The popliteal eminence shows that the intra-articular popliteal tendon supports posterolateral knee stability.

The intra-articular popliteal tendon (iPT) is responsible for the dynamic stability of the posterolateral part of the knee joint. In this study, the involvement of the iPT in posterolateral stability in response to knee flexion was investigated anatomically. Thirty-one knees from thirty formalin-fixed room cadavers (17 male knees, 14 female knees; average age 86.9 years) were used. The knee was prepared with the distal 1/3 of the lower femur and crus and was flexed at 0°, 30°, 60°, and 90° in a special jig to limit knee rotation. The series of movements was plotted on the coordinate system using the Quadrant method. The iPT was in strong contact with a thick cartilage area, which we called the "popliteal eminence", at the lateral condyle of the femur. The average iPT angles with respect to the femoral axis were 28.78°, 49.79°, 77.74°, and 115.44° at knee flexion of 0°, 30°, 60°, and 90°, respectively. The iPT was strongly associated with the popliteal eminence at 29.5° in Type I and 27.09° in Type II knee flexion. The iPT has been conventionally regarded as a secondary restraint of posterior movement, acting as a stabilizer. However, the iPT appears to work more positively on knee joint stability because it was in strong enough contact to create the popliteal eminence. The iPT supports the femur in the posterolateral region in mild knee flexion.

The function of cruciate ligaments in bi-cruciate retaining Total knee arthroplasty with asymmetrical design.

BACKGROUND: Bi-cruciate retaining total knee arthroplasty with an asymmetrical design may improve knee function and clinical outcomes. This study aimed to compare the kinematics, anteroposterior laxity, and in situ forces of the anterior and posterior cruciate ligaments of knees subjected to this treatment with those of healthy knees. METHODS: Seven fresh-frozen cadaveric knees were tested using a robotic/universal force-moment sensor system. The kinematics during passive flexion-extension motion and anteroposterior laxity for native knee, treated knee, and treated knee with cruciate ligament transection states were investigated. The motions of the intact and treated knees during each test were repeated after anterior/posterior cruciate ligament transection to calculate the in situ force in the ligaments. FINDINGS: The screw-home movement of normal knees disappeared after treatment. The in situ force of the anterior cruciate ligament in treated knees was higher than that in intact knees at ˃15° during flexion and at 60° and 90° against an anterior force. The in situ force of the posterior cruciate ligament in treated knees was higher at 0°, 15°, and 30° during flexion and at all flexion angles against a posterior force. INTERPRETATION: The screw-home movement of normal knees decreased, and the in situ force of the anterior and posterior cruciate ligaments increased after treatment.

Effect of subcutaneous adipose tissue and muscle thicknesses on rectus femoris and vastus intermedius ultrasound echo intensities: a cadaver study.

PURPOSE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: These results suggest that SCAT thickness and RF muscle thickness induce lower RF echo intensity, while RF muscle thickness induces lower VI echo intensity.

Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing.

Pathologic diabetic wound healing is caused by sequential and progressive deterioration of hemostasis, inflammation, proliferation, and resolution/remodeling. Cellular senescence promotes wound healing; however, diabetic wounds exhibit low levels of senescent factors and accumulate senescent cells, which impair the healing process. Here we show that the number of p15INK4B + PDGFRα + senescent mesenchymal cells in adipose tissue increases transiently during early phases of wound healing in both non-diabetic mice and humans. Transplantation of adipose tissue from diabetic mice into non-diabetic mice results in impaired wound healing and an altered 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 provide insight into how regulation of senescence in adipose tissue contributes to wound healing and could constitute a basis for developing therapeutic treatment for wound healing impairment in diabetes.

Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus.

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.

Effects of the Ankle Flexion Angle During Anterior Talofibular Ligament Reconstruction on Ankle Kinematics, Laxity, and In Situ Forces of the Reconstructed Graft.

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.

Injectate spread in ultrasound-guided inferior alveolar nerve block: a cadaveric study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior.

Neuropsychiatric manifestations targeting the central, peripheral, and autonomic nervous system are common in systemic lupus erythematosus (SLE); collectively, these symptoms are termed neuropsychiatric SLE (NPSLE). Among a wide variety of neuropsychiatric symptoms, depression is observed in about 24-39% of SLE patients. Several cytokines and chemokines have been identified as biomarkers or therapeutic targets of NPSLE; in particular, the levels of type 1 interferons, TNFs, and IL-6 are elevated in SLE patient's cerebrospinal fluid (CSF), and these factors contribute to the pathology of depression. Here, we show that senescent neural cells accumulate in the hippocampal cornu ammonis 3 (CA3) region in MRL/lpr SLE model mice with depressive behavior. Furthermore, oral administration of fisetin, a senolytic drug, reduced the number of senescent neural cells and reduced depressive behavior in the MRL/lpr mice. In addition, transcription of several senescence and senescence-associated secretory phenotype (SASP) factors in the hippocampal region also decreased after fisetin treatment in the MRL/lpr mice. These results indicate that the accumulation of senescent neural cells in the hippocampus plays a role in NPSLE pathogenesis, and therapies targeting senescent cells may represent a candidate approach to treat NPSLE.

Mindfulness intervention improves cognitive function in older adults by enhancing the level of miRNA-29c in neuron-derived extracellular vesicles.

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.

Potential effects of mesenchymal stem cell derived extracellular vesicles and exosomal miRNAs in neurological disorders.

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.

Sarcomere length of the vastus intermedius with the knee joint angle change.

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.

Relationship between shear elastic modulus and passive force of the human rectus femoris at multiple sites: a Thiel soft-embalmed cadaver study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Shear wave elastography may be used as an indirect method to measure the changing passive force at any site within human muscles.

Strain measurement of the deep layer of the supraspinatus tendon using fresh frozen cadaver: The influence of shoulder elevation.

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.

Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer's disease model by increasing the expression of microRNA-146a in hippocampus.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß and tau. We previously reported that administration of bone marrow mesenchymal stem cells (BM-MSCs) ameliorates diabetes-induced cognitive impairment by transferring exosomes derived from these cells into astrocytes. Here, we show that intracerebroventricularly injected BM-MSCs improve cognitive impairment in AD model mice by ameliorating astrocytic inflammation as well as synaptogenesis. Although AD model mice showed an increase in NF-κB in the hippocampus, BM-MSC-treated AD model mice did not show this increase but showed an increase in levels of microRNA (miR)-146a in the hippocampus. Intracerebroventricularly injected BM-MSCs were attached to the choroid plexus in the lateral ventricle, and thus, BM-MSCs may secrete exosomes into the cerebrospinal fluid. In vitro experiments showed that exosomal miR-146a secreted from BM-MSCs was taken up into astrocytes, and an increased level of miR-146a and a decreased level of NF-κB were observed in astrocytes. Astrocytes are key cells for the formation of synapses, and thus, restoration of astrocytic function may have led to synaptogenesis and correction of cognitive impairment. The present study indicates that exosomal transfer of miR-146a is involved in the correction of cognitive impairment in AD model mice.

Morphological characteristics of the lateral ankle ligament complex.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This study demonstrates that the lateral ankle ligaments may stabilize the ankle joint through interconnections.

Effect of Initial Graft Tension During Anterior Talofibular Ligament Reconstruction on Ankle Kinematics, Laxity, and In Situ Forces of the Reconstructed Graft.

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.

Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors.

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.

Biomechanical Analysis of Midfoot Instability After Bifurcate Ligament Injury and Ankle Brace Application: A Cadaveric Study.

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.