bluuebunny/crossref_metadata_2025 huggingface dataset:
The biggest bang for the buck or bigger bucks for the bang: the fallacy of the cost-effectiveness threshold
Authors: Birch Stephen , Gafni Amiram
Published: December 2005

It has been suggested that scepticism among decision-makers about using cost-effectiveness analysis (CEA) is caused in part by the low level of the cost-effectiveness 'thresholds' in the economic evaluation literature. This has led Ubel and colleagues to call for higher threshold values of US$200,000 or more per quality-adjusted life-year. We show that these arguments fail to identify the objective of CEA and hence do not consider whether or how the threshold relates to this objective. We show that incremental cost-effectiveness ratios (ICERs) cannot be used to identify an efficient use of resources – the 'biggest bang for the bucks' – allocated to health care. On the contrary, the practical consequence of using the ICER approach is shown to be an increase in health care expenditures, or 'bigger bucks for making a bang', without any evidence of the bang being bigger (i.e. that this leads to an increase in benefits to the population). We present an alternative approach that provides an unambiguous method of determining whether a new intervention leads to an increase in health gains from whatever resources are to be made available to health care decision-makers.
Measurement of adverse events using 'incidence flagged' diagnosis codes
Authors: Jackson Terri , Duckett Stephen , Shepheard Jennie , Baxter Kathryn
Published: December 2005

Objective: To compare two methods for identifying adverse events using routinely recorded hospital abstract data in all public and private hospitals in Victoria, Australia.

Methods: Secondary analysis of data on all admissions in the period 1 July 2000–30 June 2001 ( n = 1,645,992) to estimate the rates of adverse events using International Classification of Diseases 10th Revision Australian Modification codes alone and in combination with an 'incidence' data flag indicating complicating diagnoses which arise after hospitalization; rates of incidence and pre-existing adverse events, and rates for same-day and multi-day admissions.

Results: In total, 8% of all admissions were recorded with an adverse event. Use of ICD codes alone identified only 59% of the events identified using the combined method, giving a prevalence rate of only 5%. Incident cases, that is, those occurring in the index admission, represented 68% of identified adverse events. The adverse events incidence rate for multi-day admissions was significantly higher at 12%, compared with the same day rate of 0.4%.

Conclusion: An 'incidence flag' is essential to identify those adverse events for which a hospital has unambiguous responsibility. Using such a flag, secondary analysis of administrative data can provide hospital quality assurance programmes with a comprehensive view of all adverse events (not just 'sentinel' events) at a reasonable cost and with more timely results than more intensive methods can achieve. Although the method is likely to underestimate the true rate of adverse events (in particular, by not capturing adverse events which only manifest after discharge), in this study of Australian hospitals, rates of adverse events were found to be similar to those derived from studies using manual review of patient records.
Ethics and economics: does programme budgeting and marginal analysis contribute to fair priority setting?
Authors: Gibson Jennifer , Mitton Craig , Martin Douglas , Donaldson Cam , Singer Peter
Published: December 2005

Objective: Limited resources mean that decision-makers must set priorities among competing opportunities. Programme budgeting and marginal analysis (PBMA) is an economic approach that focuses on optimizing benefits with available resources. Accountability for reasonableness (A4R) is an ethics approach that focuses on ensuring fair priority-setting processes. PBMA and A4R have been used separately to provide decision-makers with advice about how to set priorities within limited resources. The goals of this research were to use the A4R framework to evaluate the fairness of using PBMA for priority setting and to assess how A4R might make PBMA fairer.

Methods: Qualitative case studies to describe priority setting using PBMA in the Calgary Health Region (Alberta, Canada) evaluated using A4R as a conceptual framework.

Results: The use of PBMA for priority setting was fairer than previous priority setting because of its emphasis on explicit rational decision-making. However, there were opportunities to improve the process, particularly by collecting data related to the decision criteria, by developing a communication plan to engage internal and external stakeholders about priority-setting, and by providing a formal mechanism to review priority-setting decisions and resolve disputes.

Conclusions: There is potential for combining A4R and PBMA in a more comprehensive approach to priority setting, which uses a fair priority-setting process to reach decisions aimed at achieving optimal benefits with available resources.
Efficient Lentiviral Transduction and Improved Engraftment of Human Bone Marrow Mesenchymal Cells
Authors: Van Damme An , Thorrez Lieven , Ma Ling , Vandenburgh Herman , Eyckmans Jeroen , Dell'Accio Francesco , De Bari Cosimo , Luyten Frank , Lillicrap David , Collen Désiré , VandenDriessche Thierry , Chuah Marinee K.L.
Published: December 2005

