Association between advanced glycation end-products and fall risk in older adults: The Yakumo Study.

AIM: Advanced glycation end-products (AGEs) are irreversibly and heterogeneously formed compounds during the non-enzymatic modification of macromolecules, such as proteins. Aging and lifestyle habits, such as high-fat and high-protein diets, and smoking, promote AGEs accumulation. This study aimed to investigate the relationship between fall risk and AGEs in community-dwelling older adults. METHODS: This cross-sectional study included patients from the 2022 Yakumo Study who were evaluated for fall risk index 5-items version, locomotive syndrome stage and AGEs. AGEs were evaluated using Skin autofluorescence (SAF) measured by the AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). We divided the participants into two groups according to the presence or absence of fall risk (fall risk index 5-items version ≥6 or not), and investigated the factors associated with fall risk. RESULTS: The fall risk group had a higher age and SAF, and a higher proportion of locomotive syndrome stage >2 than the without fall risk group in patients aged ≥65 years (P < 0.01). The multivariate logistic regression analysis after adjustment of age, sex and body mass index showed that locomotive syndrome stage ≥2 and SAF were independent associators of fall risk in older adults (odds ratio 3.26, P < 0.01, odds ratio 2.96, P < 0.05, respectively). The optimal cutoff value of the SAF for fall risk was 2.4 (area under the curve 0.631; 95% CI 0.53-0.733; sensitivity 0.415; specificity 0.814; P < 0.05). CONCLUSION: The accumulation of AGEs in skin tissues can be used to screen for fall risk comprehensively. Geriatr Gerontol Int 2024; 24: 517-522.

Prevalence and treatment rates of osteoporosis among individuals with rotator cuff tears.

BACKGROUND: The relationship between osteoporosis and rotator cuff tears has been reported previously. However, the treatment rate of osteoporosis in individuals with rotator cuff tear is still unknown. The aim of this study was to investigate the prevalence and treatment rate of osteoporosis in individuals with rotator cuff tears. METHODS: In this cross-sectional study, we enrolled 207 participants. Participants underwent comprehensive assessments, including shoulder ultrasonographic examinations and quantitative ultrasound measurements for bone status evaluation. Osteoporosis diagnosis was predicated on a calcaneus ultrasound bone densitometry, and the cutoff value was set as a T score of -1.455, with reference to a previous report. RESULTS: One hundred fifty-six participants were classified as individuals without rotator cuff tears (group A), and 51 participants were classified as those with (group B). The mean age in group A was significantly lower than that in group B (63 ± 10 vs. 68 ± 9, respectively; P = .003). In terms of the T score examined by quantitative ultrasound, the mean T score in group A was significantly higher than that in group B (-1.4 ± 1.3 vs. -1.9 ± 1.6, respectively; P = .0412). The percentage of subjects with a T score of -1.455 or less in group B was 60.8% (31/51). The proportion of subjects with a T score of -1.455 or less undergoing osteoporosis treatment was 14.5% (12/83) in group A and 12.9% (4/27) in group B, showing no significant difference. CONCLUSIONS: Participants with a rotator cuff tear had relatively high prevalence of osteoporosis. Among those with both a rotator cuff tear and osteoporosis, the proportion receiving osteoporosis treatment was l2.9%, a very low rate.

Double-bundle anterior cruciate ligament reconstruction in patients aged 60 years and older.

Background: This study aimed to examine the clinical outcomes of double-bundle (DB) anterior cruciate ligament (ACL) reconstruction in patients aged ≥60 years. Methods: Anatomical DB-ACL reconstruction using hamstring tendon autografts was performed in 13 patients aged ≥60 years at our institution between June 2012 and May 2018. The patients included seven men and six women, and the mean age at surgery was 65.0 years (range, 60-73 years). The mean time from injury to surgery was 80.5 months (range, 1-480 months), and the mean follow-up time was 26.2 months (range, 24-42 months). All patients were assessed based on physical examination findings, clinical scores, Kellgren-Lawrence grades preoperatively and at the final postoperative follow-up, intraoperative meniscal or chondral lesions, and perioperative complications. Status of returning to sports for all patients was assessed at the final follow-up. Results: The mean side-to-side differences by arthrometer improved from 4.3 mm (range, 2-8 mm) to 0.9 mm (range, 0-2 mm), and the positive pivot-shift test decreased from 100% to 8%. The mean extensor muscle strength was 93.3% (range, 74-116%) postoperatively. The mean Lysholm score improved from 71.1 (range, 27-85) to 95.2 (range, 89-100). Ten of the 13 patients (77%) returned to their pre-injury level of sports performance, and one patient (8%) returned to sports with less intensity. Intraoperatively, meniscal tears were observed in 10 patients (77%), and chondral lesions >grade 2 were observed in 11 (85%). One patient developed perioperative complications. At the final follow-up, the Kellgren-Lawrence grade worsened in only one patient. No re-injury or infection was observed, and revision surgery was not required for any patients. Conclusions: Anatomical DB-ACL reconstruction could provide satisfactory clinical outcomes and knee function restoration in patients aged ≥60 years. Level of evidence: A retrospective study, case series (IV).

