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Introduction: The low frequency of ectopic germinal center in labial salivary glands of patients with human T‐cell leukemia virus type 1 (HTLV‐1) antibody‐positive Sjögren's syndrome (SS) suggests that HTLV‐1 has some effects on follicular dendritic cells (FDCs). Methods: We used flow cytometry, immunofluorescence, and enzyme‐linked immunosorbent assays (ELISAs) to investigate the direct effect of HTLV‐1 on B‐cell activating factors produced by established FDC like cells obtained from excised human tonsils. We then measured the serum B‐cell activating factor (BAFF) and C‐X‐C motif ligand (CXCL) 13 concentrations of the HTLV‐1‐seropositive SS patients and the HTLV‐1‐seronegative SS patients by ELISA. Results: Among the 31 isolated specimens, 22 showed morphological characteristics of FDCs. Day 2‐cultured specimens showed expressions of CD14, CD23, CD40, intracellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1. After 2 weeks, 12 of these specimens expressed ICAM‐1, FDC, and fibroblast cell marker. Intracellular BAFF and CXCL13 were constitutively expressed regardless of stimulation. After direct coculture with the HTLV‐1‐infected T‐cell line HCT‐5 or MT‐2, the BAFF and CXCL13 expressions on the FDC‐like cells were decreased in accord with the increased number of HCT‐5 and MT‐2 cells with styliform change and without HTLV‐1 Gag protein expression. Interferons upregulated the concentration of BAFF (but not CXCL13) in the culture supernatant, which showed a declining trend under the presence of HCT‐5 or MT‐2. The serum concentrations of BAFF and CXCL13 in the HTLV‐1‐seropositive SS patients were lower than those of the HTLV‐1 seronegative SS patients. Conclusions: HTLV‐1 partially inhibited the BAFF and CXCL13 expressions of established FDC‐like cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sjögren’s syndrome (SS) is an autoimmune disease characterized by periductal lymphocytic infiltration of the salivary and lacrimal glands. SS also exhibits extra-glandular manifestations and specific autoantibodies. Salivary gland ultrasonography (SGUS) is a common procedure used to assess the severity of glandular involvement. However, the association between SGUS and extra-glandular lesions remains poorly understood. This study aimed to identify clinical indices, including disease activity, associated with glandular involvement using SGUS in patients with SS. We included 115 patients with SS and 90 without SS. Patients with SS had significantly higher ultrasonography (US) score than patients without SS. Multivariate analysis revealed focus score, Saxon test positivity, and anti-centromere antibody (ACA) positivity as independent variables associated with the US score in patients with SS. In addition, these results were similar to those obtained in patients with primary SS. Patients with SS and ACA positivity had higher US score and an increased prevalence of hyperechoic bands in the parotid glands and submandibular glands. In conclusion, this study indicated that ACA positivity is associated with the US score in patients with SS. These results suggest that US findings in patients with ACA positivity might show specific changes in the salivary glands, especially fibrosis. [ABSTRACT FROM AUTHOR]

Takei et al. [[1]] showed that not only the EBV gene but also its related proteins were identified in rheumatoid arthritis (RA) synovium. In particular, Epstein-Barr virus (EBV) and human T-cell leukemia virus type 1 (HTLV-1) are known to be involved in rheumatic diseases. Viral infection, which is one of the environmental factors, and human autoimmune diseases are often associated with each other. [Extracted from the article]

As part of the 'Central Dogma' of molecular biology, the function of proteins and nucleic acids within a cell is determined by their primary sequence. Recent work, however, has shown that within living cells the role of many proteins and RNA molecules can be influenced by the physical state in which the molecule is found. Within living cells, both protein and RNA molecules are observed to condense into non-membrane-bound yet distinct structures such as liquid droplets, hydrogels and insoluble aggregates. These unique intracellular organizations, collectively termed biomolecular condensates, have been found to be vital in both normal and pathological conditions. Here, we review the latest studies that have developed molecular tools attempting to recreate artificial biomolecular condensates in living cells. We will describe their design principles, implementation and unique characteristics, along with limitations. We will also introduce how these tools can be used to probe and perturb normal and pathological cell functions, which will then be complemented with discussions of remaining areas for technological advance under this exciting theme. [ABSTRACT FROM AUTHOR]

Highlights • CaM and CaMKII diffusion was measured with FCS in HEK293 cells and cultured neurons. • A simultaneous multiple-point FCS recording system was developed. • CaM showed activity-dependent change in diffusion properties in neurons. • FCS detected holoenzymatic forms of CaMKIIα and β and degradation by stimulation. Abstract Calcium/calmodulin-dependent protein kinase II (CaMKII) and calmodulin (CaM) play essential roles in synaptic plasticity, which is an elementary process of learning and memory. In this study, fluorescence correlation spectroscopy (FCS) revealed diffusion properties of CaM, CaMKIIα and CaMKIIβ proteins in human embryonic kidney 293 (HEK293) cells and hippocampal neurons. A simultaneous multiple-point FCS recording system was developed on a random-access two-photon microscope, which facilitated efficient analysis of molecular dynamics in neuronal compartments. The diffusion of CaM in neurons was slower than that in HEK293 cells at rest, while the diffusion in stimulated neurons was accelerated and indistinguishable from that in HEK293 cells. This implied that activity-dependent binding partners of CaM exist in neurons, which slow down the diffusion at rest. Diffusion properties of CaMKIIα and β proteins implied that major populations of these proteins exist as holoenzymatic forms. Upon stimulation of neurons, the diffusion of CaMKIIα and β proteins became faster with reduced particle brightness, indicating drastic structural changes of the proteins such as dismissal from holoenzyme structure and further fragmentation. [ABSTRACT FROM AUTHOR]

