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Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

Ultrasound-guided inferior alveolar nerve block (UGIANB) is a mandibular analgesic procedure in which local anesthetic is injected into the pterygomandibular space (PMS). Several studies have reported the clinical efficacy of UGIANB for mandibular surgeries; however, its effective range has never been investigated. We performed a cadaveric study to investigate the success rate of UGIANB injections and to determine whether injected dye could stain the mandibular nerve (MN) trunk and its branches. We performed UGIANB on the bilateral faces of 4 Thiel-embalmed cadavers. A needle was advanced to the PMS under ultrasound guidance and 5 mL of dye was injected. The cadaver was dissected and inspected for the presence of dye in the PMS; the range of dye spread to any of the inferior alveolar nerve (IAN), lingual nerve (LN), buccal nerve (BN), mandibular nerve (MN), auriculotemporal nerve (ATN), or facial nerves; and for the presence of intravascular dye. We performed eight UGIANB procedures on four cadavers. Dye was observed in the PMS in 7/8 injections. Staining was observed in all IAN, LN, and BNs that could be identified at dissection. No MN or auriculotemporal nerves (ATNs) were stained in any injections. No intravascular dye was observed in any injections. UGIANB can administer anesthetic into the PMS with high accuracy. UGIANB injections reached the IAN, LN, and BNs, but did not reach the MN or ATNs located outside the PMS. The findings of this cadaveric study indicate that UGIANB can provide sufficient analgesia for mandibular surgeries.

Estimation of muscle passive force from elasticity using shear wave elastography (SWE) has been reported. However, the relationship between the elasticity and passive force of human muscles has not been elucidated. This study investigated the elastic modulus–passive force relationship in human skeletal muscles at multiple sites. Four rectus femoris (RF) muscles were dissected from a human Thiel-embalmed cadaver. Calibration weights (0–600 g in 60-g increments) were applied to the distal tendon via a pulley system, and the shear elastic modulus as an index of elasticity was measured using SWE. The shear elastic modulus of the RF was measured at the proximal, central, and distal portions. The results demonstrated that the relationships between the elasticity in the longitudinal direction of the muscle and the passive force were nearly linear for all tested sites, with coefficients of determination ranging from 0.813 to 0.993. Shear wave elastography may be used as an indirect method to measure the changing passive force at any site within human muscles.

This cadaveric study investigated the biomechanical characteristics and stabilizing contribution of the bifurcate ligament using a multidirectional loading method and assessed the stabilizing effect of a brace after injury of the ligament. Eight freshly frozen cadaveric feet were tested for forefoot torque in inversion, eversion, adduction, and plantarflexion. Each band of the bifurcate ligament was transected sequentially, and the contribution of each portion of the ligament, as well as the stabilizing effects of the ankle brace, were examined. Stability decreased substantially after calcaneocuboid ligament transection for inversion and adduction loading. Bracing restored some stability, except for the adduction loading direction, for which it had only limited effect. The data indicate that inversion and adduction loading are strongly related to bifurcate ligament injury. The stabilizing effect of the ankle brace may have limited effectiveness for loads under adduction.

Background: Although a variety of surgical procedures for anterior talofibular ligament (ATFL) reconstruction have been reported, the effect of initial graft tension during ATFL reconstruction remains unclear. Purpose/Hypothesis: This study investigated the effects of initial graft tension on ATFL reconstruction. We hypothesized that a high degree of initial graft tension would cause abnormal kinematics and laxity. Study Design: Controlled laboratory study. Methods: Twelve cadaveric ankles were tested with a robotic system with 6 degrees of freedom to apply passive plantarflexion and dorsiflexion motions and a multidirectional load. A repeated measures experiment was designed with the intact ATFL, transected ATFL, and reconstructed ATFL at initial tension conditions of 10, 30, 50, and 70 N. The 3-dimensional path and reconstructed graft tension were simultaneously recorded, and the in situ forces of the ATFL and reconstructed graft were calculated with the principle of superposition. Results: Initial tension of 10 N was sufficient to imitate normal ankle kinematics and laxity, which were not significantly different when compared with those of the intact ankles. The in situ force on the reconstructed graft tended to increase as the initial tension increased. In situ force on the reconstructed graft >30 N was significantly greater than that of intact ankles. The in situ force on the ATFL was 19 N at 30° of plantarflexion. In situ forces of 21.9, 30.4, 38.2, and 46.8 N were observed at initial tensions of 10, 30, 50, and 70 N, respectively, at 30° of plantarflexion. Conclusion: Approximate ankle kinematic patterns and sufficient laxity, even with an initial tension of 10 N, could be obtained immediately after ATFL reconstruction. Moreover, excessive initial graft tension during ATFL reconstruction caused excessive in situ force on the reconstructed graft. Clinical Relevance: This study revealed the effects of initial graft tension during ATFL reconstruction. These data suggest that excessive tension during ATFL reconstruction should be avoided to ensure restoration of normal ankle motion.

