Regulatory T Cells in Chronic Hepatitis B Virus Infection

Worldwide 400 million people suffer from chronic hepatitis B virus (HBV) infection and approximately 1 million people die annually from HBV-related disease. To clear HBV, an effective immune response, in which several cell types and cytokines play a role, is important. It is known that patients who develop a chronic infection lack the vigorous multi-specifi c T cell response with a type 1 cytokine profi le necessary to clear the virus. One cell type that could play a role in the absence of an adequate T cell response are CD4+CD25+ regulatory T cells (Treg). These Treg are capable of inhibiting the adaptive T cell response. In chapter 2 of this thesis the proportion of Treg in the peripheral blood of patients with a chronic HBV infection, individuals with a resolved HBV infection and healthy controls was compared. Patients with a chronic HBV infection showed an increased proportion of peripheral blood Treg compared to the two other groups. Depletion of Treg resulted in an enhanced in vitro response to HBV core antigen (HBcAg). Reconstitution of Treg-depleted cells with isolated Treg showed that Treg inhibited the proliferation and interferon (IFN)-γ production to HBcAg in a dose dependent manner. Therefo

The Relationship between Strategic Information Systems Planning Situational Factors, Process Configuration and Success

This paper reports a study into the relationship between the configuration of the process of Strategic Information Systems Planning (SISP) and the success of SISP. SISP is an important activity in the alignment of information technology systems and services to business requirements. However, despite the obvious importance of a proper planning of information technology and information systems in organizations, success of SISP is not evident. And as the success of SISP is also influenced by the process followed in developing the SISP, the research question for this study was, “How does the configuration of the SISP process influence the success of the SISP?” Based on an explorative multi case study, we concluded that the specificity and comprehensiveness of strategies, goals and decisions in an organization has a positive effect on the success of SISP. Another conclusion was that a more dominant role of the IS/IT organization in the SISP process influences the quality of the SISP deliverable positively, but has a negative effect on the building of partnership between business and IT in the organization. A final conclusion was that following a formal SISP methodology does not seem to have an effect on the success of SISP. These findings provide guidance for practitioners that plan to develop an SISP as part of their efforts to align business and IT

Ebola virus glycoprotein stimulates IL-18 dependent natural killer cell responses

BACKGROUNDNK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined.METHODSThe novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analyzed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen and in response to in vitro Ebola glycoprotein stimulation of PBMCs isolated before and after vaccination.RESULTSWe show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whereas IFN-γ secretion was restricted by high concentrations of IL-10.CONCLUSIONThis study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein.TRIAL REGISTRATIONClinicalTrials.gov NCT02313077.FUNDINGUnited Kingdom Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (grant 115861) and Crucell Holland (now Janssen Vaccines and Prevention B.V.), European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA)

Antibody-Dependent Natural Killer Cell Activation after Ebola Vaccination

BACKGROUND:Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein antibodies suggest that Fc-dependent activation of effector cells, including NK cells, could play a role in vaccination against Ebola virus disease. METHODS:We analysed the effect of anti-Ebola glycoprotein antibody in the serum of U.K.-based volunteers vaccinated with the novel 2-dose heterologous Adenovirus type 26.ZEBOV, Modified Vaccinia Ankara-BN-Filo vaccine regimen, on primary human NK cell activation. RESULTS:We demonstrate primary human NK cell CD107a and IFN-γ expression, combined with downregulation of CD16, in response to recombinant Ebola virus glycoprotein and post-vaccine dose 1 and dose 2 sera. These responses varied significantly with vaccine regimen and NK cell activation was found to correlate with anti-glycoprotein antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive. CONCLUSIONS:This study thus highlights the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses

Durable natural killer cell responses after heterologous two-dose Ebola vaccination

