Numero XXXIII

<p><b>Cumulative Incidence of AUR (A) and UR (B) with FDC Soli 6 mg or 9 mg + TOCAS.</b> (A) Acute urinary retention. (B) Urinary retention. Black markers indicate 6 mg FDC dose at time of AUR/UR onset; orange markers indicate 9 mg FDC dose at time of AUR/UR onset. AUR cases were a subgroup of UR cases that required catheterization. Abbreviation: FDC, fixed-dose combination.</p

Intraoperative assessment and reporting of radical prostatectomy specimens to guide nerve-sparing surgery in prostate cancer patients (NeuroSAFE)

AIMS: Radical prostatectomy for prostate cancer is frequently complicated by urinary incontinence and erectile dysfunction. Nerve-sparing surgery reduces the risk of post-operative complications and can be optimized using intraoperative frozen sections of the adjacent neurovascular structure (NeuroSAFE). The aim of t

The Rotterdam Study: objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in the Netherlands. The study targets cardiovascular, neurological, ophthalmological and endocrine diseases. As of 2008 about 15,000 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in some 600 research articles and reports (see http://www.epib.nl/rotterdamstudy). This article gives the reasons for the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Tuolinjalan jyrsintäkiinnittimien suunnittelu

Opinnäytetyön tavoitteena oli suunnitella robotilla tehtävään kappaleenkäsittelyyn soveltuvat automaattiset jyrsintäkiinnikkeet epäsymmetrisen puusta valmistettavan tuolinjalan jyrsintään. Työ toteutettiin Savon ammatti- ja aikuisopiston puualan tiloihin rakennetussa RFID-tekniikan opetus- ja testausympäristössä. Suunnitteluvaiheessa pyrittiin hyödyntämään olemassa olevien laitteiden ja koneiden, kuten CNC-jyrsimen ja kappaleenkäsittelyrobotin ominaisuuksia jyrsintäkiinnittimien valmistuksessa. Opinnäytetyössä käytiin läpi työkappaleen, jyrsimen ja robotin asettamia vaatimuksia ja niiden huomiointia kiinnittimien suunnittelussa ja pohdittiin RFID-sirun integroinnin mahdollisuuksia työkappaleen työkierron ohjauksessa. Kiinnittimien suunnitteluun käytettiin Autodesk Inventor 3D -suunnitteluohjelmaa, jolla luotiin työn tuloksena syntyneet työkappaleen dimensioiden ja työstövaatimusten perusteella suunnitellut kiinnittimien tietokonemallit. Tietokonemallien pohjalta rakennettiin jyrsintään ja automaattiseen kappaleenvaihtoon soveltuvat jyrsintäkiinnittimet, joiden avulla tuolinjalkojen valmistus onnistuu miehittämättömään tuotantoon soveltuvassa solussa.The objective of this final year project was to design mechanical clamps which would be suitable for being used with a CNC milling machine. The clamps were designed according to the dimensions and design principles of a particular chair leg which is part of the Sakky-chair assembly. The project was commissioned by Savo Vocational Colleges and it is part of the RFID (Radio Frequency Identification) project. The design process was started by researching old manual clamps used for attaching the chair leg blank to the milling table. These manual clamps were used as design examples in the beginning of the process. The clamps were designed using Autodesk Inventor 3D CAD software. The clamps were designed to the testing phase and will be manufactured over the coming months. The new automatically controlled clamps were designed to be operated by using negative pressure that is available through the vacuum cups of the milling machines. Handling the blanks and the milled chair legs was designed to be carried out using the available material handling robot. The implementation of RFID tags for transferring milling and handling information in the blanks will be investigated. In order to get the clamp design to work, some minor tweaks to the final design might be necessary. These necessary design tweaks are mostly due to some small dimensional differences between different chair leg blanks used

Conditional live virus as a novel approach towards a safe live attenuated HIV vaccine

To control the worldwide spread of HIV, a safe and effective prophylactic vaccine is urgently needed. Studies with the simian immunodeficiency virus demonstrated that a live attenuated virus can be effective as a vaccine, but serious concerns about the safety of such a vaccine virus have arisen. We propose a conditional live virus, of which the replication can be switched on and off at will, as a novel approach for an HIV vaccin

The genetic stability of a conditional live HIV-1 variant can be improved by mutations in the Tet-On regulatory system that restrain evolution

Live attenuated human immunodeficiency virus type 1 (HIV-1) vaccines are considered unsafe because more quickly replicating pathogenic virus variants may evolve after vaccination. As an alternative vaccine approach, we have previously presented a doxycycline (dox)-dependent HIV-1 variant that was constructed by incorporating the tetracycline-inducible gene expression system (Tet-On system) into the viral genome. Replication of this HIV-rtTA variant is driven by the dox-inducible transcriptional activator rtTA and can be switched on and off at will. A large scale evolution study was performed to test the genetic stability of this conditional live vaccine candidate. In several long term cultures, we selected for HIV-rtTA variants that no longer required dox for replication. These evolved variants acquired a typical amino acid substitution either at position 19 or 37 in the rtTA protein. Both mutations caused rtTA activity and viral replication in the absence of dox. We designed a novel rtTA variant with a higher genetic barrier toward these undesired evolutionary routes. The corresponding HIV-rtTA variant did not lose dox control in long term cultures, demonstrating its improved genetic stabilit

Viral evolution as a tool to improve the tetracycline-regulated gene expression system

We present viral evolution as a novel and powerful method to optimize non-viral proteins. We used this approach to optimize the tetracycline (Tc)-regulated gene expression system (Tet system) for its function in mammalian cells. The components of the Tet system were incorporated in the human immunodeficiency virus (HIV)-1 virus such that viral replication is controlled by this regulatory system. Upon long term replication of this HIV-rtTA virus in human T cells, we obtained a virus variant with an enhanced replication potential resulting from an improved rtTA component of the introduced Tet system. We identified a single amino acid exchange, F86Y, which enhances the transcriptional activity and doxycycline (dox) sensitivity of rtTA. We generated a new rtTA variant that is 5-fold more active at high dox levels than the initial rtTA, and 25-fold more sensitive to dox, whereas the background activity in the absence of dox is not increased. This new rtTA variant will be very useful in biological applications that require a more sensitive or active Tet system. Our results demonstrate that the viral evolution strategy can be used to improve the activity of genes by making them an integral and essential part of the viru