bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function
Authors: Buckland Robert , Sugidachi Atsuhiro , Jakubowski Joseph , Storey Robert , Judge Heather 
Published: April 2010

SummaryThe thienopyridine P2Y12 receptor antagonists clopidogrel and prasugrel prevent arterial thrombosis and are routinely used following percutaneous coronary intervention. However, the optimal level of P2Y12 blockade to effectively inhibit platelet function is unknown. These studies utilised the active metabolite of prasugrel (R-138727) to achieve a range of P2Y12 blockade in vitro and assessed several aspects of platelet function. Blood from healthy volunteers was incubated with R-138727 (0–10 μM). P2Y12 receptor number was assessed using a 33P-2MeSADP binding assay. Platelet aggregation (PA) was measured by optical aggregometry with ADP 2–20 μM. VASP phosphorylation, annexin V binding, microparticle formation and P-selectin expression were assessed by flow cytometry. Increasing numbers of unblocked receptors were required for a sustained aggregation response with decreasing concentrations of ADP. A P2Y12 receptor blockade of 60–80% resulted in strong inhibition of final PA response, P-selectin expression, microparticle formation and vasodilator-stimulated phosphoprotein (VASP). PA induced by ADP 2 μM and P-selectin expression were particularly sensitive to low levels of receptor blockade whereas the VASP phosphorylation assay was relatively insensitive, requiring 60% receptor blockade to achieve substantial inhibition. Different assays varied in their ability to discriminate particular ranges of P2Y12 blockade and 80% or greater P2Y12 receptor blockade is required for consistently strong inhibition of several aspects of platelet function. These data guide the interpretation of results from different assays used to monitor the effects of P2Y12 receptor antagonists.
The role of thrombin and protease-activated receptors in pain mechanisms
Authors: García Paul , Gulati Amitabh , Levy Jerrold 
Published: April 2010

SummaryAs our knowledge of the mechanisms underlying the sensation of pain continues to expand, researchers are constantly searching for novel therapeutic targets. One such novel pain pathway involves thrombin and its associated protease-activated receptor (PAR). Besides its traditional role in haemostasis, thrombin has multiple roles in both the central and peripheral nervous system including activation of microglia, regulation of neuronal death and neurite outgrowth, and influencing the transmission of pain signals in the nociceptive circuitry. Eventually therapeutic modalities directed at these targets could provide novel therapeutic approaches for treating chronic pain. The thrombin-associ-ated PARs also have roles in inflammation, neurodevelopment, and conducting pain, both in conjunction with thrombin and independently. Recent laboratory evidence suggests that the PARs can attenuate pain mediated by the enteric nervous system in animal models (for example in pancreatitis and colitis). This review highlights several pathways in the mediation of pain sensation that can be influenced by thrombin.
Validation of the Health ABC Heart Failure Model for Incident Heart Failure Risk Prediction
Authors: Kalogeropoulos Andreas , Psaty Bruce M. , Vasan Ramachandran S. , Georgiopoulou Vasiliki , Smith Andrew L. , Smith Nicholas L. , Kritchevsky Stephen B. , Wilson Peter W.F. , Newman Anne B. , Harris Tamara B. , Butler Javed ,   for the Cardiovascular Health Study
Published: April 2010

Background—
The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.

Methods and Results—

Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow χ
2
was 14.72 (degrees of freedom, 10;
P
=0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.

Conclusions—
The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.
Public/Private Partnerships in the Public Health Sector
Authors: Burci Gian Luca 
Published: April 2010

AbstractThis article reviews and analyses the growing phenomenon of public-private partnerships in the field of international public health cooperation (PPPs). This trend has been led by the changing political dynamics surrounding international health issues as well as by the perception of the inadequacy of market mechanisms and the inability of existing international institutions for tackling pressing health problems in developing countries. The article analyses in particular the remarkable developments in international health governance that PPPs have ushered in as well as the role played and the challenges faced by the World Health Organization.
Mandate Issues in the Activities of the International Fund for Agricultural Development (IFAD)
Authors: Martha Rutsel Silvestre 
Published: April 2010