Human bone marrow (BM) mesenchymal stem/progenitor cells are potentially attractive targets for ex vivo gene therapy. The potential of lentiviral vectors for transducing BM mesenchymal cells was examined using a self-inactivating vector that expressed the green fluorescent protein (GFP) from an internal cytomegalovirus (CMV) promoter. This vector was compared with oncoretroviral vectors expressing GFP from the CMV promoter or a modified long-terminal repeat that had been optimized for long-term expression in stem cells. The percentage of GFP-positive cells was consistently higher following lentiviral versus oncoretroviral transduction, consistent with increased GFP mRNA levels and increased gene transfer efficiency measured by polymerase chain reaction and Southern blot analysis. In vitro GFP and FVIII expression lasted for several months post-transduction, although expression slowly declined. The transduced cells retained their stem/progenitor cell properties since they were still capable of differentiating along adipogenic and osteogenic lineages in vitro while maintaining high GFP and FVIII expression levels. Implantation of lentivirally transduced human BM mesenchymal cells using collagen scaffolds into immunodeficient mice resulted in efficient engraftment of gene-engineered cells and long-term transgene expression in vivo. These biocompatible BM mesenchymal implants represent a reversible, safe, and versatile protein delivery approach because they can be retrieved in the event of an unexpected adverse reaction or when expression of the protein of interest is no longer required. In conclusion, efficient gene delivery with lentiviral vectors in conjunction with the use of bioengineered reversible scaffolds improves the therapeutic prospects of this novel approach for gene therapy, protein delivery, or tissue engineering.
Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations
Authors: Roepman Ronald , Letteboer Stef J. F. , Arts Heleen H. , van Beersum Sylvia E. C. , Lu Xinrong , Krieger Elmar , Ferreira Paulo A. , Cremers Frans P. M.
Published: December 2005

RPGR-interacting protein 1 (RPGRIP1) is a key component of cone and rod photoreceptor cells, where it interacts with RPGR (retinitis pigmentosa GTPase regulator). Mutations in
RPGRIP1
lead to autosomal recessive congenital blindness [Leber congenital amaurosis (LCA)]. Most LCA-associated missense mutations in
RPGRIP1
are located in a segment that encodes two C2 domains. Based on the C2 domain of novel protein kinase Cε (PKCε), we built a 3D-homology model for the C-terminal C2 domain of RPGRIP1. This model revealed a potential Ca
2+
-binding site that was predicted to be disrupted by a missense mutation in
RPGRIP1
, which was previously identified in an LCA patient. Through yeast two-hybrid screening of a retinal cDNA library, we found this C2 domain to specifically bind to nephrocystin-4, encoded by
NPHP4
. Mutations in
NPHP4
are associated with nephronophthisis and a combination of nephronophthisis and retinitis pigmentosa called Senior–Løken syndrome (SLSN). We show that RPGRIP1 and nephrocystin-4 interact strongly
in vitro
and
in vivo
, and that they colocalize in the retina, matching the panretinal localization pattern of specific RPGRIP1 isoforms. Their interaction is disrupted by either mutations in
RPGRIP1
, found in patients with LCA, or by mutations in
NPHP4
, found in patients with nephronophthisis or SLSN. Thus, we provide evidence for the involvement of this disrupted interaction in the retinal dystrophy of both SLSN and LCA patients.
A papain-like enzyme at work: Native and acyl–enzyme intermediate structures in phytochelatin synthesis
Authors: Vivares Denis , Arnoux Pascal , Pignol David
Published: December 2005

Phytochelatin synthase (PCS) is a key enzyme for heavy-metal detoxification in plants. PCS catalyzes the production of glutathione (GSH)-derived peptides (called phytochelatins or PCs) that bind heavy-metal ions before vacuolar sequestration. The enzyme can also hydrolyze GSH and GS-conjugated xenobiotics. In the cyanobacterium
Nostoc
, the enzyme (NsPCS) contains only the catalytic domain of the eukaryotic synthase and can act as a GSH hydrolase and weakly as a peptide ligase. The crystal structure of NsPCS in its native form solved at a 2.0-Å resolution shows that NsPCS is a dimer that belongs to the papain superfamily of cysteine proteases, with a conserved catalytic machinery. Moreover, the structure of the protein solved as a complex with GSH at a 1.4-Å resolution reveals a γ-glutamyl cysteine acyl–enzyme intermediate stabilized in a cavity of the protein adjacent to a second putative GSH binding site. GSH hydrolase and PCS activities of the enzyme are discussed in the light of both structures.
Slow growth rates of Amazonian trees: Consequences for carbon cycling
Authors: Vieira Simone , Trumbore Susan , Camargo Plinio B. , Selhorst Diogo , Chambers Jeffrey Q. , Higuchi Niro , Martinelli Luiz Antonio
Published: December 2005

Quantifying age structure and tree growth rate of Amazonian forests is essential for understanding their role in the carbon cycle. Here, we use radiocarbon dating and direct measurement of diameter increment to document unexpectedly slow growth rates for trees from three locations spanning the Brazilian Amazon basin. Central Amazon trees, averaging only ≈1mm/year diameter increment, grow half as fast as those from areas with more seasonal rainfall to the east and west. Slow growth rates mean that trees can attain great ages; across our sites we estimate 17-50% of trees with diameter >10 cm have ages exceeding 300 years. Whereas a few emergent trees that make up a large portion of the biomass grow faster, small trees that are more abundant grow slowly and attain ages of hundreds of years. The mean age of carbon in living trees (60-110 years) is within the range of or slightly longer than the mean residence time calculated from C inventory divided by annual C allocation to wood growth (40-100 years). Faster C turnover is observed in stands with overall higher rates of diameter increment and a larger fraction of the biomass in large, fast-growing trees. As a consequence, forests can recover biomass relatively quickly after disturbance, whereas recovering species composition may take many centuries. Carbon cycle models that apply a single turnover time for carbon in forest biomass do not account for variations in life strategy and therefore may overestimate the carbon sequestration potential of Amazon forests.
A high-resolution whole-genome cattle–human comparative map reveals details of mammalian chromosome evolution
Authors: Wind Annelie Everts-van der , Larkin Denis M. , Green Cheryl A. , Elliott Janice S. , Olmstead Colleen A. , Chiu Readman , Schein Jacqueline E. , Marra Marco A. , Womack James E. , Lewin Harris A.
Published: December 2005

