Treatment of dementia with neurotransmission modulation

The prevalence of dementia is growing in developed countries where elderly patients are increasing in numbers. Neurotransmission modulation is one approach to the treatment of dementia. Cholinergic precursors, anticholinesterases, nicotine receptor agonists and muscarinic M-2 receptor antagonists are agents that enhance cholinergic neurotransmission and that depend on having some intact cholinergic innervation to be effective in the treatment of dementia. The cholinergic precursor choline alfoscerate may be emerging as a potential useful drug in the treatment of dementia, with few adverse effects. Of the anticholinesterases, donepezil, in addition to having a similar efficacy to tacrine in mild-to-moderate Alzheimer's disease (AD), appears to have major advantages; its use is associated with lower drop-out rates in clinical trials, a lower incidence of cholinergic-like side effects and no liver toxicity. Rivastigmine is efficacious in the treatment in dementia with Lewy bodies, a condition in which the other anticholinesterases have not been tested extensively to date. Galantamine is an anticholinesterase and also acts as an allosteric potentiating modulator at nicotinic receptors to increase the release of acetylcholine. Pooled data from clinical trials of patients with mild-to-moderate AD suggest that the benefits and safety profile of galantamine are similar to those of the anticholinesterases. Selective nicotine receptor agonists are being developed that enhance cognitive performance without influencing autonomic and skeletal muscle function, but these have not yet entered clinical trial for dementia. Unlike the cholinergic enhancers, the M, receptor agonists do not depend upon intact cholinergic nerves but on intact M, receptors for their action, which are mainly preserved in AD and dementia with Lewy bodies. The M, receptor-selective agonists developed to date have shown limited efficacy in clinical trials and have a high incidence of side effects. A major recent advancement in the treatment of dementia is memantine, a non-competitive antagonist at NMDA receptors. Memantine is beneficial in the treatment of severe and moderate to-severe AD and may also be of some benefit in the treatment of mild-to-moderate vascular dementia. Drugs that modulate 5-HT, somatostatin and noradrenergic neurotransmission are also being considered for the treatment of dementia.

The effects of alanine-substituted conantokin-G and ifenprodil on the human spermine-activated N-methyl-D-aspartate receptor

We evaluated the effects of Ala-7-conantokin-G (Con-G(A7)) and ifenprodil on the modulation by spermine of [H-3]MK801 binding to human cortical membranes. Human cortical tissue was obtained at autopsy and stored at -80 degreesC until assay. Both Con-GA7 and ifenprodil inhibited [H-3]MK801 binding, but spermine affected these inhibitions differently. Con-G(A7) IC50 changed little with spermine concentration, indicative of a non-competitive interaction, whereas the rightward shift in ifenprodil IC50 with increasing spermine concentration suggested partial competition. When the two agents were tested against the biphasic activation of [H-3]MK801 binding by spermine, they again differed in their effects. In the activation phase Con-G(A7) was a non-competitive inhibitor of spermine activation, and may even enhance the spermine EC50, while the ifenprodil data indicated a partially competitive interaction. Both agents were non-competitive in the inhibitory phase. Overall, the data suggest that Con-G(A7) and ifenprodil interact differently with the polyamine modulation of the glutamate-N-methyl-D-aspartate receptor. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

Inhibition studies of purple acid phosphatases: Implications for the catalytic mechanism

Purple acid phosphatases (PAPs) belong to the family of binuclear metallohydrolases and catalyse the hydrolysis of a large group of phosphoester substrates at acidic pH. Despite structural conservation in their active sites PAPs appear to display mechanistic versatility. Here, aspects of the catalytic mechanism of two PAPs are investigated using the inhibitors vanadate and fluoride as probes. While the magnitude of their vanadate inhibition constants are similar the two enzymes differ with respect to the mode of inhibition; vanadate interacts in a non-competitive fashion with pig PAP (K-i = 40 mu mol L-1) while it inhibits red kidney bean PAP competitively (K-i = 30 mu mol L-1). Similarly, fluoride also acts as a competitive inhibitor for red kidney bean PAP, independent of pH, while the inhibition of pig PAP by fluoride is uncompetitive at low pH and non-competitive at higher pH, independent of metal ion composition. Furthermore, while fluoride acts as a slow-binding inhibitor in pig PAP it binds rapidly to the catalytic site of the red kidney bean enzyme. Since vanadate and fluoride are proposed to act as transition state and nucleophile mimics, respectively, the observed differences in inhibition kinetics indicate subtle but distinct variations in the reaction mechanism of these enzymes.

A Complementary Economy? National Markets and International Product in Early Australian Theatre Managements

The international circulation of commercial theatre in the early twentieth century was driven not only from the centres of Great Britain and the USA, but by the specific enterprise and habitus of managers in ‘complementary’ production sites such as Australia, South Africa, and New Zealand. The activity of this period suggests a de-centred competitive trade in theatrical commodities – whether performers, scripts, or productions – wherein the perceived entertainment preferences and geographies of non-metropolitan centres were formative of international enterprise. The major producers were linked in complex bonds of partnerships, family, or common experience which crossed the globe. The fractures and commonalities displayed in the partnerships of James Cassius Williamson and George Musgrove, which came to dominate and shape the fortunes of the Australian industry for much of the century, indicate the contradictory commercial and artistic pressures bearing upon entrepreneurs seeking to provide high-quality entertainment and form advantageous combinations in competition with other local and international managements. Clarke, Meynell and Gunn mounted just such spirited competition from 1906 to 1911, and their story demonstrates both the opportunities and the centralizing logic bearing upon local managements shopping and dealing in a global market. The author, Veronica Kelly, works at the University of Queensland. She is presently undertaking a study of commercial stars and managements in late nineteenth- and early twentieth-century Australia, with a focus on the star performer as model of history, gender, and nation.

