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Hemidesmosomes (HDs) are adhesion complexes that promote epithelial-stromal attachment in stratified and complex epithelia, including the epidermis. In various biological processes, such as differentiation and migration of epidermal keratinocytes during wound healing or carcinoma invasion, quick assembly and disassembly of HDs are prerequisites. In this study, we show that inhibition of Wnt/0-catenin signaling disturbs HD organization in keratinocytes. Screening with inhibitors identified the depletion of HD components and HD-like structures through Wnt inhibition, but keratinocyte differentiation was not affected. Wnt inhibition significantly diminished plectin and type XVII collagen expression in the basal side of Wnt-inhibited cells and the dermo-epidermal junction of the Wnt-inactive murine basal epidermis. Similar to Wnt inhibition, PLEC- knockout cells or cells with plectin-type XVII collagen binding defects showed type XVII collagen reduction in the basal side of the cells, implying the possible involvement of Wnt/beta-catenin signaling in HD assembly. Atypical protein kinase C inhibition ameliorated the phenotypes of Wnt-inhibited cells. These findings show that Wnt/beta-catenin signaling regulates the localization of HD components in keratinocytes and that the atypical protein kinase C pathway is involved in Wnt inhibition-induced HD disarrangement. Our study suggests that the Wnt signaling pathway could be a potential therapeutic target for treating HD-defective diseases, such as epidermolysis bullosa.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and skin fibrosis. Recently, the presence and pathogenic role of immune complexes (ICs) of SSc patients were reported. However, the identities of antigens in these ICs are unknown. Therefore, we examined ICs in the serum of SSc patients to elucidate SSc pathogenesis. In this study, IC concentrations in serum samples from SSc and systemic lupus erythematosus (SLE) patients were measured by C1q enzyme-linked immunosorbent assays; immune complex analysis was used for comprehensive identification and comparison of antigens incorporated into ICs (IC-antigens). The expression patterns of SSc-specific IC-antigens in skin sections were investigated by immunohistochemistry. Compared with SLE patients who developed disease because of IC deposition, SSc patients had a greater number of IC-antigens and a smaller difference in IC concentrations, suggesting that SSc pathogenesis is affected by the proteins present in ICs. In contrast, the IC concentration and number of IC-antigens did not significantly differ according to the clinical phenotype of SSc. We identified 478 IC-antigens in SSc patients, including multiple RNAP II-associated proteins that were targeted by antibodies previously associated with SSc pathogenesis. The most frequently detected RNAP II-associated protein, RNA polymerase II transcription subunit 30 (MED30), was strongly expressed at lesion sites and reportedly regulates endothelial differentiation. Therefore, increased expression of MED30 in lesions may have an antigenic effect, and MED30 function may be impaired or inhibited by IC formation. RNAP II-associated proteins may SSc pathogenesis through mechanisms such as the MED30 pathway., Journal of Autoimmunity, 134, art. no. 102954; 2022

A 58-year-old Japanese woman with herpes zoster developed Behcet's disease (BD) with symptoms including orthostatic intolerance as an autonomic disorder. Multiple immune-suppressive therapies and a β-blocker successfully controlled both the disease activity of BD and the autonomic disorders. A cytokine multiplex analysis of her serum revealed the elevation of proinflammatory cytokines [interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor alfa (TNFα), and interferon gamma (IFN-γ)] and a low IL-10 concentration. IL-10 production is reported to be important for defense against herpes zoster virus (VZV). Insufficient IL-10 production is reported in BD. The reactivation of VZV with this cytokine profile suggests that BD will develop with various symptoms, including severe autonomic disorders.

© 2020, King Fahd University of Petroleum & Minerals. In areas where traffic demand is high and intersections are closely spaced, the drivers’ desire for quick discharge is demotivated by negative downstream conditions, such as long queues and poorly coordinated traffic signals, which may lead to lower saturation flow rate (SFR) for upstream lane groups. However, existing models do not consider this phenomenon. This paper proposes an improved intelligent driver model for reproducing the impacts of downstream traffic conditions on the discharging behavior of vehicles and the estimated SFR. A micro-simulation platform for two closely spaced signalized intersections is built to test the improved car-following model and to simulate the influenced SFR. Results from the sensitivity analysis and the comparison with empirical data show that the developed model could rationally and reliably reproduce the SFR reduction under different downstream conditions. As the queue in the downstream segment becomes longer and the offset becomes larger due to poor coordination, the SFR at the upstream intersection deteriorates. The developed model can be applied in traffic simulations to provide more realistic discharging behavior considering the downstream conditions.

