Dual-specificity phosphatases 13 and 27 as key switches in muscle stem cell transition from proliferation to differentiation.

Muscle regeneration depends on muscle stem cell (MuSC) activity. Myogenic regulatory factors, including myoblast determination protein 1 (MyoD), regulate the fate transition of MuSCs. However, the direct target of MYOD in the process is not completely clear. Using previously established MyoD knock-in (MyoD-KI) mice, we revealed that MyoD targets dual-specificity phosphatase (Dusp) 13 and Dusp27. In Dusp13:Dusp27 double knock-out (DKO) mice, the ability for muscle regeneration after injury was reduced. Moreover, single-cell RNA sequencing of MyoD-high expressing MuSCs from MyoD-KI mice revealed that Dusp13 and Dusp27 are expressed only in specific populations within MyoD-high MuSCs, which also express Myogenin. Overexpressing Dusp13 in MuSCs causes premature muscle differentiation. Thus, we propose a model where DUSP13 and DUSP27 contribute to the fate transition of MuSCs from proliferation to differentiation during myogenesis.

Direct Reprogramming Improves Cardiac Function and Reverses Fibrosis in Chronic Myocardial Infarction.

BACKGROUND: Because adult cardiomyocytes have little regenerative capacity, resident cardiac fibroblasts (CFs) synthesize extracellular matrix after myocardial infarction (MI) to form fibrosis, leading to cardiac dysfunction and heart failure. Therapies that can regenerate the myocardium and reverse fibrosis in chronic MI are lacking. The overexpression of cardiac transcription factors, including Mef2c/Gata4/Tbx5/Hand2 (MGTH), can directly reprogram CFs into induced cardiomyocytes (iCMs) and improve cardiac function under acute MI. However, the ability of in vivo cardiac reprogramming to repair chronic MI with established scars is undetermined. METHODS: We generated a novel Tcf21iCre/reporter/MGTH2A transgenic mouse system in which tamoxifen treatment could induce both MGTH and reporter expression in the resident CFs for cardiac reprogramming and fibroblast lineage tracing. We first tested the efficacy of this transgenic system in vitro and in vivo for acute MI. Next, we analyzed in vivo cardiac reprogramming and fusion events under chronic MI using Tcf21iCre/Tomato/MGTH2A and Tcf21iCre/mTmG/MGTH2A mice, respectively. Microarray and single-cell RNA sequencing were performed to determine the mechanism of cardiac repair by in vivo reprogramming. RESULTS: We confirmed the efficacy of transgenic in vitro and in vivo cardiac reprogramming for acute MI. In chronic MI, in vivo cardiac reprogramming converted ≈2% of resident CFs into iCMs, in which a majority of iCMs were generated by means of bona fide cardiac reprogramming rather than by fusion with cardiomyocytes. Cardiac reprogramming significantly improved myocardial contraction and reduced fibrosis in chronic MI. Microarray analyses revealed that the overexpression of MGTH activated cardiac program and concomitantly suppressed fibroblast and inflammatory signatures in chronic MI. Single-cell RNA sequencing demonstrated that resident CFs consisted of 7 subclusters, in which the profibrotic CF population increased under chronic MI. Cardiac reprogramming suppressed fibroblastic gene expression in chronic MI by means of conversion of profibrotic CFs to a quiescent antifibrotic state. MGTH overexpression induced antifibrotic effects partly by suppression of Meox1, a central regulator of fibroblast activation. CONCLUSIONS: These results demonstrate that cardiac reprogramming could repair chronic MI by means of myocardial regeneration and reduction of fibrosis. These findings present opportunities for the development of new therapies for chronic MI and heart failure.

Satellite cell expansion is mediated by P-eIF2α-dependent Tacc3 translation.

