bluuebunny/crossref_metadata_2025 huggingface dataset:
How should we treat newly diagnosed multiple myeloma patients?
Authors: Mateos María-Victoria , San Miguel Jesús F.
Published: December 2013

Multiple myeloma (MM) is the second most frequent hematological disease. Two-thirds of newly diagnosed MM patients are more than 65 years of age. Elsewhere in this issue, McCarthy et al discuss the treatment of transplantation candidates; this chapter focuses on the data available concerning therapy for non-transplantation-eligible MM patients. Treatment goals for these non-transplantation-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. Until recently, treatment options were limited to alkylators, but new up-front treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) plus alkylating agents have significantly improved outcomes. Other nonalkylator induction regimens are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Phase 3 data indicate that maintenance therapy or prolonged treatment in elderly patients also improves the quality and duration of clinical responses, extending time to progression and progression-free survival; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. The potential for novel treatment regimens to improve the adverse prognosis associated with high-risk cytogenetic profiles also requires further research. In summary, although we have probably doubled the survival of elderly patients, this group requires close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy while maintaining their quality of life.
Prognostic models in myelodysplastic syndromes
Authors: Bejar Rafael
Published: December 2013

Establishing the prognosis for patients with myelodysplastic syndromes (MDS) is a key element of their care. It helps patients understand the severity of their disease and set expectations for their future. For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider. The International Prognostic Scoring System (IPSS) has been the standard tool for MDS risk stratification since it was released in 1997. It has been used to describe patients in pivotal clinical trials and is a key element of practice guidelines. Subsequent changes to the classification scheme for MDS and an underestimation of risk in some patients from the low and intermediate-1 categories have led to the development of several newer prognostic models. The most recent is the revised IPSS (IPSS-R), which addresses several of the perceived deficiencies of its predecessor. Despite their utility, none of the available prognostic systems incorporates disease-related molecular abnormalities such as somatic mutations. These lesions are present in the nearly all cases and many have been shown to improve upon existing prognostic models. However, the interpretation of somatic mutations can be challenging and it is not yet clear how best to combine them with clinical predictors of outcome. Here I review several prognostic scoring systems developed after the IPSS and describe the emerging use of molecular markers to refine risk stratification in the MDS patient population.
Who benefits from allogeneic transplantation for myelodysplastic syndromes?: new insights
Authors: Platzbecker Uwe
Published: December 2013

Recently, a refined cytogenetic and molecular classification fundamentally changed the prognostication of patients with myelodysplastic syndromes (MDS). The increasingly complex heterogeneity of this disease entity is mirrored by life expectancy rates ranging from almost a decade for very low-risk disease down to several months in higher-risk patients, even with conventional treatments. Intensive treatment approaches are hampered by the older age of most of the patients, potentially leading to an unacceptable adverse event rate. This is especially true for allogeneic hematopoietic stem cell transplantation (HCT), which, albeit of curative intent, can lead to considerable morbidity and mortality mostly as a result of organ toxicity, infectious complications, and GVHD. Furthermore, innovative drug developments, including hypomethylating agents, have broadened the therapeutic armamentarium and, although not curative, can lead to durable responses in subgroups of patients with higher-risk MDS. In fact, there is still no prospective randomized trial available that formally demonstrates the benefit of allogeneic HCT compared with standard treatments in MDS patients. In the absence of randomized data, when considering allogeneic HCT, emphasis should be put on patient selection and optimization of the pre- and posttransplantation treatment period. In these patients, a thorough comorbidity evaluation is mandatory and stratification according to age, cytogenetics, cytopenias, disease-related quality of life, and available alternative treatments should be performed in deciding whether, when, and how to perform allogeneic HCT.
Transplantation for mantle cell lymphoma: is it the right thing to do?
Authors: Williams Michael E.
Published: December 2013

Mantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab + a high-dose cytarabine–containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab + bendamustine, or R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.
Treatment strategies for aggressive lymphomas: what works?
Authors: Wilson Wyndham H.
Published: December 2013