Effects of Unrestricted Kinematically Aligned Total Knee Arthroplasty with a Modified Soft-Tissue Respecting Technique on the Deformity of Limb Alignment in Japanese Patients.

Background and Objectives: Unrestricted kinematic alignment total knee arthroplasty (KA-TKA) with a soft-tissue respecting technique (STRT) is a soft-tissue-dependent tibial resection entailing the restoration of the original soft-tissue tension using ligamentotaxis after resurfacing the femur, based on the concept of restoring the native or pre-osteoarthritis alignment in each patient. However, there is no consensus on the indications of unrestricted KA-TKA with the STRT. We modified the STRT, followed by an investigation of the effects of surgery on the postoperative hip-knee-ankle angle (HKAA). Materials and Methods: We retrospectively analyzed the clinical background data, including the preoperative and postoperative HKAA, of 87 patients who underwent unrestricted KA-TKA with the modified STRT. Univariate and multivariate analyses were performed to determine the factors affecting the postoperative HKAA. A receiver operating characteristic (ROC) curve was plotted to investigate the change in the cut-off values of preoperative HKAA with respect to the safe zone of the postoperative HKAA. We generated two regression models, the linear regression model and generalized additive model (GAM) using machine learning, to predict the postoperative HKAA. Results: Univariate and multivariate analyses revealed the preoperative HKAA as the factor most relevant to the postoperative HKAA. ROC analysis revealed that the preoperative HKAA exhibited a high predictive utility, with a cut-off value of -10°, when the safe range of postoperative HKAA was set at ±5°. The GAM was the superior machine learning model, indicating a non-linear association between the preoperative and postoperative HKAA. Patients with preoperative HKAAs ranging from -18° to 4° were more likely to fall within the ±5° safe range of the postoperative HKAA. Conclusions: The preoperative HKAA influences the postoperative HKAA in unrestricted KA-TKA with the modified STRT. Machine learning using the GAM may contribute to the selection of patients eligible for the surgical approach.

Arthroscopic Bankart repair with peeling osteotomy of the anterior glenoid rim preserves glenoid morphology.

BACKGROUND: A decrease in the glenoid size after arthroscopic Bankart repair (ABR) was common in shoulders without osseous fragments compared with those with osseous fragments. For cases of chronic recurrent traumatic anterior glenohumeral instability without osseous fragments, we have performed ABR with peeling osteotomy of the anterior glenoid rim (ABRPO) to make an intentional osseous Bankart lesion. The aim of this study was to compare the glenoid morphology after ABRPO with it after simple ABR. METHODS: The medical records of patients who underwent arthroscopic stabilization for chronic recurrent traumatic anterior glenohumeral instability were retrospectively reviewed. Patients with an osseous fragment, with revision surgery and without complete data were excluded. Patients were assigned to 1 of 2 groups: Group A, ABR without peeling osteotomy procedure or Group B, with ABRPO procedure. Computed tomography was performed preoperatively and 1 year after surgery. The size of the glenoid bone loss was investigated by the assumed circle method. The following formula was used to calculate the decreased size of the glenoid: (Δ) = (postoperative size of the glenoid bone loss) - (preoperative size of the glenoid bone loss). The size of the glenoid 1 year after surgery was assessed to determine if it had decreased (Δ > 0%) or not decreased (Δ ≤ 0%) relative to the preoperative size. RESULTS: This study evaluated 39 shoulders divided into 2 groups: 27 shoulders in Group A and 12 shoulders in Group B. In Group A, postoperative glenoid bone loss was significantly greater than preoperative glenoid bone loss (7.8 ± 6.2 vs. 5.5 ± 5.3, respectively, P = .02). In Group B, postoperative glenoid bone loss was significantly lower than preoperative glenoid bone loss (5.6 ± 5.4 vs. 8.7 ± 4.0, respectively, P = .02). The P value for the interaction of group (A or B) × time (preoperative or postoperative) was 0.001. The decreased size of the glenoid was significantly larger in Group A than in Group B (2.1 ± 4.2 vs. -3.1 ± 4.5, respectively, P = .001). The rate of shoulders in which the size of the glenoid decreased 1 year after surgery relative to the preoperative size was significantly higher in Group A than in Group B (63% [17/27] vs. 25% [3/2], respectively, P = .04). CONCLUSIONS: The study showed that ABRPO preserved the glenoid size better than simple ABR without a peeling osteotomy procedure.

