Influence of blood lactate variations and passive exercise on cardiac responses.

[Purpose] This study aimed to investigate cardiovascular responses, including heart rate (HR) and heart rate variability (HRV), to various hyperlactatemia-passive exercise interactions. [Participants and Methods] Nine healthy male participants performed upper limb passive cycling movement, and their HR and HRV were assessed while their blood lactate levels were manipulated by sustained handgrip exercise at control, 15% maximum voluntary contraction (MVC), and 30% MVC, followed by postexercise circulatory occlusion. [Results] HR and root mean squared standard difference (rMSSD) of HRV response remained constant at all blood lactate levels during passive exercise (HR: control, 75.8 ± 3.4 bpm; 15% MVC, 76.9 ± 2.7 bpm; and 30% MVC, 77.0 ± 3.7 bpm; rMSSD: control, 33.2 ± 6.9 ms; 15% MVC, 36.3 ± 7.3 ms; and 30% MVC, 37.3 ± 8.9 ms). [Conclusion] Manipulating metaboreflex activation did not significantly alter HR or HRV during passive exercise. These results suggest that, in healthy participants, the interactions between mechanical and metabolic stimuli do not affect HR and HRV responses, implying that passive exercise may be safely implemented.

Error of intraoperative measurement of stem anteversion is decreased by measuring in neutral hip position during total hip arthroplasty.

BACKGROUND: Intraoperative stem anteversion, which is the angle between the lower leg axis and the trial-stem axis with hip flexion and adduction, is generally evaluated by the surgeon's visual estimation during total hip arthroplasty (THA). However, the conventional approach can be influenced by knee osteoarthritis or uncertain surgeon's observation point. Therefore, we developed a new method for measuring the stem anteversion angle in the neutral hip position using an original rod attached to the trial-stem perpendicular to the long axis and parallel to the stem neck. This study aimed to assess the accuracy of our method in comparison with the conventional method of measuring intraoperative stem anteversion angle. METHODS: We measured the intraoperative stem anteversion angle in consecutive 106 hips of 106 patients who underwent cementless primary THA with a tapered wedge stem. Absolute error in the stem anteversion angle was expressed as the difference between intraoperative (common vs. neutral hip positions) and postoperative computed tomography measurements, i.e., true stem anteversion. Additionally, we investigated the factors affecting these errors. RESULTS: The absolute error of measurement was significantly smaller in the neutral hip position than in the common position (3.0° ± 2.5° vs. 8.0° ± 3.9°; p < 0.0001). The factor associated with the error was advanced knee osteoarthritis in the common position, whereas it was not statistically significant in the neutral hip position. CONCLUSIONS: This study suggests that the error in the intraoperative measurement of stem anteversion is decreased by measuring in the neutral hip position during THA.

The Contribution of the Nrf2/ARE System to Mechanotransduction in Musculoskeletal and Periodontal Tissues.

Mechanosensing plays an essential role in maintaining tissue functions. Across the human body, several tissues (i.e., striated muscles, bones, tendons, ligaments, as well as cartilage) require mechanical loading to exert their physiological functions. Contrary, mechanical unloading triggers pathological remodeling of these tissues and, consequently, human body dysfunctions. At the cellular level, both mechanical loading and unloading regulate a wide spectrum of cellular pathways. Among those, pathways regulated by oxidants such as reactive oxygen species (ROS) represent an essential node critically controlling tissue organization and function. Hence, a sensitive balance between the generation and elimination of oxidants keeps them within a physiological range. Here, the Nuclear Factor-E2-related factor 2/Antioxidant response element (Nrf2/ARE) system plays an essential role as it constitutes the major cellular regulation against exogenous and endogenous oxidative stresses. Dysregulations of this system advance, i.a., liver, neurodegenerative, and cancer diseases. Herein, we extend our comprehension of the Nrf2 system to the aforementioned mechanically sensitive tissues to explore its role in their physiology and pathology. We demonstrate the relevance of it for the tissues' functionality and highlight the imperative to further explore the Nrf2 system to understand the physiology and pathology of mechanically sensitive tissues in the context of redox biology.