Over the past 30 years, many treatment platforms have been developed for diffuse large B-cell lymphoma, but none proved better than CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone). In the immunochemotherapy era, however, there is convincing evidence for superior chemotherapy platforms. A randomized study from the Groupe d'Etude des Lymphomes de l'Adulte showed that R-ACVBP (rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) was superior to rituximab plus CHOP (R-CHOP) in patients under 60 years of age, but toxicity limits its use to younger patients. Studies also suggest that DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) is more effective in some subtypes of diffuse large B-cell lymphoma and a randomized comparison with R-CHOP is now nearing completion. The simplicity and safety of R-CHOP and the long history of failed contenders, however, has set a high bar for new approaches.
Sickle cell trait testing and athletic participation: a solution in search of a problem?
Authors: Thompson Alexis A.
Published: December 2013

Carriers of a single sickle cell gene mutation generally enjoy normal lifespans without serious health consequences related to their sickle cell status, but under extreme conditions such as severe dehydration and high-intensity physical activity, complications such as exertional rhabdomyolysis, splenic infarction, and papillary necrosis can occur. Recently, the National Collegiate Athletic Association (NCAA) adopted a policy that requires sickle cell solubility testing for all incoming student athletes. However, the American Society of Hematology (ASH) and other physician organizations oppose this policy. What is the basis for this controversy and how have new findings moved the field forward? I discuss herein the epidemiology, genetics, and clinical studies of sickle cell trait; review the implications of current policies regarding sickle cell trait screening and interventions for the student athlete; and examine additional areas where more information is needed.
Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities
Authors: Socié Gérard
Published: December 2013

Allogeneic BM transplantation from an HLA-identical sibling donor leads to long-term survival in the majority of patients (> 80%). Therefore, survival is no longer the sole concern and attention has to be paid to decreasing the incidence and severity of long-term complications. For patients without a sibling donor, transplantation from a well-matched unrelated donor can be considered after failure of a previous course of immunosuppressive therapy. After transplantation from an HLA-identical sibling donor or from an unrelated one, the use of peripheral blood stem cells must be strongly discouraged because they have been systematically associated with an increased incidence of chronic GVHD compared with the use of BM as a stem cell source, leading to an unacceptably higher risk of treatment-related mortality in this setting. For as yet unknown reasons, the age limit after which transplantation results are less satisfactory remains 40 years of age.
The mononuclear metal center of type-I dihydroorotase from aquifex aeolicus
Authors: Edwards Brian FP , Fernando Roshini , Martin Philip D , Grimley Edward , Cordes Melissa , Vaishnav Asmita , Brunzelle Joseph S , Evans Hedeel Guy , Evans David R
Published: December 2013

Background

Dihydroorotase (DHO) is a zinc metalloenzyme, although the number of active site zinc ions has been controversial. E. coli DHO was initially thought to have a mononuclear metal center, but the subsequent X-ray structure clearly showed two zinc ions, α and β, at the catalytic site. Aquifex aeolicus DHO, is a dodecamer comprised of six DHO and six aspartate transcarbamoylase (ATC) subunits. The isolated DHO monomer, which lacks catalytic activity, has an intact α-site and conserved β-site ligands, but the geometry of the second metal binding site is completely disrupted. However, the putative β-site is restored when the complex with ATC is formed and DHO activity is regained. Nevertheless, the X-ray structure of the complex revealed a single zinc ion at the active site. The structure of DHO from the pathogenic organism, S. aureus showed that it also has a single active site metal ion.

Results

Zinc analysis showed that the enzyme has one zinc/DHO subunit and the addition of excess metal ion did not stimulate catalytic activity, nor alter the kinetic parameters. The metal free apoenzyme was inactive, but the full activity was restored upon the addition of one equivalent of Zn2+ or Co2+. Moreover, deletion of the β-site by replacing the His180 and His232 with alanine had no effect on catalysis in the presence or absence of excess zinc. The 2.2 Å structure of the double mutant confirmed that the β-site was eliminated but that the active site remained otherwise intact.

