bluuebunny/crossref_metadata_2025 huggingface dataset:
The Latest on Volcanic Eruptions and Climate
Authors: Robock Alan
Published: August 2013

What was the largest volcanic eruption on Earth since the historic Mount Pinatubo eruption on 15 June 1991? Was the Toba super­eruption 74,000 years ago—the largest in the past 100,000 years—responsible for a human genetic bottleneck or a 1000‐year‐long glacial advance? What role did small volcanic eruptions play in the reduced global warming of the past decade? What caused the Little Ice Age? Was the April 2010 Eyjafjallajökull eruption in Iceland important for climate change? What do volcanic eruptions teach us about new ideas on geoengineering and nuclear winter? These are some of the questions that have been answered since the review article by Robock [2000]. Reviews by Forster et al. [2007] and Timmreck [2012] go into some of these topics in much greater detail.
Introduction to Planetary Geomorphology
Authors: Farr Tom G.
Published: August 2013

The planets and moons of our solar system offer a diverse collection of landscapes shaped by geologic processes that are generally familiar to our terrestrial experience. Over the past few decades, spacecraft and astronauts have visited them all, and scientists have begun to create a consistent framework with which to classify and understand their formation and evolution. The principles of geomorphology, once exclusively bound to Earth, can now be applied to these bodies, based on the detailed images and other data collected. While we must always resist a terrestrial bias, basic processes we observe on Earth, such as volcanism, tectonism, impacts, erosion, and deposition, create and modify the landscapes we see throughout the solar system.
Clouds' effects on daily temperature
Authors: Balcerak Ernie
Published: August 2013

Clouds reflect some incoming sunlight, tending to cool Earth's surface, but they also trap some heat leaving Earth's surface, causing warming. These effects, known as cloud radiative forcing, play a key role in temperature variations on Earth's surface and thus are important for climate modeling.
Younger sediments more likely to be eroded by meandering rivers
Authors: Schult Colin
Published: August 2013

The duration of the journey that an individual grain of sand takes as it bounces its way down the length of a river is incredibly difficult, if not impossible, to determine. Finding the answer to that question could be useful because the amount of time that sediment spends in a river can affect how pollutants or other materials move through the system. At the bulk scale, sediment balance measurements, comparing the inputs and outflows of sediment, can be used to help calculate how much sediment is moving through a waterway. Figuring out the storage time of particular grains is more difficult because in meandering rivers individual grains of sediment deposited along the banks may be subsequently eroded years or even millennia later—whenever the river meanders back to where the sediment was deposited. Being able to calculate the total trip times of particular bits of sediment means being able to properly model this long‐term deposition‐storage mechanism.
Phase III Study of the Efficacy and Safety of Subcutaneous Versus Intravenous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis
Authors: Ogata Atsushi , Tanimura Kazuhide , Sugimoto Toyohiko , Inoue Hiroshi , Urata Yukitomo , Matsubara Tsukasa , Kondo Masakazu , Ueki Yukitaka , Iwahashi Mitsuhiro , Tohma Shigeto , Ohta Shuji , Saeki Yukihiko , Tanaka Toshio ,   the Musashi Study Investigators
Published: August 2013

Objective

To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ‐SC) monotherapy to intravenous TCZ infusion (TCZ‐IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease‐modifying antirheumatic drugs (DMARDs).

Methods

This study had a double‐blind, parallel‐group, double‐dummy, comparative phase III design. Patients were randomized to receive TCZ‐SC 162 mg every 2 weeks or TCZ‐IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study. The primary end point was to evaluate the noninferiority of TCZ‐SC to TCZ‐IV regarding the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20) response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic, and immunogenicity parameters were assessed.

Results

At week 24, ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZ‐SC group and in 88.5% (95% CI 83.4, 93.5) of the TCZ‐IV group; the weighted difference was −9.4% (95% CI −17.6, −1.2), confirming the noninferiority of TCZ‐SC to TCZ‐IV. Remission rates of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and the Clinical Disease Activity Index at week 24 were 49.7% and 16.4% in the TCZ‐SC group and 62.2% and 23.1% in the TCZ‐IV group, respectively. Serum trough TCZ concentrations were similar between the groups over time. Incidences of all adverse events and serious adverse events were 89.0% and 7.5% in the TCZ‐SC group and 90.8% and 5.8% in the TCZ‐IV group, respectively. Anti‐TCZ antibodies were detected in 3.5% of the TCZ‐SC group; no serious hypersensitivity was reported in these patients.

Conclusion

TCZ‐SC monotherapy demonstrated comparable efficacy and safety to TCZ‐IV monotherapy. TCZ‐SC could provide additional treatment options for patients with RA.
Epidemiology of Primary Sjögren's Syndrome in a French Multiracial/Multiethnic Area
Authors: Maldini Carla , Seror Raphaèle , Fain Olivier , Dhote Robin , Amoura Zahir , De Bandt Michel , Delassus Jean‐Luc , Falgarone Géraldine , Guillevin Loïc , Le Guern Véronique , Lhote François , Meyer Olivier , Ramanoelina Jacky , Sacré Karim , Uzunhan Yurdagul , Leroux Jean‐Louis , Mariette Xavier , Mahr Alfred
Published: August 2013

Objective

To describe the epidemiology of primary Sjögren's syndrome (SS) in a multiracial/multiethnic population.

