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The COVID-19 outbreak severely affected long-term care (LTC) service provision. This study aimed to quantitatively evaluate its impact on the utilization of LTC services by older home-dwelling adults and identify its associated factors.A retrospective repeated cross-sectional study.Data from a nationwide LTC Insurance Comprehensive Database comprising monthly claims from January 2019 to September 2020.Interrupted time series analyses and segmented negative binomial regression were employed to examine changes in use for each of the 15 LTC services. Results of the analyses were synthesized using random effects meta-analysis in 3 service types (home visit, commuting, and short-stay services).LTC service use declined in April 2020 when the state of emergency (SOE) was declared, followed by a gradual recovery in June after the SOE was lifted. There was a significant association between decline in LTC service use and SOE, whereas the association between LTC service use and the status of the infection spread was limited. Service type was associated with changes in service utilization, with a more precipitous decline in commuting and short-stay services than in home visiting services during the SOE. Service use by those with dementia was higher than that by those without dementia, particularly in commuting and short-stay services, partially canceling out the decline in service use that occurred during the SOE.There was a significant decline in LTC service utilization during the SOE. The decline varied depending on service types and the dementia severity of service users. These findings would help LTC professionals identify vulnerable groups and guide future plans geared toward effective infection prevention while alleviating unfavorable impacts by infection prevention measures. Future studies are required to examine the effects of the LTC service decline on older adults.

Objective Adipokines may influence inflammatory and/or immune responses. This study was undertaken to examine whether adiponectin affects the production of prostaglandin E2 (PGE2) by rheumatoid arthritis synovial fibroblasts (RASFs). Methods Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. Fibroblast-like cells from the third or fourth passage were used as RASFs. Expression of adiponectin receptor messenger RNA (mRNA) and protein was detected. PGE2 (converted from arachidonic acid) was measured by enzyme-linked immunosorbent assay (ELISA). Expression of mRNA and protein for cyclooxygenase 2 (COX-2) and membrane-associated PGE synthase 1 (mPGES-1), key enzymes involved in PGE2 synthesis, was detected in RASFs. The effects of RNA interference (RNAi) targeting the adiponectin receptor genes and the receptor signal inhibitors were examined. The influence of adiponectin on NF-κB activation in RASFs was measured with an ELISA kit. Results Adiponectin receptors were detected in RASFs. Adiponectin increased both COX-2 and mPGES-1 mRNA and protein expression by RASFs in a time- and concentration-dependent manner. PGE2 production by RASFs was also increased by the addition of adiponectin, and this increase was inhibited by RNAi for the adiponectin receptor gene, or coincubation with the receptor signal inhibitors. Enhancement of NF-κB activation by adiponectin as well as by interleukin-1β was observed in RASFs. Conclusion Our findings indicate that adiponectin induces COX-2 and mPGES-1 expression, resulting in the enhancement of PGE2 production by RASFs. Thus, adiponectin may play a role in the pathogenesis of synovitis in RA patients.

Background Although cardiac fibroma has been regarded as benign tumor, it presents various symptoms and may lead to death. Unfortunately, only a few studies have reported the epidemiology, embryology, and histopathology of the tumor, and the factors predicting poorer outcome are still obscured. Methods In July 2011 we searched for English and Japanese cases of cardiac fibroma using the PubMed and IgakuChuoZasshi databases. We then extracted and sampled raw data from the selected publications in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) style as much as was possible. Results Details of a total of 178 patients with cardiac fibroma were retrieved. The mean age was 11.4 years (median: 2.8 years). Tumor sizes ranged from 8.0 to 150.0 mm (mean 53.1 mm). The left ventricle was found to be the most common site associated with the tumor at a rate of 57.3%, followed by the right ventricle, and interventricular septum. The highest mortality was found in patients with septal involvement (58.6%). In all, 111 patients survived among the 160 patients with a recorded outcome. A younger age of the patient at the time of diagnosis was associated with a decreased survival rate. In addition, a significant positive association was found between ages for patients younger than 17 years of age and the diameter of the tumor at the time of diagnosis (r = 0.341, P = 0.006). Conclusions Both the younger age of patients at the time of diagnosis and septal involvement can be regarded as factors significantly indicating a poor prognosis. Furthermore, our statistical analyses support the following hypotheses. First, the high ratio of tumor-to-heart size may generate low cardiac output and therefore lead to poor outcome. Second, the ratio of the sites where cardiac fibroma occurred corresponds with the ratio of the muscular weight of the cardiac chamber. Third, cardiac fibroma involving the interventricular septum more frequently induces conduction system disease.