The purpose of this study was to examine the effect of subcutaneous adipose tissue (SCAT) thickness and rectus femoris (RF) muscle thickness on RF and vastus intermedius (VI) echo intensity using human cadavers.The echo intensity of the RF and VI was measured in 11 legs of seven cadavers under three conditions: intact condition (Model 1), SCAT removed (Model 2), and SCAT and RF removed (Model 3).RF echo intensity in Model 1 (69.2 ± 20.3 a.u.) was significantly lower than that in Model 2 (83.4 ± 15.9 a.u.) (P = 0.003). VI echo intensity in Models 1 to 3 showed similar results to RF echo intensity (P = 0.003 to 0.001). Regarding the relationship between VI echo intensity and VI muscle thickness, the regression lines shifted upward in a parallel fashion in the order Model 1, Model 2, and Model 3. Multiple regression analysis revealed that the variation in RF echo intensity was explained by RF muscle thickness (P = 0.036) and SCAT thickness (P = 0.001), while the variation in VI echo intensity was explained by RF muscle thickness (P = 0.035).These results suggest that SCAT thickness and RF muscle thickness induce lower RF echo intensity, while RF muscle thickness induces lower VI echo intensity.

Background: Some recent studies have reported the role of the posterior malleolus as an attachment of the posterior-inferior tibiofibular ligament (PITFL) and suggested that even a small fragment should be fixed. However, there are few anatomic studies of the tibial plafond attachment of the PITFL. Methods: Seven Thiel-embalmed ankles were obtained. The margin of the distal tibial joint surface and the attachments of the superficial fiber of the PITFL (sPITFL) and the deep fiber (dPITFL) were identified. In the frontal view, the percentages of the attachments of the sPITFL and dPITFL of the mediolateral dimension of the posterior tibial plafond were measured. In the lateral view, the line that started from the proximal margin of the attachment of the sPITFL and parallel to the tibial axis was drawn, and the distance between that line and the posterior edge of the joint surface was measured (AP distance of the sPITFL). Then, the percentage of the AP distance of the sPITFL of the joint surface in the anteroposterior dimension of the tibial plafond was measured. Results: In the frontal view, the mediolateral distance of the attachment of the sPITFL was 5.0 mm, and that of the dPITFL was 19.5 mm. The percentage of the attachment of the sPITFL on the tibial plafond was 20.6%, and that of the dPITFL was 78.2%. In the lateral view, the average AP distance of the sPITFL was 0.5 mm, and the percentage in the anteroposterior dimension of the tibial plafond was 1.7%. Conclusion: The PITFL was attached to less than 10% of the anteroposterior dimension of the tibial plafond in most ankles. Conversely, the PITFL attached widely in the mediolateral dimension. Clinical Relevance: This study suggests that the size of the posterior malleolar fragment in the mediolateral dimension could help estimate how much of the PITFL attaches to the fragment which may have implications for ankle stability.

Background: This study aimed to evaluate the effects of the ankle flexion angle during anterior talofibular ligament (ATFL) reconstruction on ankle kinematics, laxity, and in situ force of a graft. Methods: Twelve cadaveric ankles were evaluated using a 6–degrees of freedom robotic system to apply passive plantar flexion and dorsiflexion motions and multidirectional loads. A repeated measures experiment was designed using the intact ATFL, transected ATFL, and reconstructed ATFL. During ATFL reconstruction (ATFLR), the graft was fixed at a neutral position (ATFLR 0 degrees), 15 degrees of plantar flexion (ATFLR PF15 degrees), and 30 degrees of plantar flexion (ATFLR PF30 degrees) with a constant initial tension of 10 N. The 3-dimensional path and reconstructed graft tension were simultaneously recorded, and the in situ force of the ATFL and reconstructed grafts were calculated using the principle of superposition. Results: The in situ forces of the reconstructed grafts in ATFLR 0 degrees and ATFLR PF 15 degrees were significantly higher than those of intact ankles. The ankle kinematics and laxity produced by ATFLR PF 30 degrees were not significantly different from those of intact ankles. The in situ force on the ATFL was 19.0 N at 30 degrees of plantar flexion. In situ forces of 41.0, 33.7, and 21.9 N were observed at 30 degrees of plantar flexion in ATFLR 0, 15, and 30 degrees, respectively. Conclusion: ATFL reconstruction with the peroneus longus (PL) tendon was performed with the graft at 30 degrees of plantar flexion resulted in ankle kinematics, laxity, and in situ forces similar to those of intact ankles. ATFL reconstructions performed with the graft fixed at 0 and 15 degrees of the plantar flexion resulted in higher in situ forces on the reconstructed graft. Clinical Relevance: Fixing the ATFL tendon graft at 30 degrees of plantar flexion results in an in situ force closest to that of an intact ankle and avoids the excessive tension on the reconstructed graft.