Methods

A cross‐sectional study with 5 case‐retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American–European Consensus Group (AECG) criteria and study‐specific enlarged criteria based on the presence of ≥3 of 4 AECG items among subjective oral or ocular dryness, anti‐SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5‐source capture–recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated.

Results

In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85–1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30–1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ∼90%. Compared to subjects with European backgrounds, those with non‐European backgrounds had 2.1–2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti‐SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively).

Conclusion

The figure of 1.02–1.52 cases per 10,000 adults we found and estimates from the few other population‐based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 people (0.01–0.9%) in the general population. Non‐European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile.
Low‐ Versus High‐Dose Rituximab for Rheumatoid Arthritis: A Systematic Review and Meta‐Analysis
Authors: Bredemeier Markus , de Oliveira Fernando K. , Rocha Cláudia M.
Published: August 2013

Objective

The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 × 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower‐dose regimen (2 × 500 mg) of RTX. Our aim was to compare the efficacy and safety of low‐ and high‐dose RTX and to test the noninferiority of the low‐dose regimen.

Methods

A systematic literature review searching for randomized controlled trials (RCTs) and cohort studies comparing low‐ and high‐dose RTX for RA was conducted using the Embase, PubMed, Cochrane Library, and Web of Science databases. The primary end points were the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70 responses and the Disease Activity Score in 28 joints (DAS28) at 24 and 48 weeks. The secondary end points were patient‐reported outcomes (PROs; Health Assessment Questionnaire, Short Form 36, and Functional Assessment of Chronic Illness Therapy–Fatigue scores) and adverse events. Noninferiority of low‐dose RTX was tested using different approaches, one of which was based on the fixed margin method.

Results

In total, 6 RCTs and 2 cohort studies were identified. Four RCTs were included in the meta‐analysis of efficacy outcomes, which showed no significant differences in the primary outcomes between low‐ and high‐dose RTX. Noninferiority criteria of low‐dose RTX were met for the ACR20, ACR50, DAS28, and PROs (at 24 and 48 weeks). Serious adverse events did not differ significantly. The results of 2 additional RCTs and a meta‐analysis of 2 cohort studies corroborated the results of the meta‐analysis of RCTs.

Conclusion

Low‐dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for RA.
Determinants of Health‐Related Quality of Life in Children Newly Diagnosed With Juvenile Idiopathic Arthritis
Authors: Seid Michael , Huang Bin , Niehaus Stacey , Brunner Hermine I. , Lovell Daniel J.
Published: August 2013

Objective

To examine the degree to which nonmedical factors explain additional variance in parent proxy report and child self‐report of health‐related quality of life (HRQOL) among newly diagnosed children with juvenile idiopathic arthritis (JIA) after accounting for medical factors.

Methods

Parents (of children ages 2–16 years; n = 230) and patients (ages >5 years; n = 180) diagnosed within the previous 6 months completed surveys to assess medical (clinical parameters and functional status) and nonmedical (self‐efficacy, coping, barriers to adherence, social support, parental distress, and access to care) factors and HRQOL (Pediatric Quality of Life Inventory Generic Core Scales). Physician‐rated global assessment of disease activity, active joint count, and select laboratory variables (rheumatoid factor, antinuclear antibodies, and erythrocyte sedimentation rate) were recorded.

Results

Nonmedical factors, including self‐efficacy, coping with pain, barriers to adherence, social support, and parental distress, explained additional variance in HRQOL total, physical functioning, and psychosocial functioning scales (R2 increases of 6%, 1%, and 13% for parent proxy report and 16%, 7%, and 30% for self‐report, respectively). Parental distress was uniquely associated with parent proxy‐report HRQOL, while child self‐efficacy and social support were uniquely associated with self‐report HRQOL.

Conclusion

Nonmedical factors are associated with HRQOL in newly diagnosed patients with JIA after accounting for medical variables, particularly for psychosocial functioning.
Meeting Physical Activity Guidelines and the Risk of Incident Knee Osteoarthritis: A Population‐Based Prospective Cohort Study
Authors: Barbour K. E. , Hootman J. M. , Helmick C. G. , Murphy L. B. , Theis Kristina A. , Schwartz T. A. , Kalsbeek W. D. , Renner J. B. , Jordan J. M.
Published: August 2013

Objective

Knee osteoarthritis (OA) is a leading cause of disability and joint pain. Although other risk factors of knee OA have been identified, how physical activity affects incident knee OA remains unclear.

