bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated FEA Modeling Offers System Approach to Drillstring Optimization
Authors: Aslaksen H. , Annand M. , Duncan R. , Fjaere A. , Paez L. , Tran U.
Published: November 2009

Downhole measurement systems have reached an impressive level of accuracy and reliability. However, the predictive behavior aspect of complete drilling systems, whether it be vibrational or directional, until recently has not received the same focus. The two key components affecting the overall dynamics of a drilling system are the effect of the cutting structures of drilling tools (drill bits, underreamers, etc.) and the behavior of the BHA and drill string. Typically, these aspects have been modeled in isolation, or rudimentary assumptions are made to approximate the effect one on the other. To more accurately predict the performance of the drilling system, it is essential to consider the sum of all forces affecting the system. This must include accurate modeling of the drill bit cutting structure, based on actual bit design, rock properties and drilling parameters. The effect of these forces must be coupled with the forces generated by the BHA and drilling string, and the interaction of these forces should be modeled and understood. These issues have significant cost implications for the operator but in both cases are complex to model. A system approach is required to achieve true optimization of these two historically separate areas of drillstring design.

Typically, drillstring analysis programs currently available to the industry are run on personal computers with limited random access memory capabilities and are, therefore, restricted to modelling only the BHA portion of the drillstring. For the same reason, bit effect factors that significantly influence drillstring behavior are at best assumed.

Utilizing a suite of Finite Element Analysis (FEA) based programs running on a Unix platform; four-dimensional, time-based simulations of the complete drilling process are now possible. The exact interaction between the bit and the formation drilled are modelled using lab-derived rock mechanics. The bit and every string component are modelled individually.

The system generates the behavior of the entire drillstring, from the cutting edge of the bit to surface. The modelling accurately predicts the vibrations and accelerations often seen to have detrimental effects on directional control, tool reliability, drill string integrity and drilling performance.

The ability to pinpoint the source and effects of torsional, axial and lateral oscillations enables users to qualify design changes to the drillstring configuration and optimize parameters, prior to drilling the well, that eliminate the traditional "trial and error" approach and reduce operator risk.
Whither Financial Reform?
Authors: Litan Robert E
Published: November 2009

Robert Litan points out that much has been done already to prevent future financial crises, and tells us what remains.
First-Time Adoption of IFRS, Managerial Incentives, and Value-Relevance: Some French Evidence
Authors: Cormier Denis , Demaria Samira , Lapointe-Antunes Pascale , Teller Robert
Published: November 2009

ABSTRACT: This paper investigates whether and how managerial incentives influence the decision to elect optional exemptions when first adopting International Financial Reporting Standards (IFRS). It also examines the value-relevance of the mandatory and optional equity adjustments that must be recognized as a result of the first-time adoption of IFRS. Both questions are addressed in the context of the mandatory adoption of IFRS by French firms in 2005. Three major findings emerge from our analyses. First, managerial incentives influence the decision to strategically elect one or more optional exemptions at the transition date. Second, mandatory equity adjustments are more valued than French generally accepted accounting principles (GAAP) equity, suggesting that the first-time adoption of IFRS by French firms is perceived as a signal of an increase in the quality of their financial statements. Third, the value-relevance of optional IFRS equity adjustments depends on whether they result in the disclosure of new information.
The Riskiness of Future Benefits: The Case of Capitalization of R&D and Capital Expenditures
Authors: Ahmed Kamran , Falk Haim
Published: November 2009

ABSTRACT: This study contributes to the ongoing debate on whether to allow capitalization of R&D expenditures. Although prior studies suggest that capitalization of R&D expenditures is more value-relevant than immediate expensing, limited evidence is available outside the U.S. on whether R&D capitalization increases the riskiness of future benefits. In contrast to the U.S., where R&D capitalization is not permitted, Australian’s GAAP allowed, until 2005, capitalization of R&D expenditure if the derived benefits recovered the cost “beyond reasonable doubt.” Using this unique setting, we employ a sample of 912 Australian firm-year observations for 298 firms over the years 1988 to 2000 to examine the association between current R&D expenditure and risk in future earnings, where earnings variability is used as proxy for risk. We find that expensed R&D expenditures generate higher risk in future earnings than current capital expenditures, and that both expensed current R&D expenditures and current capital expenditures generate higher risk in future earnings than do discretionary capitalized R&D expenditures.
A Comparison of the New U.S. Expatriation Tax and the Canadian Departure Tax
Authors: Gelardi Alexander M. G.
Published: November 2009

ABSTRACT: The Heroes Earnings Assistance and Relief Tax Act of 2008 amended the anti-avoidance provisions of the Internal Revenue Code for an expatriating taxpayer. The new law requires expatriating taxpayers to report a deemed taxable sale and repurchase of assets at the time that they expatriate. This is a change from the prior law where an expatriating taxpayer could be taxed by the U.S. for ten years after expatriation. The new U.S. rules are similar to rules that have been used by Canada to tax expatriating Canadian residents. This paper sets out the new U.S. rules and compares them to the Canadian departure tax. As can be seen, there are a number of similarities between the two countries' laws. However, there are also some major differences. The U.S. rules are more limited in application than the Canadian rules. As well as income tax, the U.S. legislators are concerned with estate and gift taxes, whereas the Canadian legislators are not.
Labile A1C Is Inversely Correlated With the Hemoglobin Glycation Index in Children With Type 1 Diabetes
Authors: Chalew Stuart A. , McCarter Robert J. , Ory-Ascani Jeanine , Hempe James M.
Published: November 2009

OBJECTIVE

We hypothesized that labile A1C (LA1C) is directly correlated with stable A1C (SA1C) and between-patient differences in SA1C, which are independent of mean blood glucose (MBG).

