bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoimmune Disease–Associated Haplotypes of BLK Exhibit Lowered Thresholds for B Cell Activation and Expansion of Ig Class‐Switched B Cells
Authors: Simpfendorfer Kim R. , Armstead Brandon E. , Shih Andrew , Li Wentian , Curran Mark , Manjarrez‐Orduño Nataly , Lee Annette T. , Diamond Betty , Gregersen Peter K. 
Published: August 2015

ObjectiveB lymphoid kinase (BLK) is associated with rheumatoid arthritis (RA) and several other B cell–associated autoimmune disorders. BLK risk variants are consistently associated with reduced BLK expression, but the mechanisms by which reduced expression alters human B cell function to confer autoimmune disease susceptibility are unknown. This study was undertaken to characterize the BLK risk haplotype and to determine associated B cell functional phenotypes involved in autoimmunity.MethodsThe BLK risk haplotype association with RA (determined using whole‐genome sequencing data) was confirmed in 2,526 RA cases and 2,134 controls. Peripheral blood mononuclear cells (PBMCs) from RA patients, healthy adults, and umbilical cord blood were used to study B cell functional phenotypes associated with the BLK risk genotype. Association of the BLK haplotype with B cell phenotypes was analyzed using cell culture and flow cytometry.ResultsTwo insertion/deletions were found on the RA risk haplotype in BLK, and the reduction in BLK expression associated with the risk haplotype was confirmed in primary B lymphocytes. Carriers of the RA‐associated haplotype had evidence of lower basal B cell receptor (BCR) signaling activity, yet their B cells were hyperactivatable, with enhanced up‐regulation of CD86 after BCR crosslinking and greater T cell stimulatory capacity. The number of isotype‐switched memory B cells was also significantly increased in subjects carrying the risk haplotype.ConclusionA major mechanism underlying the BLK association with autoimmune disease involves lowered thresholds for BCR signaling, enhanced B cell–T cell interactions, and altered patterns of isotype switching.
Rheumatoid Factor Is Associated With the Distribution of Hand Joint Destruction in Rheumatoid Arthritis
Authors: Terao Chikashi , Yamakawa Noriyuki , Yano Koichiro , Markusse Iris M. , Ikari Katsunori , Yoshida Shinji , Furu Moritoshi , Hashimoto Motomu , Ito Hiromu , Fujii Takao , Ohmura Koichiro , Murakami Kosaku , Takahashi Meiko , Hamaguchi Masahide , Tabara Yasuharu , Taniguchi Atsuo , Momohara Shigeki , Raychaudhuri Soumya , Allaart Cornelia F. , Yamanaka Hisashi , Mimori Tsuneyo , Matsuda Fumihiko 
Published: August 2015

ObjectiveRheumatoid arthritis (RA) is a chronic disease leading to joint destruction. Although many studies have addressed factors potentially correlated with the speed of joint destruction, less attention has been paid to the distribution of joint destruction in patients with RA. In this study, destruction of the hand bones in patients with RA was classified into 2 anatomic subgroups, the fingers and the non‐fingers, with the aim of analyzing which factors are associated with destruction of the finger joints.MethodsA total of 1,215 Japanese patients with RA were recruited from 2 different populations. The degree of joint destruction was assessed using the total modified Sharp/van der Heijde score (SHS) of radiographic joint damage. The SHS score of joint damage in the finger joints was used as the dependent variable, and the SHS score in the non‐finger joints was used as a covariate. Age, sex, disease duration, smoking, C‐reactive protein level, treatment for RA, and positivity for and levels of anti–citrullinated protein antibodies and rheumatoid factor (RF) were evaluated as candidate correlates. Overall effect sizes were assessed in a meta‐analysis. In addition, associations observed in the Japanese patients were compared to those in a cohort of 157 Dutch RA patients in the BeSt study (a randomized, controlled trial involving 4 different strictly specified treatment strategies for early RA).ResultsNot surprisingly, disease duration in Japanese patients with RA was associated with the finger SHS score (P ≤ 0.00037). Both positivity for and levels of RF showed significant associations with the finger SHS score after adjustment for covariates (P = 0.0022 and P = 8.1 × 10−7, respectively). These associations were also true in relation to the time‐averaged finger SHS score. An association between RF positivity and the finger SHS score was also observed in Dutch patients with RA in the BeSt study (P = 0.049).ConclusionPositivity for and levels of RF are associated with finger joint destruction independent of non‐finger joint destruction and other covariates. Our findings suggest that there are different mechanisms of joint destruction operating in the finger joints of patients with RA.
Identification of Interleukin‐1β–Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal‐Onset Multisystem Inflammatory Disease
Authors: Edwan Jehad H. , Goldbach‐Mansky Raphaela , Colbert Robert A. 
Published: August 2015

ObjectiveSpontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome‐mediated interleukin‐1β (IL‐1β) processing and release and can induce rapid necrotic cell death. The cells that produce IL‐1β in neonatal‐onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL‐1β release and cell death been completely elucidated.MethodsWhole blood cells were stimulated with lipopolysaccharide (LPS) in the presence of cathepsin B and caspase 1 inhibitors, followed by ATP treatment. Supernatants were collected and incubated with IL‐1β–capturing beads. Cells were fixed, permeabilized, and stained for a combination of cell surface and intracellular markers, and a novel flow cytometry bead‐based assay was used to measure secreted IL‐1β. LPS‐stimulated cells were also evaluated using immunofluorescence microscopy.ResultsMonocytes characterized by CD14high‐CD16low expression and intracellular CD83 were increased in NOMID patients and were responsible for the majority of IL‐1β production in response to LPS stimulation. This population of monocytes also underwent a rapid death response with LPS alone that is temporally associated with IL‐1β and ASC release and has characteristic features of pyronecrotic but not pyroptotic cell death. Inhibition of cell death reduced IL‐1β production from NOMID patient cells. In addition, IL‐1 triggered cell death in monocytes from NOMID patients.ConclusionOur findings indicate that monocytes are the predominant IL‐1β–producing cell population in the peripheral blood of NOMID patients. Furthermore, they suggest that IL‐1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin‐associated periodic syndromes.
Brief Report: Endothelial‐Specific X‐Box Binding Protein 1 Deficiency Limits Tumor Necrosis Factor–Induced Leukocyte Recruitment and Vasculitis
Authors: Ziogas Athanasios , Muders Michael H. , Economopoulou Matina , Sprott David , Grossklaus Sylvia , Siegert Gabriele , Baretton Gustavo B. , Mitroulis Ioannis , Chavakis Triantafyllos 
Published: August 2015

ObjectiveEndothelial cell activation by tumor necrosis factor (TNF) and associated leukocyte infiltration are hallmarks of vasculitis. The aim of this study was to investigate the potential role of the cellular stress–associated endothelial X‐box binding protein 1 (XBP‐1) transcription factor in TNF‐induced endothelial cell inflammation and vasculitis.MethodsMice with an endothelial cell–specific XBP‐1 deficiency were used in a modified local Shwartzman reaction (LSR) model of TNF‐induced small vessel vasculitis. To address the contribution of XBP‐1 to the TNF‐mediated inflammatory response in endothelial cells, we examined the activation of XBP‐1 expression by TNF as well as the effect of XBP‐1 knockdown in endothelial cells on TNF‐induced signaling, proinflammatory gene expression, and leukocyte–endothelial cell adhesion.ResultsThe active spliced form of XBP‐1 in endothelial cells was triggered by TNF. In addition, endothelial XBP‐1 contributed to the sustained TNF‐triggered NF‐κB−dependent transcriptional activation of proinflammatory molecules, which was associated with leukocyte–endothelial cell adhesion. In the LSR model, endothelial cell–specific XBP‐1–deficient mice displayed significantly less vascular damage, accompanied by reduced perivascular neutrophil infiltration, as compared with wild‐type mice.ConclusionEndothelial XBP‐1 is activated by TNF and regulates leukocyte–endothelial cell adhesion in vitro as well as neutrophil infiltration and vascular damage in murine vasculitis.
Release of Active Peptidyl Arginine Deiminases by Neutrophils Can Explain Production of Extracellular Citrullinated Autoantigens in Rheumatoid Arthritis Synovial Fluid
Authors: Spengler Julia , Lugonja Božo , Jimmy Ytterberg A. , Zubarev Roman A. , Creese Andrew J. , Pearson Mark J. , Grant Melissa M. , Milward Michael , Lundberg Karin , Buckley Christopher D. , Filer Andrew , Raza Karim , Cooper Paul R. , Chapple Iain L. , Scheel‐Toellner Dagmar 
Published: August 2015

