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861.
Mohamed Abou-El-Enein Andy Römhild Daniel Kaiser Carola Beier Gerhard Bauer Hans-Dieter Volk Petra Reinke 《Cytotherapy》2013,15(3):362-383
Background aimsAdvanced therapy medicinal products (ATMP) have gained considerable attention in academia due to their therapeutic potential. Good Manufacturing Practice (GMP) principles ensure the quality and sterility of manufacturing these products. We developed a model for estimating the manufacturing costs of cell therapy products and optimizing the performance of academic GMP-facilities.MethodsThe “Clean-Room Technology Assessment Technique” (CTAT) was tested prospectively in the GMP facility of BCRT, Berlin, Germany, then retrospectively in the GMP facility of the University of California-Davis, California, USA. CTAT is a two-level model: level one identifies operational (core) processes and measures their fixed costs; level two identifies production (supporting) processes and measures their variable costs. The model comprises several tools to measure and optimize performance of these processes. Manufacturing costs were itemized using adjusted micro-costing system.ResultsCTAT identified GMP activities with strong correlation to the manufacturing process of cell-based products. Building best practice standards allowed for performance improvement and elimination of human errors. The model also demonstrated the unidirectional dependencies that may exist among the core GMP activities. When compared to traditional business models, the CTAT assessment resulted in a more accurate allocation of annual expenses. The estimated expenses were used to set a fee structure for both GMP facilities. A mathematical equation was also developed to provide the final product cost.ConclusionsCTAT can be a useful tool in estimating accurate costs for the ATMPs manufactured in an optimized GMP process. These estimates are useful when analyzing the cost-effectiveness of these novel interventions. 相似文献
862.
863.
Nicolas Rochereau Daniel Drocourt Eric Perouzel Vincent Pavot Pierre Redelinghuys Gordon D. Brown Gerard Tiraby Xavier Roblin Bernard Verrier Christian Genin Blaise Corthésy Stéphane Paul 《PLoS biology》2013,11(9)
Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell–mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1+ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases. 相似文献
864.
Daniel Yang Chonlisa Chariyalertsak Antika Wongthanee Surinda Kawichai Kriengkrai Yotruean Pongpun Saokhieo Thomas Guadamuz Voravit Suwanvanichkij Chris Beyrer Suwat Chariyalertsak 《PloS one》2013,8(10)
Background
Northern Thailand has a high burden HIV epidemic among MSM and TG. Oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine has demonstrated efficacy in preventing HIV among MSM and TG in Chiang Mai, Thailand. Determinants of PrEP acceptability are needed to gauge the potential uptake of this prevention strategy.Methods
From January to February 2012, 238 MSM and TG participants, who self-reported as HIV-uninfected or of unknown status, completed a self-administered survey on hand-held computers. Participants were recruited by venue-day-time sampling and asked to rate their likelihood of using oral PrEP for HIV prevention with an efficacy of 50%. PrEP acceptability was defined as being “very likely” to use PrEP. Odds ratios and 95% CIs were calculated to identify correlates of acceptability.Results
131 MSM and 107 TG responded, with mean ages of 23.7 and 21.8, respectively. 24% of MSM engaged primarily in receptive anal sex vs. 74% of TG. 21% of MSM and 44% of TG reported regular medication use. Prior awareness of PrEP was high at 66% among both MSM and TG respondents. 41% of MSM and 37% of TG were "very likely" to use PrEP. Among MSM, factors associated with PrEP acceptability included a prior history of STIs (AOR 4.6; 95%CIs 1.7-12.6), previous HIV testing (AOR 2.4 95%CIs 1.1-5.3), regularly planned sex (AOR 2.8 95%CIs 1.1-7.2), and infrequent sex (AOR 2.9 95%CIs 1.3-6.3). Among TG, factors associated with acceptability included prior awareness of PrEP (AOR 3.3; 95%CIs 1.2-9.0) and having private insurance (AOR 5.0; 95%CIs 1.3-19.0).Conclusion
MSM and TG in Northern Thailand are distinct groups in terms of sexual behaviors, patterns of medication use, and correlates of PrEP acceptability. Efforts to maximize PrEP uptake should include expanded HIV testing services and the provision of financial subsidies to reduce the cost of PrEP. 相似文献865.