A 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment. c 2019 Japanese Society of Internal Medicine.

We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. “PD responder” was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that. Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P

A 70-year-old woman presented with a fever and pain in both lower extremities and the right shoulder and right upper arm continuously for approximately 3 months. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG/PET-CT) revealed the accumulation of FDG in the right shoulder, lumbar spinous processes, both ischial tuberosities, and both hips and greater trochanters, indicating polymyalgia rheumatica (PMR). In addition, upper gastrointestinal endoscopy revealed esophageal carcinoma.After endoscopic submucosal dissection was performed, her musculoskeletal symptoms spontaneously improved,and the 18F-FDG/PET-CT findings decreased. In light of these findings, she was diagnosed with paraneoplastic syndrome. When atypical features of PMR, such as asymmetric symptoms occur, we should search for malignancies.

A 70-year-old woman presented with a fever and pain in both lower extremities and the right shoulder and right upper arm continuously for approximately 3 months. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG/PET-CT) revealed the accumulation of FDG in the right shoulder, lumbar spinous processes, both ischial tuberosities, and both hips and greater trochanters, indicating polymyalgia rheumatica (PMR). In addition, upper gastrointestinal endoscopy revealed esophageal carcinoma.After endoscopic submucosal dissection was performed, her musculoskeletal symptoms spontaneously improved,and the 18F-FDG/PET-CT findings decreased. In light of these findings, she was diagnosed with paraneoplastic syndrome. When atypical features of PMR, such as asymmetric symptoms occur, we should search for malignancies., Internal medicine, 58(6), pp.861-864; 2019

A 44-year-old Japanese man with a 14-year history of limited cutaneous systemic sclerosis (SSc) was admitted with a fever, hypertension, anemia, thrombocytopenia, and renal dysfunction. On admission, hypertension, hyperreninemia, acute renal dysfunction,hemolytic anemia, and thrombocytopenia led to the diagnosis of scleroderma renal crisis (SRC) complicated with thrombotic microangiopathy (TMA). The patient had also been infected with influenza B virus almost six days before admission. Following treatment with plasma exchange,an angiotensin-converting enzyme inhibitor, and an anti-virus agent, his general condition improved. He had no risk factors for SRC.In SSc patients, an influenza virus infection might trigger SRC complicated with TMA.

Background: Nevus is a hamartoma or malformation of one or more skin components, resulting in aberrant differentiation of the cell lineage(s) mostly during developmental stages. Although multiple lineages may be involved in a nevus, the combination of melanocyte and keratinocyte abnormalities has been rarely discussed. Objectives. To present two cases of congenital nevi with hypomelanosis and superficial fine scales. Materials & Methods: Skin specimens of the patients were analysed by immunohistochemistry and electron microscopy. Results: Morphological and immunohistochemical studies indicated aberrant epidermal differentiation in the lesional skin specimens. Electron microscopy showed defective melanosome maturation in the melanocytes of the nevi samples. Conclusion: These results demonstrate that both epidermal and melanocytic lineages can concomitantly contribute to the formation of a nevus lesion.

A 72-year-old Japanese woman diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis was admitted to our hospital with hearing loss, temporal pain, and sudden blindness. We finally diagnosed recurrent granulomatosis with polyangiitis and initiated methyl-prednisolone pulse therapy (1,000 mg) followed by prednisolone (30 mg/day) and rituximab (RTX). After the third RTX administration, she developed bloody stools along with acute thrombocytopenia and low complement levels. We diagnosed rituximab-induced acute thrombocytopenia (RIAT), and her platelet counts spontaneously recovered. This case suggests that after RTX therapy RIAT may sometimes cause severe thrombocytopenia, and that monitoring the complements may be useful for making an early diagnosis of RIAT.

