Agonists and antagonists of protease activated receptors (PARs)

Protease activated receptors (PARs) are a category of G-protein coupled receptors (GPCRs) implicated in the progression of a wide range of diseases, including thrombosis, inflammatory disorders, and proliferative diseases. Signal transduction via PARs proceeds via an unusual activation mechanism. Instead of being activated through direct interaction with an extracellular signal like most GPCRs. they are self-activated following cleavage of their extracellular N-terminus by serine proteases to generate a new receptor N-terminus that acts as an intramolecular ligand by folding back onto itself and triggering receptor activation. Short synthetic peptides corresponding to this newly exposed N-terminal tethered ligand can activate three of the four known PARs in the absence of proteases. and such PAR activating peptides (PAR-APs) have served as templates for agonist/antagonist development. In fact much of the evidence for involvement of PARs in diseases has relied upon use of PAR-APs. often of low potency and uncertain selectivity. This review summarizes current structures of PAR agonists and antagonists, the need for more selective and more potent PAR ligands that activate or antagonize this intriguing class of receptors, and outlines the background relevant to PAR activation, assay methods, and physiological properties anticipated for PAR ligands.

The sugar cane biofactory - building blocks for the future

The sugarcane plant, with its enormous genetic capacity to accumulate carbon and manufacture and store sucrose, also has the potential to accumulate carbon and metabolically create a wide range of new molecules for industrial and other commercial uses. The extent to which this change can be developed and realised commercially is a function of the technical competence of the industry's R&D capacity, the reality of the commercial drivers which support this global agenda, and the determination of the industry to achieve such goals. The outcomes of existing R&D work already strongly support the technical challenges of this opportunity in sugarcane. The current challenge remains the commercialisation of the technology in a global market in which the current business structures and systems for the manufacture and distribution of existing (competitive) products makes the development of new product lines a higher risk than might otherwise be the case. This is despite all the claims that global markets are expecting and (in some cases) legislating the creation of more sustainable production systems. The options and issues for the development of a sugarcane biofactory system are discussed.

Pesticide and herbicide residues in sediments and seagrasses from the Great Barrier Reef world heritage area and Queensland coast

Pesticides and herbicides including organochlorine compounds have had extensive current and past application by Queensland's intensive coastal agriculture industry as web as for a wide range of domestic, public health and agricultural purposes in urban areas, The persistent nature of these types of compounds together with possible continued illegal use of banned organochlorine compounds raises the potential for continued long-term chronic exposure to plants and animals of the Great Barrier Reef. Sediment and seagrass samples were collected from 16 intertidal and 25 subtidal sampling sites between Torres Strait and Townsville, near Mackay and Gladstone, and in Hervey and Moreton Bays in 1997 and 1998 and analysed for pesticide and herbicide residues. Low levels of atrazine (0.1-0.3 mug kg(-1)), diuron (0.2-10.1 mug kg(-1)), lindane (0.08-0.19 mug kg(-1)), dieldrin (0.05-0.37 mug kg(-1)), DDT (0.05-0.26 mug kg(-1)), and DDE (0.05-0.26 mug kg(-1)) were detected in sediments and/or seagrasses. Contaminants were mainly detected in samples collected along the high rainfall, tropical coast between Townsville and Port Douglas and in Moreton Bay. Of the contaminants detected, the herbicide diuron is of most concern as the concentrations detected have some potential to impact local seagrass communities, (C) 2000 Elsevier Science Ltd. All rights reserved.

Examining TCP parallelization related methods for various packet losses

The diversity of the networks (wired/wireless) prefers a TCP solution robust across a wide range of networks rather than fine-tuned for a particular one at the cost of another. TCP parallelization uses multiple virtual TCP connections to transfer data for an application process and opens a way to improve TCP performance across a wide range of environments - high bandwidth-delay product (BDP), wireless as well as conventional networks. In particular, it can significantly benefit the emerging high-speed wireless networks. Despite its potential to work well over a wide range of networks, it is not fully understood how TCP parallelization performs when experiencing various packet losses in the heterogeneous environment. This paper examines the current TCP parallelization related methods under various packet losses and shows how to improve the performance of TCP parallelization.

