bluuebunny/crossref_metadata_2025 huggingface dataset:
Marker-specific sorting of rare cells using dielectrophoresis
Authors: Hu Xiaoyuan , Bessette Paul H. , Qian Jiangrong , Meinhart Carl D. , Daugherty Patrick S. , Soh Hyongsok T.
Published: October 2005

Current techniques in high-speed cell sorting are limited by the inherent coupling among three competing parameters of performance: throughput, purity, and rare cell recovery. Microfluidics provides an alternate strategy to decouple these parameters through the use of arrayed devices that operate in parallel. To efficiently isolate rare cells from complex mixtures, an electrokinetic sorting methodology was developed that exploits dielectrophoresis (DEP) in microfluidic channels. In this approach, the dielectrophoretic amplitude response of rare target cells is modulated by labeling cells with particles that differ in polarization response. Cell mixtures were interrogated in the DEP-activated cell sorter in a continuous-flow manner, wherein the electric fields were engineered to achieve efficient separation between the dielectrophoretically labeled and unlabeled cells. To demonstrate the efficiency of marker-specific cell separation, DEP-activated cell sorting (DACS) was applied for affinity-based enrichment of rare bacteria expressing a specific surface marker from an excess of nontarget bacteria that do not express this marker. Rare target cells were enriched by >200-fold in a single round of sorting at a single-channel throughput of 10,000 cells per second. DACS offers the potential for automated, surface marker-specific cell sorting in a disposable format that is capable of simultaneously achieving high throughput, purity, and rare cell recovery.
Motivation to support a desired conclusion versus motivation to avoid an undesirable conclusion: The case of infra‐humanization
Authors: Demoulin Stéphanie , Leyens Jacques‐Philippe , Rodríguez‐Torres Ramón , Rodríguez‐Pérez Armando , Paladino Paola Maria , Fiske Susan T.
Published: October 2005

Social motivation has been shown to influence various cognitive processes. In the present paper, it is verified that people are motivated to view out‐groups as possessing a lesser degree of humanity than the in‐group (Leyens et al., 2000) and that this motivation influences logical processing in the Wason selection task. So far, studies on infra‐humanization have been shown to influence attribution of uniquely human characteristics to groups. Most of these studies focused on the attribution of secondary emotions. Results have shown that secondary emotions are preferentially attributed to in‐group members (Leyens et al., 2001). Also, people tend to react differently to in‐group and out‐group members displaying secondary emotions (Gaunt, Leyens, & Sindic, 2004; Vaes, Paladino, Castelli, Leyens, & Giovanazzi, 2003). In the present paper, it is argued that infra‐humanization is a two‐direction bias and that it does influence logical processing among perceivers. Specifically, infra‐humanization motivation impacts logical processing in two different directions. First, most motivation is spent to reach the desirable conclusion that the in‐group is uniquely human. Second, least motivation occurs to support the undesirable conclusion that the out‐group is uniquely human. These hypotheses are tested in four cross‐cultural studies that varied the status and the conflicting relations between groups. Results were in line with the predictions and further confirmed that infra‐humanization biases can be obtained independently of status and conflict (but see Cortes, Demoulin, Leyens, & de Renesse, 2005). The discussion relates these findings with in‐group favouritism and out‐group derogation (Brewer, 1999) and underlines the importance of infra‐humanization in counteracting system justification biases (Jost & Banaji, 1994).
A Gene Expression Signature that Predicts the Future Onset of Drug-Induced Renal Tubular Toxicity
Authors: Fielden Mark R. , Eynon Barrett P. , Natsoulis Georges , Jarnagin Kurt , Banas Deborah , Kolaja Kyle L.
Published: October 2005

One application of genomics in drug safety assessment is the identification of biomarkers to predict compound toxicity before it is detected using traditional approaches, such as histopathology. However, many genomic approaches have failed to demonstrate superiority to traditional methods, have not been appropriately validated on external samples, or have been derived using small data sets, thus raising concerns of their general applicability. Using kidney gene expression profiles from male SD rats treated with 64 nephrotoxic or non-nephrotoxic compound treatments, a gene signature consisting of only 35 genes was derived to predict the future development of renal tubular degeneration weeks before it appears histologically following short-term test compound administration. By comparison, histopathology or clinical chemistry fails to predict the future development of tubular degeneration, thus demonstrating the enhanced sensitivity of gene expression relative to traditional approaches. In addition, the performance of the signature was validated on 21 independent compound treatments structurally distinct from the training set. The signature correctly predicted the ability of test compounds to induce tubular degeneration 76% of the time, far better than traditional approaches. This study demonstrates that genomic data can be more sensitive than traditional methods for the early prediction of compound-induced pathology in the kidney.
Local Government and the Meanings of Political Representation: A Case Study of Bologna between 1860 and 1915
Authors: Körner Axel
Published: October 2005