ObjectiveIn the majority of patients with rheumatoid arthritis (RA), antibodies specifically recognize citrullinated autoantigens that are generated by peptidylarginine deiminases (PADs). Neutrophils express high levels of PAD and accumulate in the synovial fluid (SF) of RA patients during disease flares. This study was undertaken to test the hypothesis that neutrophil cell death, induced by either NETosis (extrusion of genomic DNA–protein complexes known as neutrophil extracellular traps [NETs]) or necrosis, can contribute to production of autoantigens in the inflamed joint.MethodsExtracellular DNA was quantified in the SF of patients with RA, patients with osteoarthritis (OA), and patients with psoriatic arthritis (PsA). Release of PAD from neutrophils was investigated by Western blotting, mass spectrometry, immunofluorescence staining, and PAD activity assays. PAD2 and PAD4 protein expression, as well as PAD enzymatic activity, were assessed in the SF of patients with RA and those with OA.ResultsExtracellular DNA was detected at significantly higher levels in RA SF than in OA SF (P < 0.001) or PsA SF (P < 0.05), and its expression levels correlated with neutrophil concentrations and PAD activity in RA SF. Necrotic neutrophils released less soluble extracellular DNA compared to NETotic cells in vitro (P < 0.05). Higher PAD activity was detected in RA SF than in OA SF (P < 0.05). The citrullinated proteins PAD2 and PAD4 were found attached to NETs and also freely diffused in the supernatant. PAD enzymatic activity was detected in supernatants of neutrophils undergoing either NETosis or necrosis.ConclusionRelease of active PAD isoforms into the SF by neutrophil cell death is a plausible explanation for the generation of extracellular autoantigens in RA.
Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Diagnosed Between 1991 and 2013
Authors: Rahmattulla Chinar , Berden Annelies E. , Wakker Sophie‐Charlotte , Reinders Marlies E. J. , Hagen Ernst C. , Wolterbeek Ron , Bruijn Jan A. , Bajema Ingeborg M. 
Published: August 2015

ObjectiveTo investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients.MethodsThe study population consisted of patients with histopathologically confirmed AAV, diagnosed between 1991 and 2013 at a large university hospital. The mean duration of followup was 10 years. Malignancy incidence was assessed using the Dutch National Pathology Database. Incidence rates from the Netherlands Cancer Registry were used to compare malignancy incidence in the AAV cohort to that in the general Dutch population.ResultsThirty‐six of 138 patients with AAV developed a total of 85 malignancies during a mean followup of 9.7 years. The sex‐, age‐, and calendar year–adjusted malignancy risk was 2.21‐fold higher (95% confidence interval [95% CI] 1.64–2.92) than that in the general population. Non‐melanoma skin cancers occurred most frequently (standardized incidence ratio 4.23 [95% CI 2.76–6.19]). The incidence rates of other malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide (CYC) therapy and, interestingly, was not increased in patients who had received CYC for <1 year.ConclusionPatients with AAV have a higher risk of malignancy than the general population, but this risk is accounted for solely by non‐melanoma skin cancers. Over the years, the risk of other malignancies—specifically bladder and hematologic malignancies—has decreased in patients with AAV. This finding reflects ongoing efforts to reduce CYC exposure by developing new treatment regimens.
Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin‐8 (CXCL8), Myeloid‐Related Protein 8/Myeloid‐Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease
Authors: Kienhorst Laura B. E. , van Lochem Ellen , Kievit Wietske , Dalbeth Nicola , Merriman Marilyn E. , Phipps‐Green Amanda , Loof Arnoud , van Heerde Waander , Vermeulen Sita , Stamp Lisa K. , van Koolwijk Elly , de Graaf Jacqueline , Holzinger Dirk , Roth Johannes , Janssens Hein J. E. M. , Merriman Tony R. , Broen Jasper C. A. , Janssen Matthijs , Radstake Timothy R. D. J. 
Published: August 2015

