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Hereditary haemorrhagic telangiectasia (HHT) is a heterogeneous multisystemic dysplasia of the vascular tissue. This autosomal dominant inherited disorder shows a wide variation in its phenotypic expression. Between 8 and 78% of the HHT patients show arteriovenous malformations of the liver. The molecular basis for hepatic manifestation is still unknown. Two genes are known to play a major role in the development of HHT: activin A receptor type II-like 1 gene ( ACVRL1) and ENG. Previously, we and others showed that hepatic involvement is associated with mutations in the ACVRL1 gene, but rarely caused by ENG mutations. Here, we report about the sequencing analysis of a new cohort of 18 adult HHT patients. In these patients, we identified eight novel (four in ACVRL1 and four in ENG) and eight already known mutations. Statistical analysis of our entire data revealed significant differences in the distribution of ACVRL1 and ENG mutations among HHT patients with and without liver involvement (p = 0.0016). The positive predictive value for type 2 HHT ( ACVRL1 positive) patients to develop liver disease until the age of 52 years is 68.4%. We conclude that molecular genetic testing of HHT patients is important for prognosis with respect to liver disease. [ABSTRACT FROM AUTHOR]

In order to provide an alternative treatment option to lung transplantation, we aim for the development of an implantable biohybrid lung (BHL), based on hollow fibre membrane (HFM) technology used in extracorporeal membrane oxygenators. Crucial for long-lasting durability of the BHL is the complete haemocompatibility of all blood contacting surfaces, which can be achieved by their endothelialisation. Indeed, HFM coating using fibronectin (FN) or albumin/heparin (AH) is essential to initially enable endothelial cell (EC) adhesion and monolayer confluence, but clinically relevant flow exposure results in EC detachment. We hypothesize, that optimized physiologic extracellular matrix (EM) synthesis increases flow-resilience for clinical BHL application. FN and AH coated HFM were endothelialized, cultivated under static conditions for 2 or 6 days and exposed to flow conditions for 24h. Quantitative cell counting after flow exposure was analyzed, EC confluence and EM-synthesis under static and dynamic conditions were assessed by immunofluorescence (IF) for VE-Cadherin (CD144) and Collagen-IV (ColIV). Expression levels of EM associated genes, like collagen-alpha-1(IV)chain (COL4A1), syndecan-2 (SDC2) Laminin-alpha4 (LAMA4), hyaluronan-synthase-2 (HAS2), exostosin-1 (EXT1) were analyzed by qRT-PCR. Regardless of HFM coating, IF indicated confluent monolayers and time-dependent augmentation of ColIV. Furthermore, higher cell numbers after flow exposure were detected after prolonged static cultivation. While COL4A1 expression levels remained constant under static and dynamic conditions, EM-associated genes SDC2, LAMA4, HAS2 and EXT1 were up-regulated under flow exposure. Prolonged static cultivation facilitates CollV augmentation improving monolayer resilience to flow exposure on both tested HFM. Moreover, further protein synthesis generating physiological EM requires flow stimulus. These results are valuable to further improve the HFM endothelialisation protocol for optimal EM-formation to resist clinically relevant flow conditions for long-term BHL application. [ABSTRACT FROM AUTHOR]