Methods

Using data from the first (1999–2004) and second (2005–2010) followup periods of the Johnston County Osteoarthritis Project study, we tested the association between meeting physical activity guidelines and incident knee outcomes among 1,522 adults ages ≥45 years. The median followup time was 6.5 years (range 4.0–10.2 years). Physical activity at baseline (moderate‐equivalent physical activity minutes/week) was calculated using the Minnesota Leisure Time Physical Activity questionnaire. Incident knee radiographic OA (ROA) was defined as the development of Kellgren/Lawrence grade ≥2 in a knee at followup. Incident knee symptomatic ROA (sROA) was defined as the development of ROA and symptoms in at least 1 knee at followup. Weibull regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for interval‐censored data.

Results

In multivariable models, meeting the 2008 Department of Health and Human Services (HHS) physical activity guidelines (≥150 minutes/week) was not significantly associated with ROA (HR 1.20 [95% CI 0.92–1.56]) or sROA (HR 1.24 [95% CI 0.87–1.76]). Adults in the highest level (≥300 minutes/week) of physical activity had a higher risk of knee ROA and sROA compared with inactive (0 to <10 minutes/week) participants; however, these associations were not statistically significant (HR 1.62 [95% CI 0.97–2.68] and HR 1.42 [95% CI 0.76–2.65], respectively).

Conclusion

Meeting the HHS physical activity guidelines was not associated with incident knee ROA or sROA in a cohort of middle‐aged and older adults.
Response Rates of Three Modes of Survey Administration and Survey Preferences of Rheumatoid Arthritis Patients
Authors: Garcia Ivett , Portugal Cecilia , Chu Li‐Hao , Kawatkar Aniket A.
Published: August 2013

Objective

To compare survey response rates and preferences for 3 modes of survey administration in rheumatoid arthritis (RA) patients.

Methods

Adult RA patients were identified from Kaiser Permanente Southern California's electronic medical records. One hundred patients each were randomly assigned to telephone, mail with followup letter, and mail with followup telephone call as modes of survey administration. Respondents completed a 7‐page survey (in English or Spanish) that included the Health Assessment Questionnaire disability index and pain scale, EuroQol 5‐dimensions, and generic questions on preferences and sociodemographics. Response rates were based on the number of completed surveys received from the total number of patients contacted (n = 295; 5 were ineligible).

Results

The mean ± SD age of the cohort was 61 ± 12.3 years, with the majority being women (141 [85%] of 166). Of the 3 modes of survey administration, telephone (63 [64%] of 99) had the highest response rate, followed by mail with followup telephone call (55 [56%] of 98) and mail with followup letter (48 [49%] of 98). When asked about preference over administration mode, 57% (95 of 166) preferred to complete the survey by mail, followed by telephone (27 [16%] of 166) and internet (17 [10%] of 166).

Conclusion

When asked about their choice of survey administration mode for reporting their health status, the majority of RA patients in this study had a strong preference for a mail survey as compared to a telephone interview. However, the response rate in the telephone administration mode of survey was the highest between the 3 modes of administration that were compared. Future studies in RA can achieve better response using telephone over mail‐in surveys.
Clinical Characteristics of Children With Juvenile Dermatomyositis: The Childhood Arthritis and Rheumatology Research Alliance Registry
Authors: Robinson Angela Byun , Hoeltzel Mark F. , Wahezi Dawn M. , Becker Mara L. , Kessler Elizabeth A. , Schmeling Heinrike , Carrasco Ruy , Huber Adam M. , Feldman Brian M. , Reed Ann M. ,   the Juvenile Myositis CARRA Subgroup, for the CARRA Registry Investigators
Published: August 2013

Objective

To investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry.

Methods

Subjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross‐sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment.

Results

A total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46–52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0–0.5), and the median physician and subject global assessment scores were 1 (IQR 0–2) and 1 (IQR 0–3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had ≥2 diagnostic studies performed, and >34% of these subjects reported ≥1 negative study. Ninety‐five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US.

Conclusion

In 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM.
Complementary and Alternative Medicine Use in African Americans With Rheumatoid Arthritis
Authors: Tamhane Ashutosh , McGwin Gerald , Redden David T. , Hughes Laura B. , Brown Elizabeth E. , Westfall Andrew O. , Conn Doyt L. , Jonas Beth L. , Smith Edwin A. , Brasington Richard D. , Moreland Larry W. , Bridges S. Louis , Callahan Leigh F.
Published: August 2013

Objective

Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.

Methods

Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t‐test, Wilcoxon's rank sum test, chi‐square test, and logistic regression analyses.

Results

Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio ≥2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.