Translational control of gene expression is an important regulator of adult stem cell quiescence, activation and self-renewal. In skeletal muscle, quiescent satellite cells maintain low levels of protein synthesis, mediated in part through the phosphorylation of eIF2α (P-eIF2α). Pharmacological inhibition of the eIF2α phosphatase with the small molecule sal003 maintains P-eIF2α and permits the expansion of satellite cells ex vivo Paradoxically, P-eIF2α also increases the translation of specific mRNAs, which is mediated by P-eIF2α-dependent read-through of inhibitory upstream open reading frames (uORFs). Here, we ask whether P-eIF2α-dependent mRNA translation enables expansion of satellite cells. Using transcriptomic and proteomic analyses, we show a number of genes associated with the assembly of the spindle pole to be upregulated at the level of protein, without corresponding change in mRNA levels, in satellite cells expanded in the presence of sal003. We show that uORFs in the 5' UTR of mRNA for the mitotic spindle stability gene Tacc3 direct P-eIF2α-dependent translation. Satellite cells deficient for TACC3 exhibit defects in expansion, self-renewal and regeneration of skeletal muscle.

Ossification of the posterior longitudinal ligament is linked to heterotopic ossification of the ankle/foot tendons.

INTRODUCTION: Systemic osteogenesis has been speculated to be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL). Our purpose was to compare the radiologic prevalence and severity of heterotopic ossification in foot tendons of Japanese patients with OPLL and to determine their association with systemic heterotopic ossification. MATERIALS AND METHODS: Clinical and radiographic data of 114 patients with OPLL were collected from 2020 to 2022. Control data were extracted from a medical database of 362 patients with ankle radiographs. Achilles and plantar tendon ossification were classified as grades 0-4, and the presence of osteophytes at five sites in the foot/ankle joint was assessed by radiography. Factors associated with the presence and severity of each ossification were evaluated by multivariable logistic regression and linear regression analysis. RESULTS: The prevalence of Achilles and plantar tendon ossification (grade ≥ 2) was 4.0-5.5 times higher in patients with OPLL (40-56%) than in the controls (10-11%). The presence of Achilles tendon ossification was associated with OPLL, age, and coexisting plantar tendon ossification, and was most strongly associated with OPLL (standardized regression coefficient, 0.79; 95% confidence interval, 1.34-2.38). The severity of Achilles and plantar tendon ossification was associated with the severity of ossification of the entire spinal ligament. CONCLUSIONS: The strong association of foot tendon ossification with OPLL suggests that patients with OPLL have a systemic osteogenesis background. These findings will provide a basis for exploring new treatment strategies for OPLL, including control of metabolic abnormalities.

Flk1 Deficiency and Hypoxia Synergistically Promote Endothelial Dysfunction, Vascular Remodeling, and Pulmonary Hypertension.

BACKGROUND: The mechanisms underlying pulmonary hypertension (PH) remain largely unknown; further, why advanced vascular remodeling preferentially occurs in arterioles is yet to be answered. VEGF (vascular endothelial growth factor) regulates angiogenesis through Flk1 (fetal liver kinase 1) and Flt1 (fms-like tyrosine kinase 1) on endothelial cells (ECs), which may be related to PH pathogenesis. However, spatiotemporal expression patterns of Flk1 and Flt1 in the pulmonary vascular system and the role of endothelial Flk1 in PH development remain poorly understood. METHODS: We analyzed multiple reporter mice, including Flk1-GFP (green fluorescent protein) bacterial artificial chromosome transgenic (Tg), Flt1-DsRed bacterial artificial chromosome Tg, and Flk1-GFP/Flt1-DsRed double Tg mice, to determine the spatiotemporal expression of Flk1 and Flt1 in hypoxia-induced PH. We also used Cdh5CreERT2/Flk1f/f/Tomato (Flk1-KO [knockout]) mice to induce EC-specific Flk1 deletion and lineage tracing in chronic hypoxia. RESULTS: Flk1 was specifically expressed in the ECs of small pulmonary vessels, including arterioles. Conversely, Flt1 was more broadly expressed in the ECs of large- to small-sized vessels in adult mouse lungs. Intriguingly, Flk1+ ECs were transiently increased in hypoxia with proliferation, whereas Flt1 expression was unchanged. Flk1-KO mice did not exhibit pulmonary vascular remodeling nor PH in normoxia; however, the arteriolar ECs changed to a cuboidal shape with protrusion. In hypoxia, Flk1 deletion exacerbated EC dysfunction and reduced their number via apoptosis. Additionally, Flk1 deletion promoted medial thickening and neointimal formation in arterioles and worsened PH. Mechanistically, lineage tracing revealed that neointimal cells were derived from Flk1-KO ECs. Moreover, RNA sequencing in pulmonary ECs demonstrated that Flk1 deletion and hypoxia synergistically activated multiple pathways, including cell cycle, senescence/apoptosis, and cytokine/growth factor, concomitant with suppression of cell adhesion and angiogenesis, to promote vascular remodeling. CONCLUSIONS: Flk1 and Flt1 were differentially expressed in pulmonary ECs. Flk1 deficiency and hypoxia jointly dysregulated arteriolar ECs to promote vascular remodeling. Thus, dysfunction of Flk1+ ECs may contribute to the pathogenesis of advanced vascular remodeling in pulmonary arterioles.