Background The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. Methods We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. Finding FAPs in AMI transiently expressed p16INK4A on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16INK4A expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16INK4A expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16INK4A-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. Interpretation MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes.

Purpose The first objective of our cadaveric study was to perform a biomechanical comparison of single-bundle (SB), double-bundle (DB), and triple-bundle (TB) anterior cruciate ligament (ACL) reconstructions using a hamstring tendon graft to determine the laxity match pre-tension (LMP) value, which is the tension within the graft required to re-create the same anterior laxity as the ACL-intact knee. The second objective was to determine the anterior laxity and force distribution during the application of both an anterior force and a simulated pivot-shift test. Methods Eleven fresh-frozen cadaveric knees were tested using a robotic/universal force-moment sensor system in the intact state, TB-reconstructed knee, DB-reconstructed knee, and SB-reconstructed knee. The LMP in each reconstruction was recorded. Each reconstructed knee was tested with an external load of 100-N anterior drawer and combined rotatory loads of 10-Nm valgus moment and 5-Nm internal rotation. The anterior tibial translation and tensile forces of each graft bundle were measured. Results The LMP values for the TB reconstruction were 1.7 N for the anteromedial-medial graft, 1.7 N for the anteromedial-lateral graft, and 3.4 N for the posterolateral graft (PLG). The LMP value was 5.6 N for the anteromedial graft and PLG in the DB reconstruction. The LMP value was 26.3 N for the whole graft in the SB reconstruction. No statistically significant difference in stability was found between TB and DB reconstructions during the anterior load and the combined rotatory load test. For force distribution, the PLG tension in the TB reconstruction was statistically lower than that in the DB reconstruction. Conclusions Anatomic TB ACL reconstruction with the lowest initial tension on the graft stabilized the knee equally to DB or SB reconstruction, which required greater initial tension. Clinical Relevance Although SB, DB, and TB ACL reconstructions through the anatomic tunnel position could equally restore stability, the initial tension on the graft required to restore stability was less in the latter 2 multi-tunnel reconstructions.

Pathologic diabetic wound healing is caused by sequential and progressive deterioration of hemostasis, inflammation, proliferation, and resolution/remodeling. Cellular senescence promotes physiological wound process; however, diabetic wounds exhibit low levels of senescent factors and accumulate senescent cells, which impair the healing process. In this study, we demonstrate that the number of p15INK4B + senescent PDGFR-α + mesenchymal cells in adipose tissue transiently increases in early phases of wound healing in non-diabetic mice and humans. Transplantation of adipose tissue from diabetic mice into non-diabetic mice results in wound healing impairment and an alteration in the cellular senescence-associated secretory phenotype (SASP), suggesting that insufficient induction of adipose tissue senescence after injury is a pathological mechanism of diabetic wound healing. These results give novel insight into how regulation of senescence in adipose tissue contributes to the wound healing process and provide the basis for the development of therapeutic approaches for wound healing impairment in diabetes.

The force–length relation of the skeletal muscles is an important factor influencing the joint torque at a given joint angle. We aimed to clarify the relationship between the resting sarcomere length and knee joint angle in the vastus intermedius (VI) and to compare it with that of the vastus lateralis (VL). The left and right legs were fixed at knee joint angles of 0° and 90°, respectively, in seven cadavers (age at the time of death: 70–91 years). Muscle tissues were dissected by necropsy of the VL and the VI, and electron microscopy images were obtained to calculate the sarcomere length. At knee joint angles of 0° and 90°, the VL sarcomere length was 2.28 ± 0.49 μm and 2.30 ± 0.48 μm, respectively, and the VI sarcomere length was 2.19 ± 0.35 μm and 2.46 ± 0.53 μm, respectively, with a significant difference between the two (p = 0.028). The magnitude of sarcomere length changes with knee joint angle changes was significantly greater for the VI (0.27 ± 0.20 μm) than for the VL (0.02 ± 0.09 μm) (p = 0.009). Thus, knee joint angle changes may affect the passive and active tension produced by the VI more than those produced by the VL., The sarcomere length of the vastus lateralis was not significantly different between joint angles, whereas that of the vastus intermedius was increased at the flexed knee joint angle compared to the extended knee joint angle.

Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to the non-MBSR group or MBSR group. In the MBSR group, the program was performed three times a week for 4 weeks. After the intervention, the score of Japanese version of the Montreal Cognitive Assessment (MoCA-J) as well as the expression of microRNA (miR)-29c in neuron-derived exosomes (NDEs) in blood was significantly increased in the MBSR group, compared to the non-MBSR group. Analysis of miR-29c target genes showed that the expression of DNA methyltransferase 3 alpha (DNMT3A), DNA methyltransferase 3 beta (DNMT3B), and signal transducer and activator of transcription 3 (STAT3) in NDEs was significantly decreased in the MBSR group. We also found that intracerebroventricular injection of a miR-29c mimic into 5xFAD mice prevented cognitive decline as well as neuronal loss in the subiculum area by down-regulating DNMT3A and STAT3 in the hippocampus. The results of the present study suggest that MBSR can prevent neuronal loss and cognitive impairment in elderly people by increasing the neuronal expression of miR-29c.

Although mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a and Dnmt3b in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.

Alzheimer’s disease (AD) is characterized by the extensive deposition of amyloid-β plaques and neurofibrillary tangles. We previously found that preserved function of astrocytes is associated with cognitively normal subjects with AD pathology. Here we show that an enriched environment (EE) can prevent cognitive impairment in AD model mice by ameliorating astrocytic inflammation and increasing synaptic density in the subiculum area of the hippocampus. In AD model mice treated with an EE, increased levels of microRNA (miR)-146a and down-regulation of NF-κB were observed in the hippocampus. In addition, increased levels of interferon (IFN)-γ were seen in serum from mice exposed to an EE. In vitro, enhanced miR-146a expression was observed in exosomes derived from the choroid plexus (CP) after IFN-γ treatment. In further in vitro experiments, we transfected miR-146a into Aβ/lipopolysaccharide-induced inflammatory astrocytes and showed that miR-146a ameliorated astrocytic inflammation by down-regulating tumor necrosis factor receptor-associated factor 6 and NF-κB. The present study indicates that following an EE, exosomal miR-146a derived from the CP cells is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment., Highlights • An enriched environment (EE) prevented the cognitive impairment in 5 ​× ​FAD mice. • An EE inhibited astrocytic inflammation and increased miR-146a in hippocampus. • An EE increased the levels of interferon-γ (IFN-γ) in serum. • IFN-γ increased the secretion of exosomal miR-146a from cultured choroid plexus. • Transfection of miR-146a down-regulated NF-κB in cultured astrocytes.

Estimation of muscle passive force from elasticity using shear wave elastography (SWE) has been reported. However, the relationship between the elasticity and passive force of human muscles has not been elucidated. This study investigated the elastic modulus-passive force relationship in human skeletal muscles at multiple sites.Four rectus femoris (RF) muscles were dissected from a human Thiel-embalmed cadaver. Calibration weights (0-600 g in 60-g increments) were applied to the distal tendon via a pulley system, and the shear elastic modulus as an index of elasticity was measured using SWE. The shear elastic modulus of the RF was measured at the proximal, central, and distal portions.The results demonstrated that the relationships between the elasticity in the longitudinal direction of the muscle and the passive force were nearly linear for all tested sites, with coefficients of determination ranging from 0.813 to 0.993.Shear wave elastography may be used as an indirect method to measure the changing passive force at any site within human muscles.

The relevance of each ligament comprising the lateral ankle ligament complex, including the anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), and posterior talofibular ligament (PTFL), has not been sufficiently elucidated; therefore, we aimed to clarify the morphological characteristics and relevance of these ligaments. Total 152 legs from 152 Japanese cadavers were investigated. The lengths and widths of the ATFL, CFL, and PTFL were measured using a caliper. The ATFL was classified according to the number of fiber bundles (Types I, II, and III corresponded to one, two, and three fiber bundles, respectively), and the lengths and widths of the three ligaments were compared between the Type groups. In addition, the ratio of each ligament’s length and width to the tibial length was calculated, and the correlation of the ratio of ligament length and width between the ATFL, CFL, and PTFL was examined about 34 legs. The ATFL, CFL, and PTFL were found to connect at the anterior/inferior tip of the lateral malleolus each other. The Type II group of the ATFL was most common (54.6%) in our investigated specimens. However, there were no significant inter-group differences in the lengths and widths of the CFL and PTFL. This study demonstrates that the lateral ankle ligaments may stabilize the ankle joint through interconnections.