Since the early nineteenth century political opposition became a central concept of political representation in constitutional monarchies. While this concept marked the political language of unified Italy on the national level, in local administration the legitimacy of political opposition remained an issue of dispute, as illustrated in this analysis of the political language in Bologna's local council. Local perceptions of national events, like the government's reaction to Garibaldi's unsuccessful Mentana-campaign, assumed major symbolic meaning in local politics and challenged traditional understandings of municipal administration by introducing the concept of political opposition. In Bologna, after Rome the second city of the former Papal State, the Moderates were able to grow into a position of political hegemony after the Unification of Italy and remained the predominant political force also after Italy's “parliamentary revolution” of 1876 and the electoral reforms of the 1880s. As a consequence of its limited influence on the local administration, Bologna's Left defined its ideological profile earlier and more clearly than the Left in other parts of Italy and integrated issues of national importance into local political discourse. Analysing the relationship between central administration and periphery, the article reveals the development of political language and the changing meanings of political representation between Unification and World War One and explains on this basis the escalation of social and political conflict in Finesecolo Italy.
Women's History and Gender History: The Italian Experience
Authors: Fiume Giovanna
Published: October 2005

Since the early nineteenth century political opposition became a central concept of political representation in constitutional monarchies. While this concept marked the political language of unified Italy on the national level, in local administration the legitimacy of political opposition remained an issue of dispute, as illustrated in this analysis of the political language in Bologna's city council. Local perceptions of national events, like Garibaldi's unsuccessful Mentana-campaign, assumed a significant symbolic meaning and challenged traditional understandings of local administration by introducing notions of political opposition. In Bologna, the second city of the former Papal State, the Moderates were able to form a political hegemony after the Unification of Italy and remained the predominant political force also after the parliamentary revolution of 1876 and the electoral reforms of the 1880s. Due to its limited influence on the local administration, Bologna's Left defined its ideological profile earlier and more clearly than the Left in other parts of Italy and integrated issues of national importance into local political discourse. Illustrating the relationship between central administration and the periphery, the article analyses the development of political language and changing meanings of political representation on the local level between Unification and World War One.
Evaluating and improving cDNA sequence quality with cQC
Authors: Hayden Celine A. , Wheeler Travis J. , Jorgensen Richard A.
Published: October 2005

Summary: Errors are prevalent in cDNA sequences but the extent to which sequence collections differ in frequencies and types of errors has not been investigated systematically. cDNA quality control, or cQC, was developed to evaluate the quality of cDNA sequence collections and to revise those sequences that differ from a higher quality genomic sequence. After removing rRNA, vector, bacterial insertion sequence and chimeric cDNA contaminants, small-scale nucleotide discrepancies were found in 51% of cDNA sequences from one Arabidopsis cDNA collection, 89% from a second Arabidopsis collection and 75% from a rice collection. These errors created premature termination codons in 4 and 42% of cDNA sequences in the respective Arabidopsis collections and in 7% of the rice cDNA sequences.

Availability: A web-based version of cQC, source code and revised cDNA collections are available at

Contact:  raj@ag.arizona.edu

Supplementary information: Further text, tables and figures are available at the above website or on Bioinformatics online.
Improving the efficiency of SPR moves in phylogenetic tree search methods based on maximum likelihood
Authors: Hordijk Wim , Gascuel Olivier
Published: October 2005

Motivation: Maximum likelihood (ML) methods have become very popular for constructing phylogenetic trees from sequence data. However, despite noticeable recent progress, with large and difficult datasets (e.g. multiple genes with conflicting signals) current ML programs still require huge computing time and can become trapped in bad local optima of the likelihood function. When this occurs, the resulting trees may still show some of the defects (e.g. long branch attraction) of starting trees obtained using fast distance or parsimony programs.

Methods: Subtree pruning and regrafting (SPR) topological rearrangements are usually sufficient to intensively search the tree space. Here, we propose two new methods to make SPR moves more efficient. The first method uses a fast distance-based approach to detect the least promising candidate SPR moves, which are then simply discarded. The second method locally estimates the change in likelihood for any remaining potential SPRs, as opposed to globally evaluating the entire tree for each possible move. These two methods are implemented in a new algorithm with a sophisticated filtering strategy, which efficiently selects potential SPRs and concentrates most of the likelihood computation on the promising moves.

Results: Experiments with real datasets comprising 35–250 taxa show that, while indeed greatly reducing the amount of computation, our approach provides likelihood values at least as good as those of the best-known ML methods so far and is very robust to poor starting trees. Furthermore, combining our new SPR algorithm with local moves such as PHYML's nearest neighbor interchanges, the time needed to find good solutions can sometimes be reduced even more.

Availability: Executables of our SPR program and the used datasets are available for download at

Contact:  gascuel@lirmm.fr; wim@santafe.edu
Prediction of protein–protein interactions using random decision forest framework
Authors: Chen Xue-Wen , Liu Mei
Published: October 2005

Motivation: Protein interactions are of biological interest because they orchestrate a number of cellular processes such as metabolic pathways and immunological recognition. Domains are the building blocks of proteins; therefore, proteins are assumed to interact as a result of their interacting domains. Many domain-based models for protein interaction prediction have been developed, and preliminary results have demonstrated their feasibility. Most of the existing domain-based methods, however, consider only single-domain pairs (one domain from one protein) and assume independence between domain–domain interactions.