AbstractQuestions of mandate are central in the actual operations of intergovernmental organizations within secretariats, in opinions of legal counsel, and in governing councils and general assemblies. Mandate issues can impose real constraints, or generate demands for action, or be brushed aside in some political circumstances. Overall they are a significant and perplexing part of the administrative law of international organizations. This paper explores the highly varied practical effect of mandate issues on operations of an international organization, through analysis of diverse approaches to mandate constraints and aspirations in ventures of the International Fund for Agricultural Development (IFAD).
Promoting Human Rights in the Administration of Justice in Southern Sudan. Mandate and Accountability Dilemmas in the Fiel Work of a DPKO Human Rights Officer
Authors: Garms Ulrich 
Published: April 2010

AbstractThe UNMIS Human Rights Section is called to promote respect for international human rights standards as part of a peacekeeping operation in a post-conflict society. As such, it is exposed to conflicting but equally legitimate demands from different stakeholders. To illustrate some of the dilemmas arising in practice from the tensions between these demands, the paper looks at three case studies taken from the work of the UNMIS Human Rights Section in Southern Sudan. They concern the tension between customary law and the protection of women's rights, the right to counsel in capital cases, and justice for atrocities committed during the civil war. The paper argues that, also because of the inherent fundamental contradictions in what a field presence such as the UNMIS Human Rights Section seeks to achieve, attempts to promote meaningful accountability of the field operation for the results obtained encounter significant limitations.
Engaging with Armed Groups: A Human Rights Field Perspective from Nepal
Authors: Rawski Frederick 
Published: April 2010

AbstractTheoretical uncertainty surrounding whether and to what extent non-state actors are obligated to abide by international human rights and humanitarian norms has impacted the policies and practices of human rights field presences, including those of the United Nations. The paper presents the case of Nepal, where international organizations have been forced by circumstance to engage with a range of non-state armed groups, to illustrate how current limitations of human rights law regarding non-state actors impact the work of human rights field monitors. Drawing upon the global administrative law paradigm, it argues for the development of a 'soft law' framework governing human rights aspects of international organizations' engagement with armed groups.
Graduating Social Work Students’ Perspectives on Domestic Violence
Authors: Black Beverly M. , Weisz Arlene N. , Bennett Larry W. 
Published: April 2010

This article reports the findings of a qualitative study that examined 124 social work students’ views on the causes and dynamics of domestic violence and their recommended interventions in a case scenario. Most students graduated from the master of social work (MSW) program with a mental health perspective on domestic violence. Only a small percentage were aware of specific interventions for domestic violence and many continued to attribute domestic violence to mental health and substance abuse problems in the victim and perpetrator. Graduates with domestic violence experience varied little from their peers in suggested domestic violence interventions or comments about the causes of domestic violence. The findings suggest that a deliberate, focused attempt to inform students about domestic violence is needed, rather than a reliance on general MSW courses. This article presents research on social work graduates’ views on the causes of domestic violence and interventions in domestic violence cases. Domestic violence continues to be a multifaceted problem that an estimated 22% of women experience over their lifetimes (Thoennes & Tjaden, 2000). Many people believe that a woman’s behavior can contribute to intimate partner violence, some believe that women want to be abused, and a large majority believe that women can easily leave abusive relationships (Worden & Carlson, 2005). Overall, most people believe that the causes of domestic violence are rooted in the individual and family; few people view domestic violence as a problem with roots in society or culture (Worden & Carlson, 2005).
Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia
Authors: Balakrishnan Kumudha , Verma Dushyant , O'Brien Susan , Kilpatrick John Michael , Chen Yuling , Tyler Brenita F. , Bickel Susan , Bantia Shanta , Keating Michael J. , Kantarjian Hagop , Gandhi Varsha , Ravandi Farhad 
Published: April 2010

AbstractForodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 × 109/L and median serum β2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300nM and did not reach desired 2μM level. PNP inhibition ranged from 57% to 89% and steady-state 2′-deoxyguanosine (dGuo) concentration median was 1.8μM. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6μM to 10μM. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20μM dGuo and forodesine (2μM) resulted in accumulation of higher levels of dGTP (40-250μM) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population. This study is registered at www.clinicaltrials.gov as #NCT00289549.
TassDB2 - A comprehensive database of subtle alternative splicing events
Authors: Sinha Rileen , Lenser Thorsten , Jahn Niels , Gausmann Ulrike , Friedel Swetlana , Szafranski Karol , Huse Klaus , Rosenstiel Philip , Hampe Jochen , Schuster Stefan , Hiller Michael , Backofen Rolf , Platzer Matthias 
Published: April 2010

