Innate Immune Responses in Viral Hepatitis: the role of Kupffer cells and liver-derived monocytes in shaping intrahepatic immunity in mice using the LCMV infection model

__Abstract__ This study was performed to elucidate the immunological role of the liver in viral hepatitis. The immune functions of the liver are shaped by the intrahepatic cells present during steady state condition, as well as the recruited immune cells during liver inflammation. Liver resident Kupffer cells, by performing endocytosis, determine the functionality of the liver as a filtering organ. Additionally, Kupffer cells produce IL-10. This function, regulated by Ctcf, suggests the potential of Kupffer cells to perform immunoregulation. Monocytes patrol the liver in the steady state, but accumulate in the liver during viral hepatitis. They show functional versatility as demonstrated in the distinct polarization towards TNF-producing and endocytic cells in LCMV-infected and LPS-treated livers, respectively. During LCMV-induced hepatitis, fractions of both Kupffer cells and inflammatory monocytes alter their F4/80 expression, posing a challenge in immunological studies using flow cytometry. Furthermore, in this study we describe distinct clinical responses induced by TLR7 treatment at different phases of LCMV infection, which are associated with distinct states of immune activation. Results from our study contribute to better understand the regulation of intrahepatic immune responses in the steady state condition and during viral hepatitis. Better insights in the functions of Kupffer cells and inflammatory monocytes will open up their potential to be targeted by HBV and HCV therapy. Furthermore, this study emphasizes the importance of characterizing the intrahepatic immune responses during chronic viral hepatitis to understand the mechanisms for the induction of adverse side-effects by TLR7 treatment. This information is valuable in order to prevent or predict the clinical outcome of TLR7-based treatment of HBV or HCV patients. Although this need to be validated in more detail, our findings suggest the significance of evaluating the TLR7 expression levels, either intrahepatic or systemic, in chronically infected patients prior to TLR7 treatment to minimalize the occurrence of adverse side-effects

Children's Databases - Safety and Privacy

This report describes in detail the policy background, the systems that are being built, the problems with them, and the legal situation in the UK. An appendix looks at Europe, and examines in particular detail how France and Germany have dealt with these issues. Our report concludes with three suggested regulatory action strategies for the Commissioner: one minimal strategy in which he tackles only the clear breaches of the law, one moderate strategy in which he seeks to educate departments and agencies and guide them towards best practice, and finally a vigorous option in which he would seek to bring UK data protection practice in these areas more in line with normal practice in Europe, and indeed with our obligations under European law

The CRISP colorectal cancer risk prediction tool: an exploratory study using simulated consultations in Australian primary care

Abstract Background In Australia, screening for colorectal cancer (CRC) with colonoscopy is meant to be reserved for people at increased risk, however, currently there is a mismatch between individuals’ risk of CRC and the type of CRC screening they receive. This paper describes the development and optimisation of a Colorectal cancer RISk Prediction tool (‘CRISP’) for use in primary care. The aim of the CRISP tool is to increase risk-appropriate CRC screening. Methods CRISP development was informed by previous experience with developing risk tools for use in primary care and a systematic review of the evidence. A CRISP prototype was used in simulated consultations by general practitioners (GPs) with actors as patients. GPs were interviewed to explore their experience of using CRISP, and practice nurses (PNs) and practice managers (PMs) were interviewed after a demonstration of CRISP. Transcribed interviews and video footage of the ‘consultations’ were qualitatively analyzed. Themes arising from the data were mapped onto Normalization Process Theory (NPT). Results Fourteen GPs, nine PNs and six PMs were recruited from 12 clinics. Results were described using the four constructs of NPT: 1) Coherence: Clinicians understood the rationale behind CRISP, particularly since they were familiar with using risk tools for other conditions; 2) Cognitive participation: GPs welcomed the opportunity CRISP provided to discuss healthy and unhealthy behaviors with their patients, but many GPs challenged the screening recommendation generated by CRISP; 3) Collective Action: CRISP disrupted clinician-patient flow if the GP was less comfortable with computers. GP consultation time was a major implementation barrier and overall consensus was that PNs have more capacity and time to use CRISP effectively; 4) Reflexive monitoring: Limited systematic monitoring of new interventions is a potential barrier to the sustainable embedding of CRISP. Conclusions CRISP has the potential to improve risk-appropriate CRC screening in primary care but was considered more likely to be successfully implemented as a nurse-led intervention

