bluuebunny/crossref_metadata_2025 huggingface dataset:
GIS, Land Use, and Representation
Authors: Bibby Peter , Shepherd John
Published: January 2006

Despite the historically close relationship between GIS and land-use studies, there has been little constructive dialogue on the relationship between GIS theory and land-use analysis. The distinctive feature of land-use studies is their grounding in the idea of social purpose. “Purpose”—the telic dimension—is one of four dimensions of meaning discussed by Moravcsik and based ultimately on the work of Aristotle. So far in GIS, however, only the formal dimension has been emphasised. In this paper we draw on the work of philosophers such as Searle and Goodman to show the significance of the telic and constitutive dimensions of meaning for GIS and land-use studies. We also consider the relationship between terms in natural language and GIS-based analysis. Against this background we consider how GIS applications can be classified in relation to their treatment of language — purpose” and “space — time”. We conclude by suggesting that familiar GIS problems such as the modifiable areal unit problem and the ecological fallacy are instances of more general philosophical problems and that insights from linguistic philosophy can contribute to GIS development.
From Global to Local: The Development of Local Geographic Information Strategies in the United Kingdom
Authors: Craglia Massimo , Signoretta Paola
Published: January 2006

The focus of recent debates over geographic data infrastructures has tended to be at the national, pan-European, or global levels. Relatively less attention has been paid to the development of local data infrastructures even though this is the level where they have the potential of making the greatest impact on everyday life. The purpose of this paper is to identify some of the opportunities and barriers to such local developments in Great Britain as a starting point for a much wider debate and sharing of experience. The paper is divided into four sections. Sections 1 and 2 introduce the topic, and provide an overview of recent policy developments at the European and national levels, respectively, that should encourage the creation of such local infrastructures. In section 3, examples are given of best practice from selected case studies being developed across the country, and in section 4 the political and organisational issues that need to be addressed to make these infrastructures work successfully are identified.
The Economies in Transition as Part of the Climate Regime: Recent Developments
Authors: Missfeldt Fanny , Villavicenco Arturo
Published: January 2006

Since the adoption of the Climate Convention in 1992 at the latest, formerly communist countries have been following the climate debate despite serious domestic economic and social problems. Since 1990 the region has contributed the most to curbing the problem of climate change, albeit accidentally, through the sharp decline in their emissions in parallel with the decline in their economies. In this paper we review the role played by the economies in transition in the climate negotiations until early 2000, especially in light of the 1997 Kyoto Protocol to the Climate Convention. We consider emissions trends and the scope for further emissions reductions. Subsequently, the potential benefits of the “Kyoto Mechanisms”, which include emissions trading, joint implementation, and the Clean Development Mechanism, are discussed. We find that the climate policies in Central and Eastern Europe and in the former Soviet Union are drifting further apart. Activities in Central and Eastern Europe are dominated by the EU accession process, while the countries further east continue to grapple with economic crises.
Financing Environmental Protection in Economies in Transition: The Role of Environmental Funds
Authors: Francis Patrick
Published: January 2006

Most countries with economies in transition in Central and Eastern Europe and the New Independent States of the former Soviet Union use earmarked, environmental funds to channel subsidised finance for environmental protection. In some Central and Eastern European countries in particular, the funds are major financiers of environmental investments. The funds are typically governmental institutions capitalised by various revenue sources, including environmental charges and fines. They generally provide grants or soft loans for a wide range of environmental protection activities. Although a number of circumstances in economies in transition may justify the provision of subsidised finance for environmental investments, and though funds have been endorsed as potentially effective transitional mechanisms, a number of concerns remain as regards their role vis-à-vis other environmental policy tools, their effectiveness and efficiency, and their impact on the development of more market-based financing mechanisms. In this paper I will review development trends among the funds, examine issues critical to their role and operation, and identify institutional strengthening needs.
Social Network Analysis as a Tool for Understanding the Diffusion of GIS Innovations: The Greek GIS Community
Authors: Assimakopoulos Dimitris G
Published: January 2006

In this paper I will show how social network analysis techniques can be used for understanding GIS diffusion at a national scale. In particular, two network models, cohesion and structural equivalence, are explored in the context of the emerging Greek GIS community. A map of this community based on GIS teams and linkages is put forward, and two social constructs, institutional setting and disciplinary background, are used to highlight the heterogeneous context within which GIS are embedded across a whole country. The findings suggest that specific actors such as the Greek ESRI vendor and relevant social groups such as the teams with a surveying engineering background take centre stage in the diffusion of GIS innovations in Greece in the early 1990s.
A Pattern Measure
Authors: Klinger Allen , Salingaros Nikos A
Published: January 2006