Conclusions

Thus, kinetically competent A. aeolicus DHO has a mononuclear metal center. In contrast, elimination of the putative second metal binding site in amidohydrolyases with a binuclear metal center, resulted in the abolition of catalytic activity. The number of active site metal ions may be a consideration in the design of inhibitors that selectively target either the mononuclear or binuclear enzymes.
Automated workflow-based exploitation of pathway databases provides new insights into genetic associations of metabolite profiles
Authors: Dharuri Harish , Henneman Peter , Demirkan Ayse , van Klinken Jan Bert , Mook-Kanamori Dennis Owen , Wang-Sattler Rui , Gieger Christian , Adamski Jerzy , Hettne Kristina , Roos Marco , Suhre Karsten , Van Duijn Cornelia M ,   EUROSPAN consortia, van Dijk Ko Willems , 't Hoen Peter AC
Published: December 2013

Background

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) that associate with clinical phenotypes, but these SNPs usually explain just a small part of the heritability and have relatively modest effect sizes. In contrast, SNPs that associate with metabolite levels generally explain a higher percentage of the genetic variation and demonstrate larger effect sizes. Still, the discovery of SNPs associated with metabolite levels is challenging since testing all metabolites measured in typical metabolomics studies with all SNPs comes with a severe multiple testing penalty. We have developed an automated workflow approach that utilizes prior knowledge of biochemical pathways present in databases like KEGG and BioCyc to generate a smaller SNP set relevant to the metabolite. This paper explores the opportunities and challenges in the analysis of GWAS of metabolomic phenotypes and provides novel insights into the genetic basis of metabolic variation through the re-analysis of published GWAS datasets.

Results

Re-analysis of the published GWAS dataset from Illig et al. (Nature Genetics, 2010) using a pathway-based workflow (http://www.myexperiment.org/packs/319.html), confirmed previously identified hits and identified a new locus of human metabolic individuality, associating Aldehyde dehydrogenase family1 L1 (ALDH1L1) with serine/glycine ratios in blood. Replication in an independent GWAS dataset of phospholipids (Demirkan et al., PLoS Genetics, 2012) identified two novel loci supported by additional literature evidence: GPAM (Glycerol-3 phosphate acyltransferase) and CBS (Cystathionine beta-synthase). In addition, the workflow approach provided novel insight into the affected pathways and relevance of some of these gene-metabolite pairs in disease development and progression.

Conclusions

We demonstrate the utility of automated exploitation of background knowledge present in pathway databases for the analysis of GWAS datasets of metabolomic phenotypes. We report novel loci and potential biochemical mechanisms that contribute to our understanding of the genetic basis of metabolic variation and its relationship to disease development and progression.
Epigenetic rather than genetic factors may explain phenotypic divergence between coastal populations of diploid and tetraploid Limonium spp. (Plumbaginaceae) in Portugal
Authors: Róis Ana Sofia , Rodríguez López Carlos M , Cortinhas Ana , Erben Matthias , Espírito-Santo Dalila , Wilkinson Michael J , Caperta Ana D
Published: December 2013

Background

The genusLimoniumMiller comprises annual and perennial halophytes that can produce sexual and/or asexual seeds (apomixis). Genetic and epigenetic (DNA methylation) variation patterns were investigated in populations of three phenotypically similar putative sexual diploid species (L. nydeggeri, L. ovalifolium,L. lanceolatum), one sexual tetraploid species (L. vulgare) and two apomict tetraploid species thought to be related (L. dodartii, L. multiflorum). The extent of morphological differentiation between these species was assessed using ten diagnostic morphometric characters.

Results

A discriminant analysis using the morphometric variables reliably assigns individuals into their respective species groups. We found that only modest genetic and epigenetic differentiation was revealed between species by Methylation Sensitive Amplification Polymorphism (MSAP). However, whilst there was little separation possible between ploidy levels on the basis of genetic profiles, there was clear and pronounced interploidy discrimination on the basis of epigenetic profiles. Here we investigate the relative contribution of genetic and epigenetic factors in explaining the complex phenotypic variability seen in problematic taxonomic groups such asLimoniumthat operate both apomixis and sexual modes of reproduction.

Conclusions

Our results suggest that epigenetic variation might be one of the drivers of the phenotypic divergence between diploid and tetraploidtaxaand discuss that intergenome silencing offers a plausible mechanistic explanation for the observed phenotypic divergence between these microspecies. These results also suggest that epigenetic profiling offer an additional tool to infer ploidy level in stored specimens and that stable epigenetic change may play an important role in apomict evolution and species recognition.
Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice
Authors: Ritze Yvonne , Böhle Maureen , Haub Synia , Hubert Astrid , Enck Paul , Zipfel Stephan , Bischoff Stephan C
Published: December 2013

Background

Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system.

Methods

C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used.