Effects of n-3 polyunsaturated fatty acid supplementation on quadriceps weakness immediately after total knee arthroplasty: a pilot, randomized, open-label clinical trial.

[Purpose] Severe quadriceps weakness immediately after total knee arthroplasty can be problematic. The n-3 long-chain polyunsaturated fatty acids have antioxidant and anti-inflammatory effects against ischemia-reperfusion injury, whereas n-6 long-chain polyunsaturated fatty acids exert pro-inflammatory effects, thereby promoting ischemia-reperfusion injury. [Participants and Methods] We explored the efficacy of preoperative n-3 long-chain polyunsaturated fatty acid supplementation against early quadriceps weakness among 20 patients scheduled for total knee arthroplasty (intervention group, n=10; control group, n=10). The intervention group received 645 mg of eicosapentaenoic acid) and 215 mg of docosahexaenoic acid daily for 30 days preoperatively. Serum eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid levels were measured preoperatively. We compared serum derivatives of reactive oxygen metabolites as oxidative stress biomarkers, knee circumference, thigh volume, knee pain during the quadriceps strength test, and quadriceps strength preoperatively and 4 days postoperatively to quantify the change. [Results] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation significantly increased the (eicosapentaenoic acid+docosahexaenoic acid)/arachidonic acid ratio in the intervention group. A significantly lower increase in quadriceps weakness was exhibited in the intervention group than in the control group. However, changes in oxidative stress, knee/thigh swelling, and knee pain during strength testing did not significantly differ between the two groups. [Conclusion] Preoperative n-3 long-chain polyunsaturated fatty acid supplementation exhibited beneficial effects on quadriceps weakness immediately after total knee arthroplasty.

Nuclear factor erythroid 2-related factor 2 (Nrf2) deficiency causes age-dependent progression of female osteoporosis.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor for cellular redox homeostasis. The association of Nrf2 with elderly female osteoporotic has yet to be fully described. The aim was to elucidate a potential age-dependent Nrf2 contribution to female osteoporosis in mice. METHODS: Eighteen female wild type (WT) and 16 Nrf2-knockout (KO) mice were sacrificed at different ages (12 weeks = young mature adult and 90 weeks = old) to analyze their femurs. The morphological properties (trabecular and cortical) were evaluated by micro-computed tomography (µCT) and compared to gold standard histochemistry analysis. The quasi-static compression tests were performed to calculate the mechanical properties of bones. Additionally, the population of bone resorbing cells and aromatase expression by osteocytes was immunohistochemically evaluated and empty osteocyte lacunae was counted in cortical bone. RESULTS: Old Nrf2-KO mice revealed a significantly reduced trabecular bone mineral density (BMD), cortical thickness, cortical area, and bone fraction compared to old WT mice, regardless of no significant difference in skeletally mature young adult mice between WT and KO. Specifically, while all old WT mice showed thin metaphyseal trabeculae, trabecular bone was completely absent in 60% of old KO mice. Additionally, old KO mice showed significantly more osteoclast-like cells and fewer aromatase-positive osteocytes than WT mice, whereas the occurrence of empty osteocyte lacunae did not differ between both groups. Nrf2-KO mice further showed an age-dependently reduced fracture resilience compared to age-matched WT mice. CONCLUSION: Our results suggest that chronic Nrf2 loss can lead to age-dependent progression of female osteoporosis.

Platelet-Released Growth Factors Influence Wound Healing-Associated Genes in Human Keratinocytes and Ex Vivo Skin Explants.

