ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients

Orientation of Galaxies in the Local Supercluster: A Review

The progress of the studies on the orientation of galaxies in the Local Supercluster (LSC) is reviewed and a summary of recent results is given. Following a brief introduction of the LSC, we describe the results of early studies based on two-dimensional analysis, which were mostly not conclusive. We describe next the three-dimensional analysis, which is used widely today. Difficulties and systematic effects are explained and the importance of selection effects is described. Then, results based on the new method and modern databases are given, which are summarized as follows. When the LSC is seen as a whole, galaxy planes tend to align perpendicular to the LSC plane with lenticulars showing the most pronounced tendency. Projections onto the LSC plane of the spin vectors of Virgo cluster member galaxies, and to some extent, those of the total LSC galaxies, tend to point to the Virgo cluster center. This tendency is more pronounced for lenticulars than for spirals. It is suggested that 'field' galaxies, i.e., those which do not belong to groups with more than three members, may be better objects than other galaxies to probe the information at the early epoch of the LSC formation through the analysis of galaxy orientations. Field lenticulars show a pronounced anisotropic distribution of spin vectors in the sense that they lay their spin vectors parallel to the LSC plane while field spirals show an isotropic spin-vector distribution.Comment: 21 pages, 10 figures; Accepted for publication in Astrophysics and Space Scienc

Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response.

Activation of dendritic cells (DC) by microbial products via Toll-like receptors (TLR) is instrumental in the induction of immunity. In particular, TLR signaling plays a major role in the instruction of Th1 responses. The development of Th2 responses has been proposed to be independent of the adapter molecule myeloid differentiation factor 88 (MyD88) involved in signal transduction by TLRs. In this study we show that flagellin, the bacterial stimulus for TLR5, drives MyD88-dependent Th2-type immunity in mice. Flagellin promotes the secretion of IL-4 and IL-13 by Ag-specific CD4(+) T cells as well as IgG1 responses. The Th2-biased responses are associated with the maturation of DCs, which are shown to express TLR5. Flagellin-mediated DC activation requires MyD88 and induces NF-kappaB-dependent transcription and the production of low levels of proinflammatory cytokines. In addition, the flagellin-specific response is characterized by the lack of secretion of the Th1-promoting cytokine IL-12 p70. In conclusion, this study suggests that flagellin and, more generally, TLR ligands can control Th2 responses in a MyD88-dependent manner

Observations of Titan's Northern lakes at 5 μm: Implications for the organic cycle and geology

Since Titan entered Northern spring in August 2009, the North Pole has been illuminated allowing observations at optical wavelengths. On June 5, 2010 the Visual and Infrared Mapping Spectrometer (VIMS) onboard the Cassini spacecraft observed the Northern Pole area with a pixel size from 3 to 7 km. Since, as we demonstrate, little of the solar flux at 5 μm is scattered by the atmosphere, these observations were obtained at relatively large incidence angles and allowed us to build a mosaic covering an area of more than 500,000 km2 that overlaps and complements observations made by the Synthetic Aperture Radar (SAR) in 2007. We find that there is an excellent correlation between the shape of the radar dark area, known as Ligeia Mare and the VIMS 5-μm dark unit. Matching most of the radar shoreline, the 2010 VIMS observations suggest that the 125,000-km2 surface area of Ligeia Mare measured by RADAR in 2007 has not significantly changed. The VIMS observations complement the radar observations to the west of Ligeia Mare and suggest that Ligeia Mare is connected to Kraken Mare by either a diffuse network similar to a swamp area, or by well-defined, sub-pixel rivers. Considering the results of recent evaporation models of methane, our preferred interpretation of the relative constancy in surface area of Ligeia is that it is principally composed of ethane although we cannot rule out the possibility that methane evaporation is balanced with replenishment by either precipitation or underground seepage. There is also strong correlation between the location of the small radar lakes and the small VIMS 5-μm dark patches. The geographic location of the small lakes are within a VIMS pixel of the SAR location, suggesting that the non-synchronous component of Titan's spin rate, if it exists, was less than 2.3 × 10‑4 deg/day between 2007 and 2010 in agreement with the recent T64 radar observations. These observations question the existence of non-synchronous rotation. Two radar-bright features appear dark at 5-μm. The simplest interpretation is that these are very shallow lakes, less than one meter deep. Three new small lakes, named Freeman, Cardiel, and Towada by the IAU, are found outside of the area mapped with the SAR. A single-scattering model describing reflection of sunlight at 5-μm suggests that the lake surface is mirror-like and that the albedo of the solid surfaces surrounding the lakes is about 8%. These observations together with information of the haze aerosols allow us to show that Titan's lakes, atmospheric ethane and aerosol haze are smaller carbon reservoirs than Titan's sand dunes and atmospheric methane. A simple model involving an outburst of methane a few hundreds of Myr ago followed by the dissociation of methane in the atmosphere leading to the formation of the haze particles that constitute the dune fields would be consistent with both the present observations and recent measurements of isotopic ratios in atmospheric methane (Mandt, K.E. et al. [2012]. Astrophys. J. 749(160), 14)