We retrospectively evaluated the effectiveness of combined use of salivary gland ultrasonography (US) and the 2016 American College of Rheumatology/European League Against Rheumatic Disease (ACR/EULAR) classification criteria for improving the diagnostic efficiency in patients with Sjögren’s syndrome (SS). A US-based salivary gland disease grading system was developed using a cohort comprising 213 SS or non-SS patients who fulfilled the minimum requirements for classifying SS based on the American-European Consensus Group (AECG) and ACR criteria. Using 62 SS or non-SS patients from the 213 patients and who had also undergone all the 5 examinations needed for the ACR/EULAR classification, we compared the diagnostic accuracy of various combinations of the ACR/EULAR and US classifications for diagnosing SS, using the clinical diagnosis of SS by rheumatologists as the gold standard. The ACR/EULAR criteria discriminated clinical SS patients with 77% and 79% accuracy for those with primary or secondary SS and for those with primary SS, respectively. However, the integrated score system of the ACR/EULAR and US classifications yielded 92% and 93% accuracy for these 2 SS patient groups, respectively, provided that US score of 3 was assigned to patients with US grade ≥2, and then patients with integrated threshold score of ≥5 were diagnosed as SS. Cross-validation also indicated improved accuracy of the integrated ACR/EULAR and US score system (91.9 and 93.0% for primary/secondary and primary SS patients, respectively) over that by the ACR/EULAR criteria alone. (74.2 and 86.0%, respectively). The integrated ACR/EULAR and US scoring system can improve the diagnosis of patients with clinical SS. [ABSTRACT FROM AUTHOR]

Background: While tumor necrosis factor alpha (TNF-a) inhibitors (TNFi) and other biologics are very effective against autoimmune diseases, they can also cause infectious diseases. Therefore, it is important to clarify whether the TNFi sometimes used to treat patients with rheumatoid arthritis (RA) complicated with human T-lymphotropic virus type-I (HTLV-I) infection have the unintended side effect of promoting HTLV-I proliferation. Methods: We used the HTLV-I-infected cell line HCT-5, derived from spinal fluid cells of a patient with HTLV-I associated myelopathy, to evaluate the production of cytokines and chemokines, TNF-á receptor (TNFR), the expression of HTLV-I associated genes, the HTLV-I proviral load (PVL), the expression of HTLV-I structural protein, and apoptosis. We used Jurkat cells as a control. Results: Supernatants of HCT-5 showed time-dependent elevations of IL-6, RANTES and ICAM-1. HCT-5 supernatants treated with infliximab, adalimumab, etanercept (ETN), golimumab and certolizumab pegol showed no significant differences in the levels of these molecules compared to the control. Neither TNFR1 nor TNFR2 expression was altered by any TNFi treatment, relative to phosphate-buffered saline (PBS) treatment, with the exception that TNFR2 was significantly decreased and internalized in HCT-5 cells by ETN treatment. The HTLV-I associated genes Tax and HBZ and the PVL levels were not significantly changed. Immunofluorescence staining of HCT-5 for an HTLV-I-associated protein, GAG, was also not significantly different between any of the TNFi treatments and the PBS treatment. DNA ladders as an index of apoptosis were not detected. Apoptotic cells were not increased by the addition of any TNFi. Conclusions: In vitro, TNFi did not affect the cytokine profiles, expression of associated genes and proteins, proviral load or apoptosis of HCT-5 cells. The results suggested that TNFi treatment of RA patients complicated with HTLV-I might have no effect on HTLV-I infection. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to reassess the prevalence and characteristics of human T lymphotropic virus type I (HTLV-I)-associated Sjögren's syndrome (SS) and SS in HTLV-I-associated myelopathy (HAM) based on the American European Consensus Group (AECG) criteria in HTLV-I endemic area, Nagasaki prefecture.Methods: The 349 patients who underwent a minor salivary gland biopsy (MSGB) for suspected SS were retrospectively classified by AECG classification criteria and divided with or without anti-HTLV-I antibody.Results: The HTLV-I data-available 294 patients were investigated. One hundred-seventy patients were classified as SS and 26.5 % were HTLV-I-seropositive. We have included 26 patients with HTLV-I-associated myelopathy (HAM) and 38.5 % were classified as having SS. The prevalences of ANA and anti-SS-A/Ro antibody of HAM + SS were significantly low compared to the HTLV-I asymptomatic carriers (AC) with SS and the HTLV-I-seronegative SS patients, although lacrimal dysfunction tended to be high in HAM + SS and significantly high in AC + SS patients compared with the patients with HTLV-I-seronegative SS. The focus scores of MSGB in the HAM + SS patients were similar to those of the AC + SS patients and the HTLV-I-seronegative patients with SS. Among the MSGB-positive patients, there was a low prevalence of ANA in the HAM + SS patients. Similar results were obtained in case of anti-SS-A/Ro or SS-B/La antibody.Conclusion: In HTLV-I endemic area, high prevalence of anti-HTLV-I antibody among SS as well as the characteristics of HAM + SS and AC + SS was still determined by AECG classification criteria. [ABSTRACT FROM AUTHOR]