Approximately 3,000 cattle bacterial artificial chromosome (BAC)-end sequences were added to the Illinois–Texas 5,000-rad RH (RH, radiation hybrid) map. The BAC-end sequences selected for mapping are ≈1 Mbp apart on the human chromosomes as determined byblastnanalysis. The map has 3,484 ordered markers, of which 3,204 are anchored in the human genome. Two hundred-and-one homologous synteny blocks (HSBs) were identified, of which 27 are previously undiscovered, 79 are extended, 26 were formed by previously unrecognized breakpoints in 18 previously defined HSBs, and 23 are the result of fusions. The comparative coverage relative to the human genome is ≈91%, or 97% of the theoretical maximum. The positions of 64% of all cattle centromeres and telomeres were reassigned relative to their positions on the previous map, thus facilitating a more detailed comparative analysis of centromere and telomere evolution. As an example of the utility of the high-resolution map, 22 cattle BAC fingerprint contigs were directly anchored to cattle chromosome 19 [Bos taurus, (BTA) 19]. The order of markers on the cattle RH and fingerprint maps of BTA19 and the sequence-based map of human chromosome 17 [Homo sapiens, (HSA) 17] were found to be highly consistent, with only two minor ordering discrepancies between the RH map and fingerprint contigs. The high-resolution Illinois-Texas 5,000-rad RH and comparative maps will facilitate identification of candidate genes for economically important traits, the phylogenomic analysis of mammalian chromosomes, proofing of the BAC fingerprint map and, ultimately, aid the assembly of cattle whole-genome sequence.
ABA-Hypersensitive Germination3Encodes a Protein Phosphatase 2C (AtPP2CA) That Strongly Regulates Abscisic Acid Signaling during Germination among Arabidopsis Protein Phosphatase 2Cs
Authors: Yoshida Tomo , Nishimura Noriyuki , Kitahata Nobutaka , Kuromori Takashi , Ito Takuya , Asami Tadao , Shinozaki Kazuo , Hirayama Takashi
Published: December 2005

The phytohormone abscisic acid (ABA) regulates physiologically important developmental processes and stress responses. Previously, we reported on Arabidopsis (Arabidopsis thaliana) L. Heynh. ahg mutants, which are hypersensitive to ABA during germination and early growth. Among them, ABA-hypersensitive germination3 (ahg3) showed the strongest ABA hypersensitivity. In this study, we found that the AHG3 gene is identical to AtPP2CA, which encodes a protein phosphatase 2C (PP2C). Although AtPP2CA has been reported to be involved in the ABA response on the basis of results obtained by reverse-genetics approaches, its physiological relevance in the ABA response has not been clarified yet. We demonstrate in vitro and in vivo that the ahg3-1 missense mutation causes the loss of PP2C activity, providing concrete confirmation that this PP2C functions as a negative regulator in ABA signaling. Furthermore, we compared the effects of disruption mutations of eight structurally related PP2C genes of Arabidopsis, including ABI1, ABI2, HAB1, and HAB2, and found that the disruptant mutant of AHG3/AtPP2CA had the strongest ABA hypersensitivity during germination, but it did not display any significant phenotypes in adult plants. Northern-blot analysis clearly showed that AHG3/AtPP2CA is the most active among those PP2C genes in seeds. These results suggest that AHG3/AtPP2CA plays a major role among PP2Cs in the ABA response in seeds and that the functions of those PP2Cs overlap, but their unique tissue- or development-specific expression confers distinct and indispensable physiological functions in the ABA response.
Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans
Authors: Bellien Jeremy , Joannides Robinson , Iacob Michele , Arnaud Philippe , Thuillez Christian
Published: December 2005