Platelet-released growth factors (PRGFs) or other thrombocyte concentrate products, e.g., Platelet-Rich Fibrin (PRF), have become efficient tools of regenerative medicine in many medical disciplines. In the context of wound healing, it has been demonstrated that treatment of chronic or complicated wounds with PRGF or PRF improves wound healing in the majority of treated patients. Nevertheless, the underlying cellular and molecular mechanism are still poorly understood. Therefore, we aimed to analyze if PRGF-treatment of human keratinocytes caused the induction of genes encoding paracrine factors associated with successful wound healing. The investigated genes were Semaphorin 7A (SEMA7A), Angiopoietin-like 4 (ANGPLT4), Fibroblast Growth Factor-2 (FGF-2), Interleukin-32 (IL-32), the CC-chemokine-ligand 20 (CCL20), the matrix-metalloproteinase-2 (MMP-2), the chemokine C-X-C motif chemokine ligand 10 (CXCL10) and the subunit B of the Platelet-Derived Growth Factor (PDGFB). We observed a significant gene induction of SEMA7A, ANGPLT4, FGF-2, IL-32, MMP-2 and PDGFB in human keratinocytes after PRGF treatment. The CCL20- and CXCL10 gene expressions were significantly inhibited by PRGF therapy. Signal transduction analyses revealed that the PRGF-mediated gene induction of SEMA7A, ANGPLT4, IL-32 and MMP-2 in human keratinocytes was transduced via the IL-6 receptor pathway. In contrast, EGF receptor signaling was not involved in the PRGF-mediated gene expression of analyzed genes in human keratinocytes. Additionally, treatment of ex vivo skin explants with PRGF confirmed a significant gene induction of SEMA7A, ANGPLT4, MMP-2 and PDGFB. Taken together, these results describe a new mechanism that could be responsible for the beneficial wound healing properties of PRGF or related thrombocytes concentrate products such as PRF.

Validity of anaerobic threshold measured in resistance exercise.

[Purpose] Intensity for resistance exercise is estimated based on the maximum muscle strength. Exercise prescription without evaluating the biological response has a challenge. This study aimed to confirm whether anaerobic threshold measured using cardiopulmonary exercise test in resistance exercise is appropriate or not. [Participants and Methods] Resistance exercise adopted for the study was right-leg knee extension. The participants were 10 healthy young males. We investigated whether the oxygen uptake kinetics achieved a steady state within 3 min during the constant-load test with knee extension at 80% anaerobic threshold using cardiopulmonary exercise test with knee extension. If oxygen uptake kinetics achieved a steady state within 3 min, the exercise intensity measured using cardiopulmonary exercise test was considered appropriate. [Results] Anaerobic threshold was measured using the conventional approach in all participants. The steady state of oxygen uptake kinetics could be achieved within 3 min. In the constant-load test with knee extension at 80% anaerobic threshold, the oxygen uptake kinetics achieved a steady state within 3 min. [Conclusion] Based on the findings, the anaerobic threshold obtained using cardiopulmonary exercise test with resistance exercise was judged as appropriate. The results of this study contribute to the accurate setting of exercise load for resistance exercise and condition setting for the evaluation of skeletal muscle function.

Platelet-Released Growth Factors Induce Genes Involved in Extracellular Matrix Formation in Human Fibroblasts.

Platelet concentrate products are increasingly used in many medical disciplines due to their regenerative properties. As they contain a variety of chemokines, cytokines, and growth factors, they are used to support the healing of chronic or complicated wounds. To date, underlying cellular mechanisms have been insufficiently investigated. Therefore, we analyzed the influence of Platelet-Released Growth Factors (PRGF) on human dermal fibroblasts. Whole transcriptome sequencing and gene ontology (GO) enrichment analysis of PRGF-treated fibroblasts revealed an induction of several genes involved in the formation of the extracellular matrix (ECM). Real-time PCR analyses of PRGF-treated fibroblasts and skin explants confirmed the induction of ECM-related genes, in particular transforming growth factor beta-induced protein (TGFBI), fibronectin 1 (FN1), matrix metalloproteinase-9 (MMP-9), transglutaminase 2 (TGM2), fermitin family member 1 (FERMT1), collagen type I alpha 1 (COL1A1), a disintegrin and metalloproteinase 19 (ADAM19), serpin family E member 1 (SERPINE1) and lysyl oxidase-like 3 (LOXL3). The induction of these genes was time-dependent and in part influenced by the epidermal growth factor receptor (EGFR). Moreover, PRGF induced migration and proliferation of the fibroblasts. Taken together, the observed effects of PRGF on human fibroblasts may contribute to the underlying mechanisms that support the beneficial wound-healing effects of thrombocyte concentrate products.