In this paper we propose numerical measures for evaluating the aesthetic interest of simple patterns. The patterns consist of elements (symbols, pixels, etc) in regular square arrays. The measures depend on two characteristics of the patterns: the number of different types of element, and the number of symmetries in their arrangement. We define two complementary composite measures L and C for the degree of pattern in a design, and compute them here for 2 × 2 and 6 × 6 arrays. The results distinguish simple from high-variation cases. We suspect that the measure L corresponds to the degree that human beings intuitively feel a design to be “interesting”, so this model would aid in quantifying the visual connection of two-dimensional designs with viewers. The other composite measure C based on these numerical properties characterizes the extent of randomness of an array. Combining symbol variety with symmetry calculations allows us to employ hierarchical scaling to count the relative impact of different levels of scale. By identifying substructures we can distinguish between organized patterns and disorganized complexity. The measures described here are related to verbal descriptors derived from work by psychologists on responses to visual environments.
Types, Numbers, and Floor Areas of Nondomestic Premises in England and Wales, Classified by Activity
Authors: Bruhns Harry R , Steadman Philip , Herring Horace , Moss Sarah , Rickaby Peter A
Published: January 2006

Estimates are given of the numbers and floor areas of all nondomestic premises in England and Wales, as of 1993/94. These are based on a wide range of data sources, of which the most important are commercial rating (property taxation) data collected by the Valuation Office of the Inland Revenue. Information has also been collated from a large number of publications and databases produced by commercial firms, central and local government departments, and professional and trade organisations. A new hierarchical classification of activities is employed, called here the primary classification. This has been developed out of a series of existing schemes by which the original data are themselves classified.
A Classification System for Services in Nondomestic Buildings
Authors: Rickaby Peter A , Gorgolewski Mark T
Published: January 2006

A classification system is described for heating, ventilation, and air-conditioning services in nondomestic buildings and is applied to data from a sample of detailed energy surveys of such buildings. Analyses are reported of the occurrences of servicing systems of different types in the surveyed premises, and of the relationships between system types, sizes of premises, built form, and the activities accommodated.
N-DEEM: The National Nondomestic Buildings Energy and Emissions Model
Authors: Pout Christine H
Published: January 2006

In this paper I will describe the bringing together of sources of data on the nondomestic building stock and its energy use, and modelling procedures that form the technologically disaggregated model of energy use in UK buildings known as N-DEEM (nondomestic buildings energy and emissions model). Methodologies for estimating carbon emissions and carbon savings are described, and summary results presented. The use of N-DEEM to develop future scenarios of energy use is discussed.
Inferences about Built Form, Construction, and Fabric in the Nondomestic Building Stock of England and Wales
Authors: Steadman Philip , Bruhns Harry R , Gakovic Bratislav
Published: January 2006

Methods are described for making inferences as regards the geometrical and physical characteristics of all nondomestic buildings in England and Wales. Estimates are made of the floor areas in built forms with framed and load-bearing structures, respectively, and of the typical numbers of floors in built forms of different types. Calculations are made of the total areas of exposed walls, roof surfaces, and glazing, and of the breakdown of the wall and roof areas by material. The results are being used by the Department of the Environment, Transport and the Regions to gain a better understanding of the patterns of energy use associated with nondomestic buildings. The “inference model” described here has been installed at the Building Research Establishment, where it forms one component of the National Non-Domestic Energy and Emissions Model (N-DEEM), whose purpose is to monitor the use of fossil fuels, estimate the emission of greenhouse gases, and evaluate fuel conservation measures (Pout, 2000). The paper is concluded with a discussion of possible refinements and tests of the inference methodology, and potential future extensions.
An Introduction to the National Non-Domestic Building Stock Database
Authors: Steadman Philip , Bruhns Harry R , Rickaby Peter A
Published: January 2006

The origins, purpose, and scope of the Non-Domestic Building Stock (NDBS) database of England and Wales are described. Nondomestic buildings are defined and sources of the data used in the database are identified. The structure of the database, and the role of the classification of nondomestic buildings, are described and discussed.
Property Taxation Data for Nondomestic Buildings in England and Wales
Authors: Bruhns Harry
Published: January 2006

In this paper I will describe data provided by the UK Valuation Office (VO) for the national Non-Domestic Building Stock database developed for the Department of the Environment, Transport and the Regions. The purpose of this database is to support policymaking for the conservation of fossil fuels and the reduction of greenhouse gas emissions. The fact that the VO data cover floor areas, activities, building construction, and building services—all of which are liable to affect the use of fuels in buildings—make them specially valuable for this application. Several tables and charts derived from the VO data are presented, containing statistics on the nondomestic building stock of England and Wales. A review is then given of the very considerable research potential of such a large administrative data source as the VO databases. Some of the problems that arise in the use of those data are examined.
Photocatalysis and the origin of life: Synthesis of nucleoside bases from formamide on TiO2(001) single surfaces
Authors: Senanayake S. D. , Idriss H.
Published: January 2006

We report the conversion of a large fraction of formamide (NH2CHO) to high-molecular-weight compounds attributed to nucleoside bases on the surface of a TiO2(001) single crystal in ultra-high vacuum conditions. If true, we present previously unreported evidence for making biologically relevant molecules from a C1 compound on any single crystal surface in high vacuum and in dry conditions. An UV light of 3.2 eV was necessary to make the reaction. This UV light excites the semiconductor surface but not directly the adsorbed formamide molecules or the reaction products. There thus is no need to use high energy in the form of photons or electrical discharge to make the carbon–carbon and carbon–nitrogen bonds necessary for life. Consequently, the reaction products may accumulate with time and may not be subject to decomposition by the excitation source. The formation of these molecules, by surface reaction of formamide, is proof that some minerals in the form of oxide semiconductors are active materials for making high-molecular-weight organic molecules that may have acted as precursors for biological compounds required for life in the universe.
Structural insights into a protein-bound iron-molybdenum cofactor precursor
Authors: Corbett Mary C. , Hu Yilin , Fay Aaron W. , Ribbe Markus W. , Hedman Britt , Hodgson Keith O.
Published: January 2006