Background:Although a variety of surgical procedures for lateral ankle ligament reconstruction have frequently been reported, little is known about the effects of initial graft tension.Purpose/Hypothesis:The purpose was to investigate the effects of initial graft tension in calcaneofibular ligament (CFL) reconstruction. It was hypothesized that a high degree of initial graft tension would cause abnormal kinematics, laxity, and excessive graft tension.Study Design:Controlled laboratory study.Methods:Twelve cadaveric ankles were tested with a 6 degrees of freedom robotic system to apply passive plantarflexion-dorsiflexion motion and multidirectional loads. A repeated-measures experiment was designed with the CFL intact, CFL transected, and CFL reconstructed with 4 initial tension conditions (10, 30, 50, and 70 N). The 3-dimensional path and reconstructed graft tension were simultaneously recorded.Results:The calcaneus in CFL reconstruction with an initial tension of 70 N had the most eversion relative to the intact condition (mean eversion translations of 1.2, 3.0, 5.0, and 6.2 mm were observed at initial tensions of 10, 30, 50, and 70 N, respectively). The calcaneus also moved more posteriorly with external rotation as the initial tension increased. The reconstructed graft tension tended to increase as the initial tension increased.Conclusion:Ankle kinematic patterns and laxity after CFL reconstruction tended to become more abnormal as the initial graft tension increased at the time of surgery. Moreover, excessive initial graft tension caused excessive tension on the reconstructed graft.Clinical Relevance:This study indicated the importance of initial graft tension during CFL reconstruction. Overtensioning during CFL reconstruction should be avoided to imitate a normal ankle.

Background Recently, supraspinatus muscle exercise has been reported to treat rotator cuff disease and to recover shoulder function. However, there have been no report on the direct measurement of strain on the supraspinatus tendon during simulated isometric gleno-humeral joint elevation. Methods Ten fresh-frozen shoulder specimens with the rotator cuff complex left intact were used as experimental models. Isometric gleno-humeral joint elevation in a sitting position was reproduced with low angle of step-by-step elevation in the scapular plane and strain was measured on the surface layer of the supraspinatus tendon. Findings In isometric conditions, applied tensile force of the supraspinatus tendon increased significantly with increases in adduction torque on the gleno-humeral joint. Significant increases in the strain on the layer were observed by increase in adduction torque, which were recorded in isometric elevation at − 10° and 0°, but little increase in the strain was observed at 10° or greater gleno-humeral elevation. Interpretation Increased strain on the surface layer of the supraspinatus tendon was observed during isometric gleno-humeral elevation from − 10 to 0°. These findings demonstrate a potential risk of inducing overstretching of the supraspinatus tendon during supraspinatus muscle exercise.

The underlying therapeutic mechanism of renal tubular epithelium repair of diabetic nephropathy (DN) by bone marrow-derived mesenchymal stem cells (BM-MSCs) has not been fully elucidated. Recently, mitochondria (Mt) transfer was reported as a novel action of BM-MSCs to rescue injured cells. We investigated Mt transfer from systemically administered BM-MSCs to renal proximal tubular epithelial cells (PTECs) in streptozotocin (STZ)-induced diabetic animals. BM-MSCs also transferred their Mt to impaired PTECs when co-cultured in vitro, which suppressed apoptosis of impaired PTECs. Additionally, BM-MSC-derived isolated Mt enhanced the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression and inhibited reactive oxygen species (ROS) production in vitro. Isolated Mt also inhibited nuclear translocation of PGC-1α and restored the expression of megalin and SGLT2 under high glucose condition (HG) in PTECs. Moreover, isolated Mt directly injected under the renal capsule of STZ rats improved the cellular morphology of STZ-PTECs, and the structure of the tubular basement membrane and brush border in vivo. This study is the first to show Mt transfer from systemically administered BM-MSCs to damaged PTECs in vivo, and the first to investigate mechanisms underlying the potential therapeutic effects of Mt transfer from BM-MSCs in DN.

Rheumatoid arthritis (RA) is an autoimmune disease caused by inflammation of the synovium and characterized by chronic polyarthritis that destroys bone and cartilage. Fibroblast-like synoviocytes (FLSs) in the synovium of patients with RA can promote cartilage and bone destruction by producing proteins such as matrix metalloproteinases and receptor activator of NF-κB ligand, thereby representing an important therapeutic target for RA. FLSs have several phenotypes depending on which cell surface proteins and adhesion factors are expressed. Identifying the cellular functions associated with different phenotypes and methods of controlling them are considered essential for developing therapeutic strategies for RA. In this study, synovial tissue was collected from patients with RA and control subjects who required surgery due to ligament injury or fracture. Immunohistological analysis was used to investigate the rates of positivity for phosphorylated platelet-derived growth factor receptor-αβ (pPDGFRαβ) and cadherin-11 (CDH11) expression, and apoptosis-related markers were assessed for each cell phenotype. Next, FLSs were isolated in vitro and stimulated with tumor necrosis factor-α (TNF-α) in addition to a combination of PDGF and transforming growth factor (2GF) to investigate pPDGFRαβ and CDH11 expression and the effects of the inhibition of TNF and cyclin-dependent kinase (CDK) 4/6 on FLSs. Immunohistological analysis showed a large percentage of pPDGFRαβ+CDH11– cells in the sub-lining layer (SL) of patients with RA. These cells exhibited increased B-cell lymphoma-2 expression, reduced TNF receptor-1 expression, resistance to cell death, and abnormal proliferation, suggesting a tendency to accumulate in the synovium. Further, in vitro 2GF stimulation of FLSs lowered, whereas 2GF + TNF stimulation increased the pPDGFRαβ/CDH11 ratio. Hypothesizing that FLSs stimulated with 2GF + TNF would accumulate in vivo in RA, we determined the therapeutic effects of TNF and CDK4/6 inhibitors. The TNF inhibitor lowered the pPDGFRαβ/CDH11 ratio, whereas the CDK4/6 inhibitor suppressed cell proliferation. However, a synergistic effect was not observed by combining both the drugs. We observed an increase in pPDGFRαβ+CDH11– cells in the SL of the RA synovium and accumulation of these cells in the synovium. We found that the TNF inhibitor suppressed FLS activity and the CDK4/6 inhibitor reduced cell proliferation.

BACKGROUND: The therapeutic benefits of mesenchymal stromal cells (MSCs) include treatment of chronic inflammation. However, given the short-lived engraftment of these cells in vivo, their therapeutic efficacy remains mysterious. Transient induction of cellular senescence contributes to activation of immune cells, which promotes clearance of damaged cells during tissue remodelling. This may occur in tissue-resident mesenchymal progenitor cells during regeneration. Elucidation of the role of senescence in tissue-resident mesenchymal progenitor cells during regeneration would provide insight into the profile of therapeutic MSCs for treatment of chronic inflammatory disease. METHODS: We evaluated multipotent mesenchymal progenitor cells, termed fibro/adipogenic progenitors (FAPs), and immune cells in acute muscle injury (AMI) model mice and mice with myosin-induced experimental autoimmune myositis, a model of chronic inflammatory myopathy (CIM). Human bone marrow MSCs were optimised for the treatment of CIM using placental extract. FINDING: FAPs in AMI transiently expressed p16(INK4A) on days 1 and 2 after injury and recruited phagocytic immune cells, whereas in CIM, p16(INK4A) expression in FAPs was low. Cellular senescence occurs during the natural maturation of the placenta. Therefore, we used human placental extract to induce p16(INK4A) expression in therapeutic human bone marrow MSCs in culture. Treatment of CIM with p16(INK4A)-expressing MSCs promoted tissue remodelling by transiently increasing the abundance of engrafted MSCs, inducing cellular senescence in innate FAPs, and recruiting phagocytic immune cells. INTERPRETATION: MSCs may exert their effect by remodelling the chronic inflammatory environment via senescence-related regenerative processes.

The therapeutic benefits of mesenchymal stromal cells (MSCs) are well documented, but given the short-lived engraftment of these cells in vivo, currently no plausible hypotheses explain their therapeutic efficacy. Transient induction of cell senescence contributes to cell clearance followed by tissue remodeling. Here, we show that p16INK4A expression by therapeutic MSCs was induced by placental extracts in culture. Cellular senescence occurs during the natural maturation program of the placenta. Treatment of chronic inflammatory myopathy (CIM) mice with p16INK4Aexpressing MSCs promoted tissue remodeling by transiently increasing the abundance of engrafted MSCs, induced cellular senescence in innate fibro/adipogenic progenitors (FAPs), and recruited phagocytic immune cells. This phenomenon was similar to the endogenous regeneration process after acute damage to skeletal muscle. Our findings reveal that MSCs may exert their effect by remodeling the chronic inflammatory environment via senescence-related regenerative processes. Funding Statement: This work supported by Medical Research Grant in Sapporo Medical University and JSPS KAKENHI Grant Number JP16K16430 Declaration of Interests: The authors declare no competing interests associated with this manuscript. Ethics Approval Statement: All animal protocols were approved by the Committee of the Animal Experimentation Center of the Sapporo Medical University School of Medicine. Collection of samples and their use for research purposes were approved by our institutional review board

Mesenchymal stem cells are multipotent cells that possess anti-inflammatory, anti-apoptotic and immunomodulatory properties. The effects of existing drugs for neurodegenerative disorders such as Alzheimer's disease are limited, thus mesenchymal stem cell therapy has been anticipated as a means of ameliorating neuronal dysfunction. Since mesenchymal stem cells are known to scarcely differentiate into neuronal cells in damaged brain after transplantation, paracrine factors secreted from mesenchymal stem cells have been suggested to exert therapeutic effects. Extracellular vesicles and exosomes are small vesicles released from mesenchymal stem cells that contain various molecules, including proteins, mRNAs and microRNAs. In recent years, administration of exosomes/extracellular vesicles in models of neurological disorders has been shown to improve neuronal dysfunctions, via exosomal transfer into damaged cells. In addition, various microRNAs derived from mesenchymal stem cells that regulate various genes and reduce neuropathological changes in various neurological disorders have been identified. This review summarizes the effects of exosomes/extracellular vesicles and exosomal microRNAs derived from mesenchymal stem cells on models of stroke, subarachnoid and intracerebral hemorrhage, traumatic brain injury, and cognitive impairments, including Alzheimer's disease.