Background: Guided parent-delivered cognitive behavioural therapy (GPD-CBT) is an effective low-intensity treatment for childhood anxiety disorder in Western countries and can increase access to evidence-based psychological therapies. Aim: This study aimed to examine its feasibility in a Japanese sample. Method: Twelve children with anxiety disorders and their parents participated in the study, and ten children and parents completed the program. Participants were assessed at pre-, post- and one-month follow-up using a diagnostic interview for anxiety disorders, self- and parent-report measures for anxiety, depression, parental behaviour, and parental anxiety. Results: Four children (40% of completers) were free from their primary diagnoses immediately following the brief treatment, and seven children (70%) at the one-month follow-up. Changes in disorder severity, child and parent reported anxiety symptoms, and child reported depression symptoms were consistent with those found in Western trials of GPD-CBT and of Japanese trials of more intensive CBT for child anxiety disorders that involves both the child and the parent. Moderate increases were also found in child reported parental autonomy behaviours; however, there were only small changes in parent self-reported anxiety. Conclusion: These results support the potential of GPD-CBT to increase access to evidence-based treatments for anxiety disorders in Japanese children. [ABSTRACT FROM AUTHOR]

A 63-year-old man with enlargement of the bilateral submandibular glands visited with elevated serum IgG4. A biopsy specimen showed plasma cell infiltration with more than 50% IgG4/IgG staining, suggesting the existence of IgG4-related disease (IgG4-RD). Positive anti-SS-A/Ro antibody and the labial salivary gland's biopsy suggested existence of primary Sjögren's syndrome (pSS). Administration of glucocorticoid improved the serum IgG4 level while reducing the submandibular gland lesions. Positive TUNEL staining suggested the coexistence of IgG4-RD and pSS. [ABSTRACT FROM AUTHOR]

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 Sjögren'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. [ABSTRACT FROM AUTHOR]

To obtain current epidemiological information on primary focal hyperhidrosis in Japan, a large epidemiological survey was conducted using a web-based questionnaire. The prevalence of primary focal hyperhidrosis was 10.0% and the site-specific prevalence was highest for primary axillary hyperhidrosis (5.9%). The proportion of respondents with primary focal hyperhidrosis who had consulted a physician was 4.6%, which was similar to the low prevalence reported previously in 2013 in Japan. A questionnaire survey for physicians and individuals with primary axillary hyperhidrosis on the current medical management of primary axillary hyperhidrosis showed that physicians recognized the existence of patients who were very worried about hyperhidrosis, but failed to provide active treatment. Regarding the information provided by patients to physicians at presentation, it was found that patients failed to provide sufficient information to the physicians about their worries in daily life. Among individuals who had sought medical care with primary axillary hyperhidrosis, 62.3% reported that they were not currently receiving treatment, highlighting a challenge to be addressed regarding continued treatment. Frequently chosen options leading to willingness to receive treatment were less expensive treatment and highly effective treatment as well as feeling free to consult a physician, suggesting a desire for an improved medical environment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a case of a 53-year old man with xerophthalmia and xerostamia, and adult T-cell leukemia (ATL) mimicking sicca symptoms (SS).

Viruses are a possible cause for Sjögren's syndrome (SS) as an environmental factor related to SS onset, which exhibits exocrine gland dysfunction and the emergence of autoantibodies. Although retroviruses may exhibit lymphocytic infiltration into exocrine glands, human T-cell leukemia virus type 1 (HTLV-1) has been postulated to be a causative agent for SS. Transgenic mice with HTLV-1 genes showed sialadenitis resembling SS, but their phenotypic symptoms differed based on the adopted region of HTLV-1 genes. The dominance of tax gene differed in labial salivary glands (LSGs) of SS patients with HTLV 1-associated myelopathy (HAM) and adult T-cell leukemia. Although HTLV-1 was transmitted to salivary gland epithelial cells (SGECs) by a biofilm-like structure, no viral synapse formation was observed. After infection to SGECs derived from SS patients, adhesion molecules and migration factors were time-dependently released from infected SGECs. The frequency of the appearance of autoantibodies including anti-Ro/SS-A, La/SS-B antibodies in SS patients complicated with HAM is unknown; the observation of less frequent ectopic germinal center formation in HTLV-1-seropositive SS patients was a breakthrough. In addition, HTLV-1 infected cells inhibited B-lymphocyte activating factor or C-X-C motif chemokine 13 through direct contact with established follicular dendritic cell-like cells. These findings show that HTLV-1 is directly involved in the pathogenesis of SS. [ABSTRACT FROM AUTHOR]

