Impact of Orthopedic Surgical Intervention on Difficult-to-Treat Rheumatoid Arthritis: A Propensity Score Matched Study.

OBJECTIVE: To elucidate the therapeutic effect of orthopedic surgical intervention (OSI) in difficult-to-treat rheumatoid arthritis (D2T RA) compared with non-D2T RA. METHODS: A total of 534 recent surgeries were analyzed only in patients who had undergone OSI since 2016 and for whom a 12-month post-operative follow-up was available. D2T RA was determined according to the EULAR definition, and patients with D2T RA were matched to patients with non-D2T RA using propensity scores calculated by a logistic regression analysis. The Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Index 28 (DAS28), face scale, and patient's assessment of general health (GH) were measured repeatedly at baseline and 6 and 12 months and were compared using a two-way analysis of variance. RESULTS: The HAQ-DI, DAS28, face scale, and GH showed significant post-operative improvements, and there were significant differences in the HAQ-DI and face scale scores between D2T RA and non-D2T RA. An additional analysis with DAS28 as a covariate showed no significant interaction for either, suggesting that these improvements in clinical assessment were due to OSI rather than improved disease activity. CONCLUSIONS: In the absence of an effective pharmacological treatment strategy, OSI may be an effective treatment modality for the management of D2T RA.

Unveiling the arthritis divide: Exploring treatment response and impact in late-onset vs. young-onset rheumatoid arthritis.

OBJECTIVES: Impact of osteoarthritis (OA) on the initial treatment response of rheumatoid arthritis (RA) by treat to target (T2T) practice was compared between the patients with an onset age ≥65 years old (late-onset RA [LORA]) and those with an onset age <65 years old (young-onset RA [YORA]). METHODS: A retrospective study was conducted on the patients with RA, who were referred to our clinic without treatment between January 2021 and July 2022. Patients with grade ≥3 OA according to the Kellgren-Lawrence (K-L) classification either in the knee or hand were classified in the OA(+) group and others were in the OA(-) group. The clinical data were compared at the diagnosis and one year after the initial treatment between the groups for 74 LORA and 59 YORA patients, respectively. RESULTS: One year after starting treatment in the LORA patients, the OA(+) group had poorer disease activity control and greater disability in the several activities of daily living (ADL) than the OA(-) group. In the YORA patients, there were no differences in ADL disability between the groups. CONCLUSIONS: In the initial treatment of the LORA patients, the prevalence of OA was high, and impact of OA on LORA was larger than on YORA.

Excess microtubule and F-actin formation mediates shortening and loss of primary cilia in response to a hyperosmotic milieu.

The primary cilium is a small organelle protruding from the cell surface that receives signals from the extracellular milieu. Although dozens of studies have reported that several genetic factors can impair the structure of primary cilia, evidence for environmental stimuli affecting primary cilia structures is limited. Here, we investigated an extracellular stress that affected primary cilia morphology and its underlying mechanisms. Hyperosmotic shock induced reversible shortening and disassembly of the primary cilia of murine intramedullary collecting duct cells. The shortening of primary cilia caused by hyperosmotic shock followed delocalization of the pericentriolar material (PCM). Excessive microtubule and F-actin formation in the cytoplasm coincided with the hyperosmotic shock-induced changes to primary cilia and the PCM. Treatment with a microtubule-disrupting agent, nocodazole, partially prevented the hyperosmotic shock-induced disassembly of primary cilia and almost completely prevented delocalization of the PCM. An actin polymerization inhibitor, latrunculin A, also partially prevented the hyperosmotic shock-induced shortening and disassembly of primary cilia and almost completely prevented delocalization of the PCM. We demonstrate that hyperosmotic shock induces reversible morphological changes in primary cilia and the PCM in a manner dependent on excessive formation of microtubule and F-actin.

More than 10 years' follow-up of the Swanson metacarpophalangeal joint arthroplasty for the rheumatoid hand.

