Simultaneous medial closing wedge distal femoral varus osteotomy and double-bundle anterior cruciate ligament reconstruction in the symptomatic femoral valgus deformity: A case report.

Distal femoral varus osteotomy (DFVO) is a widely recognized surgical procedure used to address valgus malalignment in patients with knee joint disorders. However, it still remains unclear whether anterior cruciate ligament (ACL) reconstruction can be performed in a single procedure along with DFVO. Herein, we present a 73-year-old female patient who developed lateral osteoarthritis of the knee with valgus alignment due to chronic ACL deficiency following a twisting injury during skiing. She was physiologically very active, and strongly demanded to return to sports. We performed a combined procedure involving a medial closing wedge DFVO using an anatomical locking plate, along with double-bundle ACL reconstruction. The postoperative radiograph confirmed successful correction of knee alignment, specifically achieving varus alignment with precise conformance of the anatomical plate to the medial contour of the distal femur following the osteotomy. The patient resumed her previous sports activities without experiencing knee pain. The operated knee demonstrated restored anterior stability, as indicated by negative Lachman test results, and regained full range of motion. Both the Knee Injury and Osteoarthritis Outcome Score and the 2011 Knee Society score demonstrated continuous postoperative improvements over the three-year follow-up period, indicating positive functional outcomes and joint preservation. To the best of our knowledge, this is the first case of medial closing wedge DFVO with anatomic double-bundle ACL reconstruction in the symptomatic femoral valgus deformity with chronic ACL deficiency in the literature.

A novel T cell-redirecting anti-GPRC5D × CD3 bispecific antibody with potent antitumor activity in multiple myeloma preclinical models.

G-protein-coupled receptor class 5 member D (GPRC5D) is detected in malignant plasma cells in approximately 90% of patients diagnosed with multiple myeloma (MM). Here, we constructed BsAb5003, a novel humanized bispecific monoclonal antibody targeting CD3 and GPRC5D, and evaluated its therapeutic impact on MM. BsAb5003 induced specific cytotoxicity of GPRC5D-positive MM cells with concomitant T cell activation and cytokine release. The efficacy of BsAb5003 was associated with GPRC5D expression levels in MM cell lines. Flow cytometry analysis of bone marrow mononuclear cells (BMMNCs) from 49 MM patients revealed that GPRC5D was expressed in a wide population of MM patients, including heavily treated and high-risk patients. In ex vivo assays using BMMNCs, BsAb5003 induced potent efficacy against CD138 + MM cells in both newly diagnosed and relapsed/refractory patient samples in a GPRC5D expression-dependent manner. BsAb5003 significantly enhanced T cell activation and cytokine production in combination with immunomodulatory drugs (IMiDs) against MM cell lines. BsAb5003 also demonstrated significant inhibition of in vivo tumor growth by recruiting T cells. Taken together, these results suggest that T cell-redirecting bispecific antibody targeting GPRC5D as monotherapy and combination therapy with IMiDs could be a highly potent and effective treatment approach for a wide population of MM patients.

Medial opening wedge high tibial osteotomy for the treatment of medial unicompartmental knee osteoarthritis: A state-of-the-art review.

Medial unicompartmental knee osteoarthritis is a common condition that is frequently associated with significant pain and dysfunction. Medial opening wedge high tibial osteotomy (MOWHTO) offers a unique opportunity to preserve the knee joint and potentially alter the course of the degenerative process. Recent advances in this field of surgery have enabled surgeons to perform a MOWHTO in a safe, reliable and reproducible manner. This state-of-the-art review highlights the most important advances in the field of MOWHTO. Key concepts related to patient selection, pre-operative planning, surgical accuracy and patient outcome are considered. The importance of an individualized approach is emphasized and its influence on the future direction of the procedure is discussed.

Derotational Hybrid Closed-Wedge High Tibial Osteotomy for Knee Osteoarthritis With Patellar Subluxation Caused by Tibial Torsional Deformity.

