bluuebunny/crossref_metadata_2025 huggingface dataset:
V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels
Authors: Ilyin Victor I , Hodges Dianne D , Whittemore Edward R , Carter Richard B , Cai Sui Xiong , Woodward Richard M
Published: March 2005

4‐(4‐Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole‐cell patch‐clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage‐gated Na+ channels.

V102862 blocked Na+ currents (INa) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state‐dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of INa.

The dissociation constant for the inactivated state (KI) was ∼0.6 μM, whereas the dissociation constant for the resting state (KR) was >15 μM.

The binding to inactivated channels was slow, requiring a few seconds to reach steady state at −80 mV.

The mechanism of inhibition was characterized in more detail using human embryonic kidney‐293 cells stably expressing rat brain type IIA Na+ (rNav1.2) channels, a major Na+ channel α subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state‐dependent blocker of rNav1.2 channels with a KI of ∼0.4 μM and KR ∼30 μM. V102862 binding to inactivated channels was relatively slow (k+≃1.7 μM−1 s−1). V102862 shifted the steady‐state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation.

These results suggest that inhibition of voltage‐gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics.

British Journal of Pharmacology (2005) 144, 801–812. doi:10.1038/sj.bjp.0706058
“If a Body Meet a Body”
Authors: Della Rocca Michael
Published: March 2005

What are Descartes's criteria for substance, and how many material objects meet them? A passage in the Synopsis of the Meditations has led some to portray him as a monist about extended substance and others to say that he does not even use “extended substance” as a count term. After considering Descartes's two criteria for substance (the basic subject criterion and the independence criterion), as well as his account of transubstantiation, we see that these answers are mistaken. Descartes countenances an infinity of extended substances. These are quantities of matter that can survive any rearrangement or scattering of their parts, but not the annihilation of any of them.
Teleology in Spinoza and Early Modern Rationalism
Authors: Garrett Don
Published: March 2005

This chapter seeks to establish (1) that Spinoza accepts the legitimacy of many teleological explanations; (2) that in two important respects, Leibniz's view of teleology is not more, and perhaps even less, Aristotleian than Descartes's; and (3) that among Descartes, Spinoza, and Leibniz, it is Spinoza who holds the view of teleology closest to that of Aristotle. The arguments for (1) derive from examinations of Spinoza's doctrine of conatus, critical analysis of Jonathan Bennett's proposed grounds for interpreting Spinoza as denying all teleology, and the application of Spinoza's distinction of three kinds of knowledge to the distinction between mechanistic and teleological explanation. The arguments for (2) and (3) are based on an examination of the answers given by Aristotle, Descartes, Leibniz, and Spinoza to four basic questions about the nature and range of teleology and teleological explanation. These questions concern the dependence of teleology on thought, the relation of teleology to divine will or purpose, the existence of “sub‐human” teleology, and the role of teleological explanation in natural philosophy.
United Kingdom
Authors: Lane Jan‐Erik , McKay David , Newton Kenneth
Published: March 2005

This section provides information on the most significant features of government and politics in the United Kingdom. These include data on state structure and offices, parties, government constitutions, electoral and voting systems, and basic media materials on media, education, economic interest organisations and the budget.
The Dynamics of Party Identification
Authors: Clarke Harold D. , Sanders David , Stewart Marianne C. , Whiteley Paul
Published: March 2005

Addresses important theoretical questions that arise from analyses in Chs 3 and 4 documenting that party identification is a powerful predictor of electoral preference. According to sociological models, party identification is a long-term, stable, affective orientation, whereas for models in the individual rationality framework, party identification is a summary, potentially mutable, tally of current and past party performance evaluations. Analyses of individual-level panel data show that, since the early 1960s, there has been considerable individual-level instability in party identification in Britain, and that this instability is not simply an artefact of random measurement error. Analyses of panel data and aggregate-level time series data also reveal that partisan dynamics reflect judgements about party leader performance and economic evaluations–key variables in the valence politics model of party support.
Creating Club Regulation
Authors: Moran Michael
Published: March 2005

This chapter examines the Victorian regulatory state. The key features of the wider administrative culture were congruent with the ideology of cooperative, consensual regulation practised by the inspectorates for much of the 20th century. This wider administrative culture was rooted in the system of club government that dominated metropolitan politics in Britain. This was the final important mechanism in embedding Victorian settlement for the first 60 to 70 years of the 20th century.
From Stagnation to Fiasco: the Age of the Regulatory State
Authors: Moran Michael
Published: March 2005

The age of the new regulatory state in Britain is also the age of policy fiasco. Fiasco is both a reflection of hyper-innovation and a force driving the state to even greater frenzies of hyper-innovation. It is argued that the emergent regulatory state amounts to an incomplete reconciliation with the conditions of modernity: with governing arrangements where codified knowledge matters more than tacit knowledge; where codified rules matter more than understanding; where instrumental achievement matters more than traditionally occupied positions; and where measurable accountability matters more than elite solidarity.
Permanent Challenges? Representing Greece in Brussels
Authors: Spanou Calliope
Published: March 2005

