Search

Kentaro Uchida,1 Shotaro Takano,1 Gen Inoue,1 Dai Iwase,1 Jun Aikawa,1 Ken Takata,1 Ryo Tazawa,1 Ayumu Kawakubo,1 Hiroyuki Sekiguchi,2 Masashi Takaso11Department of Orthopedic Surgery, Kitasato University School of Medicine, Sagamihara City, Kanagawa 252–0374, Japan; 2Shonan University of Medical Sciences Research Institute, Chigasaki City, Kanagawa 253–0083, JapanPurpose: While research suggests that obesity is a risk factor for knee osteoarthritis (KOA), the mechanisms are not fully understood. Mast cell (MC) numbers are increased in the osteoarthritic synovium and in the adipose tissue of obese individuals. We hypothesized that MC numbers are increased in the synovium of obese KOA patients. This study investigated MC marker and MC-generated cytokine/growth factor expression in the synovium of obese KOA patients.Patients and methods: Patients radiographically diagnosed with KOA (male: 38, female: 132) were allocated to three groups based on their body mass index (BMI): normal (

Background: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear.Methods: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25.Results: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group.Conclusions: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.). [ABSTRACT FROM AUTHOR]

Rationale: Acquired pulmonary alveolar proteinosis (PAP) is a syndrome characterized by pulmonary surfactant accumulation occurring in association with granulocyte/macrophage colony-stimulating factor autoantibodies (autoimmune PAP) or as a consequence of another disease (secondary PAP). Because PAP is rare, prior reports were based on limited patient numbers or a synthesis of historical data.Objectives: To describe the epidemiologic, clinical, physiologic, and laboratory features of autoimmune PAP in a large, contemporaneous cohort of patients with PAP.Methods: Over 6 years, 248 patients with PAP were enrolled in a Japanese national registry, including 223 with autoimmune PAP.Measurements and Main Results: Autoimmune PAP represented 89.9% of cases and had a minimum incidence and prevalence of 0.49 and 6.2 per million, respectively. The male to female ratio was 2.1:1, and the median age at diagnosis was 51 years. A history of smoking occurred in 56%, and dust exposure occurred in 23%; instances of familial onset did not occur. Dyspnea was the most common presenting symptom, occurring in 54.3%. Importantly, 31.8% of patients were asymptomatic and were identified by health screening. Intercurrent illnesses, including infections, were infrequent. A disease severity score reflecting the presence of symptoms and degree of hypoxemia correlated well with carbon monoxide diffusing capacity and serum biomarkers, less well with pulmonary function, and not with granulocyte/macrophage colony-stimulating factor autoantibody levels or duration of disease.Conclusions: Autoimmune PAP had an incidence and prevalence higher than previously reported and was not strongly linked to smoking, occupational exposure, or other illnesses. The disease severity score and biomarkers provide novel and potentially useful outcome measures in PAP. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. Objectives: To identify the responsible gene that causes pulmonary alveolar microlithiasis. Methods: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis. Measurements and Main Results: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function. Conclusion: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis. [ABSTRACT FROM AUTHOR]

The anti--granulocyte-macrophage colony--stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages. [ABSTRACT FROM AUTHOR]

Background: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK) gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood.Methods: Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, <5 mg/dl). He had suffered from frequent pneumonia since age 25 but had no history of frequent infections in his childhood or in adolescence. Sequencing of the BTK cDNA obtained from an Epstein-Barr virus-transformed B lymphoblastoid cell line derived from the bone marrow of the patient was performed to confirm a genetic defect.Results: Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT), resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain.Conclusions: This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients. [ABSTRACT FROM AUTHOR]

Abstract Background X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK) gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT), resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.

Background: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhalation may alleviate pulmonary inflammation caused by viral pneumonia. To investigate this, we evaluated its efficacy on COVID-19 pneumonia., Methods: This double-blind, randomised, placebo-controlled study (ClinicalTrials.gov: NCT04642950) evaluated patients in the first half of 2021 at seven Japanese hospitals. Hospitalised patients with COVID-19 pneumonia with moderate hypoxaemia inhaled sargramostim or placebo for 5 days. The primary endpoint was days to achieve a ≥ 2-category improvement from baseline on a modified 7-category ordinal scale. Secondary endpoints included degree of oxygenation, defined by amount of oxygen supply, and serum CCL17 level., Results: Seventy-five patients were randomly assigned in a 2:1 ratio to receive sargramostim or placebo, of which 47 and 23 were analysed, respectively. No difference was observed between groups regarding the primary endpoint (8.0 and 7.0 days for sargramostim and placebo, respectively) or in the secondary endpoints, except for CCL17. A post hoc sub-analysis indicated that endpoint assessments were influenced by concomitant corticosteroid therapy. When the cumulative corticosteroid dose was ≤500 mg during Days 1-5, recovery and oxygenation were faster in the sargramostim group than for placebo. Bolus dose corticosteroids were associated with temporarily impaired oxygenation and delayed clinical recovery. The increase in serum CCL17, a candidate prognostic factor, reflected improvement with sargramostim inhalation. The number of adverse events was similar between groups. Two serious adverse events were observed in the sargramostim group without causal relation., Conclusions: Inhaled sargramostim was likely to be effective for COVID-19 pneumonia unless the concomitant corticosteroid dose was high.