Results: In this paper, we introduce a domain-based random forest of decision trees to infer protein interactions. Our proposed method is capable of exploring all possible domain interactions and making predictions based on all the protein domains. Experimental results on Saccharomyces cerevisiae dataset demonstrate that our approach can predict protein–protein interactions with higher sensitivity (79.78%) and specificity (64.38%) compared with that of the maximum likelihood approach. Furthermore, our model can be used to infer interactions not only for single-domain pairs but also for multiple domain pairs.

Contact:  xwchen@ku.edu

Availability: Source code is written in Java and is available upon request from the authors.

Supplementary information:
Regularized ROC method for disease classification and biomarker selection with microarray data
Authors: Ma Shuangge , Huang Jian
Published: October 2005

Motivation: An important application of microarrays is to discover genomic biomarkers, among tens of thousands of genes assayed, for disease classification. Thus there is a need for developing statistical methods that can efficiently use such high-throughput genomic data, select biomarkers with discriminant power and construct classification rules. The ROC (receiver operator characteristic) technique has been widely used in disease classification with low-dimensional biomarkers because (1) it does not assume a parametric form of the class probability as required for example in the logistic regression method; (2) it accommodates case–control designs and (3) it allows treating false positives and false negatives differently. However, due to computational difficulties, the ROC-based classification has not been used with microarray data. Moreover, the standard ROC technique does not incorporate built-in biomarker selection.

Results: We propose a novel method for biomarker selection and classification using the ROC technique for microarray data. The proposed method uses a sigmoid approximation to the area under the ROC curve as the objective function for classification and the threshold gradient descent regularization method for estimation and biomarker selection. Tuning parameter selection based on the V-fold cross validation and predictive performance evaluation are also investigated. The proposed approach is demonstrated with a simulation study, the Colon data and the Estrogen data. The proposed approach yields parsimonious models with excellent classification performance.

Availability: R code is available upon request.

Contact:  jian@stat.uiowa.edu
The Uses of Putativity and Negativity in the Conflict of Laws
Authors: Crawford Elizabeth B
Published: October 2005

Putativity is a useful concept in the conflict of laws, allowing reference to be made to an outcome which was intended to have come about, but which has failed, as a result of human actings or divine intervention. To apply to something which is imperfect a consequence which would arise if it were perfect is justifiable on the pragmatic grounds of convenience, speed, and cost—and thence, through the merit of certainty, to the satisfaction (perhaps) of party expectation, or at least to the forestalling of disappointment. Reference to the putative applicable law may be permissible therefore on the ground of enabling a resolution to emerge, the more so if the result of so doing commends itself to the disinterested observer and to one, at least, of the parties; on the other hand, the result may disappoint the reasonable expectations of both parties. Whatever the rationale, it can be observed that use of the device is authorized at common law, by statute, in Convention, and Regulation. But if one does not ask whether this methodological technique begs the question, one begs the question.
Taking the Strasbourg Jurisprudence into Account: Developing a ‘Municipal Law of Human Rights’ under the Human Rights Act
Authors: Masterman Roger
Published: October 2005

Questions surrounding the legitimate extent of the judicial role have long been the source of controversy. Concerns that unelected and unrepresentative judges are ‘legislating’ rather than interpreting the law or are interfering in matters of ‘democratically endorsed’ government policy, have often been, and will continue to be, raised by academics and politicians alike. The question is one of separation of power— of the appropriate constitutional role and division of functions between the executive, judicial, and legislative branches of the United Kingdom Government. This debate has been given a new dimension by the Human Rights Act 1998 (hereafter HRA), most obviously through the courts' exercise of their power under section 3(1) of that Act—the duty to interpret primary and secondary legislation to be, as far as possible, compatible with ‘the Convention rights’. Indeed much has been made of the unique method by which the HRA reconciles the interpretative obligation under section 3(1) with the sovereignty of Parliament by way of the ‘declaration of incompatibility’ under section 4. The doctrine of parliamentary sovereignty imposes limits on the scope of section 3(1); in spite of its ‘broad and malleable’ language, which might permit ‘an interpretation which linguistically may appear strained’, it does not sanction courts to act as legislators. As Lord Nicholls of Birkenhead noted in Re S; Re W, attributing to a statutory provision ‘a meaning which departs substantially from a fundamental feature of an Act of Parliament is likely to have crossed the boundary between interpretation and amendment’. That case has been seen by some as a retreat from what has been termed the ‘far-fetched’ interpretation of section 3(1) adopted by the House of Lords in the earlier decision of R v A. Nicol, for one, has argued that Re S; Re W and Anderson taken together, clearly reject ‘the notion that “interpretations” could conflict with clear statutory words' — as R v A had arguably suggested — thereby endorsing parliamentary sovereignty, above the Convention, ‘as the country's supreme constitutional doctrine’. For it to retain its legitimacy therefore, the judicial act under section 3(1) needs to remain an exercise of ‘interpretation’: to attribute a meaning to a legislative provision ‘quite different from that which Parliament intended … would go well beyond any interpretative process sanctioned by section 3 of the 1998 Act’. It would ‘not be judicial interpretation but judicial vandalism’.
Stays of Proceedings and the Brussels Convention
Authors: Harris Jonathan
Published: October 2005