Additional file 1: Fig. S1. Changes in the serum levels of OPG over the 6-month abatacept treatment period. Serum OPG was significantly elevated at 6 months after the introduction of abatacept (Wilcoxon signed ranks test). Horizontal bar, median; boxes, 25th and 75th percentiles; bars, 5th and 95th percentiles. OPG: osteoprotegerin. Fig. S2. Comparison of the changes in the SDAI and total PD score between the patients with a low Dkk-1 (n = 30) and those with a high Dkk-1 (n = 29). Wilcoxon signed ranks test. Horizontal bar, median; boxes, 25th and 75th percentiles; bars, 5th and 95th percentiles. PD: power Doppler, SDAI: Simple Disease Activity Index. Fig. S3. Comparison of the changes in the SDAI and total PD score between the patients with a low SOST (n = 30) and those with a high SOST (n = 29). Wilcoxon signed ranks test. Horizontal bar, median; boxes, 25th and 75th percentiles; bars, 5th and 95th percentiles.

Additional file 1: Supplementary Table S1. Comparison of baseline characteristics in patients with different backgrounds.

Supplemental material, sj-pdf-1-imr-10.1177_03000605211002083 for Tocilizumab has no direct effect on cell lines infected with human T-cell leukemia virus type 1 by Yushiro Endo, Shoichi Fukui, Tomohiro Koga, Daisuke Sasaki, Hiroo Hasegawa, Katsunori Yanagihara, Akihiko Okayama, Tatsufumi Nakamura, Atsushi Kawakami and Hideki Nakamura in Journal of International Medical Research

Additional file 2: Table S1. Baseline characteristics of the patients. Table S2. Causes of death.

Objective. To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjogren's syndrome (pSS) fulfilling the 2002 classification criteria. Methods. The Big Data Sjogren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. Results. The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score >= 1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/ SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. Conclusion. Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Additional file 1: Figure S1. The attainment of a complete renal response (CR) after 6 and 12 months of induction therapy in the early- and late-onset LN groups. *p

A 56-year-old Japanese woman with muscle weakness, increased creatine kinase and aldolase levels, and characteristic cutaneous lesions was diagnosed with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 antibody)-positive dermatomyositis. She also had interstitial lung disease (ILD). After corticosteroid and tacrolimus combination therapy was started, bicytopenia and elevated serum ferritin and trans-aminase emerged. Because the bone marrow tissues were hypoplastic with hemophagocytes, she was diagnosed with concomitant autoimmune-associated hemophagocytic syndrome (HPS). Intravenous cyclophosphamide pulse therapy and plasmapheresis were performed. The laboratory findings indicated improved abnormalities, and the ILD did not progress. Anti-MDA5 antibody-positive dermatomyositis can be complicated by HPS.

RATIONALE: Idiopathic multicentric Castleman disease (iMCD) is a systemic disease with multiple regions of lymphadenopathy and systemic symptoms and associated with rheumatoid arthritis (RA) and collagen diseases. However, few reported have described the coexistence of iMCD and RA and the mechanisms by which iMCD induces arthritis remain elusive. We experienced a rare case of iMCD, wherein the patient exhibited symptoms of polyarthritis with high-grade fever. PATIENT CONCERNS: A 34-year-old woman was admitted to our hospital for further evaluation of a high fever with polyarthritis. The levels of both rheumatoid factor and anticitrullinated protein antibody were negative.F-fluorodeoxyglucose/positron emission tomography-computed tomography showed lymphadenopathy with increased fluoro-2-deoxy-D-glucose uptake. Magnetic resonance imaging and musculoskeletal ultrasonography revealed active synovitis in the hands which was consistent with RA. DIAGNOSES: We diagnosed iMCD based on human herpesvirus 8 negativity, HIV negativity, systemic lymphadenopathy, and pathologic findings of the lymph nodes. The patient did not satisfy the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for RA. Cytokine assay showed elevated serum levels of interleukin-17and CXCL10, comparable to those in patients with RA. INTERVENTIONS: We administered 15?mg/d of predonisolone. OUTCOMES:After this treatment, the patient's symptoms showed improvement. As of this writing, we tapered the prednisolone to 7.5?mg/d,and the patient's remission has been maintained for >4 months. LESSONS: The present case suggests that RA-like active synovitis may coexist in iMCD, resulting from aberrant T-cell activation and histologic examination using lymph node biopsy may help enable early diagnosis of iMCD., Medicine, 98(18), e15237 ;2019