This study aimed at ascertain whether innate immunity is involved in the apoptosis of primary cultured salivary gland epithelial cells (SGECs) in primary Sjögren's syndrome (pSS). Induction of apoptosis of SGECs was performed using a TLR3 ligand, poly (I:C). Activation of phosphorylated-Akt (pAkt) and cleaved-caspase 3 was determined by Western blotting or immunofluorescence. Expression of TLR2 and TLR3 with pAkt was observed in cultured SGECs after 24-h stimulation with each ligand. Compared with stimulation with the peptidoglycan or lipopolysaccharide, that with poly (I:C) induced significant nuclear fragmentation, as determined by Hoechst staining ( p = 0.0098). Apoptosis was confirmed by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) staining of SGECs from pSS patients and a normal subject. A significant increase in TUNEL-positive cells was observed by the addition of a PI3K inhibitor, LY294002. Poly (I:C) phosphorylated stress-activated protein kinase/Jun-terminal kinase and p44/42 MAP kinase as well as Akt. Furthermore, poly (I:C)-induced caspase 3 cleavage in SGECs was also inhibited by LY294002. Similar results were obtained using SGECs obtained from a normal subject. The results demonstrated for the first time that TLR3 induces the apoptotic cell death of SGECs via the PI3K-Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to show the clinical and pathological characteristics of anti-centromere-antibody (ACA)-seropositive Sjögren's syndrome (SS) in two anti-human T-cell leukemia virus type I (HTLV-I)-seropositive patients. Methods: One patient was an HTLV-I carrier whereas the other was diagnosed with HTLV-I-associated myelopathy (HAM). Background data including serum HTLV-I titers, viral loads, and cytokine profiles were recorded. Azocarmine with aniline blue (Azan)-Mallory staining and immunohistochemistry of the labial salivary glands (LSGs) and a muscle biopsy specimen from the HAM patient were performed. Results: Serum transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), and HTLV-I viral load were high in the HAM-SS patient compared with the HTLV-I carrier. Fibrous change in LSG was prominent in the HAM-SS patient. Although TGF-β expression was similar in the two patients, expression of HTLV-I-related proteins including p12, p28, group-specific antigen (GAG), and nuclear factor kappa-B (NF-κB) in the LSG were dominantly detected in the HAM-SS patient. Frequency of TGF-β staining in HTLV-I-seropositive SS patients without ACA, HTLV-I-seronegative SS patients with ACA, and HTLV-I-seronegative SS patients without ACA was lower than that of the previous two patients. Conclusion: A high HTLV-I viral load in situ is supposed to promote the production of cytokines, especially TGF-β, resulting in the fibrous change of LSG in ACA-seropositive SS patients. [ABSTRACT FROM AUTHOR]

A 68-year-old man with a fever of unknown origin was admitted to our hospital. Bilateral auricularis and nasal root inflammation, with auricular perichondritis positive for anti-type II collagen (CII) antibody, led to a diagnosis of relapsing polychondritis (RP). Because the patient was refractory for high-dose glucocorticoid therapy, adalimumab was used. After the initiation of 40 mg of adalimumab, a rapid improvement of clinical manifestations, with a reduction in tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), together with a titer of anti-CII antibody was observed. [ABSTRACT FROM AUTHOR]

A 68-year-old woman was admitted with bleary eyes and lacrimal gland swelling. A biopsy specimen from a right paravertebral mass lesion detected by computed tomography showed remarkable IgG4-positive plasma cells. Because serum IgG4 was elevated to 3300 mg/dl, IgG4-related disease was diagnosed, with the assistance of fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). Administration of 30 mg of oral prednisolone effectively reduced the lacrimal gland swelling and paravertebral mass volume. Nine months after the initiation of prednisolone, serum IgG4 was reduced to 31.4 mg/dl, and there was norecurrence. [ABSTRACT FROM AUTHOR]

Mutations in the plectin gene ( PLEC) generally lead to epidermolysis bullosa simplex (EBS) associated with muscular dystrophy. It has been recently demonstrated that PLEC mutations can also cause a different clinical subtype, EBS associated with pyloric atresia (EBS-PA), which shows early lethality. Prenatal diagnosis (PND) of EBS-PA using mutation screening of PLEC has not been described. This study aimed to perform DNA-based PND for an EBS-PA family. The EBS-PA proband was compound-heterozygous for a paternal c.1350G>A splice-site mutation and a maternal p.Q305X nonsense mutation. Genomic DNA was obtained from amniocytes taken from an at-risk fetus of the proband's family. Direct sequencing and restriction enzyme digestion of polymerase chain reaction products from the genomic DNA were performed. Mutational analysis showed that the fetus harbored both pathogenic mutations, suggesting that the fetus was a compound-heterozygote and therefore affected with EBS-PA. The skin sample obtained by autopsy from the abortus confirmed the absence of plectin expression at the dermal-epidermal junction. This is the first successful DNA-based PND for an EBA-PA family. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective. To assess the usefulness and performance of the American European Consensus Group (AECG) criteria based on minor salivary gland biopsy (MSGB) in Japanese patients with primary SS. [ABSTRACT FROM PUBLISHER]

Background: To clarify the clinicopathological characteristics of primary Sjögren's syndrome (pSS) with anticentromere antibody (ACA). Methods: Characteristics of 14 patients of pSS with ACA were evaluated. All patients were anti-SS-A/Ro and SS-B/La antibodies negative (ACA+ group) without sclerodactyly. The prevalence of Raynaud's phenomenon (RP), titer of IgG and focus score (FS) in the minor salivary glands (MSGs) were determined. Quantification analysis of Azan Mallory staining was performed to detect collagenous fiber. Forty eight patients in whom ACA was absent were chosen as the conventional (ACA-) pSS group. Results: Prevalence of ACA+ SS patients was 14 out of 129 (10.85%) pSS patients. RP was observed in 61.5% of the patients with ACA. The level of IgG in the ACA+ group was significantly lower than that of the ACA- group (p = 0.018). Statistical difference was also found in the FS of MSGs from the ACA+ group (1.4 ± 1.0) as compared with the ACAgroup (2.3 ± 1.6) (p = 0.035). In contrast, the amount of fibrous tissue was much higher in the ACA+ group (65052.2 ± 14520.6 μm2 versus 26251.3 ± 14249.8 μm2 ) (p = 1.3 × 10-12). Conclusions: Low cellular infiltration but with an increase in fibrous tissues may explain the clinical feature of a high prevalence of RP and normal IgG concentration in ACA+ pSS. [ABSTRACT FROM AUTHOR]

A 60-year-old male who had been treated for polymyalgia rheumatica (PMR) with Raynaud’s phenomenon was admitted to our hospital with acrocyanosis and rapid progressive anemia. Hemolytic anemia with reduction of haptoglobin and cold agglutinin was detected, and the patient had a negative Donath-Landsteiner test. A skin biopsy from his toe revealed microthromboembolism without vasculitis, resulting in the diagnosis of cold agglutinin disease (CAD). This is a first case report of CAD complicated with PMR. [ABSTRACT FROM AUTHOR]