ObjectiveThe frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.MethodsWe studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls. We measured circulating levels of interleukin‐8 (IL‐8)/CXCL8, IL‐1β, IL‐6, IL‐10, IL‐12, and tumor necrosis factor, after which we performed proteome‐wide analysis in a selection of samples to identify proteins that were possibly prognostic for the development of comorbidities. Replication analysis was performed specifically for myeloid‐related protein 8 (MRP‐8)/MRP‐14 complex.ResultsCompared to healthy controls and disease control patients, patients with gouty arthritis (n = 48) had significantly higher mean levels of CXCL8 (P < 0.001), while other cytokines were almost undetectable. Similarly, patients with intercritical gout showed high levels of CXCL8. CXCL8 was independently associated with diabetes mellitus in patients with intercritical gout (P < 0.0001). Proteome‐wide analysis in gouty arthritis (n = 18) and intercritical gout (n = 39) revealed MRP‐8 and MRP‐14 as the proteins with the greatest differential expression between low and high levels of CXCL8 and also showed a positive correlation of MRP8/MRP14 complex with CXCL8 levels (R2 = 0.49, P < 0.001). These findings were replicated in an independent cohort. The proteome of gout patients with high levels of CXCL8 was associated with diabetes mellitus (odds ratio 16.5 [95% confidence interval 2.8–96.6]) and CVD (odds ratio 3.9 [95% confidence interval 1.0–15.3]).ConclusionCirculating levels of CXCL8 are increased during both the acute and intercritical phases of gout, and they coincide with a specific circulating proteome that is associated with risk of diabetes mellitus and CVD. Further research focused on the roles of CXCL8 and MRP8/MRP14 complex in patients with gout is warranted.
Chimeric RNA Oligonucleotides with Triazole and Phosphate Linkages: Synthesis and RNA Interference
Authors: Fujino Tomoko , Kogashi Kanako , Okada Koudai , Mattarella Martin , Suzuki Takeru , Yasumoto Kenichi , Sogawa Kazuhiro , Isobe Hiroyuki 
Published: August 2015

AbstractChimeric RNA oligonucleotides with an artificial triazole linker were synthesized using solution‐phase click chemistry and solid‐phase automated synthesis. Scalable synthesis methods for jointing units for the chimeric structure have been developed, and after click‐coupling of the jointing units with triazole linkers, a series of chimeric oligonucleotides was prepared by utilizing the well‐established phosphoramidite method for the elongation. The series of chimeric 21‐mer oligonucleotides that possessed the triazole linker at different strands and positions allowed for a screening study of the RNA interference to clarify the preference of the triazole modifications in small‐interfering RNA molecules.
Luminescence and energy‐transfer properties of color‐tunable Ca2Mg0.25Al1.5Si1.25O7:Ce3+/Eu2+/Tb3+ phosphors for ultraviolet light‐emitting diodes
Authors: Yuan Bo. , Song Yanhua , Sheng Ye. , Zheng Keyan , Huo Qisheng , Xu Xuechun , Zou Haifeng 
Published: August 2015

AbstractA series of Ca2Mg0.25Al1.5Si1.25O7:Ce3+/Eu2+/Tb3+ phosphors was been prepared via a conventional high temperature solid‐state reaction and their luminescence properties were studied. The emission spectra of Ca2Mg0.25Al1.5Si1.25O7:Ce3+,Eu2+ and Ca2Mg0.25Al1.5Si1.25O7:Ce3+,Tb3+ phosphors show not only a band due to Ce3+ ions (409 nm) but also as a band due to Eu2+ (520 nm) and Tb3+ (542 nm) ions. More importantly, the effective energy transfer from Ce3+ to Eu2+ and Tb3+ ions was confirmed and investigated by emission/excitation spectra and luminescent decay behaviors. Furthermore, the energy level scheme and energy transfer mechanism were investigated and were demonstrated to be of resonant type via dipole–dipole (Ce3+ to Eu2+) and dipole–quadrupole (Ce3+ to Tb3+) reactions, respectively. Under excitation at 350 nm, the emitting color could be changed from blue to green by adjusting the relative doping concentration of Ce3+ and Eu2+ ions as well as Ce3+ and Tb3+ ions. The above results indicate that Ca2Mg0.25Al1.5Si1.25O7:Ce3+,Eu2+/Tb3+ are promising single‐phase blue‐to‐green phosphors for application in phosphor conversion white‐light‐emitting diodes. Copyright © 2015 John Wiley & Sons, Ltd.
A selective determination of copper ions in water samples based on the fluorescence quenching of thiol‐capped CdTe quantum dots
Authors: Nurerk Piyaluk , Kanatharana Proespichaya , Bunkoed Opas 
Published: August 2015

