5-Fluorouracil: mechanisms of action and clinical strategies

5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

Challenging assumptions of future coastal habitat development around the UK

One habitat management requirement forced by 21st century relative sea-level rise (RSLR), will be the need to re-comprehend the dimensions of long-term transgressive behaviour of coastal systems being forced by such RSLR. Fresh approaches to the conceptual modelling and subsequent implementation of new coastal and peri-marine habitats will be required. There is concern that existing approaches to forecasting coastal systems development (and by implication their associated scarce coastal habitats) over the next century depend on a certain premise of orderly spatial succession of habitats. This assumption is shown to be questionable given the possible future rates of RSLR, magnitude of shoreline retreat and the lack of coastal sediment to maintain the protective morphologies to low-energy coastal habitats. Of these issues, sediment deficiency is regarded as one of the major problem for future habitat development. Examples of contemporary behaviour of UK coasts show evidence of coastal sediment starvation resulting from relatively stable RSLR, anthropogenic sealing of coastal sources, and intercepted coastal sediment pathways, which together force segmentation of coastal systems. From these examples key principles are deduced which may prejudice the existence of future habitats: accelerated future sediment demand due to RSLR may not be met by supply and, if short- to medium-term hold-the-line policies predominate, long-term strategies for managed realignment and habitat enhancement may prove impossible goals. Methods of contemporary sediment husbandry may help sustain some habitats in place but otherwise, instead of integrated coastal organization, managers may need to consider coastal breakdown, segmentation and habitat reduction as the basis of 21st century coastal evolution and planning.

Microbicide delivery: formulation technologies and strategies

Purpose of review: The aim of this article is to summarize the latest information on microbicide formulations for prevention of sexual transmission of HIV infection in women. Recent findings: Although early microbicide formulations were conventionally coitally dependent gel products, new technologies are being developed for vaginal delivery of anti-HIV agents. Intravaginal rings for delivery of microbicides, for example, are being developed and evaluated clinically. Safety and acceptability data are available for many microbicide gels and for one microbicide intravaginal ring. Other microbicide formulations in development for once daily or other vaginal administration strategies include films, tablets, and ovules. Various microbicide formulations for rectal administration are also in development. Summary: New microbicide formulations in development are addressing many of the issues with the original gels such as coital dependency, frequency of use, acceptability, compliance, cost, and adaptability to large-scale production. All of these dosage forms are promising options for safe, effective, and acceptable microbicide products.

One-pot multistep synthetic strategies for the production of fenpropimorph using an ionic liquid solvent

The one-pot synthesis of the fungicide fenpropimorph has been achieved using two different synthetic strategies in an ionic liquid. The first pathway consists of a Heck coupling followed by reductive amination; the second pathway consists of an aldol condensation followed by hydrogenation/reductive amination. Homogeneous and heterogeneous palladium catalysts have been utilised in the ionic liquid to provide a catalyst/solvent system that is suitable for recycling and process optimisation.

Any Nearer to Victory in the Fifty Years War?:Assessing the European Commission’s Leadership, Weapons and Strategies towards combating Cartels

Some 50 years after its creation EU competition policy remains firmly entrenched as one of the most developed examples of supranational governance within the European Union. Although there has been a marked increase in interest among political scientists in competition policy in recent years there are still gaps in terms of overall coverage. One area that has been largely overlooked centres on cartels. Cartel policy has emerged as a highly salient issue and main priority of the Commission's competition policy since the late 1990s. Certainly, the recent restructuring of the EU cartel enforcement regime, the imposition of ever higher fines and a determined EU Competition Commissioner have fuelled growing media attention while new notices and regulations increasingly occupy the interests and minds of practitioners. The European Commission has constantly extended its activities on the competition policy front and its increasingly aggressive strategies to combat cartels provides political scientists with a fascinating case study of governance in action and illustrates the ways – such as leniency programmes, higher fines, enhanced and better equipped resources as well as internal reorganisation in which the European regulator is pursuing such conspiracies. This article traces the evolution and development of EU cartel policy since its inception and assesses the Commission's strategies and considers just to what extent the European Commission is winning its war against business cartelisation.

Localization in Sardinia and Its Obstacles: A Reply to Hospers’ “Localization in Europe’s Periphery: Tourism Development in Sardinia”

In this reply to Hospers' “Localization in Europe's Periphery: Tourism Development in Sardinia” by Gert-Jan Hospers (2003), we argue that the author's advocacy of localized economic policies as a viable means to the economic development of Sardinia does not take into account current institutional assets that prevent Sardinia from pursuing localized interests effectively. We first discuss the historical background of these institutional assets, highlighting that a top-down approach to decision-making has characterized relations between Sardinia and the central state for most of the modern era. We then discuss the institutional and economic impediments to Sardinian attempts to pursue localized policies in light of recent institutional conflicts between region and central state. Our conclusion is that the localization of economic strategies necessitates entwined localization of decision-making powers in order to be effective.