Patellar subluxation and recurrent dislocation are commonly treated with medial patellofemoral ligament reconstruction, and patients with predisposing factors for these problems often require additional bony realignment procedures. However, these procedures mainly address problems in the axial plane, and patients with medial-compartmental knee osteoarthritis may require further realignment in the coronal plane. In this Technical Note article, we introduce our technique for derotational hybrid closed-wedge high tibial osteotomy. Using this technique, simultaneous 3-dimensional realignment in the axial, coronal, and sagittal planes can be achieved in patients with medial compartmental knee osteoarthritis and patellar subluxation caused by a tibial torsional deformity. The indications for the technique and the preoperative planning assessments involving a static torsional deformity analysis on computed tomography images and a dynamic gait analysis by our walking-on-paper method are presented. This is followed by a detailed description of the surgical procedure, together with consideration of the pearls and pitfalls of the procedure. A video of the surgery performed in a representative case with medial knee osteoarthritis and patellar subluxation in the right knee owing to an outward tibial torsion deformity is also provided.

Double-Row Root Repair with Bridging Centralization Using Double Nonsliding Anchors for Medial Meniscus Posterior Root Tear.

Medial meniscal posterior root tears disrupt the "hoop" function of the meniscus and may lead to knee osteoarthritis. Although root repair could be a key to osteoarthritis prevention, this surgery does not necessarily guarantee an optimal result even when combined with meniscal centralization and high tibial osteotomy. To address this issue, we made five modifications to the original combined approach, namely two anchors to fix the root, instead of one; bridging centralization instead of single centralization; release of the meniscotibial capsule vs no release; release of valgus stress before knot tying vs no release; and prohibiting postoperative cross-legged sitting and sitting on heels. The advantages of this approach over the original approach are numerous and comprise ease of performing concurrent open wedge high tibial osteotomy, shorter fixation distance, better anatomical reattachment of the meniscal root, increased bone-meniscus contact and contact pressure, and larger contact area between the capsule and tibial rim. The disadvantages of the approach are that knot-tying is cumbersome, pie-crusting of the medial collateral ligament is necessary in patients not undergoing open wedge high tibial osteotomy, and tears >3 mm from the attachment are a contraindication. We describe the steps in this modified approach in detail.

Involvement of Degenerating 21.5 kDa Isoform of Myelin Basic Protein in the Pathogenesis of the Relapse in Murine Relapsing-Remitting Experimental Autoimmune Encephalomyelitis and MS Autopsied Brain.

Multiple sclerosis (MS) is the chronic inflammatory demyelinating disease of the CNS. Relapsing-remitting MS (RRMS) is the most common type of MS. However, the mechanisms of relapse and remission in MS have not been fully understood. While SJL mice immunized with proteolipid protein (PLP) develop relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), we have recently observed that some of these mice were resistant to the active induction of relapsing EAE after initial clinical and histological symptoms of EAE with a severity similar to the relapsing EAE mice. To clarify the mechanism of relapsing, we examined myelin morphology during PLP139-151-induced RR-EAE in the SJL mice. While RR-EAE mice showed an increased EAE severity (relapse) with CNS inflammation, demyelination with abnormal myelin morphology in the spinal cord, the resistant mice exhibited a milder EAE phenotype with diminished relapse. Compared with the RR-EAE mice, the resistant mice showed less CNS inflammation, demyelination, and abnormalities of the myelin structure. In addition, scanning electron microscopic (SEM) analysis with the osmium-maceration method displayed ultrastructural abnormalities of the myelin structure in the white matter of the RR-EAE spinal cord, but not in that of the resistant mice. While the intensity of myelin staining was reduced in the relapsing EAE spinal cord, immunohistochemistry and immunoblot analysis revealed that the 21.5 kDa isoform of degenerating myelin basic protein (MBP) was specifically induced in the relapsing EAE spinal cord. Taken together, the neuroinflammation-induced degenerating 21 kDa isoform of MBP sheds light on the development of abnormal myelin on the relapse of MS pathogenesis.