Results

Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease.

Conclusion

In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier.
Sex differences in circumstances and consequences of outdoor and indoor falls in older adults in the MOBILIZE Boston cohort study
Authors: Duckham Rachel L , Procter-Gray Elizabeth , Hannan Marian T , Leveille Suzanne G , Lipsitz Lewis A , Li Wenjun
Published: December 2013

Background

Despite extensive research on risk factors associated with falling in older adults, and current fall prevention interventions focusing on modifiable risk factors, there is a lack of detailed accounts of sex differences in risk factors, circumstances and consequences of falls in the literature. We examined the circumstances, consequences and resulting injuries of indoor and outdoor falls according to sex in a population study of older adults.

Methods

Men and women 65 years and older (N = 743) were followed for fall events from the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston prospective cohort study. Baseline measurements were collected by comprehensive clinical assessments, home visits and questionnaires. During the follow-up (median = 2.9 years), participants recorded daily fall occurrences on a monthly calendar, and fall circumstances were determined by a telephone interview. Falls were categorized by activity and place of falling. Circumstance-specific annualized fall rates were calculated and compared between men and women using negative binomial regression models.

Results

Women had lower rates of outdoor falls overall (Crude Rate Ratio (RR): 0.72, 95% Confidence Interval (CI): 0.56-0.92), in locations of recreation (RR: 0.34, 95% CI: 0.17-0.70), during vigorous activity (RR: 0.38, 95% CI: 0.18-0.81) and on snowy or icy surfaces (RR: 0.55, 95% CI: 0.36-0.86) compared to men. Women and men did not differ significantly in their rates of falls outdoors on sidewalks, streets, and curbs, and during walking. Compared to men, women had greater fall rates in the kitchen (RR: 1.88, 95% CI: 1.04-3.40) and while performing household activities (RR: 3.68, 95% CI: 1.50-8.98). The injurious outdoor fall rates were equivalent in both sexes. Women’s overall rate of injurious indoor falls was nearly twice that of men’s (RR: 1.98, 95% CI: 1.44-2.72), especially in the kitchen (RR: 6.83, 95% CI: 2.05-22.79), their own home (RR: 1.84, 95% CI: 1.30-2.59) and another residential home (RR: 4.65, 95% CI: 1.05-20.66) or other buildings (RR: 2.29, 95% CI: 1.18-4.44).

Conclusions

Significant sex differences exist in the circumstances and injury potential when older adults fall indoors and outdoors, highlighting a need for focused prevention strategies for men and women.
S-1 combined with docetaxel following doxorubicin plus cyclophosphamide as neoadjuvant therapy in breast cancer: phase II trial
Authors: Moon Yong Wha , Lee Soohyeon , Park Byeong-Woo , Kim Eun-Kyung , Kim Seung Il , Koo Ja Seung , Park Seho , Kim Min Jung , Chung Hyun Cheol , Kim Joo-Hang , Sohn Joohyuk
Published: December 2013

Background

This study evaluated the efficacy and safety of S-1 combined with docetaxel (SD) following doxorubicin plus cyclophosphamide (AC) as neoadjuvant therapy in patients with HER2-negative, stage II-III breast cancer.

Methods

Patients received AC every 3 weeks for four cycles followed by S-1 (30 mg/m2 orally b.i.d. on days 1–14) and docetaxel (75 mg/m2 i.v. on day 1) every 3 weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in breast and axillary lymph nodes.

Results

The study included 49 patients with a median age of 43 years. The median breast tumor size was 4.0 cm by palpation. All patients were positive for involvement of axillary lymph node and five patients also had supraclavicular lymph node metastasis, which was confirmed by histological examination. In total, 85.4% of patients (41/49) completed eight cycles of therapy and 95.9% of patients (47/49) received curative surgery. The pCR rate was 22.5% (n = 11). The clinical response rate was 67.4%. During SD chemotherapy, the most frequent grade 3–4 toxicity was neutropenia (8.5% by cycle). There was a single treatment-related mortality from severe neutropenia. Grade 3 S-1 specific toxicities such as epigastric pain (12.2% by person), stomatitis (4.1% by person), and diarrhea (2.0% by person) were also observed. In particular, gastrointestinal discomfort led to dose reduction of S-1 in 45.8% of patients.

