bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risks of Model Weighting in Multimodel Climate Projections
Authors: Weigel Andreas P. , Knutti Reto , Liniger Mark A. , Appenzeller Christof 
Published: March 2010

Abstract
Multimodel combination is a pragmatic approach to estimating model uncertainties and to making climate projections more reliable. The simplest way of constructing a multimodel is to give one vote to each model (“equal weighting”), while more sophisticated approaches suggest applying model weights according to some measure of performance (“optimum weighting”). In this study, a simple conceptual model of climate change projections is introduced and applied to discuss the effects of model weighting in more generic terms. The results confirm that equally weighted multimodels on average outperform the single models, and that projection errors can in principle be further reduced by optimum weighting. However, this not only requires accurate knowledge of the single model skill, but the relative contributions of the joint model error and unpredictable noise also need to be known to avoid biased weights. If weights are applied that do not appropriately represent the true underlying uncertainties, weighted multimodels perform on average worse than equally weighted ones, which is a scenario that is not unlikely, given that at present there is no consensus on how skill-based weights can be obtained. Particularly when internal variability is large, more information may be lost by inappropriate weighting than could potentially be gained by optimum weighting. These results indicate that for many applications equal weighting may be the safer and more transparent way to combine models. However, also within the presented framework eliminating models from an ensemble can be justified if they are known to lack key mechanisms that are indispensable for meaningful climate projections.
Outcome of psychiatric symptoms presenting at onset of multiple sclerosis: a retrospective study
Authors: Lo Fermo Salvatore , Barone Rita , Patti Francesco , Laisa Patrizia , Cavallaro Tiziana L , Nicoletti Alessandra , Zappia Mario 
Published: March 2010

Psychiatric disturbances may occur at the onset of multiple sclerosis. However, information on their outcome is lacking. Our objective was to document the characteristics of psychiatric symptoms at presentation of multiple sclerosis and to define the long-term evolution of psychiatric disturbances in these patients. Based on a clinical record analysis of patients with defined multiple sclerosis diagnosis and coming under the care of a university multiple sclerosis centre within the period 1997—2007, patients with both psychiatric and neurological symptoms at presentation were identified. Clinical data at onset and at last follow-up were considered. Among 682 evaluated patients, psychiatric disturbances were associated with multiple sclerosis onset in 16 cases (2.3%). Most patients (56%) presented with a mood disorder with clinical characteristics of a major depressive-like episode, five (32%) had psychotic symptoms. Initial psychiatric disturbances improved later than neurological symptoms, or never fully recovered, regardless of the concomitant use of psychotropic medications. In most of the subjects psychiatric disturbances tended to remain over the follow-up period and at last visit, after a mean follow-up of 7.6 years (±2.3), 14 subjects (87%) had a supplementary diagnosis of psychiatric illness. Psychiatric symptoms at onset of multiple sclerosis may be indicators of possible maintenance of psychiatric morbidity in a sizeable proportion of patients.
A cluster of mutations in the D3 domain of von Willebrand factor correlates with a distinct subgroup of von Willebrand disease: type 2A/IIE
Authors: Schneppenheim Reinhard , Michiels Jan Jacques , Obser Tobias , Oyen Florian , Pieconka Antje , Schneppenheim Sonja , Will Kerstin , Zieger Barbara , Budde Ulrich 
Published: March 2010

AbstractAmong the different phenotypes of von Willebrand disease (VWD) type 2A, we identified a particular subgroup with a high frequency of 29%, characterized by a relative decrease of large von Willebrand factor (VWF) multimers and decreased A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motifs, member 13 (ADAMTS13)–mediated proteolysis previously described in a single family as VWD type IIE (VWD2A/IIE). Phenotype and genotype of 57 patients from 38 unrelated families displaying a particular multimer pattern resembling the original VWD2A/IIE were studied. Pathogenicity of candidate mutations was confirmed by expression studies and phenotypic characterization of recombinant mutants. Specific mutations were identified in all patients. Twenty-two different mutations, most of them affecting cysteine residues, 17 of them being novel, are clustering mainly in the VWF D3 domain and correlate with the VWD2A/IIE phenotype. An intracellular retention of most mutants and/or a defect of multimerization seem to be the main pathogenic molecular mechanisms. ADAMTS13 proteolysis of mutant VWF was not different from wild-type VWF in a static assay, suggesting that reduced in vivo proteolysis is not an intrinsic property of mutant VWF. Our study identified a distinct VWD subtype with a common molecular background which contributes significantly to the heterogeneous spectrum of VWD.
IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production
Authors: Maeda Kenichiro , Mehta Harshini , Drevets Douglas A. , Coggeshall K. Mark 
Published: March 2010