Influence of vitamin D on sarcopenia pathophysiology: A longitudinal study in humans and basic research in knockout mice.

BACKGROUND: Vitamin D is an essential nutrient in musculoskeletal function; however, its relationship to sarcopenia remains ambiguous, and the mechanisms and targets of vitamin D activity have not been elucidated. This study aimed to clarify the role of vitamin D in mature skeletal muscle and its relationship with sarcopenia. METHODS: This epidemiological study included 1653 community residents who participated in both the fifth and seventh waves of the National Institute for Longevity Sciences, Longitudinal Study of Aging and had complete background data. Participants were classified into two groups: vitamin D-deficient (serum 25-hydroxyvitamin D < 20 ng/mL) and non-deficient (serum 25-hydroxyvitamin D ≥ 20 ng/mL); they underwent propensity-score matching for background factors (age, sex, height, weight, comorbidities, smoker, alcohol intake, energy intake, vitamin D intake, steps, activity, season and sarcopenia). Changes in muscle strength and mass over the 4-year period were compared. For basic analysis, we generated Myf6CreERT2 Vitamin D Receptor (VDR)-floxed (VdrmcKO ) mice with mature muscle fibre-specific vitamin D receptor knockout, injected tamoxifen into 8-week-old mice and analysed various phenotypes at 16 weeks of age. RESULTS: Grip strength reduction was significantly greater in the deficient group (-1.55 ± 2.47 kg) than in the non-deficient group (-1.13 ± 2.47 kg; P = 0.019). Appendicular skeletal muscle mass reduction did not differ significantly between deficient (-0.05 ± 0.79 kg) and non-deficient (-0.01 ± 0.74 kg) groups (P = 0.423). The incidence of new cases of sarcopenia was significantly higher in the deficient group (15 vs. 5 cases; P = 0.039). Skeletal muscle phenotyping of VdrmcKO mice showed no significant differences in muscle weight, myofibre percentage or myofibre cross-sectional area; however, both forelimb and four-limb muscle strength were significantly lower in VdrmcKO mice (males: forelimb, P = 0.048; four-limb, P = 0.029; females: forelimb, P < 0.001; four-limb, P < 0.001). Expression profiling revealed a significant decrease in expression of sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) 1 (P = 0.019) and SERCA2a (P = 0.049) genes in the VdrmcKO mice. In contrast, expression of non-muscle SERCA2b and myoregulin genes showed no changes. CONCLUSIONS: Vitamin D deficiency affects muscle strength and may contribute to the onset of sarcopenia. Vitamin D-VDR signalling has minimal influence on the regulation of muscle mass in mature myofibres but has a significant influence on muscle strength.

Promethazine Downregulates Wnt/ß-Catenin Signaling and Increases the Biomechanical Forces of the Injured Achilles Tendon in the Early Stage of Healing.

BACKGROUND: Wnt/ß-catenin signaling suppresses the differentiation of cultured tenocytes, but its roles in tendon repair remain mostly elusive. No chemical compounds are currently available to treat tendon injury. HYPOTHESIS: We hypothesized that the inhibition of Wnt/ß-catenin signaling would accelerate tendon healing. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon-derived cells (TDCs) were isolated from rat Achilles tendons. The right Achilles tendon was injured via a dermal punch, while the left tendon was sham operated. A Wnt/ß-catenin inhibitor, IWR-1, and an antihistamine agent, promethazine (PH), were locally and intramuscularly injected, respectively, for 2 weeks after surgery. The healing tendons were histologically and biomechanically evaluated. RESULTS: The amount of ß-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/ß-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased ß-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/ß-catenin signaling in human chondrosarcoma cells, we examined the effects of antihistamines on TDCs. We found that a first-generation antihistamine agent, PH, increased the expression of the tendon marker genes Mkx and Tnmd in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased ß-catenin in healing tendons and increased the peak force and stiffness of the healing tendons on postoperative week 2. On postoperative week 8, however, the biomechanical properties of vehicle-treated tendons became similar to those of PH-treated tendons. CONCLUSION: IWR-1 and PH suppressed Wnt/ß-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them. CLINICAL RELEVANCE: PH is a candidate repositioned drug that potentially accelerates tendon repair.