Posterolateral full-endoscopic debridement and irrigation is effective in treating thoraco-lumbar pyogenic spondylodiscitis, except in cases with large abscess cavities.

PURPOSE: To determine the efficacy and poor prognostic factors of posterolateral full-endoscopic debridement and irrigation (PEDI) surgery for thoraco-lumbar pyogenic spondylodiscitis. METHODS: We included 64 patients (46 men, 18 women; average age: 63.7 years) with thoracic/lumbar pyogenic spondylodiscitis who had undergone PEDI treatment and were followed up for more than 2 years. Clinical outcomes after PEDI surgery were retrospectively investigated to analyze the incidence and risk factors for prolonged and recurrent infection. RESULTS: Of 64 patients, 53 (82.8%) were cured of infection after PEDI surgery, and nine (17.2%) had prolonged or recurrent infection. Multivariate analysis demonstrated that significant risk factors for poor prognosis included a large intervertebral abscess cavity (P = 0.02) and multilevel intervertebral infections (P < 0.05). CONCLUSION: PEDI treatment is an effective, minimally invasive procedure for pyogenic spondylodiscitis. However, a large intervertebral abscess space could cause instability at the infected spinal column, leading to prolonged or recurrent infection after PEDI. In cases with a large abscess cavity with or without vertebral bone destruction, endoscopic drainage alone may have a poor prognosis, and spinal fixation surgery could be considered.

Urine cell image recognition using a deep-learning model for an automated slide evaluation system.

OBJECTIVES: To develop a classification system for urine cytology with artificial intelligence (AI) using a convolutional neural network algorithm that classifies urine cell images as negative (benign) or positive (atypical or malignant). PATIENTS AND METHODS: We collected 195 urine cytology slides from consecutive patients with a histologically confirmed diagnosis of urothelial cancer (between January 2016 and December 2017). Two certified cytotechnologists independently evaluated and labelled each slide; 4637 cell images with concordant diagnoses were selected, including 3128 benign cells (negative), 398 atypical cells, and 1111 cells that were malignant or suspicious for malignancy (positive). This pathologically confirmed labelled dataset was used to represent the ground truth for AI training/validation/testing. Customized CutMix (CircleCut) and Refined Data Augmentation were used for image processing. The model architecture included EfficientNet B6 and Arcface. We used 80% of the data for training and validation (4:1 ratio) and 20% for testing. Model performance was evaluated with fivefold cross-validation. A receiver-operating characteristic (ROC) analysis was used to evaluate the binary classification model. Bayesian posterior probabilities for the AI performance measure (Y) and cytotechnologist performance measure (X) were compared. RESULTS: The area under the ROC curve was 0.99 (95% confidence interval [CI] 0.98-0.99), the highest accuracy was 95% (95% CI 94-97), sensitivity was 97% (95% CI 95-99), and specificity was 95% (95% CI 93-97). The accuracy of AI surpassed the highest level of cytotechnologists for the binary classification [Pr(Y > X) = 0.95]. AI achieved >90% accuracy for all cell subtypes. In the subgroup analysis based on the clinicopathological characteristics of patients who provided the test cells, the accuracy of AI ranged between 89% and 97%. CONCLUSION: Our novel AI classification system for urine cytology successfully classified all cell subtypes with an accuracy of higher than 90%, and achieved diagnostic accuracy of malignancy superior to the highest level achieved by cytotechnologists.