BACKGROUND: In recent years, advances in pharmacotherapy for rheumatoid arthritis have dramatically improved the control of disease activity. However, a significant number of patients still develop hand deformity and require surgical reconstruction. The objective of this study was to evaluate the long-term efficacy and drawbacks of the Swanson metacarpophalangeal joint arthroplasty for patients with rheumatoid arthritis over 10 years. METHODS: Clinical and radiological evaluations were performed for 87 joints of 29 hands in 27 patients who underwent metacarpophalangeal joint arthroplasty using the Swanson implant, and who were followed up for an average of 11.4 (10-14) years. RESULTS: The number of operated tender and swollen metacarpophalangeal joints decreased from 24 (27.6%) and 28 (32.2%) to 1 (1.1%) and 2 (2.3%), respectively. The patients' general health and disease activity score 28-erythrocyte sedimentation rate improved at the last survey. Mild recurrence of ulnar drift was observed, but the deformity was generally well-corrected. Implant fracture was noted in eight joints (9.2%), and revision surgery was performed in two joints (2.3%). The average active range of extension/flexion changed from -46.3°/65.9° to -32.3°/56.6°. While a significant change was not noted in grip or pinch strength, patients were satisfied with the operation especially in terms of pain relief and improved hand appearance. CONCLUSIONS: The long-term results of Swanson metacarpophalangeal joint arthroplasty were good in pain relief and correction of deformity, but some problems remain with regard to implant durability and mobility.

Time-lapse imaging of primary cilium behavior with physiological expression of fluorescent ciliary proteins.

Almost all cell types of mammals have a small protrusion named a primary cilium on their surface. Primary cilia are enriched by cilia-specific ion channels and G-protein-coupled receptors. They are known to regulate various cellular functions that contribute to the development and homeostasis of living organisms by receiving extracellular signals and transfusing them to the cell body. All functions are performed when the structure of the primary cilia is maintained properly. Abnormalities in primary cilia or their signaling can lead to a collection of diseases in various organs called ciliopathies. The primary cilium is dynamic, static, or fixed. The length of primary cilia varies as the cell cycle progresses and is also altered by extracellular stimuli. Ligand binding to cilia-specific receptors is also known to alter the length. Thus, there is a need for a method to study the morphological changes of the primary cilium in a time-dependent manner, especially under stimuli or mechanical shocks. Time-lapse imaging of primary cilia is one of the most powerful methods to capture the time-dependent behavior of primary cilia. Overexpression of ciliary proteins fused to fluorescent proteins is commonly used for the time-lapse imaging of primary cilia. However, overexpression has drawbacks in terms of artifacts. In addition, the time-lapse imaging of the tiny primary cilia requires some technical tricks. Here, we present a detailed description of the methods for time-lapse imaging of primary cilium, from the generation of cell lines that stably express fluorescent protein-labeled cilia-localized proteins at the physiological level to image analysis, including quantification through image acquisition.

Cytochromes P450 involved in bacterial RiPP biosyntheses.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of secondary metabolites that have garnered scientific attention due to their complex scaffolds with potential roles in medicine, agriculture, and chemical ecology. RiPPs derive from the cleavage of ribosomally synthesized proteins and additional modifications, catalyzed by various enzymes to alter the peptide backbone or side chains. Of these enzymes, cytochromes P450 (P450s) are a superfamily of heme-thiolate proteins involved in many metabolic pathways, including RiPP biosyntheses. In this review, we focus our discussion on P450 involved in RiPP pathways and the unique chemical transformations they mediate. Previous studies have revealed a wealth of P450s distributed across all domains of life. While the number of characterized P450s involved in RiPP biosyntheses is relatively small, they catalyze various enzymatic reactions such as C-C or C-N bond formation. Formation of some RiPPs is catalyzed by more than one P450, enabling structural diversity. With the continuous improvement of the bioinformatic tools for RiPP prediction and advancement in synthetic biology techniques, it is expected that further cytochrome P450-mediated RiPP biosynthetic pathways will be discovered. SUMMARY: The presence of genes encoding P450s in gene clusters for ribosomally synthesized and post-translationally modified peptides expand structural and functional diversity of these secondary metabolites, and here, we review the current state of this knowledge.

The Efficacy of Biological Disease-modifying Antirheumatic Drugs on Sarcopenia in Patients with Rheumatoid Arthritis.