Although the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis. Tacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined. The mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus. IL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.

Background Although gangliocytic paraganglioma (GP) has generally been regarded as a neuroendocrine tumor, its origin remains unclear. We therefore aimed to investigate the details of this disease by carefully analyzing and extracting common features of the disease as presented in selected publications. Methods We searched for English and Japanese cases of GP using the PubMed and IgakuChuoZasshi databases on August 2010. We then extracted and sampled raw data from the selected publications and performed appropriate statistical analyses. Additionally, we evaluated the expression of hormone receptors based on our previously reported case. Results 192 patients with GP were retrieved from the databases. Patient ages ranged from 15 y to 84 y (mean: 52.3 y). The gender ratio was 114:76 (male to female, 2 not reported). Maximum diameter of the tumors ranged from 5.5 mm to 100 mm (mean: 25.0 mm). The duodenum (90.1%, 173/192) was found to be the most common site of the disease. In 173 patients with duodenal GP, gastrointestinal bleeding (45.1%, 78/173) was found to be the most common symptom of the disease, followed by abdominal pain (42.8%, 74/173), and anemia (14.5%, 25/173). Rate of lymph node metastasis was 6.9% (12/173). Our statistical analysis indicated that significant differences were found for gender between GP within the submucosal layer and exceeding the submucosal layer. Furthermore, our immunohistochemical evaluation showed that both epithelioid and pancreatic islet cells showed positive reactivity for progesterone receptors. Conclusions Our literature survey revealed that there were many more cases of GP exceeding the submucosal layer than were expected. Meanwhile, our statistical analyses and immunohistochemical evaluation supported the following two hypotheses. First, vertical growth of GP might be affected by progesterone exposure. Second, the origin of GP might be pancreatic islet cells. However, it is strongly suspected that our data have been affected by publication bias and to confirm these hypotheses, further investigation is required.

The adipokines are linked not only to metabolic regulation, but also to immune responses. Adiponectin, but not leptin or resistin induced interleukin-8 production from rheumatoid synovial fibroblasts (RSF). The culture supernatant of RSF treated with adiponectin induced chemotaxis, although adiponectin itself had no such effect. Addition of antibody against adiponectin, and inhibition of adiponectin receptor gene decreased adiponectin-induced IL-8 production. Nuclear translocation of nuclear factor-kappa B was increased by adiponectin. The induction of interleukin-8 was inhibited by mitogen-activated protein kinase inhibitors. These findings suggest that adiponectin contributes to the pathogenesis of rheumatoid arthritis.

Purpose of review The calcineurin inhibitors cyclosporine and tacrolimus are important treatments for patients with active rheumatoid arthritis, especially in cases of resistance or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Here, we discuss the mechanism, efficacy and safety of cyclosporine and tacrolimus in the treatment of rheumatoid arthritis. Recent findings Recent clinical trials of cyclosporine have shown the advantages of its combination with methotrexate, glucocorticoids and leflunomide in the treatment of active rheumatoid arthritis. In Japan, tacrolimus monotherapy was found to be quite effective and combination therapy with methotrexate had positive results in an American study. The inhibitory effects of both drugs not only on T lymphocytes, but also on human osteoclast formation, have been demonstrated in basic studies. Summary Cyclosporine and tacrolimus are clinically available disease-modifying antirheumatic drugs. Numerous clinical studies have shown the usefulness of these calcineurin inhibitors in monotherapy and also when combined with methotrexate. Although these drugs have similar effects, there are some differences in adverse reactions.

Anti-cyclic citrullinated peptide (CCP) antibodies are useful for the diagnosis of rheumatoid arthritis (RA) because of their higher specificity.1 First-generation anti-CCP (CCP1) ELISAs were based on synthetic peptides derived from human filaggrin.2 The second-generation anti-CCP (CCP2) test, which contains epitopes selected from libraries of citrullinated peptides, performs better than anti-CCP1.3 4 Recently, a third-generation anti-CCP (CCP3) test was introduced. We compare the performance of the anti-CCP3 test with that of two anti-CCP2 tests, and assess their value in diagnosing RA. A total of 502 participants were studied: 227 patients fulfilling the American College of Rheumatology criteria for RA,5 173 patients with non-RA autoimmune diseases (details are indicated …