Flexion Contracture in Knee Osteoarthritis Can Be Fully Eliminated by Hybrid Closed Wedge High Tibial Osteotomy Using a Reduction-Insertion-Compression Handle.

In conventional closed-wedge high tibial osteotomy (CWHTO) with preservation of the medial hinge, flexion contracture cannot be improved because of the two-dimensional correction. Conversely, in hybrid CWHTO, for which the name is derived from a hybrid of the lateral closing and medial opening, the medial cortex is intentionally disrupted. The medial hinge disruption enables three-dimensional correction, which helps eliminate flexion contracture by decreasing posterior tibial slope (PTS). The fine adjustment of the anterior closing distance and thigh-compression technique further facilitates PTS control. In this study, we describe the use of the Reduction-Insertion-Compression Handle (RICH), which maximizes the benefits of hybrid CWHTO. This device permits accurate osteotomy reduction, easy screw insertion, and assists with providing sufficient compressive force at the osteotomy site, as well as the elimination of the flexion contracture. This Technical Note presents the details of using the RICH and the associated advantages and disadvantages in hybrid CWHTO for medial compartmental knee arthritis.

Femoral-varus tibial-valgus osteotomy (FVTVO) for neutrally-aligned knee osteoarthritis with severe joint line obliquity enables return to sports activities: A case series study.

Background: Re-alignment surgeries for uni-compartmental knee osteoarthritis, such as high tibial osteotomy (HTO) for varus knees or distal femoral osteotomy (DFO) for valgus knees, are recognized as standard strategies. However, the treatment strategy has not been established for patients with a neutrally-aligned osteoarthritic knee with severe joint line obliquity (JLO) owing to the combination of a valgus femur and a varus tibia; i.e., type II coronal plane alignment of the knee (CPAK). total knee arthroplasty (TKA) can be an option for CPAK type II-aligned osteoarthritis in older inactive patients. Here, we hypothesized that joint line horizontalization by femoral-varus tibial-valgus osteotomy (FVTVO), which may reduce the shear stress induced by JLO, could be a treatment option for CPAK type II-aligned osteoarthritis in young active patients who wish to return to sports (RTS) activity. Our aim in this study was to evaluate the postoperative results of FVTVO with RTS. Methods: Our indications for FVTVO are as follows: JLO >5°; mechanical medial proximal tibial angle (mMPTA) < 87°; mechanical lateral distal femoral angle (mLDFA) < 87°; typical osteoarthritis patterns for CPAK type II on magnetic resonance images, namely osteoarthritic change of the lateral tibial spine, medial slip of the femur, and/or lateral meniscal extrusion from the lateral femoral condyle; and flexion contracture <10°. We enrolled patients who wished to RTS and who had a pre-symptom Tegner score ≥5 and had completed at least a 1-year follow-up. For FVTVO, closed-wedge DFO was performed in all femurs; both closed-wedge HTO and open-wedge HTO were used in the tibia, depending on the situation. Range of motion exercises began on the first postoperative day, and full weight-bearing was permitted 6 weeks postoperatively. Jogging was permitted 3 months postoperatively after confirming bone union, and patients could gradually return to their sports activity 6-12 months' postoperatively. The Japanese Orthopaedic Association (JOA) score and knee flexion range were assessed preoperatively and at the last follow-up. Tegner activity scale scores were assessed presymptom, preoperatively, and at the last follow-up. The hip-knee-ankle (HKA) angle, JLO, mMPTA, and mLDFA were evaluated radiologically, and meniscal extrusions, osteoarthritic change, and/or bone marrow edema were assessed on magnetic resonance images. Results: One man and two women were included in this case series. Two were competitive athletes and one was a mountain climber. The patients' ages were 69, 46, and 57 years (Case 1, 2, and 3, respectively). All patients' CPAK type was converted from type II to type V; i.e., neutral-aligned knee with a neutral joint line, postoperatively. All patients returned to their presymptom sports activity level by the final follow-up. The presymptom/preoperative/final follow-up Tegner scale in Case 1, 2, and 3 were 6/1/6, 5/2/5, and 7/3/7, respectively. Conclusion: Joint line horizontalization by FVTVO for patients with a neutral-aligned knee with severe JLO provided highly satisfactory clinical results and successfully led to RTS.

