Search

Objectives: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA)., Methods: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses., Results: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients., Conclusions: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Chemical modifications of cellular RNAs play key roles in gene expression and host defense. The cap-adjacent N 6 ,2'- O -dimethyladenosine (m 6 Am) is a prevalent modification of vertebrate and viral mRNAs and is catalyzed by the newly discovered N 6 methyltransferase PCIF1. However, its role in gene expression remains unclear due to conflicting reports on its effects on mRNA stability and translation. In this study, we investigated the impact of siRNA-mediated transient suppression of PCIF1 on global mRNA expression in HeLa cells. We identified a subset of differentially expressed genes (DEGs) that exhibited minimal overlap with previously reported DEGs. Subsequent validation revealed that PCIF1 positively and negatively regulates RAB23 and CNOT6 expression, respectively, at both the mRNA and protein levels. Mechanistic analyses demonstrated that PCIF1 regulates the stability of these target mRNAs rather than their transcription, and rescue experiments confirmed the requirement of PCIF1's methyltransferase activity for these regulations. Furthermore, MeRIP-qPCR analysis showed that PCIF1 suppression significantly reduced the m 6 A levels of RAB23 and CNOT6 mRNAs. These findings suggest that PCIF1 regulates the stability of specific mRNAs in opposite ways through m 6 A modification, providing new insights into the role of m 6 Am in the regulation of gene expression.

Background: Health-related quality of life (HRQoL) following total hip and knee arthroplasty (THA/TKA) may decline more in Asian countries due to lifestyle and housing factors compared with patients in Western countries., Aims: To evaluate the psychometric properties of the Japanese version of 15D and clarify the characteristics of HRQoL in Japanese patients who underwent THA/TKA compared with Finnish patients., Methods: This longitudinal study included 182 patients between 2019 and 2021. Patients' HRQoL was measured using the 15D preoperatively and 3 months postoperatively. Student's t-tests were used to compare lifestyles between Japan and Finland., Results: The Japanese version of the 15D showed good internal consistency, reliability, construct validity, and responsiveness. Patients with many steps inside their house had worse HRQoL in the dimensions of mobility, distress, and vitality in Japan. There were significant differences in mobility, distress, vitality, and sexual activity dimensions between Japan and Finland 3 months postoperatively., Conclusions: The lower HRQoL in Japan in the dimensions of mobility, distress, and vitality is likely due to Japan's traditional housing structure with many steps. Identifying differences in cultural and psychological characteristics, as well as by residential setting, will enable health care providers to help patients improve their HRQoL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations., Methods: Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined., Results: We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores ( p < 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) ( p < 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO., Conclusions: Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MH received research grants and/or speaker fee from Abbvie, Asahi Kasei, Astellas, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Taisho Toyama, Tanabe Mitsubishi. K.U. received a research and/or speaker fee from Sumitomo Pharma, outside the submitted work. A.O. received a research and/or speaker fee from Daiichi-Sankyo, AbbVie G.K., Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan, GSK, Mitsubishi Tanabe, Asahi Kasei Pharma and Pfizer Inc. R.W. received a research grant from AbbVie and speaker’s fee from Asahi Kasei, Chugai, Eli Lilly, and GSK. K.K. received a research and/or speaker fee from GSK K. K. R.N received a research and/or speaker fee from Takeda and Medical & Biological Laboratories Co. Ltd, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Actelion Pharmaceuticals, and Mitsubishi Tanabe Pharma, outside the submitted work. H.Y. has received a research grant from GSK and honoraria from Chugai, unrelated to this work. R.U. received personal fees from Eisai, Sawai Pharmaceutical, Statcom, SAS Institute Japan, and EPS Corporation, outside the submitted work. M.T. received a research and/or speaker fee from AbbVie G.K., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Eisai Co., Ltd, Eli Lilly Japan K. K., Pfizer Inc., UCB Japan Co. Ltd, Janssen Pharmaceutical K. K., Mitsubishi Tanabe Pharma Corp., Novartis Pharma K. K., Taisho Pharma Co. Ltd. K.O. received research grants and/or speaker’s fees from AbbVie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi, and Takeda while the present study was being performed. A.M. received research grants and/or speaker’s fees from Eli Lilly Japan K.K., Ono Pharmaceutical Co., Pfizer Inc., UCB Japan, AbbVie G.K., Asahi Kasei Pharma., and Chugai Pharmaceutical Co. Ltd. M.T. and M.H. and A. O are in the endowed chair and are funded by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Mitsubishi Tanabe Pharma Corp., Chugai Pharmaceutical Co. Ltd, Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp., and UCB Japan Co. Ltd). H.D., Y.T., R.I., T.K., T.Y., T.I., M.T., M.T., Y.T., M.S., H.O., H.T., S.A., K.M., W.Y., and T.I. declared no conflicts of interest. The sponsors were not involved in the study design; the collection, analysis, and interpretation of data; writing this manuscript; or the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payment or other benefits from any commercial entity related to the subject of this article.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC 50 ) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC 50 : 12.6-305 µM, MIC: 0.5-128 µg ml -1 ). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity., (© 2024. The Author(s).)