RESEARCH DESIGN AND METHODS

We measured SA1C, LA1C, MBG, and a single clinic capillary glucose (CCG) from 152 pediatric patients with type 1 diabetes. Patients were grouped as high, moderate, or low glycators by hemoglobin glycation index (HGI).

RESULTS

LA1C and SA1C were correlated with CCG and MBG. LA1C was not correlated with SA1C (r = 0.06, P = 0.453). LA1C level was significantly associated with glycator group status (P < 0.0019) and CCG (P < 0.0001). Adjusted LA1C levels were highest in the low-HGI patients and lowest in the high-HGI group.

CONCLUSIONS

A conventional model of SA1C being directly correlated with LA1C concentration was not confirmed. Between-patient differences in SA1C at the same MBG may be due to complex intracellular factors influencing formation of SA1C from LA1C.
Are Hemoglobin Levels Elevated in Type 1 Diabetes?
Authors: Conway Baqiyyah N. , Miller Rachel G. , Orchard Trevor J.
Published: November 2009

OBJECTIVE

While lower hemoglobin is generally associated with adverse events in diabetes, we have recently observed in type 1 diabetes that those with overt nephropathy had hemoglobin levels as high as 18.8 g/dl. We thus explored whether hemoglobin concentrations are generally higher in type 1 diabetes.

RESEARCH DESIGN AND METHODS

Baseline (1986–1988) hemoglobin levels from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of type 1 diabetes were compared with general population data from the National Health and Nutrition Examination Survey (NHANES) III in the same age range as the EDC population (aged 8–48 years).

RESULTS

Both male and female EDC study participants had significantly higher hemoglobin levels than their NHANES III counterparts (men: 16.0 vs. 15.1 g/dl, P < 0.0001; women: 14.1 vs. 13.3 g/dl, P < 0.0001). The difference between the two populations was greatest in adolescent female subjects.

CONCLUSIONS

Hemoglobin levels may be higher in type 1 diabetes than in the general population, which may have important clinical implications.
Validation of a Type 2 Diabetes Screening Tool in Rural Honduras
Authors: Milton Evan C. , Herman William H. , Aiello Allison E. , Danielson Kris R. , Mendoza-Avelarez Milton O. , Piette John D.
Published: November 2009

OBJECTIVE

To validate a low-cost tool for identifying diabetic patients in rural areas of Latin America.

RESEARCH DESIGN AND METHODS

A regression equation incorporating postprandial time and a random plasma glucose was used to screen 800 adults in Honduras. Patients with a probability of diabetes of ≥20% were asked to return for a fasting plasma glucose (FPG). A random fifth of those with a screener-based probability of diabetes <20% were also asked to return for follow-up. The gold standard was an FPG ≥126 mg/dl.

RESULTS

The screener had very good test characteristics (area under the receiver operating characteristic curve = 0.89). Using the screening criterion of ≥0.42, the equation had a sensitivity of 74.1% and specificity of 97.2%.

CONCLUSIONS

This screener is a valid measure of diabetes risk in Honduras and could be used to identify diabetic patients in poor clinics in Latin America.
Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes
Authors: Marcovecchio M. Loredana , Tossavainen Paivi H. , Acerini Carlo L. , Barrett Timothy G. , Edge Julie , Neil Andrew , Shield Julian , Widmer Barry , Dalton R. Neil , Dunger David B.
Published: November 2009

OBJECTIVE

Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean ± SD age 15.8 ± 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring.

RESULTS

All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP β = 0.18, 24-h DBP β = 0.22, daytime SBP β = 0.25, daytime DBP β = 0.23, and nighttime DBP β = 0.18; all P < 0.01). Maternal 24-h DBP (β = 0.19, P = 0.004), daytime DBP (β = 0.09, P = 0.04), and nighttime SBP (β = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (β = 0.16, P = 0.02), daytime DBP (β = 0.16 P = 0.02), and nighttime DBP (β = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05).

CONCLUSIONS

In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.
Birth Weight, Body Silhouette Over the Life Course, and Incident Diabetes in 91,453 Middle-Aged Women From the French Etude Epidemiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) Cohort
Authors: de Lauzon-Guillain Blandine , Balkau Beverley , Charles Marie-Aline , Romieu Isabelle , Boutron-Ruault Marie-Christine , Clavel-Chapelon Françoise
Published: November 2009

OBJECTIVE

Obesity and increases in body weight in adults are considered to be among the most important risk factors for type 2 diabetes. Low birth weight is also associated with a higher diabetes incidence. We aimed to examine to what extent the evolution of body shape, from childhood to adulthood, is related to incident diabetes in late adulthood.

RESEARCH DESIGN AND METHODS

Etude Epidemiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) is a cohort study of French women born in 1925–1950 and followed by questionnaire every 2 years. At baseline, in 1990, women were asked to report their current weight, height, and body silhouette at various ages. Birth weight was recorded in 2002. Cases of diabetes were self-reported or obtained by drug reimbursement record linkage and further validated.