Novel formulation strategies for the fabrication of lyophilised orally disintegrating tablets

Orally disintegrating Tablets (ODTs), also known as fast-disintegrating, fast-melt or fast-dissolving tablets, are a relatively novel dosage technology that involves the rapid disintegration or dissolution of the dosage form into a solution or suspension in the mouth without the need for water. The solution containing the active ingredients is swallowed, and the active ingredients are then absorbed through the gastrointestinal epithelium to reach the target and produce the desired effect. Formulation of ODTs was originally developed to address swallowing difficulties of conventional solid oral dosage forms (tablets and capsules) experienced by wide range of patient population, especially children and elderly. The current work investigates the formulation and development of ODTs prepared by freeze drying. Initial studies focused on formulation parameters that influence the manufacturing process and performance of lyophilised tablets based on excipients used in commercial products (gelatin and saccharides). The second phase of the work was followed up by comprehensive studies to address the essential need to create saccharide free ODTs using naturally accruing amino acids individually or in combinations. Furthermore, a factorial design study was carried out to investigate the feasibility of delivering multiparticulate systems of challenging drugs using a novel formulation that exploited the electrostatic associative interaction between gelatin and carrageenan. Finally, studies aimed to replace gelatin with ethically and morally accepted components to the end users were performed and the selected binder was used in factorial design studies to investigate and optimise ODT formulations that incorporated drugs with varies physicochemical properties. Our results show that formulation of elegant lyophilised ODTs with instant disintegration and adequate mechanical strength requires carful optimisation of gelatin concentration and bloom strength in addition to saccharide type and concentration. Successful formulation of saccharides free lyophilised ODTs requires amino acids that crystallise in the frozen state or display relatively high Tg', interact and integrate completely with the binder and, also, display short wetting time with the disintegrating medium. The use of an optimised mixture of gelatin, carrageenan and alanine was able to create viscous solutions to suspend multiparticulate systems and at the same time provide tablets with short disintegration times and adequate mechanical properties. On the other hand, gum arabic showed an outstanding potential for use as a binder in the formulation of lyophilised ODTs. Compared to gelatin formulations, the use of gum arabic simplified the formulation stages, shortened the freeze drying cycles and produced tablets with superior performance in terms of the disintegration time and mechanical strength. Furthermore, formulation of lyophilised ODTs based on gum arabic showed capability to deliver diverse range of drugs with advantages over commercial products.

A review of non-pharmacological and pharmacological management of seasonal and perennial allergic conjunctivitis

Allergic eye disease encompasses a group of hypersensitivity disorders which primarily affect the conjunctiva and its prevalence is increasing. It is estimated to affect 8% of patients attending optometric practice but is poorly managed and rarely involves ophthalmic assessment. Seasonal allergic conjunctivitis (SAC) is the most common form of allergic eye disease (90%), followed by perennial allergic conjunctivitis (PAC; 5%). Both are type 1 IgE mediated hypersensitivity reactions where mast cells play an important role in pathophysiology. The signs and symptoms are similar but SAC occurs periodically whereas PAC occurs year round. Despite being a relatively mild condition, the effects on the quality of life can be profound and therefore they demand attention. Primary management of SAC and PAC involves avoidance strategies depending on the responsible allergen(s) to prevent the hypersensitivity reaction. Cooled tear supplements and cold compresses may help bring relief. Pharmacological agents may become necessary as it is not possible to completely avoid the allergen(s). There are a wide range of anti-allergic medications available, such as mast cell stabilisers, antihistamines and dual-action agents. Severe cases refractory to conventional treatment require anti-inflammatories, immunomodulators or immunotherapy. Additional qualifications are required to gain access to these medications, but entry-level optometrists must offer advice and supportive therapy. Based on current evidence, the efficacy of anti-allergic medications appears equivocal so prescribing should relate to patient preference, dosing and cost. More studies with standardised methodologies are necessary elicit the most effective anti-allergic medications but those with dual-actions are likely to be first line agents.