The iron-molybdenum cofactor (FeMoco) of the nitrogenase MoFe protein is a highly complex metallocluster that provides the catalytically essential site for biological nitrogen fixation. FeMoco is assembled outside the MoFe protein in a stepwise process requiring several components, including NifB-co, an iron- and sulfur-containing FeMoco precursor, and NifEN, an intermediary assembly protein on which NifB-co is presumably converted to FeMoco. Through the comparison of
Azotobacter vinelandii
strains expressing the NifEN protein in the presence or absence of the
nifB
gene, the structure of a NifEN-bound FeMoco precursor has been analyzed by x-ray absorption spectroscopy. The results provide physical evidence to support a mechanism for FeMoco biosynthesis. The NifEN-bound precursor is found to be a molybdenum-free analog of FeMoco and not one of the more commonly suggested cluster types based on a standard [4Fe–4S] architecture. A facile scheme by which FeMoco and alternative, non-molybdenum-containing nitrogenase cofactors are constructed from this common precursor is presented that has important implications for the biosynthesis and biomimetic chemical synthesis of FeMoco.
Organization of spines on the dendrites of Purkinje cells
Authors: O'Brien John , Unwin Nigel
Published: January 2006

Dendritic spines have been investigated intensively over recent years; however, little is yet known about how they organize on the cell surface to make synaptic contacts with appropriate axons. Here we investigate spine distributions along the distal dendrites of cerebellar Purkinje cells, after biolistic labeling of intact tissue with a lipid-soluble dye. We show that the spines have a preference to form regular linear arrays and to trace short-pitch helical paths. The helical ordering is not determined by external factors that may influence how individual spines develop, because the same periodicities were present in fish and mammalian Purkinje cells, including those of
weaver
mice, which are depleted of the normal presynaptic partners for the spines. The ordering, therefore, is most likely an inherent property of the dendrite. Image reconstruction of dendrites from the different tissues showed that the helical spine distributions invariably lead to approximately equal sampling of surrounding space by the spineheads. The purpose of this organization may therefore be to maximize the opportunity of different spines to interact with different axons.
SUSPECTS: enabling fast and effective prioritization of positional candidates
Authors: Adie E. A. , Adams R. R. , Evans K. L. , Porteous D. J. , Pickard B. S.
Published: January 2006

Summary: SUSPECTS is a web-based server which combines annotation and sequence-based approaches to prioritize disease candidate genes in large regions of interest. It uses multiple lines of evidence to rank genes quickly and effectively while limiting the effect of annotation bias to significantly improve performance.

Availability: SUSPECTS is freely available at

Contact:  euan.adie@ed.ac.uk

Supplementary information: A quick-start guide in Macromedia Flash format is available at and Excel spreadsheets detailing the comparative performance of the software are included as Supplementary material.
REMORA: a pilot in the ocean of BioMoby web-services
Authors: Carrere Sébastien , Gouzy Jérôme
Published: January 2006

Summary: Emerging web-services technology allows interoperability between multiple distributed architectures. Here, we present REMORA, a web server implemented according to the BioMoby web-service specifications, providing life science researchers with an easy-to-use workflow generator and launcher, a repository of predefined workflows and a survey system.

Contact:  Jerome.Gouzy@toulouse.inra.fr

Availability: The REMORA web server is freely available at , sources are available upon request from the authors.
Validation of a symptom diary for patients with gastro‐oesophageal reflux disease
Authors: PUHAN M. A. , GUYATT G. H. , ARMSTRONG D. , WIKLUND I. , FALLONE C. A. , HEELS‐ANSDELL D. , DEGL'INNOCENTI A. , VAN ZANTEN S. J. O. VELDHUYZEN , TANSER L. , BARKUN A. N. , CHIBA N. , AUSTIN P. , EL‐DIKA S. , SCHÜNEMANN H. J.
Published: January 2006

Background  Symptom diaries are potentially attractive but, because of concerns about patient compliance, they have had limited use in clinical trials. We assessed the validity and responsiveness of a symptom diary for patients with gastro‐oesophageal reflux disease.

Methods  We included 215 patients with gastro‐oesophageal reflux disease after starting treatment for 4 weeks with 40 mg esomeprazole once daily. Patients recorded whether they experienced night‐time heartburn (yes/no), the severity of daytime heartburn on a scale from 1 (no heartburn) to 4 (severe heartburn) and their antacid use. Patients also completed a number of disease‐specific and preference‐based Health‐related Quality of Life questionnaires at baseline and follow‐up.