RESULTS

Of the 91,453 women who were nondiabetic at baseline, 2,534 developed diabetes over the 15 years of follow-up. Birth weight and body silhouette at 8 years, at menarche, and in young adulthood (20–25 years) were inversely associated with the risk of diabetes, independently of adult BMI during follow-up (all Ptrend < 0.001). In mid-adulthood (35–40 years), the association was reversed, with an increase in risk related to a larger body silhouette. An increase in body silhouette from childhood to mid-adulthood amplified the risk of diabetes.

CONCLUSIONS

Low birth weight and thinness until young adulthood may increase the risk of diabetes, independently of adult BMI during follow-up. Young women who were lean children should be especially warned against weight gain.
Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes
Authors: Landman Gijs W.D. , Kleefstra Nanne , van Hateren Kornelis J.J. , Groenier Klaas H. , Gans Rijk O.B. , Bilo Henk J.G.
Published: November 2009

OBJECTIVE

Several studies have suggested an association between specific diabetes treatment and cancer mortality. We studied the association between metformin use and cancer mortality in a prospectively followed cohort.

RESEARCH DESIGN AND METHODS

In 1998 and 1999, 1,353 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. Vital status was assessed in January 2009. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs), and the association between metformin use and cancer mortality was evaluated with a Cox proportional hazards model, taking possible confounders into account.

RESULTS

Median follow-up time was 9.6 years, average age at baseline was 68 years, and average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR for cancer mortality was 1.47 (95% CI 1.22–1.76). In patients taking metformin compared with patients not taking metformin at baseline, the adjusted hazard ratio (HR) for cancer mortality was 0.43 (95% CI 0.23–0.80), and the HR with every increase of 1 g of metformin was 0.58 (95% CI 0.36–0.93).

CONCLUSIONS

In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.
Maximum Entropy Estimation of Transition Probabilities of Reversible Markov Chains
Authors: Van der Straeten Erik
Published: November 2009

In this paper, we develop a general theory for the estimation of the transition probabilities of reversible Markov chains using the maximum entropy principle. A broad range of physical models can be studied within this approach. We use one-dimensional classical spin systems to illustrate the theoretical ideas. The examples studied in this paper are: the Ising model, the Potts model and the Blume-Emery-Griffiths model.
A Review of Water Management in Polymer Electrolyte Membrane Fuel Cells
Authors: Ji Mengbo , Wei Zidong
Published: November 2009

At present, despite the great advances in polymer electrolyte membrane fuel cell (PEMFC) technology over the past two decades through intensive research and development activities, their large-scale commercialization is still hampered by their higher materials cost and lower reliability and durability. In this review, water management is given special consideration. Water management is of vital importance to achieve maximum performance and durability from PEMFCs. On the one hand, to maintain good proton conductivity, the relative humidity of inlet gases is typically held at a large value to ensure that the membrane remains fully hydrated. On the other hand, the pores of the catalyst layer (CL) and the gas diffusion layer (GDL) are frequently flooded by excessive liquid water, resulting in a higher mass transport resistance. Thus, a subtle equilibrium has to be maintained between membrane drying and liquid water flooding to prevent fuel cell degradation and guarantee a high performance level, which is the essential problem of water management. This paper presents a comprehensive review of the state-of-the-art studies of water management, including the experimental methods and modeling and simulation for the characterization of water management and the water management strategies. As one important aspect of water management, water flooding has been extensively studied during the last two decades. Herein, the causes, detection, effects on cell performance and mitigation strategies of water flooding are overviewed in detail. In the end of the paper the emphasis is given to: (i) the delicate equilibrium of membrane drying vs. water flooding in water management; (ii) determining which phenomenon is principally responsible for the deterioration of the PEMFC performance, the flooding of the porous electrode or the gas channels in the bipolar plate, and (iii) what measures should be taken to prevent water flooding from happening in PEMFCs.
Forests: An International and Multi-disciplinary Scientific Open Access Journal
Authors: Jokela Eric J.
Published: November 2009

Natural and man-made forests serve many facets of society, including the production and consumption of forest products, provision of various environmental services such as clean air and water, soil protection, sources for critical endangered species habitats, and home for about 80% of the world’s terrestrial biodiversity. Throughout the world, forests are essential for offsetting poverty by contributing to the livelihood of the poor, and providing a foundation for the sustainable economic development of many countries. [...]
Leachability of Arsenic and Heavy Metals from Mine Tailings of Abandoned Metal Mines
Authors: Lim Mihee , Han Gi-Chun , Ahn Ji-Whan , You Kwang-Suk , Kim Hyung-Seok
Published: November 2009

Mine tailings from an abandoned metal mine in Korea contained high concentrations of arsenic (As) and heavy metals [e.g., As: 67,336, Fe: 137,180, Cu: 764, Pb: 3,572, and Zn: 12,420 (mg/kg)]. US EPA method 6010 was an effective method for analyzing total arsenic and heavy metals concentrations. Arsenic in the mine tailings showed a high residual fraction of 89% by a sequential extraction. In Toxicity Characteristic Leaching Procedure (TCLP) and Korean Standard Leaching Test (KSLT), leaching concentrations of arsenic and heavy metals were very low [e.g., As (mg/L): 0.4 for TCLP and 0.2 for KSLT; cf. As criteria (mg/L): 5.0 for TCLP and 1.5 for KSLT].
1,9-Bis(2-pyridyl)-1,2,8,9-tetrathia-5-oxanonane
Authors: Kalia Jeet , Raines Ronald
Published: November 2009