Managing human resources in the Middle-East

Managing Human Resources in the Middle East provides the reader with an understanding of the dynamics of HRM in this important region. Systematic analysis highlights the main factors and variables dictating HRM policies and practices within each country. Diverse and unique cultural, institutional and business environment factors which play a significant role in determining HRM systems in the region are also elaborated upon. The text moves from a general overview of HRM in the Middle-East to an exploration of the current status, role and strategic importance of the HR function in a wide-range of country-specific chapters, before highlighting the emerging HRM models and future challenges for research, policy and practice. This text is invaluable reading for academics, students and practitioners alike.

Evolutionary neurobusiness

Numerous scientific disciplines suffer from a common epistemological ailment. They tend to generate impressive bodies of empirical knowledge that are otherwise disjointed. The key force that shapes this reality is the lack of organizing meta-frameworks that are capable of otherwise creating a consilient body of core knowledge. In the current paper, we seek to demonstrate the synthetic value of evolutionary theory across a wide range of neuro-business disciplines including neuroeconomics, neuromarketing, neuroentrepreneurship, and organizational neuroscience. Neuroscientists operating at the junction of the brain sciences and a wide range of business disciplines stand to benefit in recognizing that the minds of Homo consumericus, Homo corporaticus, and Homo economicus have been forged by Darwinian forces that have shaped all living organisms. A complete and accurate understanding of most neuro-business phenomena requires that these be tackled at both the proximate (i.e., how something operates) and ultimate (its adaptive function) levels.

Creating demand for better health by using social marketing techniques

The most significant environmental change to support people who want to give up smoking is the legislation to ban smoking in public places. Following Scotland in March 2006, and Wales and Northern Ireland in April 2007, England moves one step closer to being smoke free on 1 July 2007, when it becomes illegal to smoke in almost every enclosed public place and workplace. Social marketing will be used to support this health promoting policy and will become more prominent in the design of health promotion campaigns of the future. Social marketing is not a new approach to promoting health but its adoption by the Government does represent a paradigm shift in the challenge to change public opinion and social norms. As a result some behaviours, like smoking or excessive alcohol consumption, will no longer be socially acceptable. The Department of Health has decided that social marketing should be used in England to guide all future health promotion efforts directed at achieving behavioural goals. This paradigm shift was announced in Chapter 2 of the “Choosing health” White Paper with its emphasis on the consumer, noting that a wide range of lifestyle choices are marketed to people, although health as a commodity itself has not been marketed. The DoH has an internal social marketing development unit to integrate social marketing principles into its work and ensure that providers deliver. The National Centre for Social Marketing has funding to provide ongoing support, to build capacity and capability in the workforce. This article describes the distinguishing features of the social marketing approach. It seeks to answer some questions. Is this really a new idea, a paradigm shift, or simply a change in terminology? What do the marketing principles offer that is new, or are they merely familiar ideas repackaged in marketing jargon? Will these principles be more effective than current health promotion practice and, if so, how does it work? Finally, what are the implications for community pharmacy?

Intelligence agents (knowledge management)

Reports some insights into knowledge management (KM) derived from UK one-day workshops with six businesses, three non-profits and one public sector organization. Lists the four questions posed to participants and discusses the themes which emerged, e.g. the need for a KM strategy to make raw information more useable, KM performance measurement etc. Stresses the need for commitment from a top-level champion and a wide range of employees to make this work and identifies three types of solutions for improving KM strategy: technological (e.g. databases and intranets), people (e.g. motivation, retention, training and networking) and processes (e.g. procedural instructions and balancing formal/informal knowledge sharing methods). Finds that accountants and senior managers do not generally see KM as very important but argues that management accountants are suitable knowledge champions who could develop explicit links between KM and organizational performance.