Whether a cytochrome P-450 (CYP)-related endothelium-derived hyperpolarizing factor (EDHF), acting through calcium-activated potassium (KCa) channels, interacts with nitric oxide (NO) to regulate the basal diameter of human peripheral conduit arteries is unexplored in vivo. Radial artery diameter (echo tracking) and blood flow (Doppler) were measured, after oral aspirin (500 mg), in eight healthy volunteers during local infusion for 8 min of tetraethylammonium chloride (TEA; 9 μmol/min), as KCachannel inhibitor, and fluconazole (0.4 μmol/min), as CYP inhibitor, alone and in combination with NG-monomethyl-l-arginine (l-NMMA; 8 μmol/min), as endothelial NO synthase inhibitor. Endothelium-independent dilatation was assessed by using sodium nitroprusside (SNP). Radial diameter was unaffected by l-NMMA (0.4 ± 0.9%) and fluconazole (−1.6 ± 0.8%) but was decreased by TEA (−5.0 ± 1.0%), l-NMMA + fluconazole (−5.3 ± 0.5%), and l-NMMA + TEA (−9.9 ± 1.3%). These effects are still significant even when the concomitant decreases in blood flow induced by l-NMMA (−24 ± 4%), TEA (−21 ± 3%), l-NMMA + fluconazole (−26 ± 5%), and l-NMMA + TEA (−35 ± 4%) were taken as covariate into analysis. Conversely, fluconazole alone slightly but not significantly increased radial flow (13 ± 6%). l-NMMA alone or with TEA and with fluconazole enhanced radial artery dilatation to SNP, whereas TEA and fluconazole alone did not modify this response. These results confirm in humans the involvement of NO and KCachannels in the regulation of basal conduit artery diameter. Moreover, the synergistic effect of combined inhibition of NO synthesis and CYP on the decrease in radial diameter in the absence of such effect after l-NMMA and fluconazole alone unmasks the role of CYP in this regulation and shows the presence of an interaction between NO and a CYP-related EDHF to maintain peripheral conduit artery diameter in vivo. Furthermore, the higher vasoconstrictor effect of TEA compared with fluconazole suggests that different KCachannel-dependent hyperpolarizing mechanisms could exist in conduit arteries.
Regionalism and Globalization: The Case of the European Union
Authors: Molchanov Mikhail
Published: December 2005

Regional groupings of states are often regarded as the appropriate response to economic and cultural strains generated by the globalization of market forces. The European Union, the most successful regional grouping in the world today, illustrates both the potential and the limitations of such organizations. In one sense, Europe has been in the vanguard of globalization, eliminating traditional barriers to the movement of labor, goods, and capital; but in another sense, the EU can be seen as a protective response to global exigencies and an attempt to safeguard Europe's cultural identity. This chapter assesses the EU in terms of these dynamic contradictions.
Differential Formation and Circulation of North Pacific Central Mode Water
Authors: Oka Eitarou , Suga Toshio
Published: December 2005

A repeat hydrographic section along 165°E was analyzed to verify a westward extension of the formation region of the North Pacific Ocean Central Mode Water (CMW) suggested by previous synoptic observations, and to investigate the relation between the formation region and thermohaline fronts. The CMW formation region extends at least as far west as 155°E, much farther than recognized in a previous study based on climatology. It is located in two interfrontal regions between the Kuroshio Extension front and the Kuroshio Bifurcation front (KBF), and between the KBF and the subarctic front, where two types of CMW—namely, the lighter variety with potential density of 25.8–26.2 kg m−3 and the denser one of 26.3–26.4 kg m−3—are formed. How this differential formation of CMW is reflected in its gyrewide distribution was examined using one-time sections of the World Ocean Circulation Experiment (WOCE) Hydrographic Program in the North Pacific. The main circulation paths of the two types of CMW diverge east of the date line; the lighter variety is located in the inner part of the eastern subtropical gyre, and the denser variety is located in the outer part. These results demonstrate that the frontal structure around the northern boundary of the subtropical gyre, particularly the existence of KBF, is essential in determining the properties and the gyrewide distribution of CMW.
Meeting Nursing Shortage Needs Through Educational Partnerships: LPN to RN Under One Roof
Authors: Brown Robin , Falkingham Eleanor , Fischbach Cheryl , Nerud Kim , Schmidt Heidi
Published: December 2005

A unique 1 + 1 licensed practical nurse (LPN) to registered nurse (RN) program is offered through a contractual partnership between Lake Area Technical Institute and the University of South Dakota. The practical nursing graduates enjoy a seamless transition from LPN to RN. A critical piece to the success of this joint venture is the mutual use of facilities and the utilization of shared faculty. Collaboration among Lake Area Technical Institute, the South Dakota Board of Education, the University of South Dakota, and the South Dakota Board of Regents has created the seamless articulation of general education and practical nursing credits. Acknowledgement of prior education is recognized through a demonstration of competencies and verification of credits. The 1 + 1 program has been a success for more than a decade as a result of two schools working together under one roof.
Nursing Clinical in Iraq
Authors: Eddy Catherine , Hill Katherine
Published: December 2005

When President Bush began the war against terrorism, it affected the lives of millions of people in the world. This article presents how the war on terrorism and the activation of troops affected nursing students. These students were from diverse parts of our country and, with this activation, experienced a very different clinical setting than was planned within nursing curricula. This article describes this unique situation from the perspective of the students who were activated, and how one student was able to complete both her theory and clinical experience while on active duty in Iraq.
Enigmas of bidri
Authors: Craddock P. T.
Published: December 2005