Background There has been no report comparing shoulder kinematics and muscle activities during axial shoulder rotation in different positions. The purpose of this study was to investigate differences in shoulder kinematics and muscle activities during axial shoulder rotation in healthy subjects between standing and supine positions using three-dimensional/two-dimensional (3D/2D) registration techniques and electromyography (EMG). Methods Eleven healthy males agreed to participate in this study. We recorded the fluoroscopy time during active shoulder axial rotation with a 90° elbow flexion in both standing and supine positions, simultaneously recording surface EMG of the infraspinatus, anterior deltoid, posterior deltoid, and biceps brachii. Three-dimensional bone models were created from CT images, and shoulder kinematics were analyzed using 3D/2D registration techniques. Muscle activities were evaluated as a ratio of mean electromyographic values to 5-sec maximum voluntary isometric contractions.  Results Scapular kinematics during axial shoulder rotation in the supine position showed similar patterns with those in the standing position. The scapula was more posteriorly tilted and more downwardly rotated in the supine posture than in standing (P < 0.001 for both). Acromiohumeral distance (AHD) in the supine posture was significantly larger than in standing. Muscle activities showed no significant differences between postures except for biceps (P < 0.001). Discussion Shoulder kinematics and muscle activities during axial rotation were similar in pattern between standing and supine postures, but there were shifts in scapular pose and AHD. The findings of this study suggest that posture may be an important consideration for the prescription of optimal shoulder therapy following surgery or for the treatment of shoulder disorders., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kenmoku et al.)

Background: We assessed damaged anterior capsulolabral motion during axial shoulder rotation in patients with anterior shoulder instability., Methods: Twenty-nine shoulders of 28 patients with anterior shoulder instability who underwent cine-magnetic resonance imaging during axial rotation of the adducted arm were included. The motion was captured after an intra-articular injection of saline solution (10-20 mL). During imaging, the shoulder was rotated passively from maximum internal rotation to maximum external rotation in the first 10 s and then back to maximum internal rotation in the subsequent 10 s. We assessed the rotational angles of the damaged labrum during compressing and pulling the humeral head against the glenoid. Evaluation of the rotational angles was performed on a series of axial images through the humeral head center., Results: The mean angles that damaged labrum compressed and pulled off against the glenoid were 12.0 ± 19.1° and 2.8 ± 21.2°, respectively. Additionally, seven of the 29 shoulders showed that the damaged labrum compressed on the glenoid rim before the rotational angle exceeded 0° during external rotation. In 13 shoulders, the damaged labrum could remain repositioned on the glenoid rim over the neutral position during internal rotation. In two shoulders, the damaged labrum was not compressed against the glenoid at the maximum external rotation. The injected saline moved from the posterior to the anterior side of the glenohumeral joint during internal rotation in each shoulder., Conclusion: The damaged labrum could be positioned on the glenoid when the arm was in a traditional internal immobilization., (© 2023 The Author(s).)

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ., Competing Interests: Conflict of interest: S.A. Papiris reports grants, personal fees and nonfinancial support from La Roche Hoffman and Boehringer Ingelheim, and other support from Savara, outside the submitted work. Conflict of interest: F. Bonella reports grants and personal fees from Savara Pharma outside the submitted work. Conflict of interest: R. Borie has received consulting fees from Boehringer Ingelheim, Roche and Sanofi, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim and Roche, outside the submitted work; support for attending meetings and/or travel received from Boehringer Ingelheim, Roche and Chiesi outside the submitted work; and participation on a data safety monitoring or advisory board for Savara, outside the submitted work. Conflict of interest: M. Molina-Molina reports personal fees and grants from Esteve-Teijin, Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: E. Jouneau reports personal fees and other support from Actelion, AIRB, AstraZeneca, Bellerophon Therapeutics, Biogen, BMS, Boehringer Ingelheim, Chiesi, FibroGen, Galecto Biotech, Genzyme, Gilead, GlaxoSmithKline, LVL, Mundipharma, Novartis, Pharm-Olam, Pfizer, Pliant Therapeutics, F. Hoffmann-La Roche, Ltd, Sanofi and Savara-Serendex, outside the submitted work. Conflict of interest: C. McCarthy is a scientific advisory board member of Savara Inc. unrelated to this work and has not received any payment from Savara Inc. for any work to date. Conflict of interest: E. Bendstrup reports grants and personal fees from Boehringer Ingelheim and Hofmann la Roche, and personal fees from Galapagos, outside the submitted work. Conflict of interest: M. Griese has received grants or contracts from Boehringer Ingelheim, outside the submitted work; has participated on a data safety or advisory board for Boehringer Ingelheim, outside the submitted work; and is the Head of chILD-EU, outside the submitted work. Conflict of interest: E.D. Manali reports personal fees and nonfinancial support from La Roche Hoffman; grants, personal fees and nonfinancial support from Boehringer Ingelheim; and other support from Savara, all outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: A previous clinical trial for autoimmune pulmonary alveolar proteinosis (APAP) demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation reduced the mean density of the lung field on computed tomography (CT) across 18 axial slice planes at a two-dimensional level. In contrast, in this study, we challenged three-dimensional analysis for changes in CT density distribution using the same datasets., Methods: As a sub-study of the trial, CT data of 31 and 27 patients who received GM-CSF and placebo, respectively, were analyzed. To overcome the difference between various shooting conditions, a newly developed automatic lung field segmentation algorithm was applied to CT data to extract the whole lung volume, and the accuracy of the segmentation was evaluated by five pulmonary physicians independently. For normalization, the percent pixel (PP) in a certain density range was calculated as a percentage of the total number of pixels from -1,000 to 0 HU., Results: The automatically segmented images revealed that the lung field was accurately extracted except for 7 patients with minor deletion or addition. Using the change in PP from baseline to week 25 (ΔPP) as the vertical axis, we created a histogram with 143 HU bins set for each patient. The most significant difference in ΔPP between GM-CSF and placebo groups was observed in two ranges: from -1,000 to -857 and -143 to 0 HU., Conclusion: Whole lung extraction followed by density histogram analysis of ΔPP may be an appropriate evaluation method for assessing CT improvement in APAP., (© 2022 S. Karger AG, Basel.)

