bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ten-year Absolute Fracture Risk and Hip Bone Strength in Canadian Women with Systemic Lupus Erythematosus
Authors: LEE JENNIFER J.Y. , AGHDASSI ELAHEH , CHEUNG ANGELA M. , MORRISON STACEY , CYMET ANNE , PEEVA VALENTINA , NEVILLE CAROLYN , HEWITT SARA , DaCOSTA DEBORAH , PINEAU CHRISTIAN , POPE JANET , FORTIN PAUL R. 
Published: June 2012

Objective.Women with systemic lupus erythematosus (SLE) are at risk of osteoporosis (OP) and fractures because of SLE or its treatments. We aimed to determine in women with SLE (1) the prevalence of low bone mass (LBM) in those < 50 years of age and OP in those > 50 years of age; (2) the 10-year absolute fracture risk in those > 40 years of age using the Canadian Fracture Risk Assessment Tool (FRAX); (3) bone quality using hip structural analysis (HSA); and (4) the associations between HSA and age, SLE duration, and corticosteroid exposure.Methods.Women without prior OP fractures were eligible. Bone mineral densities at the hip, spine, and femoral neck were determined using dual-energy x-ray absorptiometry. OP was determined using World Health Organization definitions for participants aged ≥ 50 years (32.8%), and LBM was defined as Z-scores ≤ −2.0 for those aged < 50 years. For those aged ≥ 40 years (63.5%), the 10-year probabilities of a major fracture (FRAX-Major) and hip fracture (FRAX-Hip) were calculated. FRAX-Major ≥ 20% or Hip ≥ 3% was considered high risk. HSA was done in a subgroup (n = 81) of patients.Results.The study group was 271 women. Mean (SD) age was 43.8 (13.1) years and SLE duration was 11.6 (10.4) years. OP was diagnosed in 14.6% and LBM in 8.8%. FRAX-Major ≥ 20% was seen in 9 patients (5.3%), of whom 6 were taking OP medications. FRAX-Hip ≥ 3% occurred in 16 patients (9.4%), of whom 9 were taking OP medications. Buckling ratio at the left hip narrow neck was positively correlated with FRAX-Major, FRAX-Hip, SLE duration, and duration of corticosteroid use.Conclusion.LBM is prevalent in women with SLE who are < 50 years of age. FRAX may identify those at higher risk of fractures while HSA can assess bone structure noninvasively.
Persistent or New Onset Microscopic Hematuria in Patients with Small Vessel Vasculitis in Remission: Findings on Renal Biopsy
Authors: GEETHA DUVURU , SEO PHILIP , ELLIS CARLA , KUPERMAN MICHAEL , LEVINE STUART M. 
Published: June 2012

Objective.Hematuria is considered a sign of active renal disease in patients with small-vessel vasculitis. In patients who are in apparent clinical remission, presence of persistent or new-onset microscopic hematuria may reflect active vasculitis, damage, or other glomerular pathology.Methods.We identified 74 patients from the Johns Hopkins Renal Pathology database between 1995 and 2009 with the diagnosis of pauciimmune glomerulonephritis (GN). Among them we identified 9 who were in clinical remission and underwent a renal biopsy for evaluation of persistent or new-onset hematuria.Results.Nine patients with small-vessel vasculitis, 8 antineutrophil cytoplasmic antibody (ANCA)-positive and 1 ANCA-negative, underwent a renal biopsy at variable time periods after remission of vasculitis (6 to 164 months) for persistent microscopic hematuria (n = 6) or new-onset microscopic hematuria (n = 3). All patients were in apparent clinical remission at the time of renal biopsy. Of the 3 patients presenting with new-onset hematuria, 2 had crescentic IgA nephropathy and 1 had healed crescentic pauciimmune GN. Of the 6 patients with persistent hematuria, 2 had arteriosclerosis, 2 had focal segmental glomerulosclerosis, and 2 had global and segmental glomerulosclerosis and healed crescentic GN, and none had active vasculitis.Conclusion.Microscopic hematuria in patients with renal vasculitis otherwise in remission could represent chronic glomerular injury from prior episode of vasculitis or may represent new glomerular pathology. Renal biopsy should be considered in these patients to guide therapy.
Serum S100A8/A9, But Not Follistatin-like Protein 1 and Interleukin 18, May Be a Useful Biomarker of Disease Activity in Adult-onset Still’s Disease
Authors: KIM HYOUN-AH , AN JEONG-MI , NAM JIN-YOUNG , JEON JA-YOUNG , SUH CHANG-HEE 
Published: June 2012

