Von Willebrand factor is a major determinant of ADAMTS-13 decrease during mouse sepsis induced by cecum ligation and puncture

Summary. Background: During sepsis, von Willebrand factor (VWF) is abundantly secreted; the main mechanism regulating its size involves specific proteolysis by the metalloprotease ADAMTS-13. Objectives: To determine whether ADAMTS-13 consumption due to its binding to, and/or cleavage, of VWF contributes to its decrease during sepsis and whether abrogating or enhancing ADAMTS-13 activity influences sepsis outcome. Methods: ADAMTS-13 activity was evaluated in a model of sepsis induced by cecum ligature and puncture (CLP) in wild-type and Vwf−/− mice. Sepsis outcome was studied in those mice and in Adamts-13−/− mice. Finally, survival was studied in wild-type mice injected hydrodynamically with the human ADAMTS-13 gene. Results: In wild-type mice, CLP-induced sepsis elicited a significant ADAMTS-13 decrease, and a strong negative correlation existed between VWF and ADAMTS-13. In Vwf−/− mice, CLP also induced severe sepsis, but ADAMTS-13 was not significantly diminished. Notably, Vwf−/− mice lived significantly longer than wild-type mice. In contrast, Adamts-13−/− mice and wild-type mice were comparable with regard to thrombocytopenia, VWF concentrations, absence of thrombi, and survival. Hydrodynamic hADAMTS-13 gene transfer with the pLIVE expression vector resulted in high and stable ADAMTS13 activity in CLP mice; however, no impact on survival was observed. Conclusions: VWF secretion is a major determinant of ADAMTS-13 decrease in the CLP model, and plays an important role in sepsis-induced mortality, but the complete absence of its regulating protease, ADAMTS-13, had no detectable impact in this sepsis model. Furthermore, increasing ADAMTS-13 activity had no impact on survival

In vivo imaging of DNA lipid nanocapsules after systemic administration in a melanoma mouse model

International audienceThe biodistribution of intravenously injected DNA lipid nanocapsules (DNA LNCs), encapsulating pHSV-tk, was analysed by in vivo imaging on an orthotopic melanoma mouse model and by a subsequent treatment with ganciclovir (GCV), using the gene-directed enzyme prodrug therapy (GDEPT) approach. Luminescent melanoma cells, implanted subcutaneously in the right flank of the mice, allowed us to follow tumour growth and tumour localisation with in vivo bioluminescence imaging (BLI). In parallel, DNA LNCs or PEG DNA LNCs (DNA LNCs recovered with PEG2000) encapsulating a fluorescent probe, DiD, allowed us to follow their biodistribution with in vivo biofluorescence imaging (BFI). The BF-images confirmed a prolonged circulation-time for PEG DNA LNCs as was previously observed on an ectotopic model of glioma; comparison with BL-images evidenced the colocalisation of PEG DNA LNCs and melanoma cells. After these promising results, treatment with PEG DNA LNCs and GCV on a few animals was performed and the treatment efficacy measured by BLI. The first results showed tumour growth reduction tendency and, once optimised, this therapy strategy could become a new option for melanoma treatment.</p

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Thrombosis and Hemostasi

Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels

The glycosylation profile of von Willebrand factor (VWF) is known to strongly influence its plasma levels. VWF contains several carbohydrate structures, including O-linked glycans that primarily consist of sialylated T antigen (NeuAc(α2-3)Gal-(β1-3)-[NeuAc(α2-6)]GalNAc). It is not yet known whether O-linked carbohydrates affect VWF levels. We developed an immunosorbent assay based on neuraminidase incubation allowing subsequent binding of peanut agglutinin (PNA) to desialylatedO-linked T antigen on VWF. An inverse relation was found between PNA binding and VWF antigen levels in healthy individuals (n = 111; Pearson rank - -0.43; P < .001). A similar inverse association was observed in randomly selected plasma samples from our diagnostic laboratory: 252% ± 125% for VWF levels less than 0.5 U/mL (n = 15); 131% ± 36% for VWF levels between 0.5 and 1.5 U/mL (n = 32); and 92% ± 40% for VWF levels more than 1.5 U/mL (n = 19). Reduced or increased PNA binding was also observed in patients with increased (liver cirrhosis) or reduced (von Willebrand disease [VWD] type 1) VWF antigen levels, respectively. VWD type 1 patients further displayed increased ratios of propeptide over mature VWF antigen levels (0.38 ± 0.18 versus 0.17 ± 0.03 for patients and controls, respectively; P < .001), which is indicative of reduced VWF survival in these patients. Of interest, a linear relation between PNA binding and propeptide/VWF ratio was observed (Spearman rank = 0.47), suggesting a potential association between O-linked glycosylation and VWF survival. Finally, we detected a marked decrease in PNA binding in post-DDAVP (1-deamino-8-D- arginine vasopressin) samples from various patients, indicating that the O-linked glycosylation profile of VWF stored in endothelial storage organelles may differ from circulating VWF

Corporate Failure Prediction Modeling: Distorted by Business Groups' Internal Capital Markets?

Most models in the bankruptcy prediction literature implicitly assume companies are stand-alone entities. However, in view of the importance of business groups in Continental Europe, ignoring group ties may have a negative impact on predictive reliability. We find that models encompassing both bankruptcy variables defined at subsidiary level and at group level have a substantially better fit and classification performance. Furthermore we find that the group's support causes improved survival chances for subsidiaries, especially when these subsidiaries belong to the group's core business. Overall our results are consistent with existing theoretical and empirical findings from the internal capital markets literature. Copyright 2006 The Authors Journal compilation (c) 2006 Blackwell Publishing Ltd.

Large Interferometer For Exoplanets (LIFE): I. Improved exoplanet detection yield estimates for a large mid-infrared space-interferometer mission

One of the long-term goals of exoplanet science is the atmospheric characterization of dozens of small exoplanets in order to understand their diversity and search for habitable worlds and potential biosignatures. Achieving this goal requires a space mission of sufficient scale. We seek to quantify the exoplanet detection performance of a space-based mid-infrared nulling interferometer that measures the thermal emission of exoplanets. For this, we have developed an instrument simulator that considers all major astrophysical noise sources and coupled it with Monte Carlo simulations of a synthetic exoplanet population around main-sequence stars within 20 pc. This allows us to quantify the number (and types) of exoplanets that our mission concept could detect over a certain time period. Two different scenarios to distribute the observing time among the stellar targets are discussed and different apertures sizes and wavelength ranges are considered. Within a 2.5-year initial search phase, an interferometer consisting of four 2 m apertures covering a wavelength range between 4 and 18.5 μm could detect up to ~550 exoplanets with radii between 0.5 and 6 R⊕ with an integrated SNR≥7. At least ~160 of the detected exoplanets have radii ≤1.5 R⊕. Depending on the observing scenario, ~25-45 rocky exoplanets (objects with radii between 0.5 and 1.5 ⊕) orbiting within the empirical habitable zone (eHZ) of their host stars are among the detections. With four times 3.5 m aperture size, the total number of detections can increase to up to ~770, including ~60-80 rocky, eHZ planets. With four times 1 m aperture size, the maximum detection yield is ~315 exoplanets, including ≤20 rocky, eHZ planets. In terms of predicted detection yield, such a mission can compete with large single-aperture reflected light missions