Abstract: Heterogeneous Sonogashira coupling of terminal alkynes with aryl halides was studied over a quinoline-2-carboimine palladium complex immobilized on MCM-41 (Pd-2QC-MCM) catalyst. The cross-coupling reaction occurred within 3h at 80°C by adding a piperidine in N-methyl-2-pyrolidone (NMP) solvent. By varying the combination of alkynes and aryl halides, Pd-2QC-MCM showed effective catalytic activities to produce corresponding tolane derivatives with moderate to excellent yields. Pd-2QC-MCM can be reused without significant loss of its catalytic activity until the fourth recycle under aerobic conditions because of negligible leaching of palladium metal and a high turnover number (∼2850) in the reaction of phenyl acetylene with iodobenzene. The excellent catalytic performance of Pd-2QC-MCM indicates that the reactions effectively occurred by a palladium complex immobilized on mesoporous silica. [Copyright &y& Elsevier]

In transport terms, Japan has an enviable reputation for operating effectively an incredibly complex road and rail system. However, relatively little is known about how this is done or about the issues that are facing policy-makers and shapers in the country. The purpose of this paper, then, is to investigate how land passenger transport is organized in Japan, and to begin to evaluate its effectiveness. This is done by drawing on a literature review and on findings from a scoping study based on a series of semi-structured in-depth interviews with key practitioners. Overall, the findings suggest that national and local transport policy in Japan faces a number of key challenges across all modes in the land passenger transport system, in particular relating to the fragmented approach to policy development, implementation, and operation and to the growing role of the car. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) exerts tropic effects on salivary epithelial cells. We examined EGF-mediated signaling pathways in the salivary epithelial cells of patients with Sjögren’s syndrome (SS). We compared the immunohistochemical expression of EGF receptor (EGF-R), phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor kappa B (NF-κB) in the labial salivary glands of SS patients ( n = 6) with those of control subjects ( n = 2). EGF-mediated signaling pathways were further studied in vitro ( n = 3) using primary salivary epithelial cells; NF-κB p65 nuclear translocation and Akt phosphorylation were examined by immunofluorescence and western blotting, respectively. The phosphorylation of EGF-R and Akt, and the nuclear expression of NF-κB p65, were increased in situ in the salivary epithelial cells of SS patients compared with those of control subjects. Epidermal growth factor induced rapid EGF-R phosphorylation and NF-κB p65 nuclear translocation in primary salivary epithelial cells in vitro. However, EGF also induced late Akt phosphorylation (after 12 h). Chemical inhibition of PI3K-Akt by LY294002/wortmannin did not affect EGF-mediated NF-κB p65 nuclear translocation; and NF-κB inhibition by Bay 11-7082 did not suppress Akt phosphorylation. Our data suggest that EGF stimulates both the PI3K-Akt pathway and NF-κB via distinct mechanisms, promoting tropic effects in SS salivary epithelial cells. [ABSTRACT FROM AUTHOR]

A 67-year-old woman, suffering from continuous hemoptysis, was admitted to our hospital where she was managed with mechanical ventilation. Computed tomography of the chest demonstrated bilateral massive alveolar hemorrhage without evidence of infectious disease. She was diagnosed with anti-myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated diffuse alveolar hemorrhage because a high titer of MPO-ANCA was found in the serum. Plasmapheresis as well as methylprednisolone pulse therapy were initiated, followed by intravenous administration of cyclophosphamide. Tacrolimus was employed for the maintenance therapy, and the oral prednisolone dosage could successfully be tapered without recurrence, along with the decrement of the titer of MPO-ANCA. [ABSTRACT FROM AUTHOR]

We wanted to determine via immunohistochemistry, whether or not c-Jun NH2-terminal kinase (JNK) cascade is activated in labial salivary infiltrating T cells in patients with Sjögren’s syndrome (SS). Six patients with primary SS were selected for this study. Phosphorylation of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) (SEK1), JNK, and c-Jun in salivary infiltrating T cells was studied using immunohistochemistry assay, including mirror section technique. Phosphorylated forms of MKK4, JNK, and c-Jun were detected in salivary infiltrating mononuclear cells. Expression of phosphorylated JNK was found in both CD4+ T cells and CD8+ T cells. Moreover, co-expression of phosphorylated JNK and c-Jun was demonstrated in the mirror sections. The results of this study suggest that the JNK cascade is activated in salivary infiltrating CD4+ T cells and CD8+ T cells in SS patients, which appears to contribute to the inflammatory salivary microenvironment of SS. [ABSTRACT FROM AUTHOR]

Abstract: Tumor necrosis factor-alpha (TNF-α) is a potent cytokine that is central to normal immune responses as well as autoimmune inflammatory diseases. The production of TNF-α protein is thus tightly regulated at multiple levels. Translational control is one of the means by which TNF-α production is repressed in unstimulated cells. To examine the mechanism by which the translation of TNF-α mRNA transcripts is repressed, we have used an in vitro translation system. The AU-rich element (ARE) in the 3′ UTR of TNF-α transcripts was sufficient to confer translational repression. This effect was observed using transcripts containing a 5′ m7G cap but not uncapped transcripts, and was independent of a poly(A) tail. Sucrose gradient analysis revealed that ARE-containing transcripts were present at relatively lower amounts in 80S-associated fractions and higher amounts in non-ribosome-bound RNA fractions, with no accumulation of 48S-associated transcripts. ARE-mediated translational repression was competitively inhibited by ARE-containing transcripts. These data indicate that a TNF-α ARE-binding trans-acting factor(s) inhibits the association of the 43S complex with RNA transcripts. [Copyright &y& Elsevier]