The Court of Justice has ruled in Owusu v Jackson that the Brussels Convention is applicable even where a case has objective connections to only one Contracting State and to a non-Contracting State. It has also held that where the court of a Contracting State to the Brussels Convention has jurisdiction on the basis of the defendant's domicile pursuant to Article 2, it has no general discretion to stay its proceedings in favour of the court of a non-Contracting State on the basis that the latter is the natural forum for resolution of the dispute. However, the ruling leaves a number of important questions unresolved. This article considers the reasoning behind, and implications of the ruling, and the permissibility of staying proceedings in other situations falling within the scope of the Brussels regime post-Owusu.
Denying Foreign State Immunity for Commission of International Crimes: The Ferrini Decision
Authors: Focarelli Carlo
Published: October 2005

The Italian Court of Cassation has recently delivered a judgment of great interest denying State immunity to Germany for commission of crimes under customary international law on the exclusive basis of international law.
The Continuing Debate on a un Convention on State Responsibility
Authors: Crawford James , Olleson Simon
Published: October 2005

At its 59th session in 2004, the General Assembly revisited the question of what should be done with the Articles on Responsibility of States for Internationally Wrongful Acts (‘the Articles’), adopted by the International Law Commission (‘ILC’) in 2001. By Resolution 59/35, adopted by consensus on 2 December 2004 on the recommendation of the Sixth Committee, the General Assembly once again resolved to defer further consideration and any decision on the final form of the Articles, postponing the matter to its 62nd session in 2007. It also asked the Secretariat to prepare a compendium of jurisprudence and State practice to assist the Assembly in its consideration of the topic at that time.
I. Social Policy
Authors: McMahon Joe , Szyszczak Erika
Published: October 2005

The wide range of developments in social policy has necessitated dividing this commentary into two parts. The first part will examine discrimination law developments; the second part, published inthe next issue, will look at general employment law developments.
Six characters (and a few more) in search of an author: how to rescue rural development before it's too late
Authors: Maxwell Simon
Published: October 2005

Rural development has not received the priority and attention warranted by the present and future concentration of poverty in rural areas. Is this perhaps because rural development agencies present conflicting narratives? A framework is presented within which to answer that question, and is then applied to the recent policy statements of the European Union (EU), Food and Agriculture Organization (FAO), International Fund for Agricultural Deveopment (IFAD), and the World Bank. Each policy statement is compelling in its own way, but the strategies are not consistent. A narrative is needed, which recognizes the rapid pace of change in rural areas, acknowledges the need for diversification out of agriculture, builds market institutions for growth, and works effectively within the current international consensus on poverty reduction, emphasising opportunity, empowerment, and security.
Achieving success in rural development: toward implementation of an integral approach
Authors: De Janvry Alain , Sadoulet Elisabeth
Published: October 2005

Starting from an analysis of the reasons for failure of previous “integrated” approaches to rural development, we propose here a conceptual framework for an “integral” approach better in tune with current opportunities for and constraints on rural poverty reduction. The approach is centered on the process whereby well‐being is determined, linking household asset positions, the context where the assets are used, pathways from poverty through specific livelihood strategies, and well‐being outcomes. This in turn identifies entry points for policies and programs to improve the well‐being outcomes that consist in interventions to: increase access to assets, improve context, provide social protection, and achieve social incorporation of the rural poor.
Will food safety jeopardize food security?
Authors: Kinsey Jean
Published: October 2005

By a new definition proposed here, food safety is not just about safe food but the safe consumption of food. This draws attention to the issue of overeating as well as undernourishment. With the transition of diets and a rapid rise in obesity, worldwide, chronic illnesses join acute illness (from microbiological contamination) as health issues related to food consumption. The economics of obesity overwhelms the costs of microbiological contamination, with large impacts on private and social health care costs. In food‐insecure areas, producing and consuming unsafe food does not build a healthy population nor does it allow export of food to other nations. Safety and security must work hand in hand to enhance human health.
Food safety, the media, and the information market
Authors: Swinnen Johan F. M. , McCluskey Jill , Francken Nathalie
Published: October 2005

Availability of information has increased rapidly over the past decades. Yet, information on food safety is still considered problematic. Economists have extensively researched the effects of imperfect information. However, little attention has been paid to the institutional organization of the supply of information and the incentive schemes in the information market. This paper analyzes how and when information is supplied by media organizations, and what the implications are. We first develop a theoretical framework and afterwards provide empirical evidence from media coverage of two recent food safety crises in Europe.
Resource degradation, low agricultural productivity, and poverty in sub‐Saharan Africa: pathways out of the spiral
Authors: Ehui Simeon , Pender John
Published: October 2005

