bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis
Authors: Mullazehi Mohammed , Wick Marius C , Klareskog Lars , van Vollenhoven Ronald , Rönnelid Johan 
Published: May 2012

Abstract

Introduction

We have previously reported that high levels of antibodies specific for native human type II collagen (anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was associated with CII/anti-CII immune complex (IC)-induced production of pro-inflammatory cytokines in vitro. In contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with early erosions.

Methods

Two-hundred-and-fifty-six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were quantified using the 32-joints Larsen erosion score.

Results

Levels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303), CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients.

Conclusion

In contrary to anti-CCP, anti-CII-positive patients with RA have increased joint destruction and HAQ score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype might account for part of the elderly acute onset RA phenotype with rather good prognosis.
New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus
Authors: Wang Fang-Fang , Zhu Li-An , Zou Yu-Qiong , Zheng Hui , Wilson Alisa , Yang Cheng-De , Shen Nan , Wallace Daniel J , Weisman Michael H , Chen Shun-Le , Lu Liang-Jing 
Published: May 2012

Abstract

Introduction

Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.

Methods

Sixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.

Results

MIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.

Conclusions

Our results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.
Differential effect of CD69 targeting on bystander and antigen-specific T cell proliferation
Authors: Alari-Pahissa Elisenda , Vega-Ramos Javier , Zhang Jian-Guo , Castaño A Raúl , Turley Shannon J , Villadangos José A , Lauzurica Pilar 
Published: April 2012

Abstract
CD69 targeting induces bystander T cell proliferation but does not affect antigen-specific proliferation.
In spite of an initially proposed role as a costimulatory molecule for CD69, in vivo studies showed it as a regulator of immune responses and lymphocyte egress. We found constitutive CD69 expression by T cell subsets and pDC. We examined a possible effect of CD69 on T cell proliferation using transfer models and in vitro assays. In mice locally expressing or receiving antigen, anti-CD692.2 treatment did not affect the proliferation of antigen-specific transgenic T cells in ADLN, although we observed the presence of proliferated T cells in non-ADLN and spleen. This was not affected by FTY720 treatment and thus, not contributed by increased egress of proliferated lymphocytes from ADLN. In the absence of antigen, anti-CD69 2.2 treatment induced bystander proliferation of transferred memory phenotype T cells. This proliferation was mediated by IL-2, as it was inhibited by anti-IL-2 or anti-CD25 antibodies in vitro and by anti-CD25 antibodies in vivo. It was also dependent on CD69 expression by donor T cells and recipient cells. CD69 targeting on T cells enhanced IL-2-mediated proliferation and CD25 expression. However, it did not lead to increased early IL-2 production by T cells. No T cell subset was found to be specifically required in the recipient. Instead, CD69 targeting on pDC induced their expression of IL-2 and CD25, and pDC depletion showed that this subset was involved in the proliferation induction. These results indicate that CD69 targeting induces bystander T cell proliferation through pDC IL-2 production and T cell sensitization to IL-2 without affecting antigen-driven T cell proliferation.
Regulation of alveolar macrophage p40phox: hierarchy of activating kinases and their inhibition by PGE2
Authors: Bourdonnay Emilie , Serezani Carlos H , Aronoff David M , Peters-Golden Marc 
Published: April 2012

Abstract
In lung macrophages, inhibition of p40phox by PGE2 represents a brake on bacterial killing, and likely contributes to impaired lung innate immunity.
PGE2, produced in the lung during infection with microbes such as Klebsiella pneumoniae, inhibits alveolar macrophage (AM) antimicrobial functions by preventing H2O2 production by NADPH oxidase (NADPHox). Activation of the NADPHox complex is poorly understood in AMs, although in neutrophils it is known to be mediated by kinases including PI3K/Akt, protein kinase C (PKC) δ, p21-activated protein kinase (PAK), casein kinase 2 (CK2), and MAPKs. The p40phox cytosolic subunit of NADPHox has been recently recognized to function as a carrier protein for other subunits and a positive regulator of oxidase activation, a role previously considered unique to another subunit, p47phox. The regulation of p40phox remains poorly understood, and the effect of PGE2 on its activation is completely undefined. We addressed these issues in rat AMs activated with IgG-opsonized K. pneumoniae. The kinetics of kinase activation and the consequences of kinase inhibition and silencing revealed a critical role for a PKCδ-PAK-class I PI3K/Akt1 cascade in the regulation of p40phox activation upon bacterial challenge in AMs; PKCα, ERK, and CK2 were not involved. PGE2 inhibited the activation of p40phox, and its effects were mediated by protein kinase A type II, were independent of interactions with anchoring proteins, and were directed at the distal class I PI3K/Akt1 activation step. Defining the kinases that control AM p40phox activation and that are the targets for inhibition by PGE2 provides new insights into immunoregulation in the infected lung.
Direct in vivo evidence of CD4+ T cell requirement for CTL response and memory via pMHC-I targeting and CD40L signaling
Authors: Ahmed Khawaja Ashfaque , Wang Lu , Munegowda Manjunatha Ankathatti , Mulligan Sean J , Gordon John R , Griebel Philip , Xiang Jim 
Published: April 2012