Real-world persistence of twice-weekly teriparatide and factors associated with the discontinuation in patients with osteoporosis.

INTRODUCTION: A 28.2 µg twice-weekly formulation of teriparatide (2/W-TPD) was developed to provide comparably high efficacy for osteoporosis to a 56.5 µg once-weekly formulation while improving the safety and persistence rate. In the current study, we aimed to elucidate the real-world persistence of 2/W-TPD and to identify the factors associated with the discontinuation of 2/W-TPD in patients with severe osteoporosis. MATERIALS AND METHODS: This retrospective study included 90 patients who were treated with 2/W-TPD at three hospitals in Japan. Patient information was collected, including age, sex, distance to the hospital, family structure, comorbidities, previous treatment for osteoporosis, timing of the injection, side effects and duration of 2/W-TPD treatment, barthel index (BI), and bone mineral density (BMD) of the lumbar spine and femoral neck. We examined the factors influencing 2/W-TPD discontinuation using the Cox proportional hazards model. RESULTS: The 12 month completion rate of 2/W-TPD therapy was 47.5%. The Cox hazard analysis identified side effects [Hazard Ratio (HR) = 14.59, P < 0.001], low BMD of the femoral neck (HR = 0.04, P = 0.002), and morning injection (HR = 3.29, P = 0.006) as risk factors influencing the discontinuation of 2/W-TPD. Other variables, including age, did not contribute to the continuation of 2/W-TPD. CONCLUSION: One year continuation rate of 2/W-TPD was higher than the previously reported value of the once-weekly formulation in real-world setting, probably due to the lower incidence of side effects. Introducing injection of 2/W-TPD may further improve the persistence of TPD therapy for osteoporosis.

Association between obesity and ossification of spinal ligaments in 622 asymptomatic subjects: a cross-sectional study.

INTRODUCTION: Previous studies on patients with symptoms of spinal ligament ossification, including ossification of the posterior longitudinal ligament (OPLL) and ligamentum flavum (OLF), have not clarified whether obesity is a cause or consequence of these diseases and were limited by selection bias. Thus, we investigated the association between obesity and the prevalence of spinal ligament ossification in randomly selected asymptomatic subjects. MATERIALS AND METHODS: Between April 2020 and March 2021, 622 asymptomatic Japanese subjects who underwent computed tomography of neck to pelvis for medical check-up purposes were included. All subjects were divided into the following three groups: normal weight (body mass index [BMI] < 25 kg/m2), obese I (25 ≤ BMI < 30 kg/m2), and obese II (BMI ≥ 30 kg/m2). The relationship between factors affecting the presence of each spinal ligament ossification was evaluated using multivariate logistic regression analysis. RESULTS: The proportion of subjects with thoracic OPLL was significantly higher in the obese II group than in the other two groups (vs. normal weight, P < 0.001; vs. obese I, P < 0.001). BMI was associated with the prevalence of OLF, cervical OPLL, thoracic OPLL, and ossification of the anterior longitudinal ligament (OALL). BMI was most significantly associated with the prevalence of thoracic OPLL (ß, 0.28; 95% confidence interval, 0.17-0.39). CONCLUSION: BMI was associated with the prevalence of OALL, cervical OPLL, thoracic OPLL, and OLF in asymptomatic subjects, suggesting that obesity is associated with the development of heterotopic ossification of the spinal ligaments.

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

INTRODUCTION: Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. MATERIALS AND METHODS: We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7 years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). RESULTS: Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. CONCLUSION: Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Accuracy of pedicle screw placement using patient-specific template guide system.