Objective Sarcopenia is characterized by a loss of muscle mass and strength, which leads to frailty and mortality. Rheumatoid arthritis (RA) is considered to be a cause of sarcopenia. The present study assessed the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) on sarcopenia. Methods This was a prospective cohort study including 48 patients [11 men, 37 women; 67.5 (57.0-74.8) years old] with RA who started bDMARDs in Niigata Rheumatic Center. We monitored the physical ability, nutritional status and body composition at the baseline, 6 months and 12 months. The physical activity was measured by the Health Assessment Questionnaire (HAQ) and 10-m walking test (10MWT). The nutritional status was assessed by the controlling nutrition status (CONUT) score. Results Among the 48 patients who started bDMARDs, 21 were classified as having sarcopenia. The physical activity and nutritional status were significantly ameliorated after 12 months of bDMARDs. The body composition analysis showed a significant increase in the body weight but no significant increase in the skeletal muscle mass index. The proportion of patients diagnosed with sarcopenia decreased significantly after 12 months of bDMARDs (43.8% vs. 27.1%, p=0.039). Among the 21 patients who were diagnosed with sarcopenia when starting bDMARDs, the skeletal muscle index was significantly increased after 12 months of bDMARDs. [5.22 (4.76-5.43) kg/m2 vs. 5.44 (4.84-5.77), p=0.039]. Conclusion Biologics may be useful in the treatment of sarcopenia through mechanisms such as improving the disease activity, physical activity and nutritional status.

More than 20 years' follow-up of metatarsal neck shortening oblique osteotomy for rheumatoid forefoot deformity.

BACKGROUND: In recent years, advances in pharmacotherapy for rheumatoid arthritis (RA) have dramatically improved the control of disease activity. However, a significant number of patients still develop forefoot deformity. The purpose of this study was to investigate the results of more than 20 years' follow-up of metatarsal neck shortening oblique osteotomy (SOO) for forefoot deformity in patients with RA. METHODS: The metatarsal neck SOO was performed on 163 feet in 108 patients between January 1985 and December 1996 in the authors' hospital. For the patients, who met the survey criteria, an observational study was performed clinically and radiologically at the baseline and at more than 20 years after surgery. RESULTS: A retrospective cohort study was conducted on 36 feet in 22 patients, all of whom were female, and the mean age at surgery was 45.6 (35.0-63.0) years old. The follow-up period was 25.1 (21.0-31.0) years. The presence of painful callosities in the surgically treated feet without revised surgeries decreased from 32 feet (100%) to 4 feet (12.5%) at the last follow-up with mild pain that did not cause any footwear problems. Re-osteotomy at the metatarsal of the lessor toe was performed on four feet in two patients. Radiologically, among 128 toes without revised surgeries, 85% were able to have the joint space preserved, and 89% maintained a pain-free condition without any recurrence of deformity. The mean total Japanese Society for Surgery for the Foot (JSSF) RA foot and ankle score was 64.0/100, and the visual analogue scale (VAS) of overall satisfaction was 62 (0: dissatisfied, 100: highly satisfied). The overall satisfaction had a positive correlation with calcaneal pitch and negative correlation with joint space narrowing at the talocrural joint. CONCLUSIONS: Metatarsal neck SOO appeared to be effective for patients with RA. The deformity was corrected and retained for a long time.

Comparative and pangenomic analysis of the genus Streptomyces.

Streptomycetes are highly metabolically gifted bacteria with the abilities to produce bioproducts that have profound economic and societal importance. These bioproducts are produced by metabolic pathways including those for the biosynthesis of secondary metabolites and catabolism of plant biomass constituents. Advancements in genome sequencing technologies have revealed a wealth of untapped metabolic potential from Streptomyces genomes. Here, we report the largest Streptomyces pangenome generated by using 205 complete genomes. Metabolic potentials of the pangenome and individual genomes were analyzed, revealing degrees of conservation of individual metabolic pathways and strains potentially suitable for metabolic engineering. Of them, Streptomyces bingchenggensis was identified as a potent degrader of plant biomass. Polyketide, non-ribosomal peptide, and gamma-butyrolactone biosynthetic enzymes are primarily strain specific while ectoine and some terpene biosynthetic pathways are highly conserved. A large number of transcription factors associated with secondary metabolism are strain-specific while those controlling basic biological processes are highly conserved. Although the majority of genes involved in morphological development are highly conserved, there are strain-specific varieties which may contribute to fine tuning the timing of cellular differentiation. Overall, these results provide insights into the metabolic potential, regulation and physiology of streptomycetes, which will facilitate further exploitation of these important bacteria.

ActinoBase: tools and protocols for researchers working on Streptomyces and other filamentous actinobacteria.