“Suffragettes in Satin Shorts”? Gender and Competitive Boxing

This study is an empirical and theoretical contribution to the burgeoning literature on gender and competitive boxing. By using Connell's concepts of labor, power, cathexis, and representation and a combination of content and semiotic analysis, interviews, and observations, we argue that competitive boxing can be studied productively as a paradoxical gender regime that simultaneously enables and constrains how women do gender. On one hand, the sport encourages individual women to display physical aggression when such behavior traditionally has been deemed the antithesis of femininity. Some feminists argue that this form of physical feminism enables women to transcend essentialist discourses that restrict their corporeal power. On the other hand, women boxers in general also encounter resistance to their aspirations. For example, they are still positioned by essentialist discourses about both their bodies and capacity to develop the requisite form of controlled aggression. Strongly gendered links between bodily labor and bodily capital also mean that women have less access to resources than do men and, consequently, fewer opportunities to develop their pugilistic capital. We also maintain that competitive women boxers are implicated in a body project that tends to replicate sporting practices that some feminists and pro-feminists argue are damaging to both men and women.

Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant N-methyl-D-aspartate receptors

ATP and glutamate are fast excitatory neurotransmitters in the central nervous system acting primarily on ionotropic P2X and glutamate [N-methyl-D-aspartate (NMDA) and non-NMDA] receptors, respectively. Both neurotransmitters regulate synaptic plasticity and long-term potentiation in hippocampal neurons. NMDA receptors are responsible primarily for the modulatory action of glutamate, but the mechanism underlying the modulatory effect of ATP remains uncertain. In the present study, the effect of ATP on recombinant NR1a + 2A, NR1a + 2B, and NR1a + 2C NMDA receptors expressed in Xenopus laevis oocytes was investigated. ATP inhibited NR1a + 2A and NR1a + 2B receptor currents evoked by low concentrations of glutamate but potentiated currents evoked by saturating glutamate concentrations. In contrast, ATP potentiated NR1a + 2C receptor currents evoked by nonsaturating glutamate concentrations. ATP shifted the glutamate concentration-response curve to the right, indicating a competitive interaction at the agonist binding site. ATP inhibition and potentiation of glutamate-evoked currents was voltage-independent, indicating that ATP acts outside the membrane electric field. Other nucleotides, including ADP, GTP, CTP, and UTP, inhibited glutamate-evoked currents with different potencies, revealing that the inhibition is dependent on both the phosphate chain and nucleotide ring structure. At high concentrations, glutamate outcompetes ATP at the agonist binding site, revealing a potentiation of the current. This effect must be caused by ATP binding at a separate site, where it acts as a positive allosteric modulator of channel gating. A simple model of the NMDA receptor, with ATP acting both as a competitive antagonist at the glutamate binding site and as a positive allosteric modulator at a separate site, reproduced the main features of the data.

Zero-non-zero patterned vector error correction modeling for I(2) cointegrated time series with applications in testing PPP and stock market relationships

Vector error-correction models (VECMs) have become increasingly important in their application to financial markets. Standard full-order VECM models assume non-zero entries in all their coefficient matrices. However, applications of VECM models to financial market data have revealed that zero entries are often a necessary part of efficient modelling. In such cases, the use of full-order VECM models may lead to incorrect inferences. Specifically, if indirect causality or Granger non-causality exists among the variables, the use of over-parameterised full-order VECM models may weaken the power of statistical inference. In this paper, it is argued that the zero–non-zero (ZNZ) patterned VECM is a more straightforward and effective means of testing for both indirect causality and Granger non-causality. For a ZNZ patterned VECM framework for time series of integrated order two, we provide a new algorithm to select cointegrating and loading vectors that can contain zero entries. Two case studies are used to demonstrate the usefulness of the algorithm in tests of purchasing power parity and a three-variable system involving the stock market.

Are there non-linearities in short-term interest rates?

The present paper investigates the characteristics of short-term interest rates in several countries. We examine the importance of nonlinearities in the mean reversion and volatility of short-term interest rates. We examine various models that allow the conditional mean (drift) and conditional variance (diffusion) to be functions of the current short rate.We find that different markets require different models. In particular, we find evidence of nonlinear mean reversion in some of the countries that we examine, linear mean reversion in others and no mean reversion in some countries. For all countries we examine, there is strong evidence of the need for the volatility of interest rate changes to be highly sensitive to the level of the short-term interest rate. Out-of-sample forecasting performance of one-factor short rate models is poor, stemming from the inability of the models to accommodate jumps and discontinuities in the time series data.

Optimal dispatch of spinning reserve in a competitive electricity market using genetic algorithms

Ancillary service plays a key role in maintaining operation security of the power system in a competitive electricity market. The spinning reserve is one of the most important ancillary services that should be provided effectively. This paper presents the design of an integrated market for energy and spinning reserve service with particular emphasis on coordinated dispatch of bulk power and spinning reserve services. A new market dispatching mechanism has been developed to minimize the cost of service while maintaining system security. Genetic algorithms (GA) are used for finding the global optimal solutions for this dispatch problem. Case studies and corresponding analyses have been carried out to demonstrate and discuss the efficiency and usefulness of the proposed method.