Anteromedial plating without filling the gap in open wedge high tibial osteotomy may increase the risk of screw breakage, which can be reduced by medial plating and bone-substitute insertion.

BACKGROUND: Open wedge high tibial osteotomy (OWHTO) brings new complications such as screw breakages with or without correction loss and time-dependent increased posterior tibial slopes (PTS) due to the opening gap. For preventive purposes, we changed our OWHTO procedure from anteromedial plating without filling the gap (non-grafted group, n = 40, 2009-2012) to medial plating with bone-substitute insertion (grafted group, n = 45, 2012-2015). The objectives of this study were to evaluate the complication patterns and the effects of the modifications. METHODS: Patients undergoing OWHTO with TomoFix plates were included in this retrospective study. Demographics, clinical outcomes (flexion range and Japanese Orthopaedic Association score) and radiological outcomes (femorotibial angle) were assessed in both groups pre-operatively and 2-years postoperatively. The plate installation angle [PIA] and screw insertion depth [SID] were measured on computed tomographic slices at 6 months. PIA/SID was defined as the angle between the tibial anteroposterior axis and plate-width axis/the distance between the proximal screw tip and the proximal tibiofibular joint. The non-grafted group was further divided into complication and non-complication subgroups. Screw breakages were assessed during plate removal (1.5-2.5 years postoperatively). RESULTS: There were no differences in baseline characteristics or radiological/clinical outcomes between the non-grafted and grafted groups. There were 0 and 11 complications in the grafted and non-grafted groups, respectively. Complications included 7 screw breakages, 4 correction losses, and 5 time-dependent increased PTS with some overlaps. PIA and SID were significantly lower (p < 0.001) and higher (p < 0.001), respectively, in the grafted group and significantly lower (p = 0.018) and higher (p = 0.040), respectively, in the non-complication subgroup within the non-grafted group. The cutoff value of PIA for complications was calculated at 48.0°. CONCLUSIONS: Medial plating OWHTO (PIA<48°) using bone-substitute with deeper screw insertion reinforces the opening gap for better angular stability compared with anteromedial plating without bone-substitute.

Proximal tibiofibular joint (PTFJ) dislocation due to Ehlers-Danlos syndrome: posterolateral open-wedge high tibial osteotomy combined with medial closed-wedge distal femoral osteotomy can correct the severe valgus deformity with a markedly increased tibial posterior slope.

Ehlers-Danlos syndrome (EDS) causes joint hypermobility and joint dislocation. Since there are no reports of proximal tibiofibular joint (PTFJ) dislocation caused by EDS, little is known about the long-term course of this disease. A woman in her 40s presented with a posterolaterally depressed tibial condyle and severe valgus deformity caused by a long-standing PTFJ dislocation due to EDS. Considering the pathology, posterolateral open-wedge high tibial osteotomy (PLOWHTO) and medial closed-wedge distal femoral osteotomy were performed according to the deformity analysis. A favourable short-term clinical outcome was obtained and the PTFJ dislocation was reduced over time. Although PLOWHTO has several pitfalls, it is a logical and useful surgical technique that can help treat posterolateral dysplasia of the tibial plateau concomitant with severe valgus deformity, regardless of joint laxity, if performed with attention to pitfalls.

Around-knee osteotomy conversion for failed high tibial osteotomy: Re-correction high tibial osteotomy and additional distal femoral osteotomy may enable return to sporting activities.

