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Oral Diseases (2012) 18, 132-139 Objectives: Autoantibodies from the sera of Sjögren's syndrome patients (SS IgG) have been suggested to inhibit muscarinic receptor function. However, the acute nature of such an inhibitory effect remains controversial. In this study, we investigated the acute effects of SS IgG on muscarinic receptor function in human submandibular gland (HSG) cells. Methods: The effects of autoantibodies on muscarinic receptor function were studied using microspectrofluorimetry, whole-cell patch clamp, immunofluorescence confocal microscopy, and a co-immunoprecipitation assay. Results: Carbachol (CCh) was found to consistently increase intracellular calcium concentration ([Ca2+]i) and activate K+ current in HSG cells. However, pretreatment of the cells with SS IgG for 5 or 30 min significantly attenuated these responses, with a substantially more prominent effect after 30 min of treatment. Like CCh, adenosine 5′-triphosphate (ATP) also increased [Ca2+]i and activated K+ currents in HSG cells, although pretreatment with SS IgG did not affect the cellular response to ATP. CCh was found to reorganize α-fodrin in HSG cells in a Ca2+-dependent manner. However, pretreatment with SS IgG prevented the cytoskeletal reorganization of α-fodrin induced by CCh. Conclusions: SS IgG acutely and reversibly inhibited muscarinic receptor function, thereby inhibiting the Ca2+ mobilization necessary for the activation of K+ currents and α-fodrin reorganization in HSG cells. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. METHODS: A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. RESULTS: The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P = 8.16 x 10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P = 7.61 x 10(-8)) and DPB1*0901 (P = 2.55 x 10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P = 7.58 x 10(-17)/4.84 x 10(-16)) or anticentromere autoantibodies (P = 1.12 x 10(-3)/3.2 x 10(-5)), respectively. CONCLUSION: The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies. [ABSTRACT FROM AUTHOR]