Conclusion

CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
Rapid Prototyping of Concave Microwells for the Formation of 3D Multicellular Cancer Aggregates for Drug Screening
Authors: Tu Ting‐Yuan , Wang Zhe , Bai Jing , Sun Wei , Peng Weng Kung , Huang Ruby Yun‐Ju , Thiery Jean‐Paul , Kamm Roger D.
Published: August 2013

Microwell technology has revolutionized many aspects of in vitro cellular studies from 2D traditional cultures to 3D in vivo‐like functional assays. However, existing lithography‐based approaches are often costly and time‐consuming. This study presents a rapid, low‐cost prototyping method of CO2laser ablation of a conventional untreated culture dish to create concave microwells used for generating multicellular aggregates, which can be readily available for general laboratories. Polymethylmethacrylate (PMMA), polydimethylsiloxane (PDMS), and polystyrene (PS) microwells are investigated, and each produces distinctive microwell features. Among these three materials, PS cell culture dishes produce the optimal surface smoothness and roundness. A549 lung cancer cells are grown to form cancer aggregates of controllable size from ≈40 to ≈80 μm in PS microwells. Functional assays of spheroids are performed to study migration on 2D substrates and in 3D hydrogel conditions as a step towards recapitulating the dissemination of cancer cells. Preclinical anti‐cancer drug screening is investigated and reveals considerable differences between 2D and 3D conditions, indicating the importance of assay type as well as the utility of the present approach.
Molecular and thermodynamic basis for EGCG‐Keratin interaction‐part I: Molecular dynamics simulations
Authors: Marzinek Jan K. , Lian Guoping , Marzinek Jan K. , Mantalaris Athanasios , Pistikopoulos Efstratios N. , Zhao Yanyan , Han Lujia , Chen Longjian , Bond Peter J. , Noro Massimo G.
Published: August 2013

Nonspecific binding of small molecules to proteins influences transdermal permeation and intestinal absorption, yet understanding of the molecular and thermodynamic basis is still limited. In this study, we report all‐atom, fully solvated molecular dynamics simulations of the thermodynamic characteristics of epigallocatechin‐3‐gallate (EGCG) binding keratin. Experimental validation is reported in Part II. Herein, 18 µs of simulation sampling was calculated. We show that the binding process is a combination of hydrophobic interaction, hydrogen bonding and aromatic interaction. The umbrella sampling technique was used to calculate the binding free energy of EGCG with keratin segments. By extracting EGCG from the keratin‐EGCG complex using steered molecular dynamics, the rupture force was observed to be linearly related to the binding free energy. Multilayer binding of EGCG clusters to keratin has been shown. The binding free energy of −6.2 kcal mol−1 obtained from the simulations was in excellent agreement with the experimental Part II. © 2013 American Institute of Chemical Engineers AIChE J, 59: 4816–4823, 2013
Functionalized assembly of solid membranes for chiral separation using polyelectrolytes and chiral ionic liquid
Authors: Meng Hong , Li Sumin , Xiao Ling , Li Chunxi
Published: August 2013

The successful assembly of a new solid membrane for chiral separation, assembled via the formation of complexes of a polyelectrolyte and β‐cyclodextrins chiral ionic liquid (β‐CD‐IL) is presented. Before the assembly, the β‐CD‐IL, used as a chiral selector, was synthesized and characterized by1H NMR. To tune the chiral separation capability of the solid membrane, β‐CD‐IL was subsequently immobilized on to porous supporting membranes through layer‐by‐layer assembly of the β‐CD‐IL and polyelectrolytes. The resulting membrane was used in the chiral separation of D, L‐tryptophan racemate enantiomer. The membrane structure and surface morphologies were systematically analyzed by FT‐IR, UV–vis, SEM and AFM. The effects of layer number on the chiral separation were investigated. It was found that the more β‐CD‐IL was immobilized on the membranes; the higher average separation factor could be obtained. The stability of the multilayer membrane was improved by coating with crosslinked polymer layer. © 2013 American Institute of Chemical EngineersAIChE J, 59: 4772–4779, 2013
Deletion of the Transforming Growth Factor β Receptor Type II Gene in Articular Chondrocytes Leads to a Progressive Osteoarthritis‐like Phenotype in Mice
Authors: Shen Jie , Li Jia , Wang Baoli , Jin Hongting , Wang Meina , Zhang Yejia , Yang Yunzhi , Im Hee‐Jeong , O'Keefe Regis , Chen Di
Published: August 2013

Objective

While transforming growth factor β (TGFβ) signaling plays a critical role in chondrocyte metabolism, the TGFβ signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFβ signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling.

Methods

TGFβ receptor type II (TGFβRII)–conditional knockout (KO) (TGFβRIICol2ER) mice were generated by breeding TGFβRIIflox/flox mice with Col2‐CreER–transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFβ signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFβ signaling, TGFβRII/matrix metalloproteinase 13 (MMP‐13)– and TGFβRII/ADAMTS‐5–double‐KO mice were generated and analyzed.

Results

Inhibition of TGFβ signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up‐regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFβRIICol2ER mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA‐like phenotype induced by the loss of TGFβ signaling. Treatment of TGFβRIICol2ER mice with an MMP‐13 inhibitor also slowed OA progression.

Conclusion

Mmp13 and Adamts5 are critical downstream target genes involved in the TGFβ signaling pathway during the development of OA.
Local Synovial Engagement of Angiogenic TIE‐2 Is Associated With the Development of Persistent Erosive Rheumatoid Arthritis in Patients With Early Arthritis
Authors: van de Sande Marleen G. H. , de Launay Daphne , de Hair Maria J. H. , García Samuel , van de Sande Gijs P. M. , Wijbrandts Carla A. , Gerlag Danielle M. , Reedquist Kris A. , Tak Paul P.
Published: August 2013

Objective

To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis.