Funding, ideology and the aesthetics of the development film in postcolonial Zimbabwe

This article considers the relationships between aesthetics and ideology in donor-funded ‘development’ film-making from Zimbabwe, examining in particular how the films’ producers have attempted to popularize a genre of film-making that has its roots in colonial cinema. Making close reference to two productions from the Harare-based Media for Development Trust (MFD) – Neria (Godwin Mawaru, 1992), and Everyone’s Child (Tsitsi Dangarembga, 1996) (both of which may be regarded as archetypal examples of their genre) – the article demonstrates how the films deploy a range of aesthetic strategies to imbue a set of narratives drawn from colonial development films with greater impact and cultural resonance for contemporary local audiences. The article also suggests that close analysis of these strategies may provide insights into the relationships between the films’ aesthetic dimensions and wider ideological issues in the region.

Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin (R) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Inflammation and Anti-inflammatory strategies for alzheimer disease a mini review

Until recently, the central nervous system (CNS) has been thought to be an immune privileged organ. However, it is now understood that neuroinflammation is linked with the development of several CNS diseases including late-onset Alzheimer's disease (LOAD). The development of inflammation is a complex process involving a wide array of molecular interactions which in the CNS remains to be further characterized. The development of neuroinflammation may represent an important link between the early stages of LOAD and its pathological outcome. It is proposed that risks for LOAD, which include genetic, biological and environmental factors can each contribute to impairment of normal CNS regulation and function. The links between risk factors and the development of neuroinflammation are numerous and involve many complex interactions which contribute to vascular compromise, oxidative stress and ultimately neuroinflammation. Once this cascade of events is initiated, the process of neuroinflammation can become overactivated resulting in further cellular damage and loss of neuronal function. Additionally, neuroinflammation has been associated with the formation of amyloid plaques and neurofibrillary tangles, the pathological hallmarks of LOAD. Increased levels of inflammatory markers have been correlated with an advanced cognitive impairment. Based on this knowledge, new therapies aimed at limiting onset of neuroinflammation could arrest or even reverse the development of the disease.

Mapping NGO Competency to Reduce Human Vulnerability in Post-disaster Communities: Comparing Strategies in Sri Lanka and Bangladesh

Natural hazards trigger disasters, the scale of which is largely determined by vulnerability. Developing countries suffer the most from disasters due to various conditions of vulnerability which exist and there is an opportunity after disasters to take mitigative action. NGOs implementing post-disaster rehabilitation projects must be able to address the issues causing communities to live at risk of disaster and therefore must build dynamic capacity, capabilities and competencies, enabling them to operate in unstable environments. This research is built upon a theoretical framework of dynamic competency established by combining elements of disaster management, strategic management and project management theory. A number of NGOs which have implemented reconstruction and rehabilitation projects both in Sri Lanka following the Asian Tsunami and Bangladesh following Cyclone Sidr are being investigated in great depth using a causal mapping procedure. ‘Event’ specific maps have been developed for each organization in each disaster. This data will be analysed with a view to discovering the strategies which lead to vulnerability reduction in post-disaster communities and the competencies that NGOs must possess in order to achieve favourable outcomes. It is hypothesized that by building organizational capacity, capabilities and competencies to be dynamic in nature, while focusing on a more emergent strategic approach, with emphasis on adaptive capability and innovation, NGOs will be better equipped to contribute to sustainable community development through reconstruction. We believe that through this study it will be possible to glean a new understanding of social processes that emerge within community rehabilitation projects.

The Effect of Risk Sensitivity on Collaborative New Product Development in a Supply Chain

The increasing risks and costs of new product development require firms to collaborate with their supply chain partners in product management. In this paper, a supply chain model is proposed with one risk-neutral supplier and one risk-averse manufacturer. The manufacturer has an opportunity to enhance demand by developing a new product, but both the actual demand for new product and the supplier’s wholesale price are uncertain. The supplier has an incentive to share risks of new product development via an advance commitment to wholesale price for its own profit maximization. The effects of the manufacturer’s risk sensitivity on the players’ optimal strategies are analyzed and the trade-off between innovation incentives and pricing flexibility is investigated from the perspective of the supplier. The results highlight the significant role of risk sensitivity in collaborative new product development, and it is found that the manufacturer’s innovation level and retail price are always decreasing in the risk sensitivity, and the supplier prefers commitment to wholesale price only when the risk sensitivity is below a certain threshold.