AbstractSrc homology 2 domain-containing inositol 5-phosphatase (SHIP−/−) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of macrophages, and requires a stimulus present in vivo. The IL-6–rich peritoneal cavity of SHIP−/− mice shows more than 700-fold more immunoglobulin G (IgG) than wild-type, approximately 20% of which is aggregated or in an immune complex and contains B220+ cells that secrete IgG. The SHIP-deficient peritoneal macrophages show evidence of IgG receptor stimulation. Animals lacking both the signal-transducing γ-chain of IgG receptors and SHIP or Ig and SHIP produce less IL-6. The data indicate a feed-forward process in which peripheral macrophages, responding through IgG receptors to secreted IgG, produce IL-6, to support further B-cell production of IgG. Because of the proinflammatory phenotype of SHIP−/− animals, these findings emphasize the importance of IL-6–neutralizing strategies in autoimmune and proinflammatory diseases.
Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool
Authors: Shahani Tina , Lavend'homme Renaud , Luttun Aernout , Saint-Remy Jean-Marie , Peerlinck Kathelijne , Jacquemin Marc 
Published: March 2010

AbstractAlthough the liver is known to be the main site of factor VIII (FVIII) production, other organs are probably also important for the regulation of FVIII secretion. However, the study of the regulation of extrahepatic FVIII production has been hampered by the lack of definitive identification of human tissues able to secrete FVIII. Recent studies have shown that lung endothelial cells can synthesize FVIII. We therefore studied the production of FVIII by endothelial cells purified from other vascular beds. Because physiologic stress results in a rapid elevation of FVIII, we also investigated whether endothelial cells can store FVIII and secrete it after treatment with agonists. Microvascular endothelial cells from lung, heart, intestine, and skin as well as endothelial cells from pulmonary artery constitutively secreted FVIII and released it after treatment with phorbol-myristate acetate and epinephrine. By contrast, endothelial cells from the aorta, umbilical artery and umbilical vein did not constitutively secrete FVIII or release it after treatment with agonists, probably because of a lack of FVIII synthesis. Extrahepatic endothelial cells from certain vascular beds therefore appear to be an important FVIII production and storage site with the potential to regulate FVIII secretion in chronic and acute conditions.
Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma
Authors: Kikuchi Jiro , Wada Taeko , Shimizu Rumi , Izumi Tohru , Akutsu Miyuki , Mitsunaga Kanae , Noborio-Hatano Kaoru , Nobuyoshi Masaharu , Ozawa Keiya , Kano Yasuhiko , Furukawa Yusuke 
Published: March 2010

AbstractBortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-κB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8–dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Authors: Krawczyk Connie M. , Holowka Thomas , Sun Jie , Blagih Julianna , Amiel Eyal , DeBerardinis Ralph J. , Cross Justin R. , Jung Euihye , Thompson Craig B. , Jones Russell G. , Pearce Edward J. 
Published: March 2010

Abstract
Dendritic cells (DCs) are key regulators of innate and acquired immunity. The maturation of DCs is directed by signal transduction events downstream of toll-like receptors (TLRs) and other pattern recognition receptors. Here, we demonstrate that, in mouse DCs, TLR agonists stimulate a profound metabolic transition to aerobic glycolysis, similar to the Warburg metabolism displayed by cancer cells. This metabolic switch depends on the phosphatidyl inositol 3′-kinase/Akt pathway, is antagonized by the adenosine monophosphate (AMP)–activated protein kinase (AMPK), and is required for DC maturation. The metabolic switch induced by DC activation is antagonized by the antiinflammatory cytokine interleukin-10. Our data pinpoint TLR-mediated metabolic conversion as essential for DC maturation and function and reveal it as a potential target for intervention in the control of excessive inflammation and inappropriately regulated immune responses.
An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells
Authors: Kang Jinjoo , Yoo Jaehyuk , Lee Sunju , Tang Wanli , Aguilar Berenice , Ramu Swapnika , Choi Inho , Otu Hasan H. , Shin Jay W. , Dotto G. Paolo , Koh Chester J. , Detmar Michael , Hong Young-Kwon 
Published: March 2010

AbstractArteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may coreside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators.
Long-acting β2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD
Authors: de Vries F. , Setakis E. , Zhang B. , van Staa T.P. 
Published: March 2010

The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting β2-agonists (LABA), short-acting β2-agonists (SABA) or inhaled corticosteroids (ICS) in general practice.The study population included β2-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure.Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.
Epidermal growth factor receptor signalling contributes to house dust mite-induced epithelial barrier dysfunction
Authors: Heijink I.H. , van Oosterhout A. , Kapus A. 
Published: March 2010