Non-metallic cold-cathode electron emission from composite metal-insulator microstructures

A detailed investigation has been undertaken into a field-induced electron emission (FIEE) mechanism that occurs at microscopically localised `sites' on uncoated, dielectric-coated and composite-coated metallic cathodes. An optical imaging technique has been used to observe and characterize the spatial and temporal behaviour of the populations of emission sites on these cathodes under various experimental conditions, e.g. pulsed-fields, gas environment etc. This study has shown that, for applied fields of 20MVm^-1, thin dielectric (750AA) and composite metal-insulator (MI) overlayers result in a dramatic increase in the total number of emission sites (typically 30cm^-2), and hence emission current. The emission process has been further investigated by a complementary electron spectroscopy technique which has revealed that the localised emission sites on these cathodes display field-dependent spectral shifts and half-widths, i.e. indicative of a `non-metallic' emission mechanism. Details are also given of a comprehensive investigation into the effects of the residual gas environment on the FIEE process from uncoated Cu-cathodes. This latter study has revealed that the well-known Gas Conditioning process can be performed with a wide range of gas species (e.g. O_2, N_2 etc), and furthermore, the degree of conditioning is influenced by both a `Voltage' and `Temperature' effect. These experimental findings have been shown to be particularly important to the technology of high-voltage vacuum-insulation and cold-cathode electron sources. The FIEE mechanism has been interpreted in terms of a hot-electron process that is associated with `electroformed' conducting channels in MI, MIM and MIMI surface microstructures.

The biotechnological applications of transglutaminases

Transglutaminases catalyse a diverse range of reactions leading to the modification of proteins and peptides such that their physical, chemical and biological properties become changed. They are found in many different living organisms and as a consequence display subtle differences in their biochemical and physical properties. it is therefore not surprising that this group of enzymes have been exploited as applied biocatalysts in a wide range of commercial sectors varying from the textile industry to the highly lucrative cosmetic industry. in addition the pathophysiological importance of this group of enzymes has increased significantly over the last decade with their involvement noted in a number of human diseases. As a consequence their identification as therapeutic targets or as monitoring aids for a range of different diseases has caused significant interest from the diagnostics and pharmaceutical industries. This review describes some of the current applications of transglutaminases; together with their potential strategic importance and future uses.

Clinical evaluation of the Grand Seiko Auto Ref/Keratometer WAM-5500

Purpose: A clinical evaluation of the Grand Seiko Auto Ref/Keratometer WAM-5500 (Japan) was performed to evaluate validity and repeatability compared with non-cycloplegic subjective refraction and Javal–Schiotz keratometry. An investigation into the dynamic recording capabilities of the instrument was also conducted. Methods: Refractive error measurements were obtained from 150 eyes of 75 subjects (aged 25.12 ± 9.03 years), subjectively by a masked optometrist, and objectively with the WAM-5500 at a second session. Keratometry measurements from the WAM-5500 were compared to Javal–Schiotz readings. Intratest variability was examined on all subjects, whilst intertest variability was assessed on a subgroup of 44 eyes 7–14 days after the initial objective measures. The accuracy of the dynamic recording mode of the instrument and its tolerance to longitudinal movement was evaluated using a model eye. An additional evaluation of the dynamic mode was performed using a human eye in relaxed and accommodated states. Results: Refractive error determined by the WAM-5500 was found to be very similar (p = 0.77) to subjective refraction (difference, -0.01 ± 0.38 D). The instrument was accurate and reliable over a wide range of refractive errors (-6.38 to +4.88 D). WAM-5500 keratometry values were steeper by approximately 0.05 mm in both the vertical and horizontal meridians. High intertest repeatability was demonstrated for all parameters measured: for sphere, cylinder power and MSE, over 90% of retest values fell within ±0.50 D of initial testing. In dynamic (high-speed) mode, the root-mean-square of the fluctuations was 0.005 ± 0.0005 D and a high level of recording accuracy was maintained when the measurement ring was significantly blurred by longitudinal movement of the instrument head. Conclusion: The WAM-5500 Auto Ref/Keratometer represents a reliable and valid objective refraction tool for general optometric practice, with important additional features allowing pupil size determination and easy conversion into high-speed mode, increasing its usefulness post-surgically following accommodating intra-ocular lens implantation, and as a research tool in the study of accommodation.

