Determinants of biological activity of nanomaterials in innate immunity cells: the role of aspect ratio, environmental contaminants and protein corona

As defined by the European Union, “ ’Nanomaterial’ (NM) means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or agglomerate, where, for 50 % or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm-100 nm ” (2011/696/UE). Given their peculiar physico-chemical features, nanostructured materials are largely used in many industrial fields (e.g. cosmetics, electronics, agriculture, biomedical) and their applications have astonishingly increased in the last fifteen years. Nanostructured materials are endowed with very large specific surface area that, besides making them very useful in many industrial processes, renders them very reactive towards the biological systems and, hence, potentially endowed with significant hazard for human health. For these reasons, in recent years, many studies have been focused on the identification of toxic properties of nanostructured materials, investigating, in particular, the mechanisms behind their toxic effects as well as their determinants of toxicity. This thesis investigates two types of nanostructured TiO2 materials, TiO2 nanoparticles (NP), which are yearly produced in tonnage quantities, and TiO2 nanofibres (NF), a relatively novel nanomaterial. Moreover, several preparations of MultiWalled Carbon Nanotubes (MWCNT), another nanomaterial widely present in many products, are also investigated.- Although many in vitro and in vivo studies have characterized the toxic properties of these materials, the identification of their determinants of toxicity is still incomplete. The aim of this thesis is to identify the structural determinants of toxicity, using several in vitro models. Specific fields of investigation have been a) the role of shape and the aspect ratio in the determination of biological effects of TiO2 nanofibres of different length; b) the synergistic effect of LPS and TiO2 NP on the expression of inflammatory markers and the role played therein by TLR-4; c) the role of functionalization and agglomeration in the biological effects of MWCNT. As far as biological effects elicited by TiO2 NF are concerned, the first part of the thesis demonstrates that long TiO2 nanofibres caused frustrated phagocytosis, cytotoxicity, hemolysis, oxidative stress and epithelial barrier perturbation. All these effects were mitigated by fibre shortening through ball-milling. However, short TiO2 NF exhibited enhanced ability to activate acute pro-inflammatory effects in macrophages, an effect dependent on phagocytosis. Therefore, aspect ratio reduction mitigated toxic effects, while enhanced macrophage activation, likely rendering the NF more prone to phagocytosis. These results suggest that, under in vivo conditions, short NF will be associated with acute inflammatory reaction, but will undergo a relatively rapid clearance, while long NF, although associated with a relatively smaller acute activation of innate immunity cells, are not expected to be removed efficiently and, therefore, may be associated to chronic inflammatory responses. As far as the relationship between the effects of TiO2 NP and LPS, investigated in the second part of the thesis, are concerned, TiO2 NP markedly enhanced macrophage activation by LPS through a TLR-4-dependent intracellular pathway. The adsorption of LPS onto the surface of TiO2 NP led to the formation of a specific bio-corona, suggesting that, when bound to TiO2 NP, LPS exerts a much more powerful pro-inflammatory effect. These data suggest that the inflammatory changes observed upon exposure to TiO2 NP may be due, at least in part, to their capability to bind LPS and, possibly, other TLR agonists, thus enhancing their biological activities. Finally, the last part of the thesis demonstrates that surface functionalization of MWCNT with amino or carboxylic groups mitigates the toxic effects of MWCNT in terms of macrophage activation and capability to perturb epithelial barriers. Interestingly, surface chemistry (in particular surface charge) influenced the protein adsorption onto the MWCNT surface, allowing to the formation of different protein coronae and the tendency to form agglomerates of different size. In particular functionalization a) changed the amount and the type of proteins adsorbed to MWCNT and b) enhanced the tendency of MWCNT to form large agglomerates. These data suggest that the different biological behavior of functionalized and pristine MWCNT may be due, at least in part, to the different tendency to form large agglomerates, which is significantly influenced by their different capability to interact with proteins contained in biological fluids. All together, these data demonstrate that the interaction between physico-chemical properties of nanostructured materials and the environment (cells + biological fluids) in which these materials are present is of pivotal importance for the understanding of the biological effects of NM. In particular, bio-persistence and the capability to elicit an effective inflammatory response are attributable to the interaction between NM and macrophages. However, the interaction NM-cells is heavily influenced by the formation at the nano-bio interface of specific bio-coronae that confer a novel biological identity to the nanostructured materials, setting the basis for their specific biological activities.