Using fresh cadavers, the biomechanical testing were used to examine the pullout strength of each pedicle screw.The aim of this study was to evaluate pullout strength of (1) a redirected pedicle screw following lateral wall breach; (2) a redirected pedicle screw following end-plate breach; and (3) a pedicle without redirection after end-plate breach without redirection.Screw malposition, such as lateral wall breach or end-plate breach, is one of the main pitfalls of inserting pedicle screws.From 17 fresh spines, 54 vertebrae were harvested. In each vertebra on one pedicle, the screw was inserted correctly down the axis of the pedicle, while on the other pedicle, the screw was inserted to breach the lateral wall or the end-plate. The 18 pedicle screws that breached the lateral wall were then removed and redirected along the correct axis of the pedicle. The 18 pedicle screws that breached the end-plate were removed and redirected along the correct axis of the pedicle. The 18 other pedicle screws that had breached the end-plate were not removed. The pullout force of pedicle screws was measured.First, the mean pullout strength for the redirected screws following lateral wall breach was 24.0% less as compared with the correctly aligned screws. Second, the mean pullout strength for the redirected screws following end-plate breach was 23.3% less as compared with the correctly aligned screws. Third, the mean pullout strength for the pedicle screws end-plate breach was 7.6% less as compared with the correctly aligned screws.The pullout strength of redirected pedicle screws after either a lateral pedicle breach or end-plate breach is significantly less than the pullout strength of correctly aligned screw. A pedicle screw that is not redirected after end-plate breach is weaker than a pedicle screw correctly aligned; however, the difference is not significant.N/A.

Abstarct Background The shoulder is a uniquely complex large joint. Effective and safe physical therapy efforts towards rehabilitating injured and repaired shoulders requires a thorough understanding of shoulder mechanics from both generalized and very specific perspectives. Numerous biomechanical studies have been published on the shoulder. None of the studies, to our knowledge, considered the strain of the deep layers of the supraspinatus tendon for scapular plane elevation. Methods Ten unilateral fresh-frozen human cadaveric specimens were used for the study. Scapular plane angles ranging from −10 to 30 degrees were evaluated for tensile loads, ranging from 0 to 120 Newtons, exerted on the supraspinatus tendon. Strain measurements that specifically targeted the deep layer of the supraspinatus tendon during tensile loading were recorded. Findings Strains recorded in the supraspinatus deep layer while increasing tendon force of the supraspinatus were significant for isometric gleno-humeral elevation of 30° and 20°. The response of strain to tendon force was less pronounced for 10° or less of gleno-humeral elevation. Interpretation When performing isometric shoulder exercise regimens, rotator cuff forces and both surface and deep tendon strain, relative to scapular positioning, are relevant and should be considered.

Although shear wave elastography (SWE) has been used to indirectly measure passive tension in muscle tissues, it is unknown whether SWE can adequately evaluate passive tension in capsule tissues. This study investigated the relationship between the shear modulus and passive tension in the posterior shoulder capsule using SWE. Ten posterior middle and ten posterior inferior shoulder capsules were dissected from ten fresh-frozen cadavers; humeral head-capsule-glenoid specimens were created from each capsule. The humeral head and glenoid were immobilized with clamps in a custom-built device. Loads (0-400 g, in 25-g increments) were applied to each capsule via a pulley system; elasticity was simultaneously measured using SWE. The elasticity-load relationship of each tested capsule was analyzed by fitting a least-squares regression line to the data. Elasticity change due to creep or hysteresis effects was evaluated by comparing the elastic modulus for a 100-g load during and after the stepwise application of the loads. The observed relationship between the shear modulus and passive capsule tension was highly linear for all twenty tested capsules (p 0.01). The mean coefficient of determination was 0.882 ± 0.075 and 0.901 ± 0.050 for the posterior middle and posterior inferior capsules, respectively. There was no difference in the shear modulus between the two 100-g load assessments for both the posterior middle (p = 0.205) and posterior inferior capsules (p = 0.161). Thus, SWE is a valid and useful method for indirectly evaluating the change in the passive tension under loading in specific posterior shoulder capsule.