Objective.S100A8/A9, follistatin-like protein 1, and interleukin 18 (IL-18) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still’s disease (AOSD). We investigated the clinical significance of these factors in AOSD.Methods.Blood samples were collected from 36 patients with AOSD, 40 patients with rheumatoid arthritis (RA), and 33 healthy controls. Of the patients with AOSD, followup samples were collected from 16 patients after resolution of disease activity.Results.Serum levels of S100A8/A9 (11.77 ± 8.84 μg/ml) in AOSD patients were higher than those in RA patients (3.53 ± 3.43 μg/ml; p < 0.001) and controls (2.49 ± 1.83 μg/ml; p < 0.001). Follistatin-like protein 1 levels in AOSD were not different from those in RA and controls. IL-18 levels in AOSD (7560.3 ± 7577.6 pg/ml) were higher than those in RA (217.7 ± 292.1 pg/ml; p < 0.001) and controls (139.2 ± 86.2 pg/ml; p < 0.001). The sensitivity and specificity of IL-18 for diagnosing AOSD was highest with a cutoff value of 366.1 pg/ml. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein, ferritin, and systemic disease score; however, IL-18 correlated only with ferritin and systemic disease score. S100A8/A9 was decreased after disease activity was resolved in followup of AOSD patients (9.96 ± 7.35 μg/ml in active AOSD vs 3.6 ± 4.77 μg/ml in resolved cases; p = 0.001). The change of S100A8/A9 was well correlated with that of systemic disease score.Conclusion.The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in patients with AOSD.
Myeloid Dendritic Cells from B6.NZM Sle1/Sle2/Sle3 Lupus-Prone Mice Express an IFN Signature That Precedes Disease Onset
Authors: Sriram Uma , Varghese Linda , Bennett Heather L. , Jog Neelakshi R. , Shivers Debra K. , Ning Yue , Behrens Edward M. , Caricchio Roberto , Gallucci Stefania 
Published: June 2012

Abstract
Patients with systemic lupus erythematosus show an overexpression of type I IFN-responsive genes that is referred to as “IFN signature.” We found that B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an IFN signature compared with non-autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs) (GM-CSF bone marrow-derived dendritic cells; BMDCs) from Sle1,2,3 mice constitutively overexpressed IFN-responsive genes such as IFN-β, Oas-3, Mx-1, ISG-15, and CXCL10 and members of the IFN signaling pathway STAT1, STAT2, and IRF7. The IFN signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the IFN signature in mDCs precedes disease onset and is independent from the autoantibodies. Sle1,2,3 BMDCs hyperresponded to stimulation with IFN-α and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyperresponse is induced by the IFN signature and only partially contributes to the signature, as oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive IFN signature, and pre-exposure to IFN-α induced the same hyperresponse in wild-type BMDCs as in Sle1,2,3 BMDCs. In vivo, mDCs and to a lesser extent T and B cells from young prediseased Sle1,2,3 mice also expressed the IFN signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the IFN signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the IFN signature in lupus pathogenesis.
Comprehensive Analysis of CD4+ T Cells in the Decision between Tolerance and Immunity In Vivo Reveals a Pivotal Role for ICOS
Authors: Lischke Timo , Hegemann Anika , Gurka Stephanie , Vu Van Dana , Burmeister Yvonne , Lam Kong-Peng , Kershaw Olivia , Mollenkopf Hans-Joachim , Mages Hans Werner , Hutloff Andreas , Kroczek Richard A. 
Published: June 2012