This account of the Greek permanent representation at Brussels starts by describing the Greek administrative system as characterized by sectorization and fragmentation, low co-ordination, centralization and hierarchical structure, importance of informal networks and personal strategies, and weak institutionalization of horizontal and staff functions. Deficient steering at the top and lack of clearly set priorities are deeper reasons for co-ordination deficiencies at the national and sectoral level. In that sense, the co-ordination scheme for Greek EU policy can be seen as a ‘truncated pyramid’, even though, more recently, major national priorities represent an exception to the rule. This chapter argues that the EU environment and its functional imperatives put pressure on the Greek permanent representation to compensate for defensive attitudes and domestic administrative weaknesses, while at the same time being affected by them. It discusses the organization of the Greek permanent representation, and its tasks and functions (including communication with the centre, internal functioning and working methods, transmission of national positions and instructions, presentation and negotiation of national positions, and networking), and finally gives a brief assessment of the situation.
Social Mobility in Europe between 1970 and 2000
Authors: Breen Richard , Luijkx Ruud
Published: March 2005

Presents the results of the comparative analyses of absolute mobility and social fluidity in 11 European countries covering the period 1970 to 2000. Findings are presented separately for men and for women. We find a marked convergence between countries in their patterns and rates of absolute social mobility. There is also a widespread tendency for class inequalities in mobility chances to diminish over time, though there remain quite substantial variations in this respect between countries.
Social Mobility in Norway 1973–95
Authors: Ringdal Kristen
Published: March 2005

This chapter, based on four surveys covering the period from 1973 to 1995, focuses on changes in the Norwegian class structure, and on trends in absolute as well as in relative social mobility. The access to rewarded positions in Norway has become easier for all due to the expansion of the service class in the period studied. The pervasive sex segregation in work does, however, show few signs of weakening: women are still concentrated in the lower service class and in routine non-manual work. The analysis of both absolute and relative social mobility shows that, despite educational expansion, privileged social background is still important in Norway, although this study points to a weakening of the vertical barriers to social mobility between 1973 and 1995.
Audit Regulation, Audit Quality, and Audit Research in the Post-Enron Era: An Analysis of Nonaudit Services
Authors: Ewert Ralf
Published: March 2005

Despite reservations voiced by the scientific community, the perception that combining non-audit services (NAS) and auditing for the same client may be largely responsible for recently observed accounting and audit failures seems to have gained momentum, and currently, it appears that any auditor offering NAS to auditees automatically endangers ‘independence in appearance’. This chapter addresses the question of whether such opinions can be justified by existing research on the issue of combining NAS and auditing. While there are already some reviews of former empirical papers, there is essentially no survey of the related theoretical research and the more recent empirical work. Here, the focus is mainly on the theoretical side, which is critically reviewed and somewhat extended in Section 2 of the chapter, while Section 3 reviews and interprets some new empirical work in the light of the theories presented before. The final section presents conclusions and directions for further research; the conclusion is that there is no evidence that a simultaneous offering of auditing and NAS to the same client unequivocally and systematically impairs auditor independence, and that, in fact, there are instances where NAS are likely to enhance the quality of the audit because they increase the auditors’ capital that is at stake.
Changing Conceptions of Family and Gender Relations in European Welfare States and the Third Way
Authors: Daly Mary
Published: March 2005

Explores the idea of the social investment state in the context of Third Way thinking and practice. It considers the social investment state as: a normative ideal; a pragmatic response to the perceived economic and social challenges facing mature welfare states; and an analytical tool. Following a discussion of its evolution and key elements, the chapter explores the emergence of the social investment state in the UK and Canada. It offers a critical analysis of the treatment of children as citizen-workers of the future, drawing out the implications for children and also women.
What is New Labour? Can it Deliver on Social Policy?
Authors: Lewis Jane
Published: March 2005

Presents a comparative overview of non-profit or third-sector organizations in a wider welfare policy and civil society context. It addresses the social, economic, and political developments that have made this set of institutions more central to policy debates in developed market economies; in particular, within a broad policy framework known as the Third Way, which, unlike other policy approaches, pays the greatest and most systematic attention to the non-profit sector. The chapter finds that the strength of the Third Way stance toward the non-profit sector is closely related to its weakness: Because its basic perspective towards voluntarism and civil society overlaps significantly with those of neo-liberalism on the one hand, and with approaches in reformed minded post-corporatists countries, its distinct policy thrust is hard to fathom. Indeed, many countries practice some form of ‘third-wayism’ in their search for new policy approaches to modernize the welfare state.
Explaining Expenditure Outcomes
Authors: Castles Francis G.
Published: March 2005

Uses statistical techniques to model the determinants of aggregate social expenditure change in 21 OECD countries over the period 1980 to 1998. The main focus is on testing hypotheses relating to the impact of economic globalization and the so-called ‘new politics’ of the welfare state. The analysis suggests that neither of these accounts is persuasive. Instead, the main factors shaping recent expenditure change appear to have been programme maturation, economic growth, deindustrialization and left partisan politics.
Who's Afraid of a Poor Old Age? Risk Perception in Risk Management Decisions
Authors: Weber Elke U.
Published: March 2005