COLREGs-based collision avoidance strategies for unmanned surface vehicles

The aim of this paper is to report the preliminary development of an automatic collision avoidance technique for unmanned marine craft based on standardised rules, COLREGs, defined by the International Maritime Organisation. It is noted that all marine surface vessels are required to adhere to COLREGs at all times in order to minimise or eliminate the risk of collisions. The approach presented is essentially a reactive path planning algorithm which provides feedback to the autopilot of an unmanned vessel or the human captain of a manned ship for steering the craft safely. The proposed strategy consists of waypoint guidance by line-of-sight coupled with a manual biasing scheme. This is applied to the dynamic model of an unmanned surface vehicle. A simple PID autopilot is incorporated to ensure that the vessel adheres to the generated seaway. It is shown through simulations that the resulting scheme is able to generate viable trajectories in the presence of both stationary and dynamic obstacles. Rules 8 and 14 of the COLREGs, which apply to the amount of manoeuvre and to a head-on scenario respectively are simulated. A comparison is also made with an offline or deliberative grid-based path planning algorithm which has been modified to generate COLREGs-compliant routes.

Devolution and the politics of development in Northern Ireland

The reintroduction of devolution in Northern Ireland is widely interpreted as the working out of the Belfast Agreement (1998) which aimed to embed political consensus in shared institutions of the state. However, such analysis tends to be limited with regard to wider political economy readings of the devolution project and historic struggles to find an appropriate institutional fix to manage different
forms of crisis. Peace and stability have, it is argued, permitted Northern Ireland's reentry to global markets and circuits of capital with new governance structures being assembled to reconfigure `post- conflict' economic space. We argue that the onset of devolution has promoted a mix between ethnosectarian resource competition and a constantly expanding neoliberal model of governance.
Devolved neoliberal structures that sustain social polarisation may perpetuate strategies of resistance that could cut across and challenge ethnosectarian politics and deepening social segregation.

An evaluation of the effect of altering nutrition and nutritional strategies in early lactation on reproductive performance and estrous behavior of high-yielding Holstein-Friesian dairy cows

Reproductive performance in the high-yielding dairy cow has severely decreased in the last 40 yr. The aim of this study was to compare the effectiveness of 4 nutritional strategies in improving the reproductive performance of high-yielding dairy cows. It was hypothesized that offering cows a high-starch ration in early lactation would enhance the onset of luteal activity, and that decreasing the severity of negative energy balance in the early postcalving period would improve reproductive parameters. Nutritional regimens aimed at improving fertility were applied to 96 Holstein-Friesian dairy animals. Upon calving, animals were allocated in a balanced manner to one of 4 dietary treatments. Primiparous animals were balanced according to live weight, body condition score and calving date. Multiparous animals were balanced according to parity, previous lactation milk yield, liveweight, body condition score and calving date. Treatment 1 was based on an industry best practice diet (control) to contain 170 g of crude protein/kg of dry matter. Treatment 2 was an individual cow feeding strategy, whereby the energy balance (EB) of individual animals was managed so as to achieve a predetermined target daily EB profile (+/- 10 MJ/d). Treatment 3 was a high-starch/high-fat combination treatment, whereby an insulinogenic (high-starch) diet was offered in early lactation to encourage cyclicity and followed by a lipogenic (low-starch, high-fat) diet to promote embryo development. Treatment 4 was a low-protein diet, containing 140 g of crude protein/kg of dry matter, supplemented with protected methionine at an inclusion level of 40 g per animal per day. The nutritional strategies implemented in this study had no statistically significant effects on cow fertility measures, which included the onset of luteal activity, conception rate, in-calf rate, and the incidence of atypical cycles. The individual cow feeding strategy improved EB in early lactation but had no benefit on conception rate to first insemination. However, conception rate to second insemination, 100-d pregnancy rate (from the commencement of breeding), and overall pregnancy rate tended to be higher in this group. The high-starch/high-fat treatment tended to decrease the proportion of delayed ovulations and increase the proportion of animals cycling by d 50 postcalving. Animals that failed to conceive to first insemination had a significantly longer luteal phase in the first cycle postpartum and a longer inter-ovulatory interval in the second cycle postpartum. With regards to estrous behavior, results indicate that as the size of the sexually active group increased, the intensity of estrus and the expression of mounting or attempting to mount another cow also increased. Furthermore, cows that became pregnant displayed more intense estrous behavior than cows that failed to become pregnant.