Methods

Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease‐modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang‐1), Ang‐2, TIE‐2, and activated p–TIE‐2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang‐1, and Ang‐2 were measured by enzyme‐linked immunosorbent assay. Secreted products of macrophages stimulated with Ang‐1 and Ang‐2 were measured using a multiplex system.

Results

Expression of Ang‐1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE‐2 and p–TIE‐2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang‐1 significantly enhanced the tumor necrosis factor–dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE‐2 activation predicted the development of erosive disease (R2 = 0.35, P < 0.05).

Conclusion

Local engagement of synovial TIE‐2 is observed during the earliest phases of RA, suggesting that TIE‐2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE‐2 signaling may be useful in improving outcome in arthritis.
Role of Fms‐like Tyrosine Kinase 3 Ligand as a Potential Biologic Marker of Lymphoma in Primary Sjögren's Syndrome
Authors: Tobón Gabriel J. , Saraux Alain , Gottenberg Jacques‐Eric , Quartuccio Luca , Fabris Martina , Seror Raphaèle , Devauchelle‐Pensec Valérie , Morel Jacques , Rist Stéphanie , Mariette Xavier , De Vita Salvatore , Youinou Pierre , Pers Jacques‐Olivier
Published: August 2013

Objective

Patients with primary Sjögren's syndrome (SS) are at greater risk of developing lymphoma. This study was undertaken to evaluate whether the Fms‐like tyrosine kinase 3 ligand (Flt‐3L) might be associated with lymphoma in primary SS.

Methods

Serum levels of Flt‐3L were measured in 369 patients with primary SS from the French Assessment of Systemic Signs and Evolution of Sjögren's Syndrome study cohort and in 10 patients with primary SS at the time of lymphoma diagnosis in an Italian cohort. Associations between increased levels of Flt‐3L and a history of lymphoma, history of previously diagnosed criteria related to a high risk of lymphoma, and greater extent of disease activity were evaluated.

Results

Among patients with primary SS, higher levels of Flt‐3L were significantly associated with a history of lymphoma (P = 0.0001). Previous markers for risk of lymphoma development, such as presence of purpura, low levels of C4, presence of lymphocytopenia, low levels of IgM, high levels of β2‐microglobulin, and a higher primary SS disease activity score, were all associated with higher levels of Flt‐3L. The levels of Flt‐3L were also increased in serum obtained from patients with primary SS at the time of lymphoma diagnosis. Furthermore, the Flt‐3L levels were elevated in the serum of 6 patients up to 94 months (mean 46 months) prior to the diagnosis of lymphoma. Receiver operating characteristic curve analysis showed that an Flt‐3L level of 175 pg/ml was the ideal cutoff value for demonstrating an association with lymphoma (specificity 97.5%, sensitivity 44%, negative predictive value 97%).

Conclusion

Flt‐3L is associated with lymphoma in primary SS, and constitutes a good biologic marker. Higher levels of this cytokine are present several years before the diagnosis of lymphoma, and may be useful as a predictive marker of lymphoproliferative disorders in primary SS.
The Peroxisome Proliferator–Activated Receptor γ Agonist Pioglitazone Preserves Bone Microarchitecture in Experimental Arthritis by Reducing the Interleukin‐17–Dependent Osteoclastogenic Pathway
Authors: Koufany Meriem , Chappard Daniel , Netter Patrick , Bastien Claire , Weryha Georges , Jouzeau Jean‐Yves , Moulin David
Published: August 2013

Objective

To investigate the effect of pioglitazone on inflammation‐induced bone loss and changes in bone microarchitecture in rats with adjuvant‐induced arthritis (AIA), focusing on the contribution of interleukin‐17 (IL‐17) and the balance of RANKL and osteoprotegerin (OPG).

Methods

Male Lewis rats sensitized with Freund's complete adjuvant were treated orally for 21 days with 30 mg/kg/day of pioglitazone or vehicle. Arthritis severity was evaluated by clinical and histologic examination. Bone mineral density (BMD) was assessed by dual x‐ray absorptiometry. The therapeutic effect of pioglitazone on changes of the bone architecture was determined by micro–computed tomography (micro‐CT). Levels of RANKL, OPG, and IL‐17 were determined by serum immunoassay and by synovial tissue immunohistochemistry. Messenger RNA for IL‐17 and retinoic acid receptor–related orphan nuclear receptor γt (RORγt) was evaluated by quantitative reverse transcription–polymerase chain reaction and IL‐17 promoter activity by gene‐reporter assay.

