Suchergebnisse

The basic reproduction number R0 and the effective reproduction number R are pivotal parameters in infectious disease epidemiology, quantifying the transmission potential of an infection in a population. We estimate both parameters from 13 pre-vaccination serological data sets on varicella zoster virus (VZV) in 12 European countries and from population-based social contact surveys under the commonly made assumptions of endemic and demographic equilibrium. The fit to the serology is evaluated using the inferred effective reproduction number R as a model eligibility criterion combined with AIC as a model selection criterion. For only 2 out of 12 countries, the common choice of a constant proportionality factor is sufficient to provide a good fit to the seroprevalence data. For the other countries, an age-specific proportionality factor provides a better fit, assuming physical contacts lasting longer than 15 min are a good proxy for potential varicella transmission events. In all countries, primary infection with VZV most often occurs in early childhood, but there is substantial variation in transmission potential with R0 ranging from 2.8 in England and Wales to 7.6 in The Netherlands. Two non-parametric methods, the maximal information coefficient (MIC) and a random forest approach, are used to explain these differences in R0 in terms of relevant country-specific characteristics. Our results suggest an association with three general factors: inequality in wealth, infant vaccination coverage and child care attendance. This illustrates the need to consider fundamental differences between European countries when formulating and parameterizing infectious disease models. ; ES acknowledges support from a Methusalem research grant from the Flemish Government. NG is beneficiary of a postdoctoral grant from the AXA Research Fund. NH acknowledges support from the Antwerp University scientific chair in Evidence-Based Vaccinology, financed in 2009-2014 by an unrestricted gift from Pfizer. AM is currently receiving funding from the European Research Council under the European Union's Seventh Framework Program(FP7/2007-2013)/ERC Starting Grant [Agreement No. 283955]. Support from the IAP Research Network P7/06 of the Belgian State(Belgian Science Policy) is gratefully acknowledged. The computational resources and services used in this work were provided by the Hercules Foundation and the Flemish Government - department EWI. This study was initiated as part of POLYMOD, a European Commission project funded within the Sixth Framework Programme, Contract number: SSP22-CT-2004-502084.

While multiple rodent preclinical studies, and to a lesser extent human clinical trials, claim the feasibility, safety, and potential clinical benefit of cell grafting in the central nervous system (CNS), currently only little convincing knowledge exists regarding the actual fate of the grafted cells and their effect on the surrounding environment (or vice versa). Our preceding studies already indicated that only a minor fraction of the initially grafted cell population survives the grafting process, while the surviving cell population becomes invaded by highly activated microglia/macrophages and surrounded by reactive astrogliosis. In the current study, we further elaborate on early cellular and inflammatory events following syngeneic grafting of eGFP(+) mouse embryonic fibroblasts (mEFs) in the CNS of immunocompetent mice. Based on obtained quantitative histological data, we here propose a detailed mathematically derived working model that sequentially comprises hypoxia-induced apoptosis of grafted mEFs, neutrophil invasion, neoangiogenesis, microglia/macrophage recruitment, astrogliosis, and eventually survival of a limited number of grafted mEFs. Simultaneously, we observed that the cellular events following mEF grafting activates the subventricular zone neural stem and progenitor cell compartment. This proposed model therefore further contributes to our understanding of cell graft-induced cellular responses and will eventually allow for successful manipulation of this intervention. ; This work was supported by research grants G.0136.11 and G.0130.11 (granted to Zwi Berneman, Annemie Van der Linden, and Peter Ponsaerts) of the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium), in part by a Methusalem research grant from the Flemish government (granted to Zwi Berneman and Herman Goossens) and in part by funding received from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 278850 (INMiND; granted to Annemie Van der Linden). Debbie Le Blon holds a Ph.D.-studentship from the Flemish Institute for Science and Technology (IWT-Vlaanderen). Chloe Hoornaert holds a Ph.D.-studentship from the FWO-Vlaanderen. The authors declare no conflict of interest.