Results  Consistent with a priori predictions, daytime heartburn showed moderate to strong correlations with the Quality of Life in Reflux and Dyspepsia questionnaire (0.36–0.67) and four scales of symptom severity (0.36–0.70) for baseline, follow‐up and change scores, but low correlations with the Standard Gamble. Responsiveness of the daytime heartburn item was excellent with a mean change from baseline to follow‐up of −1.3 (95% CI −1.4 to −1.1) and a standardized response mean of 1.33 while responsiveness of the daily antacid use item was moderate (mean change scores −1.8 tablets taken, 95% CI −2.3 to −1.3 and standardized response mean of 0.64).

Conclusions  The excellent psychometric properties of this simple gastro‐oesophageal reflux disease diary make it an attractive measure for future trials.
Healing of lymphocytic gastritis after Helicobacter pylori eradication therapy – a randomized, double‐blind, placebo‐controlled multicentre trial
Authors: MADISCH A. , MIEHLKE S. , NEUBER F. , MORGNER A. , KUHLISCH E. , RAPPEL S. , LEHN N. , BAYERDÖRFFER E. , SEITZ G. , STOLTE M.
Published: January 2006

Background  An association between Helicobacter pylori infection and lymphocytic gastritis has been postulated.

Aim  To assess the long‐term effect of H. pylori eradication therapy on lymphocytic gastritis in a double‐blind, placebo‐controlled, multicentre trial.

Methods  Patients with lymphocytic gastritis were randomized to receive either 1‐week triple therapy for eradication of H. pylori or omeprazole plus placebo. Endoscopy and histology was performed at baseline and after 3 and 12 months. Patients of the omeprazole/placebo group with persistent lymphocytic gastritis after 12 months received crossover open‐label triple therapy.

Results  Fifty‐one patients were randomized. Intention‐to‐treat analysis revealed a trend to a higher healing rate of lymphocytic gastritis 3 months after triple therapy compared with omeprazole/placebo (83.3% vs. 57.7%, 95% CI for RR: 0.8–2.8, P = 0.06). After 12 months, the healing rate of lymphocytic gastritis was significantly higher after triple therapy compared with omeprazole/placebo (intention‐to‐treat 95.8% vs. 53.8%, 95% CI for RR: 1.1–3.5, P = 0.01). All patients (n = 5) who received crossover triple therapy, showed healing of lymphocytic gastritis after further 12 months.

Conclusion  Our study demonstrates that 1‐week triple therapy aiming at eradication of H. pylori leads to a complete and long‐lasting resolution of lymphocytic gastritis in the majority of patients.
Variants of OCTN1–2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis
Authors: PALMIERI O. , LATIANO A. , VALVANO R. , D'INCÀ R. , VECCHI M. , STURNIOLO G. C. , SAIBENI S. , PEYVANDI F. , BOSSA F. , ZAGARIA C. , ANDRIULLI A. , DEVOTO M. , ANNESE V.
Published: January 2006

Background  Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD).

Aim  To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes.

Methods  Case–control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G→C and 1672C→T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI‐7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively.

Results  The 1672TT and −207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P ≤ 0.01) and UC (36% vs. 45%, P ≤ 0.01). The frequency of the TC haplotype was 43% in CARD15‐positive and 44% in CARD15‐negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno‐fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004).

Conclusions  Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.
Upper gastrointestinal mucosal abnormalities and blood loss complicating low‐dose aspirin and antithrombotic therapy
Authors: TAHA A. S. , ANGERSON W. J. , KNILL‐JONES R. P. , BLATCHFORD O.
Published: January 2006

Background  Little is known about the site and nature of bleeding lesions related to low‐dose aspirin and other antithrombotic agents.

Aim  To describe the mucosal abnormalities in patients presenting with upper gastrointestinal bleeding while being treated with these drugs.

Methods  The endoscopic findings and clinical details were analysed in all patients presenting with haematemesis and/or melaena at a single centre during three calendar years. Associations between endoscopic findings and risk factors, including the intake of non‐steroidal anti‐inflammatory drugs, low‐dose aspirin (75 mg daily) and other antithrombotic drugs including warfarin, clopidogrel, and dipyridamole, were assessed by logistic regression analysis.

Results  In 674 upper gastrointestinal bleeders, we found that the odds ratio for the presence of erosive oesophagitis in aspirin users was 2 (95% CI, 1–3; P = 0.03) and 3 (2–5; P = 0.0003) in patients taking other antithrombotic agents. In 41 patients with oesophagitis and taking these drugs, 36 (88%) had cardiovascular disease and only 4 (10%) had peptic symptoms.

Conclusions  Erosive oesophagitis is common in patients with upper gastrointestinal bleeding taking low‐dose aspirin or antithrombotic agents, and could potentially be confused with the coexisting heart disease.
Efficacy and safety of rifabutin‐containing ‘rescue therapy’ for resistant Helicobacter pylori infection
Authors: BORODY T. J. , PANG G. , WETTSTEIN A. R. , CLANCY R. , HERDMAN K. , SURACE R. , LLORENTE R. , NG C.
Published: January 2006

Background  Current ‘rescue’ therapies provide inadequate Helicobacter pylori eradication rates because of antibiotic resistance.