This chapter argues that the lack of any visceral perception of risk or danger is the main obstacle to the retirement savings. It reviews theory and empirical evidence to document two claims: that affect is the wellspring of action; and that perceived risk, particularly visceral reactions to risky situations, has little correspondence to other measures of risk. It concludes by considering the implications of psychological models of decisionmaking for designing procedures or institutions that improve on the current situation.
Aphid Resistance inMedicago truncatulaInvolves Antixenosis and Phloem-Specific, Inducible Antibiosis, and Maps to a Single Locus Flanked by NBS-LRR Resistance Gene Analogs
Authors: Klingler John , Creasy Robert , Gao Lingling , Nair Ramakrishnan M. , Calix Alonso Suazo , Jacob Helen Spafford , Edwards Owain R. , Singh Karam B.
Published: March 2005

Aphids and related insects feed from a single cell type in plants: the phloem sieve element. Genetic resistance to Acyrthosiphon kondoi Shinji (bluegreen aphid or blue alfalfa aphid) has been identified in Medicago truncatula Gaert. (barrel medic) and backcrossed into susceptible cultivars. The status of M. truncatula as a model legume allows an in-depth study of defense against this aphid at physiological, biochemical, and molecular levels. In this study, two closely related resistant and susceptible genotypes were used to characterize the aphid-resistance phenotype. Resistance conditions antixenosis since migratory aphids were deterred from settling on resistant plants within 6 h of release, preferring to settle on susceptible plants. Analysis of feeding behavior revealed the trait affects A. kondoi at the level of the phloem sieve element. Aphid reproduction on excised shoots demonstrated that resistance requires an intact plant. Antibiosis against A. kondoi is enhanced by prior infestation, indicating induction of this phloem-specific defense. Resistance segregates as a single dominant gene, AKR (Acyrthosiphon kondoi resistance), in two mapping populations, which have been used to map the locus to a region flanked by resistance gene analogs predicted to encode the CC-NBS-LRR subfamily of resistance proteins. This work provides the basis for future molecular analysis of defense against phloem parasitism in a plant model system.
Overlaps in the Transcriptional Profiles ofMedicago truncatulaRoots Inoculated with Two Different Glomus Fungi Provide Insights into the Genetic Program Activated during Arbuscular Mycorrhiza
Authors: Hohnjec Natalija , Vieweg Martin F. , Pühler Alfred , Becker Anke , Küster Helge
Published: March 2005

Arbuscular mycorrhiza (AM) is a widespread symbiotic association between plants and fungal microsymbionts that supports plant development under nutrient-limiting and various stress conditions. In this study, we focused on the overlapping genetic program activated by two commonly studied microsymbionts in addition to identifying AM-related genes. We thus applied 16,086 probe microarrays to profile the transcriptome of the model legume Medicago truncatula during interactions with Glomus mosseae and Glomus intraradices and specified a total of 201 plant genes as significantly coinduced at least 2-fold, with more than 160 being reported as AM induced for the first time. Several hundred genes were additionally up-regulated during a sole interaction, indicating that the plant genetic program activated in AM to some extent depends on the colonizing microsymbiont. Genes induced during both interactions specified AM-related nitrate, ion, and sugar transporters, enzymes involved in secondary metabolism, proteases, and Kunitz-type protease inhibitors. Furthermore, coinduced genes encoded receptor kinases and other components of signal transduction pathways as well as AM-induced transcriptional regulators, thus reflecting changes in signaling. By the use of reporter gene expression, we demonstrated that one member of the AM-induced gene family encoding blue copper binding proteins (MtBcp1) was both specifically and strongly up-regulated in arbuscule-containing regions of mycorrhizal roots. A comparison of the AM expression profiles to those of nitrogen-fixing root nodules suggested only a limited overlap between the genetic programs orchestrating root endosymbioses.
A Linear Model for Managing the Risk of Antimicrobial Resistance Originating in Food Animals
Authors: Bartholomew Mary J. , Vose David J. , Tollefson Linda R. , Travis Curtis C.
Published: March 2005

A linear population risk model used by the U.S. Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) estimates the risk of human cases of campylobacteriosis caused by fluoroquinolone‐resistant Campylobacter. Among the cases of campylobacteriosis attributed to domestically produced chicken, the fluoroquinolone resistance is assumed to result from the use of fluoroquinolones in poultry in the United States. Properties of the linear population risk model are contrasted with those of a farm‐to‐fork model commonly used for microbial risk assessments. The utility of the linear population model for the purpose for which it was used by CVM is discussed.
Logic and Motivation in Risk Research: A Nuclear Waste Test Case
Authors: Brown Rex V.
Published: March 2005