Results

Micro‐CT analysis revealed that pioglitazone treatment reduced arthritis severity and bone erosion scores and increased BMD in comparison to vehicle treatment. Cortical bone thickness was preserved, although the major beneficial effect of pioglitazone was on indices of the trabeculae, especially trabecular separation. Pioglitazone reduced the ratio of RANKL to OPG, in both the serum and the inflamed synovium. Circulating levels of IL‐17 were significantly reduced by pioglitazone treatment, as were the percentages of IL‐17–positive cells, mainly polymorphonuclear cells, in the inflamed synovium. Induction of IL‐17 was strictly dependent on the binding of RORγt to IL‐17 promoter, and lentiviral overexpression of peroxisome proliferator–activated receptor γ (PPARγ) reduced the expression of RORγt.

Conclusion

Pioglitazone decreased the level of inflammatory bone destruction and protected the bone microarchitecture in rats with AIA by controlling the circulating and local expression of IL‐17, with a subsequent decrease in the RANKL‐to‐OPG ratio. Along with the inhibition of RORγt expression after PPARγ overexpression, these findings provide evidence of the major contribution of reduced IL‐17/RANKL‐dependent osteoclastogenesis.
Sulforaphane Represses Matrix‐Degrading Proteases and Protects Cartilage From Destruction In Vitro and In Vivo
Authors: Davidson Rose K. , Jupp Orla , de Ferrars Rachel , Kay Colin D. , Culley Kirsty L. , Norton Rosemary , Driscoll Clare , Vincent Tonia L. , Donell Simon T. , Bao Yongping , Clark Ian M.
Published: August 2013

Objective

Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis.

Methods

Gene expression, histone acetylation, and signaling of the transcription factors NF‐E2–related factor 2 (Nrf2) and NF‐κB were examined in vitro. The bovine nasal cartilage explant model and the destabilization of the medial meniscus (DMM) model of osteoarthritis in the mouse were used to assess chondroprotection at the tissue and whole‐animal levels.

Results

SFN inhibited cytokine‐induced metalloproteinase expression in primary human articular chondrocytes and in fibroblast‐like synovial cells. SFN acted independently of Nrf2 and histone deacetylase activity to regulate metalloproteinase expression in human articular chondrocytes but did mediate prolonged activation of JNK and p38 MAPK. SFN attenuated NF‐κB signaling at least through inhibition of DNA binding in human articular chondrocytes, with decreased expression of several NF‐κB–dependent genes. Compared with cytokines alone, SFN (10 μM) abrogated cytokine‐induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. An SFN‐rich diet (3 μmoles/day SFN versus control chow) decreased the arthritis score in the DMM model of osteoarthritis in the mouse, with a concurrent block of early DMM‐induced gene expression changes.

Conclusion

SFN inhibits the expression of key metalloproteinases implicated in osteoarthritis, independently of Nrf2, and blocks inflammation at the level of NF‐κB to protect against cartilage destruction in vitro and in vivo.
A Novel p53/microRNA‐22/Cyr61 Axis in Synovial Cells Regulates Inflammation in Rheumatoid Arthritis
Authors: Lin Jinpiao , Huo Rongfen , Xiao Lianbo , Zhu Xianjin , Xie Jun , Sun Songtao , He Yong , Zhang Jie , Sun Yue , Zhou Zhou , Wu Pinru , Shen Baihua , Li Dangsheng , Li Ningli
Published: August 2013

Objective

We previously showed that Cyr61 acts to promote fibroblast‐like synoviocyte (FLS) proliferation and Th17 cell differentiation, suggesting that Cyr61 plays an important role in mediating the joint inflammation and damage in rheumatoid arthritis (RA). The aim of this study was to investigate whether Cyr61 expression is regulated at the posttranscription level, and if so, how this regulation connects to other etiologic factors in RA.

Methods

Expression of microRNA‐22 (miR‐22) in synovial tissue was detected by real‐time polymerase chain reaction (PCR) using miRNA‐specific TaqMan MGB probes. MicroRNA‐22 promoter activity was analyzed using a Dual‐Luciferase Reporter Assay. Cytokine expression was measured by enzyme‐linked immunosorbent assay, and the expression of other factors was measured by real‐time PCR or Western blotting.

Results

MicroRNA‐22 directly targeted the 3′‐untranslated region of Cyr61 messenger RNA and inhibited Cyr61 expression. Expression of miR‐22 was down‐regulated and was negatively correlated with Cyr61 expression in RA synovial tissue. Furthermore, wild‐type p53 activated miR‐22 transcription by binding to the promoter region of the miR‐22 gene, while the mutant forms of p53 frequently found in RA synovial tissue were shown to have lost the ability to activate miR‐22 expression. As a result, miR‐22 was down‐regulated, contributing to the overexpression of Cyr61 in RA FLS.

Conclusion

Our results not only reveal a novel mechanism whereby p53 is involved in the posttranscriptional regulation of Cyr61 expression via miRNA‐22, but also provide a molecular explanation for the role of somatic mutations of p53, which are frequently observed in RA synovial tissue, in the etiology of this autoimmune disease.
Chronic Kidney Disease and the Risk of Incident Gout Among Middle‐Aged Men: A Seven‐Year Prospective Observational Study
Authors: Krishnan Eswar
Published: August 2013

Objective

The kidney is the major organ that facilitates excretion of urate in humans. Surprisingly, few studies have assessed whether a reduced glomerular filtration rate (GFR) and/or kidney damage is associated with a higher incidence of gout, and this study was undertaken to address this question.