Abstract

Background
Subtle alternative splicing events involving tandem splice sites separated by a short (2-12 nucleotides) distance are frequent and evolutionarily widespread in eukaryotes, and a major contributor to the complexity of transcriptomes and proteomes. However, these events have been either omitted altogether in databases on alternative splicing, or only the cases of experimentally confirmed alternative splicing have been reported. Thus, a database which covers all confirmed cases of subtle alternative splicing as well as the numerous putative tandem splice sites (which might be confirmed once more transcript data becomes available), and allows to search for tandem splice sites with specific features and download the results, is a valuable resource for targeted experimental studies and large-scale bioinformatics analyses of tandem splice sites. Towards this goal we recently set up TassDB (Tandem Splice Site DataBase, version 1), which stores data about alternative splicing events at tandem splice sites separated by 3 nt in eight species.

Description
We have substantially revised and extended TassDB. The currently available version 2 contains extensive information about tandem splice sites separated by 2-12 nt for the human and mouse transcriptomes including data on the conservation of the tandem motifs in five vertebrates. TassDB2 offers a user-friendly interface to search for specific genes or for genes containing tandem splice sites with specific features as well as the possibility to download result datasets. For example, users can search for cases of alternative splicing where the proportion of EST/mRNA evidence supporting the minor isoform exceeds a specific threshold, or where the difference in splice site scores is specified by the user. The predicted impact of each event on the protein is also reported, along with information about being a putative target for the nonsense-mediated decay (NMD) pathway. Links are provided to the UCSC genome browser and other external resources.

Conclusion
TassDB2, available via http://www.tassdb.info, provides comprehensive resources for researchers interested in both targeted experimental studies and large-scale bioinformatics analyses of short distance tandem splice sites.
Adaptive coarse-grained Monte Carlo simulation of reaction and diffusion dynamics in heterogeneous plasma membranes
Authors: Collins Stuart , Stamatakis Michail , Vlachos Dionisios G 
Published: April 2010

Abstract

Background
An adaptive coarse-grained (kinetic) Monte Carlo (ACGMC) simulation framework is applied to reaction and diffusion dynamics in inhomogeneous domains. The presented model is relevant to the diffusion and dimerization dynamics of epidermal growth factor receptor (EGFR) in the presence of plasma membrane heterogeneity and specifically receptor clustering. We perform simulations representing EGFR cluster dissipation in heterogeneous plasma membranes consisting of higher density clusters of receptors surrounded by low population areas using the ACGMC method. We further investigate the effect of key parameters on the cluster lifetime.

Results
Coarse-graining of dimerization, rather than of diffusion, may lead to computational error. It is shown that the ACGMC method is an effective technique to minimize error in diffusion-reaction processes and is superior to the microscopic kinetic Monte Carlo simulation in terms of computational cost while retaining accuracy. The low computational cost enables sensitivity analysis calculations. Sensitivity analysis indicates that it may be possible to retain clusters of receptors over the time scale of minutes under suitable conditions and the cluster lifetime may depend on both receptor density and cluster size.

Conclusions
The ACGMC method is an ideal platform to resolve large length and time scales in heterogeneous biological systems well beyond the plasma membrane and the EGFR system studied here. Our results demonstrate that cluster size must be considered in conjunction with receptor density, as they synergistically affect EGFR cluster lifetime. Further, the cluster lifetime being of the order of several seconds suggests that any mechanisms responsible for EGFR aggregation must operate on shorter timescales (at most a fraction of a second), to overcome dissipation and produce stable clusters observed experimentally.
WaveletQuant, an improved quantification software based on wavelet signal threshold de-noising for labeled quantitative proteomic analysis
Authors: Mo Fan , Mo Qun , Chen Yuanyuan , Goodlett David R , Hood Leroy , Omenn Gilbert S , Li Song , Lin Biaoyang 
Published: April 2010

Abstract

Background
Quantitative proteomics technologies have been developed to comprehensively identify and quantify proteins in two or more complex samples. Quantitative proteomics based on differential stable isotope labeling is one of the proteomics quantification technologies. Mass spectrometric data generated for peptide quantification are often noisy, and peak detection and definition require various smoothing filters to remove noise in order to achieve accurate peptide quantification. Many traditional smoothing filters, such as the moving average filter, Savitzky-Golay filter and Gaussian filter, have been used to reduce noise in MS peaks. However, limitations of these filtering approaches often result in inaccurate peptide quantification. Here we present the WaveletQuant program, based on wavelet theory, for better or alternative MS-based proteomic quantification.