Meclozine ameliorates skeletal muscle pathology and increases muscle forces in mdx mice.

We screened pre-approved drugs for the survival of the Hu5/KD3 human myogenic progenitors. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, promoted the proliferation and survival of Hu5/KD3 cells. Meclozine increased expression of MyoD, but reduced expression of myosin heavy chain and suppressed myotube formation. Withdrawal of meclozine, however, resumed the ability of Hu5/KD3 cells to differentiate into myotubes. We examined the effects of meclozine on mdx mouse carrying a nonsense mutation in the dystrophin gene and modeling for Duchenne muscular dystrophy. Intragastric administration of meclozine in mdx mouse increased the body weight, the muscle mass in the lower limbs, the cross-sectional area of the paravertebral muscle, and improved exercise performances. Previous reports show that inhibition of phosphorylation of ERK1/2 improves muscle functions in mouse models for Emery-Dreifuss muscular dystrophy and cancer cachexia, as well as in mdx mice. We and others previously showed that meclozine blocks the phosphorylation of ERK1/2 in cultured cells. We currently showed that meclozine decreased phosphorylation of ERK1/2 in muscles in mdx mice but not in wild-type mice. This was likely to be one of the underlying mechanisms of the effects of meclozine on mdx mice.

Outcomes of pediatric anterior cruciate ligament reconstructions in patients with and without bucket handle meniscus repairs.

The purpose of this study was to report the outcomes of concomitant bucket handle meniscal tear (BHMT) repair and anterior cruciate ligament (ACL) reconstruction and to compare the outcomes with those after isolated ACL reconstruction in patients aged ≤16 years. Patients in our database from 2013 to 2017 were retrospectively analyzed. Patients were assigned to one of two treatment groups based on the presence of BHMTs: no meniscal tear group (group A) and BHMT group (group B). All BHMTs were repaired using the combined inside-out with all-inside technique. This study included 64 knees divided into two groups: 47 knees in group A and 17 knees in group B. There was a significant difference in the interval between ACL injury and surgery between groups A and B (69 vs. 150 days, respectively; P < 0.001). Mean postoperative International Knee Documentation Committee and Lysholm scores in group A were slightly, although significantly, improved compared to those in group B (96.5 vs. 92.6, respectively; P < 0.05, and 98 vs. 95, respectively; P < 0.05). There were no significant differences in postoperative anteroposterior laxity and graft failure rate between the groups. In group B, four patients (23.5%) required surgery for incomplete meniscal healing. Postoperative International Knee Documentation Committee and Lysholm scores of patients with BHMTs were significantly lower than those of patients without any meniscal tear, although with significant improvement in the amount of instability. Level of evidence was Level III.

Biceps tenotomy versus soft-tissue tenodesis in females aged 60 years and older with rotator cuff tears.

BACKGROUND: Recently, to treat the long head of the biceps tendon lesions in addition to rotator cuff repair has been recommended. However, the differences in clinical outcomes between biceps tenotomy and tenodesis for middle-aged and elderly females remains unclear. The purpose of this study was to compare the outcomes of biceps tenotomy and soft-tissue tenodesis that were performed concurrently with arthroscopic rotator cuff repair in ≥60-year-old females. METHODS: Female shoulders that underwent arthroscopic rotator cuff repair in our institute in 2016 were retrospectively reviewed. This study included 66 shoulders with concurrent biceps tenotomy or soft-tissue tenodesis: tenotomy group, 41 shoulders; soft-tissue tenodesis group, 25 shoulders. Clinical scores, biceps pain (visual analogue scale, VAS), Popeye deformity, and biceps strength (%contralateral side) were compared between the two groups. RESULTS: The mean age was significantly higher in the tenotomy group than the soft-tissue tenodesis group (72 ± 4 and 68 ± 6 years, respectively; P = 0.002). There were no significant differences in post-operative JOA and UCLA scores between the groups. VAS for biceps pain was significantly higher at postoperative 6 months in the tenotomy group than the soft-tissue tenodesis group (2.9 ± 2.5 and 1.7 ± 1.6, respectively, P = 0.03), though there were no significant differences at postoperative 3, 12, and ≥24 months. Subjective evaluation of Popeye deformity was not significantly different between the groups. Postoperative biceps strength was significantly lower in the tenotomy group than the soft-tissue tenodesis group (89.9% and 102.8%, respectively, P = 0.02). CONCLUSIONS: Both biceps tenotomy and soft-tissue tenodesis concurrent with rotator cuff repair in ≥60-year-old female patients resulted in good outcomes. Shoulders with soft-tissue tenodesis demonstrated earlier improvement in postoperative biceps pain and better postoperative biceps strength than those with tenotomy. There were no differences in objective and subjective Popeye deformity between tenotomy and soft-tissue tenodesis. The LHB procedures, tenotomy or tenodesis, can be selected depending on surgeons' preference.