Background Several patients with rheumatoid arthritis (RA) have different comorbidities and have to take other drugs at the same time. It is important to recognize such comorbidities in RA patients and consider them before initiating both pharmacotherapy and surgical therapy. Most of comorbidities in RA patients may affect therapeutic choice. Objectives To evaluate the impact of comorbidities to physical functions and treatment selection of patients with RA, we studied comorbidity index in patients with rheumatoid arthritis in our Japanese cohort. Methods A cohort of 413 Japanese patients with RA, who attended Toho University Ohmori hospital Rheumatology center during the period from 2005 to 2010, was retrospectively analyzed until the end 2010. Clinical data containing comorbidity profile and disease activity obtained from medical records. Comorbidity index used Charson comorbidity index; CCI established by Charlson M. et al. We analyzed relationship between the number of comorbidities, CCI and therapeutic processes of patients with rheumatoid arthritis. Results In this cohort data profiles of RA patients were average age 65±14, female ratio 88%, average disease duration 8.3±8.8years, biologics usage 29%, DAS28-ESR 2.9±1.3 and Health Assessment Questionnaire disability index (HAQ-DI) was 0.6±0.7. Frequency of comorbidity was 53% in patients of this cohort. Comorbidities of RA patients were 27.9% hypertension, 12.3% diabetes mellitus, 12.3% interstitial peumonitis, 6.6% cardiovascular disease, 6.6% malignancy, 5.4% thyroid disease, and 2.7% renal diseases. The Japanese RA patient had low percentage of ischemic heart disease compared with a European and American report. Mean of CCI was 0.5±0.8. CCI was correlated with age and functional class classification. RA patients with low CCI included in RA functional class I group. CCI were also correlated with HAQ-DI and DAS28 ESR. RA patients with high CCI score (2$ p p p =0.39). Conclusions CCI is one of the useful index in patients with RA. Therapeutic process of RA patients have been affected by several comorbidites. It is necessary to do treatment preferences in consideration of comorbidities. The therapy that we can choose without being concerned with a comorbidities is necessary in patients with rheumatoid arthritis. Disclosure of Interest None Declared

Background Since proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, play major pathophysiological roles in rheumatoid arthritis (RA), their inhibitors have recently been developed as potent biological anti-rheumatic drugs. However, they are not curative and the effects are still partial, with many patients failing to respond. Leptin is the product of the ob gene, and is a peptide hormone synthesized almost exclusively by adipocytes that regulates appetite and energy expenditure. It is also suggested that leptin may contribute to inflammation and autoimmunity. We previously reported that serum leptin level was elevated in patients with RA [[1][1]]. Accordingly, we examined the direct effects of leptin on cultured rheumatoid synovial fibroblasts (RSFs) in the present study. Objectives To determine the effects of leptin on the production of proinflammatory cytokines by RSFs. Methods Synovial tissue was obtained at total knee replacement operation from patients with RA who gave consent. RSFs were harvested from the synovial tissues of these patients. Leptin receptor mRNAs were detected by reverse transcription–polymerase chain reaction. Productions of mRNA by RSFs and protein concentrations of TNF-α, IL-1β, and IL-6 in the culture medium were detected by real-time PCR and ELISA kit, respectively. Small interfering RNA (siRNA) was transfected into RSFs to down-regulate the expression of leptin receptor. Effects of inhibitors of janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) on IL-6 production were evaluated. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in RSFs were determined by Western blot analysis. This study was approved (No. 19021) by Ethics Committee of Toho University School of Medicine. Results We detected leptin receptor mRNAs in RSFs. Expressions of IL-1β and IL-6 mRNAs were enhanced in a concentration-dependent manner by addition of leptin to RSFs. IL-6 secretion by RSFs showed an increase after leptin stimulation, while IL-1β did not increase in the culture media. Leptin-induced production of IL-6 by RSFs was decreased after exposure to siRNA targeting leptin receptor (Ob-Rb). A JAK2 inhibitor, but not PI3K and MAPK inhibitors, decreased leptin-induced IL-6 production. Enhanced phosphorylation of STAT3 was observed in RSFs after stimulation by leptin. Conclusions Leptin possibly acts as a proinflammatory cytokine that up-regulates IL-6 production in RSFs via activation of JAK2/STAT3 in RSFs. Leptin and JAK/STAT pathway may represent a new alternative therapeutic target in the treatment of RA. References 1. Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, Hasunuma T, Kawai S. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med. 2011;50:269. Disclosure of Interest None Declared [1]: #p-6

