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Ruder T.D.,University of Bern | Thali Y.,University of Bern | Schindera S.T.,University of Bern | Torre S.A.D.,Swiss Agency for Therapeutic Products | And 4 more authors.
Forensic Science International | Year: 2012

Objective: To assess the reliability of computed tomography (CT) numbers, also known as Hounsfield-units (HU) in the differentiation and identification of forensically relevant materials and to provide instructions to improve the reproducibility of HU measurements in daily forensic practice. Materials and methods: We scanned a phantom containing non-organic materials (glass, rocks and metals) on three different CT scanners with standardized parameters. The . t-test was used to assess the influence of the scanner, the size and shape of different types of regions-of-interest (ROI), the composition and shape of the object, and the reader performance on HU measurements. Intra-class correlation coefficient was used to assess intra- and inter-reader reliability. Results: HU values did not change significantly as a function of ROI-shape or -size (. p>. 0.05). Intra-reader reliability reached ICC values >0.929 (. p<. 0.001). Inter-reader reliability was also excellent with an ICC of 0.994 (. p<. 0.001). Four of seven objects yielded significantly different CT numbers at different levels within the object (. p<. 0.05). In 6/7 objects the HU changed significantly from CT scanner to CT scanner (. p<. 0.05). Conclusion: Reproducible CT number measurements can be achieved through correct ROI-placement and repeat measurements within the object of interest. However, HU may differ from CT-scanner to CT-scanner. In order to obtain comparable CT numbers we suggest that a dedicated Forensic Reference Phantom be developed. © 2012 Elsevier Ireland Ltd. Source

Ding Y.,University of Alabama at Birmingham | Li J.,University of Alabama at Birmingham | Yang P.,University of Alabama at Birmingham | Luo B.,University of Alabama at Birmingham | And 5 more authors.
Arthritis and Rheumatology | Year: 2014

Objective. Follicular regulatory T (Tfr) cells act as the regulatory counterpart of follicular helper T (Tfh) cells to suppress germinal center (GC) B cell differentiation. We recently showed that interleukin-21 (IL-21) promoted Tfh cell differentiation in autoimmune BXD2 mice that develop spontaneous GCs. This study was undertaken to determine the modulatory effects of IL-21 on Tfr cells and the Tfr cell to Tfh cell balance in BXD2 mice. Methods. The percentage and phenotype of Tfr cells were determined in BXD2 and BXD2-IL21-/- mice. The effects of IL-21 on Tfr cells and the Tfr cell:Tfh cell ratio were evaluated. Sorted Tfr cells from BXD2-IL21-/- mice were cocultured with Tfh cells and B cells, or transferred into BXD2 mice to determine their function. Results. The percentages and numbers of GC B cells and Tfh cells were significantly reduced, but the percentage of Tfr cells was 2-fold higher in BXD2-IL21-/- mice than in wild-type BXD2 mice. Administration of AdIL-21 to BXD2-IL21-/- mice decreased the percentages and numbers of Tfr cells and the Tfr cell:Tfh cell ratio but increased the number of GC B cells in the spleen. Recombinant murine IL-21 suppressed FoxP3 and significantly reduced Tgfb1, Il2, and Gitr but enhanced Il21, Il6, Pd1, Cxcr5, and Icos expression in Tfr cells. IL-21 also counteracted Tfr cell-mediated inhibition of antibody secretion in the Tfh cell-B cell coculture system. Transfer of Tfr cells into young BXD2 mice reduced GC size and decreased the numbers of autoantibody-producing B cells. Conclusion. Our findings indicate that high levels of IL-21 selectively enhance Tfh cell differentiation but inhibit Tfr cell commitment and the suppressive function of Tfr cells on Tfh cells and B cells, suggesting that IL-21 skews the balance from Tfr cells to Tfh cells to promote autoreactive GC reactions in BXD2 mice. © 2014, American College of Rheumatology. Source

Molzon J.A.,U.S. Food and Drug Administration | Giaquinto A.,PhRMA Inc | Lindstrom L.,European Commission | Tominaga T.,Pharmaceuticals and Medical Devices Agency | And 4 more authors.
Clinical Pharmacology and Therapeutics | Year: 2011