Abstract
We have established a comprehensive in vivo mouse model for the CD4+ T cell response to an “innocuous” versus “dangerous” exogenous Ag and developed an in vivo test for tolerance. In this model, specific gene-expression signatures, distinctive upregulation of early T cell-communication molecules, and differential expansion of effector T cells (Teff) and regulatory T cells (Treg) were identified as central correlates of T cell tolerance and T cell immunity. Different from essentially all other T cell-activation molecules, ICOS was found to be induced in the immunity response and not by T cells activated under tolerogenic conditions. If expressed, ICOS did not act as a general T cell costimulator but selectively caused a massive expansion of effector CD4+ T cells, leaving the regulatory CD4+ T cell compartment largely undisturbed. Thus, ICOS strongly contributed to the dramatic change in the balance between Ag-specific Teff and Treg from ∼1:1 at steady state to 21:1 at the height of the immune response. This newly defined role for the balance of Teff to Treg, together with its known key function in T cell help for B cells, establishes ICOS as a central mediator of immunity. Given its exceptionally selective induction on CD4+ T cells under inflammatory, but not tolerogenic, conditions, ICOS emerges as a pivotal effector molecule in the early decision between tolerance and immunity to exogenous Ag.
B7-H1, Which Represses EBV-Immortalized B Cell Killing by Autologous T and NK Cells, Is Oppositely Regulated by c-Myc and EBV Latency III Program at Both mRNA and Secretory Lysosome Levels
Authors: Durand-Panteix Stéphanie , Farhat Mona , Youlyouz-Marfak Ibtissam , Rouaud Pauline , Ouk-Martin Catherine , David Amandine , Faumont Nathalie , Feuillard Jean , Jayat-Vignoles Chantal 
Published: June 2012

Abstract
EBV-immortalized B cells induce a complex immune response such that the virus persists as a clinically silent infection for the lifetime of the infected host. B7-H1, also called PD-L1, is a cosignaling molecule of the B7 family that can inhibit activated T cell effectors by interaction with its receptor PD-1. In this work, we have studied the dependence of B7-H1 on NF-κB and c-Myc, the two main transcription factors in EBV latency III proliferating B cells, on various lymphoblastoid and Burkitt lymphoma cell lines, some of them being inducible or not for the EBV latency III program and/or for c-Myc. We found that B7-H1 repressed killing of EBV-immortalized B cells by their autologous T and NK cells. At the mRNA level, NF-κB was a weak inducer whereas c-Myc was a strong repressor of B7-H1 expression, an effect mediated by STAT1 inhibition. At the protein level, B7-H1 molecules were stored in both degradative and unconventional secretory lysosomes. Surface membrane B7-H1 molecules were constitutively internalized and proteolyzed in lysosomes. The EBV latency III program increased the amounts of B7-H1–containing secretory lysosomes and their export to the surface membrane. By repressing actin polymerization, c-Myc blocked secretory lysosome migration and B7-H1 surface membrane export. In addition to B7-H1, various immunoregulatory molecules participating in the immunological synapse are stored in secretory lysosomes. By playing on actin polymerization, c-Myc could thus globally regulate the immunogenicity of transformed B cells, acting on export of secretory lysosomes to plasma membrane.
Cutting Edge: MicroRNA Regulation of Macrophage Fusion into Multinucleated Giant Cells
Authors: Sissons James R. , Peschon Jacques J. , Schmitz Frank , Suen Rosa , Gilchrist Mark , Aderem Alan 
Published: June 2012

Abstract
Cellular fusion of macrophages into multinucleated giant cells is a distinguishing feature of the granulomatous response to inflammation, infection, and foreign bodies (Kawai and Akira. 2011. Immunity 34: 637–650). We observed a marked increase in fusion of macrophages genetically deficient in Dicer, an enzyme required for canonical microRNA (miRNA) biogenesis. Gene expression profiling of miRNA-deficient macrophages revealed an upregulation of the IL-4–responsive fusion protein Tm7sf4, and analyses identified miR-7a-1 as a negative regulator of macrophage fusion, functioning by directly targeting Tm7sf4 mRNA. miR-7a-1 is itself an IL-4–responsive gene in macrophages, suggesting feedback control of cellular fusion. Collectively, these data indicate that miR-7a-1 functions to regulate IL-4–directed multinucleated giant cell formation.
Retinoid X Receptor Agonists Impair Arterial Mononuclear Cell Recruitment through Peroxisome Proliferator-Activated Receptor-γ Activation
Authors: Sanz Maria-Jesus , Albertos Fernando , Otero Eduardo , Juez Marina , Morcillo Esteban J. , Piqueras Laura 
Published: June 2012

Abstract
Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)α on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXRα expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-α. Interestingly, under physiological flow conditions, TNF-α–induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-α–induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-α and MCP-1 release. Suppression of RXRα expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-κB pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXRα/peroxisome proliferator-activated receptor (PPAR)γ interaction, since endothelial PPARγ silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPARγ interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-α–induced mononuclear leukocyte arrest by 60–65%. In vivo, bexarotene dose-dependently inhibited TNF-α–induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease.
TLR5, a Novel and Unidentified Inflammatory Mediator in Rheumatoid Arthritis that Correlates with Disease Activity Score and Joint TNF-α Levels
Authors: Chamberlain Nathan D. , Vila Olga M. , Volin Michael V. , Volkov Suncica , Pope Richard M. , Swedler William , Mandelin Arthur M. , Shahrara Shiva 
Published: June 2012