ESRA (E-Survey of Road users’ Attitudes) is a joint initiative of road safety institutes, research centres, public services, and private sponsors from all over the world. The aim is to collect and analyse comparable data on road safety performance, in particular road safety culture and behaviour of road users. The ESRA data are used as a basis for a large set of road safety indicators. These provide scientific evidence for policy making at national and international levels. Vias institute in Brussels (Belgium) initiated and coordinates ESRA, in cooperation with eleven core group partners (BASt, BFU, CTL, IATSS, IFSTTAR, ITS, KFV, NTUA, PRP, SWOV, TIRF). At the heart of ESRA is a jointly developed questionnaire survey, which is translated into national language versions. The themes covered include self-declared behaviour, attitudes and opinions on unsafe traffic behaviour, enforcement experiences and support for policy measures. The survey addresses different road safety topics (e.g. driving under the influence of alcohol, drugs and medicines, speeding, distraction) and targets car occupants, motorcycle and moped drivers, cyclists and pedestrians.

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Background: When multipass transmembrane molecules are located on the cell surface, there may be interaction with not only bioactive molecules but also pathogenic molecules in areas protruding outside the cell. In antibody-mediated autoimmune disorders, it has been found that the autoantibodies occasionally attack membrane molecules on the cell surface, thus causing the disease such as myasthenia gravis. In such cases, highly sensitive autoantibody detection technology is required for early diagnosis. However, autoantibody analysis technology that is specialized for membrane molecules is still under development. Here we demonstrate a novel method for detecting of antibodies against the extracellular portions of multipass transmembrane molecules. Methods: Antibodies for muscarinic acetylcholine receptor type3 (M3R) were detected with two kinds of luciferase immunoprecipitaion systems (LIPS), conventional LIPS (cLIPS) and its modified application, termed modified LIPS (mLIPS). In mLIPS, antibodies against extracellular portions of membrane molecules could be preferentially detected. Results: An antibody to the amino-terminal portion of human M3R was detected with modified LIPS with a high sensitivity. In contrast, an antibody to the carboxyl-terminal portion was not detected with mLIPS, because it did not interact with intracellular portions of M3R in living cells. We also found antibodies for M3R in a patient serum with Sjogren’s syndrome. Conclusion: Our technology has a promising future, and we hope that it will be applied in the analysis of antibodies against a diverse range of multipass transmembrane molecules, including GPCRs., Acta medica Nagasakiensia, 60(2), pp.69-76; 2016

A 78-year-old woman diagnosed with cyclic neutropenia 5 years previously had been treated with recombinant granulocyte-colony stimulating factor (G-CSF). She developed fever, tenderness and distension of temporal arteries after the treatment with G-CSF. Magnetic resonance imaging and ultrasonography revealed wall thickening of the temporal arteries. She was therefore diagnosed with giant cell arteritis (GCA). Small vessel vasculitis has been reported as a complication of G-CSF. However, the development of large vessel vasculitis after G-CSF treatment is quite rare. To our knowledge, the present case is the first report of GCA suspected to be associated with coexisting cyclic neutropenia and G-CSF treatment.

We herein report a woman in her 50s with systemic lupus erythematosus (SLE) who developed swelling and pain in her fingers; the symptoms were more prominent in winter. Magnetic resonance imaging (MRI) revealed bone edema in the phalanges of both hands, which was compatible with phalangeal microgeodic syndrome (PMS). This is the first reported case of PMS in a patient with SLE and suggests that performing MRI should be considered for patients with SLE in order to assess the nature of finger symptoms and signs more precisely.