Metal surfaces of objet d'art were usually kept highly polished in the past and chemical patination as a decorative technique was rare before the 19th century. The best known exceptions are the Japanese irogane alloys and their occidental precursors. Another less well known patinated metal are the bidri wares of India. The items are sand castings of an alloy containing ∼95% of zinc and 5% of copper. After casting the pieces are heavily inlaid with silver wires and foils and then treated to produce a rich black patina. Bidri wares are still made in quantity in the Deccan of central India, including at Bidar in the state of Karnataka, the traditional centre of the industry from which bidri takes its name. Zinc metal was first prepared in India ∼1000 years ago and so an association between zinc production and zinc artefacts seems natural. However, this is not really the case, and the origins are really quite mysterious. Bidri has always been made in the Moslem parts of India by Moslem craftsmen who claim that the technique began in the Middle East, but where there was no zinc. Zinc was produced only at Zawar in the Hindu Rajput states of Rajasthan, well over 1000 km from the nearest bidri maker, and furthermore the few lead isotope analyses performed on the early bidri wares show the zinc did not come from Zawar. Thus the origins of the technique and the source of the zinc are shrouded in mystery, and a further mystery concerns the chemical nature of the patinated layer itself. None of the minerals identified in the patinated layer by X-ray diffraction should be black, but clearly some form of finely divided and probably amorphous copper oxide must be responsible. Whatever its origins and composition, bidri wares continue to be made and to provide a quintessential craft product of India.
Tinned surface in Spanish Late Bronze Age swords
Authors: Rovira S.
Published: December 2005

Two weapons showing grey silver like surfaces of the Spanish Late Bronze Age were investigated using SEM and metallography. The coating layer in the best preserved dagger is δ phase tin. This is not in agreement with the experimental results and analytical studies of archaeological items tinned by cassiterite reduction that are described in previous literature. Some conjectures are made to explain this coating layer.
Wear surface studies on blasting nozzles in abrasive surface treatment
Authors: Deng J.-X.
Published: December 2005

In this study, B4C and Al2O3–TiC ceramics, WC–Co (YG8) cemented carbide and hardened steel were produced to be used as nozzle materials. Abrasive blasting surface treatment with these nozzles was carried out. The wear surface features of the nozzles made from these materials were examined. The results showed the ceramic nozzles to be entirely brittle in nature, with evidence of large scale chipping, and a brittle fracture induced removal process at the nozzle entry bore section; at the nozzle centre bore area, the ceramic nozzles showed a polishing effect with a very smooth surface, and the grain size and distribution could be clearly seen. Examination of the eroded bore surface of the WC–Co cemented carbide nozzles demonstrated that the wear occurred through preferential removal of the metal binder (Co) followed by pluck-out of the exposed WC grains, while the primary wear mechanisms of 45# hardened steel nozzle were ploughing and microcutting by the abrasive particles.
Low temperature gaseous nitriding and carburising of stainless steel
Authors: Christiansen T. , Somers M. A. J.
Published: December 2005

The response of various austenitic and duplex stainless steel grades to low temperature gaseous nitriding and carburising was investigated. Gaseous nitriding was performed in ammonia/hydrogen mixtures at temperatures <723 K; gaseous carburising was carried out in carbon monoxide/hydrogen mixtures for temperatures ≤783 K. The case developed by thermochemical treatment was examined using reflected light microscopy, X-ray diffraction analysis and microhardness testing. Both nitriding and carburising led to the development of expanded austenite in the surface adjacent zone, irrespective of the phase constitution of the substrate. A two step process, consisting of carburising followed by nitriding, provides great flexibility with regard to adjusting the hardness–depth profile.
Agrarian diet and diseases of affluence – Do evolutionary novel dietary lectins cause leptin resistance?
Authors: Jönsson Tommy , Olsson Stefan , Ahrén Bo , Bøg-Hansen Thorkild C , Dole Anita , Lindeberg Staffan
Published: December 2005

Background

The global pattern of varying prevalence of diseases of affluence, such as obesity, cardiovascular disease and diabetes, suggests that some environmental factor specific to agrarian societies could initiate these diseases.

Presentation of the hypothesis

We propose that a cereal-based diet could be such an environmental factor. Through previous studies in archaeology and molecular evolution we conclude that humans and the human leptin system are not specifically adapted to a cereal-based diet, and that leptin resistance associated with diseases of affluence could be a sign of insufficient adaptation to such a diet. We further propose lectins as a cereal constituent with sufficient properties to cause leptin resistance, either through effects on metabolism central to the proper functions of the leptin system, and/or directly through binding to human leptin or human leptin receptor, thereby affecting the function.

Testing the hypothesis

Dietary interventions should compare effects of agrarian and non-agrarian diets on incidence of diseases of affluence, related risk factors and leptin resistance. A non-significant (p = 0.10) increase of cardiovascular mortality was noted in patients advised to eat more whole-grain cereals. Our lab conducted a study on 24 domestic pigs in which a cereal-free hunter-gatherer diet promoted significantly higher insulin sensitivity, lower diastolic blood pressure and lower C-reactive protein as compared to a cereal-based swine feed. Testing should also evaluate the effects of grass lectins on the leptin system in vivo by diet interventions, and in vitro in various leptin and leptin receptor models. Our group currently conducts such studies.

Implications of the hypothesis

If an agrarian diet initiates diseases of affluence it should be possible to identify the responsible constituents and modify or remove them so as to make an agrarian diet healthier.
Systemic coagulation parameters in mice after treatment with vascular targeting agents
Authors: Unruh Maike , Grunow Andrea , Gottstein Claudia
Published: December 2005

Background

Vascular targeting of malignant tumors has become a clinically validated new treatment approach with clear patient benefit. However clinical studies have also revealed that some types of vascular targeting agents (VTAs) are prone to coagulation system side effects. It is therefore essential to predetermine coagulation parameters in preclinical studies. As of to date, this has rarely been done, predominantly due to technical issues.