The International Conference on Harmonisation (ICH) is an unparalleled undertaking, which has brought together drug regulatory authorities and pharmaceutical trade associations from Europe, Japan, and the United States, to discuss the scientific and technical aspects of medical product registration. Launched in 1990, the value and benefits of ICH to regulators are being realized. ICH has harmonized submission requirements and created a harmonized submission format that is relieving both companies and regulatory authorities of the burdens of assembling and reviewing separate submissions for each region. As more countries embrace ICH guidelines, we anticipate additional benefits, including the promotion of good review practices and, ultimately, a common regulatory language that will facilitate further interactions among global drug regulatory authorities. © 2011 ASCPT. Source

Fennessy D.,University of Manchester | Grallert A.,University of Manchester | Krapp A.,Ecole Polytechnique Federale de Lausanne | Cokoja A.,Ecole Polytechnique Federale de Lausanne | And 13 more authors.
PLoS ONE | Year: 2014

Targeted alteration of the genome lies at the heart of the exploitation of S. pombe as a model system. The rate of analysis is often determined by the efficiency with which a target locus can be manipulated. For most loci this is not a problem, however for some loci, such as fin1+, rates of gene targeting below 5% can limit the scope and scale of manipulations that are feasible within a reasonable time frame. We now describe a simple modification of transformation procedure for directing integration of genomic sequences that leads to a 5-fold increase in the transformation efficiency when antibiotic based dominant selection markers are used. We also show that removal of the pku70+ and pku80+ genes, which encode DNA end binding proteins required for the non-homologous end joining DNA repair pathway, increases the efficiency of gene targeting at fin1+ to around 75-80% (a 16-fold increase). We describe how a natMX6/rpl42+ cassette can be used for positive and negative selection for integration at a targeted locus. To facilitate the evaluation of the impact of a series of mutations on the function of a gene of interest we have generated three vector series that rely upon different selectable markers to direct the expression of tagged/untagged molecules from distinct genomic integration sites. pINTL and pINTK vectors use ura4+ selection to direct disruptive integration of leu1+ and lys1+ respectively, while pINTH vectors exploit nourseothricin resistance to detect the targeted disruption of a hygromycin B resistance conferring hphMX6 cassette that has been integrated on chromosome III. Finally, we have generated a series of multi-copy expression vectors that use resistance to nourseothricin or kanamycin/G418 to select for propagation in prototrophic hosts. Collectively these protocol modifications and vectors extend the versatility of this key model system. © 2014 Fennessy et al. Source

Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,University of Groningen | Sachs B.,Federal Institute for Drugs and Medical Devices BfArM | Harrison-Woolrych M.,University of Otago | And 2 more authors.
Drug Safety | Year: 2011

Background: Levonorgestrel-releasing intrauterine devices (LNG-IUD) are commonly used for contraception and other indications in many countries. National pharmacovigilance centres have been receiving reports from healthcare professionals and patients of uterine perforation associated with the use of these LNG-IUDs. Methods: National pharmacovigilance centres in the Netherlands, New Zealand, Switzerland and Germany did a search on their adverse drug reaction databases for reports of cases of uterine perforation after insertion of a LNG-IUD received between the introduction of the LNG-IUD onto the market in the late 1990s and 15 July 2007. The number of women affected and patient characteristics such as age, parity and breastfeeding status were examined. In addition, the method of detection of the perforation and the time until discovery of the perforation were analysed. Results: Between the introduction of the LNG-IUD onto the market in each country and 15 July 2007, 701 cases of uterine perforation with a LNG-IUD were reported; 8.5% of the perforations were detected at the time of insertion. Abdominal pain and control/check-up visits were the most common events that lead to the detection of a perforation. Of 462 women known to be parous, 192 (42%) were breastfeeding at the time the perforation was discovered. Conclusions: Uterine perforations can be asymptomatic and may remain undetected for a long time after IUD insertion. Abdominal pain, control/ check-up visits or changes in bleeding patterns are triggers for detection of perforation and should therefore be taken seriously. © 2011 Adis Data Information BV. All rights reserved. Source

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