RATIONALE: Rare cases of reactive arthritis induced by active extra-articular tuberculosis (Poncet disease) have been reported. Complete response to antitubercular treatment and evidence of active extra-articular tuberculosis are the most important clinical features of Poncet disease. We report the case of successfully treated a patient with reactive arthritis induced by active extra-articular tuberculosis with a TNF inhibitor after sufficient antitubercular treatment. PATIENT CONCERNS: A 56-year-old Japanese man was admitted to our department with polyarthralgia, low back pain, and high fever. The results of rheumatoid factor, anti-citrullinated protein antibody, human leukocyte antigen B27, and the assays for the detection of infections (with an exception of T-SPOT.TB) were all negative. Fluoro-deoxy-D-glucose-positron emission tomography with CT (PET/CT) showed moderate uptake in the right cervical, right supraclavicular, mediastinal, and abdominal lymph nodes. As magnetic resonance imaging and power Doppler ultrasonography showed peripheral inflammation (tendinitis, tenosynovitis, ligamentitis, and enthesitis in the limbs). DIAGNOSIS: A diagnosis of tuberculous lymphadenitis was eventually established on the basis of lymph node biopsy results. There was no evidence of a bacterial infection including acid-fast bacteria in his joints, and the symptoms of polyarthralgia and low back pain were improved but not completely resolved with NSAID therapy; in addition, a diagnosis of reactive arthritis induced by active extraarticular tuberculosis was made. INTERVENTIONS: The patient experienced persistent peripheral inflammation despite antitubercular treatment for more than nine months and was then successfully treated with a tumor necrosis factor inhibitor (adalimumab 40 mg every 2 weeks). OUTCOMES: Finally, the patient responded to the treatment and has been in remission for over 4 months as of this writing. LESSONS: In patients who present with symptoms associated with spondyloarthritis, it is important to distinguish between classic reactive arthritis and reactive arthritis induced by extra-articular tuberculosis infection. Introduction of biological agents should be carefully considered in settings where reactive arthritis induced by active extra-articular tuberculosis shows progression to chronicity despite sufficient antitubercular treatment., Medicine, 98(49), e18008; 2019

Rationale:The pathology of gouty arthritis and reactive arthritis (ReA) partially overlaps, and both diseases are characterized by the production of inflammatory cytokines associated with the activation of monocytes and macrophages. However, the precise cytokine profile of cases with a coexistence of both diseases is unknown, and there are few reports on the course of treatment in patients with both gouty arthritis and ReA.Patient concerns:A 39-year-old man with a recurrent episode of gouty arthritis presented prednisolone-resistant polyarthritis with high level of C-reactive protein (CRP). He had the features of gouty arthritis such as active synovitis of the first manifestation of metatarsophalangeal (MTP) joints and the presence of monosodium urate (MSU) crystals from synovial fluid. But he also had the features of ReA such as the presence of tenosynovitis in the upper limb, the positivity of human leukocyte antigen (HLA)-B27, a history of sexual contact and positive findings of anti-Chlamydia trachomatis-specific IgA and IgG serum antibodies.Diagnoses:He was diagnosed with HLA-B27 associated Chlamydia-induced ReA accompanied by gout flares.Interventions:He was treated with 180 mg/day of loxoprofen, 1 mg/day of colchicine, and 10 mg/day of prednisolone for gout flares. However, his polyarthritis worsened with an increased level of CRP (23.16 mg/dL). Accordingly, we added 500 mg/day of salazosulfapyridine followed by adalimumab (ADA) 40 mg once every 2 weeks.Outcomes:After starting ADA, the patient's symptoms and laboratory findings showed rapid improvement and he achieved clinical remission 1 month after initiation of ADA treatment. As of this writing, the patient's clinical remission has been maintained for >1 year.Lessons:This case suggests that with exacerbation of arthritis during gouty arthritis, coexistence with other pathologies such as peripheral spondyloarthritis should be considered, and early intensive treatment including tumor necrosis factor inhibitors may be necessary., Medicine, 98(40), e17233; 2019

Table S1. Association between growth differentiation factor 15 (GDF-15) and organ involvements. Table S2. Changes of serum biomarkers and immunoglobulin G4-related disease responder index (IgG4-RD RI) score after glucocorticoid treatment in 13 patients. (DOCX 18 kb)

