Givosiran is a novel approach to treat patients with acute intermittent porphyrias (AIP) by silencing of ∂-ALA-synthase 1, the first enzyme of heme biosynthesis in the liver. We included two patients in the Envision study who responded clinically well to this treatment. However, in both patients, therapy had to be discontinued because of severe adverse effects: One patient (A) developed local injection reactions which continued to spread all over her body with increasing number of injections and eventually caused a severe systemic allergic reaction. Patient B was hospitalized because of a fulminant pancreatitis. Searching for possible causes, we also measured the patients plasma homocysteine (Hcy) levels in fluoride-containing collection tubes: by LC–MS/MS unexpectedly, plasma Hcy levels were 100 and 200 in patient A and between 100 and 400 μmol/l in patient B. Searching for germline mutations in 10 genes that are relevant for homocysteine metabolism only revealed hetero- and homozygous polymorphisms in the MTHFR gene. Alternatively, an acquired inhibition of cystathionine-beta-synthase which is important for homocysteine metabolism could explain the plasma homocysteine increase. This enzyme is heme-dependent: when we gave heme arginate to our patients, Hcy levels rapidly dropped. Hence, we conclude that inhibition of ∂-ALA-synthase 1 by givosiran causes a drop of free heme in the hepatocyte and therefore the excessive increase of plasma homocysteine. Hyperhomocysteinemia may contribute to the adverse effects seen in givosiran-treated patients which may be due to protein-N-homocysteinylation.
The number of digital images that are available online today has reached unprecedented levels. Recent statistics showed that by the end of 2013 there were over 250 billion photographs stored in just one of the major social media sites, with a daily average upload of 300 million photos. These photos, apart from documenting personal lives, often relate to experiences in well-known places of cultural interest, throughout several periods of time. Thus from the viewpoint of Cultural Heritage professionals, they constitute valuable and freely available digital cultural content. Advances in the fields of Photogrammetry and Computer Vision have led to significant breakthroughs such as the Structure from Motion algorithm which creates 3D models of objects using their 2D photographs. The existence of powerful and affordable computational machinery enables the reconstruction not only of single structures such as artefacts, but also of entire cities. This paper presents an overview of our methodology for producing cost-effective 4D – i.e. in space and time – models of Cultural Heritage structures such as monuments and artefacts from 2D data (pictures, video) and semantic information, freely available ‘in the wild’, i.e. in Internet repositories and social media. State-of-the-art methods from Computer Vision, Photogrammetry, 3D Reconstruction and Semantic representation are incorporated in an innovative workflow with the main goal to enable historians, architects, archaeologists, urban planners and other cultural heritage professionals to reconstruct cost-effective views of historical structures out of the billions of free images floating around the web and subsequently interact with those reconstructions.
ABSTRACT:The advent of technology in digital cameras and their incorporation into virtually any smart mobile device has led to an explosion of the number of photographs taken every day. Today, the number of images stored online and available freely has reached unprecedented levels. It is estimated that in 2011, there were over 100 billion photographs stored in just one of the major social media sites. This number is growing exponentially. Moreover, advances in the fields of Photogrammetry and Computer Vision have led to significant breakthroughs such as the Structure from Motion algorithm which creates 3D models of objects using their twodimensional photographs. The existence of powerful and affordable computational machinery not only the reconstruction of complex structures but also entire cities. This paper illustrates an overview of our methodology for producing 3D models of Cultural Heritage structures such as monuments and artefacts from 2D data (pictures, video), available on Internet repositories, social media, Google Maps, Bing, etc. We also present new approaches to semantic enrichment of the end results and their subsequent export to Europeana, the European digital library, for integrated, interactive 3D visualisation within regular web browsers using WebGl and X3D. Our main goal is to enable historians, architects, archaeologists, urban planners and affiliated professionals to reconstruct views of historical structures from millions of images floating around the web and interact with them.
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