Following the onset of the ongoing COVID-19 pandemic throughout the world, a large fraction of the global population is or has been under strict measures of physical distancing and quarantine, with many countries being in partial or full lockdown. These measures are imposed in order to reduce the spread of the disease and to lift the pressure on healthcare systems. Estimating the impact of such interventions as well as monitoring the gradual relaxing of these stringent measures is quintessential to understand how resurgence of the COVID-19 epidemic can be controlled for in the future. In this paper we use a stochastic age-structured discrete time compartmental model to describe the transmission of COVID-19 in Belgium. Our model explicitly accounts for age-structure by integrating data on social contacts to (i) assess the impact of the lockdown as implemented on March 13, 2020 on the number of new hospitalizations in Belgium; (ii) conduct a scenario analysis estimating the impact of possible exit strategies on potential future COVID-19 waves. More specifically, the aforementioned model is fitted to hospital admission data, data on the daily number of COVID-19 deaths and serial serological survey data informing the (sero)prevalence of the disease in the population while relying on a Bayesian MCMC approach. Our age-structured stochastic model describes the observed outbreak data well, both in terms of hospitalizations as well as COVID-19 related deaths in the Belgian population. Despite an extensive exploration of various projections for the future course of the epidemic, based on the impact of adherence to measures of physical distancing and a potential increase in contacts as a result of the relaxation of the stringent lockdown measures, a lot of uncertainty remains about the evolution of the epidemic in the next months. ; We thank several researchers from the SIMID COVID-19 consortium from the University of Antwerp and Hasselt University for numerous constructive discussions and meetings. SA and NH gratefully acknowledge support from the Research Foundation Flanders (FWO), Belgium (RESTORE project — G0G2920N). This work also received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (PC and NH, grant number 682540 – TransMID project, NH, PB grant number 101003688 – EpiPose project). The authors are also very grateful for access to the data from the Belgian Scientific Institute for Public Health, Sciensano, and from the Vaccine & Infectious Disease Institute (VaxInfectio), University of Antwerp. LW and PL gratefully acknowledge funding from the Research Foundation Flanders, Belgium (postdoctoral fellowships 1234620N and 1242021N). We acknowledge support from the Antwerp Study Centre for Infectious Diseases (ASCID). The resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the FWO and the Flemish Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors contributed to the final version of the paper and approved the final version of the manuscript.

Despite long-standing two-dose measles-mumpsrubella (MMR) vaccination, measles outbreaks still occur in highly vaccinated European populations. For instance, large measles outbreaks occurred in France (2008–13), the United Kingdom (2012–13) and the Netherlands (2012). Based on a multicohort model approach, using spatial serological survey data, MMR vaccination coverage data and data on social contacts, we found effective reproduction numbers significantly higher than 1 for measles in Belgium. This indicates that at one of the expected re-introductions, a measles outbreak is likely to spread, especially when it occurs during school term. The predicted average effective reproduction number increased over a 30-year time span from 1.3 to 2.2 and from 1.9 to 3.2 for basic reproduction numbers of 12 and 18, respectively. The expected relative measles incidence was highest in infants under one year of age, in adolescents and young adults. In conclusion, gradually increasing proportions of susceptible adolescents and young adults provide through their highly active social life an avenue for measles to resurge in large outbreaks upon re-introduction in Belgium, especially during school terms. Infants form an important vulnerable group during future measles outbreaks. ; The authors would like to acknowledge the colleagues of the Flemish Agency for Care and Health, the Scientific Institute of Public Health and the measles elimination committee for fruitful discussions related to this research. NH acknowledges support of the University of Antwerp Scientific Chair in Evidence-based Vaccinology sponsored in 2009-2014 by a gift from Pfizer. SA acknowledges support by the Research Fund of Hasselt University (Grant BOF11NI31). ES and HG acknowledge support from a Methusalem research grant from the Flemish government. NG is beneficiary of a postdoctoral grant from the AXA Research Fund. Support from the IAP Research Network P7/06 of the Belgian State (Belgian Science Policy) is gratefully acknowledged. HT and EL are postdoctoral researchers for the Fund of Scientific Research - Flanders (FWO). The computational resources and services used in this work were provided by the Hercules Foundation and the Flemish Government - department EWI.

Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (H-1-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a wellestablished mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX(3)CL1/CX(3)CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX(3)CR1(+/-) C57BL/6 mice and wild type CX3CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1(-/-) C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing cuprizone-treated CX3CR1(-/-) mice showing mild demyelination with cuprizone-treated CX3CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, H-1-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizoneinduced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright (C) 2015 John Wiley & Sons, Ltd. ; This work was supported by research grants G.0136.11 and G.0130.11 (granted to ZB, AVdL and PP) of the Fund for Scientific Research - Flanders (FWO - Vlaanderen, Belgium) and in addition by an "FWO - Krediet aan Navorsers" grant of the Fund for Scientific Research - Flanders (FWO -Vlaanderen, Belgium, granted to MV); next, by a Methusalem research grant from the Flemish government (granted to ZB) and in part by funding received from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 278850 (INMiND) (granted to AVdL). Caroline Guglielmetti is holder of an IWT PhD grant (Institute for the Promotion of Innovation through Science and Technology in Flanders, IWT - Vlaanderen). Firat Kara is holder of an "FWO - Postdoc" grant of the Fund for Scientific Research - Flanders (FWO - Vlaanderen, Belgium). MRI equipment was funded by the Flemish Impulse funding for heavy scientific equipment (granted to AVdL).

Although intracerebral transplantation of various fibroblast(-like) cell populations has been shown feasible, little is known about the actual in vivo remodeling of these cellular grafts and their environment. In this study, we aimed to compare the in vitro and in vivo behavior of two phenotypically similar but developmentally distinct fibroblast-like cell populations, namely, mouse embryonic fibroblasts (mEFs) and mouse fetal membrane-derived stromal cells (mFMSCs). While both mEFs and mFMSCs are readily able to reduce TNF-alpha secretion by LPS/IFN-gamma-activated BV-2 microglia, mFMSCs and mEFs display strikingly opposite behavior with regard to VEGF production under normal and inflammatory conditions. Whereas mFMSCs downregulate VEGF production upon coculture with LPS/IFN-gamma-activated BV-2 microglia, mEFs upregulate VEGF production in the presence of LPS/IFN-gamma-activated BV-2 microglia. Subsequently, in vivo grafting of mFMSCs and IDEFs revealed no difference in microglial and astroglial responses toward the cellular grafts. However, mFMSC grafts displayed a lower degree of neoangiogenesis compared to mEF grafts, thereby potentially explaining the lower cell number able to survive in mFMSC grafts. In summary, our results suggest that physiological differences between fibroblast-like cell populations might lie at the basis of variations in histopathological and/or clinical outcome following cell grafting in mouse brain. ; This work was supported by research grants G.0136.11 and G.0130.11 (granted to Z.B. and P.P.) of the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium) and in part by a Methusalem research grant from the Flemish government (granted to Z.B. and H.G.). Nathalie De Vocht and Chloe Hoornaert hold a Ph.D.-studentship from the FWO-Vlaanderen. Debbie Le Blon holds a Ph.D.-studentship from the Flemish Institute for Science and Technology (IWT). The authors declare no conflicts of interest.

Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T-2-weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination. Second, following IL-13 immune gene therapy in cuprizone-treated eGFP(+) bone marrow chimeric mice, we provide evidence that IL-13 directs the polarization of both brain-resident microglia and infiltrating macrophages towards an alternatively activated phenotype, thereby promoting the conversion of a pro-inflammatory environment toward an anti-inflammatory environment, as further evidenced by gene expression analyses. Finally, we show that IL-13 immune gene therapy is also able to limit lesion severity in a pre-existing inflammatory environment. In conclusion, these results highlight the potential of IL-13 to modulate microglia/macrophage responses and to improve disease outcome in a mouse model for MS. ; This work was supported by research grants G.0136.11 (granted to PP, AVDL and ZB), G.0130.11 (granted to PP, AVDL and ZB) and G.0834.11 (granted to PP and SH) of the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium), in part by a Methusalem research grant from the Flemish government (granted to HG), in part by funding received from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 278850 (INMiND) (granted to AVdL and AMP), in part by the Brainpath project (MSCA IAPP project granted to AVdL) and in part by funding received from the Belgian Charcot Foundation (granted to PP and AVdL). DLB, DS and CG hold a PhD-studentship from the Flemish Institute for Science and Technology (IWT-Vlaanderen). NDV and CH hold a PhD-studentship from the FWO-Vlaanderen. FK and JP hold a post-doctoral fellowship from the FWO-Vlaanderen.