Table S1. Association between growth differentiation factor 15 (GDF-15) and organ involvements. Table S2. Changes of serum biomarkers and immunoglobulin G4-related disease responder index (IgG4-RD RI) score after glucocorticoid treatment in 13 patients. (DOCX 18 kb)

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Objective To investigate whether human T lymphotropic virus type I (HTLV-I) directly infects salivary gland epithelial cells (SGECs) and induces the niche of the salivary glands in patients with Sjogren's syndrome (SS). Methods SGECs were cultured with the HTLV-I-producing CD4+ T cell line HCT-5 or with Jurkat cells. Antibody arrays, immunofluorescence analysis, and enzyme-linked immunosorbent assay (ELISA) were used to determine the profiles of inflammation-related molecules, and the profiles of apoptosis-related molecules were determined by antibody array and immunofluorescence analysis. The presence of HTLV-I-related molecules was assessed by immunofluorescence analysis and in situ polymerase chain reaction. Apoptosis of SGECs was evaluated by TUNEL staining. Results Among the SGECs, 7.8 ± 1.3% (mean ± SD) were positive for HTLV-I-related proteins after 96-hour coculture with HCT-5 cells. Nuclear NF-κB p65 was also detected in 10% of the SGECs. The presence of HTLV-I proviral DNA in SGECs after coculture with HCT-5 cells was detected by in situ polymerase chain reaction. After coculture of SGECs with HCT-5, the expression of cytokines and chemokines, including soluble intercellular adhesion molecule 1, RANTES, and interferon γ-induced protein 10 kd (IP-10/CXCL10) was increased in a time-dependent manner. The expression of proapoptotic molecules (e.g., cytochrome c and Fas) and antiapoptotic molecules (e.g., Bcl-2, Heme oxygenase 2, and Hsp27) was increased in the SGECs cocultured with HCT-5, showing that apoptosis of SGECs was not detected after coculture with HCT-5 or Jurkat cells. Conclusion HTLV-I is thought to infect SGECs and alter their cellular functions. These changes may induce the niche of SS and contribute to the development of SS in anti-HTLV-I antibody-positive individuals., Arthritis & Rheumatology, 67(4), pp.1096-1106; 2015

Objective To investigate the relationship between the intercellular transmission efficiency of human T-lymphotropic virus type I (HTLV-I) and the signaling involved in actin polymerization during cytoskeletal reorganization in a comparative study of HTLV-I-infected T-cell lines derived from an HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient or an HTLV-I carrier. Methods HCT-5 and TL-Su cells derived from an HAM/TSP patient and an HTLV-I carrier, respectively, were used as HTLV-I-infected T-cell lines. After co-cultivation of each HTLV-I-infected T-cell line with H9/K30 luc reporter cells, the relative luc activities were calculated to analyze the efficiency of intercellular transmission of HTLV-I. The intracellular levels of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) were measured in enzyme-linked immunoassays. The expression of phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) was analyzed by western blotting. Results Treatment of HCT-5 cells with latrunculin B, an inhibitor of actin polymerization, significantly suppressed the relative luc activity. Western blotting analysis of HCT-5 cells treated with the adenylyl cyclase activator forskolin showed upregulation of p-VASP, with a concomitant and significant increase in the intracellular cAMP concentration. Furthermore, the relative luc activity was significantly decreased. The intracellular cAMP, but not cGMP levels, were significantly lower in HCT-5 than in TL-Su. Vasodilator-stimulated phosphoprotein appeared less phosphorylated in HCT-5 than in TL-Su. The relative luc activity was significantly higher in HCT-5 than in TL-Su. Conclusions The intracellular cAMP concentration regulates the efficiency of intercellular HTLV-I transmission under the control of p-VASP expression, suggesting the intercellular transmission potential of HTLV-I-infected T cells of HAM/TSP patients is enhanced by downregulated intracellular cAMP levels.