Raising the bar for systematic conservation planning

Mathematical methods in systematic conservation planning (SCP) represent a significant step toward cost-effective, transparent allocation of resources for biodiversity conservation. However, research demonstrates important consequences of uncertainties in SCP. Current research often relies on simplified case studies with unknown forms and amounts of uncertainty and low statistical power for generalizing results. Consequently, conservation managers have little evidence for the true performance of conservation planning methods in their own complex, uncertain applications. SCP needs to build evidence for predictive models of error and robustness to multiple, simultaneous uncertainties across a wide range of problems of known complexity. Only then can we determine true performance rather than how a method appears to perform on data with unknown uncertainty.

Interlamellar modification of smectite clays

Clay minerals, both natural and synthetic, have a wide range of applications. Smectite clays are not true insulators, their slight conductivity has been utilized by the paper industry in the development of mildly conducting paper. In particular, the synthetic hectorite clay, laponite, is employed to produce paper which is used in automated drawing offices where electro graphic printing is common. The primary objective of this thesis was to modify smectite clays, particularly laponite, to achieve enhanced conductivity. The primary objective was more readily achieved if the subsidiary objective of understanding the mechanism of conductivity was defined. The cyclic voltammograms of some cobalt complexes were studied in free solution and as clay modified electrodes to investigate the origin of electroactivity in clay modified electrodes. The electroactivity of clay modified electrodes prepared using our method can be attributed to ion pairs sorbed to the surface of the electrode, in excess of the cationic exchange capacity. However, some new observations were made concerning the co-ordination chemistry of the tri-2-pyridylamine complexes used which needed clarification. The a.c. conductivity of pressed discs of laponite RD was studied over the frequency range 12Hz- 100kHz using three electrode systems namely silver-loaded epoxy resin (paste), stainless-steel and aluminium. The a. c. conductivity of laponite consists of two components, reactive (minor) and ionic (major) which can be observed almost independently by utilizing the different electrode systems. When the temperature is increased the conductivity of laponite increases and the activation energy for conductivity can be calculated. Measurement of the conductivity of thin films of laponite RD in two crystal planes shows a degree of anisotropy in the a.c. conductivity. Powder X-ray diffraction and 119Sn Mossbauer spectroscopy studies have shown that attempts to intercalate some phenyltin compounds into laponite RD under ambient conditions result in the formation of tin(IV) oxide pillars. 119Sn Mossbauer data indicate that the order of effectiveness of conversion to pillars is in the order: Ph3SnCl > (Ph3Sn)2O, Ph2SnCl2 The organic product of the pillaring process was identified by 13C m.a.s.n.m.r. spectroscopy as trapped in the pillared lattice. This pillaring reaction is much more rapid when carried out in Teflon containers in a simple domestic microwave oven. These pillared clays are novel materials since the pillaring is achieved via neutral precursors rather than sacrificial reaction of the exchangeable cation. The pillaring reaction depends on electrophilic attack on the aryl tin bond by Brønsted acid sites within the clay. Two methods of interlamellar modification were identified which lead to enhanced conductivity of laponite, namely ion exchange and tin(IV) oxide pillaring. A monoionic potassium exchanged laponite shows a four fold increase in a.c. conductivity compared to sodium exchanged laponite RD. The increased conductivity is due to the appearence of an ionic component. The conductivity is independent of relative humidity and increases with temperature. Tin(IV) oxide pillared laponite RD samples show a significant increase in conductivity. Samples prepared from Ph2SnCl2 show an increase in excess of an order of magnitude. The conductivity of tin(IV) oxide pillared laponite samples is dominated by an ionic component.