Abstract
The innate immune system plays an important role in rheumatoid arthritis (RA) pathogenesis. Previous studies support the role of TLR2 and 4 in RA and experimental arthritis models; however, the regulation and pathogenic effect of TLR5 is undefined in RA. In this study, we show that TLR5 is elevated in RA and osteoarthritis ST lining and sublining macrophages and endothelial cells compared with normal individuals. Furthermore, expression of TLR5 is elevated in RA synovial fluid macrophages and RA peripheral blood monocytes compared with RA and normal peripheral blood in vitro-differentiated macrophages. We also found that TLR5 on RA monocytes is an important modulator of TNF-α in RA synovial fluid and that TLR5 expression on these cells strongly correlates with RA disease activity and TNF-α levels. Interestingly, TNF-α has a feedback regulation with TLR5 expression in RA monocytes, whereas expression of this receptor is regulated by IL-17 and IL-8 in RA macrophages and fibroblasts. We show that RA monocytes and macrophages are more responsive to TLR5 ligation compared with fibroblasts despite the proinflammatory response being mediated through the same signaling pathways in macrophages and fibroblasts. In conclusion, we document the potential role of TLR5 ligation in modulating transcription of TNF-α from RA synovial fluid and the strong correlation of TLR5 and TNF-α with each other and with disease activity score in RA monocytes. Our results suggest that expression of TLR5 may be a predictor for RA disease progression and that targeting TLR5 may suppress RA.
TLR Signaling Prevents Hyperoxia-Induced Lung Injury by Protecting the Alveolar Epithelium from Oxidant-Mediated Death
Authors: Ballinger Megan N. , Newstead Michael W. , Zeng Xianying , Bhan Urvashi , Horowitz Jeffrey C. , Moore Bethany B. , Pinsky David J. , Flavell Richard A. , Standiford Theodore J. 
Published: June 2012

Abstract
Mechanical ventilation using high oxygen tensions is often necessary to treat patients with respiratory failure. Recently, TLRs were identified as regulators of noninfectious oxidative lung injury. IRAK-M is an inhibitor of MyD88-dependent TLR signaling. Exposure of mice deficient in IRAK-M (IRAK-M−/−) to 95% oxygen resulted in reduced mortality compared with wild-type mice and occurred in association with decreased alveolar permeability and cell death. Using a bone marrow chimera model, we determined that IRAK-M’s effects were mediated by structural cells rather than bone marrow-derived cells. We confirmed the expression of IRAK-M in alveolar epithelial cells (AECs) and showed that hyperoxia can induce the expression of this protein. In addition, IRAK-M−/− AECs exposed to hyperoxia experienced a decrease in cell death. IRAK-M may potentiate hyperoxic injury by suppression of key antioxidant pathways, because lungs and AECs isolated from IRAK-M−/− mice have increased expression/activity of heme oxygenase-1, a phase II antioxidant, and NF (erythroid-derived)-related factor-2, a transcription factor that initiates antioxidant generation. Treatment of IRAK-M−/− mice in vivo and IRAK-M−/− AECs in vitro with the heme oxygenase-1 inhibitor, tin protoporphyrin, substantially decreased survival and significantly reduced the number of live cells after hyperoxia exposure. Collectively, our data suggest that IRAK-M inhibits the induction of antioxidants essential for protecting the lungs against cell death, resulting in enhanced susceptibility to hyperoxic lung injury.
Hepatitis B Virus-Induced Calreticulin Protein Is Involved in IFN Resistance
Authors: Yue Xin , Wang Hui , Zhao Fanpeng , Liu Shi , Wu Jianguo , Ren Wendan , Zhu Ying 
Published: June 2012