Long-Term Survivorship of Closed-Wedge High Tibial Osteotomy for Severe Knee Osteoarthritis: Outcomes After 10 to 37 Years.

BACKGROUND: High tibial osteotomy (HTO) was developed as a joint-preserving procedure to treat relatively young patients with isolated medial compartmental knee osteoarthritis (OA). Long-term survivorship after HTO is important to determine whether patients will need additional surgery. PURPOSE: To determine the long-term (>35-year) survivorship and prognostic factors for closed-wedge HTO (CWHTO) for severe medial OA. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We retrospectively evaluated patients who underwent CWHTO for severe medial knee OA between 1983 and 2009 at our institution, Nagoya University Graduate School of Medicine (Nagoya, Japan). Patient demographics, follow-up period, and pre- and postoperative femoral-tibial angle (FTA) were reviewed. The patients or the relatives of the patients were interviewed by telephone to record postoperative status, including conversion to total knee arthroplasty (TKA). RESULTS: Of the 74 CWHTO procedures performed, we evaluated 56 procedures in 45 patients (mean age at time of surgery, 56.8 years). The mean follow-up period was 17.1 years. Nine knees (16.1%) underwent conversion to TKA. The mean time to TKA conversion was 15.6 years. Kaplan-Meier analysis revealed a 10-year survival rate of 90.1%, a 15-year rate of 83.8%, a 20-year rate of 75.9%, and a 35-year rate of 75.9%. Log-rank test showed that age ≥55 years (P = .044), body mass index (BMI) ≥25 kg/m2 (P = .0016), and preoperative FTA <185° (P = .0034) were risk factors associated with TKA conversion. Multivariate analyses adjusted for age and sex identified BMI ≥25 kg/m2 (hazard ratio [HR], 13.4; 95% CI, 1.7-106.9; P = .014) and preoperative FTA <185° (HR, 4.2; 95% CI, 1.1-16.6; P = .04) as risk factors associated with TKA conversion. CONCLUSION: The survival rate of CWHTO for severe medial knee OA was 90.1% at 10 years, 83.8% at 15 years, and 75.9% at 20 years and 35 years. Furthermore, a BMI ≥25 kg/m2 and FTA <185° were the independent risk factors associated with TKA conversion after CWHTO.

Deep flexion helps to avoid popliteal artery injury during all-inside lateral meniscal repair: A cadaveric study.

BACKGROUND: Arthroscopic meniscus repair rarely leads to major complications such as popliteal artery injury. The distance between the suturing device and the popliteal artery, and the risk of popliteal artery injury at different knee flexion angles during all-inside lateral meniscal repair remain unclear. METHODS: All-inside devices were inserted into 10 human cadaveric knees at the posterior horn of the lateral meniscus through the anterolateral portal at 60°, 90°, and 120° knee flexion; posterior segment of the lateral meniscus through the anterolateral portal at 60°, 90°, and 120°; and anteromedial portal at 90°. Distance and positional relationship between the device and popliteal artery were measured radiographically. RESULTS: In posterior horn repair through the anterolateral portal, the median distance increased from 5.7 mm at 60° to 9.1 mm at 90° (P = 0.63) and 18.0 mm at 120° (P = 0.02). The device pushed the wire at 60° in three cases, 90° in one case, and 120° in 0 cases. In posterior segment repair through the anterolateral portal, the median distance was 12.6 mm at 60°, 10.4 mm at 90°, and 18.3 mm at 120° (P = 0.08). The median distance at 90° was 18.1 mm through the anteromedial portal, the same as that at 120° through the anterolateral portal (P = 0.43), but greater than that at 90° through the anterolateral portal (P = 0.04). The wire was not pushed in any case. CONCLUSION: Although all-inside repair of the posterior part of the lateral meniscus through the anterolateral portal is risky, deeper knee flexion reduces the risk of popliteal artery injury.