Abstract
New in vivo evidence of CD4+ T cells capable of directly stimulating effective CTL response.
CD4+ T cell help contributes critically to DC-induced CD8+ CTL immunity. However, precisely how these three cell populations interact and how CD4+ T cell signals are delivered to CD8+ T cells in vivo have been unclear. In this study, we developed a novel, two-step approach, wherein CD4+ T cells and antigen-presenting DCs productively engaged one another in vivo in the absence of cognate CD8+ T cells, after which, we selectively depleted the previously engaged CD4+ T cells or DCs before allowing interactions of either population alone with naïve CD8+ T cells. This protocol thus allows us to clearly document the importance of CD4+ T-licensed DCs and DC-primed CD4+ T cells in CTL immunity. Here, we provide direct in vivo evidence that primed CD4+ T cells or licensed DCs can stimulate CTL response and memory, independent of DC-CD4+ T cell clusters. Our results suggest that primed CD4+ T cells with acquired pMHC-I from DCs represent crucial “immune intermediates” for rapid induction of CTL responses and for functional memory via CD40L signaling. Importantly, intravital, two-photon microscopy elegantly provide unequivocal in vivo evidence for direct CD4-CD8+ T cell interactions via pMHC-I engagement. This study corroborates the coexistence of direct and indirect mechanisms of T cell help for a CTL response in noninflammatory situations. These data suggest a new “dynamic model of three-cell interactions” for CTL immunity derived from stimulation by dissociated, licensed DCs, primed CD4+ T cells, and DC-CD4+ T cell clusters and may have significant implications for autoimmunity and vaccine design.
Dynamic Pricing with Financial Milestones: Feedback-Form Policies
Authors: Besbes Omar , Maglaras Costis 
Published: April 2012

We study a seller that starts with an initial inventory of goods, has a target horizon over which to sell the goods, and is subject to a set of financial milestone constraints on the revenues and sales that need to be achieved at different time points along the sales horizon. We characterize the revenue maximizing dynamic pricing policy for the seller and highlight the effect of revenue and sales milestones on its structure. The optimal policy can be written in feedback form, where the price at each point in time is selected so as to track the most stringent among all future milestones. Building on that observation, we propose a discrete-review policy that aims to dynamically track the appropriate milestone constraint and show that this simple and practical policy is near optimal in settings with large initial capacity and long sales horizons even in settings with no advance demand model information. One motivating application comes from the sales of new multiunit, residential real estate developments, where intermediate milestone constraints play an important role in their financing and construction.This paper was accepted by Gérard P. Cachon, stochastic models and simulation.
Psychological Pressure in Competitive Environments: New Evidence from Randomized Natural Experiments
Authors: Kocher Martin G. , Lenz Marc V. , Sutter Matthias 
Published: April 2012

Dynamic competitive settings may create psychological pressure when feedback about the performance of competitors is provided before the end of the competition. Such psychological pressure could produce a first-mover advantage, despite a priori equal winning probabilities. Using data from a randomized natural experiment—penalty shootouts in soccer—we reexamine evidence by Apesteguia and Palacios-Huerta [Apesteguia J, Palacios-Huerta I (2010) Psychological pressure in competitive environments: Evidence from a randomized natural experiment. Amer. Econom. Rev. 100(5):2548–2564]. They report a 21-percentage-point advantage for first movers over second movers in terms of winning probabilities. Extending their sample of 129 shootouts to 540, we fail to detect any significant first-mover advantage. Our results are fully consistent with recent evidence from other sports contests. This paper was accepted by Teck Ho, behavioral economics.
Consumer Valuation of Modularly Upgradeable Products
Authors: Ülkü Sezer , Dimofte Claudiu V. , Schmidt Glen M. 
Published: April 2012

