Identification of selective norbornane-type aspartate analogue inhibitors of the glutamate transporter 1 (GLT-1) from the chemical universe generated database (GDB)

A variety of conformationally constrained aspartate and glutamate analogues inhibit the glutamate transporter 1 (GLT-1, also known as EAAT2). To expand the search for such analogues, a virtual library of aliphatic aspartate and glutamate analogues was generated starting from the chemical universe database GDB-11, which contains 26.4 million possible molecules up to 11 atoms of C, N, O, F, resulting in 101026 aspartate analogues and 151285 glutamate analogues. Virtual screening was realized by high-throughput docking to the glutamate binding site of the glutamate transporter homologue from Pyrococcus horikoshii (PDB code: 1XFH ) using Autodock. Norbornane-type aspartate analogues were selected from the top-scoring virtual hits and synthesized. Testing and optimization led to the identification of (1R*,2R*,3S*,4R*,6R*)-2-amino-6-phenethyl-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid as a new inhibitor of GLT-1 with IC(50) = 1.4 ?M against GLT-1 and no inhibition of the related transporter EAAC1. The systematic diversification of known ligands by enumeration with help of GDB followed by virtual screening, synthesis, and testing as exemplified here provides a general strategy for drug discovery.

The James Lind Library: explaining and illustrating the evolution of fair tests of medical treatments

The James Lind Library (www.jameslindlibrary.org) has been established to improve public and professional general knowledge about fair tests of treatments in healthcare and their history. Its foundation was laid ten years ago at the Royal College of Physicians of Edinburgh, and its administrative centre is in the College's Sibbald Library, one of the most important collections of historic medical manuscripts, papers and books in the world. The James Lind Library is a website that introduces visitors to the principles of fair tests of treatments, with a series of short, illustrated essays, which are currently available in English, Arabic, Chinese, French, Portuguese, Russian and Spanish. A 100-page book-- Testing Treatments--is now available free through the website, both in English and in Arabic and Spanish translations. To illustrate the evolution of ideas related to fair tests of treatments from 2000 BC to the present, the James Lind Library contains key passages and images from manuscripts, books and journal articles, many of them accompanied by commentaries, biographies, portraits and other relevant documents and images, including audio and video files. New material is being added to the website continuously, as relevant new records are identified and as methods for testing treatments evolve. A multinational, multilingual editorial team oversees the development of the website, which currently receives tens of thousands of visitors every month.

The Virtual Skeleton Database: An Open Access Repository for Biomedical Research and Collaboration

Background: Statistical shape models are widely used in biomedical research. They are routinely implemented for automatic image segmentation or object identification in medical images. In these fields, however, the acquisition of the large training datasets, required to develop these models, is usually a time-consuming process. Even after this effort, the collections of datasets are often lost or mishandled resulting in replication of work. Objective: To solve these problems, the Virtual Skeleton Database (VSD) is proposed as a centralized storage system where the data necessary to build statistical shape models can be stored and shared. Methods: The VSD provides an online repository system tailored to the needs of the medical research community. The processing of the most common image file types, a statistical shape model framework, and an ontology-based search provide the generic tools to store, exchange, and retrieve digital medical datasets. The hosted data are accessible to the community, and collaborative research catalyzes their productivity. Results: To illustrate the need for an online repository for medical research, three exemplary projects of the VSD are presented: (1) an international collaboration to achieve improvement in cochlear surgery and implant optimization, (2) a population-based analysis of femoral fracture risk between genders, and (3) an online application developed for the evaluation and comparison of the segmentation of brain tumors. Conclusions: The VSD is a novel system for scientific collaboration for the medical image community with a data-centric concept and semantically driven search option for anatomical structures. The repository has been proven to be a useful tool for collaborative model building, as a resource for biomechanical population studies, or to enhance segmentation algorithms.

Evaluation and Comparison of Anatomical Landmark Detection Methods for Cephalometric X-Ray Images: A Grand Challenge

Cephalometric analysis is an essential clinical and research tool in orthodontics for the orthodontic analysis and treatment planning. This paper presents the evaluation of the methods submitted to the Automatic Cephalometric X-Ray Landmark Detection Challenge, held at the IEEE International Symposium on Biomedical Imaging 2014 with an on-site competition. The challenge was set to explore and compare automatic landmark detection methods in application to cephalometric X-ray images. Methods were evaluated on a common database including cephalograms of 300 patients aged six to 60 years, collected from the Dental Department, Tri-Service General Hospital, Taiwan, and manually marked anatomical landmarks as the ground truth data, generated by two experienced medical doctors. Quantitative evaluation was performed to compare the results of a representative selection of current methods submitted to the challenge. Experimental results show that three methods are able to achieve detection rates greater than 80% using the 4 mm precision range, but only one method achieves a detection rate greater than 70% using the 2 mm precision range, which is the acceptable precision range in clinical practice. The study provides insights into the performance of different landmark detection approaches under real-world conditions and highlights achievements and limitations of current image analysis techniques.