Background: A combination of synthetic porous materials and BMP-2 has been used to promote fracture healing. For bone healing to be successful, it is important to use growth factor delivery systems that enable continuous release of BMP-2 at the fracture site. We previously reported that in situ-formed gels (IFGs) consisting of hyaluronan (HyA)-tyramine (TA), horseradish peroxidase and hydrogen peroxide enhance the bone formation ability of hydroxyapatite (Hap)/BMP-2 composites in a posterior lumbar fusion model., Objective: We examined the effectiveness of IFGs-HyA/Hap/BMP-2 composites for facilitating osteogenesis in refractory fracture model mice., Methods: After establishing the refractory fracture model, animals were either treated at the site of fracture with Hap harboring BMP-2 (Hap/BMP-2) or IFGs-HyA with Hap harboring BMP-2 (IFGs-HyA/Hap/BMP-2) (n = 10 each). Animals that underwent the fracture surgery but did not receive any treatment were considered the control group (n = 10). We determined the extent of bone formation at the fracture site according to findings on micro-computed tomography and histological studies four weeks following treatment., Results: Animals treated with IFGs-HyA/Hap/BMP-2 demonstrated significantly greater bone volume, bone mineral content and bone union than those treated with vehicle or IFG-HyA/Hap alone., Conclusions: IFGs-HyA/Hap/BMP-2 could be an effective treatment option for refractory fractures.

Hypothesis And/or Background: Increased flexor digitorum superficialis (FDS) tendon activity can be a therapeutic target for elbow disorders in adolescent baseball players. The proportion of adolescent baseball players who can use FDS independently is unknown, and which finger is most often used remains unclear. This study investigated whether adolescent baseball players intentionally used FDS on each finger., Methods: Adolescent baseball players were recruited and assessed for FDS function for each finger using the standard technique., Results: Sixty-nine participants (mean age: 10.4 years) were recruited. Participants numbered 33, 56, 59, and 25 on the throwing side and those numbered 28, 46, 54, and 33 on the nonthrowing side could independently flex the proximal interphalangeal joint while holding their palms in the index, middle, ring, and small fingers, respectively. When assessing both throwing and nonthrowing participants, a significant number of participants could independently flex the proximal interphalangeals of the ring and middle fingers but had difficulty with the index and small fingers ( P  < .001). No significant difference was noted between the throwing and nonthrowing participants in any finger ( P  > .05)., Discussion And/or Conclusion: One study reported that participating baseball players with elbow pain have more medial elbow joint space than those without pain symptoms. In another study on finger movements during pitching motion, the force of the thumb, index, middle, and ring fingers was greatest immediately before maximum external rotation. According to both reports, FDS function, especially in the index finger, can be a therapeutic target for medial-sided elbow injuries in adolescent baseball players., (© 2022 The Author(s).)

As shown in our previous studies, the intratracheal-administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

Expression of the apelin receptor, APJ, in skeletal muscle (SM) is known to decrease with age, but the underlying mechanism remains unclear. Increased tumor necrosis factor (TNF)-α levels are observed in SM with age and are associated with muscle atrophy. To investigate the possible interconnection between TNF-α elevation and APJ reduction with aging, we investigated the effect of TNF-α on APJ expression in cells derived from the quadriceps femoris of C57BL/6J mice. Expression of Tnfa and Apj in the quadriceps femoris was compared between 4- (young) and 24-month-old (old) C57BL/6J mice ( n = 10 each) using qPCR. Additionally, APJ-positive cells and TNF-α protein were analyzed by flow cytometry and Western blotting, respectively. Further, quadricep-derived cells were exposed to 0 (control) or 25 ng/mL TNF-α, and the effect on Apj expression was examined by qRT-PCR. Apj expression and the ratio of APJ-positive cells among quadricep cells were significantly lower in old compared to young mice. In contrast, levels of Tnfa mRNA and TNF-α protein were significantly elevated in old compared to young mice. Exposing young and old derived quadricep cells to TNF-α for 8 and 24 h caused Apj levels to significantly decrease. TNF-α suppresses APJ expression in muscle cells in vitro. The increase in TNF-α observed in SM with age may induce a decrease in APJ expression.

Background: The coronavirus disease 2019 (COVID-19) pandemic has restricted people’s activities and necessitated the discontinuation of cardiac rehabilitation (CR) programs for outpatients. In our hospital, CR for outpatients had to be discontinued for 3 months. We investigated the influence of this discontinuation of CR on physical activity, body composition, and dietary intake in cardiovascular outpatients. Method: Seventy-eight outpatients who restarted CR were investigated. We measured body composition, balance test, stage of locomotive syndrome, and food frequency questionnaire (FFQ) results at restart and 3 months later. We also investigated the results of examination that were obtained before discontinuation. Results: With regard to baseline characteristics, the percentage of male was 62.7% (n = 49), and average age and body mass index were 74.1 ± 8.5 years and 24.9 ± 7.0 kg/m2, respectively. Stage of locomotive syndrome and the results of FFQ did not change significantly. The one-leg standing time with eyes open test significantly worsened at restart (p < 0.001) and significantly improved 3 months later (p = 0.007). With regard to body composition, all limb muscle masses were decreased at restart and decreased even further 3 months later. Conclusions: Discontinuation of CR influenced standing balance and limb muscle mass. While the restart of CR may improve a patient’s balance, more time is required for additional daily physical activities. The recent pandemic-related interruption of CR should inspire the development of alternatives that could ensure the continuity of CR in a future crisis.

Hypothesis: We hypothesized that the treatment of recalcitrant lateral epicondylitis requires accurate identification of the painful area to promote remodeling of the degenerated extensor insertion and to stabilize the tendon origin during tendon healing. Thus, we performed tenodesis with bone marrow venting under local anesthesia for recalcitrant lateral epicondylitis., Methods: Twenty patients (21 elbows) were treated with bone marrow venting at the painful area of the lateral epicondyle of the elbow and tenodesis using 2 soft anchors lateral to the capitellum (immediately distal to the painful area) and were followed up for ≥2 years. Patients were assessed using the numerical rating scale for pain and the Quick Disabilities of the Arm, Shoulder, and Hand questionnaire, and objective evaluation included active range of motion., Results: The mean preoperative and postoperative pain scores were 7.5 and 0.5, respectively, indicating significant pain relief ( P  < .001). The mean preoperative and postoperative Quick Disabilities of the Arm, Shoulder, and Hand questionnaire scores were 44.2 and 1.0, respectively ( P  < .001). Two elbows had a slightly positive Thomsen test at the final visit. No recurrence of intra-articular symptoms induced by synovial fringe impingement was observed. Patients experienced more pain at the bone-tendon junction of extensors than at the tendon parenchyma., Conclusion: Tenodesis with bone marrow venting under local anesthesia was effective for subjective patient satisfaction and positive clinical outcomes at ≥2 years of follow-up in patients with recalcitrant lateral epicondylitis. Intra-articular symptoms can be improved by stabilization of the lateral soft tissue without treatment for intra-articular lesions., (© 2022 The Author(s).)

