Involvement of adiponectin in age-related increases in tear production in mice

Common age-related changes in the human eye contribute to the development of dry eye, including decreases in aqueous tear production. Although the infiltration of lymphocytes into the lacrimal glands occurs with age, age-related increases in tear production have also been observed in mice; however, the mechanisms underlying this increase remain unclear. We herein demonstrated that increases in tear production were not dependent on body weight gain or systemic conditions, such as insulin resistance, using aged mice and high-fat diet-fed mice. The results obtained also showed that senescence-associated T (SA-T) cells accumulated in the lacrimal glands of aged mice, particularly females. Expression levels of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) in whole lacrimal glands and epithelial cells isolated from lacrimal glands were significantly higher in aged mice than in young mice. The expression levels of adiponectin and one of its receptors, AdipoR2, also increased in the lacrimal glands of aged mice, but not in those of high-fat diet-fed mice. Collectively, the present results indicate that PPARγ and adiponectin-mediated signaling contribute to age-related increases in tear production in mice and have potential as therapeutic targets for the treatment of dry eye in humans

Chemokines Up-Regulated in Epithelial Cells Control Senescence-Associated T Cell Accumulation in Salivary Glands of Aged and Sjögren’s Syndrome Model Mice

Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren’s syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis

Study of assessment of knowledge and understanding for coping with sick days among patients with diabetes in community pharmacy: a cluster randomized controlled trial (SAKURA trial)

[Background] Awareness regarding coping with sick days among patients with diabetes is limited. Thus, we evaluated the effectiveness of sick-day education by community pharmacists among patients with type 2 diabetes (T2D) using sick-day educational materials (sick-day cards). [Methods] A cluster randomized controlled trial was conducted. Pharmacists in the intervention group educated patients with T2D on coping with sick days (adjusting medication dosage and seeking medical advice) using sick-day cards compared with the usual counseling. Differences in questionnaire scores (“Anxiety”, “Intention”, “Attitude”, and “Knowledge” about sick days) before and after the intervention were compared between the groups. [Results] Overall, 318 patients with T2D (intervention, 119; control, 199) participated in this study, and 270 (intervention, 92; control, 178) patients were examined. There were no significant differences in “Anxiety”, “Intention”, or “Attitude” scores between the two groups, but “Knowledge” scores improved in the intervention group. For all intervention groups (92/92), a physician reviewed and approved medication and adjustment doses for sick days on the cards. [Conclusions] According to patients’ responses, sick-day education using teaching materials improved patient knowledge. This may help patients and their caregivers cope with sick days appropriately through medication dose adjustment and fluid intake. Research registration number: UMIN000043161 (February 1, 2021), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr.cgifunction=brows&action=brows&recptno=R000048124&type=summary&language=

ROLE OF CXCL12 AND CXCR4 IN A MOUSE MODEL OF SS

Objective. Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T-cell infiltration into target tissues, but the specific cytokines, receptors, and T-cell populations remain largely unidentified. Role of the potent chemokine CXCL12 and its receptor CXCR4 in T-cell autoimmune response was examined using alymphoplasia (aly)/aly mice, a Sjögren’s syndrome (SS) model. Methods. T-cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunological analysis. In vitro migration assay was used to assess T-cell migratory activity toward several chemokines. Gene expression of chemokine receptors, and transforming growth factor (TGF)β receptors was measured with quantitative reverse transcription-polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice to evaluate its suppressive effect on autoimmune lesions. Results. Effector memory T (TEM) cells derived from aly/aly mice demonstrated higher in vitro migratory activity toward CXCL12 than aly/+ TEM cells. CXCL12 expression was specifically upregulated in the SS target cells of aly/aly mice. TEM cells from RelB−/− mice, but not nuclear factor (NF)-κB1−/− mice, also showed high migratory activity toward CXCL12, implicating a nonclassical NF-κB2/RelB pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFβ receptors I and II. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration. Conclusion. Our results suggest that the NF-κB2/RelB pathway regulates T-cell migration to autoimmune targets through TGFβ/TGFβR-dependent regulation of CXCL12−CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for treating autoimmune diseases