High tibial osteotomy (HTO) for knee osteoarthritis achieves excellent short- and long-term results. However, failure of HTO due to undercorrection or correction loss may necessitate conversion surgery. For patients with HTO failure who desire a return to sporting activities (RTS), non-prosthetic joint-preserving solutions such as conversion to around-knee osteotomies (AKO-conversion) may be more appropriate than total knee arthroplasty. The present study aimed to introduce potential non-prosthetic joint-preserving solutions for failed HTO and investigate the postoperative RTS. Among the patients who received non-prosthetic solutions for failed HTO from 2015 to 2020, this case series included those who were eager to RTS, were participating in a sporting activity with a Tegner activity scale score of ≥5 immediately before being affected by knee osteoarthritis, and had at least 2 years of follow-up. Deformity analysis for the preoperative planning of the AKO-conversion was based on the mechanical lateral distal femoral angle, joint line convergence angle, and mechanical medial proximal tibial angle. Four patients met the study inclusion criteria: two patients who underwent re-correction HTO and two who received additional distal femoral osteotomy (DFO). The average ages at primary HTO and AKO-conversion were 69.5 ± 11.8 years and 71.5 ± 10.9 years, respectively. The hip-knee-ankle angle was corrected from -2.8 ± 1.5° before conversion surgery to 3.3 ± 1.5° at 2 years after AKO-conversion. All four patients finally achieved a better sporting performance after AKO-conversion than preoperatively, and the Tegner activity scale score was improved from 2.5 ± 1.0 before AKO-conversion to 5.8 ± 0.5 at the 2-year follow-up. The duration between AKO-conversion and full RTS was 11.8 ± 6.7 months. In conclusion, two patients who underwent re-correction HTO and two who underwent additional DFO for undercorrection or correction loss after primary HTO achieved highly satisfactory clinical results, including RTS. The present findings suggest that non-prosthetic joint-preserving solutions using AKO for failed HTO should be considered as options to enable RTS.

Open Wedge High Tibial Osteotomy with Pes Anserinus Preservation and Insertion of Bone Substitutes.

Biplanar open wedge high tibial osteotomy (OWHTO) has become common since the introduction of OWHTO-specific plates. However, the management of soft tissues, including skin, the pes anserinus, and the superficial medial collateral ligament (sMCL) release vary among surgeons. We introduce an OWHTO methodology that avoids pes incision and repair, uses bone substitute insertion into the opening gap and includes management of soft tissues to minimize complications. We adopted a reversed curved oblique incision to reduce the risk of saphenous nerve injury. We avoided pes incision, taking advantage of its posterior component force to allow it to function as a compressor of the ascending osteotomy site. The proximal component force of the pes provides compression between the bone substitute insertions and the proximal/distal cortices. This allows postoperative weight bearing to be distributed to the substitute, which may reduce the risk of implant failure. The sMCL is detached from the distal tibial attachment without cutting, enabling its return to its original position underneath the pes and to be repaired. This sMCL release with complete pes preservation may reduce the risk of deep infection or medial laxity during total knee arthroplasty conversion, and further reduce the risks of OWHTO.

A spreading roots sign: Characteristic sign of the preliminary stage of medial meniscus posterior root tear on magnetic resonance imaging.

BACKGROUND: Medial meniscus posterior root tears (MMPRTs) can result in the development of osteoarthritis or osteonecrosis. Clinical experience suggests that symptoms such as dull pain or discomfort in the popliteal area or the calf area, which are sometimes misdiagnosed as sciatic nerve pain, may precede impending rupture. We found that bone marrow edema emanating from the meniscal root on magnetic resonance imaging (MRI) scans-spreading roots sign-may indicate the preliminary stage of an MMPRT. The purpose of this study was to evaluate the efficacy of the spreading roots sign as an MMPRT-predictor. METHODS: In a retrospective study, we reviewed the chart data and MRI results of patients who had required surgery for an acute MMPRT. We grouped patients by whether or not they had reported the above-mentioned precursory symptoms prior to acute rupture (precursory symptom group/non-precursor group), and when possible, we examined MRI scans to identify with which events the appearance/disappearance of the spreading roots sign coincided. Sex, age, body mass index, bone mineral density, radiological parameters, and MRI parameters were compared between groups. RESULTS: Data from 24 patients (precursory symptom group, n = 17 [70.8 %]; non-precursor group, n = 7 [29.2 %]) were included; data from 5 patients included MRI scans prior to acute rupture. There were no significant differences between precursory symptom and non-precursor groups, except for the ratio of the presence of the spreading roots sign (p = 0.005). The appearance of the spreading roots sign on MRI scans coincided with the onset of precursory symptoms, and its disappearance coincided with acute rupture and the appearance of other MRI signs typical of MMPRT (white meniscus/truncation/meniscal extrusion/giraffe neck signs). CONCLUSIONS: Our findings suggest that the spreading roots sign can be used as a unique precursory sign for MMPRT.