Abstract: The effect of SEA0400, a novel Na+-Ca2+ exchanger inhibitor, on mechanical and electrophysiological parameters of coronary-perfused guinea-pig right ventricular tissue preparation was examined during no-flow ischemia and reperfusion. Contractile force and action potential duration were decreased during no-flow ischemia, while the resting tension was increased. Upon reperfusion, transient arrhythmias were observed and contractile force returned to less than 50% of preischemic values. SEA0400 (1 μM) had no effect on the decline in contractile force during the no-flow ischemia, but abolished the rise in resting tension. SEA0400 significantly improved the recovery of contractile force after reperfusion to about 80% of the preischemic value. SEA0400 had no effect on the action potential under normal conditions and during ischemia, but significantly improved the recovery of action potential duration after reperfusion. Enhancement of the recovery of contractile force during reperfusion by SEA0400 was also observed when the drug was applied only before and during the ischemic period and when the drug was applied only during reperfusion. The present results indicate that inhibition of Na+-Ca2+ exchanger either during ischemia or during reperfusion exerts cardioprotective effects and enhances the recovery of myocardial contractile function. [Copyright &y& Elsevier]

Abstract: A comparative study of Heck vinylation of various aryl iodides with methyl acrylate, by either Ru(III) and Pt(IV) complexes immobilized on quinoline–carboimine functionalized FSM-16 (Ru-2QC, Pt-2QC) or Ru and Pt chlorides loaded impregnated on the same support (Ru-FSM, Pt-FSM) has been performed. The catalysts exhibit high activity and selectivity towards Heck vinylation of aryl iodides with methyl acrylate, even at low concentrations of metals (0.05–0.1mol% with respect to aryl halide). Conversion of various aryl iodides of 100% within 3–8h reaction and selectivity for trans-stereoisomer higher than 99% has been achieved over ruthenium containing catalysts (Ru-FSM, Ru-2QC). Platinum catalysts (Pt-FSM, Pt-2QC) were less active, resulting in the conversion of aryl iodides of 50–70%. The method of the modification influenced on heterogeneous character of reaction. The leaching was negligible in the case of Ru(III) and Pt(IV) complexes immobilized on quinoline–carboimine functionalized FSM-16, while metal species of transition metals supported on FSM-16 were leached to the solution. [Copyright &y& Elsevier]

Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor which is known to affect oxidative stress and PPARα ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARα ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA+WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARα ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver. [Copyright &y& Elsevier]

The safety and effectiveness of a Vero cell-derived inactivated Japanese encephalitis (JE) vaccine were compared with those of a current JE vaccine in non-clinical studies and a phase I clinical trial. The single-dose toxicity study showed no toxicity of either the current JE vaccine or the investigational Vero cell-derived JE vaccine. In a local irritation study, the degree of irritation caused by both vaccines was determined to be the same as that induced by normal saline. To investigate genotoxicity, a chromosomal aberration test was conducted and the results were negative. Both JE vaccines were administered to a group of 30 subjects who were seronegative (neutralizing antibody titer <101) for JEV virus (Beijing-1 Strain). Each subject was subcutaneously inoculated twice at an interval of 1–4 weeks, followed by an additional booster inoculation 4–8 weeks later, and clinical reactions and serological responses were subsequently investigated. Adverse drug reactions of local reaction, headache and malaise were mild, occurring at a rate of 6.7 and 20.0% after administration of the Vero cell-derived JE vaccine and the current JE vaccine, respectively. The seroconversion rate after three doses of both JE vaccines was 100%, while the geometric mean titer for the Vero cell-derived and current JE vaccines was 102.35 and 102.03, respectively. These results suggest that the safety and effectiveness of the Vero cell-derived inactivated JE vaccine are equal to those of the currently available conventional vaccine in humans, and that the Vero cell-derived vaccine could be a useful second-generation JE vaccine. [Copyright &y& Elsevier]

Abstract:We evaluated the relationship between the clinical benefit of filtration leukocytapheresis (LCP) and the number of removed leukocytes in patients with rheumatoid arthritis (RA). LCP was performed in 31 drug-resistant RA patients. LCP was carried out 3 times with 1 week separating each session. Assessment of RA before and after LCP showed a substantial and rapid improvement in tender joint counts, swollen joint counts, and patients' and physicians' assessments. Careful analysis indicated that 19 of 31 patients with RA showed ≥20% improvement following LCP therapy. The number of leukocytes in the peripheral blood significantly decreased during each session of LCP. However, there was no significant decrease in the number of circulating blood cells during the study period. No adverse reactions or complications were noted. There was no significant difference in any indices of clinical activity and the removal rates of leukocytes between responders and nonresponders. The total numbers of removed lymphocytes in responders were significantly higher than those in nonresponders (responders 64.1 × 108 versus nonresponders 50.7 ×108 , p < 0.05). The relationship between clinical effectiveness and the number of removed granulocytes and monocytes was not statistically significant. Our results suggest that filtration LCP to remove leukocytes from the peripheral blood, especially lymphocytes, exerts an immunomodulatory effect in patients with RA. [ABSTRACT FROM AUTHOR]