Aim: To test whether early implant placement into the extraction socket containing an uncalcified provisional matrix leads to successful osseointegration and stable marginal bone levels., Materials and Methods: In six mongrel dogs, the mandibular molars were extracted. Three weeks later, early implant placement was performed according to three experimental protocols: (i) flapless implant placement with preservation of the provisional matrix; (ii) flap elevation, socket debridement and implant placement; and (iii) flap elevation, socket debridement, implant placement and guided bone regeneration (GBR). One untreated extraction socket served as a control group. Data analyses were based on histologic slides 3 months after implant placement., Results: There were no differences in bone-to-implant contact between the three experimental groups (66.97%, 58.89% and 60.89%, respectively) (inter-group comparison p = .42). Marginal bone levels, first bone-to-implant contact as well as the thickness of the connective tissue did not reveal any significant differences between the groups (p = .85, .60 and .65, respectively)., Conclusions: Flapless early implant placement into posterior extraction sockets was as effective as an open flap approach in conjunction with GBR. Mineralization of the socket seems to occur irrespective of the presence of dental implants or biomaterials., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To investigate whether transmucosal healing is as effective as submerged healing in terms of buccal bone regeneration when guided bone regeneration (GBR) is performed simultaneously with implant placement., Materials and Methods: In six dogs, buccal dehiscence defects were created in the edentulous mandibular ridge, sized 5 × 5 × 3 mm (length × height × depth). In each defect, a bone-level implant was placed, and four experimental groups were randomly assigned as follows: (i) transmucosal healing with GBR (T-GBR), (ii) transmucosal healing without GBR (T-control), (iii) submerged healing with GBR (S-GBR) and (iv) submerged healing without GBR (S-control). Data analyses were based on histological slides 5 months after implant placement., Results: The T-GBR group showed significant differences compared to the control groups regarding defect height resolution, buccal bone thickness and mineralized tissue area (p < .05), but showed no significant differences when compared with the S-GBR group (p > .05)., Conclusions: The mode of healing (transmucosal vs. submerged) does not influence bone regeneration at implant sites. The clinician may therefore choose the approach based on further clinical and patient-specific parameters., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To compare the peri-implant soft-tissue dimensional changes following guided bone regeneration between particulate (particle group) and collagenated soft-block-type (block group) biphasic calcium phosphate (BCP)., Materials and Methods: This study investigated 35 subjects: 18 in the particle group and 17 in the block group. Cone-beam computed tomography obtained at 6 months post surgery and optical impressions taken periodically (before surgery, 6 months post surgery, and 1 year post surgery) were superimposed. The ridge contour changes over time and the peri-implant mucosal thicknesses were measured diagonally and horizontally, and analysed statistically., Results: The increases in diagonal (1.12 ± 0.78 mm) and horizontal (2.79 ± 1.90 mm) ridge contour of the block group were significantly higher than those in the particle group during the first 6 months (p < .05); however, the contour hardly changed thereafter (diagonal: 0.07 ± 0.75 mm; horizontal: -0.34 ± 1.26 mm), resulting in the 1-year contour changes similar between the two groups. Regardless of the type of BCP, the ridge contour increased significantly over 1 year when the dehiscence defect had a contained configuration (p < .05)., Conclusions: The increase in soft-tissue dimensions for 1 year was similar between the two groups. The mucosal contour increase was larger when the surgery was conducted in a more contained defect, and this was not influenced by the type of BCP., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To test the effect of membrane fixation on ridge volume stability and new bone formation using guided bone regeneration., Materials and Methods: In eight beagle dogs, after bilateral extraction of the maxillary pre-molars, a box-shaped defect was created on each side. All defect sites were augmented with a particulate bone substitute material, covered with either one of two non-cross-linked collagen membranes (CM1 or CM2) with or without fixation (-F or -UF). Samples were collected after 8 weeks. Histomorphometric and micro-computed tomography analyses were performed., Results: Membrane fixation made no significant difference to the total augmented volume for both membranes (p > .05). Histological data indicated that at the ridge crest the augmented tissue width amounted to 2.4 ± 0.4 mm in the group CM1-F and 2.4 ± 0.5 mm in the group CM1-UF, with no significant difference between the groups. Conversely, in CM2-F the augmented tissue width was significantly larger than in CM2-UF (2.3 ± 0.1 vs. 1.57 ± 0.27, p < .05)., Conclusions: Membrane fixation in contained defects failed to improve ridge volume stability regardless of the membrane type. However, it may enhance the width of the augmented ridge at the coronal portion depending on the type of membrane., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To test whether soft-type block bone substitute used for guided bone regeneration (GBR) of peri-implant defects leads to a different dimension of the augmented hard tissue than particulate bone substitute., Materials and Methods: In 40 patients, 40 two-piece dental implants were placed >2 months after tooth extraction. Following random allocation, 20 peri-implant bone dehiscences were grafted with a soft-type block made of synthetic biphasic calcium phosphate (BCP) + collagen and 20 bone dehiscences with particulate BCP. All the sites were covered with a collagen membrane stabilized with titanium pins. Immediately after wound closure and after 6 months, the horizontal dimension (HD) of the augmented hard tissue was measured at the level of implant shoulder using cone beam computed tomography. During re-entry at 6 months, the defect fill was clinically assessed., Results: At 6 months, the median HD measured 1.15 mm (mean: 1.31 mm) in the soft-block group and 0.93 mm (mean: 1.05 mm) in the particulate group (p = .6). At 6 months, 7.1% of contained defects and 61.9% of non-contained defects showed an incomplete vertical defect fill., Conclusions: Soft-type block of BCP + collagen used for GBR of peri-implant defects did not differ from particulate BCP regarding the dimension of the augmented hard tissue after 6 months of healing., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To assess the effect of Schneiderian membrane (SM) perforation on bone formation by applying a particulate deproteinized bovine bone