Association between pulmonary oxygen uptake on-kinetics and acute cardiovascular responses to resistance exercise in patients with coronary artery disease: a preliminary study.

[Purpose] This study aimed to examine whether pulmonary oxygen uptake on-kinetics at the onset of moderate-intensity exercise can predict acute cardiovascular responses to resistance exercise. [Participants and Methods] The association between pulmonary oxygen uptake on-kinetics and acute cardiovascular responses to a single resistance exercise session was investigated in seven patients with low-risk coronary artery disease who underwent revascularization through percutaneous coronary intervention. The participants performed a cardiopulmonary exercise test on a cycle ergometer and a single resistance exercise session at 30% of maximum voluntary contraction on a bilateral leg-extension machine 1 week after surgery. We measured the ventilatory anaerobic threshold and pulmonary oxygen uptake on-kinetics during the cardiopulmonary exercise test; left ventricular ejection fraction at rest; and heart rate, systolic blood pressure, and rate pressure product during the single resistance exercise session. [Results] Pulmonary oxygen uptake on-kinetics showed a positive association with the amount of increase in systolic blood pressure and rate pressure product during the single resistance exercise session, but had no association with the amount of increase in heart rate. Ventilatory anaerobic threshold and left ventricular ejection fraction were not associated with these parameters. [Conclusion] These data suggested that pulmonary oxygen uptake on-kinetics can be a useful evaluation index for predicting acute systolic blood pressure and rate pressure product responses to low-intensity resistance exercise 1 week after percutaneous coronary intervention in patients with low-risk coronary artery disease.

Distribution of Femoral Head Subchondral Fracture Site Relates to Contact Pressures, Age, and Acetabular Structure.

OBJECTIVE. Nontraumatic subchondral fracture of the femoral head (FH) is often seen in elderly patients with osteoporosis and acetabular dysplasia. Although this injury can also occur in young people, even those without osteoporosis, it remains unclear who is at risk. We examined the acetabular structure and sites of subchondral fracture of the FH in young patients compared with those in middle-aged and older patients. MATERIALS AND METHODS. Forty-eight hips with nontraumatic subchondral fracture of the FH were divided into two groups according to patient age: young (< 40 years) and middle-aged and older (≥ 40 years). Dysplasia and retroversion were defined as a lateral center-edge angle of < 20° and crossover sign on anterosuperior radiographs, respectively. Locations and extents of fracture were evaluated by measuring the edge location of low-signal-intensity bands on coronal T1-weighted MR images. Stress distribution on subchondral bone in young patients was evaluated in contralateral unaffected hips with the same acetabular structure using finite element modeling based on CT. RESULTS. Twelve hips were in young patients and 36 were in middle-aged and older patients. Hips in young patients showed retroversion in 41.7%, whereas those in middle-aged and older patients had dysplasia in 38.9%. Young patients had larger mediolateral fractures; fractures in middle-aged and older patients were laterally located. Anterosuperior fractures were seen in both groups. Contact stress in patients with retroversion was mainly distributed on the mediolateral and superior sides but was concentrated laterally and superiorly in one patient with dysplasia. CONCLUSION. Mediolateral and anterosuperior fractures and stress distribution by retroversion were commonly observed in young patients, suggesting partial involvement of retroversion in the mechanism of injury of nontraumatic subchondral fractures of the FH in young patients.