Sub‐Saharan Africa (SSA) has the lowest agricultural productivity in the world, while almost half of the population lives below US$1 per day. The biggest development policy challenge is to find appropriate solutions to end hunger and poverty in the region. Building on several years of empirical research conducted in East Africa, this paper identifies potential strategies for sustainable development in this region. In general, the empirical evidence reviewed confirms that different strategies are needed in different development domains of SSA. Nevertheless, some elements will be common to all successful strategies, including assurance of peace and security, a stable macroeconomic environment, provision of incentives through markets where markets function, development of market institutions where they do not, and public and private investment in an appropriate mix of physical, human, natural, and social capital. The differences in strategies across these domains mainly reflect differences in the mix of those investments as influenced by different comparative advantages.
General practitioners’ adoption of new drugs and previous prescribing of drugs belonging to the same therapeutic class: a pharmacoepidemiological study
Authors: Dybdahl Torben , Andersen Morten , Kragstrup Jakob , Kristiansen Ivar Sønbø , Søndergaard Jens
Published: October 2005

Aim

To test the hypothesis that general practitioners (GPs) with high prescribing levels of certain drugs will adopt new drugs belonging to the same therapeutic group faster than those with low prescribing levels.

Methods

The adoption of four new drugs: esomeprazol, selective cyclo‐oxygenase‐2 inhibitors, new triptans, and angiotensin‐II receptor blockers were analysed using population‐based prescription data. We used the preference proportion (prescriptions for new rather than older alternatives for the same indication) to measure GPs’ adoption rate. Annual prescribing volume and prevalence were used to measure previous prescribing of older drug alternatives. We modelled the preference proportion using multiple linear regression analysis and the prescribing of older drugs as independent variables. We controlled for the GPs’ general prescribing level and weighted for practice size. In the first three analyses, we dichotomized data using the median, lower and upper quartile as cut‐off point. Next, we grouped data into quartiles and finally, we used continuous data.

Results

For esomeprazol and new triptans there was a higher preference for new drugs among ‘high prescribers’, but only when this term was defined as the upper quarter and the upper half of previous prescribing levels, respectively (mean difference in preference proportion: 10.2% (99% confidence interval = 1.3%, 19.1%) and 8.2% (0.2%, 16.2%)). For the remaining two drug classes the associations were weak and almost all statistically nonsignificant.

Conclusion

There is no consistent association between GPs’ level of drug prescribing and their adoption of new drugs of the same therapeutic group.
Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment
Authors: Holmes Gregory , Galitz Lawrence , Hu Peter , Lyness William
Published: October 2005

Aims

To assess the effects of body mass index, renal impairment (creatinine clearance), and hepatic impairment (Child‐Pugh Score) on the pharmacokinetics of insulin aspart.

Methods

Pharmacokinetics of insulin aspart (injected subcutaneously in the abdomen immediately before a Boost® standardized meal) were characterized in: (1) diabetic subjects with four ranges of BMI values (n = 23); (2) diabetic subjects with varying degrees of renal impairment (normal, n = 6 vs. two ranges of impairment, n = 12); and (3) nondiabetic patients with varying degrees of hepatic impairment (normal, n = 6 vs. three ranges of impairment, n = 18).

Results

There was no correlation between any pharmacokinetic variable and the degree of renal or hepatic impairment. Increasing obesity was associated with a decreased apparent clearance per kg body weight (β = −0.0005, SE = 0.0001; P = 0.002), an increased t½ (β = 3.513, SE = 1.636; P = 0.044), and an increased ln(AUC0−360) and ln(AUC0−1440) (β = 0.030, SE = 0.013; P = 0.032 and β = 0.039, SE = 0.0132; P = 0.006, respectively). However, obesity‐related changes were smaller than individual variations in parameters.

Conclusions

Renal impairment, hepatic impairment, or BMI do not affect the pharmacokinetics of insulin aspart in a clinically significant manner.

Abbreviations

AUC0–1440, area under the plasma concentration curve; BMI, body‐mass index; CLcr, renal clearance of creatinine; CL/F, apparent clearance; CL/F/kg, body weight‐adjusted apparent clearance; Cmax, maximal plasma concentration; FBG, fasting blood glucose; GFR, glomerular filtration rate; HI, human insulin; MRT, mean residence time; PK, pharmacokinetics; t½, half life; tmax, time to maximum concentration; Vz/F, apparent volume of distribution.
Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997–2003
Authors: Walley T. , Folino‐Gallo P. , Stephens P. , Van Ganse E. ,   EuroMedStat group
Published: October 2005

Aims

To describe trends in utilization and prescribing of statins and other lipid lowering drugs across Europe from data in routine administrative databases.

Methods

Observational study in EU member states and Norway. Comparison of annual utilization data for lipid lowering agents by class and drug from national administrative databases for reimbursement over the period 1997–2003, measured in DDDs per 1000 inhabitants/day. Prescribed daily doses (PDD) of statins obtained from a commercial database (IMS Health) for 2000 and 2003, and used to calculate numbers of ‘patient treatment days’ (PTD) in each country in each year. Analysis of PTD to explain increased utilization of statins.