Purpose: Providing support for older adults after spousal bereavement is crucial for psychological recovery through the grieving process and for promoting a healthy and happy remainder of life. The current study aimed to understand factors influencing well-being among Japanese community-dwelling older adults who experienced spousal bereavement by evaluating how their roles and activities affected their psychological well-being following the loss., Method: We conducted a cross-sectional, anonymous, self-administered questionnaire survey of 332 older adults who had experienced death of a spouse in later adulthood., Results: Identified factors that affected well-being after spousal loss were sex, ability to go out without assistance from others, long duration since spousal loss, having a hobby, and adopting a life-oriented approach to cope with bereavement. Well-being following spousal loss was influenced by participants' activities and roles., Conclusion: Findings of the current study provide potentially valuable suggestions for surviving spouses and their supporters when coping with grief following spousal loss. [ Research in Gerontological Nursing, 17 (3), 121-130.].

The health benefits of young barley leaves, rich in dietary fiber, have been studied for several decades; however, their beneficial effects on the intestinal microenvironment remain to be elucidated. To investigate the effects of young barley leaf-derived dietary fiber (YB) on the gut microbiota and immunity, mice were fed an AIN-93G diet containing cellulose or YB and subjected to subsequent analysis. The population of MHC-II-positive conventional dendritic cells (cDCs) and CD86 expression in the cDCs of Peyer's patches were elevated in the YB-fed mice. MHC-II and CD86 expression was also elevated in the bone marrow-derived DCs treated with YB. 16S-based metagenomic analysis revealed that the gut microbiota composition was markedly altered by YB feeding. Among the gut microbiota, Lachnospiraceae, mainly comprising butyrate-producing NK4A136 spp., were overrepresented in the YB-fed mice. In fact, fecal butyrate concentration was also augmented in the YB-fed mice, which coincided with increased retinaldehyde dehydrogenase (RALDH) activity in the CD103 + cDCs of the mesenteric lymph nodes. Consistent with elevated RALDH activity, the population of colonic IgA + plasma cells was higher in the YB-fed mice than in the parental control mice. In conclusion, YB has beneficial effects on the gut microbiota and intestinal immune system.

Cardiac glycosides, known as inhibitors of Na + ,K + -ATPase, have anti-cancer effects such as suppression of cancer cell proliferation and induction of cancer cell death. Here, we examined the signaling pathway elicited by cardiac glycosides in the human hepatocellular carcinoma HepG2 cells and human epidermoid carcinoma KB cells. Three kinds of cardiac glycosides (ouabain, oleandrin, and digoxin) inhibited the cancer cell proliferation and decreased the expression level of thyroid adenoma-associated protein (THADA). Interestingly, the knockdown of THADA inhibited cancer cell proliferation, and the proliferation was significantly rescued by re-expression of THADA in the THADA-knockdown cells. In addition, the THADA-knockdown markedly decreased the expression level of L-type amino acid transporter LAT1. Cardiac glycosides also reduced the LAT1 expression. The LAT1 inhibitor, JPH203, significantly weakened the cancer cell proliferation. These results suggest that the binding of cardiac glycosides to Na + ,K + -ATPase negatively regulates the THADA-LAT1 pathway, exerting the anti-proliferative effect in cancer cells., (© 2024. The Author(s).)