mineral (PBBM)., Materials and Methods: Bilateral sinus augmentation was performed in eight rabbits. The same amount of PBBM was placed at a sinus where the SM was intentionally perforated for the perforation group (standardized to 3 mm diameter) and the other sinus with an intact SM that served as the intact group. At 12 weeks, all animals were euthanized for radiographic and histomorphometric analyses., Results: The area of the newly formed bone in the perforation group was significantly less than that in the intact group (18.7% and 25.5%, respectively, p = .028). The newly formed bone in the area close to the perforated SM was significantly less than that in the intact group (18.7% and 26.1%, respectively, p < .05). However, there was no significant difference in the total augmented area (p = .234) and the total augmented volume (p = .382) between the two groups., Conclusion: SM perforation had an adverse effect on new bone formation, predominantly close to the area of membrane perforation. However, no significant difference was found in the total augmented volume between the SM perforation and the intact groups., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To compare the efficacy of a collagenated synthetic bone substitute (C-SBS) to a particulated synthetic bone substitute (P-SBS) in volume maintenance and new bone formations in a rabbit sinus model., Materials and Methods: Either C-SBS or P-SBS was grafted in both sinuses of 16 rabbits. Four (N = 8) or 12 (N = 8) weeks after the surgery, total augmented volume (TAV) and area (TAA), as well as new bone volume (NBV) and area (NBA), were statistically compared by radiographic and histomorphometric analyses (p < .05)., Results: The differences in TAV, NBV, TAA and NBA between C-SBS and P-SBS groups at 4 weeks were not statistically significant. The TAV (267.13 ± 62.08 vs. 200.18 ± 40.32 mm 3 ) and NBV (103.26 ± 10.50 vs. 71.10 ± 7.58 mm 3 ) in group C-SBS were significantly higher than in group P-SBS at 12 weeks (p < .05). The TAA (19.36 ± 2.88 vs. 14.48 ± 2.08 mm 2 ) and NBA (5.43 ± 1.20 vs. 3.76 ± 0.78 mm 2 ) in group C-SBS were significantly higher than in group P-SBS at 12 weeks (p < .05)., Conclusions: Collagenated synthetic bone substitute grafted in rabbit sinuses demonstrated more favourable outcomes across all outcome measures compared to P-SBS at 12 weeks., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: The purpose of this retrospective study was to determine clinical benefits of ridge preservation in terms of surgical invasiveness of implant placement compared to natural healing in the maxilla., Materials & Methods: This study included 178 patients with 206 implants placed at ridge-preserved sites and 493 patients with 656 implants placed at naturally healed sites in maxillary anterior and posterior regions. Patient- and implant-related data were collected from electronic dental records including additional augmentation procedures performed before or during implant placement and surgical complications. Cumulative survival rate was assessed using Kaplan-Meier method. The annual peri-implant marginal bone loss between the two groups was compared using the Mann-Whitney U test., Results: The follow-up period was 24.4 ± 18.1 months (mean ± standard deviation) for ridge-preserved sites and 45.7 ± 29.6 months for naturally healed sites. Sinus augmentation was performed at similar frequencies in the two groups, but lateral approach was applied significantly more at naturally healed sites (37.2%) than ridge-preserved sites (8.3%, p ≤ .001). There was no intergroup difference in the cumulative survival rate or annual peri-implant marginal bone loss., Conclusion: Ridge preservation can be clinically beneficial for minimizing the invasiveness of implant surgery by simplifying the procedure when sinus augmentation is expected in the maxilla., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: To evaluate the histologic and volumetric changes of gingival tissues following grafting with collagen-based matrices at labial aspect of teeth in canines., Materials and Methods: Gingival augmentation was performed in the mandibular incisor area using two types of xenogeneic cross-linked collagen matrices (CCMs), bovine CCM for BCCM group and porcine CCM for PCCM group, whereas the contralateral sides remained untreated (B-control group and P-control group). Descriptive histology, histometric and volumetric analyses were performed after 12 weeks. For statistical comparison between each test group and respective control group, paired t test was used for histometric analysis, and repeated-measured analysis of variance was used for volumetric analysis (p < 0.05)., Results: An increased number of rete pegs and an enhanced formation of new blood vessels were observed at both grafted sites compared to the corresponding control sites. There was statistically significant gain of horizontal thickness only in BCCM group (1.36 ± 0.27 mm vs. 1.26 ± 0.34 mm; p < 0.05) compared to the B-control groups., Conclusion: BCCM was effective for gingival augmentation in terms of horizontal thickness at the labial aspect of teeth at 12 weeks post-surgery., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: To investigate the role of post-operative intensity-modulated radiotherapy (IMRT) in patients receiving narrow-margin hepatectomy for hepatocellular carcinoma (HCC) located close to the major vessels., Methods: This exploratory study involved 181 HCC patients. Of them, 116 were treated with narrow-margin (<1.0 cm) hepatectomy. Thirty-three of the 116 underwent postoperative IMRT (Group A), while 83 did not receive radiotherapy (Group B). The remaining 65 patients underwent wide-margin (≥1.0 cm) hepatectomy (Group C). Prognosis and patterns of recurrence were assessed in the three groups., Results: The 3-year overall survival (OS) and disease-free survival (DFS) rates were 89.1 and 64.2% in Group A, 67.7 and 52.2% in Group B and 86.0 and 60.1% in Group C respectively. The OS and DFS of Group A and Group C patients surpassed those of Group B patients (Group A vs. B, P = 0.009 and P = 0.038; and Group C vs. B, P = 0.002 and P = 0.010). Patients in Groups A and C experienced significantly fewer early recurrences than did patients in Group B (P = 0.002). Furthermore, patients in Groups A and C experienced substantially fewer intrahepatic marginal (P = 0.048) and diffuse recurrences (P = 0.018) and extrahepatic metastases (P = 0.038) than did patients in Group B. No patient developed radiation-induced liver disease., Conclusions: Post-operative IMRT following narrow-margin hepatectomy may be a favourable therapy for both its safety profile and clinical benefit in patients with HCC located close to the major vessels., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported., Methods: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure., Results: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies., Conclusion: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX., (Copyright © 2013 by the American College of Rheumatology.)