Aim  To test the efficacy of a modified triple regimen combining rifabutin, pantoprazole and amoxicillin as rescue therapy for patients in whom eradication of H. pylori had failed standard clarithromycin‐based triple therapy.

Methods  One hundred and thirty patients (mean age 51.7 ± 14.8 years) who had failed one or more eradication attempts with omeprazole, clarithromycin and amoxicillin were treated for 12 days with rifabutin 150 mg daily, amoxicillin 1 g or 1.5 g t.d.s, and pantoprazole 80 mg t.d.s.

Results  The intention‐to‐treat and per‐protocol eradication rates were 90.8/90.8%. Metronidazole or/and clarithromycin resistance had no significant impact on H. pylori eradication rates. A higher overall eradication rate of 96.6% (95% CI: 92.1–101%) was obtained in patients treated with a regimen containing 1.5 g amoxicillin t.d.s compared with 90.7% (95% CI: 82–98.6%) using a regimen with 1 g amoxicillin t.d.s but the difference was not significant. Side‐effects reported in 40% of patients were mild.

Conclusion  A 12‐day course of low dose of rifabutin with an increased dose of amoxicillin and pantoprazole is well‐tolerated and highly effective against dual‐resistant H. pylori infection after failure of triple therapy.
Genome‐wide linkage disequilibrium in two Japanese beef cattle breeds
Authors: Odani M. , Narita A. , Watanabe T. , Yokouchi K. , Sugimoto Y. , Fujita T. , Oguni T. , Matsumoto M. , Sasaki Y.
Published: January 2006

There is little knowledge about the degree of linkage disequilibrium (LD) in beef cattle. This study aims to perform a genome‐wide search for LD in Japanese Black and Japanese Brown beef cattle and to compare the level of LD between these two breeds. Parameter D′ (the LD coefficient) was used as a measure of LD, and LD was tested for significance of allelic associations between syntenic and between non‐syntenic marker pairs. Effects of breed, chromosome, genetic map distance and their interactions with D′ were tested based on least squares analyses. Both breeds showed high levels of LD, which ranged over several tens of cM and declined as the marker distance increased for syntenic marker pairs. A rapid decline of the D′ value was observed between markers that were spaced 5 and 20 cM apart. LD was significant in most cases for marker pairs <40 cM apart but was not significant between non‐syntenic loci. The pattern of LD found in these two breeds was similar to that previously published for dairy cattle. The D′ value between breeds was not significantly different (P > 0.05), but the interaction between breed and chromosome was highly significant (P <  0.001). Genetic selection seems to have caused the heterogeneity of the D′ values among chromosomes within breed. These results indicate that LD mapping is a useful tool for fine‐mapping quantitative trait loci of economically important traits in Japanese beef cattle.
Association of the melanocortin 4 receptor with feed intake and daily gain in F2 Mangalitsa × Piétrain pigs
Authors: Meidtner K. , Wermter A‐K. , Hinney A. , Remschmidt H. , Hebebrand J. , Fries R.
Published: January 2006

The melanocortin 4 receptor (MC4R) is a key factor in the regulation of energy balance and body weight. Hence it is a candidate for feed intake and energy homeostasis‐related traits. Studies in humans and swine have revealed several sequence variants in the gene that are associated with some of these traits. In pigs the coding non‐synonymous missense variant Asp298Asn in MC4R has been associated with feed intake, fatness and growth. Here we confirm the association of this Piétrain‐derived polymorphism with feed intake and daily gain in the F2 generation of a Mangalitsa × Piétrain cross. In one Piétrain founder animal, we detected an additional non‐synonymous missense variant Arg236His. Thus, the MC4R gene could be a useful marker for increased growth in the relatively slow‐growing Piétrain breed.
Orphan drug development is progressing too slowly
Authors: Joppi Roberta , Bertele Vittorio , Garattini Silvio
Published: January 2006

Aims

To assess the methodological quality of OMP dossiers and to discuss possible reasons for the small number of products licensed.

Methods

Information about orphan drug designation and approval was obtained from the website of the European Commission‐Enterprise and Industry DG and from the European Public Assessment Reports.

Results

Out of 255 OMP designations, only 18 were approved (7.1%). Their dossiers often showed methodological limitations such as inappropriate clinical design, lack of active comparator where available and use of surrogate end‐points.

Conclusions

The paucity of European incentives for manufacturers and the poor documentation underpinning the applications may have limited the number of new OMP. The over 5000 rare diseases awaiting therapy are an important public health issue.
Kinetics and dynamics of the peripheral neurokinin‐1 receptor antagonist SLV317 in healthy individuals
Authors: Hesse Christiane , Luntz Steffen P. , Siedler Heike , Unnebrink Kristina , Mikus Gerd , de Bruijn Marianne , Zondag Edu , de Vries Michiel , Seibert‐Grafe Monika , Haefeli Walter E.
Published: January 2006

Aims

To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin‐1 receptor antagonist SLV317.

Methods

In a randomized, double‐blind, placebo‐controlled cross‐over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method.

Results

Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (± SEM) of 77 ± 9 ng ml−1 within 47 ± 3 min; the mean half‐life was 9.9 ± 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 ± 8% and 49 ± 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P‐induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 ± 8% and was observed after 1.47 ± 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 ± 67% h−1; 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 ± 12% h−1; 95% CI −24, 122; P < 0.001).