Abstract
IFN-α is a widely used treatment for hepatitis B virus (HBV) infection, and IFN resistance caused by viral and/or host factors is currently a challenging clinical problem. A better understanding of the molecular mechanisms underlying IFN immunotherapy in the treatment of viral infection would be very beneficial clinically and is of immense clinical importance. Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding chaperone that is involved in the regulation of calcium homoeostasis, the folding of newly synthesized proteins, and many other cellular functions. However, little is known about the role of CRT in HBV infection. In this study, we observed high levels of CRT expression in the sera and PBMCs of patients with HBV relative to those of healthy individuals. HBV upregulated the expression of CRT at the transcriptional level. Further investigation showed that HBV-induced CRT enhanced HBV replication by antagonizing the IFN pathway. CRT suppressed the production of endogenous IFN-α by reducing the nuclear translocation of IFN regulatory factor-7 but not IFN regulatory factor-3. Furthermore, CRT also suppressed the antiviral activity of IFN-α by inhibiting the phosphorylation of STAT1 and decreasing the expression of two IFN-α downstream effectors, protein kinase R and 2',5′-oligoadenylate synthetase. Our results offer new insights into the pathogenesis of HBV infection and may provide potential targets for anti-HBV therapy.
Zinc Supplementation during Pregnancy Protects against Lipopolysaccharide-Induced Fetal Growth Restriction and Demise through Its Anti-inflammatory Effect
Authors: Chen Yuan-Hua , Zhao Mei , Chen Xue , Zhang Ying , Wang Hua , Huang Ying-Ying , Wang Zhen , Zhang Zhi-Hui , Zhang Cheng , Xu De-Xiang 
Published: June 2012

Abstract
LPS is associated with adverse developmental outcomes, including preterm delivery, fetal death, teratogenicity, and intrauterine growth restriction (IUGR). Previous reports showed that zinc protected against LPS-induced teratogenicity. In the current study, we investigated the effects of zinc supplementation during pregnancy on LPS-induced preterm delivery, fetal death and IUGR. All pregnant mice except controls were i.p. injected with LPS (75 μg/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were administered zinc sulfate through drinking water (75 mg elemental Zn per liter) throughout the pregnancy. As expected, an i.p. injection with LPS daily from GD15 to GD17 resulted in 36.4% (4/11) of dams delivered before GD18. In dams that completed the pregnancy, 63.2% of fetuses were dead. Moreover, LPS significantly reduced fetal weight and crown–rump length. Of interest, zinc supplementation during pregnancy protected mice from LPS-induced preterm delivery and fetal death. In addition, zinc supplementation significantly alleviated LPS-induced IUGR and skeletal development retardation. Further experiments showed that zinc supplementation significantly attenuated LPS-induced expression of placental inflammatory cytokines and cyclooxygenase-2. Zinc supplementation also significantly attenuated LPS-induced activation of NF-κB and MAPK signaling in mononuclear sinusoidal trophoblast giant cells of the labyrinth zone. It inhibited LPS-induced placental AKT phosphorylation as well. In conclusion, zinc supplementation during pregnancy protects against LPS-induced fetal growth restriction and demise through its anti-inflammatory effect.
B7-H3 Participates in the Development of Experimental Pneumococcal Meningitis by Augmentation of the Inflammatory Response via a TLR2-Dependent Mechanism
Authors: Chen Xuqin , Quinn Edel M. , Ni Hong , Wang Jian , Blankson Siobhan , Redmond H. Paul , Wang Jiang Huai , Feng Xing 
Published: June 2012

Abstract
In addition to a well-documented role in regulating T cell-mediated immune responses, B7-H3, a newly discovered member of the B7 superfamily, has been recently identified as a costimulator in the innate immunity-mediated inflammatory response. In this study, we further report that B7-H3 participates in the development of pneumococcal meningitis in a murine model. Exogenous administration of B7-H3 strongly amplified the inflammatory response, exacerbated blood–brain barrier disruption, and aggravated the clinical disease status in Streptococcus pneumoniae-infected C3H/HeN wild-type mice. Consistent with the in vivo findings, B7-H3 substantially augmented proinflammatory cytokine and chemokine production, upregulated NF-κB p65 and MAPK p38 phosphorylation, and enhanced the nuclear transactivation of NF-κB p65 at both TNF-α and IL-6 promoters in S. pneumoniae-stimulated primary murine microglia cells. These B7-H3–associated in vitro and in vivo effects appeared to be dependent on TLR2 signaling, as B7-H3 almost completely lost its amplifying actions in both TLR2-deficient microglial cells and TLR2-deficient mice. Furthermore, administration of the anti–B7-H3 mAb (MIH35) attenuated the inflammatory response and ameliorated blood–brain barrier disruption in S. pneumoniae-infected wild-type mice. Collectively, our results indicate that B7-H3 plays a contributory role in the development of S. pneumoniae infection-induced bacterial meningitis.