Sediments of Lake Vens (SW European Alps, France) record large-magnitude earthquake events

We studied sediment cores from Lake Vens (2,327 m asl), in the Tinée Valley of the SW Alps, to test the paleoseismic archive potential of the lake sediments in this particularly earthquake-sensitive area. The historical earthquake catalogue shows that moderate to strong earthquakes, with intensities of IX–X, have impacted the Southern Alps during the last millennium. Sedimentological (X-ray images, grain size distribution) and geochemical (major elements and organic matter) analyses show that Lake Vens sediments consist of a terrigenous, silty material (minerals and organic matter) sourced from the watershed and diatom frustules. A combination of X-ray images, grain-size distribution, major elements and magnetic properties shows the presence of six homogenite-type deposits interbedded in the sedimentary background. These sedimentological features are ascribed to sediment reworking and grain sorting caused by earthquake-generated seiches. The presence of microfaults that cross-cut the sediment supports the hypothesis of seismic deposits in this system. A preliminary sediment chronology is provided by 210Pb measurement and AMS 14C ages. According to the chronology, the most recent homogenite events are attributable to damaging historic earthquakes in AD 1887 (Ligure) and 1564 (Roquebillière). Hence, the Lake Vens sediment recorded large-magnitude earthquakes in the region and permits a preliminary estimate of recurrence time for such events of ~400 years.

A new universal, standardized implant database for product identification: a unique tool for arthroplasty registries.

INTRODUCTION Every joint registry aims to improve patient care by identifying implants that have an inferior performance. For this reason, each registry records the implant name that has been used in the individual patient. In most registries, a paper-based approach has been utilized for this purpose. However, in addition to being time-consuming, this approach does not account for the fact that failure patterns are not necessarily implant specific but can be associated with design features that are used in a number of implants. Therefore, we aimed to develop and evaluate an implant product library that allows both time saving barcode scanning on site in the hospital for the registration of the implant components and a detailed description of implant specifications. MATERIALS AND METHODS A task force consisting of representatives of the German Arthroplasty Registry, industry, and computer specialists agreed on a solution that allows barcode scanning of implant components and that also uses a detailed standardized classification describing arthroplasty components. The manufacturers classified all their components that are sold in Germany according to this classification. The implant database was analyzed regarding the completeness of components by algorithms and real-time data. RESULTS The implant library could be set up successfully. At this point, the implant database includes more than 38,000 items, of which all were classified by the manufacturers according to the predefined scheme. Using patient data from the German Arthroplasty Registry, several errors in the database were detected, all of which were corrected by the respective implant manufacturers. CONCLUSIONS The implant library that was developed for the German Arthroplasty Registry allows not only on-site barcode scanning for the registration of the implant components but also its classification tree allows a sophisticated analysis regarding implant characteristics, regardless of brand or manufacturer. The database is maintained by the implant manufacturers, thereby allowing registries to focus their resources on other areas of research. The database might represent a possible global model, which might encourage harmonization between joint replacement registries enabling comparisons between joint replacement registries.

Earthquake- induced Geomorphology: A Neotectonic Study at the Front of the Alps (Lake Thun & Aare Valley, Switzerland)

We present a multi-disciplinary two-step approach to assess the potential for seismic hazard of the Aare valley and perialpine Lake Thun (Switzerland). High-resolution seismic images and multibeam-bathymetric data, complemented by field observations represent the tools to identify potentially active seismogenic fault structures. Several second-order earthquake effects such as subaqueous mass movements, seismites and liquefaction structures have been observed in Lake Thun and ultimately document the seismic activity of the study area. A first investigation of possibly first-order active structures is presented in the scope of this study. Recently acquired bathymetric data in Lake Thun reveal significant morphologic depressions aligning with an observed lineament on land. Furthermore, high-resolution seismic images indicate potential fault structures in Lake Thun. However, their continuation with depth has to be verified with a multichannel seismic campaign, scheduled for March 2015.