After two decades of massive investigation, federal approval of a nuclear waste site is drawing to a close. Large‐scale research to assure that major hazards such as this one are socially acceptable is often highly inefficient, as here. A regulatory remedy would be to require not only that risk currently assessed be acceptable, but also that risk would remain acceptable given any new information. Research to test compliance with these rules has to be cost effective. Research activities should be managed according to an explicit discipline that can be imposed on powerful conflicting interests. They might be required to (1) set targets for the first‐ and second‐order risk assessments, (2) allocate research resources to close any gap between current and target assessments cost effectively, and (3) reallocate resources, as evolving findings dictate. The interests of license applicant (Department of Energy, DOE) and society are distinguished: the former would want the application approved; the latter would want to reject an unacceptable facility.
Do New Objects Capture Attention?
Authors: Franconeri Steven L. , Hollingworth Andrew , Simons Daniel J.
Published: March 2005

The visual system relies on several heuristics to direct attention to important locations and objects. One of these mechanisms directs attention to sudden changes in the environment. Although a substantial body of research suggests that this capture of attention occurs only for the abrupt appearance of a new perceptual object, more recent evidence shows that some luminance-based transients (e.g., motion and looming) and some types of brightness change also capture attention. These findings show that new objects are not necessary for attention capture. The present study tested whether they are even sufficient. That is, does a new object attract attention because the visual system is sensitive to new objects or because it is sensitive to the transients that new objects create? In two experiments using a visual search task, new objects did not capture attention unless they created a strong local luminance transient.
Clinical trials in urology: how many patients are required to achieve statistically significant results?
Authors: Parazzini Fabio , Colli Enrico , Chatenoud Liliane , Malvezzi Matteo , Olivieri Lorenza , Montorsi Francesco , La Vecchia Carlo
Published: March 2005

During the clinical validation of a new drug there are several clinical phases. Once phase II studies have defined the efficacy of a new drug, clinical research is used to evaluate its significance in clinical practice, comparing it with other drugs or treatments in use for similar clinical conditions. The group of patients undergoing standard treatment (either untreated or treated with placebo) is thus used as a control; these phase III studies are termed ‘controlled clinical studies’. The general condition for comparing patients treated with the new drug is that they do not have characteristics (relevant to the study) that are systematically different from those in the control group. Randomization guarantees comparability between treated and untreated (or otherwise treated) patients. The comparability of the observations of the studied events are guaranteed by blinding and placebo. The fundamental question when designing a controlled clinical study to evaluate whether there are differences between two or more treatments is how many patients are needed. Generally, the smaller the clinically relevant differences in efficacy between treatments, the more patients are required, to provide sufficient statistical power and meaningful clinical results. A group of randomized patients represents the final point of sequential steps. Also of importance is to what kind of ‘population’ the results from the studied sample can be applied (qualitatively, not necessarily quantitatively), i.e. the general applicability of a study, or whether the findings can be used to treat future patients with the same or similar characteristics as those randomized, or to all patients with the same pathology. Answers to these questions depend on many aspects of the randomized selection mechanisms, the disease characteristics, and knowledge of the biological effects of the drug to be tested.
The origins, early development and status of Bourdieu's concept of ‘cultural capital’
Authors: Robbins Derek
Published: March 2005

The paper examines the context of the first introduction of the concept of ‘cultural capital’ in the sociology of education analyses undertaken in the early 1960s and published by Bourdieu in collaboration with Jean‐Claude Passeron in ‘Les étudiants et leurs études’ (1964a) and Les Héritiers (1964b). It first considers the cultural contexts within which Bourdieu's thinking about culture originated – both in relation to his social origins and in relation to his intellectual training. It then examines the extent to which Bourdieu's early anthropological research in Algeria was influenced by his knowledge of American acculturation theory. It concludes that Bourdieu sought to use acculturation theory in a distinctive way – one which he articulated more confidently as he explored the relationship between agency and structural explanation in the late 1960s and early 1970s. The specific educational researches which stimulated the articulation of the concept of ‘linguistic’ or ‘cultural’ capital belonged to the period in which Bourdieu was only just beginning to refine his post‐structuralist philosophy of social scientific explanation. To use these concepts now involves deploying them reflexively in accordance with Bourdieu's later thinking rather than at face value as they were first developed during the period in which he and Passeron were ‘apprentice’ researchers.
A follow up study of vibration induced white finger in compensation claimants
Authors: Bovenzi M , Della Vedova A , Negro C
Published: March 2005

Aims:To follow up vibration induced white finger (VWF) in a selected group of 73 vibration exposed workers who claimed unsuccessfully for VWF compensation at a first examination.

Methods:The VWF claimants were sent to our unit by the National Insurance Institute. The basic compensatory criteria included a positive history of VWF and abnormal cold response of the digital arteries. Following the first unsuccessful examination, over a mean time period of 4.1 (range 1–11) years the National Insurance Institute requested a second examination for all 73 claimants and a third examination for 29. During the follow up period, all subjects continued to work with vibratory tools.