Objective: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects., Methods: Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort., Results: Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032., Conclusion: Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis., (Copyright © 2013 by the American College of Rheumatology.)

Objective: T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac., Methods: We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction., Results: A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007)., Conclusion: Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians., (Copyright © 2011 by the American College of Rheumatology.)

Objective: A previous genome-wide association study conducted in a population of European ancestry identified rs4963128, a KIAA1542 single-nucleotide polymorphism (SNP) 23 kb telomeric to IRF7 (the gene for interferon regulatory factor 7 [IRF-7]), to be strongly associated with systemic lupus erythematosus (SLE). This study was undertaken to investigate whether genetic polymorphism within IRF7 is a risk factor for the development of SLE., Methods: We genotyped one KIAA1542 SNP (rs4963128) and one IRF7 SNP (rs1131665 [Q412R]) in an Asian population (1,302 cases, 1,479 controls), to assess their association with SLE. Subsequently, rs1131665 was further genotyped in independent panels of Chinese subjects (528 cases, 527 controls), European American subjects (446 cases, 461 controls), and African American subjects (159 cases, 115 controls) by TaqMan genotyping assay, to seek confirmation of association in various ethnic groups. A luciferase reporter assay was used to assess the effect of Q412R polymorphism on the activation of IRF-7., Results: Consistent association of rs1131665 (Q412R) with SLE was identified in Asian, European American, and African American populations (total 2,435 cases and 2,582 controls) (P(meta) = 6.18 × 10(-6) , odds ratio 1.42 [95% confidence interval 1.22-1.65]). Expression of the IRF7 412Q risk allele resulted in a 2-fold increase in interferon-stimulated response element transcriptional activity compared with expression of IRF7 412R (P = 0.0003), suggesting that IRF7 412Q confers elevated IRF-7 activity and may therefore affect a downstream interferon pathway., Conclusion: These findings show that the major allele of a nonsynonymous SNP, rs1131665 (412Q) in IRF7, confers elevated activation of IRF-7 and predisposes to the development of SLE in multiple ethnic groups. This result provides direct genetic evidence that IRF7 may be a risk gene for human SLE., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Interferon-gamma-inducible protein 10 (IP-10; also called CXCL10), a chemokine important in the migration and proliferation of T cells, is induced in a wide variety of cell types. However, the role of IP-10 in rheumatoid arthritis (RA) remains largely unknown. The purpose of this study was to examine the potential role of IP-10 in bone resorption and RA through examination of a mouse model of collagen-induced arthritis (CIA)., Methods: The effects of IP-10 on mouse T cells during osteoclast differentiation were examined in migration assays. The bone-erosive activity of IP-10 was determined in vivo in a mouse model of CIA by histologic and immunostaining analyses. Cytokine levels in serum and culture medium were measured with sandwich enzyme-linked immunosorbent assays., Results: Serum concentrations of IP-10 were significantly higher in mice with CIA than in control mice. RANKL greatly induced IP-10 expression in osteoclast precursors, but not in mature osteoclasts. IP-10 stimulated the expression of RANKL and tumor necrosis factor alpha (TNFalpha) in CD4+ T cells and induced osteoclastogenesis in cocultures of CD4+ T cells and osteoclast precursors. However, IP-10 did not induce RANKL or TNFalpha in CD8+ T cells. Treatment with neutralizing antibody to IP-10 significantly inhibited the infiltration of CD4+ T cells and F4/80+ macrophages into the synovium and attenuated bone destruction in mice with CIA. Furthermore, levels of RANKL and TNFalpha were inhibited by antibody to IP-10. Bone erosion was observed in mice infected with an IP-10 retrovirus., Conclusion: Our findings suggest that IP-10 plays a critical role in the infiltration of CD4+ T cells and F4/80+ macrophages into inflamed joints and causes bone destruction. Our results provide the first evidence that IP-10 contributes to the recruitment of inflammatory cells and is involved in bone erosion in inflamed joints.