Impaired airway epithelial barrier function has emerged as a key factor in the pathogenesis of allergic asthma. We aimed to discern the involvement of the epidermal growth factor receptor (EGFR) in allergen-induced epithelial barrier impairment, as we previously observed that house dust mite (HDM) signals through EGFR.We investigated the junctional integrity of human bronchial epithelial cells using electric cell-substrate impedance sensing and immunofluorescent staining.HDM induced a rapid, transient fall in epithelial resistance, concomitant with delocalisation of E-cadherin and zona occludens (ZO)-1, and proteolytic cleavage of the latter. EGFR inhibition by AG1478 reduced the HDM-triggered decrease in epithelial resistance and improved restoration of epithelial junctions. Similarly, AG1478 increased epithelial barrier recovery upon electroporation-induced injury, although it delayed the migration phase of the wound healing response. HDM-promoted redistribution of E-cadherin was mediatedviaEGFR-dependent activation of protease-activated receptor (PAR)-2, while the concomitant ZO-1 degradation was PAR-2/EGFR-independent. Importantly, the fibrogenic cytokine transforming growth factor (TGF)-β prolonged HDM-induced EGFR phosphorylation and inhibited ligand-induced EGFR internalisation/degradation, which resulted in sustained E-cadherin and ZO-1 redistribution.Thus, allergen-induced, PAR-2/EGFR-mediated signalling decreases epithelial resistance and promotes junction disassembly. The TGF-β-enhanced EGFR signalling may be an important contributor to barrier dysfunction and increased epithelial vulnerability in response to HDM.
The occupational contribution to severe exacerbation of asthma
Authors: Henneberger P.K. , Mirabelli M.C. , Kogevinas M. , Antó J.M. , Plana E. , Dahlman-Höglund A. , Jarvis D.L. , Kromhout H. , Lillienberg L. , Norbäck D. , Olivieri M. , Radon K. , Torén K. , Urrutia I. , Villani S. , Zock J.P. 
Published: March 2010

The goal of this study was to identify occupational risk factors for severe exacerbation of asthma and estimate the extent to which occupation contributes to these events.The 966 participants were working adults with current asthma who participated in the follow-up phase of the European Community Respiratory Health Survey. Severe exacerbation of asthma was defined as self-reported unplanned care for asthma in the past 12 months. Occupations held in the same period were combined with a general population job-exposure matrix to assess occupational exposures.74 participants reported having had at least one severe exacerbation event, for a 1-yr cumulative incidence of 7.7%. From regression models that controlled for confounders, the relative risk (RR) was statistically significant for low (RR 1.7, 95% CI 1.1–2.6) and high (RR 3.6, 95% CI 2.2–5.8) biological dust exposure, high mineral dust exposure (RR 1.8, 95% CI 1.02–3.2), and high gas and fumes exposure (RR 2.5, 95% CI 1.2–5.5). The summary category of high dust, gas, or fumes exposure had RR 3.1 (95% CI 1.9–5.1). Based on this RR, the population attributable risk was 14.7% among workers with current asthma.These results suggest occupation contributes to approximately one in seven cases of severe exacerbation of asthma in a working population, and various agents play a role.
Predicting outcomes and drug resistance with standardised treatment of active tuberculosis
Authors: Oxlade O. , Schwartzman K. , Pai M. , Heymann J. , Benedetti A. , Royce S. , Menzies D. 
Published: March 2010

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment.A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance.Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48–86 fewer persons will require retreatment, and 3–12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50–94% of failures and 3–56% of relapses will have multidrug-resistant TB.We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.
Exposure to volatile organic compounds and loss of pulmonary function in the elderly
Authors: Yoon H.I. , Hong Y-C. , Cho S-H. , Kim H. , Kim Y.H. , Sohn J.R. , Kwon M. , Park S-H. , Cho M-H. , Cheong H-K. 
Published: March 2010

Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population.A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2′-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests.We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow at 25–75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters.This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.
The role of per cent predicted 6-min walk distance in pulmonary arterial hypertension
Authors: Lee W-T.N. , Peacock A.J. , Johnson M.K. 
Published: March 2010

Absolute 6-min walk distance (6MWD) predicts mortality in pulmonary arterial hypertension (PAH), but varies greatly between normal individuals due to physiological factors such as age, sex, height and weight. The % predicted 6MWD adjusts for these factors and may predict mortality more reliably. The aim of the study was to compare the strength of mortality prediction by absolute and % predicted 6MWD in PAH at baseline and on treatment.% predicted 6MWD was calculated using four different reference equations in 137 PAH patients (idiopathic and connective tissue disease associated) diagnosed between November 2000 and November 2009. Cox proportional hazards and receiver-operating characteristic (ROC) analyses were used to compare the prognostic strength of absolute and % predicted 6MWD.% predicted 6MWD was predictive of all-cause mortality at baseline (hazard ratio 0.74–0.83 per 10% increase; p<0.05) and on treatment (0.67–0.75 per 10% increase; p<0.01), but each respective area under the ROC curve was not different from that of absolute 6MWD for predicting 2-yr mortality at baseline (absoluteversus% predicted: 0.74versus0.71–0.75) or on treatment (0.77versus0.72–0.78).In conclusion, % predicted 6MWD may help clinicians interpret the 6-min walk test, but its prognostic value is not superior to that of absolute 6MWD.