Conclusions

This study demonstrates that the neurokinin‐1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P‐induced effects in humans.
Autotransplantation versus HLA‐matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research
Authors: Lazarus Hillard M. , Pérez Waleska S. , Klein John P. , Kollman Craig , Bate‐Boyle B. , Bredeson Christopher N. , Gale Robert Peter , Geller Robert B. , Keating Armand , Litzow Mark R. , Marks David I. , Miller Carole B. , Douglas Rizzo J. , Spitzer Thomas R. , Weisdorf Daniel J. , Zhang Mei‐Jie , Horowitz Mary M.
Published: January 2006

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen‐identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant‐related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3‐year survival probabilities were: in CR1 57 (53–61)% with autotransplants and 44 (37–51)% URD (P = 0·002), in CR2 46 (39–53)% and 33 (28–38)% respectively (P = 0·006). Adjusted 3‐year leukaemia‐free survival (LFS) probabilities were: CR1 53 (48–57)% with autotransplants and 43 (36–50)% with URD (P = 0·021), CR2 39 (32–46)% and 33 (27–38)% respectively (P = 0·169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3‐year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two‐thirds of patients and treatment bias cannot be eliminated.
Risk of recurrent venous thromboembolism or bleeding in relation to thrombophilic risk factors in patients receiving ximelagatran or placebo for long‐term secondary prevention of venous thromboembolism
Authors: Wåhlander Karin , Eriksson Henry , Lundström Torbjörn , Clason Solveig Billing , Wall Ulrika , Nyström Per , Wessman Peter , Schulman Sam ,   THRIVE III Investigators
Published: January 2006

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long‐term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention‐to‐treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had ≥2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.
Distinct comparative genomic hybridisation profiles in gastric mucosa‐associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21)
Authors: Zhou Yuanping , Ye Hongtao , Martin‐Subero Jose I. , Hamoudi Rifat , Lu Yong‐Jie , Wang Rubin , Siebert Reiner , Shipley Janet , Isaacson Peter G. , Dogan Ahmet , Du Ming‐Qing
Published: January 2006

t(11;18)(q21;q21) occurs specifically in mucosa‐associated lymphoid tissue (MALT) lymphoma and the translocation generates a functional API2‐MALT1 fusion product that activates nuclear factor (NF)κB. t(11;18) positive lymphomas usually lack the chromosomal aberrations and microsatellite alterations frequently seen in the translocation‐negative MALT lymphomas. To further understand their genetic differences, we investigated gastric MALT lymphomas with and without t(11;18) by comparative genomic hybridisation. In general, both chromosomal gains and losses were far more frequent in t(11;18)‐negative (median = 3·4 imbalances) than t(11;18)‐positive cases (median = 1·6 imbalances), with gains being more frequent than losses. Recurrent chromosomal gains involving whole or major parts of a chromosome were seen for chromosomes 3, 12, 18 and 22 (23%, 19%, 19% and 27% respectively). Discrete recurrent chromosomal gains were found at 9q34 (11/26 = 42%). Bioinformatic analysis of genes mapping to 9q34 revealed potential targets. Among them, TRAF2 and CARD9 are known interaction partners of BCL10, playing a role in NFκB activation. Interphase fluorescent in situ hybridisation confirmed genomic gain of the TRAF2, CARD9 and MALT1 loci in 5/6 and 2/2 cases showing chromosomal gains at 9q34 and 18q21 respectively. The results further highlight the genetic difference between MALT lymphomas with and without t(11;18). Moreover, our findings suggest that genomic gain of genes that modulate NFκB activation, such as MALT1, TRAF2 and CARD9, may play a role in the pathogenesis of the translocation‐negative MALT lymphoma.
Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index
Authors: Møller M. B. , Pedersen N. T. , Christensen B. E.
Published: January 2006

The International Prognostic Index (IPI) is the most commonly used prognostic model for mantle cell lymphoma (MCL). However, the prognostic value of the IPI is limited. The recently published Follicular Lymphoma International Prognostic Index (FLIPI) is built on variables, which are pertinent to MCL. This study was conducted to evaluate the prognostic value of FLIPI in a population‐based series of 93 patients with MCL diagnosed in a 7‐year period. End points of the study were response to therapy, overall survival, and disease‐free survival (DFS) according to the IPI and FLIPI. Applied to the whole series, the FLIPI identified three risk groups with markedly different outcome with 5‐year overall survival rates of 65%, 42%, and 8% respectively. Notably, the high‐risk group comprised 53% of patients. In contrast, the IPI only allocated 16% of cases to the high‐risk group and had a lower overall predictive capacity. When both the FLIPI and IPI were included in a multivariate analysis, only the FLIPI was related to survival. Multivariate analysis of DFS also identified the FLIPI, and not the IPI, as independently significant. Thus, in the present study, the FLIPI was superior as a prognostic model compared with the IPI and can therefore be recommended as a clinical prognostic index for MCL.
High‐density mapping and follow‐up studies on chromosomal regions 1, 3, 6, 12, 13 and 17 in 28 families with chronic lymphocytic leukaemia
Authors: Ng David , Marti Gerald E. , Fontaine Laura , Toro Jorge R. , Caporaso Neil , Goldin Lynn R.
Published: January 2006