4-Methylumbelliferone suppresses catabolic activation in anterior cruciate ligament-derived cells via a mechanism independent of hyaluronan inhibition.

BACKGROUND: The anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joints, and ACL dysfunction caused by traumatic or degenerative rupture accelerates osteoarthritis progression. Thus, it is important to prevent the degenerative rupture of the ACL. 4-Methylumbelliferone (4-MU), a pre-approved drug, exerts anti-inflammatory effects in osteoarthritis chondrocytes. It was originally used as an inhibitor of hyaluronan synthesis in chondrocytes. METHODS: In this study, we investigated whether 4-MU affects the expression of catabolic factors, such as matrix metalloproteinase (MMP)-1, MMP-3, and interleukin (IL)-6, in ACL-derived cells and ACL explant cultures using immunohistochemistry, real-time RT-qPCR, and capillary western immunoassay. Furthermore, the hyaluronan concentration was evaluated using a colorimetric assay. Statistical analyses were conducted using analysis of variance for multi-group comparisons, followed by Tukey or Tukey-Kramer post hoc test. RESULTS: Our results revealed, for the first time, that 4-MU suppressed the IL-ß-induced upregulation of pro-catabolic factors, such as MMP-1, MMP-3, and IL-6, in ACL-derived cells. This suppressive effect was also observed in the cultured ligament tissues in ex vivo experiments. 4-MU also reversed an enhanced dependence on glycolysis in IL-1ß-activated ACL-derived cells. Furthermore, we found that the suppressive effects of 4-MU were exerted directly and not through the inhibition of hyaluronan synthesis. CONCLUSIONS: We conclude that 4-MU could be an effective and useful treatment for knee osteoarthritis, owing to its anti-inflammatory effect on, not only chondrocytes but also on ligament cells.

Association Between Knee Alignment and Meniscal Tear in Pediatric Patients with Anterior Cruciate Ligament Injury.

BACKGROUND: The present study aimed to evaluate the association between elapsed time from anterior cruciate ligament (ACL) injury to surgical treatment and the incidence of meniscal tears in a cohort of patients ≤16 years old with varus-aligned and non-varus-aligned knees. METHODS: The study cohort included 123 patients ≤16 years old who underwent primary ACL reconstruction between January 2016 and March 2020. Knee alignment was expressed as the hip-knee-ankle angle (HKAA), as measured preoperatively on an anteroposterior view of 3-dimensional computed tomography of the full length of the lower limb. Varus alignment was defined as an HKAA ≥181.0°, and non-varus alignment was defined as an HKAA <181.0°. Patients were divided into groups according to knee alignment and the elapsed time from injury to surgical treatment: early-treatment group (<60 days) and delayed-treatment group (≥60 days). RESULTS: A total of 64 varus-aligned and 59 non-varus-aligned knees were identified. Among patients with varus-aligned knees, those in the delayed-treatment group showed a significantly lower rate of lateral meniscal tears (6 of 30, 20%) compared with those in the early-treatment group (17 of 34, 50%; p = 0.015). Among patients with non-varus-aligned knees, there was no significant difference in meniscal tears of any type between the early and delayed-treatment groups. Among patients without medial meniscal injury identified on initial magnetic resonance imaging, those with varus-aligned knees in the delayed-treatment group showed a significantly higher rate of medial meniscal tears at the time of the surgical procedure (8 of 20, 40%) compared with those with non-varus-aligned knees (1 of 18, 6%; p = 0.015). CONCLUSIONS: Delayed ACL reconstruction in patients ≤16 years old with varus-aligned knees might be associated with an increased incidence of secondary medial meniscal tears. Accordingly, earlier ACL reconstruction in patients with varus-aligned knees should be considered. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Delayed anterior cruciate ligament reconstruction increases the incidence of medial meniscal bucket handle tears and medial compartment chondral injuries in patients aged 40 years and older.