Disulfide crosslinking of proteins is typically performed by treating proteins bearing cysteine residues with small-molecule disulfide reagents. The process results in the formation of a mixed disulfide intermediate, which then reacts with the cysteine residue of another protein molecule to form the crosslinked product. This second step requires the intimate association of two large reactants. The ensuing steric hindrance can result in poor crosslinking yields. Here, we introduce a bis(disulfide) reagent in which activated disulfides are separated by linkers that can alleviate steric hindrance and thereby potentially increase the efficiency of crosslinking.
Inhibitory Effect of N,N-Didesmethylgrossularine-1 on Inflammatory Cytokine Production in Lipopolysaccharide-Stimulated RAW 264.7 Cells
Authors: Oda Taiko , Lee Jong-Soo , Sato Yuta , Kabe Yasuaki , Sakamoto Satoshi , Handa Hiroshi , Mangindaan Remy E. P. , Namikoshi Michio
Published: November 2009

N,N-Didesmethylgrossularine-1 (DDMG-1), a compound with a rare α-carboline structure, was isolated from an Indonesian ascidian Polycarpa aurata as responsible for the observed inhibitory activity against TNF-α production in lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells. DDMG-1 inhibited the mRNA level of mTNF-α, IκB-α degradation, and binding of NF-κB to the target DNA site in LPS-stimulated RAW 264.7 cells. Moreover, DDMG-1 had an inhibitory effect on the production of IL-8, which is produced in CD14+-THP-1 cells stimulated by LPS. DDMG-1 is thus a promising drug candidate lead compound for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis.
MODIS Hotspot Validation over Thailand
Authors: Tanpipat Veerachai , Honda Kiyoshi , Nuchaiya Prayoonyong
Published: November 2009

To ensure remote sensing MODIS hotspot (also known as active fire products or hotspots) quality and precision in forest fire control and management in Thailand, an increased level of confidence is needed. Accuracy assessment of MODIS hotspots utilizing field survey data validation is described. A quantitative evaluation of MODIS hotspot products has been carried out since the 2007 forest fire season. The carefully chosen hotspots were scattered throughout the country and within the protected areas of the National Parks and Wildlife Sanctuaries. Three areas were selected as test sites for validation guidelines. Both ground and aerial field surveys were also conducted in this study by the Forest Fire Control Division, National Park, Wildlife and Plant Conversation Department, Ministry of Natural Resources and Environment, Thailand. High accuracy of 91.84 %, 95.60% and 97.53% for the 2007, 2008 and 2009 fire seasons were observed, resulting in increased confidence in the use of MODIS hotspots for forest fire control and management in Thailand.
Electrosprayed Metal Oxide Semiconductor Films for Sensitive and Selective Detection of Hydrogen Sulfide
Authors: Ghimbeu Camelia Matei , Lumbreras Martine , Schoonman Joop , Siadat Maryam
Published: November 2009

Semiconductor metal oxide films of copper-doped tin oxide (Cu-SnO2), tungsten oxide (WO3) and indium oxide (In2O3) were deposited on a platinum coated alumina substrate employing the electrostatic spray deposition technique (ESD). The morphology studied with scanning electron microscopy (SEM) and atomic force microscopy (AFM) shows porous homogeneous films comprising uniformly distributed aggregates of nano particles. The X-ray diffraction technique (XRD) proves the formation of crystalline phases with no impurities. Besides, the Raman cartographies provided information about the structural homogeneity. Some of the films are highly sensitive to low concentrations of H2S (10 ppm) at low operating temperatures (100 and 200 °C) and the best response in terms of Rair/Rgas is given by Cu-SnO2 films (2500) followed by WO3 (1200) and In2O3 (75). Moreover, all the films exhibit no cross-sensitivity to other reducing (SO2) or oxidizing (NO2) gases.
Reporter Proteins in Whole-Cell Optical Bioreporter Detection Systems, Biosensor Integrations, and Biosensing Applications
Authors: Close Dan M. , Ripp Steven , Sayler Gary S.
Published: November 2009

Whole-cell, genetically modified bioreporters are designed to emit detectable signals in response to a target analyte or related group of analytes. When integrated with a transducer capable of measuring those signals, a biosensor results that acts as a self-contained analytical system useful in basic and applied environmental, medical, pharmacological, and agricultural sciences. Historically, these devices have focused on signaling proteins such as green fluorescent protein, aequorin, firefly luciferase, and/or bacterial luciferase. The biochemistry and genetic development of these sensor systems as well as the advantages, challenges, and common applications of each one will be discussed.
Sustainability in Agricultural Mechanization: Assessment of a Combined Photovoltaic and Electric Multipurpose System for Farmers
Authors: Mousazadeh Hossein , Keyhani Alireza , Mobli Hossein , Bardi Ugo , El Asmar Toufic
Published: November 2009