Background Osteoporosis is a serious complication of systemic glucocorticoid (GC) therapy. Bisphosphonate is recommended, however insufficient result have been reported in some cases. Menatetrenone (vitamin K 2 ;VK) is a stimulator of bone formation in vitro and in vivo . We recently have reported that severity of GC-induced osteoporosis might be determined by serum basal sRANKL levels in patients with systemic autoimmune disease [1]. In the present study, we conducted post-hoc analysis to determine whether VK influenced bone metabolism markers in these patients. Objectives To study the efficacy of VK on serum bone metabolism markers and on bone mineral density (BMD) in patients under GC therapy. Methods This study was approved by the Ethics Committee at Toho University Omori Hospital (No. 21-61). Detailed study design was previously shown elsewhere [1]. Briefly, sixty patients (40 women) with systemic lupus erythematosus (n=21), vasculitis syndrome (n=19), polymyositis/dermatomyositis (n=15), and adult-onset Still’s disease (n=5) who were started to received prednisolone (30-60mg daily) were enrolled. Serum samples were obtained just before and 1 to 4 weeks after the start of GC therapy. All patients received bisphosphonate for our regimen of GC therapy. Twenty patients received VK 45 mg daily from 2 weeks after GC therapy. As bone formation markers, serum levels of osteocalcin (OC), procollagen type I N-terminal peptide (PINP), undercarboxylated OC (ucOC), and bone alkaline phosphatase (BAP) were measured. As bone resorption markers, serum levels of type I collagen cross-linked N-telopeptide (NTx) and tartrate resistant acid phosphatase isoform 5b (TRACP-5b) were measured. The BMD of lumbar spine was measured before and after (at 15 months) GC therapy. Results Serum levels of OC and ucOC were significantly (P Conclusions Additional use of VK partially restored serum OC level from the suppressed level by GC therapy. In addition, the BMD value in the VK group was not changed after GC therapy. These results suggest that VK may possibly provide some effects on bisphosphonate therapy to prevent from GC-induced osteoporosis. References Kaneko K, et al. Changes of serum soluble receptor activator for nuclear factor-κB ligand after glucocorticoid therapy reflect regulation of its expression by osteoblast. J Clin Endocrinol Metab . 2012; 97:E1909-1917. Disclosure of Interest None Declared

Background Leiomyosarcoma occurring as a primary cardiac tumor has been known as an extremely rare condition. Previous studies of leiomyosarcoma with rhabdomyoblastic differentiation have conducted to those arisen from another site, and they indicated a poorer prognosis of this tumor. Case presentation A 69-year-old woman was referred to our hospital for an operation concerning umbilical hernia. Subsequent imaging examinations before an operation indicated the presence of primary cardiac malignant tumor due to its atypical shape. And then, it was surgically removed. Histopathologically, tumor cells consisted of two different types: spindle and polyhedral cells. Immunohistochemically, it is interesting to note that 2.1% of spindle cells and 23.1% of polyhedral cells showed positive reactivity for myogenin. Furthermore, we performed double-immunostaining for alpha-smooth muscle actin (SMA) and myogenin. The rates of alpha-SMA and myogenin double negative, alpha-SMA single positive, myogenin single positive, and alpha-SMA and myogenin double positive in spindle cells were estimated as 69.1%, 28.8%, 1.1% and 1.0%, respectively. In contrast, the rates in polyhedral cells were estimated as 76.9%, 0.0%, 23.1%, and 0.0%, respectively. Conclusion Our immunohistochemical evaluation suggested that rhabdomyoblastic differentiation in leiomyosarcoma might be generated not only by de novo generation from mesenchymal cells. To the best of our knowledge, this is the first case of primary cardiac leiomyosarcoma with partial rhabdomyoblastic differentiation.

Liquid chromatographic influence on changing the solvent system from the non-volatile buffer containing inorganic salts or phosphates to some volatile buffers suitable for the direct coupled liquid chromatography/mass spectrometry was investigated by means of the reversed-phase high-performance liquid chromatography. On a separation of ten methylxanthines including methyluric acids, almost the same chromatograms of the mixture were obtained among all buffers examined. Similar modifications on the solvent system were tried to separate a mixture of nine non-steroidal anti-inflammatory drugs and anthranilic acid. In an application of the modified buffer to the FRIT-FAB liquid chromatography/mass spectrometry, informative negative ion mass spectra of acetyl-coenzyme A and structurally related compounds could be obtained by using diethanolamine-acetic acid buffer. Diethanolamine, its acetate in the buffer, acts effectively as a matrix for the FRIT-FAB liquid chromatography/mass spectrometry.