Cause, effect and benefits of a standardised corporate visual identity system of UK companies operating in Malaysia

Investigates the degree of global standardisation of a corporate visual identity system (CVIS) in multinational operations. A special emphasis of this research is accorded to UK companies operating in Malaysia. In particular, the study seeks to reveal the reasons for developing a standardised CVIS; the behavioural issues associated with CVIS; and the determination in selecting a graphic design agency. The findings of the research revealed that multinational corporations in an increasingly corporate environment adopted a standardised CVIS for several reasons, including, aiding the sale of products and services, creating an attractive environment for hiring employees, and increasing the company’s stature and presence. Further findings show that the interest in global identity was stimulated by global restructuring, merger or acquisition. The above trends help explain why increased focus has been accorded to CVIS over the past five years by many UK companies operating in Malaysia. Additional findings reveal that both the UK design agencies and in-house design department are used in the development of the firms’ CVIS.

Type 2 diabetes:assessing the relative risks and benefits of glucose-lowering medications

The selection of appropriate pharmacologic therapy for any disease requires a careful assessment of benefit and risk. In the case of type 2 diabetes, this decision typically balances the benefits accrued from improved glycemic control with the risks inherent in glucose-lowering medications. This review is intended to assist therapeutic decision-making by carefully assessing the potential benefit from improved metabolic control relative to the potential risks of a wide array of currently prescribed glucose-lowering agents. Wherever possible, risks and benefits have been expressed in terms of absolute rates (events per 1000 patient-years) to facilitate cross-study comparisons. The review incorporates data from new studies (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation, Action to Control Cardiovascular Risk in Diabetes, and the Veterans Affairs Diabetes Trial), as well as safety issues associated with newer glucose-lowering medications. © 2010 Elsevier Inc. All rights reserved.

The influence of fixation points on contrast detection and discrimination of patches of grating: Masking and facilitation

The use of fixation points (FPs) in visual psychophysics is common practice, though the costs and benefits of different fixation regimens have not been compared. Here we investigate the influence of several different types of FP configurations on the contrast detection of patches of sine-wave gratings. We find that for small targets (1°), the addition of a superimposed central FP can increase thresholds by a factor of 1.3 (2.5 dB) in comparison with no FP, and a factor of 1.5 (3.6 dB) in comparison with FPs that surround the target. These results are consistent with (i) a suppressive influence on the central region of the target from a central FP, and (ii) facilitatory influences from surrounding FPs. Our analysis of the slope of the psychometric function suggests that the facilitatory influence is not due to reduction of uncertainty. Plausible candidate causes for the facilitation are: (i) sensory interactions, (ii) aids to ocular accommodation and convergence, (iii) a reduction in eye-movements and (iv) more accurate placement of the observer’s window of attention. Masking by a central FP is not found for the suprathreshold task of contrast discrimination, suggesting that the masking effects of pedestal and FP do not combine linearly. This means that estimates of the level of masking produced by a contrast pedestal can depend on the details of the fixation point.

Rural road accidents in Iran: analysis, comparison and the cost

In the general introduction of the road-accident phenomenon inside and outside Iran, the results of previous research-works and international conferences and seminars on road-safety have been reviewed. Also a sample-road between Tehran and Mashad has been investigated as a case-study. Examining the road-accident data and iriformation,first: the information presented in road-accident report-forms in developed countries is discussed and, second: the procedures for road-accident data collection in Iran are investigated in detail. The data supplied by Iran Road-Police Central Statistics Office, is analysed, different rates are computed, due comparisons with other nations are made, and the results are discussed. Also such analysis and comparisons are presented for different provinces of Iran. It is concluded that each province with its own natural, geographical, social and economical characteristics possesses its own reasons for the quality and quantity of road-accidents and therefore must receive its own appropriate remedial solutions. The question~ of "what is the cost of road-accidents", "why and how evaluate the cost", "what is the appropriate way of approach to such evaluation" are all discussed and then "the cost of road-accidents in Iran" based on two different approaches: "Gross National Output"and "court award" is computed. It is concluded that this cost is about 1.5 per cent of the country's national product. In Appendix 3 an impressive example is given of the trend of costs and benefits that can be attributed to investment in road-safety measures.