Fast ray-tracing algorithm for circumstellar structures (FRACS) I. Algorithm description and parameter-space study for mid-IR interferometry of B[e] stars

The physical interpretation of spectro-interferometric data is strongly model-dependent. On one hand, models involving elaborate radiative transfer solvers are too time consuming in general to perform an automatic fitting procedure and derive astrophysical quantities and their related errors. On the other hand, using simple geometrical models does not give sufficient insights into the physics of the object. We propose to stand in between these two extreme approaches by using a physical but still simple parameterised model for the object under consideration. Based on this philosophy, we developed a numerical tool optimised for mid-infrared (mid-IR) interferometry, the fast ray-tracing algorithm for circumstellar structures (FRACS) which can be used as a stand-alone model, or as an aid for a more advanced physical description or even for elaborating observation strategies. FRACS is based on the ray-tracing technique without scattering, but supplemented with the use of quadtree meshes and the full symmetries of the axisymmetrical problem to significantly decrease the necessary computing time to obtain e.g. monochromatic images and visibilities. We applied FRACS in a theoretical study of the dusty circumstellar environments (CSEs) of B[e] supergiants (sgB[e]) in order to determine which information (physical parameters) can be retrieved from present mid-IR interferometry (flux and visibility). From a set of selected dusty CSE models typical of sgB[e] stars we show that together with the geometrical parameters (position angle, inclination, inner radius), the temperature structure (inner dust temperature and gradient) can be well constrained by the mid-IR data alone. Our results also indicate that the determination of the parameters characterising the CSE density structure is more challenging but, in some cases, upper limits as well as correlations on the parameters characterising the mass loss can be obtained. Good constraints for the sgB[e] central continuum emission (central star and inner gas emissions) can be obtained whenever its contribution to the total mid-IR flux is only as high as a few percents. Ray-tracing parameterised models such as FRACS are thus well adapted to prepare and/or interpret long wavelengths (from mid-IR to radio) observations at present (e.g. VLTI/MIDI) and near-future (e.g. VLTI/MATISSE, ALMA) interferometers

Comparison of dynamic occlusal contacts during chewing between working and balancing sides

Objectives: Mastication is a crucial function for the elderly, and promotes oral health status, cognitive function and the physical constitution. Most reports about occlusion patterns and occlusal glide of adults have reported the jaw movement at the lower incisal point due to easiness of evaluating masticatory performance. The purpose of this study was to test the hypothesis that dynamic occlusal contact area (OCA) during chewing differ for each tooth on the working vs. the balancing chewing side. Design: In thirteen healthy Japanese females, OCA was estimated with a measurement system combining 3-D tracking of mandibular movements with 3-D digitization of tooth shape. Results: The starting of occlusal contact between teeth at working side and balancing side did not differ significantly. In contrast, ending of occlusal contact of teeth at balancing side were markedly longer than that of teeth at working side at lateral incisor, canine, and first premolar. The dynamic sum of OCAs for all teeth was symmetrical around maximum closed position (MCP) when chewing on the working side. In contrast, the dynamic sum of OCA peaked after MCP when chewing on the balancing side. In working and balancing side, sums of maximum OCA at all posterior teeth accounted for 93%, 86% of sum OCA for all teeth at working and balancing sides, respectively. Conclusion: Our result suggested that the hypothesis that dynamic OCA during chewing differ for each tooth on the working vs. the balancing chewing side was not accepted at molars

Cross-talk between autoimmunity and tumor immunity

Both autoimmunity and tumor immunity are immune responses against self-tissues or cells. However, the precise similarity or difference between them remains unclear. In this study, to understand a novel mechanism of tumor immunity, we performed transplantation experiments with a murine autoimmune model, C57BL/6J (B6)/lpr mice. A melanoma cell line, B16F10 cells, or granulocyte macrophage colony-stimulating factor- overexpressing B16F10 (B16F10/mGM) cells were transplanted into B6 or B6/lpr mice. Tumor growth by transplanted B16F10/mGM cells was significantly accelerated in B6/lpr mice compared with that in B6 mice. The accumulation of M1 macrophages in the tumor tissues of B6/lpr recipient mice was significantly lower compared with that in the control mice. In vitro co-culture experiment showed that impaired differentiation into M1 macrophages was observed in B6/lpr mice. The number of tumor vessels and vascular endothelial growth factor (VEGF) expression were also significantly enhanced in the tumor tissues of B6/lpr mice compared with those in the B6 mice. Moreover, VEGF expression was correlated with the increased expression of hypoxia-inducible factor-1α in the tumor tissues of B6/lpr mice. These results suggest that dysfunctional tumor immunity and enhanced angiogenesis in autoimmunity influence tumor growth