A subset of chronic lymphocytic leukaemia (CLL) shows familial aggregation. Studies show an increased risk for CLL and other lymphoproliferative disease among first‐degree relatives of affected individuals. A genome‐wide scan of 18 CLL families in 2003 detected LOD or non‐parametric linkage scores ≥1·0 on chromosomes 1, 3, 6, 12, 13 and 17. Follow‐up study with 28 families showed no evidence of linkage at 1p22.1–p21.2, 3q22.1, 3q26.2, 6q22.31–q23.2, 12q24.23, 14q32.13, 17p13.3. Chromosome 13q21.33 remains a region of interest with a P‐value of 0·013 (marker D13S1291) and warrants additional molecular investigation as a susceptibility region for CLL.
Signal transducer and activator of transcription 6 down‐regulates toll‐like receptor‐4 expression of a monocytic cell line
Authors: Fiset P. O. , Tulic M. K. , Skrablin P. S. A. , Grover S. M. , Létuvé S. , Mazer B. D. , Hamid Q.
Published: January 2006

Background
Toll‐like receptor 4 (TLR4), part of the bacterial lipopolysaccharide (LPS) receptor, is an important bridge between innate and adaptive immunity. Our previous studies have indicated reduced expression of TLR4 and reduced responsiveness to LPS in nasal mucosa of atopic adults compared with non‐atopic adults. IL‐4 and signal transducer and activator of transcription 6 (STAT6), which are increased in atopic patients, may have a role in modulating TLR4.

Objective
To examine direct effects of IL‐4 and STAT6 on TLR4 expression of U‐937 monocytic cells.

Methods
LPS responsiveness, under different conditions of U‐937 cells was measured by nuclear factor (NF)‐κB activation of transcription. TLR4 mRNA was quantified by real‐time PCR and TLR4 surface expression was measured by flow cytometry. The promoter and 4.3 kb of the upstream region of TLR4 were cloned into a plasmid vector and transiently transfected into U‐937 cells. Transfected cells were incubated with IL‐4 and transcriptional activity was assayed by the luciferase assay. STAT6 was transfected to evaluate overexpression of this transcription factor. Cells were also incubated with Tyrphostin AG490 to inhibit tyrosine kinases.

Results
NF‐κB activation by LPS was inhibited by IL‐4 pre‐incubation but not when IL‐4 was added at the same time as LPS. TLR4 mRNA expression was inhibited by IL‐4 as early as 6 h but the effect was lost by 24 h. Surface expression of TLR4 was inhibited by IL‐4 at 12 and 24 h, but returned to baseline at 48 h. IL‐4 inhibited activity of the TLR4 promoter as early as 6 h, but, like the mRNA, these effects were transient. STAT6 overexpression enhanced the inhibition of the TLR4 promoter and prolonged it. Inhibition of TLR4 by IL‐4 was abolished by pre‐incubation with the tyrosine kinase inhibitor Tyrphostin AG490.

Conclusion
Our findings demonstrate that IL‐4, through STAT6, can modulate TLR4 expression and suggests that Th2 cytokines can impact on the LPS responsiveness of cells.
Genome‐wide linkage analysis of allergic rhinoconjunctivitis in a Swedish population
Authors: Bu L. M. , Bradley M. , Söderhäll C. , Wahlgren C. F. , Kockum I. , Nordenskjöld M.
Published: January 2006

Background
Allergic rhinoconjunctivitis is a common complex disorder characterized by itching and irritation in the nose, bouts of sneezing, watery rhinorrhoea, nasal congestion and itchy eyes with tears and swelling. Like other atopic disorders such as allergic asthma and atopic dermatitis, the development involves complex interactions of genes and environmental factors.

Objective
The purpose of this study was to identify susceptibility loci for allergic rhinoconjunctivitis.

Methods
We conducted a genome‐wide linkage analysis using a non‐parametric, affected‐relative‐pair method. The 250 families used were collected originally for an atopic dermatitis linkage study.

Results
Three regions showed favour in evidence of linkage to allergic rhinoconjunctivitis: 3q13 (D3S1278: logarithm of odds ratio (LOD)=1.64, P<0.003), 4q34–35 (D4S1652: LOD=1.49, P<0.005) and 18q12 (D18S535: LOD=1.94, P<0.002). In addition, four regions showed weaker evidence in favour of linkage: 6p22–24 (D6S1959: LOD=1.39, P<0.006), 9p11–q12 (D9S1118: LOD=1.15, P<0.02), 9q33.2–34.3 (D9S915: LOD=1.29, P<0.01) and 17q11.2 (D17S1294: LOD=1.13, P<0.02). In single‐point analysis, one locus on chromosome 3 close to marker D3S1278 reaches the suggestive level (LOD=2.28, P<6 × 10−4) while one on chromosome 17 close to marker D17S921 almost reaches this level (LOD=2.17, P<8 × 10−4, Table 3).