Eva C. Schulte Immanuel Stahl Darina Czamara Daniel C. Ellwanger Sebastian Eck Elisabeth Graf Brit Mollenhauer Alexander Zimprich Peter Lichtner Dietrich Haubenberger Walter Pirker Thomas Brücke Benjamin Bereznai Maria J. Molnar Annette Peters Christian Gieger Bertram Müller-Myhsok Claudia Trenkwalder Juliane Winkelmann 《PloS one》2013,8(11)
Approximately 20% of individuals with Parkinson’s disease (PD) report a positive family history. Yet, a large portion of causal and disease-modifying variants is still unknown. We used exome sequencing in two affected individuals from a family with late-onset familial PD followed by frequency assessment in 975 PD cases and 1014 ethnically-matched controls and linkage analysis to identify potentially causal variants. Based on the predicted penetrance and the frequencies, a variant in PLXNA4 proved to be the best candidate and PLXNA4 was screened for additional variants in 862 PD cases and 940 controls, revealing an excess of rare non-synonymous coding variants in PLXNA4 in individuals with PD. Although we cannot conclude that the variant in PLXNA4 is indeed the causative variant, these findings are interesting in the light of a surfacing role of axonal guidance mechanisms in neurodegenerative disorders but, at the same time, highlight the difficulties encountered in the study of rare variants identified by next-generation sequencing in diseases with autosomal dominant or complex patterns of inheritance. 相似文献
866.
Derryck Klarkowski Kathryn Glass Daniel O’Brien Kamalini Lokuge Erwan Piriou Leslie Shanks 《PloS one》2013,8(11)
Background
Recent trends to earlier access to anti-retroviral treatment underline the importance of accurate HIV diagnosis. The WHO HIV testing strategy recommends the use of two or three rapid diagnostic tests (RDTs) combined in an algorithm and assume a population is serologically stable over time. Yet RDTs are prone to cross reactivity which can lead to false positive or discordant results. This paper uses discordancy data from Médecins Sans Frontières (MSF) programmes to test the hypothesis that the specificity of RDTs change over place and time.Methods
Data was drawn from all MSF test centres in 2007-8 using a parallel testing algorithm. A Bayesian approach was used to derive estimates of disease prevalence, and of test sensitivity and specificity using the software WinBUGS. A comparison of models with different levels of complexity was performed to assess the evidence for changes in test characteristics by location and over time.Results
106, 035 individuals were included from 51 centres in 10 countries using 7 different RDTs. Discordancy patterns were found to vary by location and time. Model fit statistics confirmed this, with improved fit to the data when test specificity and sensitivity were allowed to vary by centre and over time. Two examples show evidence of variation in specificity between different testing locations within a single country. Finally, within a single test centre, variation in specificity was seen over time with one test becoming more specific and the other less specific.Conclusion
This analysis demonstrates the variable specificity of multiple HIV RDTs over geographic location and time. This variability suggests that cross reactivity is occurring and indicates a higher than previously appreciated risk of false positive HIV results using the current WHO testing guidelines. Given the significant consequences of false HIV diagnosis, we suggest that current testing and evaluation strategies be reviewed. 相似文献867.