Conclusions

Given all axillary lymph node positive diseases, neoadjuvant S-1 combined with docetaxel following AC showed a favorable anti-tumor activity but gastrointestinal discomfort should be carefully considered for future studies.

Trial registration

NCT00994968
Robust c-prototypes algorithms for color image segmentation
Authors: Mújica-Vargas Dante , Gallegos-Funes Francisco J , Rosales-Silva Alberto J , de Jesús Rubio José
Published: December 2013

In this paper, we present a modified clustering algorithm to segment color images. The proposed technique is based on the robust c-prototypes algorithm with some modifications in its objective function and updating equations. The JK chromatic subspace of the IJK color space is used to segment color images. The algorithm performance is tested on real images with natural artifacts that make the segmentation process difficult. Additionally, a remote sensing image is segmented to demonstrate that the proposed algorithm can be used in real applications. Simulation results indicate that the proposed method is more effective than others proposed in the literature in terms of objective and subjective criteria.
Diagram-based Analysis of Causal Systems (DACS): elucidating inter-relationships between determinants of acute lower respiratory infections among children in sub-Saharan Africa
Authors: Rehfuess Eva A , Best Nicky , Briggs David J , Joffe Mike
Published: December 2013

Background

Effective interventions require evidence on how individual causal pathways jointly determine disease. Based on the concept of systems epidemiology, this paper develops Diagram-based Analysis of Causal Systems (DACS) as an approach to analyze complex systems, and applies it by examining the contributions of proximal and distal determinants of childhood acute lower respiratory infections (ALRI) in sub-Saharan Africa.

Results

Diagram-based Analysis of Causal Systems combines the use of causal diagrams with multiple routinely available data sources, using a variety of statistical techniques. In a step-by-step process, the causal diagram evolves from conceptual based on a priori knowledge and assumptions, through operational informed by data availability which then undergoes empirical testing, to integrated which synthesizes information from multiple datasets. In our application, we apply different regression techniques to Demographic and Health Survey (DHS) datasets for Benin, Ethiopia, Kenya and Namibia and a pooled World Health Survey (WHS) dataset for sixteen African countries. Explicit strategies are employed to make decisions transparent about the inclusion/omission of arrows, the sign and strength of the relationships and homogeneity/heterogeneity across settings.

Findings about the current state of evidence on the complex web of socio-economic, environmental, behavioral and healthcare factors influencing childhood ALRI, based on DHS and WHS data, are summarized in an integrated causal diagram. Notably, solid fuel use is structured by socio-economic factors and increases the risk of childhood ALRI mortality.

Conclusions

Diagram-based Analysis of Causal Systems is a means of organizing the current state of knowledge about a specific area of research, and a framework for integrating statistical analyses across a whole system. This partly a priori approach is explicit about causal assumptions guiding the analysis and about researcher judgment, and wrong assumptions can be reversed following empirical testing. This approach is well-suited to dealing with complex systems, in particular where data are scarce.
Accessibility evaluation system for site layout planning – a tractor trailer example
Authors: Lin Jacob Je-Chian , Yang Chi-En , Hung Wei-Han , Kang Shih-Chung
Published: December 2013

Background

Accessibility is a critical issue in site planning. A good accessibility plan can avoid possible conflicts involving equipment and allows for smooth transportation during the entire project. It can also ensure that sufficient space is available so that all onsite equipment, such as trucks, cranes and excavators can be safely operated. In current practice, the evaluation of accessibility is done manually, relying heavily on the experience of the construction planners. However, the evaluation needs to deal with temporal and spatial information simultaneously, which make the manual evaluations very challenging.

Methods

This research develops a sandbox environment for construction planners. As tractor-trailers are usually critical in accessibility evaluations, the simulation specifically focuses on these two-section vehicles. Four major steps were involved: Step 1: deriving a generic tractor-trailer mathematical model allowing real-time, physics-based computer simulation; Step 2: digitalizing a 2D site plan to the 3D virtual environment; Step 3: developing evaluation methods for accessibility, considering both safety and operability; Step 4: visualizing the evaluation results. We implemented these four steps using Microsoft XNA (a game platform) and Nvidia PhysX (a game engine). An example case is presented which uses the sandbox environment to evaluate the accessibility of a construction site.