Methods

Data from a 7‐year followup of patients enrolled in the Multiple Risk Factor Intervention Trial, a primary prevention trial for cardiovascular disease among 12,866 men ages 35–57 years, were used for the present investigation. Presence of gout was determined by the study physicians from the original trial. Chronic kidney disease was defined using criteria similar to those proposed by the National Kidney Foundation. The Cox proportional hazards regression model was used to assess the association between gout and chronic kidney disease, after accounting for the effects of potential confounders.

Results

Overall, there were 722 cases of physician‐ diagnosed incident gout over 76,602 person‐years of followup. The standardized incidence ratio of gout among those with chronic kidney disease was 1,217 (95% confidence interval [95% CI] 1,191–1,244). The adjusted hazard ratio (HR) among those with chronic kidney disease was 1.61 (95% CI 1.60–1.61). Each standard deviation decline in the estimated GFR was associated with an HR of 1.43 (95% CI 1.35–1.51). Including the serum urate level, as well as the urate–chronic kidney disease interaction term, as variables in the second analysis did not attenuate the HR. Proteinuria and hematuria, two markers of kidney damage, were associated with an elevated risk of gout independent of the estimated GFR.

Conclusion

Chronic kidney disease manifesting as reduced glomerular function or as presence of blood or protein in the urine increases the risk of incident gout.
A passage extractor for classification of disease aspect information
Authors: Liu Rey‐Long
Published: August 2013

Retrieval of disease information is often based on several key aspects such as etiology, diagnosis, treatment, prevention, and symptoms of diseases. Automatic identification of disease aspect information is thus essential. In this article, I model the aspect identification problem as a text classification (TC) problem in which a disease aspect corresponds to a category. The disease aspect classification problem poses two challenges to classifiers: (a) a medical text often contains information about multiple aspects of a disease and hence produces noise for the classifiers and (b) text classifiers often cannot extract the textual parts (i.e., passages) about the categories of interest. I thus develop a technique, PETC (Passage Extractor for Text Classification), that extracts passages (from medical texts) for the underlying text classifiers to classify. Case studies on thousands of Chinese and English medical texts show that PETC enhances a support vector machine (SVM) classifier in classifying disease aspect information. PETC also performs better than three state‐of‐the‐art classifier enhancement techniques, including two passage extraction techniques for text classifiers and a technique that employs term proximity information to enhance text classifiers. The contribution is of significance to evidence‐based medicine, health education, and healthcare decision support. PETC can be used in those application domains in which a text to be classified may have several parts about different categories.
Stabilization of the Triphosphallyl Ligand η3‐P3{P(O)H} at Iridium via Alkaline Activation of P4
Authors: Mirabello Vincenzo , Caporali Maria , Gonsalvi Luca , Manca Gabriele , Ienco Andrea , Peruzzini Maurizio
Published: August 2013

The selective functionalization of the polyphosphorus moiety Ph2PCH2PPh2PPPP present as a tetrahapto‐ligand in complex [Ir(dppm)(Ph2PCH2PPh2PPPP)]+ (1, dppm=Ph2PCH2PPh2) was obtained by reaction of 1 with water under basic conditions at room temperature. The formation of the new triphosphaallyl moiety η3‐P3{P(O)H} was determined in solution by NMR spectroscopy, and confirmed in the solid state by a single‐crystal X‐ray structure of the stable product [Ir(κ2‐dppm)(κ1‐dppm)(η3‐P3{P(O)H})] (2). In solution, 2 has a fluxional behavior attributable to the four P atoms belonging to the tetraphosphorus moiety in 1 and exhibits a chemical exchange process involving the two PPh2 moieties of the same bidentate ligand, as determined by 1D and 2D NMR spectroscopy experiments carried out at variable temperature. The mechanism of the reaction was investigated at the DFT level, which suggested a selective attack of an in‐situ generated OH− anion on one of the non‐coordinated phosphorus atoms of the P4 moiety. The reaction then evolves through an acid‐assisted tautomerization, which leads to the final compound 2. Bonding analysis pointed out that the new unsubstituted P3‐unit in the η3‐P3{P(O)H} moiety behaves as a triphosphallyl ligand.
Long‐term biomass yields of giant reed, mimosa and switchgrass in Alabama
Authors: Ping Huang , Bransby David I. , van Santen Edzard
Published: August 2013