Background: Epidemiological studies have reported a positive association between hypercholesterolemia and shoulder disease. Previous studies have focused on the effect of hypercholesterolemia on tendinopathy. Moreover, hypercholesterolemia has also been linked to joint pathology in the knee and hand. However, the effect of hyperlipidemia on glenohumeral joint remain unclear. A hypercholesterolemic condition has been reported to alter levels of A Disintegrin and Metalloprotease with Thrombospondin Motifs (ADAMTSs) and matrix metalloproteases (MMPs) in synovium of the knee joint. Here, we evaluated the mRNA expression of ADAMTSs and MMPs in the glenohumeral synovium of patients with and without hypercholesterolemia., Methods: Study participants were 73 patients who underwent arthroscopic rotator cuff repair for degenerative rotator cuff tears. They were divided into two groups according to total cholesterol (TC) and triglyceride levels. Synovial membrane samples were harvested at the rotator interval during surgery, and mRNA expression levels of the aggrecanases ADAM-TS4 and ADAM-TS5 and MMPs (MMP-1, 3, 9, and 13) were analyzed quantitatively., Results: ADAM-TS5 and MMP1 mRNA levels were significantly higher in the high TC group than in the low TC group (P = 0.023 and P = 0.025, respectively). In contrast, no significant differences were observed in ADAMTS4 or MMPs 3, 9, and 13 (ADAMTS4, P = 0.547; MMP3, P = 0.55; MMP9, P = 0.521; and MMP13, P = 0.785)., Conclusion: Hypercholesterolemia may alter MMP1 and ADAMTS5 expression in the synovium of the glenohumeral joint., (© 2022. The Author(s).)

Objective: Approximately two-thirds of patients with history of shoulder dislocation may develop osteoarthritis (OA) of the glenohumeral joint. However, the biochemical mechanisms underlying the association between dislocation and OA are largely unknown. This study aimed to investigate macrophage markers and inflammatory cytokine expression associated with shoulder instability (SI) in comparison to rotator cuff tears (RCTs)., Design: This study included 30 patients with SI and 30 patients with RCTs. Synovial membrane samples were harvested from the rotator interval during the arthroscopic anatomical repair for both groups. The localization of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and cluster of differentiation (CD) 68 in synovial membranes was determined by immunohistochemistry. Transcript-level expressions of the inflammatory cytokines ( TNFA and IL1B ) and macrophage markers pan- CD68 and -M1 ( CD80 and CD86 ) were quantified. CD80 and CD86 expression in macrophages from the SI group was confirmed using flow cytometry., Results: TNF-α, IL-1β, and CD68 were expressed in the synovial lining layer of the synovial tissue in both groups. In addition, the mRNA expressions of TNFA , IL1B , CD68 , and CD80 were significantly higher in the SI group compared to the RCT group (P ​= ​0.012, 0.014, 0.022, 0.003, respectively). In samples from the SI group, 96.3% of CD68+/CD14+ macrophages were CD86-positive, whereas 2.5% of CD68+/CD14+/CD86+ cells were CD80-positive., Conclusions: Patients with SI had higher mRNA levels of TNFA , IL1B , CD68 , and CD80 than those with RCTs. These findings may partially explain the biochemical mechanism underlying the frequent development and progression of osteoarthritis in patients with SI., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 The Authors.)

Background: Cardiac rehabilitation (CR) combined with stress management training has been shown to be associated with fewer clinical events than CR alone. However, there have been no reports on the associations of CR with the psychological condition and detailed physical activities evaluated on the same day., Method: One hundred outpatients who participated in a CR program were graded on the hospital anxiety and depression scale (HADS). We divided them into a high HADS group ( n = 32) and a normal HADS group ( n = 68) and investigated by whole patients, ischemic heart disease (IHD) patients, and heart failure patients., Results: Overall, the patient age was 70.5 ± 9.6 years, the percentage of males was 73.0%, and the body mass index was 23.4 (21.7-26.0) kg/m 2 . In the high HADS group, overall functional mobility was poor and the distance in a two-minute walking test was short. Especially in IHD patients, the high HADS group showed high fat mass in body composition and low exercise tolerance and ventilator equivalents in cardiopulmonary exercise test., Conclusions: Depression and anxiety involved poor physical performance in CR outpatients and particularly involved low exercise tolerance in IHD patients. To evaluate accurate physical performance, it is necessary to investigate psychological condition.

Background: Impaired fracture healing results in extensive and prolonged disability and long-term pain. Previous studies reported that nerve growth factor (NGF) was expressed during fracture healing and that anti-NGF antibody improves physical activity associate with facture pain. However, NGF expression levels in delayed or non-union are not fully understood., Objective: We compared chronological changes in NGF in the callus of young mice after femur fracture with those in aged mice after femur fracture as a model of bone fracture in the elderly., Methods: We used young (age 8 weeks) and aged (age 10 months) male C57BL/6J mice. A fracture was generated in the femur. At 5, 7, 10, 14, 17, and 21 days after creation of a fracture, mRNA expression levels of Col2a1, Col10a1, NGF were evaluated using quantitative PCR. We examined NGF protein expression levels and localization in the callus at day 14 using ELISA and immunohistochemistry, respectively., Results: Expression of NGF in the callus after femur fracture in aged mice was significantly greater than that in young mice at days 5, 7, 10, 17, and 21 days. NGF protein levels in the callus of aged mice were also significantly higher than that in young mice. Immunohistochemical staining showed that NGF was heavily expressed in hypertrophic chondrocytes in the callus in aged mice., Conclusions: It is suggested that delayed Col2a1 and Col10a1 expression reflects delayed chondrocyte formation and delayed chondrocyte maturation in aged mice and that higher NGF expression in aged mice at day 14 may be associated with the presence of remaining hypertrophic chondrocytes in callus with delaying endochondral ossification.