Results:There were 14 new cases who reported white finger during the follow up period. In the new VWF cases, finger blanching attacks became visible after about 3.5 years since the first examination. All incident cases of anamnestic VWF showed an abnormal cold response in the digital arteries and obtained compensation according to the basic compensatory criteria. In the entire sample of VWF claimants, there was a discrepancy between positive history of VWF symptoms at medical interview (55%) and abnormal cold provocation outcomes (19%). Digital arterial hyperresponsiveness to cold was associated with both VWF symptoms and the duration of vibration exposure since the first examination. Over the follow up period, a significant increase in the vasoconstrictor response to cold was observed in the vibration exposed workers with no symptoms of finger whiteness. Abnormal cold response was not associated with either age or smoking habit.

Conclusions:Cold test measuring finger systolic blood pressure may be considered a useful laboratory method to confirm objectively VWF symptoms and to disclose abnormal cold induced vasoconstrictor response in vibration exposed workers with a negative history of VWF. Medical interview outcomes should be interpreted with caution in medicolegal situations involving VWF claimants.
Adsorption of boron from landfill leachate by peat and the effect of environmental factors
Authors: Sartaj Majid , Fernandes Leta
Published: March 2005

The effect of different environmental factors including drying, shaking, soil-to-solution ratio, competing ions, solution composition, time, pH, and temperature on adsorption of boron from landfill leachate by peat was investigated. The statistical comparison of experimental results showed that shaking of adsorption samples, soil-to-solution ratio, long-term adsorption, and competing ions did not have any significant effect on boron adsorption. However, solution composition, drying of peat prior to adsorption tests, pH, and temperature had a significant effect on the adsorption of boron by peat. Diluting leachate samples with distilled water had a negative effect on the adsorption capacity. Drying peat significantly reduced its boron adsorption capacity. Boron adsorption reached maximum level at a pH range of 9–9.5. Temperature had a negative effect on the adsorption of boron. The results of two-level factorial design experiments showed that pH had the strongest effect on the adsorption of boron by peat. Key words: boron, peat, landfill, leachate, adsorption, pH, temperature, factorial design.
Spectral impact of inactivating light on photoreactivation of Escherichia coli
Authors: Oguma Kumiko , Katayama Hiroyuki , Ohgaki Shinichiro
Published: March 2005

The spectral impact of inactivating light on subsequent photoreactivation of Escherichia coli K12 was investigated. Ultraviolet-induced pyrimidine dimers in the genome of E. coli were determined, while the survival of E. coli was also examined. A medium-pressure UV lamp (MP: 220–580 nm) was equipped with an optical bandpass filter with the peak emission at 230 nm, 254 nm, or 300 nm, in order to characterize the photoreactivation properties. As references, a MP lamp without a filter, a MP lamp with a glass plate (MPG: 300–580 nm), and a low-pressure UV lamp (LP: 254 nm) were also used for inactivation. Medium pressure inactivation at 230 nm, 254 nm, or 300 nm was followed by the photoreactivation of survival ratio, which was comparable to that after LP exposure. Meanwhile, a repressed survival recovery was observed after MP or MPG inactivation. It was therefore indicated that the MP lamp was effective at repressing photoreactivation of E. coli, which was not attributable to the specific MP emission either at 230 nm, 254 nm, or 300 nm. Rather, the simultaneous exposure to broad wavelengths might provide the MP lamp with the repair repressive effect. Key words: endonuclease sensitive site (ESS), Escherichia coli, medium-pressure UV lamp, photoreactivation, spectral impact, ultraviolet (UV) disinfection.
The Safety and Effectiveness of Newer Antiepileptics: A Comparative Postmarketing Cohort Study
Authors: Acharya Nayan V. , Pickering Ruth M. , Wilton Lynda W. , Shakir Saad A. W.
Published: March 2005

Clinical trials for the newer antiepileptic drugs (AEDs) have provided inconclusive information to evaluate comparative risk benefit. The authors use data from postmarketing observational cohort studies to compare the failure of treatment with lamotrigine, vigabatrin, and gabapentin in patients with refractory epilepsy. The Drug Safety Research Unit has conducted prescription event monitoring (PEM) studies for lamotrigine, vigabatrin, and gabapentin to monitor their safety when used in primary care. The primary outcome of this study was time to treatment failure in patients who had been prescribed the drug after the start of the PEM study. Patients on gabapentin had reduced time to treatment failure compared to those on the other 2 drugs. The age‐ and sex‐adjusted hazard ratio of failure was 1.53 (95% confidence interval [CI] = 1.38–1.70) for gabapentin compared to lamotrigine and 1.19 (95% CI = 1.10–1.30) for vigabatrin compared to lamotrigine. The observed differences between the 3 study drugs might be confounded by a higher proportion of patients treated with gabapentin having refractory epilepsy, a shorter duration of the gabapentin PEM study, and a lower relative dose of gabapentin (approved at the time of the PEM study). The current study provides information about the routine usage of newer AEDs, which complements evidence from clinical trials regarding the efficacy and safety of these AEDs. Although this study showed differences on times to treatment failure between lamotrigine, vigabatrin, and gabapentin, the results are only useful when considered together with results from other studies seeking to answer the same questions.
Potential Utility of Data‐Mining Algorithms for Early Detection of Potentially Fatal/Disabling Adverse Drug Reactions: A Retrospective Evaluation
Authors: Hauben Manfred , Reich Lester
Published: March 2005