Objective: To examine genetic polymorphisms in the chemokine pathway, and to assess their interactions in relation to susceptibility to systemic sclerosis (SSc)., Methods: To identify the risk of SSc conferred by genetic polymorphisms in the chemokine pathway, 10 single-nucleotide polymorphisms (SNPs) from 8 candidate genes were studied in 99 patients with SSc and 198 age- and sex-matched controls in a Korean population. SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism or sequence-specific primer methods. Genetic associations between each SNP and SSc risk, calculated as odds ratios with 95% confidence intervals, were estimated using chi-square tests. Haplotypes for the 2 polymorphisms in the gene CCL5 (RANTES) were constructed, and their associations with SSc were tested. Gene-gene interactions were investigated using a recently described novel method, and the results were confirmed by conditional logistic regression. Adjustment for multiple testing was based on Bonferroni correction., Results: There was significant evidence of gene-gene interaction between polymorphisms in the genes CXCL8 (interleukin-8) and CCL5, and both of these were associated with an increased risk of SSc. This SNP-SNP interaction was confirmed by 2 independent statistical methods. The associations remained significant after Bonferroni adjustment for multiple testing. No significant association between each individual SNP or haplotype and the risk of SSc was found., Conclusion: Crosstalk between the 2 chemokines CXCL8 and CCL5 may contribute to the susceptibility to SSc.

Objective: We have previously described anti-KS autoantibodies and provided evidence that they are directed against asparaginyl-transfer RNA (tRNA) synthetase (AsnRS). The aim of the present study was to identify patients with anti-AsnRS autoantibodies and elucidate the clinical significance of this sixth antisynthetase antibody. In particular, we studied whether it was associated with the syndrome of myositis (polymyositis or dermatomyositis [DM]), interstitial lung disease (ILD), arthritis, and other features that had been previously associated with the 5 other anti-aminoacyl-tRNA synthetase autoantibodies., Methods: More than 2,500 sera from patients with connective tissue disease (including myositis and ILD) and controls were examined for anti-AsnRS autoantibodies by immunoprecipitation (IP). Positive and control sera were tested for the ability to inhibit AsnRS by preincubation of the enzyme source with the serum. The HLA class II (DRB1, DQA1, DQB1, DPB1) alleles were identified from restriction fragment length polymorphism of polymerase chain reaction-amplified genomic DNA., Results: Anti-AsnRS antibodies were identified in the sera of 8 patients (5 Japanese, 1 American, 1 German, and 1 Korean) by IP of the same distinctive set of tRNA and protein that differed from those precipitated by the other 5 antisynthetases, and these antibodies showed specific inhibition of AsnRS activity. Two of these patients had DM, but 7 of 8 (88%) had ILD. Four patients (50%) had arthritis, and 1 had Raynaud's phenomenon. This antisynthetase was very rare among myositis patients (present in 0% of Japanese myositis patients), but it was found in 3% of Japanese ILD patients. Thus, most patients with anti-AsnRS had chronic ILD with or without features of connective tissue disease. Interestingly, all 4 Japanese patients tested had DR2 (DRB1*1501/1502), compared with 33% of healthy controls., Conclusion: These results indicate that anti-AsnRS autoantibodies, like anti-alanyl-tRNA synthetase autoantibodies, have a stronger association with ILD than with myositis and may be associated with the DR2 phenotype.

In the title compound, catena-poly[[trisilver(I)-tri-mu3-N,N-diethyldithiocarbamato-3'kappaS:1kappaS':2kappaS;1kappaS:2kappaS':3kappaS;2kappaS:3kappa2S,S':1'kappaS'], [Ag3(C5H10NS2)3]n, the trigonally and tetrahedrally coordinated Ag atoms are mu3-bridged by kappa3- and kappa4-S2CNEt2 ligands to form a ribbon structure along the c axis. There is a twofold axis parallel to the b axis and passing through the tetrahedrally coordinated Ag atom. The S2CNEt2 ligands coordinate the Ag atoms in eta1,eta2- and eta2,eta2-fashions, depending on the bridging S atoms. The distances between the trigonal Ag and S atoms are 2.4915 (11)-2.6205 (11) A, while those between the tetrahedral Ag and S atoms are 2.5457 (11) and 2.7145 (10) A. The shortest Ag...Ag distance between trigonal Ag atoms is 2.8336 (7) A, which indicates a weak Ag...Ag interaction, whereas the shortest distance between trigonal and tetrahedral Ag atoms is 3.463 (6) A, which is considered as non-bonding.