Background: The rotator cuff undergoes natural degeneration with age, leading to age-related rotator cuff tear; however, the precise mechanism remains unclear. Transforming growth factor-beta (TGF-β) concentrations rise with age and TGF-β contributes to the pathophysiology of skeletal muscle. TGF-β has also been shown to suppress expression of the myokine, apelin, in skin fibroblasts. We hypothesized that TGF-β expression in the rotator cuff changes with age and regulates apelin expression, thereby contributing to rotator cuff degeneration., Methods: We used quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) to measure the expression of apelin and tendon-related genes (Tnmd, Col1a1, and Col3a1) in the rotator cuff of young (12 weeks), adult (24 weeks), and old (48 weeks) rats. Using Q-RT-PCR and enzyme-linked immunosorbent assay, we also measured Tgfb mRNA and TGF-β protein levels, respectively. Furthermore, we used Q-RT-PCR to measure apelin mRNA levels in rotator cuff-derived cells after treatment with 0 (control) and 10 ng/mL recombinant TGF-β., Results: Apelin mRNA levels were significantly lower in old compared to young and adult rats. Similarly, tendon-related genes, Tnmd, Col1a1, and Col3a1, were significantly lower in adult and old rats than young rats. In contrast, Tgfb mRNA and TGF-β protein were significantly higher in old compared to young rats. Stimulation with exogenous TGF-β significantly decreased Apelin mRNA expression compared to control., Conclusions: TGF-β regulates apelin expression in the rotator cuff and may play a key role in the degenerative pathology of the rotator cuff with age., (© 2021. The Author(s).)

Background: Cardiac rehabilitation (CR) is a requisite component of care for patients with heart failure (HF). We aimed to evaluate the clinical outcomes in outpatients with HF with preserved ejection fraction (HFpEF) compared to those in patients with non-HFpEF who did and did not continue a 5-month CR program., Methods: 173 outpatients with HF who participated in a 5-month CR program were registered. We divided them into two groups: HFpEF ( n = 84, EF 63 ± 7%) and non-HFpEF ( n = 89, EF 31 ± 11%). We further divided the patients into those who continued the CR program (continued group) and those who did not (discontinued group) in the HFpEF and non-HFpEF groups. The clinical outcomes at 5 months were compared among the groups., Results: There were no significant differences in patient characteristics at baseline between the continued and discontinued groups in the HFpEF and non-HFpEF groups except for % diabetes mellitus in the non-HFpEF group. The rates of all-cause death and hospital admissions in the continued group in both the HFpEF and non-HFpEF groups were significantly lower than those in the discontinued group. The all-cause death and hospital admissions in each group were independently associated with the continuation of the CR program., Conclusions: The continuation of a 5-month CR program was associated with the prevention of all-cause death and hospital admissions in both the HFpEF and non-HFpEF groups.

Miso is a traditional Japanese seasoning paste produced by fermenting soybeans using the power of koji mold. A recent Japanese cohort study has shown that increased consumption of fermented soybean products is associated with a reduced risk of death in both men and women. In this review, we briefly explain what miso means in the Japanese culture and food industry, varieties of miso available today, and steps involved in miso making. Then, we review early and latest scientific researches in koji mold species, their safety, and beneficial enzymes they produce during fermentation and maturation processes, which play a major part in determining the quality and sensory profile of miso .

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.

Background: Subacromial impingement syndrome is a common disorder associated with functional impairment and disability of the shoulder. Internal/external glenohumeral rotation is important for shoulder function. However, because it is difficult to measure the glenohumeral joint rotation angle physically, the relationship between this angle and the clinical symptoms of subacromial impingement syndrome is still largely unknown. Using advanced cine-magnetic resonance imaging techniques, we designed a study to improve our understanding of the nature of this relationship., Methods: We evaluated 100 shoulders with subacromial impingement syndrome. Patients underwent cine-magnetic resonance imaging during axial rotation with the arm adducted. During imaging, patients rotated their shoulder from maximum internal rotation to maximum external rotation over 10 seconds and then to maximum internal rotation over 10 seconds. The rotation angles were then evaluated using a series of axial images. The Constant-Murley (Constant) and UCLA scores for each patient were determined, and the correlation between the scores and rotational angles was assessed. Patients were divided into 3 groups according to the Constant pain score, and the rotational angles of each group were compared. Rotational angles were also compared between shoulders with and without night pain., Results: The external rotation angle showed a significant but low correlation with the Constant and UCLA scores (ρ = 0.24 and 0.24, respectively), whereas the internal rotation angle did not. In comparing the pain groups of Constant score and UCLA score, the external rotation angle significantly decreased as pain increased ( P  < .01), demonstrating a negative correlation (ρ = -0.47, -0.41, respectively). Additionally, the shoulders of patients with night pain showed significantly more restriction of external rotation angles than the shoulders of those without night pain ( P  = .01)., Conclusions: Limitation of the glenohumeral joint's external rotation is correlated with pain, for which we explore possible explanations. The results suggest that night pain can be effectively reduced using therapeutic interventions that target external rotational dysfunction., (© 2021 The Author(s).)