The US Department of Energy conducted two studies to estimate the potential of cellulosic biomass crops for production of biofuels on a national scale. However, limited long‐term experimental information is available to support the resultant yield projections. The objectives of this research were: (i) to determine long‐term (>10 years) biomass yields and soil impacts of switchgrass (Panicum virgatum L.), giant reed (Arundo donax L.) and mimosa (Albizia julibrissin Durazz.) in Alabama; and (ii) to establish relationships between precipitation and yields of these perennial biomass crops, and yields of cotton, maize, and soybean. Mimosa and giant reed received no fertilizer and were harvested once each year while switchgrass received 84 kg ha–1 of N fertilizer annually, and was harvested twice each year. Cotton, maize, and soybean were managed according to traditional practices for these crops in this region. Average annual biomass yields of mimosa, giant reed, and switchgrass were 40.1, 35.5 and 23.5 kg ha–1 over 16‐, 11‐ and 22‐year periods, respectively, with corresponding estimated annual N accumulation in aboveground biomass of 388, 372 and 163 kg ha–1. Yields of maize, cotton and soybean decreased sharply with decreasing precipitation, but there was no corresponding decrease in yield of the three perennial biomass crops. Changes in the yields of the biomass crops with age were also relatively small. Analysis of topsoil samples suggested considerably less removal of P, K, Ca, and Mg than was estimated from yield and concentrations of these elements in the biomass that was actually removed. © 2013 Society of Chemical Industry and John Wiley & Sons, Ltd
Spectrofluorimetric determination of aluminum ions via complexation with luteolin in absolute ethanol
Authors: Sun Jinyu , Wu You , Xiao Dan , Lin Xia , Li Hui
Published: August 2013

An optimized and validated spectrofluorimetric method has been developed for the rapid determination of aluminum in absolute ethanol. The method is based on the chelation of aluminum and luteolin which results in a complex exhibiting an intense emission signal. The characterization of Al–luteolin complex was studied using ultraviolet–visible spectrometry, infrared spectrometry, fluorescence and mass spectrometry. The complex stoichiometry ratio of aluminum:luteolin was 1:2. The fluorescence of the complex was monitored at an emission wavelength of 545 nm with excitation at 518 nm. The linear concentration range was 6.5 × 10‐7 to 4.0 × 10‐5 M with a correlation coefficient of r = 0.998. The detection limit was 5.0 × 10‐7 M. The method was appropriately validated and yielded relative standard deviations of < 2.3% (n = 5), which was considered acceptable. The method was successfully applied in the determination of aluminum in river water, skin care products and pharmaceutical samples. Copyright © 2013 John Wiley & Sons, Ltd.
Structural glance into a novel anti‐staphylococcal peptide
Authors: Iannucci N. B. , Curto L. M. , Albericio F. , Cascone O. , Delfino J. M.
Published: August 2013

Novel antimicrobial peptides are valuable molecules for developing anti‐infective drugs to counteract the contemporary spread of microbial drug‐resistance. Here we focus on a novel peptide (RKWVWWRNR‐NH2) derived from the fragment 107–115 of the human lysozyme that displays a 20‐fold increase in anti‐staphylococcal activity. The conformational analysis of this peptide and its interaction with model lipidic phases—as assayed by circular dichroism and fluorescence spectroscopy—show a noteworthy spectral change, which might be related to its anti‐staphylococcal activity. The secondary structure of peptide [K108W111] 107–115 hLz was dramatically affected through a single substitution at position 111 (Ala by Trp). Therefore, this conformational change might improve the interaction of the novel peptide with the bacterial plasma membrane. These results highlight the role of peptide secondary structure and the distribution of polar/nonpolar residues for the effective interaction of this peptide with the bacterial plasma membrane, a key step for triggering its lethal effect. This knowledge may contribute to the rational design of a new generation of antimicrobial peptides with increased efficacy developed from natural sources by simple screening tools. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 49–57, 2014.
Structural characterization of the regulatory domain of brain carnitine palmitoyltransferase 1
Authors: Samanta Soma , Situ Alan J. , Ulmer Tobias S.
Published: August 2013

Neurons contain a mammalian‐specific isoform of the enzyme carnitine palmitoyltransferase 1 (CPT1C) that couples malonyl‐CoA to ceramide levels thereby contributing to systemic energy homeostasis and feeding behavior. In contrast to CPT1A, which controls the rate‐limiting step of long‐chain fatty acid β‐oxidation in all tissues, the biochemical context and regulatory mechanism of CPT1C are unknown. CPT1 enzymes are comprised of an N‐terminal regulatory domain and a C‐terminal catalytic domain (CD) that are separated by two transmembrane helices. In CPT1A, the regulatory domain, termed N, adopts an inhibitory and non‐inhibitory state, Nα and Nβ, respectively, which differ in their association with the CD. To provide insight into the regulatory mechanism of CPT1C, we have determined the structure of its regulatory domain (residues Met1‐Phe50) by NMR spectroscopy. In relation to CPT1A, the inhibitory Nα state was found to be structurally homologues whereas the non‐inhibitory Nβ state was severely destabilized, suggesting a change in overall regulation. The destabilization of Nβ may contribute to the low catalytic activity of CPT1C relative to CPT1A and makes its association with the CD unlikely. In analogy to the stabilization of Nβ by the CPT1A CD, non‐inhibitory interactions of N of CPT1C with another protein may exist. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 398–405, 2014.