Actinobacteria is an ancient phylum of Gram-positive bacteria with a characteristic high GC content to their DNA. The ActinoBase Wiki is focused on the filamentous actinobacteria, such as Streptomyces species, and the techniques and growth conditions used to study them. These organisms are studied because of their complex developmental life cycles and diverse specialised metabolism which produces many of the antibiotics currently used in the clinic. ActinoBase is a community effort that provides valuable and freely accessible resources, including protocols and practical information about filamentous actinobacteria. It is aimed at enabling knowledge exchange between members of the international research community working with these fascinating bacteria. ActinoBase is an anchor platform that underpins worldwide efforts to understand the ecology, biology and metabolic potential of these organisms. There are two key differences that set ActinoBase apart from other Wiki-based platforms: [1] ActinoBase is specifically aimed at researchers working on filamentous actinobacteria and is tailored to help users overcome challenges working with these bacteria and [2] it provides a freely accessible resource with global networking opportunities for researchers with a broad range of experience in this field.

Effectiveness and Safety of Golimumab for Patients ≥75 Years Old with Rheumatoid Arthritis.

Objective Treatment of elderly patients with rheumatoid arthritis (RA) has been controversial because they often have serious comorbidities and cannot use methotrexate (MTX). In Japan, golimumab (GLM) 100 mg without MTX is approved. We investigated the effectiveness and safety of GLM in elderly patients with RA. Methods The GLM survival rate was evaluated using the Kaplan-Meier method. Disease activities, laboratory findings, and treatments were evaluated. Patients We enrolled 168 patients with RA in our hospital. Using age ≥75 years old to identify elderly patients, younger (n=111) and elderly (n=57) groups were established. Elderly patients were divided into 2 groups according to the MTX treatment status (with, n=27; without, n=25). Results The GLM survival rates were 80.8% and 82.3% in elderly and younger patients, respectively (p=0.762). At 52 weeks, the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) was improved in elderly patients (4.26 vs. 3.31, p<0.001); the Health Assessment Questionnaire Disability Index (HAQ-DI) was unchanged (1.12 vs. 0.88, p=0.694). When elderly patients were compared according to the MTX treatment status, the DAS28-ESR had improved in both groups (with MTX: 3.82 vs. 2.68, p<0.001; without MTX: 4.76 vs. 4.25, p=0.026); however, the HAQ-DI had not. The GLM survival rates at 52 weeks were 85% and 76% in patients with and without MTX, respectively. Conclusion In elderly patients with RA, GLM was effective, regardless of MTX treatment status, but it did not affect the HAQ-DI. GLM survival rates were comparable between elderly and younger patients. GLM may be a suitable option for elderly patients with RA who cannot use MTX.

RIViT-seq enables systematic identification of regulons of transcriptional machineries.

Transcriptional regulation is a critical process to ensure expression of genes necessary for growth and survival in diverse environments. Transcription is mediated by multiple transcription factors including activators, repressors and sigma factors. Accurate computational prediction of the regulon of target genes for transcription factors is difficult and experimental identification is laborious and not scalable. Here, we demonstrate regulon identification by in vitro transcription-sequencing (RIViT-seq) that enables systematic identification of regulons of transcription factors by combining an in vitro transcription assay and RNA-sequencing. Using this technology, target genes of 11 sigma factors were identified in Streptomyces coelicolor A3(2). The RIViT-seq data expands the transcriptional regulatory network in this bacterium, discovering regulatory cascades and crosstalk between sigma factors. Implementation of RIViT-seq with other transcription factors and in other organisms will improve our understanding of transcriptional regulatory networks across biology.

Correction of rheumatoid swan-neck deformity of the finger using the modified Thompson-Littler method.

OBJECTIVES: To investigate the outcomes of the modified Thompson-Littler (m-TL) method, a corrective surgical method utilising a dynamic tenodesis, in patients with rheumatoid swan-neck deformity. METHODS: Twenty-seven fingers in 10 patients with rheumatoid arthritis (RA) underwent surgical correction. The mean age at the time of surgery was 60.3 (45-77) years, the mean duration of RA was 19.3 (4-34) years, and the mean postoperative follow-up period was 2.4 (0.5-6) years. RESULTS: The deformity was corrected and the proximal interphalangeal (PIP) joint pain disappeared in all operated fingers. The mean pinch power between the thumb and the operated finger increased. The active extension decreased, the active flexion increased, and the total arc of motion decreased. Comparing the range of motion by Nalebuff's type classification, the postoperative arc of motion decreased as the type advanced. CONCLUSIONS: The m-TL method provided a favourable outcome in cases of Type ≤III rheumatoid swan-neck deformity without severe joint deterioration at the PIP joint. Aesthetic and functional improvements were observed and the patients were satisfied with the operation.

The Combination of Modified Mitchell's Osteotomy and Shortening Oblique Osteotomy for Patients with Rheumatoid Arthritis: An Analysis of Changes in Plantar Pressure Distribution.