Results
We developed a novel discrete wavelet transform (DWT) and a 'Spatial Adaptive Algorithm' to remove noise and to identify true peaks. We programmed and compiled WaveletQuant using Visual C++ 2005 Express Edition. We then incorporated the WaveletQuant program in the Trans-Proteomic Pipeline (TPP), a commonly used open source proteomics analysis pipeline.

Conclusions
We showed that WaveletQuant was able to quantify more proteins and to quantify them more accurately than the ASAPRatio, a program that performs quantification in the TPP pipeline, first using known mixed ratios of yeast extracts and then using a data set from ovarian cancer cell lysates. The program and its documentation can be downloaded from our website at http://systemsbiozju.org/data/WaveletQuant.
Divergence of imprinted genes during mammalian evolution
Authors: Hutter Barbara , Bieg Matthias , Helms Volkhard , Paulsen Martina 
Published: April 2010

Abstract

Background
In contrast to the majority of mammalian genes, imprinted genes are monoallelically expressed with the choice of the active allele depending on its parental origin. Due to their special inheritance patterns, maternally and paternally expressed genes might be under different evolutionary pressure. Here, we aimed at assessing the evolutionary history of imprinted genes.

Results
In this study, we investigated the conservation of imprinted genes in vertebrate genomes and their exposition to natural selection. In a genome-wide comparison, orthologs of imprinted genes show a stronger divergence on cDNA and protein level in mammals. This pattern is most pronounced for maternally expressed genes in rodents in comparison to their non-rodent orthologs. The divergence is not attributable to increased mutation of CpG positions. It is contrasted by strong conservation of paternally expressed genes in mouse and rat. Interestingly, we found that the early divergence of imprinted genes was accompanied by an unusually strict conservation of their paralogs.

Conclusions
The apparent degeneration of maternally expressed genes may reflect a relaxation of selective pressure due to counteracting effects on maternal and embryonic fitness. Functional redundancy provided by the presence of highly conserved (non-imprinted) paralogs may have facilitated the divergence. Moreover, intensification of imprinting in modern rodents seems to have shifted the evolutionary fate of imprinted genes towards strong purifying selection.
Syphilis epidemiology in Norway, 1992-2008: resurgence among men who have sex with men
Authors: Jakopanec Irena , Grjibovski Andrej M , Nilsen Øivind , Aavitsland Preben 
Published: April 2010

Abstract

Background
In recent years, the number of syphilis cases has stabilised in many countries of Western Europe, however several countries have reported increases among men who have sex with men (MSM). The aim of this article was to describe the epidemiology of early syphilis in Norway in 1992-2008.

Methods
Cases of early syphilis and congenital syphilis reported to the Norwegian Surveillance System for Communicable Diseases (MSIS) 1992-2008 were described by route of transmission, gender, age, birthplace, stage of disease, HIV co-infection, source partner and place of infection.

Results
The incidence of reported syphilis ranged from 0.05 (1992) to 1.50 (2002) per 100 000 person-years. Of 562 cases reported to MSIS during the study period, 62% were men infected by another man. The proportion of those, infected homosexually increased from 0 (1992-1994) to 77% (2008). Most of them were Norwegians (83%). The proportion of HIV co-infection among homosexually infected increased over time and reached 39% in 2008. The majority reported being infected by a casual partner (73%) and in the municipality of Oslo (72%). Of 152 heterosexually infected men 64% were Norwegians; 51% were infected by casual contacts and 20% by commercial sex workers; 73% were infected abroad. Among 56 women, 57% were Norwegians, 57% were infected by a steady partner and 40% were infected abroad. Almost half (46%) were diagnosed in the early latent stage. Four cases had congenital syphilis, two of whom were adopted from abroad.

Conclusions
Syphilis is rare in Norway, but MSM represent almost two thirds of cases. The increase of HIV co-infected cases among MSM may enhance transmission of both infections. We recommend sexually active MSM to be tested for syphilis 2-4 times a year. Due to its variable clinical course, syphilis might be difficult to recognise at an early stage among women in a low-prevalence population. We estimate current practice of prenatal screening in Norway as sufficient.