Background: Several biomechanical studies on subtrochanteric femur fractures have reported that use of an intramedullary nail is superior to extramedullary implant. However, the optimal choice of intramedullary nail for the treatment of comminuted subtrochanteric femur fracture remains unclear. Here, we evaluated the biomechanical properties of comminuted subtrochanteric femur fracture treated with four different internal fixations., Methods: A comminuted subtrochanteric femur fracture model was created with a 2-cm gap below the lessor trochanter in 20 synthetic femurs. The fractures were fixed with one of four implants - Antegrade Femoral Nail (AFN), Trochanteric Fixation Nail Advanced with a femoral neck blade (TFNA blade), TFNA with a femoral neck screw (TFNA screw), and the reversed distal femoral locking compression plate (DF-LCP) - all manufactured by DePuy Synthes. Axial compression tests and torsion tests were performed and the stiffness of each implant was compared., Results: For compression, the TFNA blade, TFNA screw, and AFN provided significantly higher stiffness than DF-LCP (p < 0.001, p < 0.001, p = 0.001, respectively), and the TFNA blade provided significantly higher stiffness than AFN (p = 0.049). For torsion, there were no significant differences among the groups in internal rotation, while the TFNA screw had significantly lower torsional stiffness than the AFN, TFNA blade and DF-LCP in external rotation (p = 0.036, p = 0.034, p = 0.037, respectively)., Conclusions: These findings could help to provide biomechanical evidence regarding choice of implant for the treatment of comminuted subtrochanteric femur fracture. The TFNA blade may be more suitable for the treatment of comminuted subtrochanteric femur fracture., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: The failure rate of operations involving the cephalomedullary nail technique for unstable femoral trochanteric fractures is 3-12%. Changing the reduction strategy may improve the stability. This study aimed to confirm whether reducing the proximal fragment with the medial calcar contact, as opposed to utilizing an intramedullary reduction, would improve the stability of such fractures., Materials and Methods: The unstable femoral trochanteric fracture model was created with fixation by cephalomedullary nails in 22 imitation bones. The 2 reduction patterns were as follows: one was with the proximal head-neck fragment external to the distal bone in the frontal plane and anterior in the sagittal plane as "Extramedullary," while the other was the opposite reduction position, that is, bone in the frontal plane and sagittal plane as "Intramedullary." We evaluated the tip-apex distance, compression stiffness, change in femoral neck-shaft angle, amount of blade telescoping, and diameter of the distal screw hole after the compression test. Statistical analysis was conducted using the Mann-Whitney U test., Results: No significant differences were seen in compression stiffness ( p = 0.804) and femoral neck-shaft angle change ( p = 0.644). Although the "Extramedullary" tip-apex distance was larger than the "Intramedullary" distance ( p = 0.001), it indicated clinically acceptable lengths. The amount of blade telescoping and the distal screw hole diameter were significantly larger in "Intramedullary" than in "Extramedullary" ( p < 0.001, p = 0.019, respectively). Our results showed that "Intramedullary" had significantly larger blade telescoping and distal screw hole diameters than "Extramedullary," and contrary to our hypothesis, no significant differences were seen in compression stiffness and femoral neck-shaft angle change., Conclusions: As opposed to the "Intramedullary" reduction pattern, the biomechanical properties of the "Extramedullary" reduction pattern improved stability during testing and decreased sliding., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10 -12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10 -12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 -7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Background: An enzymatic crosslinking strategy using hydrogen peroxide and horseradish peroxidase is receiving increasing attention for application with in situ-formed hydrogels (IFHGs). IFHGs may also be ideal carrier materials for bone repair, although their ability to carry bone morphogenetic protein-2 (BMP2) has yet to be examined., Objective: We examined the effectiveness of an IFHG made of hyaluronan (IFHG-HA) containing BMP2 for promoting bone formation in a mouse critical size bone defect model., Methods: C57/BL6J mice received a 2-mm femoral critical-sized bone defect before being randomly assigned to one of the following treatment groups (n = 6): control (no treatment), IFHG-HA only, PBS with BMP2, and IFHG-HA with BMP2. X-ray radiographs were utilized to track new bone formation, and micro-computed tomography and histological examination were performed on new bone formed at the bone defect site two weeks after surgery., Results: Mice treated with PBS with BMP2 and IFHG-HA with BMP2 had greater bone volume (BV) and bone mineral content (BMC) than those receiving control, and successfully achieved consolidation. Mice treated with IFHG-HA with BMP2 had significantly higher BV and BMC than those treated with PBS with BMP2., Conclusions: IFHG-HA may be an effective carrier for BMP2 to enable delivery for bone defect repair.

Background: Rotator cuff tears (RCTs) are often associated with severe shoulder pain. Non-steroidal anti-inflammatory drugs, not recommended for long-term use, do not effectively manage RCT-induced pain, resulting in reduced quality of life. To improve management, a better understanding of the fundamental properties of RCT pain is needed. Here, we aimed to compare the expression levels of nerve growth factor (NGF) and cyclooxygenase-2 (COX-2) mRNA in the synovial tissues of patients with RCT-induced pain and patients with non-painful recurrent shoulder dislocation (RSD)., Methods: The study included 32 patients with RCT who underwent arthroscopic rotator cuff repair and 28 patients with non-painful RSD who underwent arthroscopic Bankart repair. Synovial tissue samples were harvested from subacromial bursa and rotator interval of RCT patients and from the rotator interval of RSD patients. Samples were analyzed quantitatively expression levels for NGF and COX2 mRNA and NGF protein., Results: NGF mRNA and protein levels were significantly higher in the rotator interval of RCT patients than in the rotator interval of RSD patients ( p  = 0.0017, p  = 0.012, respectively), while COX2 mRNA levels did not differ significantly between the two patient groups. In RCT patients, COX2 mRNA was more highly expressed in the rotator interval than in the subacromial bursa ( p  = 0.038), whereas the mRNA and protein levels of NGF did not differ between the two tissues. The expression of NGF mRNA in the synovium of the rotator interval was significantly correlated with the numeric rating scale of pain (ρ = 0.38, p  = 0.004)., Conclusion: NGF mRNA and protein levels were elevated in patients with painful RCT compared with those in patients with non-painful RSD, whereas COX-2 levels were comparable in the two patient groups. These findings provide insights into novel potential strategies for clinical management of RCT.