The goal of this study was to establish and apply a standardized process, whereby systemic coagulation activation can be routinely measured in mice.

Results

We have evaluated a number of sampling techniques and coagulation tests regarding their suitability for this purpose. We were able to adapt two assays measuring soluble fibrin, a marker for a prethrombotic status. Thus, soluble fibrin could be measured for the first time in mice. All assays were validated in a positive control model for systemic coagulation activation, i.e. lipopolysaccharide-induced endotoxemia.

Based on our results, we selected a panel of coagulation tests, which are both feasable and informative for preclinical testing of VTAs: soluble fibrin, thrombin-antithrombin complexes, free antithrombin III, white blood cell counts and platelet counts. The effect of tumor transplants on coagulation parameters was evaluated using this panel. We then applied this set of assays in treatment studies with a VTA developed in our laboratory to investigate a potential systemic coagulation activation.

Conclusion

We have established a standardized panel of assays that can be used to test murine blood samples for coagulation activation in preclinical studies. All tests are feasible to perform in any research laboratory without specialized equipment. In addition, this is the first report to measure soluble fibrin, an early marker of systemic coagulation activation, in mice. The panel was applied on tumor bearing mice and mice treated with a VTA. We suggest its general application for coagulation activation analyses in mice.
‘Now nobody falls through the net’: practitioners’ perspectives on the Gold Standards Framework for community palliative care
Authors: King Nigel , Thomas Keri , Martin Nina , Bell Dennise , Farrell Sharon
Published: December 2005

The Gold Standards Framework (GSF) seeks to facilitate consistent and high quality community palliative care through a set of guidelines, mechanisms and assessment tools. The present study set out to examine practitioners’ perspectives on the GSF during its first national roll-out. Two general practices that had adopted the GSF were recruited in each of four geographical areas, and each matched as closely as possible with a non-GSF practice. Sixty-eight semi-structured telephone interviews were carried out with general practitioners and district nurses in 16 selected practices, along with the GSF facilitator and up to four other ‘stakeholders’ in each area. Analysis revealed that the majority of GSF participants felt that the framework had strengthened their provision of community palliative care. In particular, communication within primary health care teams and co-ordination of services improved, aspects which were better in the GSF practices than in the matched non-GSF practices. Practitioners felt there was more consistency of care, with a reduced likelihood that individual patients would ‘slip through the net’. The most common areas of concern were in relation to the workload associated with the role of the GSF co-ordinator. Implications for the development and effective implementation of the framework and for further research are discussed.
Do the incentive payments in the new NHS contract for primary care reflect likely population health gains?
Authors: Fleetcroft Robert , Cookson Richard
Published: December 2005

Objective: The new contract for primary care in the UK offers fee-for-service (FFS) payments for a wide range of activities in a quality outcomes framework (QOF), with payments designed to reflect likely workload. This study aims to explore the link between these financial incentives and the likely population health gains.

Methods: The study examines a subset of eight preventive interventions covering 38 of the 81 clinical indicators in the quality framework. The maximum payment for each service was calculated and compared with the likely population health gain in terms of lives saved per 100,000 population based on evidence from McColl et al. (1998).

Results: Maximum payments for the eight interventions examined make up 57% of the total maximum payment for all clinical interventions in the (QOF). There appears to be no relationship between pay and health gain across these eight interventions. Two of the eight interventions (warfarin in atrial fibrillation and statins in primary prevention) receive no incentive.

Conclusions: Payments in the new contract do not reflect likely population health gain. There is a danger that clinical activity may be skewed towards high-workload activities that are only marginally effective, to the detriment of more cost-effective activities. If improving population health is the primary goal of the NHS, then FFS incentives should be designed to reflect likely health gain rather than likely workload.
Advances in the assessment of suicide risk
Authors: Bryan Craig J. , Rudd M. David
Published: December 2005

This article reviews and integrates empirically grounded advances in the assessment of suicidality. The practices discussed are consistent with existing standards of care, practice guidelines, and applicable research. The authors differentiate between risk assessment and prediction and then emphasize the important role of time in risk assessment. We present and illustrate a continuum of suicidality for risk assessment and offer practical recommendations for clinical decision making and treatment. © 2005 Wiley Periodicals, Inc. J Clin Psychol: In Session 62: 185–200, 2006.
Mindfulness‐Based cognitive therapy for prevention of recurrence of suicidal behavior
Authors: Williams J. Mark G. , Duggan Danielle S. , Crane Catherine , Fennell Melanie J. V.
Published: December 2005

Once suicidal thoughts have emerged as a feature of depression they are likely to be reactivated as part of a suicidal mode of mind whenever sad mood reappears. This article reviews the methods and the usefulness of mindfulness‐based cognitive therapy (MBCT) as a treatment for the prevention of the reactivation of the suicidal mode. MBCT integrates mindfulness meditation practices and cognitive therapy techniques. It teaches participants to develop moment‐by‐moment awareness, approaching ongoing experience with an attitude of nonjudgment and acceptance. Participants are increasingly able to see their thoughts as mental events rather than facts (metacognitive awareness). A case example illustrates how mindfulness skills develop with MBCT and how they relate to the cognitive processes that fuel suicidal crises. An ongoing controlled trial will provide further evidence, but pilot work suggests that MBCT is a promising intervention for those who have experienced suicidal ideation in the past. © 2005 Wiley Periodicals, Inc. J Clin Psychol: In Session 62: 201–210, 2006.
Note on an inequality
Authors: Xu Yongzhong
Published: December 2005