BACKGROUND: Despite repeated efforts for accurate cervical pedicle screw insertion, malpositioning of the inserted screw is commonly noted. To avoid neurovascular complications during cervical pedicle screw insertion, we have developed a new patient-specific screw guide system. This study aimed to evaluate the accuracy of cervical PS placement using the new patient-specific screw guide system. METHODS: This study is a retrospective clinical evaluation of prospectively enrolled patients. Seventeen consecutively enrolled patients who underwent posterior cervical fusion using the guide system were included. Firstly, three-dimensional planning of pedicle screw placement was done using simulation software. A screw guide for each vertebra was constructed preoperatively. A total of 77 screws were inserted with the guides. Postoperative computed tomography was used to evaluate pedicle perforation, and screw deviations, between the planned and actual screw positions, were measured. RESULTS: A total of 76 screws (98.7%) were completely inside the pedicle (C3-7), without neurovascular injuries. The mean screw deviations from the planned trajectory at the narrowest point of the pedicle and at the entry point in the axial and sagittal planes were 0.56 ± 0.43 mm and 0.43 ± 0.35 mm and 0.43 ± 0.30 mm and 0.63 ± 0.50 mm, respectively. There were no significant differences in any parameter at different spinal levels. Angular deviations in the sagittal and axial planes were 2.94 ± 2.04° and 2.53 ± 1.85°, respectively. Sagittal angular deviations tended to increase in the cranial vertebra (C3 and C4) compared to the middle cervical spine. CONCLUSIONS: We demonstrated that our patient-specific screw guide is vital for guiding precise screw insertion in the cervical pedicle. This technique may be an effective solution for achieving precise screw insertion and reducing the incidence of complications.

[A Rare Case of Primary Splenic Malignant Lymphoma Associated with Esophagogastric Junction Neuroendocrine Carcinoma(NEC)].

A 75-year-old man was showed wall thickening just below esophagogastric junction(EGJ)by gastroscopy(GS). Biopsy indicated mucinous carcinoma. He was referred to our hospital. Computed tomography(CT), PET-CT showed EGJ cancer and splenic tumor. EGJ cancer was diagnosed GE, Siewert Type Ⅱ, GrePostAnt, Type 1, cT2, cN0, cM0, cStage Ⅰ. The patient underwent total gastrectomy, lower esophagectomy, D2+ #19, 20, 110, 111, 112 lymph nodes dissection, Rou-en- Y reconstruction, distal pancreatectomy, splenectomy, cholecystectomy, and enterostomy. Postoperative complication was pancreatic fistula(Grade Ⅱ). Pathological diagnosis was esophagogastric junction cancer, neuroendocrine carcinoma(NEC), GE, Siewert Type Ⅱ, GrePostAnt, Type 1, pT2(MP), pN1, pM0, pStage ⅡA. Splenic tumor was diagnosed splenic malignant lymphoma, large B-cell, diffuse(DLBCL), NOS, low-immediate risk. Patient was discharged 15 days after the operation and underwent adjuvant chemotherapy with S-1. In this case, he started taking S-1 because the prognosis of NEC is poorer than PSML. There was no evidence of recurrence after 5 months from gastrectomy. As a result of searching for"neuroendocrine tumor"and"malignant lymphoma"in the JAMAS, there was no report of NEC associated with malignant lymphoma. We experienced the rare case of primary splenic malignant lymphoma associated with EGJ NEC. In the case of gastric cancer with splenic tumor, malignant lymphoma of spleen should be concerned.

Direct reprogramming with Sendai virus vectors repaired infarct hearts at the chronic stage.