Although product modularity is often advocated as a design strategy in the operations management literature, little is known about how consumers respond to modular products. In this research we undertake several experiments to explore consumer response to modularly upgradeable products in settings featuring technological change. We consider both the initial product choice (between a modularly upgradeable product and an integral one) and the subsequent upgrade decision (replacement of a module versus full product replacement). First, we show that consumers tend to discount the cost savings associated with modular upgrades excessively (insufficiently) when the time between the initial purchase and the upgrade is short (long). This suggests that modular upgradability as a product feature has higher profit potential for slowly rather than rapidly improving products. Second, we observe a preference reversal between the initial purchase and the point of upgrade: At the point of initial purchase, people foresee making a full product replacement in the future, yet, when faced with the actual upgrade decision, they are more likely to revert to modular upgrades. Finally, we discuss and test several pricing and product design strategies that the firm can use to respond to these cognitive biases. This paper was accepted by Kamalini Ramdas, entrepreneurship and innovation.
Contingent Capital with a Capital-Ratio Trigger
Authors: Glasserman Paul , Nouri Behzad 
Published: April 2012

Contingent capital in the form of debt that converts to equity when a bank faces financial distress has been proposed as a mechanism to enhance financial stability and avoid costly government rescues. Specific proposals vary in their choice of conversion trigger and conversion mechanism. We analyze the case of contingent capital with a capital-ratio trigger and partial and ongoing conversion. The capital ratio we use is based on accounting or book values to approximate the regulatory ratios that determine capital requirements for banks. The conversion process is partial and ongoing in the sense that each time a bank's capital ratio reaches the minimum threshold, just enough debt is converted to equity to meet the capital requirement, so long as the contingent capital has not been depleted. We derive closed-form expressions for the market value of such securities when the firm's asset value is modeled as geometric Brownian motion, and from these we get formulas for the fair yield spread on the convertible debt. A key step in the analysis is an explicit expression for the fraction of equity held by the original shareholders and the fraction held by converted investors in the contingent capital. This paper was accepted by Gérard P. Cachon, stochastic models and simulation.
Asset Pricing Restrictions on Predictability: Frictions Matter
Authors: de Roon Frans , Szymanowska Marta 
Published: April 2012

U.S. stock portfolios sorted on size; momentum; transaction costs; market-to-book, investment-to-assets, and return-on-assets (ROA) ratios; and industry classification show considerable levels and variation of return predictability, inconsistent with asset pricing models. This means that a predictable risk premium is not equal to compensation for systematic risk as implied by asset pricing theory. We show that introducing market frictions relaxes these asset pricing moments from a strict equality to a range. Empirically, it is not short sales constraints but transaction costs (below 35 basis points) that help to reconcile the observed predictability with linear portfolio return-based factor models, and partly with the durable consumption model. Across the sorts, predictability in industry returns can be reconciled with all models considered with only a 25 basis point transaction cost, whereas for momentum and ROA portfolios, up to 115 basis points are needed. This paper was accepted by Wei Xiong, finance.
Cost-Effectiveness of Adjunctive Therapy with Atypical Antipsychotics for Acute Treatment of Major Depressive Disorder
Authors: Taneja Charu , Papakostas George I , Jing Yonghua , Baker Ross A , Forbes Robert A , Oster Gerry 
Published: May 2012

Background: While the clinical utility of atypical antipsychotics has been established in patients with major depressive disorder (MDD) who are refractory to antidepressant therapy, their cost-effectiveness is unknown. Objective: To examine the cost-effectiveness of aripiprazole, quetiapine, and olanzapine/fluoxetine in adults with MDD who are refractory to antidepressant therapy. Methods: Using techniques of decision analysis, we estimated expected outcomes and costs over 6 weeks in adults with MDD receiving (1) aripiprazole 2-20 mg/day and antidepressant therapy; (2) quetiapine 150 mg/day or 300 mg/day and antidepressant therapy; (3) the fixed-dose combination of olanzapine 6, 12, or 18 mg/day with fluoxetine 50 mg/day; or (4) antidepressant therapy alone. Cost-effectiveness was assessed in terms of the cost per additional responder at 6 weeks, defined as the ratio of the difference in the cost of MDD-related care over 6 weeks versus antidepressant therapy afone to the difference in the number of patients achieving clinical response by 6 weeks. We estimated the model using data from Phase 3 clinical trials of atypical antipsychotics along with other secondary data sources. Results: With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%. Aripiprazole, quetiapine 150 mg/day, quetiapine 300 mg/day, and olanzapine/fluoxetine were estimated to increase clinical response at 6 weeks to 49%, 34%, 38%, and 45%. respectively. Costs of MDD-related care over 6 weeks were estimated to be $192 for antidepressant therapy, $847 for aripiprazole, $541 for quetiapine 150 mg/day, $672 for quetiapine 300 mg/day plus antidepressant therapy, and $791 for olanzapine/fluoxetine. Costs per additional responder (vs antidepressant therapy) over a 6-week period were estimated to be $3447 for aripiprazole, $8725 for quetiapine 150 mg/day, $6000 for quetiapine 300 mg/day, and $3993 for olanzapine/fluoxetine. Conclusions: Atypical antipsychotics substantially increase clinical response at 6 weeks. Cost per additional responder is lower for aripiprazole than for quetiapine or olanzapine/fluoxetine.
Antihypertensive Drugs in Patients Treated with Antiretroviral
Authors: Peyriere Hélène , Eiden Céline , Macia Jean-Christophe , Reynes Jacques 
Published: May 2012