Neonicotinoid pesticides (NNs) have been associated with numerous neurobehavioral effects in rodents, raising concerns about their impact on cognitive function. Clothianidin (CLO), a type of NN, was orally administered to male mice (10 weeks old, C57BL/6N) at the no-observed-adverse-effect level (NOAEL) of 50 mg/kg/day as indicated in the pesticide risk assessment report. Behavioral tests (novel location recognition and rotarod tests) evaluated hippocampal memory and cerebellar motor learning. After each test, plasma monoamines (3-methoxytyramine, histamine, serotonin, tryptamine) were measured by LC-ESI/MS/MS (Liquid chromatography-electrospray ionization/tandem mass spectrometry), and cerebellar mRNA expression was quantified by microarray and qRT-PCR analyses. The NOAEL of CLO was found to impair hippocampal memory, leading to decreased spontaneous locomotor activity and motor function. We reported, for the first time, multiple alterations of gene expression in the cerebellum associated with motor dysfunction.

Durvalumab consolidation after chemoradiotherapy for stage III non-small cell lung cancer (NSCLC) has become the standard of care. Single-center results were examined for treatment outcomes and patterns of pneumonitis in clinical practice. Patients with stage III NSCLC who underwent chemoradiotherapy at our institution (n = 150) were included. The patients were treated with chemoradiotherapy and durvalumab consolidation (Group D, n = 69) or chemoradiotherapy alone (Group N, n = 81). The overall survival (OS), progression-free survival (PFS), and the incidence of and risk factors for 12-month pneumonitis grade ≥ 2 (G2) were investigated. Two-year OS rates were 71.6% in Group D and 52.7% in Group N ( p = 0.052). Two-year PFS rates were 43.0% in Group D and 26.5% in Group N ( p = 0.010), although a propensity score matched analysis showed no significant difference. The incidence of 12-month pneumonitis ≥ G2 tended to be higher in Group D than in Group N (41.9% vs. 26.3%, p = 0.080). However, there was no difference in pneumonitis ≥ G3 rates (10.5% vs. 12.6%, p = 0.657). A multivariate analysis showed that the lung volume spared from 5 Gy (VS5) < 1800 cm 3 was a risk factor for pneumonitis ≥ G2 in Group D. Durvalumab consolidation showed the potential to prolong PFS without increasing the severity of pneumonitis.

Electromagnetic fields (EMFs) noninvasively promote fracture healing, prevent osteoporosis, promote diaphyseal growth, enhance differentiation, and stimulate cell division. However, no good model systems for analyzing bone regeneration have been reported. In this study, we examined the in vivo regeneration of scales having osteoblasts and osteoclasts using a new magnetic field generator for exposing aquatic animals to EMFs at a sine-wave frequency of 60 Hz. Goldfish scales were put into a fish-breeding space with the developed magnetic field generator and exposed to extremely low-frequency electromagnetic fields (ELF-EMFs) of 60 Hz at an intensity of 1, 3, and 5 mT for 10 days while being regenerated the scales. After exposure, alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activities in the goldfish scales were measured as markers of osteoblasts and osteoclasts, respectively. As a result, both ALP and TRAP activities in regenerating scales exposed to 3 mT ELF-EMFs were higher than those in regenerating scales exposed to 1 and 5 mT ELF-EMFs. Exposure of scales to 3 mT ELF-EMFs significantly enhanced the scale regeneration rate. Exposure of rat calvaria to 3 mT ELF-EMFs also increased both ALP and TRAP activities like in goldfish scales. Thus, we concluded that 3 mT ELF-EMFs contribute to the medical treatment of bone diseases.