Effect of a Specific Questionnaire Sheet on Subclassification of Osteonecrosis of the Femoral Head.

BACKGROUND This study examined whether use of a specific questionnaire sheet for nontraumatic osteonecrosis of the femoral head (ONFH) could affect the subclassification of ONFH compared with a conventional medical interview. MATERIAL AND METHODS Study participants consisted of 400 patients with ONFH who visited our hospital between February 2011 and March 2015. Data on history of systemic steroid therapy and habitual alcohol intake were obtained during a conventional medical interview at the first visit and were re-evaluated using a specific questionnaire sheet at another visit. Patients were subclassified into 4 groups: steroid-associated, alcohol-associated, steroid/alcohol-associated, or idiopathic ONFH. RESULTS Use of the specific questionnaire sheet resulted in a 4.0% increase in the proportion of patients with a history of systemic steroid therapy, from 57.3% (n=229) to 61.3% (n=245), and a 14.3% increase for history of habitual alcohol intake, from 35.0% (n=140) to 49.3% (n=197). The proportion of patients with steroid/alcohol-associated ONFH increased from 2.5% (n=10) to 17.8% (n=71), while the proportion in the other 3 groups decreased: steroid-associated ONFH from 54.8% (n=219) to 43.5% (n=174); alcohol-associated ONFH from 32.5% (n=130) to 31.5% (n=126); and idiopathic ONFH from 10.2% (n=41) to 7.2% (n=29). Ninety-six patients (24.0%) were classified into a different subgroup based on the specific questionnaire sheet. CONCLUSIONS The use of a specific questionnaire sheet can change the distribution of ONFH subclassifications compared with use of a conventional medical history interview. Use of a specific questionnaire sheet can allow for more detailed self-reporting regarding potential causative factors for nontraumatic ONFH, especially habitual alcohol intake.

Effects of anterior boundary of the necrotic lesion on the progressive collapse after varus osteotomy for osteonecrosis of the femoral head.

BACKGROUND: Anterior localization of the necrotic lesion was recently proposed as an important factor for the occurrence of collapse even in medially located osteonecrosis of the femoral head (ONFH). We examined the effects of the anterior boundary of the necrotic lesion on progressive collapse after varus osteotomy for ONFH. METHODS: We reviewed the outcomes of 31 hips in 27 patients with ONFH treated by transtrochanteric curved varus osteotomy (CVO) from 2000 to 2012 with a mean follow-up of 10.5 years. The occurrence of progressive collapse of the anterior necrotic lesion was defined as the presence of ≥2 mm collapse using follow-up lateral radiographs. Postoperative osteoarthritic change was defined as ≥1 mm progression of joint space narrowing on follow-up radiographs. The location of the anterior boundary of the necrotic lesion was assessed using the anterior necrotic angle (the angle between the midline of the femoral neck shaft and the line passing from the femoral head center to the anterior boundary of the necrotic lesion on a mid-slice oblique magnetic resonance image). RESULTS: All hips had a postoperative intact ratio of ≥34% (percentage of the transposed intact articular surface of the femoral head to the weight-bearing area of the acetabulum after femoral osteotomy). Progressive collapse of the anterior necrotic lesion was seen in five hips (16%) during a mean of 2.2 years after CVO. Of these, four hips (80%) proceeded to develop osteoarthritic change at an average of 4.3 years after the collapse. Multivariate analysis revealed that the anterior necrotic angle was independently associated with progressive collapse of the anterior necrotic lesion as well as the postoperative intact ratio. CONCLUSIONS: This study suggests that hips with anterior localization of the necrotic lesion have a possible risk of progressive collapse of the anterior necrotic lesion after CVO, which can frequently lead to subsequent osteoarthritic change.