Objective: To review the literature for information regarding pharmacokinetic interactions between antiretrovirals and antihypertensive agents, evaluate the clinical significance of these interactions, and analyze the effect of antihypertensive drugs on the metabolic complications frequently observed in HIV-infected patients to emphasize the advantages and inconveniences of every class of antihypertensive drugs in association with antiretrovirals. Data Sources: A literature search was conducted via PubMed and MEDLINE (1950-November 2011) using the search terms drug interactions, cytochrome P450, names of antiretrovirals, names of commonly prescribed antihypertensive drugs, pharmacokinetics, and metabolic complications. Reference citations from relevant publications, manufacturers’ product information, and www.HIV-druginteracttons.org were also reviewed. Study Selection And Data Extractions: All articles with an English abstract identified through the data search were examined. Of these, pharmacologic reviews, studies, and case reports were evaluated. Data Synthesis: Antihypertensive drugs interact with several antiretroviral drugs, non nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) in particular. Pharmacokinetic interactions are less expected with diuretics, jî-blockers excreted by the kidney, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) other than losartan and irbesartan. Calcium channel blockers (CCBs) are metabolized by CYP3A4, with the potential for interaction with NNRTIs and Pls. Because CCBs do not adversely affect glucose or lipid metabolism or renal function, they may be preferred in patients with such complications. ACE inhibitors and ARBs may exert favorable effects on glucose homeostasis. In addition, they may significantly reduce protein excretion and further slow the progression of renal disease. Conclusions: The choice of antihypertensive drugs in HIV-infected patients is complex and must take into account the metabolic pathways of antiretroviral drugs and antihypertensive drugs with the potential of pharmacokinetic interactions, as well as the effect of antihypertensive drugs on some biological parameters.
Agency without Avoidability: Defusing a New Threat to Frankfurt's Counterexample Strategy
Authors: Shabo Seth 
Published: April 2012

Many believe that we are not morally responsible for what we cannot help doing. Call this ‘the Traditional View of Responsible Agency.’ Some forty years ago, Harry Frankfurt (1969) challenged this view, thereby initiating a new stage of the free-will debate. In contrast to the previous stage, in which debate centered on how best to accommodate the Traditional View, contemporary theorists have focused on whether this view should be accepted at all. If the link between moral responsibility and avoidability is severed, an important threat to compatibilism is neutralized.In the wake of Frankfurt's challenge, a tremendous literature has sprung up, with many ingenious responses matched by equally thoughtful extensions of Frankfurt's original argument. Quite recently, an altogether new line of response has been proposed. This new approach, versions of which have been advanced by Maria Alvarez (2009) and Helen Steward (2009), attempts to support the Traditional View indirectly, by appealing to the conditions for action, rather than to the conditions for moral responsibilityper se.
The Grimaldi Shakspere
Authors: Schoch Richard 
Published: April 2012

The 1850s saw the publication of two fake editions of Shakespeare: John Payne Collier's famous and fraudulent "Perkins Folio," and its little-known satiric counterpart, The Grimaldi Shakspere . This essay, the first sustained investigation of the latter text, argues that it is far from a harmless parody, instead constituting the first charge of forgery against Collier at a time when public opinion was still in his favour. To this end, the article breaks down the history of the Collier controversy and the composition of The Grimaldi Shakspere , and undertakes a fresh inquiry into the identity of its author. The processes by which theatrical practice may become literary criticism are brought into focus, both specifically (Collier's false marginalia allegedly interpolated from prompt-books; the comparison of the forger to clown and contortionist Joey Grimaldi) and in the broader sense, as satirists, clowns and charlatans alike mix the grave and the absurd.