 Single‐point linkage analysis for allergic rhinoconjunctivitis

Marker
Map position (cM)*
LOD
P‐value†

D3S1278
129.73
2.28
<6 × 10−4

D3S1267
139.12
1.63
<0.004

D4S1625
145.98
1.18
<0.01

D4S1652
208.07
1.77
<0.003

D6STNFa
63.41
1.14
<0.05

D9S257
91.87
1.10
<0.05

D17S921
36.12
2.17
<8 × 10−4

D17S1294
50.74
1.78
<0.005

D18S843
28.1
1.23
<0.001

Position in centiMorgan (cM) of markers from p‐ter to q‐ter based on the Marshfield map (http//research.marshfieldclinic.org/genetics).

P‐values estimated using P (LOD)=0.5 × (χ21 > 2 ln 10 × LOD).

Conclusion
Our results support the linkage to allergic rhinoconjunctivitis on 3q13, 6p23–p24 and 9q34.3 shown in previous investigations.
Involvement of reduced sensitivity to Ca2+ in β‐adrenergic action on airway smooth muscle
Authors: Oguma T. , Kume H. , Ito S. , Takeda N. , Honjo H. , Kodama I. , Shimokata K. , Kamiya K.
Published: January 2006

Background
It is well known that β‐adrenoceptor agonists (β‐agonists) cause relaxation in airway smooth muscle mediated by a reduction in the concentration of intracellular Ca2+ ([Ca2+]i). However, little is currently known regarding whether reduced sensitization to Ca2+ is involved in the β‐adrenergic relaxation.

Objective
This study was designed to determine the intracellular mechanisms underlying suppression of Ca2+ sensitization in β‐adrenergic relaxation (Ca2+‐independent relaxation by β‐agonists).

Methods
Isometric tension and [Ca2+]i were simultaneously measured in fura‐2‐loaded strips isolated from guinea‐pig tracheal smooth muscles. The relationships between tension and [Ca2+]i were examined in the inhibitory action of isoprenaline (ISO) and other cAMP‐related agents against methacholine‐induced contraction.

Results
The concentration‐inhibition curve for ISO against methacholine in tension was significantly dissociated from the curve for ISO in [Ca2+]i. In ISO‐induced relaxation, a reduction in tension was significantly greater than that in [Ca2+]i. This phenomenon was mimicked by other cAMP‐related agents: forskolin and dibutyryl‐cAMP. In contrast, the inhibitory action of SKF‐96365, a non‐selective inhibitor of Ca2+ channels, was associated with that in [Ca2+]i. In the presence of Rp‐cAMPS, an inhibitor of protein kinase A (PKA), ISO caused an equivalent relaxation with less reduction in [Ca2+]i. The effects of ISO were not affected by Y‐27632, an inhibitor of Rho‐kinase, or by bisindolylmaleimide, an inhibitor of protein kinase C. ISO failed to inhibit contraction elicited by calyculin A, an inhibitor of myosin phosphatase.

Conclusion
β‐Adrenergic action antagonizes not only Ca2+ mobilization but also Ca2+ sensitization in methacholine‐induced contraction. The cAMP/PKA‐independent, Gs‐direct action is more potent in Ca2+‐independent relaxation by β‐agonists than the cAMP/PKA‐dependent pathway. Moreover, myosin phosphatase is a fundamentally affected protein in the reduced response to Ca2+ mediated by β‐agonist. Our results may provide evidence that this Ca2+ desensitization is a novel target for a reliever medication using rapid‐acting β‐agonists in acute asthma management.
Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population
Authors: Tanino Y. , Hizawa N. , Konno S. , Fukui Y. , Takahashi D. , Maeda Y. , Huang S. K. , Nishimura M.
Published: January 2006

Background
Secreted phosphoprotein 1 (SPP1) is a cytokine with pleiotrophic immunological activities, including activation of macrophage chemotaxis and T‐helper type 1 (Th1) immune responses. SPP1 gene polymorphisms have been shown to be associated with several immune inflammatory diseases including multiple sclerosis (MS), which is characterized by fewer allergic symptoms and lower numbers of allergen sensitizations.

Objective
The present study examined whether SPP1 gene polymorphisms are associated with total serum IgE levels, atopy and asthma in a Japanese population.

Methods
This case–control association analysis examined 611 subjects, including 268 subjects with asthma. We genotyped three promoter and two exon polymorphisms at SPP1: −1687A/G; −381T/C; −94 deletion/G; 5891C/T; and 7052T/C.

Results
Association analyses of SPP1 polymorphisms showed that homozygosities for the 5891T allele (P=0.009) and 7052C allele (P=0.001) were significantly associated with increased levels of total IgE in non‐asthmatic subjects. However, these variants were not associated with asthma and atopy. Interestingly, individuals carrying the 5891C allele, which is more prevalent in patients with MS in Japanese populations, displayed significantly lower levels of total serum IgE. Individuals homozygous for the 7052C allele, which is associated with development of systemic lupus erythematosus, displayed significantly higher total serum IgE levels.

Conclusion
These findings suggest that genetic polymorphisms in SPP1 may play a role in controlling basal levels of total serum IgE, independent of atopy.