This study is dedicated to the assessment of the possibility of replacing fossil fuels with renewable energy as a source of power in modern agriculture. We examined the use of a completely sustainable agricultural mechanization system based on a renewable energy system and a battery powered, multi-purpose agricultural vehicle. This assessment is based on the RAMseS project, financed by the European Commission under the 6th Framework Program, which has led to the actual manufacturing of the system, at present being tested in Lebanon. In the present study, we assess the environmental and economic performance of the RAMseS system. We evaluate the external costs by means of a specific model that takes into account the life-cycle cost (LCC), economical indexes, and life-cycle emissions for the vehicle during its life span. The results are compared with those of a standard vehicle based on the internal combustion engine (ICEV). The results show that the RAMseS system can avoid the emission of about 23 ton of CO2equ per year. The life cycle cost (LCC) assessment using MATLAB software shows that the LCC for the RAMseS vehicle and the ICEV are the same for a fuel unit price (pf) of 1.45 €/L. Finally, we show that almost 52 % of the RAMseS LCC is due to the batteries of the electric vehicle. A 50% decrease in batteries unit cost would cause the LCC of two system to be the same at a fuel cost of 0.8 €/L. The final result is that the RAMseS system remains—at present— marginally more expensive than an equivalent system based on conventional fuels and internal combustion engines. Nevertheless, with the gradual depletion of fossil fuels, all electric agricultural mechanized system provide an alternative solution that is dependent only on renewable energy and recyclable resources.
Incorporating User Performance Criteria into Building Sustainability Rating Tools (BSRTs) for Buildings in Operation
Authors: Baird George
Published: November 2009

Current Building Sustainability Rating Tools (BSRTs) are concerned mainly with the technical features of new designs. The author argues for the inclusion of user performance criteria in BSRTs for buildings in operation. The case is based on insights gained from surveys of users of sustainable buildings worldwide, and a review of the pioneering NABERS protocol. The paper advocates the establishment of a set of user performance criteria for existing buildings, as a key ingredient in making progress towards a truly sustainable building stock as buildings that perform poorly from the users‘ point of view are unlikely to ever be sustainable.
Serum Concentrations of Interleukin 1ß, CXCL10, and Interferon-γ in Mixed Cryoglobulinemia Associated with Hepatitis C Infection
Authors: ANTONELLI ALESSANDRO , FERRI CLODOVEO , FERRARI SILVIA MARTINA , GHIRI EMILIANO , MARCHI SANTINO , SEBASTIANI MARCO , FALLAHI POUPAK
Published: November 2009

Objective.

Mixed cryoglobulinemia (MC) is a systemic vasculitis of small and medium-size vessels, often associated with the hepatitis C virus. Research has shown an emerging role for chemokines and type 1 cytokines in the pathophysiology of this vasculitis. Interleukin 1 (IL-1) plays a role in initiating the cascade of immunoinflammatory responses, and levels of the interferon-γ (IFN-γ) inducible chemokine CXCL10 have been shown to be significantly associated with the presence of active vasculitis in patients with MC. We evaluated serum levels of IL-1ß, IFN-γ, and CXCL10 in a series of patients with hepatitis C-related MC (MC+HCV), and correlated these measurements with clinical disease features.

Methods.

Serum IL-1ß, IFN-γ, and CXCL10 were assayed in 54 patients with MC+HCV, in 54 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 54 controls.

Results.

MC+HCV patients showed significantly higher mean IL-1ß and CXCL10 serum levels than controls (p < 0.01) or HCV+ patients (p < 0.01). CXCL10 was significantly increased in 14 cryoglobulinemic patients with active vasculitis (necrotizing vasculitis or vasculitic skin ulcers) compared to those without (p < 0.001); IL-1ß was increased in cryoglobulinemic patients with active vasculitis (p = 0.06). No differences were observed for serum IFN-γ levels.

Conclusion.

Serum levels of IL-1ß and CXCL10 were high in patients with MC+HCV. Increased CXCL10 and IL-1ß levels were associated with the presence of active vasculitis in MC+HCV patients.
Baseline Glucocorticoid Dose and Bone Mineral Density Response with Teriparatide or Alendronate Therapy in Patients with Glucocorticoid-induced Osteoporosis
Authors: DEVOGELAER JEAN-PIERRE , ADLER ROBERT A. , RECKNOR CHRIS , SEE KYOUNGAH , WARNER MARGARET R. , WONG MAYME , KROHN KELLY
Published: November 2009

Objective.

This post-hoc analysis studied the effect of baseline glucocorticoid dose on the 18-month bone mineral density (BMD) response to teriparatide 20μg/day or alendronate 10 mg/day in 387 patients with glucocorticoid-induced osteoporosis (GIO) from a randomized, double-blind trial.

Methods.

Lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD were measured at baseline and 18 months. Mean baseline glucocorticoid dose was categorized as low (≤ 5 mg/day), medium (> 5 and < 15 mg/day), or high (≥ 15 mg/day).

Results.

Baseline LS, FN, and TH BMD were similar between groups, and between glucocorticoid dose categories within each group. LS BMD increases at the low, medium, and high glucocorticoid doses were 8.1%, 6.6%, and 4.6%, respectively, with teriparatide, and 3.6%, 2.8%, and 2.3% with alendronate. Analyzed as a continuous variable, higher glucocorticoid doses had a negative, but non-significant, effect on the percentage increase in LS BMD in both groups. Glucocorticoid dose did not significantly affect FN or TH BMD increases in either group. Across the 3 glucocorticoid dose categories, the overall LS BMD increases were different for both treatments combined (p = 0.033), but the relative differences between the treatment groups were not different (interaction, p = 0.52).