Tomas Vega-Zuniga Felipe S. Medina Felipe Fredes Claudio Zuniga Daniel Severín Adrián G. Palacios Harvey J. Karten Jorge Mpodozis 《PloS one》2013,8(12)
Binocular vision is a visual property that allows fine discrimination of in-depth distance (stereopsis), as well as enhanced light and contrast sensitivity. In mammals enhanced binocular vision is structurally associated with a large degree of frontal binocular overlap, the presence of a corresponding retinal specialization containing a fovea or an area centralis, and well-developed ipsilateral retinal projections to the lateral thalamus (GLd). We compared these visual traits in two visually active species of the genus Octodon that exhibit contrasting visual habits: the diurnal Octodon degus, and the nocturnal Octodon lunatus. The O. lunatus visual field has a prominent 100° frontal binocular overlap, much larger than the 50° of overlap found in O. degus. Cells in the retinal ganglion cell layer were 40% fewer in O. lunatus (180,000) than in O. degus (300,000). O. lunatus has a poorly developed visual streak, but a well developed area centralis, located centrally near the optic disk (peak density of 4,352 cells/mm2). O. degus has a highly developed visual streak, and an area centralis located more temporally (peak density of 6,384 cells/mm2). The volumes of the contralateral GLd and superior colliculus (SC) are 15% larger in O. degus compared to O. lunatus. However, the ipsilateral projections to GLd and SC are 500% larger in O. lunatus than in O. degus. Other retinorecipient structures related to ocular movements and circadian activity showed no statistical differences between species. Our findings strongly suggest that nocturnal visual behavior leads to an enhancement of the structures associated with binocular vision, at least in the case of these rodents. Expansion of the binocular visual field in nocturnal species may have a beneficial effect in light and contrast sensitivity, but not necessarily in stereopsis. We discuss whether these conclusions can be extended to other mammalian and non-mammalian amniotes. 相似文献
868.
Shibu Yooseph Cynthia Andrews-Pfannkoch Aaron Tenney Jeff McQuaid Shannon Williamson Mathangi Thiagarajan Daniel Brami Lisa Zeigler-Allen Jeff Hoffman Johannes B. Goll Douglas Fadrosh John Glass Mark D. Adams Robert Friedman J. Craig Venter 《PloS one》2013,8(12)
Understanding the microbial content of the air has important scientific, health, and economic implications. While studies have primarily characterized the taxonomic content of air samples by sequencing the 16S or 18S ribosomal RNA gene, direct analysis of the genomic content of airborne microorganisms has not been possible due to the extremely low density of biological material in airborne environments. We developed sampling and amplification methods to enable adequate DNA recovery to allow metagenomic profiling of air samples collected from indoor and outdoor environments. Air samples were collected from a large urban building, a medical center, a house, and a pier. Analyses of metagenomic data generated from these samples reveal airborne communities with a high degree of diversity and different genera abundance profiles. The identities of many of the taxonomic groups and protein families also allows for the identification of the likely sources of the sampled airborne bacteria. 相似文献
869.
Sarah K. Oettl Jana Gerstmeier Shafaat Y. Khan Katja Wiechmann Julia Bauer Atanas G. Atanasov Clemens Malainer Ezzat M. Awad Pavel Uhrin Elke H. Heiss Birgit Waltenberger Daniel Remias Johannes M. Breuss Joel Boustie Verena M. Dirsch Hermann Stuppner Oliver Werz Judith M. Rollinger 《PloS one》2013,8(10)
In vitro screening of 17 Alpine lichen species for their inhibitory activity against 5-lipoxygenase, microsomal prostaglandin E2 synthase-1 and nuclear factor kappa B revealed Cetrelia monachorum (Zahlbr.) W.L. Culb. & C.F. Culb. As conceivable source for novel anti-inflammatory compounds. Phytochemical investigation of the ethanolic crude extract resulted in the isolation and identification of 11 constituents, belonging to depsides and derivatives of orsellinic acid, olivetolic acid and olivetol. The two depsides imbricaric acid (4) and perlatolic acid (5) approved dual inhibitory activities on microsomal prostaglandin E2 synthase-1 (IC50 = 1.9 and 0.4 µM, resp.) and on 5-lipoxygenase tested in a cell-based assay (IC50 = 5.3 and 1.8 µM, resp.) and on purified enzyme (IC50 = 3.5 and 0.4 µM, resp.). Additionally, these two main constituents quantified in the extract with 15.22% (4) and 9.10% (5) showed significant inhibition of tumor necrosis factor alpha-induced nuclear factor kappa B activation in luciferase reporter cells with IC50 values of 2.0 and 7.0 µM, respectively. In a murine in vivo model of inflammation, 5 impaired the inflammatory, thioglycollate-induced recruitment of leukocytes to the peritoneum. The potent inhibitory effects on the three identified targets attest 4 and 5 a pronounced multi-target anti-inflammatory profile which warrants further investigation on their pharmacokinetics and in vivo efficacy. 相似文献