Results

Use of lipid lowering agents varied among countries (in 2003, highest in Ireland and Norway, and lowest in Italy), but increased in all countries studied (between 2000 and  2003  by  274% in  Ireland  and  by  56% in  France).  This  increase  was  entirely  due to increases in statin use. Prescribed daily doses of statins increased in all countries for which data was available between 2000 and 2003, but still usually fell below the doses used in the major trials of statins. As a result, the numbers of PTDs increased to a lesser extent than suggested by utilization (e.g. by 192% in Ireland and by 35% in France). One‐third of the total rise in utilization was explained by increased PDD, and two‐thirds by an increase in numbers of PTDs. Statins dominated the markets in all countries, although fibrates remained strong in France and Belgium (approximately 25% of all lipid lowering agents) and to a lesser extent Germany (10%).

Conclusions

Use of statins across Europe has increased hugely over the study period. Some of the increase in use is due to higher prescribed daily doses, but two‐thirds is due to increases in numbers of patient days of treatment, either due to more patients treated or less likely to better compliance.
Mirtazapine‐induced arthralgia
Authors: Passier Anneke , Van Puijenbroek Eugène
Published: October 2005

Aim

With this article, we intend to corroborate the assumed association between mirtazapine and arthralgia by presentation of eight case reports, and we describe a possible mechanism of action.

Methods and results

The Netherlands Pharmacovigilance Centre Lareb received eight case reports on arthralgia associated with use of mirtazapine. These case reports are presented in short. We also present worldwide data on this association.

Conclusions

The Lareb reports support the association between mirtazapine and arthralgia. A comparison is made between mirtazapine, mianserin and nefazodone, as these antidepressants show similarities in their mode of action and are all associated with arthralgia. We suggest that this adverse drug reaction may be induced by enhanced 5HT1‐mediated neurotransmission.
Calcium antagonists and deep gingival pockets in the population‐based SHIP study
Authors: Meisel Peter , Schwahn Christian , John Ulrich , Kroemer Heyo K. , Kocher Thomas
Published: October 2005

Aim

Gingival overgrowth is a common undesired side‐effect in patients taking calcium channel blockers. Different reports have suggested that the drug‐induced gingival hyperplasia may aggravate inflammatory periodontal disease. However, representative epidemiological data are lacking. We investigated the association between the intake of calcium antagonists and periodontitis in a population‐based analysis including the most important risk factors of periodontitis.

Methods

In a cross‐sectional epidemiological investigation involving 4290 subjects aged 20–80 years, we recorded periodontal risk factors and identified participants using calcium antagonists. Periodontal parameters, attachment loss, probing depth and number of teeth were assessed. In a subgroup analysis with matched pairs, 456 subjects using calcium antagonists and 456 without were compared for periodontal status.

Results

Subjects treated with calcium antagonistic drugs had significantly deeper gingival pockets than their drug‐free counterparts. This was observed in the total population of 4290 and confirmed by logistic regression analyses (P < 0.001) controlled for the known risk factors of periodontitis (age, sex, smoking, education). In the matched‐pair analysis only the probing depth was increased: extent probing depth ≥ 4 mm median 23.5 vs. 17.0% (P < 0.001); mean probing depth 3.0 ± 0.8 vs. 2.7 ± 0.9 mm (P < 0.001). No differences were found in extent and severity of clinical attachment loss and in the number of teeth. The risk of gingival overgrowth was aggravated in smokers.

Conclusion

In the general population, treatment with calcium antagonists leads to gingival overgrowth without an aggravation of periodontal disease. Interaction with smoking indicates the multifactorial background of the undesired effect of calcium antagonists.
Population plasma pharmacokinetics of 11C‐flumazenil at tracer concentrations
Authors: Van Rij Catharina M. , Huitema Alwin D. R. , Swart Eleonora L. , Greuter Henricus N. J. M. , Lammertsma Adriaan A. , Van Loenen Arie C. , Franssen Eric J. F.
Published: October 2005

Objective

The objectives of the study were to develop a population pharmacokinetic model for 11C‐flumazenil at tracer concentrations, to assess the effects of patient‐related covariates and to derive an optimal sampling protocol for clinical use.

Methods

A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ∼370 MBq (1–4 µg) of 11C‐flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established.

Results

The population pharmacokinetics of tracer quantities of 11C‐flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (P < 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min−1 (6.6%), V1 24.8 × 103 mL (3.8%), V2 27.3 × 103 mL (5.4%), and Q 2510 mL min−1 (6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V1 was 0.55% kg−1. For the prediction of the AUC, a combination of two time points at t = 30 and 60 min post injection was considered optimal (bias −0.7% (95% CI −2.2 to 0.8%), precision 5.7% (95% CI 4.5–6.9%)). The optimal sampling strategy was cross‐validated (observed AUC = 296 MBql−1 min−1 (95% CI 102–490), predicted AUC = 288 MBql−1 min−1 (95% CI 70–506)).