We prove in this article the case of three masses, of an inequality of discrete type (which might have a continuous extension) which is still a conjecture for any

p

points in

\mathbb{R}^{3}

. The inequality appears naturally in the derivation of Morse Lemma at infinity for Yamabe problems with changing signs. We also explain why this inequality might hold in general.

Nous prouvons dans cet article le cas

p = 3

, d'une inégalité discrète (qui s'étend peut-être au cas continu) qui est une conjecture pour

p

points quelconques de

\mathbb{R}^{3}

. Cette inégalité apparaît naturellement dans la démonstration du Lemme de Morse à l'infini [A. Bahri, Critical Points at Infinity in Some Variational Problems, Pitman Res. Notes Math. Ser., vol. 182, Longman Scientific & Technical, Harlow, 1989] pour les problèmes de Yamabe avec changement de signe. Nous montrons par la suite pourquoi l'inégalité devrait être vraie en général.
Mitochondrial targeting of growth suppressor protein DLC2 through the START domain
Authors: Ng David Chi-Heng , Chan Shing-Fai , Kok Kin Hang , Yam Judy Wai Ping , Ching Yick-Pang , Ng Irene Oi-lin , Jin Dong-Yan
Published: December 2005

Deleted in liver cancer 2 (DLC2) is a candidate tumor suppressor frequently found to be deleted in hepatocellular carcinoma. In this study, we determined the subcellular localization of DLC2. Co‐localization and biochemical fractionation studies revealed that DLC2 localized to mitochondria. In addition, the DLC2‐containing cytoplasmic speckles were in proximity to lipid droplets. A DLC2 mutant containing the steroidogenic acute regulatory protein‐related lipid transfer (START) domain only showed a localization pattern identical to that of DLC2. Taken together, we have provided the first evidence for mitochondrial localization of DLC2 through the START domain. These findings might have implications in liver physiology and carcinogenesis.
Evidence for phosphorylation of rat liver glucose‐regulated protein 58, GRP58/ERp57/ER‐60, induced by fasting and leptin
Authors: Kita Kanako , Okumura Nobuaki , Takao Toshifumi , Watanabe Makoto , Matsubara Toshiya , Nishimura Osamu , Nagai Katsuya
Published: December 2005

Glucose‐regulated protein 58 (GRP58)‐like immunoreactivity in rat liver obtained in the evening or after fasting underwent an electrophoretic band‐shift, which disappeared after phosphatase‐treatment. Since mass spectrometric analysis raised a possibility that Ser150 of GRP58 is phosphorylated, an antibody against the phosphoserine150 GRP58 was generated. Immunoreactivity to this antibody was increased in the evening and after fasting. Since GRP58 was shown to interact with signal transducer and activator of transduction 3 (STAT3), a leptin‐related protein, the effect of leptin was examined. Immunoreactivity to the anti‐phosphoGRP58 antibody was markedly elevated after the leptin injection, indicating that Ser150 of GRP58 is phosphorylated after fasting and leptin‐treatment.
A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parametersin vivo
Authors: Mitsukawa Kayo , Yamamoto Rina , Ofner Silvio , Nozulak Joachim , Pescott Oliver , Lukic Snezana , Stoehr Natacha , Mombereau Cedric , Kuhn Rainer , McAllister Kevin H. , van der Putten Herman , Cryan John F. , Flor Peter J.
Published: December 2005

Metabotropic glutamate receptor (mGluR) subtypes (mGluR1 to mGluR8) act as important pre- and postsynaptic regulators of neurotransmission in the CNS. These receptors consist of two domains, an extracellular region containing the orthosteric agonist site and a transmembrane heptahelical domain involved in G protein activation and recognition of several recently synthesized pharmacological modulators. The presynaptic receptor mGluR7 shows the highest evolutionary conservation within the family, but no selective pharmacological tool was known. Here we characterize an mGluR7-selective agonist,N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), which directly activates receptor signaling via an allosteric site in the transmembrane domain. At transfected mammalian cells expressing mGluR7, AMN082 potently inhibits cAMP accumulation and stimulates GTPγS binding (EC50-values, 64-290 nM) with agonist efficacies comparable with those ofl-2-amino-4-phosphonobutyrate (L-AP4) and superior to those ofl-glutamate. AMN082 (≤10 μM) failed to show appreciable activating or inhibitory effects at other mGluR subtypes and selected ionotropic GluRs. Chimeric receptor studies position the binding site of AMN082 in the transmembrane region of mGluR7, and we demonstrate that this allosteric agonist has little, if any, effect on the potency of orthosteric ligands. Here we provide evidence for full agonist activity mediated by the heptahelical domain of family 3 G protein-coupled receptors (which have mGluR-like structure) that may lead to drug development opportunities. Further, AMN082 is orally active, penetrates the blood-brain barrier, and elevates the plasma stress hormones corticosterone and corticotropin in an mGluR7-dependent fashion. Therefore, AMN082 is a valuable tool for unraveling the role of mGluR7 in stress-related CNS disorders.
Use of Two-Color Fluorescence-Tagged Transgenes to Study Interphase Chromosomes in Living Plants
Authors: Matzke Antonius J.M. , Huettel Bruno , van der Winden Johannes , Matzke Marjori
Published: December 2005