Results

From the case study, we found that realistic visualizations and simulations provide solid references for construction planners. They are able to identify potential accessibility problems and unsafe situations in the sandbox environment and avoid them early on in the design and planning stages.

Conclusion

This paper proposed an innovative approach for evaluating accessibility during pre-construction site layout planning. It can present an intuitive and easily understood visualization result which clearly indicated the unsafe parts of the site layout plan.
Serum level of adiponectin is a surrogate independent biomarker of radiographic disease progression in early rheumatoid arthritis: results from the ESPOIR cohort
Authors: Meyer Magali , Sellam Jérémie , Fellahi Soraya , Kotti Salma , Bastard Jean-Philippe , Meyer Olivier , Lioté Frédéric , Simon Tabassome , Capeau Jacqueline , Berenbaum Francis
Published: December 2013

Introduction

Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.

Methods

In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).

Results

Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).

Conclusion

Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.
What Is Lyric Philosophy?
Authors: Zwicky Jan
Published: December 2013

These sixty-one numbered paragraphs offer an overview of the idea and practice of lyric philosophy. They draw heavily on the author's texts Lyric Philosophy (1992, 2011), Wisdom & Metaphor (2003), and “Bringhurst's Presocratics: Lyric and Ecology” (1995). The present essay outlines key concepts — clarity as resonance, metaphor as gestalt shift, meaning as gesture, the overlap between philosophy and poetry, the nature of lyric truth — and suggests that they are essential to an adequate epistemology. These concepts allow us to address serious gaps in our understanding of how humans think, gaps that have arisen owing to the limitations of linguified intelligence coupled with a disinclination to admit the existence of these limitations. The overview also describes fundamental differences between lyric philosophy and analytic philosophy, while insisting on a robust conception of truth and on the existence of a knowable mind-independent world. The importance of a lyric approach for our understanding of a range of ecological questions is discussed, and lyric philosophy is positioned, politically, as a critique of technocracy.
Lady Oracle
Authors: Krajewski Bruce
Published: December 2013

In this contribution to an exchange of views about “lyric philosophy,” the author argues that the philosopher-poet Jan Zwicky, beginning as early as her dissertation at the University of Toronto, has championed the nonlogical, including the ineffable, the oracular, and the mystical, and that more recently those concerns have merged in a more focused way in her attention to ecological issues. The impulse to fix philosophy and the environment depends in her work mainly on further linguistic statements and declarations, and on occasional overt rejections of traditional political remedies. Thus, the audience for her campaign against analytic philosophy, for example, does not seem to reach beyond the walls of higher education in North America. Zwicky has aligned herself with an esoteric philosophical tradition (Heraclitus, Plato, Nietzsche, Heidegger) that has sought to achieve its aims covertly — meaning, for one thing, that it becomes difficult to measure the success of those aims, since they are deliberately meant to be unavailable to public scrutiny. Those aims are not dependent on the general populace's involvement or engagement. Indeed, the author concludes, the general populace has been viewed consistently in the esoteric philosophical tradition as weak and resistant, if not hostile, to philosophical thought.
Perplexity and Plausibility
Authors: Koethe John
Published: December 2013

As part of an exchange of views on what Jan Zwicky calls “lyric philosophy,” this contribution suggests a way of understanding it that brings out affinities between it and the standard discursive model of philosophy with which she is dissatisfied. Good discursive philosophy is based on perplexity and plausibility: on finding that protophilosophical experiences give rise to philosophical puzzlement, and then finding that some ways of responding to such puzzlement are more compelling than others. This philosophical mode involves the same conceptual “gestalt” that Zwicky identifies with lyric philosophy: being struck by how certain combinations of experiences and ideas feel inherently problematic and grasping how certain combinations of ideas that attempt to address these problems hang together while others do not. Moreover, the thought and language in which discursive philosophical reflection is conducted are frequently affective and couched in deeply metaphorical terms. Thus, this essay concludes, the mode of making sense that is supposed to distinguish lyric philosophy from its discursive counterpart is one that is central to the discursive model of philosophy as well.
A zebrafish model of chordoma initiated by notochord-driven expression of HRASV12
Authors: Burger Alexa , Vasilyev Aleksandr , Tomar Ritu , Selig Martin K. , Nielsen G. Petur , Peterson Randall T. , Drummond Iain A. , Haber Daniel A.
Published: December 2013