Case: We performed arthroscopic superior capsule reconstruction (ASCR) for cuff tear arthropathy (CTA) with humeral head deformity. A 62-year-old man presented with severely limited shoulder motion and recalcitrant omalgia. He had a history of dental implant removal due to metal allergy, and his Constant score was 21 points. We diagnosed CTA with Hamada classification grade 5 and performed ASCR to avoid allergic reactions. Severe night pain improved within 1 week of ASCR, and his Constant score after 2 years was 74 points., Conclusion: ASCR may be an effective alternative treatment for patients with CTA with humeral head deformity., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B328)., (Copyright © 2020 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Delivery of bone morphogenetic protein-2 (BMP-2) via animal-derived absorbable collagen materials is used for the treatment of large bone defects. However, the administration of bovine proteins to humans is associated with the risk of zoonotic complications. We therefore examined the effect of combining BMP-2 with collagen-like peptides, poly(POG)n, in a critical-sized bone defect mouse model., Methods: A 2-mm critical-sized bone defect was created in the femur of 9-week-old male C57/BL6J mice. Mice were randomly allocated into one of four treatment groups (n = 6 each): control (no treatment), poly(POG)n only, 0.2 μg, or 2.0 μg BMP-2 with poly(POG)n. New bone formation was monitored using soft X-ray radiographs, and bone formation at the bone defect site was examined using micro-computed tomography and histological examination at 4 weeks after surgery., Results: Administration of 2.0 μg of BMP-2 with poly(POG)n promoted new bone formation and resulted in greater bone volume and bone mineral content than that observed in the control group and successfully achieved consolidation. In contrast, bone formation in all other groups was scarce., Conclusions: Our findings suggest the potential of BMP-2 with poly(POG)n as a material, free from animal-derived collagen, for the treatment of large bone defects.

Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL -1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases., Competing Interests: Conflict of interest: K. Nakata reports grants, personal fees and nonfinancial support from Medical and Biological Laboratories during the conduct of the study. In addition, K. Nakata has a patent “Anti-GM-CSF autoantibodies and reagents” (Japan patent office number 4372904). K. Nakata provided Medical and Biological Laboratories exclusive use of patent. In return, Medical and Biological Laboratories paid royalities to K. Nakata. Conflict of interest: T. Sugi has nothing to disclose. Conflict of interest: K. Kuroda has nothing to disclose. Conflict of interest: K. Yoshizawa has nothing to disclose. Conflict of interest: T. Takada has nothing to disclose. Conflict of interest: R. Tazawa has nothing to disclose. Conflict of interest: T. Ueda has nothing to disclose. Conflict of interest: A. Aoki has nothing to disclose. Conflict of interest: M. Abe has nothing to disclose. Conflict of interest: K. Tatsumi has nothing to disclose. Conflict of interest: R. Eda has nothing to disclose. Conflict of interest: S. Kondoh has nothing to disclose. Conflict of interest: K. Morimoto has nothing to disclose. Conflict of interest: T. Tanaka has nothing to disclose. Conflict of interest: E. Yamaguchi has nothing to disclose. Conflict of interest: A. Takahashi has nothing to disclose. Conflict of interest: M. Oda has nothing to disclose. Conflict of interest: H. Ishii has nothing to disclose. Conflict of interest: S. Izumi has nothing to disclose. Conflict of interest: H. Sugiyama has nothing to disclose. Conflict of interest: A. Nakagawa has nothing to disclose. Conflict of interest: K. Tomii has nothing to disclose. Conflict of interest: M. Suzuki has nothing to disclose. Conflict of interest: S. Konno has nothing to disclose. Conflict of interest: S. Ohkouchi has nothing to disclose. Conflict of interest: T. Hirano has nothing to disclose. Conflict of interest: T. Handa has nothing to disclose. Conflict of interest: T. Hirai has nothing to disclose. Conflict of interest: Y. Inoue has nothing to disclose. Conflict of interest: T. Arai has nothing to disclose. Conflict of interest: K. Asakawa has nothing to disclose. Conflict of interest: T. Sakagami has nothing to disclose. Conflict of interest: T. Tanaka has nothing to disclose. Conflict of interest: A. Mikami has nothing to disclose. Conflict of interest: N. Kitamura has nothing to disclose., (Copyright ©ERS 2020.)

Recent evidence suggests that synovial macrophage activation may be involved in cartilage destruction and pain in osteoarthritis (OA). The macrophage-inducible C-type lectin (Mincle) Clec4e is expressed in macrophages and is regulated in inflammatory conditions. Given that the regulation of Mincle in synovial macrophages has not been elucidated, we investigated the expression and regulation of Mincle in human synovial tissue (ST) harvested from patients with radiographic knee OA during total knee arthroplasty. Immunohistochemical and flow cytometric analyses were used to identify cells with Mincle expression in resected tissues. CD14-positive (CD14 + ; macrophage-rich cell fraction) and CD14-negative (CD14 - ; fibroblast-rich cell fraction) cells were extracted from the ST and used to assess MINCLE mRNA expression levels. To determine the role of tumor necrosis factor alpha (TNF-α) in the regulation of MINCLE expression, TNF-α was used to stimulate cultured CD14 + cells. Immunohistochemical staining revealed Mincle-positive cells in the synovial lining layer. Flow cytometric analysis showed that CD45 + CD14 + cells were Mincle positive while CD45 - /CD14 - cells were Mincle negative. MINCLE expression was significantly higher in CD14+ cells than in CD14 - cells. Stimulation of cultured CD14+ macrophages with TNF-α significantly increased MINCLE mRNA expression, while stimulation with TNF-α neutralizing antibody significantly decreased expression. That Mincle expression was observed in synovial macrophages and its expression was induced by TNF-α suggests that Mincle might have a key role in synovial inflammation in the osteoarthritic synovium., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Termedia.)