Natural killer (NK) cells are implicated among immune effectors after vaccination against viral pathogens, including Ebola virus. The two-dose heterologous Ebola virus vaccine regimen, adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo (EBOVAC2 consortium, EU Innovative Medicines Initiative), induces NK cell activation and anti-Ebola glycoprotein (GP) antibody-dependent NK cell activation post-dose 1, which is further elevated post-dose 2. Here, in a multicentre, phase 2 clinical trial (EBL2001), we demonstrate durable ex vivo NK cell activation 180 days after dose 2, with responses enriched in CD56(bright) NK cells. In vitro antibody-dependent responses to immobilised Ebola GP increased after dose 1, and remained elevated compared to pre-vaccination levels in serum collected 180 days later. Peak NK cell responses were observed post-dose 2 and NK cell IFN-γ responses remained significantly elevated at 180 days post-dose 2. Individual variation in NK cell responses were influenced by both anti-Ebola GP antibody concentrations and intrinsic interindividual differences in NK cell functional capacity. In summary, this study demonstrates durable NK cell responses after Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccination and could inform the immunological evaluation of future iterations of the vaccine regimen and vaccination schedules

Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair and mild palmoplantar keratoderma, but without a cardiac phenotype, we identified a homozygous splice site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of tuftelin 1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients' phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma

Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair and mild palmoplantar keratoderma, but without a cardiac phenotype, we identified a homozygous splice site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of tuftelin 1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients' phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma.</p

Suitability and managerial implications of a Master Surgical Scheduling approach

Abstract: Operating room (OR) planning and scheduling is a popular and challenging subject within the operational research applied to health services research (ORAHS). However, the impact in practice is very limited. The organization and culture of a hospital and the inherent characteristics of its processes impose specific implementation issues that affect the success of planning approaches. Current tactical OR planning approaches often fail to account for these issues.Master surgical scheduling (MSS) is a promising approach for hospitals to optimize resource utilization and patient flows. We discuss the pros and cons of MSS and compare MSS with centralized and decentralized planning approaches. Finally, we address various implementation issues of MSS and discuss its suitability for hospitals with different organizational foci and culture

Measuring well-being in the Netherlands: The SCP index from 1974 to 1997

index of well-being, living conditions, living conditions index, Netherlands, SCP (Social and Cultural Planning Office), social indicators, well-being,

Revive the pride : social process, political economy and a fan-based grassroots movement

Europeanen krijgen steeds meer met elkaar te maken, zo maakte een aantal ontwikkelingen ook in 2015 weer duidelijk. De economische crisis, de solidariteit tussen landen en de houding tegenover migranten en asielzoekers raken de kern van Europese integratie en verbondenheid. In welke mate zijn burgers en landen in Europa solidair en bereid elkaar te helpen? Of breder gezien: in welke mate is er in Europa sprake van gelijksoortige opinies, waarden en normen? In deze publicatie kijken we naar gedeelde en niet-gedeelde opinies, houdingen, waarden en normen in Europa. We vergelijken de stemming in Nederland met de stemming in andere Europese landen. Dat doen we op basis van het European Social Survey, een grootschalig tweejaarlijks onderzoek dat zich richt op de oordelen en waarden van mensen. In totaal hebben 36 landen minimaal eenmaal meegedaan, en 16 landen in alle zes ronden van 2002 tot en met 2013. We peilen de stemming in Europa breed en kijken naar onder meer meningen over de democratie, vertrouwen in andere mensen en tevredenheid met het leven. Op dat laatste gaan we dieper in, evenals op opvattingen over migranten, politiek vertrouwen en het oordeel van mannen en vrouwen over het verdelen van werk en gezinstaken. We laten zien hoe de stemming in Europa zich tussen 2002 en 2013 heeft ontwikkeld en hoe de meningen en opinies van Nederlanders lijken op die van andere Europeanen, of juist daarvan afwijken. Jeroen Boelhouwer werkt bij de onderzoeksgroep Participatie, Cultuur en Leefomgeving van het SCP. Hij doet onderzoek naar kwaliteit van leven, leefsituatie en geluk.. Gerbert Kraaykamp is hoogleraar bij de sectie sociologie van de Radboud Universiteit en tevens  directeur van het Nijmegen Institute for Social and Cultural Research. Sinds 2013 is hij de Nationaal Coördinator van het European Social Survey in Nederland. Ineke Stoop is senior methodoloog bij het SCP en houdt zich daar vooral bezig met de kwaliteit van data. Ze is ook Deputy Director Methodological van het European Social Survey