Acyl glucuronide reactivity in perspective: biological consequences

The metabolic conjugation of exogenous and endogenous carboxylic acid substrates with endogenous glucuronic acid, mediated by the uridine diphosphoglucuronosyl transferase (UGT) superfamily of enzymes, leads to the formation of acyl glucuronide metabolites. Since the late 1970s, acyl glucuronides have been increasingly identified as reactive electrophilic metabolites, capable of undergoing three reactions: intramolecular rearrangement, hydrolysis, and intermolecular reactions with proteins leading to covalent drug-protein adducts. This essential dogma has been accepted for over a decade. The key question proposed by researchers, and now the pharmaceutical industry, is: does or can the covalent modification of endogenous proteins, mediated by reactive acyl glucuronide metabolites, lead to adverse drug reactions, perhaps idiosyncratic in nature? This review evaluates the evidence for acyl glucuronide-derived perturbation of homeostasis, particularly that which might result from the covalent modification of endogenous proteins and other macromolecules. Because of the availability of acyl glucuronides for test tube/in vitro experiments, there is now a substantial literature documenting their rearrangement, hydrolysis and covalent modification of proteins in vitro. It is certain from in vitro experiments that serum albumin, dipeptidyl peptidase IV, tubulin and UGTs are covalently modified by acyl glucuronides. However, these in vitro experiments have been specifically designed to amplify any interference with a biological process in order to find biological effects. The in vivo situation is not at all clear. Certainly it must be concluded that all humans taking carboxylate drugs that form reactive acyl glucuronides will form covalent drug-protein adducts, and it must also be concluded that this in itself is normally benign. However, there is enough in vivo evidence implicating acyl glucuronides, which, when backed up by in vivo circumstantial and documented in vitro evidence, supports the view that reactive acyl glucuronides may initiate toxicity/immune responses. In summary, though acyl glucuronide-derived covalent modification of endogenous macromolecules is well-defined, the work ahead needs to provide detailed links between such modification and its possible biological consequences. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Bayesian estimation of g-and-k distributions using MCMC

In this paper we investigate a Bayesian procedure for the estimation of a flexible generalised distribution, notably the MacGillivray adaptation of the g-and-κ distribution. This distribution, described through its inverse cdf or quantile function, generalises the standard normal through extra parameters which together describe skewness and kurtosis. The standard quantile-based methods for estimating the parameters of generalised distributions are often arbitrary and do not rely on computation of the likelihood. MCMC, however, provides a simulation-based alternative for obtaining the maximum likelihood estimates of parameters of these distributions or for deriving posterior estimates of the parameters through a Bayesian framework. In this paper we adopt the latter approach, The proposed methodology is illustrated through an application in which the parameter of interest is slightly skewed.

Interspecific variation in the use of carotenoid-based coloration in birds: diet, life history and phylogeny

Birds show striking interspecific variation in their use of carotenoid-based coloration. Theory predicts that the use of carotenoids for coloration is closely associated with the availability of carotenoids in the diet but, although this prediction has been supported in single-species studies and those using small numbers of closely related species, there have been no broad-scale quantitative tests of the link between carotenoid coloration and diet. Here we test for such a link using modern comparative methods, a database on 140 families of birds and two alternative avian phylogenies. We show that carotenoid pigmentation is more common in the bare parts (legs, bill and skin) than in plumage, and that yellow coloration is more common than red. We also show that there is no simple, general association between the availability of carotenoids in the diet and the overall use of carotenoid-based coloration. However, when we look at plumage coloration separately from bare part coloration, we find there is a robust and significant association between diet and plumage coloration, but not between diet and bare part coloration. Similarly, when we look at yellow and red plumage colours separately, we find that the association between diet and coloration is typically stronger for red coloration than it is for yellow coloration. Finally, when we build multivariate models to explain variation in each type of carotenoid-based coloration we find that a variety of life history and ecological factors are associated with different aspects of coloration, with dietary carotenoids only being a consistent significant factor in the case of variation in plumage. All of these results remain qualitatively unchanged irrespective of the phylogeny used in the analyses, although in some cases the precise life history and ecological variables included in the multivariate models do vary. Taken together, these results indicate that the predicted link between carotenoid coloration and diet is idiosyncratic rather than general, being strongest with respect to plumage colours and weakest for bare part coloration. We therefore suggest that, although the carotenoid-based bird plumage may a good model for diet-mediated signalling, the use of carotenoids in bare part pigmentation may have a very different functional basis and may be more strongly influenced by genetic and physiological mechanisms, which currently remain relatively understudied.

Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report [Dapson-induzierte agranulozytose. Die rolle fremdstoffmetabolisierender enzyme am beispiel einer kasuistik]

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring.

Using extreme value theory to measure value-at-risk for daily electricity spot prices

The recent deregulation in electricity markets worldwide has heightened the importance of risk management in energy markets. Assessing Value-at-Risk (VaR) in electricity markets is arguably more difficult than in traditional financial markets because the distinctive features of the former result in a highly unusual distribution of returns-electricity returns are highly volatile, display seasonalities in both their mean and volatility, exhibit leverage effects and clustering in volatility, and feature extreme levels of skewness and kurtosis. With electricity applications in mind, this paper proposes a model that accommodates autoregression and weekly seasonals in both the conditional mean and conditional volatility of returns, as well as leverage effects via an EGARCH specification. In addition, extreme value theory (EVT) is adopted to explicitly model the tails of the return distribution. Compared to a number of other parametric models and simple historical simulation based approaches, the proposed EVT-based model performs well in forecasting out-of-sample VaR. In addition, statistical tests show that the proposed model provides appropriate interval coverage in both unconditional and, more importantly, conditional contexts. Overall, the results are encouraging in suggesting that the proposed EVT-based model is a useful technique in forecasting VaR in electricity markets. (c) 2005 International Institute of Forecasters. Published by Elsevier B.V. All rights reserved.

Convergence analysis of a discrete-time single-unit gradient ICA algorithm

We revisit the one-unit gradient ICA algorithm derived from the kurtosis function. By carefully studying properties of the stationary points of the discrete-time one-unit gradient ICA algorithm, with suitable condition on the learning rate, convergence can be proved. The condition on the learning rate helps alleviate the guesswork that accompanies the problem of choosing suitable learning rate in practical computation. These results may be useful to extract independent source signals on-line.

A Research Agenda for Strategic Management Research in Developing Countries

This paper explores the extent to which it is possible to address issues pertaining to developing countries with significant socio-cultural and political interventions. Examples from the Sri Lankan tea plantations are used to illustrate the necessity to understand the context from actors’ perspectives using rigorous case study research, before making prescriptive recommendations. Current problems faced by the Sri Lankan tea industry are identified as not merely micro-institutional or managerial. We argue that their roots lie in reproduction of social struggles at the level of production. We propose a research agenda, in the doctrine of critical theory, for exploring the formation and implementation of business strategies in developing countries, using the tea plantation sector as a case. Our primary attempt here is to conceptualize strategic management in the context of political economy and to identify central issues to be addressed. Accordingly, we argue that researching historical dynamics of strategic management facilitates understanding and interpreting the articulation of modes of production in a given social formation. We further argue that a highly context specific research agenda is required to fully comprehend idiosyncratic characteristics of Sri Lankan strategy structures and organizational forms. Then, it is proposed that explaining the role of social formation in shaping and reshaping strategy relations should be at the centre of the research due to the social significance attached to ‘strategy’. Finally, methodological and epistemological necessities arising from the nature of strategy relationships are discussed.