Nonlinear biomolecular interactions on membranes drive membrane remodeling crucial for biological processes including chemotaxis, cytokinesis, and endocytosis. The complexity of biomolecular interactions, their redundancy, and the importance of spatiotemporal context in membrane organization impede understanding of the physical principles governing membrane mechanics. Developing a minimal in vitro system that mimics molecular signaling and membrane remodeling while maintaining physiological fidelity poses a major challenge. Inspired by chemotaxis, we reconstructed chemically regulated actin polymerization inside vesicles, guiding membrane self-organization. An external, undirected chemical input induced directed actin polymerization and membrane deformation uncorrelated with upstream biochemical cues, suggesting symmetry breaking. A biophysical model incorporating actin dynamics and membrane mechanics proposes that uneven actin distributions cause nonlinear membrane deformations, consistent with experimental findings. This protocellular system illuminates the interplay between actin dynamics and membrane shape during symmetry breaking, offering insights into chemotaxis and other cell biological processes. [ABSTRACT FROM AUTHOR]

We show a noncommutative Rohlin type theorem for automorphisms of a certain class of purely infinite simple C*-algebras. This class consists of the purely infinite unital simple C*-algebras which are in the bootstrap category N and have trivial K[sub 1]-groups. [ABSTRACT FROM AUTHOR]

This article explains deviations from formal expectations regarding choice behavior in settings where economic rationality (i.e., own payoff maximization) dictates either cooperating (full contribution) or free tiding (no contribution) in the provision of public goods via the voluntary contribution mechanism. The authors find that the difference between full contribution and the observed level of contribution is greater than or equal to the corresponding difference when flee riding is the best strategy. This surprising result is interpreted as the "spiteful" behavior of subjects whose first priority is not the total amount of payoff they receive but the ranking among them. [ABSTRACT FROM AUTHOR]

• Risk index as a safety performance measure for roundabout designing was proposed. • Risk index combines the invisibility probability and the crash impact. • Model formula of risk index was presented through the numerical simulation. • Evaluation with risk index is expected to help improvement of roundabout designing. In the geometric design of roundabouts, safety-oriented approaches are required rather than specification design ones that simply determine the dimensions of the geometric structural elements. We herein propose a risk index (RI) that combines the invisibility probability and the crash impact as a performance measure for evaluating the safety of the geometric designs of roundabouts, and we also describe a method for calculating this index. Invisibility probability represents the probability that an entering vehicle cannot view a vehicle coming from the upstream in a circulatory roadway and crash impact represents the amount of lost kinetic energy at the time of collision corresponds to the impact of the crash. A numerical simulation to model this RI on the basis of various geometric conditions is further presented. It is demonstrated that the invisibility probability is large when the entry angle is small and that the crash impact increases when the deviation angle decreases. The proposed approach is expected to help resolve issues with currently existing roundabouts and improve the design of future roundabouts to enhance their safety performance. [ABSTRACT FROM AUTHOR]

47-year-old woman who had been treated for systemic lupus erythematosus (SLE) with myasthenia gravis (MG) was admitted to our hospital with acute onset of severe anemia after administration of isoniazid. Pure red cell aplasia (PRCA) was confirmed by elevated serum iron levels, reticulocytopenia and bone marrow aspiration showing a remarkable reduction of erythroblasts. Finally, cyclosporine A successfully improved PRCA. Although both SLE and MG have the potential complication of PRCA, we report here a case of isoniazid-triggered PRCA. [ABSTRACT FROM AUTHOR]

A 60-year-old man who had been diagnosed as rheumatoid arthritis admitted to our hospital by dysesthesia on his legs with edema. Nerve conduction velocity test led to diagnosis of mononeuritis multiplex. Magnetic resonance imaging (MRI) of lower legs showed high intensity in slow tau inversion recovery. Typical vasculitis with neutrophil-dominant cell infiltration was observed by muscle biopsy without inflammatory myopathy or fascitis. Diagnosis was made by rheumatoid vasculitis found in crural muscles. Intravenous cyclophosphamide with oral tacrolimus effectively improved dysesthesia with reduction of inflammatory response. [ABSTRACT FROM AUTHOR]

A 66-year-old woman showing renal dysfunction with elevated serum alkaline phosphatase and anti-SS-A antibody was admitted. A labial salivary gland biopsy showing infiltration of mononuclear cells and positive anti-SS-A antibody with sicca symptoms led to a diagnosis of primary Sjögren’s syndrome (SS). Fanconi’s syndrome was diagnosed by renal tubular acidosis along with renal glucosuria or aminoaciduria and multiple bone fractures on bone scintigraphy. Typical bilateral pulmonary shadows were confirmed as organizing pneumonia (OP) determined by the analysis of bronchoalveolar lavage fluid and transbronchial lung biopsy. A rare complication of Fanconi’s syndrome with OP in SS is described. [ABSTRACT FROM AUTHOR]

A 54-year-old female was diagnosed as mixed connective tissue disease (MCTD) complicated with secondary Sjögren’s syndrome. Although she had no dyspnea on exertion, the chest X-ray showed cardiomegaly with interstitial pneumonia. The echocardiogram demonstrated asymmetric hypertrophy of the interventricular septum. Diagnosis of hypertrophic obstructive cardiomyopathy (HOCM) was confirmed by left ventriculography and myocardial biopsy. She was treated with prednisolone, resulting in improvement of swollen hand, elevated muscle enzymes and interstitial pneumonia. A rare complication of HOCM with MCTD was described. [ABSTRACT FROM AUTHOR]