The objective of this study was to apply 2 data‐mining algorithms to a drug safety database to determine if these methods would have flagged potentially fatal/disabling adverse drug reactions that triggered black box warnings/drug withdrawals in advance of initial identification via “traditional” methods. Relevant drug‐event combinations were identified from a journal publication. Data‐mining algorithms using commonly cited disproportionality thresholds were then applied to the US Food and Drug Administration database. Seventy drug‐event combinations were considered sufficiently specific for retrospective data mining. In a minority of instances, potential signals of disproportionate reporting were provided clearly in advance of initial identification via traditional pharmacovigilance methods. Data‐mining algorithms have the potential to improve pharmacovigilance screening; however, for the majority of drug‐event combinations, there was no substantial benefit of either over traditional methods. They should be considered as potential supplements to, and not substitutes for, traditional pharmacovigilance strategies. More research and experience will be needed to optimize deployment of data‐mining algorithms in pharmacovigilance.
Premature Ejaculation Revisited—2005
Authors: Renshaw Domeena C.
Published: March 2005

Although premature ejaculation is an ancient, not uncommon sexual problem, an acceptable definition remains controversial. Although highly treatable, the symptom has been clinically neglected; the patient is usually medically checked, has a rectal examination, and is told he is normal without further direction. Education, guidance, and support can significantly lessen the patient’s performance anxiety and prevent erectile dysfunction and loss of desire, which are known to follow the symptom. In resistant cases, there are now effective medications, as discussed.
Sublethal effects of Orimulsion-400® on eggs and larvae of Atlantic herring (Clupea harengus L.)
Authors: Williams Jim , Roderick Carol , Alexander Ross
Published: March 2005

Orimulsion-400® is a novel bitumen-emulsion power plant fuel. We exposed Atlantic herring (Clupea harengus L.) eggs to 0, 0.1, 1.0, 10, 100, and 1,000 mg/L concentrations of an oil-in-water dispersion of Orimulsion-400 for a 24-h period. No significant differences were found in daily mortality or percent hatch. The 1,000 mg/L exposure resulted in a significantly higher incidence of premature hatch, indicated by significantly shorter incubation time, significantly smaller total length and notochord length, and significantly greater yolk sac depth. The larvae exposed to the 1,000 mg/L treatment also had a significantly higher incidence of abnormalities than all other treatments.
Uptake and depuration of cadmium, nickel, and lead in laboratory-exposed Tubifex tubifex and corresponding changes in the concentration of a metallothionein-like protein
Authors: Gillis Patricia L. , Dixon D. George , Borgmann Uwe , Reynoldson Trefor B.
Published: March 2005

Based on weight loss in water, 2 4h is recommended for Tubifex tubifex gut clearance. Biota-to-sediment accumulation factors (BSAFs) in gut-cleared T. tubifex following six weeks of exposure to Cd-, Ni-, and Pb-spiked sediment were 12.4, 3.0, and 19.0, respectively. Tissue Ni concentrations peaked after 12 h, whereas Cd and Pb were accumulated for the duration of the exposure. Tubifex tubifex were transferred to either water (24 h) or sediment (10 weeks) to monitor changes in internal metal concentrations. After 24 h in water, only Ni concentration had declined significantly (p < 0.05), suggesting that the majority of Ni was associated with the gut content, while Cd and Pb were accumulated in the tissues. Metal depuration in sediment was described with two-compartment, first-order kinetic models (r2 = 0.7–0.8; p < 0.001), indicating that T. tubifex has both a quickly depurated and a more tightly bound pool of accumulated metal. Tubifex tubifex were also exposed to sediment spiked with just Cd (3.66 μmol/g). Cadmium uptake and induction of metallothionein-like protein (MTLP) were rapid; both parameters were significantly elevated within 24 h of exposure. Metallothionein-like protein (8.7 ± 1.8 nmol/g) and Cd (60.8 ± 11.0 μmol/g) reached maximum concentrations after 96 h and four weeks, respectively.
Combination of microautoradiography and fluorescence in situ hybridization for identification of microorganisms degrading xenobiotic contaminants
Authors: Yang Yanru , Zarda Annatina , Zeyer Josef
Published: March 2005

One of the central topics in environmental bioremediation research is to identify microorganisms that are capable of degrading the contaminants of interest. Here we report application of combined microautoradiography (MAR) and fluorescence in situ hybridization (FISH). The method has previously been used in a number of systems; however, here we demonstrate its feasibility in studying the degradation of xenobiotic compounds. With a model system (coculture of Pseudomonas putida B2 and Sphingomonas stygia incubated with [14C] o-nitrophenol), combination of MAR and FISH was shown to be able to successfully identify the microorganisms degrading o-nitrophenol. Compared with the conventional techniques, MAR-FISH allows fast and accurate identification of the microorganisms involved in environmental contaminant degradation.
Toward detoxifying mercury-polluted aquatic sediments with rice genetically engineered for mercury resistance
Authors: Heaton Andrew C. P. , Rugh Clayton L. , Kim Tehryung , Wang Nianjie J. , Meagher Richard B.
Published: March 2005