We herein report the case of a 21-year-old woman with refractory adult-onset Still's disease who developed central venous catheter-related methicillin-resistant Staphylococcus aureus sepsis during aggressive immunosuppressive therapy. She subsequently experienced septic pulmonary embolism (SPE) and sacroiliitis during treatment with intravenous vancomycin and was successfully treated with long-term oral linezolid therapy. This case suggests that the occurrence of methicillin-resistant Staphylococcus aureus infection in immunosuppressive patients can trigger severe clinical manifestations such as SPE and septic sacroiliitis and that linezolid is suitable for treating such conditions.

A 73-year-old man with a history of myasthenia gravis (MG) was diagnosed with rheumatoid arthritis (RA) based on a history of polyarthritis and positivity for anti-citrullinated protein antibodies (ACPA). He presented with a high level of serum vascular endothelial growth factor (VEGF) and RS3PE syndrome-like pitting edema in the extremities, which improved following treatment with low-dose prednisolone. This is an interesting case of ACPA-positive RA associated with RS3PE syndrome-like pitting edema and a high VEGF level.

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Tocilizumab (TCZ) was administered from 2004 to 2008 in a 52-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate (MTX) as a clinical trial. TCZ therapy with MTX was resumed in March 2009 due to exacerbation of RA. The patient was an human T-lymphotropic virus type I (HTLV-I) carrier, and, in April 2011, a peripheral blood smear showed many atypical lymphocytes, thus leading to a diagnosis of adult T-cell leukemia (ATL). Complete remission of ATL was achieved with a standard therapeutic regimen.

A 21-year-old man was admitted to our hospital with a fever, erythema, cervical lymphadenopathy and pancytopenia. A diagnosis of Sweet's syndrome (SS) with Kikuchi's disease (KD) and hemophagocytic syndrome (HPS) was made based on the results of a bone marrow aspiration along with the results from biopsy specimens of the brachial skin and a cervical lymph node. The expression of retinoic acid-inducible gene-I (RIG-I) in the skin epidermal basal layer as well as in a cervical lymph node was revealed through immunohistochemistry. He successfully entered remission through treatment with prednisolone. This findings of this case indicate that when SS with KD presents as HPS, it may suggest an association with an RIG-I-related innate immunity.

Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV). The present study was undertaken to investigate the role of CaMKIV in podocyte function in lupus nephritis (LN).We treated kidney podocytes with IgG derived from healthy individuals or patients with LN and then analyzed gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining, with or without silencing of neonatal Fc receptor (FcRn). In addition, we silenced CAMK4 in podocytes and analyzed the expression of selected genes. We also examined the expression of CD86 in kidney podocytes from MRL/lpr, MRL/lpr.camkiv(-/-), and MRL/MPJ mice by in situ hybridization.We found that exposure of podocytes to IgG resulted in entry of IgG into the cytoplasm. IgG entered podocytes via the FcRn because less IgG was found in the cytoplasm of podocytes treated with FcRn small interfering RNA. DNA microarray studies of podocytes exposed to LN-derived IgG revealed up-regulation of genes related to the activation of immune cells or podocyte damage. Interestingly, CD86 expression decreased after silencing CAMK4 in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv(-/-) mice.LN-derived IgG enters podocytes and up-regulates CAMK4, which is followed by increased expression of genes known to be linked to podocyte damage and T cell activation. Targeted inhibition of CAMK4 in podocytes may prove to be clinically useful in patients with LN.

We herein report the case of a female with Sjogren's syndrome (SS) complicated with trigeminal nerve palsy. Although her sicca symptoms had been unnoticed, head magnetic resonance imaging (MRI) for detecting brain abnormalities revealed parotid gland changes associated with SS. SS should be considerd as a possible cause of trigeminal nerve disturbances. In addition, parotid gland changes related to SS should be aware in examination of cranial nerve disturbances with MRI.

We examine the relationships among the estimators of each sample and the pooled sample. We demonstrate that after allowing different constant terms, the covariance matrix of the estimators of the pooled sample is smaller than those of each sample.