This study aimed to investigate whether a single injection of recombinant human bone morphogenetic protein-2-loaded artificial collagen-like peptide gel (rhBMP-2/ACG) accelerates consolidation at the bone defect site and bone union at the docking site in a mouse segmental bone transport (SBT) model. A critical sized bone defect (2 mm) was created in the femur of mice and subsequently reconstructed using SBT with an external fixator. Mice were divided into four treatment groups: Group CONT (immobile control), Group 0.2 (bone segments moved 0.2 mm/day for 10 days), Group 1.0 (bone segments moved 1.0 mm/day for 2 days), and Group 1.0/BMP-2 (rhBMP-2/ACG injected into the bone defect and segments moved 1.0 mm/day for 2 days). Consolidation at the bone defect site and bone union at the docking site was evaluated radiologically and histologically across eight weeks. Bone volume and bone mineral content were significantly higher in Group 0.2 than in Group 1.0. Group 0.2 showed evidence of rebuilding of the medullary canal eight weeks after surgery at the bone defect site. However, in Group 1.0, maturation of regenerative bone at the bone defect site was poor, with the central area between the proximal and distal bone composed mainly of masses of fibrous and adipose tissue. Group 1.0/BMP-2 had higher bone volume and bone mineral content compared to Group 1.0, and all mice achieved bone union at the bone defect and docking sites. Single injection of rhBMP-2/ACG combined with SBT may be effective for enhancing bone healing in large bone defects., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Ryo Tazawa et al.)

Background: The purpose of this study to compare glenohumeral joint motion during active shoulder axial rotation between subacromial impingement syndrome (SIS) shoulders and asymptomatic shoulders using cine-magnetic resonance imaging (cine-MRI). Measurement of glenohumeral joint motion via manual intervention does not assess the usual glenohumeral joint motion, and the glenoid surface cannot be confirmed manually. However, cine-MRI can produce clear images of glenohumeral joint rotation. Therefore, we sought to measure the active ROM of the glenohumeral rotation using cine-MRI., Methods: Seventy-three shoulders in 42 asymptomatic volunteers and 110 SIS shoulders in 103 consecutive patients were included in this study. We evaluated 36 matched pairs (72 shoulders in total) adjusting for baseline characteristics with propensity score matching method. The patients underwent cine-MRI during axial rotation of the adducted arm. During imaging, participants rotated their shoulder from the maximum internal rotation to the maximum external rotation over the first 10 s and then back to the maximum internal rotation over the subsequent 10 s. We assessed internal/external rotation, and compared the asymptomatic and SIS shoulders in this regard. Evaluation of rotation angles was performed on a series of axial images through the humeral head center., Results: The mean internal rotation angles of the asymptomatic and patient groups were 55° ± 10° and 41° ± 23°, respectively, (P = .002; 95% Confidence Interval [CI], 51-58 vs 33-49); the mean external rotation angles were 47° ± 15° and 21° ± 25°, respectively, (P < .001; CI, 42-52 vs 13-29)., Conclusions: Compared to asymptomatic shoulders, SIS shoulders showed significantly restricted glenohumeral rotation as determined by cine-MRI. Our results suggested that the significant limitation of active glenohumeral rotation might be associated with rotator cuff dysfunction.

The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects., (Copyright © 2019 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Background: Chronic inflammation with aging contributes to sarcopenia. Previous studies have suggested that the accumulation of adipose tissue in skeletal muscle, referred to as intermuscular adipose tissue (IMAT), increases with age and is associated with inflammation. However, the mechanism governing ectopic inflammation in skeletal muscle due to aging is not fully understood. Leptin, an adipocytokine derived from adipose tissue, is an important mediator of inflammatory processes. We examined changes in leptin levels with age and whether leptin contributes to ectopic inflammation., Methods: To evaluate ectopic inflammation in skeletal muscle, we measured alterations to the expression of inflammatory cytokine genes (Il1b, Il6, and Tnfa) and muscle break down-related gene (MuRF1 and Atrogin1) in the quadricep muscles of young (10 weeks) and aged (48 weeks) female rats using quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR). Histological examination was performed to identify the extent of IMAT. Leptin mRNA and leptin protein expression were examined using Q-RT-PCR and enzyme-linked immunosorbent assay, respectively. The effect of leptin on the mRNA expression of Il1b, Il6, and Tnfa in quadricep muscle-derived cells was also examined by stimulating the cells with 0 (control), 1, or 10 μg/mL rat recombinant leptin using Q-RT-PCR., Results: Aged rats had significantly higher Il6, MuRF1, and Atrogin1 but not Il1b and Tnfa, expression and greater levels of IMAT in their quadricep muscles than young rats. Aged rats also had significantly higher leptin expression and leptin protein concentration in their quadricep muscles than young rats. The addition of exogenous leptin to quadricep muscle-derived cells significantly increased the gene expression of Il1b and Il6 but not Tnfa., Conclusions: Our results suggest that elevated leptin levels due to aging cause ectopic inflammation through IL-6 in the skeletal muscle of aged rats.

The incidence and prevalence of autoimmune pulmonary alveolar proteinosis in Japan were previously estimated to be 0.49 and 6.2 per million, respectively. Thereafter, an increase in serological diagnosis forced a re-estimation of the incidence based on more contemporaneous data using more robust methods. Sera of 702 patients were positive for granulocyte-macrophage colony-stimulating factor autoantibody during the 2006-2016 period (group A). Of these patients, 43 were actively surveyed in Niigata prefecture (group B) for estimation of the incidence. To estimate the survival period, 103 patients (group C) were investigated retrospectively for the 1999-2017 period using restricted mean survival time. In group A, the number of patients diagnosed in each prefecture was closely correlated with the corresponding population, indicating no regional integration of onset. In group B, a total of 43 patients were diagnosed, the annual number followed a Poisson distribution and the incidence was thus estimated to be 1.65 per million. In group C, the retrospective cohort study revealed the mean survival period to be 16.1 years. Taken together, the prevalence was estimated to be 26.6 per million, indicating that the previous data for incidence and prevalence was an underestimation., Competing Interests: Conflict of interest: None declared.