Mercury contamination of soil and water is a serious problem at many sites in the United States and throughout the world. Plant species expressing the bacterial mercuric reductase gene, merA, convert ionic mercury, Hg(II), from growth substrates to the less toxic metallic mercury, Hg(0). This activity confers mercury resistance to plants and removes mercury from the plant and substrates through volatilization. Our goal is to develop plants that intercept and remove Hg(II) from polluted aquatic systems before it can undergo bacterially mediated methylation to the neurotoxic methylmercury. Therefore, the merA gene under the control of a monocot promoter was introduced into Oryza sativa L. (rice) by particle gun bombardment. This is the first monocot and first wetland-adapted species to express the gene. The merA-expressing rice germinated and grew on semisolid growth medium spiked with sufficient Hg(II) to kill the nonengineered (wild-type) controls. To confirm that the resistance mechanism was the conversion of Hg(II) to Hg(0), seedlings of merA-expressing O. sativa were grown in Hg(II)-spiked liquid medium or water-saturated soil media and were shown to volatilize significantly more Hg(0) than wild-type counterparts. Further genetic manipulation could yield plants with increased efficiency to extract soil Hg(II) and volatilize it as Hg(0) or with the novel ability to directly convert methylmercury to Hg(0).
Speciation of heavy metals in recent sediments of three coastal ecosystems in the Gulf of Cadiz, Southwest Iberian Peninsula
Authors: Sáenz Veronica , Blasco Julián , Gómez-Parra Abelardo
Published: March 2005

A five-step sequential extraction technique was used to determine the partitioning of Cr, Mn, Fe, Cu, Zn, Cd, and Pb among the operative sedimentary phases (exchangeable ions, carbonates, manganese and iron oxides, sulfides and organic matter, and residual minerals) in coastal sediment from three locations in the southwest Iberian Peninsula. Two sites are located close to industrial areas, the salt marshes of the Odiel River and Bay of Cádiz, and one in a nonindustrial area, the Barbate River salt marshes. The Odiel River salt marshes also receive the drainage from mining activities in the Huelva region. In the sediments from the Bay of Cádiz and Barbate River salt marshes, Cr, Cu, Fe, and Zn were extracted from the residual fraction at percentages higher than 60%. In the sediments from the Odiel River salt marshes, concentrations of all the metals, except Cu, zn, and cd, exceeded 60% in the residual fraction as well. In the sediments from the Bay of Cádiz and Barbate River salt marshes, the main bioavailable metals were Mn and Cd; in those from the Odiel River salt marshes, the main bioavailable metals were Zn and Cd, respectively. The environmental risk was determined by employing the environmental risk factor (ERF), defined as ERF = (CSQV — Ci/CSQV), where Ci is the heavy metal concentration in the first four fractions and CSQV is concentration sediment quality value (the highest concentration with no associated biological effect). Our results showed that the sediments from the Cádiz Bay and Barbate River salt marshes do not constitute any environmental risk under the current natural conditions. In contrast, in the Odiel River salt marshes, Cu, Zn, and Pb yielded ERFs of less than zero at several sampling stations and, consequently, pose a potential threat for the organisms in the area. This is a consequence of the high levels of metals in the area derived from the mining activity (pyrite) and industrial activities and the association of these heavy metals with more labile fractions of the sediments.
Predicting toxic equivalence factors from 13C nuclear magnetic resonance spectra for dioxins, furans, and polychlorinated biphenyls using linear and nonlinear pattern recognition methods
Authors: Buzatu Dan A. , Beger Richard D. , Wilkes Jon G. , Lay Jackson O.
Published: March 2005

Two quantitative spectrometric data-activity relationships (QSDAR) models have been developed relating 29 dioxin or dioxin-like molecules to their toxic equivalence factors (TEFs). These models were based on patterns in simulated 13C nuclear magnetic resonance (NMR) data with the patterns defined by comparative spectral analysis (CoSA). Two versions of CoSA multiple linear regression (MLR) models using 7 or 10 spectral bins had, respectively, explained variances (r2) of 0.88 and 0.95, and leave-one-out (LOO) cross-validated variances (q2) of 0.78 and 0.88. A third, artificial neural network model—using a feed forward, back propagating, three-layer neural network—produced an r2 of 0.99, a LOO q2 of 0.82, and a leave-three-out q2 of 0.81. A postulated reason that the results of these QSDAR models are better than traditional quantitative structure-activity relationship (QSAR) models is based on the difference in descriptors rather than on any differences in pattern recognition approach. Results suggest that the 13C NMR spectral data contain molecular quantum mechanical information more reflective of each molecule's biochemical properties than do the calculated electrostatic potentials and molecular alignment assumptions used in developing QSAR models. The QSDAR models provide a rapid, simple way to model the toxicity of dioxin and dioxin-like compounds.
Alterations to gonadal development and reproductive success in japanese medaka (Oryzias latipes) exposed to 17α-ethinylestradiol
Authors: Balch Gordon C. , Mackenzie Constanze A. , Metcalfe Chris D.
Published: March 2005