Ankle-Angle-Adjusting Fibular Osteotomy in Closed Wedge High Tibial Osteotomy.

Closed-wedge high tibial osteotomy (CWHTO) may be carried out to realign the knee in patients with knee osteoarthritis who do not meet the criteria for open-wedge high tibial osteotomy or total knee arthroplasty. The procedure involves both fibular and tibial osteotomy, and care is needed to prevent peroneal nerve and vessel injury during fibular osteotomy. Notably, use of a tourniquet may mask the development of hematomas or aneurysms until after surgery. We developed a 3-step ankle-angle-adjusting (triple-A) technique to relax the muscles, allowing easy retraction of the peroneal vessels. Crucially, the procedure does not require a tourniquet, thus allowing bleeding to be detected and stopped during surgery. The process involves adjusting the ankle angle by plantar-flexion and applying varus stress to highlight the tension difference between the lateral and posterior compartments; plantar-flexion of the great toe to loosen the flexor hallucis longus muscle, thus exposing the fibular posterior aspect; and valgus stress to loosen the peroneus longus muscle. The muscles can then be retracted sufficiently to allow distal and proximal osteotomies to be performed, and any bleeding can be detected and resolved before wound closure. This technique may improve the ease and safety of fibular osteotomy in patients undergoing CWHTO.

Medial Closed Wedge Distal Femoral Osteotomy Using a Novel Plate With an Optimal Compression System.

Medial closed wedge distal femoral osteotomy (MCWDFO) has been widely performed for lateral-compartment osteoarthritis since the development of a biplanar osteotomy technique using existing MCWDFO-specific plates. To further improve this system and the technique, we have developed a newly designed MCWDFO plate (TriS-MDFO; Olympus Terumo Biomaterials). The improved shape of the plate consists of a larger head-shaft angle to fit the distal femur after MCWDFO, more distally oriented distal screws to enable longer screw insertion, and a diamond-shaped plate head to avoid interference with the medial patellofemoral ligament. Technically, to overcome the difficulty in inserting proximal screws through the vastus medialis muscle, a cannulated screw system was employed. This system can prevent difficulties in removing the screw due to cross-threading when plate removal is required. Furthermore, we designed a novel compression hook device with a bulb-shaped head to hook on a screw hole to apply a compressive force to the osteotomized site. On the plate side, a characteristic 1.5 mm-thickness stopper is installed to prevent slippage of the hook device. This optimal compression system can minimize the risk of lateral hinge fracture during the compression procedure. These improvements in the TriS-MDFO may increase the ease and safety of MCWDFO.

Outcome after treatment of osteoarthritis with open-wedge high-tibial osteotomy with a plate: 2-year results of a Japanese cohort study.