Sixteen distinct sites distributed on all five Arabidopsis (Arabidopsis thaliana) chromosomes have been tagged using different fluorescent proteins and one of two different bacterial operator-repressor systems: (1) a yellow fluorescent protein-Tet repressor fusion protein bound to tet operator sequences, or (2) a green or red fluorescent protein-Lac repressor fusion protein bound to lac operator sequences. Individual homozygous lines and progeny of intercrosses between lines have been used to study various aspects of interphase chromosome organization in root cells of living, untreated seedlings. Features reported here include distances between transgene alleles, distances between transgene inserts on different chromosomes, distances between transgene inserts on the same chromatin fiber, alignment of homologous chromosomes, and chromatin movement. The overall findings are consistent with a random and largely static arrangement of interphase chromosomes in nuclei of root cells. These transgenic lines provide tools for in-depth analyses of interphase chromosome organization, expression, and dynamics in living plants.
The Membrane-Anchored BOTRYTIS-INDUCED KINASE1 Plays Distinct Roles in Arabidopsis Resistance to Necrotrophic and Biotrophic Pathogens
Authors: Veronese Paola , Nakagami Hirofumi , Bluhm Burton , AbuQamar Synan , Chen Xi , Salmeron John , Dietrich Robert A. , Hirt Heribert , Mengiste Tesfaye
Published: December 2005

Plant resistance to disease is controlled by the combination of defense response pathways that are activated depending on the nature of the pathogen. We identified the Arabidopsis thaliana  BOTRYTIS-INDUCED KINASE1 (BIK1) gene that is transcriptionally regulated by Botrytis cinerea infection. Inactivation of BIK1 causes severe susceptibility to necrotrophic fungal pathogens but enhances resistance to a virulent strain of the bacterial pathogen Pseudomonas syringae pv tomato. The response to an avirulent bacterial strain is unchanged, limiting the role of BIK1 to basal defense rather than race-specific resistance. The jasmonate- and ethylene-regulated defense response, generally associated with resistance to necrotrophic fungi, is attenuated in the bik1 mutant based on the expression of the plant defensin PDF1.2 gene. bik1 mutants show altered root growth, producing more and longer root hairs, demonstrating that BIK1 is also required for normal plant growth and development. Whereas the pathogen responses of bik1 are mostly dependent on salicylic acid (SA) levels, the nondefense responses are independent of SA. BIK1 is membrane-localized, suggesting possible involvement in early stages of the recognition or transduction of pathogen response. Our data suggest that BIK1 modulates the signaling of cellular factors required for defense responses to pathogen infection and normal root hair growth, linking defense response regulation with that of growth and development.
A New Role for theArabidopsisAP2 Transcription Factor, LEAFY PETIOLE, in Gibberellin-Induced Germination Is Revealed by the Misexpression of a Homologous Gene,SOB2/DRN-LIKE
Authors: Ward Jason M. , Smith Alison M. , Shah Purvi K. , Galanti Sarah E. , Yi Hankuil , Demianski Agnes J. , van der Graaff Eric , Keller Beat , Neff Michael M.
Published: December 2005

Gibberellic acid (GA) promotes germination, stem/hypocotyl elongation, and leaf expansion during seedling development. Using activation-tagging mutagenesis, we identified a mutation, sob2-D (for suppressor of phytochromeB-4 [phyB-4]#2 dominant), which suppresses the long-hypocotyl phenotype of a phyB missense allele, phyB-4. This mutant phenotype is caused by the overexpression of an APETALA2 transcription factor, SOB2, also called DRN-like. SOB2/DRN-like transcript is not detectable in wild-type seedling or adult tissues via RT-PCR analysis, suggesting that SOB2/DRN-like may not be involved in seedling development under normal conditions. Adult sob2-D phyB-4 plants have curled leaves and club-like siliques, resembling plants that overexpress a closely related gene, LEAFY PETIOLE (LEP). Hypocotyls of a LEP-null allele, lep-1, are shorter in the light and dark, suggesting LEP involvement in seedling development. This aberrant hypocotyl phenotype is due at least in part to a delay in germination. In addition, lep-1 is less responsive to GA and more sensitive to the GA biosynthesis inhibitor paclobutrazol, indicating that LEP is a positive regulator of GA-induced germination. RT-PCR shows that LEP transcript accumulates in wild-type seeds during imbibition and germination, and the transcript levels of REPRESSOR OF ga1-3-LIKE2 (RGL2), a negative regulator of GA signaling during germination, is unaffected in lep-1. These results suggest LEP is a positive regulator of GA-induced germination acting independently of RGL2. An alternative model places LEP downstream of RGL2 in the GA-signaling cascade.