The present study aims to evaluate changes in plantar pressure distribution after joint-preserving surgery for rheumatoid forefoot deformity. A retrospective study was performed on 26 feet of 23 patients with rheumatoid arthritis (RA) who underwent the following surgical combination: modified Mitchell's osteotomy (mMO) of the first metatarsal and shortening oblique osteotomy of the lateral four metatarsals. Plantar pressure distribution and clinical background parameters were evaluated preoperatively and one year postoperatively. A comparison of preoperative and postoperative values indicated a significant improvement in the visual analog scale, Japanese Society for Surgery of the Foot scale, and radiographic parameters, such as the hallux valgus angle. A significant increase in peak pressure was observed at the first metatarsophalangeal joint (MTPJ) (0.045 vs. 0.082 kg/cm2; p < 0.05) and a significant decrease at the second and third MTPJs (0.081 vs. 0.048 kg/cm2; p < 0.05, 0.097 vs. 0.054 kg/cm2; p < 0.05). While overloading at the lateral metatarsal heads following mMO has been reported in previous studies, no increase in peak pressure at the lateral MTPJs was observed in our study. The results of our study show that this surgical combination can be an effective and beneficial surgical combination for RA patients with mild to moderate joint deformity.

Functional reconstruction of a hand that was severely deformed due to Jaccoud's arthropathy.

A 54-year-old woman suspected of having localised systemic sclerosis (SSc) started steroid treatment around 40 years old. She had Jaccoud's arthropathy in her right hand with severe deformities but no bone erosion. The metacarpophalangeal (MP) joint of the index through the little fingers was dislocated palmo-ulnarly with flexion contracture of about 120° and a swan-neck deformity. The palmar skin crease was digging deeply into the skin and was soggy. Severe boutonnière deformity of the thumb was also noted. Due to her severely deformed hand, she could not grasp large objects or show her hand in public. Reconstructive surgery was performed in two stages using finger joint arthroplasty or fusion at the digital joints. After surgery, the appearance as well as the function of the hand was successfully restored. She was able to grasp the steering wheel of her car and was extremely satisfied with the results of the surgery.

[A Case of Adenoid Cystic Carcinoma of the Breast].

Primary adenoid cystic carcinoma(ACC)of the breast is a rare type of breast cancer. A 53-year-old woman with a right breast mass was examined at our institute. Ultrasonography showed 12.5×10.3×8.4 mm sized an ill-defined hypoechoic mass at zone C of the right breast. Pathological examination of core needle biopsy revealed atypical cells with solid and cribriform growth pattern. Computed tomography did not reveal lymph node metastases or distant metastases. The preoperative diagnosis was Stage ⅠA(cT1cN0M0, ER/PgR/HER2=-/-/1+)invasive ductal carcinoma or ACC. Surgery consisted of breast-conserving surgery and sentinel node biopsy. Pathological examination of the excised specimen revealed a so- called adenoid cystic pattern, so the final diagnosis was Stage ⅠA(pT1cN0M0, ER/PgR/HER2=-/-/1+)ACC. After 1 year of observation without adjuvant treatment, there has been no recurrence.

Twenty years' follow-up of radiocarpal arthrodesis for rheumatoid wrists.

OBJECTIVES: A pain-free stable wrist is a prerequisite for patients with rheumatoid arthritis to improve their activity of daily life. The present study investigated whether or not radiocarpal arthrodesis yielded good results for more than 20 years. METHODS: A retrospective study was performed on 20 unstable wrists in 17 patients with rheumatoid arthritis. Radiocarpal arthrodesis combined with synovectomy and the Darrach procedure was performed. Wrist pain, grip power, the range of motion, pharmacotherapy, ESR, CRP, and serial radiographs were investigated at the baseline and 20 years after the operation. Patient-reported outcomes using the mHAQ, DASH and patient's satisfaction level were investigated at the final follow-up. RESULTS: Pain had disappeared completely in all patients at 20 years after the operation. The average grip power increased in 16 wrists (80%) and decreased in 4 wrists (20%). Wrist extension and flexion significantly decreased, and supination and pronation remained within the functional range. Radiographically, ulnar shift and palmar subluxation initially improved and remained unchanged for a long time. Fourteen patients (82.4%) with 17 wrists were satisfied with this operation. CONCLUSION: Radiocarpal arthrodesis for rheumatoid wrists provided painless stability for a long period for 20 years or more.