Conclusions

The population pharmacokinetics of tracer quantities of 11C‐flumazenil are well described by a two‐compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of 11C‐flumazenil PET.
Circulating microparticles are elevated in haemophiliacs and non‐haemophilic individuals aged <18 years
Authors: Proulle Valérie , Hugel Bénédicte , Guillet Benoit , Grunebaum Lélia , Lambert Thierry , Freyssinet Jean‐Marie , Dreyfus Marie
Published: October 2005

Platelet and cell stimulation lead to plasma membrane remodelling, resulting in phosphatidylserine (PS) externalisation in the outer leaflet of the membrane, associated with the shedding of PS‐rich microparticles (MPs), and contributes to thrombin generation by promoting the assembly of coagulation enzyme complexes. A previous study assessed MP levels in haemophiliacs after haemostatic treatment. To further investigate in vivo membrane remodelling, MP levels and characteristics were studied in 79 haemophiliacs and in 62 non‐haemophiliacs. Both groups showed heterogeneity in MP levels, with higher values in individuals <18 years. This finding should be considered when studying MP levels in individuals <18 years.
Circulating CD10−/CD16low neutrophils provide a quantitative index of active bone marrow neutrophil release
Authors: Orr Y. , Taylor J. M. , Bannon P. G. , Geczy C. , Kritharides L.
Published: October 2005

Circulating neutrophil phenotype and function are altered during neutrophilia associated with acute inflammatory states, however, the contribution of bone marrow neutrophil release to these changes has been difficult to quantify in humans. Accelerated release of neutrophils, with potentially distinct attributes, from the bone marrow and their dilution within the circulating pool may produce these apparent changes. Unfortunately selective analysis of these newly emergent neutrophils is difficult given their morphologic similarity to those already in the circulation and the coincident effect of soluble inflammatory mediators on circulating neutrophil phenotype and function. Using whole blood flow cytometry and cardiac surgery as an inflammatory stimulus, we demonstrate the emergence of a unique subpopulation of circulating neutrophils characterised as CD10−/CD16low, indicative of active bone marrow neutrophil release peri‐operatively. CD10−/CD16low neutrophils emerge at the same operative stages as band forms and a left shift, yet represent over 40% of circulating neutrophils postoperatively, and generate a greater stimulus‐induced [Ca2+]i flux than their CD10+ counterparts. We conclude that CD10−/CD16low neutrophils represent a significant proportion of the circulating pool after cardiac surgery and that bone marrow release, a major contributor to neutrophilia, influences the phenotype and functional activity of circulating neutrophils following this acute inflammatory stimulus.
The synthetic furanonaphthoquinone induces growth arrest, apoptosis and differentiation in a variety of leukaemias and multiple myeloma cells
Authors: Desmond Julian C. , Kawabata Hiroshi , Mueller‐Tidow Carsten , Simamura Eriko , Heber David , Hirai Kei‐Ichi , Phillip Koeffler H.
Published: October 2005

2‐Methyl‐naphtho[2,3‐b]furan‐4,9‐dione (FNQ3), a synthetic analogue of the quinone kigelinone, has demonstrated a real potential for use in the treatment of a variety of solid tumours. Unlike other quinones, such as mitomycin‐C and adriamycin, the cytotoxicity of FNQ3 is often 10‐ to 14‐fold more potent towards the tumour cells than their normal counterparts. We report, for the first time, that the drug had activity against a broad spectrum of leukaemias and multiple myeloma cells. It decreased the growth of acute myeloid leukaemia (AML) and multiple myeloma cell lines in a dose‐dependent fashion (50% inhibitory concentration ≈1·25 μg/ml against most of the leukaemia cell lines). This dose apparently initiated mitochondrial collapse as measured by depolarisation of the mitochondrial membrane. FNQ3 potentiated the differentiation of HL‐60 myeloid cells in the presence of either 1α, 25(OH)2 dihydroxyvitamin D3 [1α,25(OH)2D3] or all‐trans‐retinoic acid (ATRA). FNQ3 inhibited the proliferation of primary AML cells while inducing apoptosis. Eleven of 14 (79%) AML marrow samples had a prominent decrease in their clonogenic growth when cultured in the presence of the drug. In summary, this drug has growth inhibitory, apoptotic and differentiative effects against myeloid leukaemias and multiple myeloma cells. FNQ3 may represent a new therapeutic approach to these malignancies.
Management of Evans syndrome
Authors: Norton Alice , Roberts Irene
Published: October 2005