Transtrochanteric Anterior Rotational Osteotomy Combined with Re-Sphericalization of the Collapsed Femoral Head Using Calcium Phosphate Cement Filling.

INTRODUCTION: Transtrochanteric anterior rotational osteotomy (ARO) is an established joint-preserving surgery for collapsed osteonecrosis of the femoral head (ONFH) in which the collapsed necrotic lesion is rotated anteriorly. Recently, preoperative collapse of more than 2.98mm was reported to be the most influential factor for progressive collapse of the anteriorly transposed necrotic lesion after ARO, the main cause of secondary osteoarthritic changes and clinical failure. We attempted to prevent progressive collapse with re-sphericalization of the collapsed femoral head using calcium phosphate cement (CPC) filling in conjunction with ARO. MATERIALS AND METHODS: Between May 2015 and April 2018, five consecutive hips with ONFH, femoral head collapse of ³3mm, and one-third or more of the posterior region of the femoral head intact, were prospectively recruited for re-sphericalization with ARO. This report describes intraoperative surgical techniques focusing on re-sphericalization of the collapsed femoral head using CPC and short-term effects of this additional procedure on progressive collapse of the transposed necrotic lesion, defined as ³2mm progression on lateral radiographs. RESULTS: After anterior rotation of the proximal fragment, followed by fixation of the transtrochanteric osteotomy site, a 5mm fenestration was made in the collapsed region of the anterior femoral head cartilage, through which the collapsed surface was carefully lifted with an elevatrium. Subsequently, CPC paste was injected into the lifted subchondral space with a small needle. After CPC paste injection, the femoral head was maintained at 40°C for 10 minutes to promote solidification of the CPC paste. With the re-sphericalization method, the mean level of collapse decreased from 4.1mm before surgery to 2.0mm after surgery. Subsequently, progressive collapse of the transposed necrotic lesion was confirmed in two hips. One of these hips had a deep infection that required complete curettage of CPC three weeks after the initial surgery. All hip joints have been preserved without conversion to prosthesis during a mean follow up of 2.1 years. CONCLUSION: A joint-preserving procedure for ONFH with severe collapse remains a challenging problem for surgeons. When ARO is indicated based on one-third or more of the posterior region of the femoral head being intact, the current re-sphericalization method could be worth considering as an additional procedure in cases with severe collapse.

Different Frequency of Cyclic Tensile Strain Relates to Anabolic/Catabolic Conditions Consistent with Immunohistochemical Staining Intensity in Tenocytes.

Tenocytes are mechanosensitive cells intimately adapting their expression profile and hence, their phenotype to their respective mechanomilieu. The immunolocalization and expression intensity of tenogenic, anabolic and catabolic markers in tenocytes in response to in vitro mechanical loading have not been monitored by immunohistochemical staining (IHC). Thus, we investigated the association between IHC intensities, different stimulation frequencies, and tenogenic metabolism using a versatile mechanical stretcher. Primary tenocytes obtained from murine Achilles tendons were transferred to poly(dimethylsiloxane) (PDMS) elastomeric chamber. Chambers were cyclically stretched by 5% in uniaxial direction at a variation of tensile frequency (1 or 2 Hz) for 3 h. After stretching, cell physiology, IHC intensities of tendon-related markers, and protein level of the angiogenesis marker vascular endothelial growth factor (VEGF) were evaluated. Cell proliferation in tenocytes stimulated with 1 Hz stretch was significantly higher than with 2 Hz or without stretch, while 2 Hz stretch induced significantly reduced cell viability and proliferation with microscopically detectable apoptotic cell changes. The amount of scleraxis translocated into the nuclei and tenomodulin immunoreactivity of tenocytes treated with stretch were significantly higher than of non-stretched cells. The collagen type-1 expression level in tenocytes stretched at 1 Hz was significantly higher than in those cultivated with 2 Hz or without stretching, whereas the matrix metalloproteinase (MMP)-1 and MMP-13 immunoreactivities of cells stretched at 2 Hz were significantly higher than in those stimulated with 1 Hz or without stretching. The secreted VEGF-protein level of tenocytes stretched at 2 Hz was significantly higher than without stretching. Our IHC findings consistent with cell physiology suggest that appropriate stretching can reproduce in vitro short-term tenogenic anabolic/catabolic conditions and allow us to identify an anabolic stretching profile.

