Essentials
Heparin‐induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat.
We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT.
...One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery.
Rivaroxaban may be an effective and safe treatment option for HIT.
Summary
Background
Rivaroxaban is a direct oral anti‐Xa inhibitor that has the potential to greatly simplify treatment of heparin‐induced thrombocytopenia (HIT).
Objectives
To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single‐arm, prospective cohort study of patients with suspected or confirmed HIT.
Patients/Methods
Twenty‐two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30.
Results and Conclusions
The primary outcome measure, incidence of new symptomatic, objectively‐confirmed venous and arterial thromboembolism at 30 days, occurred in one HIT‐positive participant (4.5%; 95% confidence interval CI, 0–23.5%) and one HIT‐positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT‐positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.
The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic ...mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.
This paper introduces a generic, transparent and compact model for the evaluation of the aerodynamic performance of insect-like flapping wings in hovering flight. The model is generic in that it can ...be applied to wings of arbitrary morphology and kinematics without the use of experimental data, is transparent in that the aerodynamic components of the model are linked directly to morphology and kinematics via physical relationships and is compact in the sense that it can be efficiently evaluated for use within a design optimization environment. An important aspect of the model is the method by which translational force coefficients for the aerodynamic model are obtained from first principles; however important insights are also provided for the morphological and kinematic treatments that improve the clarity and efficiency of the overall model. A thorough analysis of the leading-edge suction analogy model is provided and comparison of the aerodynamic model with results from application of the leading-edge suction analogy shows good agreement. The full model is evaluated against experimental data for revolving wings and good agreement is obtained for lift and drag up to 90° incidence. Comparison of the model output with data from computational fluid dynamics studies on a range of different insect species also shows good agreement with predicted weight support ratio and specific power. The validated model is used to evaluate the relative impact of different contributors to the induced power factor for the hoverfly and fruitfly. It is shown that the assumption of an ideal induced power factor (k = 1) for a normal hovering hoverfly leads to a 23% overestimation of the generated force owing to flapping.
Filamentous inclusions made of α -synuclein constitute the defining neuropathological characteristic of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Rare familial ...cases of Parkinson's disease are associated with mutations A53T and A30P in α -synuclein. We report here the assembly properties and secondary structure characteristics of recombinant α -synuclein. Carboxy-terminally truncated human α -synuclein (1-87) and (1-120) showed the fastest rates of assembly, followed by human A53T α -synuclein, and rat and zebra finch α -synuclein. Wild-type human α -synuclein and the A30P mutant showed slower rates of assembly. Upon shaking, filaments formed within 48 h at 37 degrees C. The related proteins β - and γ -synuclein only assembled after several weeks of incubation. Synthetic human α -synuclein filaments were decorated by an antibody directed against the carboxy-terminal 10 amino acids of α -synuclein, as were filaments extracted from dementia with Lewy bodies and multiple system atrophy brains. Circular dichroism spectroscopy indicated that α -synuclein undergoes a conformational change from random coil to β -sheet structure during assembly. X-ray diffraction and electron diffraction of the α -synuclein assemblies showed a cross-β conformation characteristic of amyloid.
Hepatitis B is a small enveloped DNA virus that poses a major hazard to human health. The crystal structure of the T = 4 capsid has been solved at 3.3 A resolution, revealing a largely helical ...protein fold that is unusual for icosahedral viruses. The monomer fold is stabilized by a hydrophobic core that is highly conserved among human viral variants. Association of two amphipathic alpha-helical hairpins results in formation of a dimer with a four-helix bundle as the major central feature. The capsid is assembled from dimers via interactions involving a highly conserved region near the C terminus of the truncated protein used for crystallization. The major immunodominant region lies at the tips of the alpha-helical hairpins that form spikes on the capsid surface.
Lewy bodies and Lewy neurites are the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. They are made of abnormal filamentous assemblies of unknown ...composition. We show here that Lewy bodies and Lewy neurites from Parkinson's disease and dementia with Lewy bodies are stained strongly by antibodies directed against amino-terminal and carboxyl-terminal sequences of α -synuclein, showing the presence of full-length or close to full-length α -synuclein. The number of α -synuclein-stained structures exceeded that immunoreactive for ubiquitin, which is currently the most sensitive marker of Lewy bodies and Lewy neurites. Staining for α -synuclein thus will replace staining for ubiquitin as the preferred method for detecting Lewy bodies and Lewy neurites. We have isolated Lewy body filaments by a method used for the extraction of paired helical filaments from Alzheimer's disease brain. By immunoelectron microscopy, extracted filaments were labeled strongly by anti-α -synuclein antibodies. The morphologies of the 5- to 10-nm filaments and their staining characteristics suggest that extended α -synuclein molecules run parallel to the filament axis and that the filaments are polar structures. These findings indicate that α -synuclein forms the major filamentous component of Lewy bodies and Lewy neurites.
The presence of a stable leading edge vortex (LEV) on steadily revolving wings increases the maximum lift coefficient that can be generated from the wing and its role is important to understanding ...natural flyers and flapping wing vehicles. In this paper, the role of LEV in lift augmentation is discussed under two hypotheses referred to as ‘additional lift' and ‘absence of stall’. The ‘additional lift' hypothesis represents the traditional view. It presumes that an additional suction/circulation from the LEV increases the lift above that of a potential flow solution. This behaviour may be represented through either the ‘Polhamus leading edge suction' model or the so-called ‘trapped vortex' model. The ‘absence of stall' hypothesis is a more recent contender that presumes that the LEV prevents stall at high angles of attack where flow separation would normally occur. This behaviour is represented through the so-called ‘normal force' model. We show that all three models can be written in the form of the same potential flow kernel with modifiers to account for the presence of a LEV. The modelling is built on previous work on quasi-steady models for hovering wings such that model parameters are determined from first principles, which allows a fair comparison between the models themselves, and the models and experimental data. We show that the two models which directly include the LEV as a lift generating component are built on a physical picture that does not represent the available experimental data. The simpler ‘normal force' model, which does not explicitly model the LEV, performs best against data in the literature. We conclude that under steady conditions the LEV as an ‘absence of stall’ model/mechanism is the most satisfying explanation for observed aerodynamic behaviour.
PDF