Evans syndrome is an uncommon condition defined by the combination (either simultaneously or sequentially) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA) with a positive direct antiglobulin test (DAT) in the absence of known underlying aetiology. This condition generally runs a chronic course and is characterised by frequent exacerbations and remissions. First‐line therapy is usually corticosteroids and/or intravenous immunoglobulin, to which most patients respond; however, relapse is frequent. Options for second‐line therapy include immunosuppressive drugs, especially ciclosporin or mycophenolate mofetil; vincristine; danazol or a combination of these agents. More recently a small number of patients have been treated with rituximab, which induces remission in the majority although such responses are often sustained for <12 months and the long‐term effects in children are unclear. Splenectomy may also be considered although long‐term remissions are less frequent than in uncomplicated ITP. For very severe and refractory cases stem cell transplantation (SCT) offers the only chance of long‐term cure. The limited data available suggest that allogeneic SCT may be superior to autologous SCT but both carry risks of severe morbidity and of transplant‐related mortality. Cure following reduced‐intensity conditioning has now been reported and should be considered for younger patients in the context of controlled clinical trials.
Up‐regulation of the T cell quiescence factor KLF2 in a leukaemic T‐cell line after expression of the inositol 5′‐phosphatase SHIP‐1
Authors: García‐Palma Lizet , Horn Stefan , Haag Friedrich , Diessenbacher Philip , Streichert Thomas , Mayr Georg W. , Jücker Manfred
Published: October 2005

Inositol 5′‐phosphatase SHIP‐1 (SHIP) is a negative regulator of signal transduction in haematopoietic cells. SHIP inactivation may be involved in the pathogenesis of leukaemia. An inducible expression system was combined with microarray analysis to identify target genes regulated by SHIP in the human T‐cell leukaemia cell line Jurkat. One gene identified was Krüppel‐like factor 2 (KLF2), which was up‐regulated two to threefold at the RNA and protein level after the induced expression of SHIP. KLF2, a negative regulator of T cell proliferation, has been implicated in T cell quiescence. KLF2 or SHIP expression in Jurkat cells caused 45% or 60% reduction of proliferation, respectively. SHIP can up‐regulate KLF2 expression, implicating KLF2 in the SHIP‐mediated growth inhibition of a human leukaemic T‐cell line.
Can the evolutionary‐rates hypothesis explain species‐energy relationships?
Authors: EVANS K. L. , GASTON K. J.
Published: October 2005

There is growing consensus that much of the marked broad‐scale spatial variation in species richness is associated with variation in environmental energy availability, but at least nine principal mechanisms have been proposed that may explain these patterns.

The evolutionary‐rates hypothesis suggests that high environmental energy availability elevates rates of molecular evolution, promoting faster speciation, so that more species occur in high‐energy areas because more evolve there. Direct tests of this hypothesis are rare and their conclusions inconsistent. Here we focus on assessing the support for its underlying assumptions.

First, the evolutionary‐rates hypothesis assumes that high energy levels promote mutation. There is certainly evidence that high levels of ultraviolet radiation increase mutation rates. High temperatures may also reduce generation times and elevate metabolic rates, which may promote mutation. On balance, data support a link between rates of metabolism and mutation, but a link between the latter and generation time is more equivocal and is particularly unlikely in plants.

Second, the evolutionary‐rates hypothesis assumes that mutation rates limit speciation rates. This may be true if all else was equal, but correlations between mutation and speciation are probably very noisy as many other factors may influence rates both of sympatric and allopatric speciation, including the occurrence of physical isolation barriers, the magnitude of selection and population size.

Third, the evolutionary‐rates hypothesis assumes that there is a strong correlation between current and historical energy levels. Factors such as tectonic drift may weaken such relationships, but are likely to have had negligible effects over the time period during which the majority of extant species evolved.

Fourth, the evolutionary‐rates hypothesis assumes that changes in species ranges following speciation do not sufficiently weaken the correlation between the rate of speciation in an area and species richness. The ranges of many species appear to alter dramatically following speciation, and this may markedly reduce the strength of the relationship, but to what extent is unclear.

In sum, the degree to which the evolutionary‐rates hypothesis can explain spatial variation in species richness remains surprisingly uncertain. We suggest directions for further research.
Effect of food level and rearing temperature on burst speed and muscle composition of Western Spadefoot Toad (Spea hammondii)
Authors: ARENDT J. , HOANG L.
Published: October 2005

Past studies on phenotypic plasticity usually focus on ultimate (evolutionary) issues. More recently, proximate (developmental) factors explaining how plasticity is achieved are starting to be addressed.

Here, we examine the importance of resource level and temperature on growth rate and burst swimming speed in tadpoles ofSpea hammondii(Western Spadefoot Toad).

Food and temperature manipulations alter growth rate via different developmental processes (cell growth and cell recruitment, respectively) and these processes appear to have consequences for swimming performance in tadpoles.

Tadpoles reared at warm temperatures were slower swimmers than those reared at cooler temperatures while food level had no effect on size‐specific burst speed. Tadpoles reared at warm temperatures also had more fibres in the tail muscle, probably due to an earlier onset of recruitment. Tadpoles reared at higher food levels had larger muscle fibres, but little differences in fibre number compared to those reared at low food levels.

These results indicate that growth by adding cells comes at a performance cost not seen when growth is due to increasing cell size. This developmental difference also has implications for how body size manipulations are carried out in behavioural and ecological studies.