Fas-Independent T-Cell Apoptosis by Dendritic Cells Controls Autoimmune Arthritis in MRL/lpr Mice

Background: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-kB ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity. Methods and Finding: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4+ T, B, and CD4‾CD8‾ double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice. Conclusion: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice

Multiple barriers against successful care provision for depressed patients in general internal medicine in a Japanese rural hospital: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>A general internist has an important role in primary care, especially for the elderly in rural areas of Japan. Although effective intervention models for depressed patients in general practice and primary care settings have been developed in the US and UK medical systems, there is little information regarding even the recognition rate and prescription rate of psychotropic medication by general internists in Japan. The present study surveyed these data cross-sectionally in a general internal medicine outpatient clinic of a Japanese rural hospital.</p> <p>Methods</p> <p>Patients were consecutively recruited and evaluated for major depressive disorder or any mood disorder using the Patient Health Questionnaire (PHQ). Physicians who were blinded to the results of the PHQ were asked to diagnose whether the patients had any mental disorders, and if so, whether they had mood disorders or not. Data regarding prescription of psychotropic medicines were collected from medical records.</p> <p>Results</p> <p>Among 312 patients, 27 (8.7%) and 52 (16.7%) were identified with major depressive disorder and any mood disorder using the PHQ, respectively. Among those with major depressive disorder, 21 (77.8%) were recognized by physicians as having a mental disorder, but only three (11.1%) were diagnosed as having a mood disorder.</p> <p>Only two patients with major depressive disorder (7.4%) had been prescribed antidepressants. Even among those (n = 15) whom physicians diagnosed with a mood disorder irrespective of the PHQ results, only four (26.7%) were prescribed an antidepressant.</p> <p>Conclusions</p> <p>Despite a high prevalence of depression, physicians did not often recognize depression in patients. In addition, most patients who were diagnosed by physicians as having a mood disorder were not prescribed antidepressants. Multiple barriers to providing appropriate care for depressed patients exist, such as recognizing depression, prescribing appropriate medications, and appropriately referring patients to mental health specialists.</p

EWSR1-ATF1融合遺伝子を持つ歯原性明細胞癌細胞株の樹立と性状解析

Objective: Clear cell odontogenic carcinoma (CCOC) is a rare malignant odontogenic tumor (MOT) characterized by sheets and lobules of vacuolated and clear cells. To understand the biology of CCOC, we established a new cell line, CCOC-T, with EWSR1-ATF1 fusion gene from a mandible tumor with distant metastasis and characterized this cell line. Materials and methods: To detect the EWSR1-ATF1 fusion gene, we used three CCOC cases, including the present case, by RT-PCR and FISH analysis. We characterized established CCOC-T cells by checking cell growth, invasion and the expression of odontogenic factors and bone-related factors. Moreover, the gene expression profile of CCOC-T cells was examined by microarray analysis. Results: Histologically, the primary tumor was comprised of cords and nests containing clear and squamoid cells separated by fibrous septa. In addition, ameloblastomatous islands with palisaded peripheral cells were observed, indicating probable odontogenic origin. This tumor expressed the fusion gene EWSR1-ATF1, which underlies the etiology of hyalinizing clear cell carcinoma (HCCC) and potentially that of CCOC. We found a breakpoint in the EWSR1-ATF1 fusion to be the same as that reported in HCCC. Established CCOC-T cells grew extremely slowly, but the cells showed highly invasive activity. Moreover, CCOC-T cells expressed bone-related molecules, odontogenic factors, and epithelial mesenchymal transition (EMT)-related molecules. Conclusion: To the best of our knowledge, this is the first report on the establishment of a CCOC cell line. CCOC-T cells serve as a useful in vitro model for understanding the pathogenesis and nature of MOT