INTRODUCTION: No widely accepted evidence-based indications exist for the initial surgical management of patients with anterior cruciate ligament (ACL) injuries ≥ 40 years old, and treatment for these patients remains controversial. This study aimed to evaluate the association between elapsed time from ACL injury to surgery and the incidence of meniscal tears and chondral injury in patients aged ≥ 40 years. MATERIALS AND METHODS: The patients who underwent primary ACL reconstruction were divided into two groups based on elapsed time from injury to surgery: early group, < 12 months; and delayed group, ≥ 12 months. Patient records were reviewed for incidence and types of meniscal tears and chondral injuries in each group. Chondral injury grades were evaluated with International Cartilage Regeneration and Joint Preservation Society (ICRS) Criteria. RESULTS: This study evaluated 67 knees in the early group and 33 knees in the delayed group. Mean ages in each group were 46.9 ± 6.5 and 46.9 ± 6.0. The delayed group showed significantly higher rates of medial meniscal tear [31 of 33, 93.9% vs 29 of 67, 43.3%; P < 0.0001; odds ratio (OR), 20.31; 95% confidence interval (CI), 4.49-91.9], medial femoral condyle chondral injuries ≥ ICRS grade II (15 of 33, 45.5% vs 8 of 67, 11.9%; P < 0.001; OR, 6.15; 95% CI 2.24-16.83), and medial tibial chondral injuries ≥ ICRS grade II (7 of 33, 21.2% vs 3 of 67, 4.5%; P < 0.05; OR, 5.74; 95% CI 1.38-23.9) compared with the early group. With respect to types of medial meniscal tear, the delayed group showed a significantly higher frequency of bucket handle tears (11 of 33, 33.3%) compared with the early group (2 of 67, 3.0%; P < 0.0001; OR, 16.25; 95% CI 3.34-79.1). CONCLUSIONS: Delayed ACL reconstruction was associated with increased incidence of chondral injuries and medial meniscal tears, particularly bucket handle tears in this cohort. LEVEL OF EVIDENCE: Level III.

Incidence of Medial and Lateral Meniscal Tears After Delayed Anterior Cruciate Ligament Reconstruction in Pediatric Patients.

BACKGROUND: The treatment of pediatric anterior cruciate ligament (ACL) injuries is controversial, and no clear management guidelines have been established. PURPOSE: To evaluate the association between elapsed time from ACL injury to surgery and the incidence of meniscal tears and chondral injuries in patients aged ≤16 years. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between December 2012 and April 2019, a total of 207 consecutive knees in 207 patients aged ≤16 years underwent primary ACL reconstruction and were included in this study. Patients were divided into 1 of 2 groups (early group [≤150 days] and delayed group [>150 days]) based on the time between injury and surgery. Patient records, including arthroscopic findings identified by 2 experienced knee surgeons at the time of surgery, were reviewed for demographic information, incidence and types of medial and lateral meniscal tears, and chondral injuries and their locations in each group. RESULTS: There were 180 knees in the early group and 27 knees in the delayed group. The delayed group showed a significantly higher rate of medial meniscal tears than the early group: 16 of 27 (59.2%) and 46 of 180 (25.6%), respectively (odds ratio [OR], 4.24 [95% CI, 1.83-9.33]; P = .0011). The delayed group had a significantly lower rate of lateral meniscal tears than the early group: 6 of 27 (22.2%) and 90 of 180 (50.0%), respectively (OR, 0.29 [95% CI, 0.11-0.70]; P = .007). The delayed group had significantly higher rates of chondral injuries in the medial femoral condyle and the medial tibial plateau than the early group: 8 of 27 (29.6%) and 25 of 180 (13.9%), respectively (OR, 2.61 [95% CI, 1.03-6.62]; P = .049), and 2 of 27 (7.4%) and 1 of 180 (0.6%), respectively (OR, 14.32 [95% CI, 1.58-208.10]; P = .045). CONCLUSION: Delayed ACL reconstruction was associated with an increased incidence of medial chondral injuries and medial meniscal tears but with a decreased incidence of lateral meniscal tears.

Associations of Serum MicroRNA with Bone Mineral Density in Community-Dwelling Subjects: The Yakumo Study.

Osteoporosis is a disease characterized by deterioration of bone tissue and mass, with an increasing global prevalence. Therefore, the discovery of biomarkers for osteoporosis would help to guide appropriate treatment. Circulating microRNAs (miRNAs) have become increasingly recognized as biomarkers for detecting diseases. However, few studies have investigated the association of circulating miRNA with osteoporosis in the general population. The aim of this study was to identify miRNA associated with osteoporosis in a general resident health check-up for potential use as an osteoporosis biomarker. We conducted a cross-sectional study as part of a health check-up program and recruited 352 volunteers (139 men, 213 women, mean age 64.1 ± 9.6 years). Osteoporosis was diagnosed according to the WHO classification. Twenty-two candidate microRNAs were screened through real-time quantitative PCR, and miRNAs associated with osteoporosis were analyzed using logistic regression analysis including other risk factors. In total, 95 females and 30 males were diagnosed with osteoporosis with bone mineral density tests (BMD: T-score < -2.5). We found that miR195 was significantly lower in females, while miR150 and miR222 were significantly higher in males. The results of the logistic regression analysis indicated that in females, higher age and lower miR195 (odds ratio: 0.45, 95% confidential interval: 0.03-0.98) were significant risk factors for lower BMD, while the presence of a smoking habit and lower miR150 (odds ratio: 1.35, 95% confidential interval: 1.02-1.79) were significant risk factors for osteoporosis. Serum levels of miR195 and miR150 are independently associated with low bone mineral density in females and males, respectively.