Impact of Uniaxial Stretching on Both Gliding and Traction Areas of Tendon Explants in a Novel Bioreactor.

The effects of mechanical stress on cells and their extracellular matrix, especially in gliding sections of tendon, are still poorly understood. This study sought to compare the effects of uniaxial stretching on both gliding and traction areas in the same tendon. Flexor digitorum longus muscle tendons explanted from rats were subjected to stretching in a bioreactor for 6, 24, or 48 h, respectively, at 1 Hz and an amplitude of 2.5%. After stimulation, marker expression was quantified by histological and immunohistochemical staining in both gliding and traction areas. We observed a heightened intensity of scleraxis after 6 and 24 h of stimulation in both tendon types, though it had declined again 48 h after stimulation. We observed induced matrix metalloproteinase-1 and -13 protein expression in both tendon types. The bioreactor produced an increase in the mechanical structural strength of the tendon during the first half of the loading time and a decrease during the latter half. Uniaxial stretching of flexor tendon in our set-up can serve as an overloading model. A combination of mechanical and histological data allows us to improve the conditions for cultivating tendon tissues.

Effects of Strontium-Doped ß-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model.

It was hypothesized that strontium (Sr)-doped ß-tricalcium phosphate (TCP)-based scaffolds have a positive effect on the regeneration of large bone defects (LBD). Readouts in our mice models were nuclear factor-kappa beta (NF-κB) activity and vascular endothelial growth factor receptor-2 (VEGFR-2) promoter activity during the healing process. A 2-mm critical-size femoral fracture was performed in transgenic NF-κB- and VEGFR-2-luciferase reporter mice. The fracture was filled with a 3D-printed ß-TCP scaffold with or without Sr. A bioluminescence in-vivo imaging system was used to sequentially investigate NF-κB and VEGFR-2 expression for two months. After sacrifice, soft and osseous tissue formation in the fracture sites was histologically examined. NF-κB activity increased in the ß-TCP + Sr group in the latter stage (day 40-60). VEGFR-2 activity increased in the + Sr group from days 0-15 but decreased and showed significantly less activity than the ß-TCP and non-scaffold groups from days 40-60. The new bone formation and soft tissue formation in the + Sr group were significantly higher than in the ß-TCP group, whereas the percentage of osseous tissue formation in the ß-TCP group was significantly higher than in the ß-TCP + Sr group. We analyzed longitudinal VEGFR-2 promoter activity and NF-κB activity profiles, as respective agents of angiogenesis and inflammation, during LBD healing. The extended inflammation phase and eventually more rapid resorption of scaffold caused by the addition of strontium accelerates temporary bridging of the fracture gaps. This finding has the potential to inform an improved treatment strategy for patients who suffer from osteoporosis.

Long-term hip survival and factors influencing patient-reported outcomes after transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head: A minimum 10-year follow-up case series.

Objectives: This retrospective study aimed to assess long-term hip survival after transtrochanteric anterior rotational osteotomy (ARO) for osteonecrosis of the femoral head (ONFH) and identify factors influencing patient-reported outcome measures (PROMs) in patients with preserved joints.Methods: Altogether, 95 consecutive hips in 85 ONFH patients who underwent ARO during 2000-2007 (86.7% follow-up) were studied. Controls were 35 patients with 41 hips with ONFH managed conservatively for >1 year after collapse. We analyzed hip survival using the Kaplan-Meier method, with the endpoint defined as any therapeutic surgery related to ONFH. We also evaluated PROMs for both groups in patients with surviving hips and available radiographs at the final follow-up.Results: The 10-year hip survival rate after ARO was 85.4%, which was significantly higher than the 5-year rate in the control group (50.4%). Multiple regression analyses showed that the presence of osteoarthritic change after ARO was significantly associated with poor scores for both the Oxford Hip Score and the Short Form-12 Health Survey Physical Component Summary.Conclusions: ARO could effectively preserve hip joints with post-collapse ONFH, although the presence of osteoarthritic change could lead to lower satisfaction even among patients with long-term hip survival after ARO.

Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress.

Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.

Volume of hip synovitis detected on contrast-enhanced magnetic resonance imaging is associated with disease severity after collapse in osteonecrosis of the femoral head.

OBJECTIVE: To evaluate the relationship between the volume of hip synovitis detected on contrast-enhanced magnetic resonance imaging (MRI) and the disease stage of osteonecrosis of the femoral head (ONFH). MATERIALS AND METHODS: Sixty-three consecutive hips in 40 ONFH patients were reviewed using contrast-enhanced MRI. Ten unaffected hips in 10 patients with unilateral ONFH were used as controls. Based on the Japanese Investigation Committee system, these hips were classified according to stage and type. The volume and location of hip synovitis were semi-quantitatively measured on contrast-enhanced MRI. Clinicoradiological factors were statistically analyzed to determine the relationship with the volume of hip synovitis. RESULTS: The mean synovial volume was significantly larger in ONFH hips (8,020 ± 6,900 mm3) than in controls (910 ± 1,320 mm3; p = 0.001). The area of synovitis in the anterior portion of the hip joint was double (mean: 2.17 ± 1.77) that in the posterior portion. The volume of synovitis was small in pre-collapse-stage hips (stage 1: 680 ± 690 mm3, stage 2: 1,460 ± 1,200 mm3), but significantly larger in post-collapse-stage hips (stage 3A: 7,820 ± 4,490 mm3, stage 3B: 13,850 ± 7,110 mm3; p < 0.001). Multiple regression analysis showed that disease stage was the only factor related to hip synovitis. CONCLUSIONS: Our study suggests that hip synovitis in ONFH might occur after femoral head collapse and worsen with collapse progression, mainly in the anterior portion.

The effect of the anterior boundary of necrotic lesion on the occurrence of collapse in osteonecrosis of the femoral head.

PURPOSE: The location of the necrotic lesion is one of the important factors for collapse in osteonecrosis of the femoral head (ONFH). The significance of anterior localization has been little studied. This study evaluated the effects of anterior boundary of a necrotic lesion on collapse. METHODS: We reviewed the outcomes of 113 consecutive non-collapsed asymptomatic hips in 98 ONFH patients with mean follow-up of 4.7 years (2.0-11.8) after the initial magnetic resonance (MR) imaging. The presence or absence of collapse was investigated using follow-up radiographs. The location of the anterior boundary of a necrotic lesion was assessed using the anterior necrotic angle between the midline of the femoral neck shaft and the line passing from the femoral head centre to the anterior boundary on mid-oblique MR imaging. Multivariate analysis was performed to identify risk factors for collapse, and further analyses were executed according to the lateral boundary of the necrotic lesion. RESULTS: During the follow-up period, collapse was confirmed in 61 hips (54.0%). Multivariate analysis revealed that the anterior necrotic angle was independently associated with collapse as well as the lateral boundary of the necrotic lesion. When the lateral boundary was located at the middle third of weight-bearing portion (32 hips), that was generally categorized as a low risk of collapse, all five cases with anterior necrotic angle ≥ 79° developed collapse, whereas only one of 27 cases (3.7%) with an anterior necrotic angle < 79° developed collapse (p < 0.0001). CONCLUSIONS: This study indicates that ONFH patients with anterior localization of a necrotic lesion can develop collapse even if the necrotic lesion is medially located.