Chordoma is a malignant tumor thought to arise from remnants of the embryonic notochord with its origin in the bones of the axial skeleton. Surgical resection is the standard treatment usually in combination with radiation therapy, but neither chemotherapeutic nor targeted therapeutic approaches have demonstrated success. No animal model and only few chordoma cell lines are available for preclinical drug testing, and while no drugable genetic drivers have been identified, activation of EGFR and downstream AKT/PI3K pathways have been described. Here, we report a zebrafish model of chordoma, based on stable transgene-driven expression of HRASV12 in notochord cells during development. Extensive intra-notochordal tumor formation is evident within days of transgene expression, ultimately leading to larval death. The zebrafish tumors share characteristics of human chordoma as demonstrated by immunohistochemistry and electron microscopy. The mTORC1 inhibitor rapamycin, which has some demonstrated activity in a chordoma cell line, delays the onset of tumor formation in our zebrafish model, and improves survival of tumor-bearing fish. Consequently, the HRASV12-driven zebrafish model of chordoma may enable high-throughput screening of potential therapeutic agents for the treatment of this refractory cancer.
TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS
Authors: Thompson Michelle L. , Chen Pan , Yan Xiaohui , Kim Hanna , Borom Akeem R. , Roberts Nathan B. , Caldwell Kim A. , Caldwell Guy A.
Published: December 2013

Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis, and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular chaperone-like activity, both in vitro and in vivo. While mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA appears cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded protein stress as it pertains to the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mice models harboring mutations in the superoxide dismutase, SOD1, has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wildtype or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing a mechanistic insight into the activity torsinA has on aggregate prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS, while simultaneously highlighting the potential for torsinA as a novel target for therapeutic development.
A comparative analysis of marine mammal tracheas
Authors: Moore Colby , Moore Michael , Trumble Stephen , Niemeyer Misty , Lentell Betty , McLellan William , Costidis Alexander , Fahlman Andreas
Published: December 2013

In 1940, Scholander suggested that stiffened upper airways remained open and received air from highly compressible alveoli during marine mammal diving. There are little data available on the structural and functional adaptations of the marine mammal respiratory system. The aim of this research was to investigate the anatomical (gross) and structural (compliance) characteristics of excised marine mammal tracheas. Here we defined different types of tracheal structures, categorizing pinniped tracheas by varying degrees of continuity of cartilage (categories 1-4) and cetacean tracheas by varying compliance values (categories 5A and 5B). Some tracheas fell into more than one category, along their length, for example, the harbor seal (Phoca vitulina) demonstrated complete rings cranially, and as the trachea progressed caudally tracheal rings changed morphology. Dolphins and porpoises had less stiff, more compliant spiraling rings while beaked whales had very stiff, less compliant spiraling rings. The pressure-volume (P-V) relationships of isolated tracheas from different species were measured to assess structural differences between species. These findings lend evidence for pressure-induced collapse and re-inflation of lungs, perhaps influencing variability in dive depth or ventilation rates of the species investigated.
Daphnia's dilemma of adjusting carbon budgets when facing limitations by food quantity and the essential organic compound cholesterol
Authors: Lukas Marcus , Wacker Alexander
Published: December 2013

We studied the carbon metabolism in Daphnia when the amount of carbon (food quantity) and/or the content of biochemical nutrients (food quality) are limiting. Growth performances and carbon (C) budgets of Daphnia magna (assimilation, faeces egestion, excretion and respiration measured by [14C]-tracing) were analysed when animals were raised on different food quantities and concentrations of cholesterol, an essential biochemical food compound. Cholesterol is of special interest because it not only acts as limiting nutrient but also contributes to the overall carbon pool of the animals. As the tissue cholesterol concentration in Daphnia is quite low, we hypothesized the selective exclusion of cholesterol from carbon budgeting and tested this by using radiolabelled cholesterol. Somatic growth rates of D. magna were highest at high quantity and quality and were reduced to a moderate value if either the food quantity or the cholesterol concentration was low. Growth was lowest at low food quantity and quality. The measurements of C budgets revealed high regulative response to low food quality at high food quantity only. Here, low dietary cholesterol caused that bulk carbon assimilation efficiency (AE) decreased and that assimilated (excess) carbon was increasingly respired. Additionally, Daphnia enhanced efficient adjustment of C budgets when facing cholesterol limitation by (i) increasing the AE of the cholesterol itself and (ii) not changing cholesterol respiration which was still not detectable. In contrast, at low food quantity Daphnia has the dilemma to be unable to adjust for low food quality emphasizing that food quantity limitation could overrule food quality effects.
Adult fruit fly attraction to larvae biases experience and mediates social learning
Authors: Durisko Zachary , Anderson Blake , Dukas Reuven
Published: December 2013