Bicruciate-retaining total knee arthroplasty (BCR-TKA) is attracting attention because of the functional and satisfaction outcomes associated with keeping the anterior cruciate ligament (ACL) intact. However, knowledge of the functional importance of the ACL after BCR-TKA is limited. We performed a biomechanical investigation of ACL function following BCR-TKA compared with that in the intact knee.We investigated 8 fresh-frozen human cadaveric knees using a 6-degrees-of-freedom robotic system that allowed natural joint motion. Three knee states-intact knee, BCR-TKA, and BCR-TKA with ACL transection (BCR-TKA + ACLT)-were evaluated. For each knee state, the kinematics during passive flexion-extension motion (from 0° to 120°) and anteroposterior laxity at 0°, 15°, 30°, 60°, and 90° of flexion in response to a 100-N load were investigated. The recorded knee motions of the intact and BCR-TKA knees during each test were repeated after ACLT to calculate the ACL in situ force.The femur in the BCR-TKA group translated posteriorly and rotated externally during passive knee flexion and was in an anterior position compared with the femur in the intact-knee state. After ACLT, the femur translated posteriorly, compared with the BCR-TKA group, at 0° and 10° (p0.05). The anteroposterior laxities of the BCR-TKA and intact knees were comparable at all flexion angles and increased 2-fold or more after ACLT (p0.01). The ACL in situ force in the BCR-TKA knees was 2-fold to 6-fold higher than that in the intact knees at 0°, 15°, 90°, and 120° during a passive path (p0.05) and equivalent to that in the intact knees under anterior loading.The preserved ACL in the BCR-TKA knees was functional, like the ACL in the intact knees, under anterior tibial loading and contributed to good anteroposterior stability. However, the kinematics and ACL in situ force differed between the intact and BCR-TKA knees during passive flexion-extension movements.Surgeons may not be able to prevent overtensioning of the ACL during a standardized BCR-TKA procedure, which could potentially limit range of motion.

Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote FAP senescence or resistance against tumor necrosis factor–mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses FAP apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of FAP senescence after exercise leads to muscle degeneration with FAP accumulation. FAP-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy., Some exercises exacerbate chronic inflammation and muscle fibrosis in chronic myopathy. Here, the authors show that senescence of fibro-adipogenic progenitors (FAPs) in response to exercise induces muscle regeneration, and impaired FAP senescence worsens inflammation and fibrosis in chronic myopathy in mice.

The in vitro unconstrained Achilles tendon is nearly straight, while in vivo experiments reveal that the proximal region of the Achilles tendon, adjacent to Kager’s fat pad, bends ventrally during plantarflexion but remains nearly straight during dorsiflexion. Tendon bending is an important factor in determining the displacement of the foot compared to the shortening of the muscle fibers. The objective of this study was to elucidate the various mechanisms that could cause tendon bending, which currently remain unknown. Examination of Thiel-embalmed cadavers, with preservation of native articular joint mobility, revealed that the Achilles tendon still bent ventrally even when its surrounding tissues, including the skin surface, Kager’s fat pad, and distal portions of the soleus muscle were removed. Shear modulus and collagen fiber orientation were distributed homogeneously with respect to the longitudinal line of the tendon, minimizing their causative contributions to the bending. Given that tendon bending is not caused by either the nature of the deformations of the tissues surrounding the Achilles tendon or its physical properties, we conclude that it results from the geometric architecture of the Achilles tendon and its configuration with respect to the surrounding tissues.

Pulling the wrist into flexion with the elbow in extension and forearm in pronation has been used as the stretching technique of wrist extensors for lateral epicondylitis. Simultaneous stretching of the fingers in addition to the wrist flexion has also been applied. However, the mechanism of this simultaneous stretching has not been clarified. This study is designed to clarify the mechanism underlying this simultaneous stretching technique based on the anatomical features of the origins of the extensor carpi radialis brevis (ECRB) and extensor digitorum communis (EDC).Thirty-nine arms from formalin-embalmed Japanese human specimens were dissected. The features of the origins of the ECRB and EDC were macroscopically observed, and the locations of each origin on the lateral epicondyle were measured.The ECRB had a long and wide, purely tendinous origin which originated from the anterior slope of the lateral epicondyle. The tendinous origin of the index finger of the EDC (EDC-IF) arose from the posterior aspect of the ECRB tendinous origin, with a coexisting muscular portion observed at the level of the proximal forearm. The middle finger of the EDC (EDC-MF) had a short tendinous origin with an associated muscular portion and originated proximo-laterally to the origin of the ECRB on the lateral epicondyle. In addition, the muscular origin of the EDC-MF arose on the superficial and posterior aspect of the ECRB tendinous origin. In contrast, the ring and little fingers of the EDC originated from the tendinous septum of the extensor digiti minimi and extensor carpi ulnaris, and had no connection with the ECRB tendinous origin.On the basis of our anatomical findings, simultaneous stretching of the wrist extensors by wrist, index and middle fingers flexion could provide stretching force to both the tendinous origins of the ECRB and EDC through the EDC-IF and EDC-MF.