Conclusion.

Teriparatide and alendronate increased LS and hip BMD across a range of baseline glucocorticoid doses. LS BMD increases with teriparatide were greater in the low-dose category than in the high-dose category. Overall LS BMD increases were significantly greater with teriparatide compared with alendronate, which may reflect the respective anabolic and antiresorptive mechanisms of action. Clinical Trial Registry Number: NCT00051558.
Heterogeneity Within the Fibromyalgia Population: Theoretical Implications of Variable Tender Point Severity Ratings
Authors: WILSON HILARY D. , STARZ TERENCE W. , ROBINSON JAMES P. , TURK DENNIS C.
Published: November 2009

Objective.

The American College of Rheumatology (ACR) tender point (TP) criterion is used in diagnosing fibromyalgia syndrome (FM). There has been little research investigating patterns of positive TP. We investigated response patterns of TP in a sample of patients with FM.

Methods.

Manual TP survey data were available on 1433 patients with FM. Factor analysis was conducted on ACR TP and control (CON) points. Factor scores were cluster analyzed to identify subgroups based on TP scores. Subgroups were compared on demographic and psychosocial variables.

Results.

Factor analysis resulted in 4 TP groupings: neck/shoulder girdle, gluteal/trochanteric, and upper extremity regions, and a set of CON TP. Cluster analysis revealed 3 clusters. Group 1 was high on all 3 TP regions and the CON set; Group 2 moderate on the 3 TP regions, low on the CON set; and Group 3 was relatively low on all 3 TP regions and the CON set. The group highest on the CON and TP regions reported the greatest pain (7.58 ± 1.23; p < 0.001), sleep disturbance (7.05 ± 1.61; p < 0.001), anxiety (10.14 ± 4.57; p < 0.001), and depression (8.42 ± 4.4; p < 0.001).

Conclusion.

TP severity ratings varied among cluster groups, suggesting patients with FM are not homogeneous. Variations in TP severity provide information regarding the degree to which FM affects patients’ quality of life. Patients with elevated scores on the CON TP demonstrated a general pattern reflecting lower thresholds for symptom reporting and, perhaps, disease severity. Research is needed to elucidate mechanisms underlying heterogeneity among the FM population.
Monitoring Methotrexate Toxicity in Juvenile Idiopathic Arthritis
Authors: KOCHARLA LAKSHMI , TAYLOR JANALEE , WEILER TRACEY , TING TRACY V. , LUGGEN MICHAEL , BRUNNER HERMINE I.
Published: November 2009

Objective.

To determine the frequency of laboratory abnormalities with methotrexate (MTX) use in patients with juvenile idiopathic arthritis (JIA); to identify potential risk factors for MTX toxicity requiring medical interventions; and to compare the frequency of liver function abnormalities in patients treated with MTX to those not treated with MTX.

Methods.

Results of MTX surveillance laboratory testing (SLT) available in clinical databases were reviewed for 588 children with JIA. Information on demographics, JIA features, and factors previously associated with increased frequency of SLT abnormalities was obtained.

Results.

Results of SLT performed in at least 4-month intervals were available for 138 JIA patients whose JIA was not treated with MTX, and for 198 JIA patients treated with MTX plus folic acid. On SLT of the MTX-treated patients, there were 44 of 2650 (1.7%) AST tests and 90 of 2647 (3.4%) ALT tests that exceeded 2 times the upper limit of normal (> 2 ULN) in 30 children (15%). AST or ALT tests at > 2 ULN occurred more often with systemic JIA (p = 0.04), macrophage activation syndrome, during infections, in systemic antibiotic use, and after intensifying JIA drug regimens. AST or ALT results at > 2 ULN were as frequent among MTX-treated children as those not treated with MTX. Renal and hematological abnormalities with MTX were uncommon.

Conclusion.

Liver enzyme abnormalities > 2 ULN are rare in JIA, irrespective of MTX exposure. These data suggest that the adult standard of SLT every 4–8 weeks may not be necessary in children treated with MTX, especially if certain risk factors are absent.
Calcium-Independent Phospholipase A2β-Akt Signaling Is Involved in Lipopolysaccharide-Induced NADPH Oxidase 1 Expression and Foam Cell Formation
Authors: Lee Sun-Hye , Park Dae-Weon , Park Sung Chul , Park Yun-Ki , Hong Seong Yeon , Kim Jae-Ryong , Lee Chu-Hee , Baek Suk-Hwan
Published: November 2009

Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion. This LPS-induced ROS production and foam cell formation could be abrogated by pretreatment of macrophages with N-acetyl cysteine or apocynin. LPS increased Nox1 promoter activity, and resultant expression of mRNA and protein. Small interfering RNA mediated inhibition of Nox1 expression decreased LPS-induced ROS production and foam cell formation. LPS-mediated Nox1 expression and the responses occurred in a calcium-independent phospholipase A2 (iPLA2)-dependent manner. The iPLA2β-specific inhibitor S-BEL or iPLA2β small interfering RNA attenuated LPS-induced Nox1 expression, ROS production, and foam cell formation. In addition, activation of iPLA2β by LPS caused Akt phosphorylation and was followed by increased Nox1 expression. These results suggest that the binding of LPS and TLR4 increases Nox1 expression through the iPLA2β-Akt signaling pathway, and control ROS production and foam cell formation.
Deciphering the Immune Function and Regulation by a TLR of the Cytokine EMAPII in the Lesioned Central Nervous System Using a Leech Model
Authors: Schikorski David , Cuvillier-Hot Virginie , Boidin-Wichlacz Céline , Slomianny Christian , Salzet Michel , Tasiemski Aurélie
Published: November 2009