We investigated whether adult fruit flies (Drosophila melanogaster) use cues of larvae as social information in their food patch choice decisions. Adult male and female fruit flies showed attraction to odours emanating from foraging larvae, and females preferred to lay eggs on food patches occupied by larvae over similar unoccupied patches. Females learned and subsequently preferred to lay eggs at patches with novel flavours previously associated with feeding larvae over patches with novel flavours previously associated with no larvae. However, when we controlled for the duration of exposure to each flavoured patch, females no longer preferred the flavour previously associated with feeding larvae. This suggests that social learning in this context is indirect, due to strong social attraction biasing experience.
Syntheses and Properties of Buckybowls Bearing Electron-withdrawing Groups
Authors: Schmidt Bernd M , Lentz Dieter
Published: December 2013

This review provides an overview on recent advances in the novel field of electron-poor buckybowls. Whereas buckybowl chemistry has now been studied for more than two decades, only recent developments have drawn attention to this type of compound. The syntheses of these buckybowls and their distinct and characteristic properties are described.
Kairomonal communication in mice is concentration-dependent with a proportional discrimination threshold
Authors: Vasudevan Anand , Vyas Ajai
Published: December 2013

Odors of predators are often co-opted by prey species to serve as warning signals. Perceptual properties of such kairomonal communication are under studied despite their common use in many mammals. We demonstrate that the kairomonal response in mice to rat odors varies monotonically with the volume of rat odor. Moreover, the ability of mice to differentiate between two strengths of rat odors is dependent on the ratio of the two concentrations. These results show that mice can compare kairomonal strength over a large range of values, and that kairomonal communication follows Weber’s law.
The phenomenon of «Born Global»: early internationalization of enterprises
Authors: Толедо  , Toledo John Jairo Gil
Published: December 2013

According to Knight and Cavusgil (2004) a course that can be split to consider

the phenomenon of the Born Global, is to accept that the creation of new

enterprises is one of the fundamental pillars of the economic and social

development of a country, especially those of this type because they allow to

successfully address international markets, by the permanent implementation

of innovation processes the application of deep knowledge and skills in the field

of international undertaking on the part of their owners and through their

processes of export, leverage a distinctive mix of strategies and guidelines that

make it easier for them to get more successfully to internationalize your

products and services, making the process of internationalization of a country,

enabling the processes of trade between blocks, regions, countries, etc.

Colombia to increase the number of international treaties with various countries

in very different latitudes allows you to extend the possibility of participating in

a greater crucible of possibilities for trading goods and services; invites us to

analyze what is happening at this time with the formation of companies with

international orientation in our country; Government policies that support this

kind of intentions, the regulatory framework that underpins the processes of

enterprise internationalization, among other elements, and its impact on

employers, who are facing the challenge of meeting the new global demands.

The theoretical basis that occurs, is based on studies on Born Global companies,

obtained through interviews to this type of business in the city of Bogotá; such

as the innovative capacity of the latter, knowledge of international trade as an

alternative to successfully enter foreign markets, a significant number of

contacts abroad, international entrepreneurship culture, the permanent search

for effects of differentiating its products and services, allowing them to access

positions of privilege within market segments in that move.
SEARCH AND SELECTION OF EXPERTS ON THE BASIS OF SEARCH EXECUTIVE TECHNOLOGIES: METHODOLOGY AND PRACTICAL ASPECTS
Authors: Долженкова  , Dolzhenkova Yuliya , Руденко  , Rudenko Galina
Published: December 2013

The executive search relates to the least understood among the

recruitment directions. However in recent years it is booming in

Russia and abroad. Its peculiarity is that the search for potential

candidates is performing among the experts who are employed and

not looking for work. Now there is scientifi c understanding of executive

search techniques and technologies, as well as formation of

its principles.