A 50-year-old Japanese woman, a patient with systemic lupus erythematosus (SLE) complicated with chronic lupus peritonitis, developed massive small intestinal hemorrhaging. She was treated with intravenous pulse of methylprednisolone, intravenous pulse of cyclophosphamide (IVCY), and immunoabsorption, but the peritonitis was refractory to these treatments. Subsequently, she was treated with oral corticosteroid and tacrolimus, and received IVCY monthly, but she developed massive small intestinal hemorrhaging 1 year after. Abdominal angiography detected multiple bleeding sites from the jejunal and ileal arteries. After transarterial embolization treatment, the melena disappeared. The pathology of this case appeared to be lupus mesenteric vasculitis.

We discovered novel peroxisome proliferator-activated receptor δ agonists with a characteristic benzisoxazole ring. Compound 5 exhibited potent human PPARδ transactivation activity. Furthermore, it stimulated the differentiation of oligodendrocyte precursor cells in vitro. This indicates that this potential drug may be effective for the treatment of demyelinating disorders such as multiple sclerosis.

A 36-year-old female patient who was diagnosed with chronic myocarditis as an initial manifestation of systemic lupus erythematosus (SLE) was admitted to our hospital. At her third occurrence of heart failure, we performed an endomyocardial biopsy and proved chronic myocarditis with SLE. Subsequently, she was treated with prednisolone and the immunosuppressive agent mizoribine (MZR), and her cardiac function improved. We describe for the first time treatment with MZR for chronic cardiac involvement of SLE.

Rationale: Among all dermatomyositis (DM) patients, antimelanoma differentiation-Associated gene 5 antibody (anti-MDA5 Ab) positive patients have significantly poor short-Term mortality, whereas they experience less relapses over the long term after the remission. We report the case of a patient with anti-MDA5 Ab-positive clinically amyopathic dermatomyositis (CADM) with the recurrence of interstitial lung disease (ILD) after 7 years of remission. There has been no case report of an anti-MDA5 Ab-positive DM patient with the recurrence of ILD after 7 years of long-Term remission. Patient concerns: A 70-year-old Japanese woman was diagnosed with anti-MDA5 Ab-positive CADM and ILD. After achieving 7 years long-Term remission, she was admitted to our department with erythema on the fingers and interstitial pneumonia. Her anti-MDA5 Ab titer was elevated. Diagnoses: We diagnosed recurrent CADM complicated with ILD. Interventions: We successfully treated her with 1,000 mg of methyl-prednisolone pulse and intravenous cyclophosphamide therapy followed by prednisolone 50 mg/day and an increase of cyclosporine. Outcomes: After that treatment, the patient's skin symptoms and interstitial pneumonia were relieved. All laboratory investigations such as ferritin, the serum markers of interstitial pneumonia (i.e., SP-A, SP-D), and the titer of anti-MDA5 Ab showed signs of improvement. Lessons: Her case suggests that careful physical examinations and monitoring the serum markers are important even after long-Term remission is achieved., Medicine, 97(26), art. no. e11024; 2018

A 72-year-old man who had been diagnosed with polymyositis (PM) was admitted to our hospital for pneumonia with exacerbation of muscle weakness, elevation of muscle enzymes, and positive magnetic resonance imaging findings. The patient had been refractory to cyclosporine A or azathioprine and hoped to avoid administration of high-dose steroids; IV immunoglobulin (IVIG) was therefore administered after improvement of the pneumonia. Two weeks after the IVIG therapy, muscle test scores, activities of daily living, and muscle enzymes were drastically improved. Twenty months after IVIG, no relapse of PM was observed.

Type B insulin resistance is characterized by the appearance of autoantibodies to the insulin receptor. We present a 59-year-old Japanese man with type B insulin resistance complicated with systemic lupus erythematosus (SLE). A high titer of anti-insulin receptor autoantibodies was revealed when SLE was defined as active disease. Intravenous boluses of cyclophosphamide (IVCY) with oral prednisolone and cyclosporin A induced remission of SLE, and a subsequent disappearance of anti-insulin receptor autoantibodies, followed by a recovery of glucose intolerance. This is a rare and important case report showing a clear correlation between anti-insulin receptor autoantibodies of type B insulin resistance and SLE disease activity.

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.