A highly conserved ortholog of the human complex p43/endothelial monocyte-activating polypeptide II (EMAPII) was characterized in the CNS of the leech Hirudo medicinalis. As observed in mammals, the leech complex is processed to release the cytokine HmEMAPII. Taking advantages of these similarities, we have attempted to elucidate the role of EMAPII in the CNS using the leech model. Although EMAPII is considered a modulator of inflammatory reactions within the peripheral innate immune response in humans, its function in CNS immunity has yet to be described. Chemotaxis assays were conducted, revealing the ability of EMAPII to exert a chemoattractant effect on both leech and human microglial cells, indicating a novel function of this cytokine in the human brain. Quantitative RT-PCR analysis together with in situ hybridization and immunohistochemistry approaches showed that bacterial challenge induced the expression of HmEMAPII at the lesion site where microglial cells accumulated. Moreover, gene silencing experiments have demonstrated that the gene expression of HmEMAPII is under the control of a signaling pathway associated with the TLR HmTLR1, newly characterized in the CNS of our model. To the best of our knowledge, this is the first report showing evidence for (1) the chemoattractant properties of EMAPII on leech and human microglial cells, (2) the regulation by a TLR of the expression of a gene encoding a cytokine in the CNS of an invertebrate, and (3) an immune function of a TLR in a lophotrochozoan model.
Apoptotic Dendritic Cells Induce Tolerance in Mice through Suppression of Dendritic Cell Maturation and Induction of Antigen-Specific Regulatory T Cells
Authors: Kushwah Rahul , Oliver Jordan R. , Zhang Jinyi , Siminovitch Katherine A. , Hu Jim
Published: November 2009

Dendritic cell (DC) apoptosis has been shown to play a role in maintaining a balance between tolerance and immunity. However, the mechanisms of how DC apoptosis affects the immune response are unclear. We have shown that in vitro culture of apoptotic DCs with immature DCs, results in their uptake by immature DCs, which subsequently turn into tolerogenic DCs, which then secrete TGF-β1 and induce Foxp3+ regulatory T cells (Tregs). In this study we looked at the effects of apoptotic DCs in vivo. Here we show that apoptotic DCs are taken up by viable DCs in vivo, which suppresses the ability of viable DCs to undergo maturation and subsequent migration to the lymph nodes in response to LPS. Additionally, delivery of apoptotic DCs to LPS inflamed lungs results in resolution of inflammation, which is mediated by the ability of apoptotic DCs to suppress response of viable DCs to LPS. Additionally, apoptotic DCs also induce TGF-β1 secretion in the mediastinal lymph nodes, which results in expansion of Foxp3+ Tregs. Most importantly, we show that delivery of apoptotic DCs followed by OVA in CFA to mice suppresses T cell response to OVA and instead induces de novo generation of OVA-specific Tregs. Furthermore, delivery of apoptotic DCs followed by OVA in CFA results in expansion of Tregs in TCR transgenic (OT-II) mice. These findings demonstrate that apoptotic DCs are taken up by viable DCs in vivo, which promotes tolerance through suppression of DC maturation and induction of Tregs.
Dendritic Cells Matured by Inflammation Induce CD86-Dependent Priming of Naive CD8+ T Cells in the Absence of Their Cognate Peptide Antigen
Authors: Maroof Asher , Beattie Lynette , Kirby Alun , Coles Mark , Kaye Paul M.
Published: November 2009

Dendritic cells (DC) licensed by the interaction between pathogen products and pattern recognition receptors can activate naive T cells to undergo Ag-dependent proliferation and cytokine production. In contrast, DC induced to mature by trans-acting inflammatory stimuli are believed to only be capable of supporting Ag-dependent proliferative responses. In this study, we show that uninfected DC matured as a consequence of Leishmania-induced inflammation induce CD8+ T cells to proliferate in the absence of their cognate Ag. We separated splenic DC from Leishmania donovani-infected mice into those that contained parasites and had been activated to induce IL-12p40, from those that had undergone only partial maturation, measured by increased CD86 expression in the absence of IL-12p40 induction. We then showed that these partially matured DC could induce exogenous peptide-independent proliferation of OT-I and F5 CD8+ TCR transgenic T cells, as well as polyclonal CD8+ T cells. Proliferation of OT-I cells was significantly inhibited in vitro and in vivo by anti-CD86 mAb but not by anti-CD80 mAb and could also be inhibited by cyclosporine A. Proliferating OT-I cells did not produce IFN-γ, even when re-exposed to mature DC. However, these primed OT-I cells subsequently produced effector cytokines, not just on exposure to their cognate peptide but, more importantly, to weak exogenous TCR agonists that otherwise failed to induce IFN-γ. We further showed that OT-I cells undergoing locally driven proliferation to another pathogen, Streptococcus pneumoniae, rapidly seeded other lymphoid tissues, suggesting that CD8+ T cells primed in this way may play a role in rapidly countering pathogen dissemination.
Fms-Like Tyrosine Kinase 3 Ligand Regulates Migratory Pattern and Antigen Uptake of Lung Dendritic Cell Subsets in a Murine Model of Allergic Airway Inflammation
Authors: Shao Zhifei , Makinde Toluwalope O. , McGee Halvor S. , Wang Xiang , Agrawal Devendra K.
Published: November 2009