Viruses are possible pathogenic agents in several autoimmune diseases. Sjögren's syndrome (SS), which involves exocrine dysfunction and the appearance of autoantibodies, shows salivary gland- and lacrimal gland-oriented clinical features. Epstein-Barr virus (EBV) is the most investigated pathogen as a candidate that directly induces the phenotype found in SS. The reactivation of the virus with various stimuli induced a dysregulated form of EBV that has the potential to infect SS-specific B cells and plasma cells that are closely associated with the function of an ectopic lymphoid structure that contains a germinal center (GC) in the salivary glands of individuals with SS. The involvement of human T-cell leukemia virus type 1 (HTLV-1) in SS has been epidemiologically established, but the disease concept of HTLV-1-associated SS remains unexplained due to limited evidence from basic research. Unlike the cell-to-cell contact between lymphocytes, biofilm-like structures are candidates as the mode of HTLV-1 infection of salivary gland epithelial cells (SGECs). HTLV-1 can infect SGECs with enhanced levels of inflammatory cytokines and chemokines that are secreted from SGECs. Regardless of the different targets that viruses have with respect to affinitive lymphocytes, viruses are involved in the formation of pathological alterations with immunological modifications in SS. [ABSTRACT FROM AUTHOR]

• The HTLV-1-infected cells have the extracellular matrix and linker proteins on their surface. • Biofilm-like components including agrin and tetherin were involved in transmission of HTLV-1 toward SGECs. • An electron microscopy confirmed transmission of virions at the interface between HCT-5 cells and SGECs. The initial phase of the human T cell leukemia virus-1 (HTLV-1) infection of salivary gland epithelial cells (SGECs) was examined. SGECs of patients with Sjögren's syndrome (SS) and non-SS subjects were co-cultured with the HTLV-1-infected cell line HCT-5 or MOLT-4, then immunofluorescence (IF), scanning and transmission electron microscopy (SEM/TEM) were employed. The extracellular matrix and linker proteins galectin-3, agrin, and tetherin were expressed on the surfaces of both HCT-5 and MOLT-4 cells. HTLV-1 Gag-positive spots were observed on adjacent SGECs after 1 h of co-culture with HCT-5. Both in subjects with and those without SS, agrin and tetherin were co-expressed with HTLV-1 Gag on SGECs after co-culture with HCT-5, although no polarization of HTLV-1 Gag and relevant molecules was observed. SEM showed HTLV-1 virions that were found on HCT-5 were observed in the interfaces between HCT-5 cells and SGECs. TEM imaging showed that HTLV-1 virions were transmitted to SGECs at the interface with thin film-like structure, while HTLV-1 virions were released from the surface of HCT-5 cells. No endogenous retroviruses were observed. These results showed that the initial phase of HTLV-1 infection toward SGECs of SS was mediated not by viral synapses, but by biofilm-like components. [ABSTRACT FROM AUTHOR]

The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients’ SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor. [ABSTRACT FROM AUTHOR]

Traditional carbon materials such as graphite are currently extremely useful and have recently been applied to cutting-edge materials. However, it is a concern that as production will increase much more in the future, the impact on the environment during preparation will become a problem. Recently, we have succeeded in obtaining an extremely high orientation structure using a carbonization process in a strong magnetic field ["Magnetic orientation of hexagonal carbon layers at high temperature" Chem. Lett. 41, 1576 (2012)]. Because graphite has a two-dimensional structure in which graphene sheets are laminated, we expect that graphitization should be easily performed by using a precursor that originally has an oriented structure. When two types of precursors prepared in the absence and presence of a magnetic field of 6 T were graphitized under the same conditions, graphitization was promoted by 50 to 100 K for the precursor to which a strong magnetic field was applied. If we fabricate products with the same degree of graphitization, it is calculated that the graphitization energy can be suppressed by as much as 10% by using a magnetic field. Applying this technology to the preparation of graphite in industry is proposed to result in substantial energy savings. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome, is caused by the incessant activation of lymphocytes and macrophages, resulting in damage to organs, including hematopoietic organs. Recently, we demonstrated that repeated lipopolysaccharide (LPS) treatment induces HLH-like features in senescence-accelerated (SAMP1/TA-1) mice but not in senescence-resistant control (SAMR1) mice. Hematopoietic failure in LPS-treated SAMP1/TA-1 mice was attributed to hematopoietic microenvironment dysfunction, concomitant with severely imbalanced M1 and M2 macrophage polarization. Macrophages are a major component of the bone marrow (BM) hematopoietic microenvironment. Clodronate liposomes are useful tools for in vivo macrophage depletion. In this study, we depleted macrophages using clodronate liposomes to determine their role in the hematopoietic microenvironment in SAMP1/TA-1 and SAMR1 mice. Under clodronate liposome treatment, the response between SAMR1 and SAMP1/TA-1 mice differed as follows: (1) increase in the number of activated M1 and M2 macrophages derived from newly generated macrophages and M2-dominant and imbalanced M1 and M2 macrophage polarization in the BM and spleen; (2) severe anemia and thrombocytopenia; (3) high mortality rate; (4) decrease in erythroid progenitors and B cell progenitors in the BM; and (5) decrease in the mRNA expression of erythroid-positive regulators such as erythropoietin and increase in that of erythroid- and B lymphoid-negative regulators such as interferon-γ in the BM. Depletion of residual macrophages in SAMP1/TA-1 mice impaired hematopoietic homeostasis, particularly erythropoiesis and B lymphopoiesis, owing to functional impairment of the hematopoietic microenvironment accompanied by persistently imbalanced M1/M2 polarization. Thus, macrophages play a vital role in regulating the hematopoietic microenvironment to maintain homeostasis. [ABSTRACT FROM AUTHOR]