Objective: Microchimeric cells have been identified in lesions and peripheral blood of patients with systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM), and HLA-DQA1*0501 is a risk factor for these diseases in some populations. Furthermore, DQA1*0501 has been associated with T lymphocyte microchimerism in SSc. To better define the strength of this association, we assessed the relationship among DQA1 alleles and microchimerism., Methods: DNA from whole peripheral blood or magnetically sorted T cells was tested for microchimeric cells by polymerase chain reaction of the Y chromosome or of HLA-Cw in 87 SSc patients, 28 juvenile IIM patients, and 88 healthy controls. Thirty-seven mother-son pairs were also analyzed for microchimerism and DQA1*0501., Results: We were unable to demonstrate that DQA1*0501 is associated with microchimerism in T lymphocytes or in whole peripheral blood DNA in patients with SSc or juvenile IIM or in healthy individuals. In the 37 mother-son pairs, we were unable to demonstrate an association of DQA1*0501 with microchimerism in peripheral blood DNA or T lymphocytes, and compatibility between the donor's and recipient's HLA alleles did not influence microchimerism in the recipient., Conclusion: These data suggest that HLA-DQA1 alleles do not appear to play a role in the persistence of microchimerism in the peripheral blood or T lymphocytes of patients with selected autoimmune diseases or in healthy individuals.

Objective: To assess the impact of the FcgammaRIIA-R/H131 polymorphism on the risk for antiphospholipid syndrome (APS), both primary and secondary to systemic lupus erythematosus (SLE)., Methods: This international meta-analysis combined data from 9 research teams. FcgammaRIIA-R/H131 genotypes were determined in 481 APS cases (206 with primary APS), 1,420 SLE controls, and 1,655 disease-free controls. Data were combined using fixed-effects and random-effects models., Results: Compared with disease-free controls, the RR genotype was enriched in the entire group of APS cases (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.28-2.14); this was driven mostly by patients with secondary APS (OR 1.95, 95% CI 1.45-2.63). The excess of RR homozygotes but not heterozygotes among APS patients suggested a recessive mode of inheritance, rather than the additive model seen for SLE susceptibility, where RR conferred greatest risk, and RH intermediate risk, for SLE. This probably reflected the additional influence of another opposing genetic effect of HH homozygosity on APS predisposition (OR 0.72 for RH versus HH, 95% CI 0.55-0.96). Among SLE patients, those with APS were more frequently HH homozygotes than heterozygotes (OR 0.56 for RH versus HH, 95% CI 0.39-0.81). HH homozygosity also tended to predominate in primary APS compared with secondary APS (OR 0.50 for RR versus HH, 95% CI 0.25-0.99 by fixed-effects model). There was no significant between-study heterogeneity for any of these effects., Conclusion: The FcgammaRIIA-R/H131 polymorphism is an important determinant of predisposition to APS, with different influences on SLE and APS susceptibility per se.

Objective: Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA-B27 could play a role in this process, but does not account for the many HLA-B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA)., Methods: Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase-polymerase chain reaction., Results: Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues., Conclusion: Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.