Fms-like tyrosine kinase 3 ligand (Flt3L) reverses the features of allergic airway inflammation and increases a Th2-suppressive regulatory lung CD11chighCD11blow dendritic cell (DC) subset in a mouse model. We examined the migratory pattern and Ag uptake efficiency of lung DC subsets in the therapeutic effect of Flt3L. Lung CD11chighCD11blow and CD11clowCD11bhigh DCs from PBS-treated, OVA-sensitized, and Flt3L-treated/OVA-sensitized BALB/c mice were sorted using MACS and FACS for phenotype analysis. Lymphatic chemokine expression in thoracic lymph nodes was determined by immunohistochemistry. Migration of two lung DC subsets to lymphatic chemokines was examined in vitro using a Transwell chemotaxis assay. Labeled Ag was intranasally delivered into mouse lung to track the migration and Ag uptake of lung DCs. The in vitro cytokine secretion of mediastinal lymph node cells was determined using ELISA. CD11clowCD11bhigh DCs have higher expression of CCR5, CCR6, and CCR7, but lower expression of CCR2 than CD11chighCD11blow DCs. CD11clowCD11bhigh DCs in Flt3L-treated/OVA-sensitized mice demonstrated a less mature phenotype, inefficiency in Ag uptake, and impaired migration in vitro to lymphatic chemokine than those in OVA-sensitized mice. Administration of Flt3L decreased the expression of CCR5 and CCR7 in CD11clowCD11bhigh DCs in OVA-sensitized mice. Fewer Ag-carrying cells were detected in the lungs and lymph nodes in Flt3L-treated/OVA-sensitized mice than OVA-sensitized mice with a greater decrease in CD11clowCD11bhigh DCs. Mediastinal lymph node cells from Flt3L-treated mice secreted higher levels of Th1 cytokines and IL-10 than OVA-sensitized mice in vitro. In conclusion, Flt3L-generated lung immunogenic CD11clowCD11bhigh DCs have a less mature phenotype, impaired Ag uptake, and impaired migration to draining lymph nodes.
The Oxazolidinone Derivative Locostatin Induces Cytokine Appeasement
Authors: Ménoret Antoine , McAleer Jeremy P. , Ngoi Soo-Mun , Ray Swagatam , Eddy Nicholas A. , Fenteany Gabriel , Lee Seung-Joo , Rossi Robert J. , Mukherji Bijay , Allen David L. , Chakraborty Nitya G. , Vella Anthony T.
Published: November 2009

Damaging inflammation arising from autoimmune pathology and septic responses results in severe cases of disease. In both instances, anti-inflammatory compounds are used to limit the excessive or deregulated cytokine responses. We used a model of robust T cell stimulation to identify new proteins involved in triggering a cytokine storm. A comparative proteomic mining approach revealed the differential mapping of Raf kinase inhibitory protein after T cell recall in vivo. Treatment with locostatin, an Raf kinase inhibitory protein inhibitor, induced T cell anergy by blocking cytokine production after Ag recall. This was associated with a reduction in Erk phosphorylation. Importantly, in vivo treatment with locostatin profoundly inhibited TNF-α production upon triggering the Ag-specific T cells. This effect was not limited to a murine model because locostatin efficiently inhibited cytokine secretion by human lymphocytes. Therefore, locostatin should be a useful therapeutic to control inflammation, sepsis, and autoimmune diseases.
Neonatal Innate TLR-Mediated Responses Are Distinct from Those of Adults
Authors: Kollmann Tobias R. , Crabtree Juliet , Rein-Weston Annie , Blimkie Darren , Thommai Francis , Wang Xiu Yu , Lavoie Pascal M. , Furlong Jeff , Fortuno Edgardo S. , Hajjar Adeline M. , Hawkins Natalie R. , Self Steven G. , Wilson Christopher B.
Published: November 2009

The human neonate and infant are unduly susceptible to infection with a wide variety of microbes. This susceptibility is thought to reflect differences from adults in innate and adaptive immunity, but the nature of these differences is incompletely characterized. The innate immune response directs the subsequent adaptive immune response after integrating information from TLRs and other environmental sensors. We set out to provide a comprehensive analysis defining differences in response to TLR ligation between human neonates and adults. In response to most TLR ligands, neonatal innate immune cells, including monocytes and conventional and plasmacytoid dendritic cells produced less IL-12p70 and IFN-α (and consequently induced less IFN-γ), moderately less TNF-α, but as much or even more IL-1β, IL-6, IL-23, and IL-10 than adult cells. At the single-cell level, neonatal innate cells generally were less capable of producing multiple cytokines simultaneously, i.e., were less polyfunctional. Overall, our data suggest a robust if not enhanced capacity of the neonate vs the adult white-blood cell TLR-mediated response to support Th17- and Th2-type immunity, which promotes defense against extracellular pathogens, but a reduced capacity to support Th1-type responses, which promote defense against intracellular pathogens.