoscale eddies may be an important source of energy for deep interior mixing in the ocean.
Warming and Freshening in the Abyssal Southeastern Indian Ocean*
Authors: Johnson Gregory C. , Purkey Sarah G. , Bullister John L. 
Published: April 2008

Abstract
Warming and freshening of abyssal waters in the eastern Indian Ocean between 1994/95 and 2007 are quantified using data from two closely sampled high-quality occupations of a hydrographic section extending from Antarctica northward to the equator. These changes are limited to abyssal waters in the Princess Elizabeth Trough and the Australian–Antarctic Basin, with little abyssal change evident north of the Southeast Indian Ridge. As in previous studies, significant cooling and freshening is observed in the bottom potential temperature–salinity relations in these two southern basins. In addition, analysis on pressure surfaces shows abyssal warming of about 0.05°C and freshening of about 0.01 Practical Salinity Scale 1978 (PSS-78) in the Princess Elizabeth Trough, and warming of 0.1°C with freshening of about 0.005 in the abyssal Australian–Antarctic Basin. These 12-yr differences are statistically significant from zero at 95% confidence intervals over the bottom few to several hundred decibars of the water column in both deep basins. Both warming and freshening reduce the density of seawater, contributing to the vertical expansion of the water column. The changes below 3000 dbar in these basins suggest local contributions approaching 1 and 4 cm of sea level rise, respectively. Transient tracer data from the 2007 occupation qualitatively suggest that the abyssal waters in the two southern basins exhibiting changes have significant components that have been exposed to the ocean surface within the last few decades, whereas north of the Southeast Indian Ridge, where changes are not found, the component of abyssal waters that have undergone such ventilation is much reduced.
The Effect of Breaking Waves on a Coupled Model of Wind and Ocean Surface Waves. Part II: Growing Seas
Authors: Kukulka Tobias , Hara Tetsu 
Published: April 2008

Abstract
This is the second part of a two-part investigation of a coupled wind and wave model that includes the enhanced form drag of breaking waves. The model is based on the wave energy balance and the conservation of air-side momentum and energy. In Part I, coupled nonlinear advance–delay differential equations were derived, which govern the wave height spectrum, the distribution of breaking waves, and vertical air side profiles of the turbulent stress and wind speed. Numeric solutions were determined for mature seas. Here, numeric solutions for a wide range of wind and wave conditions are obtained, including young, strongly forced wind waves. Furthermore, the “spatial sheltering effect” is introduced so that smaller waves in airflow separation regions of breaking longer waves cannot be forced by the wind. The solutions strongly depend on the wave height curvature spectrum at high wavenumbers (the “threshold saturation level”). As the threshold saturation level is reduced, the effect of breaking waves becomes stronger. For young strongly forced waves (laboratory conditions), breaking waves close to the spectral peak dominate the wind input and previous solutions of a model with only input to breaking waves are recovered. Model results of the normalized roughness length are generally consistent with previous laboratory and field measurements. For field conditions, the wind stress depends sensitively on the wave height spectrum. The spatial sheltering may modify the number of breaking shorter waves, in particular, for younger seas.