AbstractCdTe quantum dots (QDs) capped with different stabilizers, i.e. thioglycolic acid (TGA), 3‐mercaptopropionic acid (MPA) and glutathione (GSH) were investigated as fluorescent probes for the determination of Cu2+. The stabilizer was shown to play an important role in both the sensitivity and selectivity for the determination of Cu2+. TGA‐capped CdTe QDs showed the highest sensitivity, followed by the MPA and GSH‐capped CdTe QDs, respectively. The TGA‐ and MPA‐capped CdTe QDs were not selective for Cu2+ that was affected by Ag+. The GSH‐capped CdTe QDs were insensitive to Ag+ and were used to determine Cu2+ in water samples. Under optimal conditions, quenching of the fluorescence intensity (F0/F) increased linearly with the concentration of Cu2+ over a range of 0.10–4.0 µg/mL and the detection limit was 0.06 µg/mL. The developed method was successfully applied to the determination of Cu2+ in water samples. Good recoveries of 93–104%, with a relative standard deviation of < 6% demonstrated that the developed simple method was accurate and reliable. The quenching mechanisms were also described. Copyright © 2015 John Wiley & Sons, Ltd.
Twisting Tourniquet© Technique: introducing Schnogh, a novel device and its effectiveness in treating primary and secondary lymphedema of extremities
Authors: Chanwimalueang Narumon , Ekataksin Wichai , Piyaman Parkpoom , Pattanapen Gedsuda , Hanboon Borimas K. 
Published: August 2015

AbstractTwisting Tourniquet© or in Thai “Schnogh” is a new invention for compression therapy of lymphedema. Twisting Tourniquet© Technique (TTT) is totally noninvasive for lymphedema management. After the amazing successful evidence in the first series of 28 patients, we have conducted preliminary studies in lymphedema clinics. It was found that the combination of gradually increasing constriction force by Schnogh until desired pressure was reached and maintained for 15 min, followed by a 5‐min release, doing repeatedly this compression‐decompression for at least 10 sessions a day, can generate acceptable results. The aim of the study was to evaluate the scientific effectiveness and establish a treatment protocol of TTT proposed as a therapeutic approach for clinical management of lymphedema. During 2006–2013, from over 3500 patients, 647 with primary/secondary lymphedema passed inclusion criteria, 307 for upper, and 340 for lower extremity. In the 5‐day course of TTT, each day patients underwent 10 sessions of a 15‐min compression followed by a 5‐min decompression. Vegan diet was encouraged as an adjuvant therapy. Among lymphedema patients whose spectrum of edema severity ranged from mild to gigantic, TTT yielded an average volume reduction rate (VR) at 50.2% and 55.6%, making the average edema reduction volume attained at 463 and 1856 mL for upper and lower limb, respectively. The uniformed practice by Schnogh which supports a continual compression–decompression maneuver over 3.5 h daily for five consecutive days could induce an average VR at above half of the swelling in extremities of 647 patients. Schnogh is therefore effective in clinical management of lymphedema under TTT treatment of fibroblastic interstitium.
Valsartan protects HK‐2 cells from contrast media‐induced apoptosis by inhibiting endoplasmic reticulum stress
Authors: Peng Ping‐an , Wang Le , Ma Qian , Xin Yi , Zhang Ou , Han Hong‐ya , Liu Xiao‐li , Ji Qing‐wei , Zhou Yu‐jie , Zhao Ying‐xin 
Published: August 2015

AbstractContrast‐induced acute kidney injury (CI‐AKI) is associated with increasing in‐hospital and long‐term adverse clinical outcomes in high‐risk patients undergoing percutaneous coronary intervention (PCI). Contrast media (CM)‐induced renal tubular cell apoptosis is reported to participate in this process by activating endoplasmic reticulum (ER) stress. An angiotensin II type 1 receptor (AT1R) antagonist can alleviate ER stress‐induced renal apoptosis in streptozotocin (STZ)‐induced diabetic mice and can reduce CM‐induced renal apoptosis by reducing oxidative stress and reversing the enhancement of bax mRNA and the reduction of bcl‐2 mRNA, but the effect of the AT1R blocker on ER stress in the pathogenesis of CI‐AKI is still unknown. In this study, we explored the effect of valsartan on meglumine diatrizoate‐induced human renal tubular cell apoptosis by measuring changes in ER stress‐related biomarkers. The results showed that meglumine diatrizoate caused significant cell apoptosis by up‐regulating the expression of ER stress markers, including glucose‐regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), CCAAT/enhancer‐binding protein‐homologous protein (CHOP) and caspase 12, in a time‐ and dose‐dependent manner, which could be alleviated by preincubation with valsartan. In conclusion, valsartan had a potential nephroprotective effect on meglumine diatrizoate‐induced renal cell apoptosis by inhibiting ER stress.