The algebra of lexical semantics

Abstract. The current generative theory of the lexicon relies primar-ily on tools from formal language theory and mathematical logic. Here we describe how a different formal apparatus, taken from algebra and automata theory, resolves many of the known problems with the gener-ative lexicon. We develop a finite state theory of word meaning based on machines in the sense of Eilenberg [11], a formalism capable of de-scribing discrepancies between syntactic type (lexical category) and se-mantic type (number of arguments). This mechanism is compared both to the standard linguistic approaches and to the formalisms developed in AI/KR. 1 Problem Statement In developing a formal theory of lexicography our starting point will be the informal practice of lexicography, rather than the more immediately related for-mal theories of Artificial Intelligence (AI) and Knowledge Representation (KR). Lexicography is a relatively mature field, with centuries of work experience an

Expressiveness of Temporal Query Languages: On the Modelling of Intervals, Interval Relationships and States

Storing and retrieving time-related information are important, or even critical, tasks on many areas of Computer Science (CS) and in particular for Artificial Intelligence (AI). The expressive power of temporal databases/query languages has been studied from different perspectives, but the kind of temporal information they are able to store and retrieve is not always conveniently addressed. Here we assess a number of temporal query languages with respect to the modelling of time intervals, interval relationships and states, which can be thought of as the building blocks to represent and reason about a large and important class of historic information. To survey the facilities and issues which are particular to certain temporal query languages not only gives an idea about how useful they can be in particular contexts, but also gives an interesting insight in how these issues are, in many cases, ultimately inherent to the database paradigm. While in the area of AI declarative languages are usually the preferred choice, other areas of CS heavily rely on the extended relational paradigm. This paper, then, will be concerned with the representation of historic information in two well known temporal query languages: it Templog in the context of temporal deductive databases, and it TSQL2 in the context of temporal relational databases. We hope the results highlighted here will increase cross-fertilisation between different communities. This article can be related to recent publications drawing the attention towards the different approaches followed by the Databases and AI communities when using time-related concepts

Liver monocytes and kupffer cells remain transcriptionally distinct during chronic viral infection

Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt cli

Mineral chemistry of igneous melanite garnets from analcite-bearing volcanic rocks, Alberta, Canada

The mineral chemistry of melanite garnets from the Crowsnest volcanic rocks of SW Alberta, Canada, has been investigated by using electron microprobe scans, quantitative analyses and multivariate statistical analysis. The garnets occur with aegirine-augite, sanidine, analcite and rare plagioclase as phenocrysts in trachyte and phonolite flows, agglomerates and tuffs. Wavelength dispersive microprobe scans reveal complex zonation patterns, both normal and oscillatory. The results of fifty quantitative analyses were subjected to R-mode factor analysis to delineate the chemical exchanges producing the zonation. The chemical zonation of the garnets may be attributed to four independent binary exchanges; Al-Fe3+, Si-Ti, Ca-Mn and Mg-Fe2+. The stoichiometry of these garnets, based on microprobe and wet chemical Fe analyses, combined with the strongly antithetic behavior of Si and Ti lead us to infer that the Ti in these garnets is dominantly tetravalent. It is clear from this study that quantitative modelling of the processes of crystal growth and zonation of melanite garnets in alkaline, undersaturated igneous rocks should be aimed at simulating the four chemical exchanges listed above

Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population

Children's databases - safety and privacy: a report for the information commissioner

The Foundation for Information Policy Research (FIPR) was awarded a tender by the Information Commissioner to undertake a research project on ‘identifying the growth in children’s databases and assessing the data protection and privacy implications’. Its aim is to provide the Commissioner with a comprehensive view of current and proposed databases, particularly in the public sector, their extent, their role, and their potential effect on the privacy of individuals. It is also to provide an authoritative basis from which the Commissioner can develop his policy on data protection, and contribute more widely to the debate on this issue, and to public policy generally

A cross dialectal view of the Arabic dative alternation

This paper is concerned with the syntax of ditransitive verbs in Arabic.We concentrate on the vernaculars, focussing in particular on three geographically spread dialects: Egyptian Cairene Arabic, the dominant vernacular in Egypt, Hijazi Arabic, spoken in Western Saudi Arabia and Maltese, a mixed language with a Magrebi/Siculo-Arabic stratum. We show that all three exhibit an alternation (the dative alternation) between a ditransitive ('double object') construction and a corresponding prepositional dative construction, and outline a number of differences between these constructions in the different varieties of Arabic. We consider the distribution of verbs exhibiting the dative alternation in the light of Ryding's (2011) observations concerning Modern Standard Arabic