Priority evaluation in transportation policies and programmes

This work is concerned with the development of techniques for the evaluation of large-scale highway schemes with particular reference to the assessment of their costs and benefits in the context of the current transport planning (T.P.P.) process. It has been carried out in close cooperation with West Midlands County Council, although its application and results are applicable elsewhere. The background to highway evaluation and its development in recent years has been described and the emergence of a number of deficiencies in current planning practise noted. One deficiency in particular stood out, that stemming from inadequate methods of scheme generation and the research has concentrated upon improving this stage of appraisal, to ensure that subsequent stages of design, assessment and implementation are based upon a consistent and responsive foundation. Deficiencies of scheme evaluation were found to stem from inadequate development of appraisal methodologies suffering from difficulties of valuation, measurement and aggregation of the disparate variables that characterise highway evaluation. A failure to respond to local policy priorities was also noted. A 'problem' rather than 'goals' based approach to scheme generation was taken, as it represented the current and foreseeable resource allocation context more realistically. A review of techniques with potential for highway problem based scheme generation, which would work within a series of practical and theoretical constraints were assessed and that of multivariate analysis, and classical factor analysis in particular, was selected, because it offerred considerable application to the difficulties of valuation, measurement and aggregation that existed. Computer programs were written to adapt classical factor analysis to the requirements of T.P.P. highway evaluation, using it to derive a limited number of factors which described the extensive quantity of highway problem data. From this, a series of composite problem scores for 1979 were derived for a case study area of south Birmingham, based upon the factorial solutions, and used to assess highway sites in terms of local policy issues. The methodology was assessed in the light of its ability to describe highway problems in both aggregate and disaggregate terms, to guide scheme design, coordinate with current scheme evaluation methods, and in general to improve upon current appraisal. Analysis of the results was both in subjective, 'common-sense' terms and using statistical methods to assess the changes in problem definition, distribution and priorities that emerged. Overall, the technique was found to improve upon current scheme generation methods in all respects and in particular in overcoming the problems of valuation, measurement and aggregation without recourse to unsubstantiated and questionable assumptions. A number of deficiencies which remained have been outlined and a series of research priorities described which need to be reviewed in the light of current and future evaluation needs.

Costs and efficiency of higher education institutions in England:a DEA analysis

As student numbers in higher education in the UK have expanded during recent years, it has become increasingly important to understand its cost structure. This study applies Data Envelopment Analysis (DEA) to higher education institutions in England to assess their cost structure, efficiency and productivity. The paper complements an earlier study that used parametric methods to analyse the same panel data. Interestingly, DEA provides estimates of subject-specific unit costs that are in the same ballpark as those provided by the parametric methods. The paper then extends the previous analysis and finds that further student number increases of the order of 20–27% are feasible through exploiting operating and scale efficiency gains and also adjusting student mix. Finally the paper uses a Malmquist index approach to assess productivity change in the UK higher education. The results reveal that for a majority of institutions productivity has actually decreased during the study period.

Risks and benefits of selective (re)presentation of interviewees' talk:some insights from discourse analysis

Purpose: The purpose of this paper is to examine the quality of evidence collected during interview. Current UK national guidance on the interviewing of victims and witnesses recommends a phased approach, allowing the interviewee to deliver their free report before any questioning takes place, and stipulating that during this free report the interviewee should not be interrupted. Interviewers, therefore, often find it necessary during questioning to reactivate parts of the interviewee's free report for further elaboration. Design/methodology/approach: The first section of this paper draws on a collection of police interviews with women reporting rape, and discusses one method by which this is achieved - the indirect quotation of the interviewee by the interviewer - exploring the potential implications for the quality of evidence collected during this type of interview. The second section of the paper draws on the same data set and concerns itself with a particular method by which information provided by an interviewee has its meaning "fixed" by the interviewer. Findings: It is found that "formulating" is a recurrent practice arising from the need to clarify elements of the account for the benefit of what is termed the "overhearing audience" - in this context, the police scribe, CPS, and potentially the Court. Since the means by which this "fixing" is achieved necessarily involves the foregrounding of elements of the account deemed to be particularly salient at the expense of other elements which may be entirely deleted, formulations are rarely entirely neutral. Their production, therefore, has the potential to exert undue interviewer influence over the negotiated "final version" of interviewees' accounts. Originality/value: The paper highlights the fact that accurate re-presentations of interviewees' accounts are a crucial tool in ensuring smooth progression of interviews and that re-stated speech and formulation often have implications for the quality of evidence collected during significant witness interviews. © Emerald Group Publishing Limited.