Objective: Recently, chondrocytes were shown to undergo apoptosis by the addition of nitric oxide and by coupling of Fas/Fas ligand in vitro, suggesting the possibility that chondrocytes have an inherent programmed cell death pathway that operates in adult cartilage. Chondrocyte apoptosis was verified in situ in articular cartilage samples from humans with osteoarthritis (OA) and from an animal model of OA. The present study investigates apoptotic chondrocyte death and the expression of Bcl-2 and Fas in rheumatoid arthritis (RA) cartilage., Methods: Cartilage samples were obtained from 13 RA patients at the time of joint replacement surgery and from 8 normal subjects at autopsy. Apoptotic chondrocytes were observed and counted in hematoxylin and eosin-stained cartilage specimens. Apoptosis was verified by TUNEL, electron microscopy, and DNA ladder assay. Bcl-2 and Fas expression were evaluated by immunohistochemistry., Results: Apoptotic cells were frequently observed in RA cartilage, whereas normal cartilage rarely showed apoptotic cells (3.01% versus 0.15%, respectively), a finding that was further confirmed by TUNEL staining. On electron microscopy, numerous apoptotic cells with typical chromatin condensation were observed in RA cartilage. DNA from RA cartilage also revealed 180-basepair nucleosome ladders on electrophoresis. Bcl-2 expression was significantly lower in RA cartilage than in normal cartilage (23.3% versus 43.1%, respectively), whereas Fas expression was not statistically different., Conclusion: Apoptotic chondrocyte death and decreased Bcl-2 expression were verified in RA cartilage. They might provide a novel model system for the research of cartilage breakdown and joint destruction in RA.

Objective: To better understand genetic contributions to autoimmunity, immunogenetic markers were studied in two racially discrete and geographically isolated populations of patients with idiopathic inflammatory myopathy (IIM)., Methods: Clinical characteristics, as well as clinical and autoantibody subsets, were defined in 151 American white patients and 50 Korean patients with IIM. HLA-DRB1 and DQA1 genotyping was performed on patients and racially matched controls by standard molecular techniques. Gm allotypes and phenotypes were determined by the hemagglutination-inhibition method., Results: HLA-DRB1*0301, the linked allele DQA1*0501, and DRB1 alleles sharing the first hypervariable region motif 9EYSTS13 were major genetic risk factors for the development of myositis in whites (corrected P [Pcorr] < 0.0004, odds ratio [OR] 11.2, 4.5, and 3.1, respectively, for each factor versus controls). Although both the white and Korean patients had a similar distribution of clinical characteristics, autoantibody profiles, and clinical groups, no HLA-DRB1 nor DQA1 allele or motif was found to be a risk factor for IIM in the Korean patients. However, DRB1*14 was a protective factor in Korean patients without myositis-specific autoantibodies (Pcorr = 0.004, OR 0.046). In addition, although no Gm phenotype or allotype was identified as a risk factor in whites, Gm 21 was a protective factor for the development of IIM in Koreans (Pcorr = 0.024, OR 0.3)., Conclusion: Although myositis patients in the US and Korea share similar clinical and serologic features, the immune response genes predisposing to and protecting from myositis in each of these ethnic groups differ at two chromosomal loci. These data suggest that multiple genetic loci should be studied to identify risk and protective factors for some autoimmune diseases in various ethnic populations.

Objective: Abnormal immune complex clearance is a feature of systemic lupus erythematosus (SLE). Polymorphisms of the Fc gamma receptor type IIa (Fc gammaRIIa) genes (the receptor binds IgG2 and IgG3) are important disease susceptibility factors in some populations. This study sought to determine the effects of these polymorphisms among Korean patients with SLE., Methods: Polymerase chain reaction of genomic DNA and allele-specific oligonucleotide hybridization were used to determine Fc gammaRIIa genotypes in Korean patients with SLE and healthy control subjects. Clinical manifestations were analyzed in each patient and correlated with the genotypes., Results: Among the 73 SLE patients, there was an abnormal distribution of Fc gammaRIIa alleles when compared with 64 controls: 11.0% of the SLE patients were homozygous for Fc gammaRIIa-H131 compared with 34.4% of the controls (odds ratio [OR] 0.20, 95% confidence interval [95% CI] 0.04-0.95, chi2 = 5.7, P = 0.01699). The allelic frequency of Fc gammaRIIa-H131 was significantly lower in the SLE patients than in the controls (49.3% versus 63.3%; P = 0.02019), and it was also significantly lower in lupus patients with nephritis compared with the normal population (OR 0.53, 95% CI 0.29-0.95, chi2 = 5.15, P = 0.02330), but was not significantly lower in lupus patients without nephritis (P = 0.13663 versus controls). Clinically, the level of proteinuria was significantly higher in the lupus nephritis patients who had R/R131 than in those who had H/H131 or R/H131., Conclusion: An abnormal distribution of Fc gammaRIIa polymorphisms was associated with SLE in Korean patients. There was a significant decrease in the Fc gammaRIIa-H/H131 genotype and H131 allelic frequency in SLE patients, particularly in those with nephritis. This suggests that the H131 allele confers some protection from SLE in this population.