Suppression of murine osteoarthritis by 4-methylumbelliferone.

Using in vitro models, we previously reported that 4-methylumbelliferone (4-MU) blocked many of the pro-catabolic features of activated chondrocytes. 4-MU also blocked safranin O loss from human cartilage explants exposed to interleukin 1ß (IL1ß) in vitro. However, the mechanism for this chondroprotective effect was independent of the action of 4-MU as a hyaluronan (HA) inhibitor. Interestingly, overexpression of HA synthase 2 (HAS2) also blocked the same pro-catabolic features of activated chondrocytes as 4-MU via a mechanism independent of extracellular HA accumulation. Data suggest that altering UDP-sugars may be behind these changes in chondrocyte metabolism. However, all of our previous experiments with 4-MU or HAS2 overexpression were performed in vitro. The purpose of this study was to confirm whether 4-MU was effective at limiting the effects of osteoarthritis (OA) on articular cartilage in vivo. The progression of OA was evaluated after destabilization of the medial meniscus (DMM) surgery on C57BL/6 mice in the presence or absence of 4-MU-containing chow. Mice fed 4-MU after DMM surgery exhibited significant suppression of OA starting from an early stage in vivo. Mice fed 4-MU exhibited lower OARSI scores after DMM; reduced osteophyte formation and reduced MMP3 and MMP13 immunostaining. 4-MU also exerted pronounced chondroprotective effects on murine joint cartilage exposed to IL1ß in vitro and, blocked IL1ß-enhanced lactate production in cartilage explants. Therefore, 4-MU is effective at significantly reducing the loss of proteoglycan and reducing MMP production both in vitro and in vivo as well as cartilage damage and osteophyte formation in vivo after DMM. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. 38:1122-1131, 2020.

Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronan.

Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HA synthase-2 viral overexpression; HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA >100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13, and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein (TSG6)) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1ß (IL1ß), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides. However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the procatabolic phenotype of neighboring nontransduced chondrocytes as we had expected. Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells. In addition, high HA biosynthesis rates, especially in transduced procatabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs.

Expression of tenocyte lineage-related factors in regenerated tissue at sites of tendon defect.

BACKGROUND: The healing mechanism of ruptured or injured tendons is poorly understood. To date, some lineage-specific factors, such as scleraxis and tenomodulin, have been reported as markers of tenocyte differentiation. Because few studies have focused on tenocyte lineage-related factors with respect to the repaired tissue of healing tendons, the aim of this study was to investigate their expression during the tendon healing process. METHODS: Defects were created in the patellar tendons of rats, and the patellae and patellar tendons were harvested at 3 days and at 1, 2, 3, 6, 12, and 20 weeks after surgery. They were studied using micro-computed tomography, and paraffin-embedded sections were then prepared for histological evaluation. Reverse transcription-polymerase chain reactions were performed to analyze the expression of genes related to the tenocyte lineage, chondrogenesis, and ossification. RESULTS: Repaired tissue became increasingly fibrous over time and contained a greater number of vessels than normal tendons, even in the later period. Safranin O staining revealed the existence of proteoglycan at 1 week and its persistence through 20 weeks. Ossification was detected in all tendons at 12 weeks. The expression of tenocyte lineage-related genes was high at 1 and 2 weeks. Chondrogenic genes were up-regulated until 6 weeks. Runt-related transcription factor 2, an osteogenic gene, was up-regulated at 20 weeks. CONCLUSIONS: In our tendon defect model, cells participating in the tendon healing process appeared to differentiate toward tenocyte lineage only in the early phase, and chondrogenesis seemed to occur from the early phase onward. To improve tendon repair, it will be necessary to promote and maintain tenogenesis and to inhibit chondrogenesis, especially in the early phase, in order to avoid erroneous differentiation of stem cells.