The Japanese medaka (Oryzias latipes) was used as an in vivo model to evaluate the effects of exposure to the synthetic estrogen 17α-ethinylestradiol (EE2) on reproductive behavior and reproductive success in fish. Exposures to EE2 began within 2 to 5 d posthatch and continued until medaka were sexually mature, between four and six months of age. Among male and female medaka exposed to EE2 at nominal concentrations of 0.2 and 2 ng/L, mating behavior and reproductive success were normal in reproductive trials. However, reproductive behavior (i.e., copulations) was suppressed in the treatment with 10 ng/L EE2. Among 19 males exposed to 10 ng/L EE2 and placed with unexposed females in reproductive trials, 16 males did not copulate and reproductive success was very low. None of the females exposed to 10 ng/L of EE2 participated in reproductive behavior with unexposed males. The reproductive trials in combination with a histological survey indicated that male fish with gonadal intersex (i.e., testis-ova) were still capable of reproductive behavior and could fertilize eggs. Even though females exposed to 10 ng/L EE2 had poor reproductive success, their ovaries showed normal development and oogenesis. These data are relevant to observations of intersex in feral fish populations. Although intersex in male fish may be an indicator of exposure to estrogenic compounds, it appears that the presence of oocytes in testicular tissue may not directly impact the reproductive capability of the male fish. However, it is clear that concentrations of endocrine disrupting chemicals (EDCs) that cause gonadal intersex are sufficient to reduce reproductive performance.
Investigating the role of desorption on the bioavailability of sediment-associated 3,4,3′,4′-tetrachlorobiphenyl in benthic invertebrates
Authors: Leppänen Matti T. , Landrum Peter F. , Kukkonen Jussi V. K. , Greenberg Marc S. , Burton G. Allen , Robinson Sander D. , Gossiaux Duane C.
Published: March 2005

Only a fraction of all sediment-associated hydrophobic organic contaminants are bioavailable, and a simple Tenax® extraction procedure may estimate this fraction. Bioavailability is assumed to coincide with the rapidly and, possibly, slowly desorbing sediment-associated contaminant. River sediment was spiked with radiolabeled (14C) and nonradiolabeled (12C) 3,4,3,4′-tetrachlorobiphenyl (TCBP), and desorption kinetics using Tenax extraction were obtained at 10°C and 22°C. Bioaccumulation was measured in Lumbriculus variegatus, Chironomus tentans, and Hyalella azteca. Desorption of TCBP was triphasic at 22°C and slowed at 10°C to show only biphasic kinetics. The rapidly desorbing fractions decreased with increasing TCBP sediment concentration. The biota sediment accumulation factors, biota accumulation factors, and sediment clearance coefficients (ks) also decreased with increasing sediment TCBP concentration. The rapidly plus slowly desorbing fractions and the total TCBP desorbed when 99.9% of the rapidly desorbing fraction had desorbed were used to estimate bioavailable TCBP. These Tenax-based fractions did not explain the decreasing bioavailability with increasing TCBP load. Several factors, such as animal behavior and TCBP water solubility limitations, were evaluated to explain the concentration effect, but the most likely cause was severe diffusion limitations in whole sediment that were not predicted by the fully mixed Tenax extraction. Therefore, desorbing fractions determined by Tenax extraction overestimated the bioavailable fractions in sediments.
Effects of sublethal fenitrothion ingestion on cholinesterase inhibition, standard metabolism, thermal preference, and prey-capture ability in the Australian central bearded dragon (Pogona vitticeps, agamidae)
Authors: Bain David , Buttemer William A. , Astheimer Lee , Fildes Karen , Hooper Michael J.
Published: March 2005

The central bearded dragon (Pogona vitticeps) is a medium-sized lizard that is common in semiarid habitats in Australia and that potentially is at risk of fenitrothion exposure from use of the chemical in plague locust control. We examined the effects of single sublethal doses of this organophosphate (OP; low dose = 2.0 mg/kg; high dose = 20 mg/kg; control = vehicle alone) on lizard thermal preference, standard metabolic rate, and prey-capture ability. We also measured activities of plasma total cholinesterase (ChE) and acetylcholinesterase before and at 0, 2, 8, 24, 120, and 504 h after OP dosing. Predose plasma total ChE activity differed significantly between sexes and averaged 0.66 ± 0.06 and 0.45 ± 0.06 μmol/min/ml for males and females, respectively. Approximately 75% of total ChE activity was attributable to butyrylcholinesterase. Peak ChE inhibition reached 19% 2 h after OP ingestion in the low-dose group, and 68% 8 h after ingestion in high-dose animals. Neither OP doses significantly affected diurnal body temperature, standard metabolic rate, or feeding rate. Plasma total ChE levels remained substantially depressed up to 21 d after dosing in the high-dose group, making this species a useful long-term biomonitor of OP exposure in its habitat.