Adult hearts have limited regenerative capacity. Hence, after acute myocardial infarction (MI), dead myocardial tissues are digested by immune cells and replaced by fibrosis, leading to ventricular remodeling and heart failure at the chronic stage. Direct reprogramming of the cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) with cardiac transcription factors, including Gata4, Mef2c, and Tbx5 (GMT), may have significant potential for cardiac repair. Sendai virus (SeV) vectors expressing GMT have been reported to reprogram the mouse cardiac fibroblasts into iCMs without any risk of insertional mutagenesis. In vivo reprogramming improved the cardiac function after acute MI in immunodeficient mice. However, it is unknown whether the newly generated iCMs could exist in infarct hearts for a prolonged period and SeV-GMT can improve cardiac function after MI at the chronic stage in immunocompetent mice. Here, we show that SeV vectors efficiently infect CFs in vivo and reprogram them into iCMs, which existed for at least four weeks after MI, in fibroblast-linage tracing mice. Moreover, SeV-GMT improved cardiac function and reduced fibrosis and collagen I expression at 12 weeks after MI in immunocompetent mice. Thus, direct cardiac reprogramming with SeV vectors could be a promising therapy for MI.

Effects after starting or switching from bisphosphonate to romosozumab or denosumab in Japanese postmenopausal patients.

PURPOSE: We aimed to investigate the longitudinal changes in bone metabolic markers and bone mineral density (BMD) after starting or switching from bisphosphonate (BP) to romosozumab (ROMO) or denosumab (DENO) therapies over 12 months and to determine predictors that establish associations with changes in BMD among the patients received the ROMO therapy. METHODS: Postmenopausal osteoporosis patients with a high risk of fracture-154 in total-were recruited; their therapies were switched to ROMO or DENO from BP/naïve or vitamin D (ND) (ND-ROMO: 43, BP-ROMO: 38, ND-DENO: 38, and BP-DENO: 35). Longitudinal changes in bone metabolic markers and BMD were evaluated. RESULTS: ROMO groups showed significant increases in BMD of the lumbar spine at 6 and 12 months and femoral neck at 12 months compared to the DENO groups. Although BP-ROMO showed significant increase in the lumbar spine BMD compared to BP-DENO, there were no significant differences in femoral neck and total hip BMDs between BP-ROMO and BP-DENO. Among the ROMO groups, % changes of BMD from baseline to 12 months were associated with bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months. CONCLUSIONS: ROMO continuously increased BMD for 12 months and performed better than DENO. On the other hand, effects of ROMO switched from BP on BMD of femoral neck and total hip were almost same with DENO. Bone metabolic markers at baseline and changes in TRACP-5b from baseline to 3 months may predict the efficacy of ROMO after 12 months of administration.

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

Correlations Between Range of Motion and Elasticity of the Coracohumeral Ligament Evaluated With Shear-Wave Elastography.

CONTEXT: Range of motion (ROM) in the glenohumeral joint decreases with age in healthy subjects; however, the underlying mechanism remains unclear. The process of aging of the joint capsule, including the coracohumeral ligament (CHL), could affect ROM limitation. OBJECTIVE: This study investigated correlations between elasticity of the CHL, evaluated by means of shear-wave elastography, and age, side dominance, and ROM in healthy individuals. DESIGN: Experimental study. SETTING: Laboratory. SUBJECTS: Eighty-four healthy volunteers (39 men and 45 women, mean age: 42.6 y) were included. MAIN OUTCOME MEASURES: Subjects were divided into 3 age groups: younger (20-39 y), middle (40-59 y), and older (≥60 y) age groups. With participants in the supine position, CHL elasticity in both shoulders was evaluated in both neutral and 30° external rotation, with arms at the sides. ROM, including forward flexion, lateral elevation, external rotation, 90° abduction with external rotation, and hand behind the back were measured with participants in the standing position. RESULTS: The CHL elastic modulus was higher in the older group than in the younger group in the neutral (78.4 kPa [SD: 37.1] and 56.6 kPa [SD: 31.7], respectively) and 30° external rotation positions (135.5 kPa [SD: 63.5] and 71.4 kPa [SD: 32.2], respectively). Negative correlations were found between the CHL elastic modulus and ROM in terms of 30° external rotation and both external rotation (R = -.59, P = .02) and 90° abduction with external rotation (R = -.71, P = .003) in the older group, with correlation coefficients increasing with age. CONCLUSIONS: Significant correlations were identified between CHL elasticity and ROM in both external rotation and 90° abduction with external rotation with increasing age. Decreased CHL elasticity was strongly associated with decreased shoulder ROM in middle-aged and older individuals.

Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.

Muscle mitochondria are crucial for systemic metabolic function, yet their regulation remains unclear. The zinc finger MYND domain-containing protein 17 (Zmynd17) was recently identified as a muscle-specific gene in mammals. Here, we investigated the role of Zmynd17 in mice. We found Zmynd17 predominantly expressed in skeletal muscle, especially in fast glycolytic muscle. Genetic Zmynd17 inactivation led to morphologic and functional abnormalities in muscle mitochondria, resulting in decreased respiratory function. Metabolic stress induced by a high-fat diet upregulated Zmynd17 expression and further exacerbated muscle mitochondrial morphology in Zmynd17-deficient mice. Strikingly, Zmynd17 deficiency significantly aggravated metabolic stress-induced hepatic steatosis, glucose intolerance, and insulin resistance. Furthermore, middle-aged mice lacking Zmynd17 exhibited impaired aerobic exercise performance, glucose intolerance, and insulin resistance. Thus, our results indicate that Zmynd17 is a metabolic stress-inducible factor that maintains muscle mitochondrial integrity, with its deficiency profoundly affecting whole-body glucose metabolism.-Fujita, R., Yoshioka, K., Seko, D., Suematsu, T., Mitsuhashi, S., Senoo, N., Miura, S., Nishino, I., Ono, Y. Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.

Retrospective study to evaluate the clinical significance of a second rise in C-reactive protein level following instrumented spinal fusion surgery.

BACKGROUND: This study aimed to identify the incidence and causes of a second rise in C-reactive protein (CRP) levels following spinal instrumentation surgery and to help determine how an abnormal CRP response should be interpreted and managed during postoperative care. METHODS: The medical records of 948 patients who underwent instrumented spine fusion surgery and met the inclusion criteria were retrospectively reviewed to assess the frequency and causes of a second rise (SR) of CRP. A SR of CRP was defined when the CRP level after postoperative day 7 increased by more than 0.5 mg/dl from that at the previous time-point. The diagnostic cut-off value of CRP elevation for detection of surgical site infection (SSI) was determined. Cut-off values were analyzed using receiver operating characteristic (ROC) curves. Bayes' theorem was used to determine blood test posterior probabilities for SSI-positive cases using cutoff values of re-evaluated CRP levels. RESULTS: SR of CRP occurred in 107 of the 948 patients. Of the patients with SR of CRP, 38 (35%) patients had developed SSI, 33 (31%) patients had causes other than SSI, and the remaining 36 patients had unidentified causes. Among the patients with SR, excluding those with causes other than SSI, the best diagnostic cut-off value of SR for detection of SSI was 3.04 mg/dl (area under the curve was 0.74). The posterior test probability was 84.4%. CONCLUSIONS: For patients with SR of CRP, who had no causes other than SSI, an SR value of 3.04 mg/dl correlated with a high probability of developing SSI.

Prenatal myonuclei play a crucial role in skeletal muscle hypertrophy in rodents.

Multinucleated muscle fibers are formed by the fusion of myogenic progenitor cells during embryonic and fetal myogenesis. However, the role of prenatally incorporated myonuclei in the skeletal muscle fibers of adult animals is poorly understood. We demonstrated, using muscle-specific reporter mice, that the prenatal myonuclei remained in the adult soleus muscle, although cardiotoxin injection caused the loss of prenatal myonuclei. Overloading by the tendon transection of synergists failed to induce compensatory hypertrophy in regenerated soleus muscle fibers of adult rats, whereas unloading by tail suspension normally induced the fiber atrophy. Loss of hypertrophying function correlated with the lowered histone acetylation at the transcription start site of Igf1r gene, which was one of the genes that did not respond to the overloading. These parameters were improved by the transplantation of cells harvested from the juvenile soleus muscles of neonatal rats in association with enhanced histone acetylation of Igf1r gene. These results indicated that the presence of prenatal myonuclei was closely related to the status of histone acetylation, which could regulate the responsiveness of muscle fibers to physiological stimuli.