PURPOSE: This prospective multicenter study evaluated patient reported outcomes (PROs) in individuals undergoing medial open-wedge high-tibial osteotomy (OWHTO) with plate stabilization compared to conservative care or no treatment. METHODS: One hundred eighteen of 148 patients older than 40 years were elected for OWHTO with plate treatment. Thirty patients declined surgery and were followed as a conservative group. The primary outcome measure was the Knee Injury and Osteoarthritis Outcome Score (KOOS) at 2 years. Secondary measures included Oxford knee score, Western Ontario and McMaster Universities osteoarthritis index, range of motion (ROM), joint space width (JSW), femorotibial angle (FTA), and weight-bearing line ratio (WBLR). RESULTS: Patient enrollment and baseline characteristics were heterogeneously distributed and led to group characteristics that were not comparable. Therefore, the comparison of the KOOS between the groups showing no differences must be treated with caution. In the OWHTO plate group, all PROs and the ROM significantly improved between baseline and 2-year follow-up. JSW remained stable in the OWHTO group. The FTA and WBLR significantly changed from a mean of 179.3 (95% confidence interval (CI): 178.7, 179.9) to 169.8 (95% CI: 169.2, 170.5) and from 23.1 (95% CI: 20.7, 25.5) to 62.4 (95% CI 59.0, 65.8), respectively. Treatment failure with conversion to total knee arthroplasty occurred in 1% of the OWHTO group; and in the conservative group, 10% converted to HTO or knee arthroplasty. CONCLUSIONS: OWHTO with plate leads to significant improvement of PROs and function 2 years after intervention and demonstrates reliable mechanical axis correction with subsequent shift of weight-bearing.

High tibial osteotomy solely for the purpose of return to lifelong sporting activities among elderly patients: A case series study.

Knee osteoarthritis (KOA) is a common joint disease among older individuals, associated with increased mortality rates. The current study was conducted to examine whether open wedge high tibial osteotomy (OWHTO) is an effective treatment for elderly patients with a desire to return to sporting activities (RTS) who do not report inconvenience or pain in activities of daily living. We examined a case series of 9 KOA patients (12 knees) aged 50 or above with a desire for RTS, who underwent HTO. We assessed patients before surgery and 2 years after surgery to evaluate surgical outcomes and RTS. The results revealed that patients' average Japanese Orthopaedic Association score was significantly improved at 2 years after surgery (97.5 ±â€¯4.5), compared with the preoperative score (87.9 ±â€¯7.2; p = 0.008). In addition, the average Tegner activity level score was significantly improved at 2-year follow-up (5.8 ±â€¯1.1) compared with the preoperative score (2.8 ±â€¯1.1; p < 0.001). Eight of nine cases except a marathon runner returned to pre-symptom sporting performance levels. Overall, the current findings suggest that OWHTO provides an appropriate treatment for older KOA patients with a desire for RTS.

Safety assessment of a novel C-type natriuretic peptide derivative and the mechanism of bone- and cartilage-specific toxicity.

ASB20123, a C-type natriuretic peptide/ghrelin chimeric peptide, was designed as a novel peptide and demonstrated full agonistic activity for natriuretic-peptide receptor B and a significantly longer half-life in plasma compared with the native peptide. We researched the toxicological profile of ASB20123, the correlation between the morphological change of the epiphyseal plate and bone and cartilage toxicity, and biomarkers to detect the toxicity. ASB20123 was systemically administered to male and female rats at daily dose levels of 0.5, 1.5, and 5.0 mg/kg/day for 4 weeks. In this study, toxicity was observed as changes related to bone and cartilage tissues, and no other toxicological changes were observed in all animals. Next, ASB20123 was administered to 12-month-old rats with a little epiphyseal plate. The toxic changes related to bone and cartilage tissues were not observed in any animal with a closed epiphyseal plate, indicating that the toxic changes were triggered by the growth-accelerating effect on the bone and cartilage. Furthermore, we searched for the biomarker related to the bone and cartilage toxicity using rats treated with ASB20123 at doses of 0.005, 0.05, 0.5, and 5.0 mg/kg/day for 4 weeks. A close correlation between necrosis/fibrosis in the epiphysis and metaphysis and thickness of the epiphyseal plate in the femur was confirmed in this study. A decrease in the bone mineral density (BMD) of the femur also was associated with the appearance of bone toxicity. These results indicated that the toxicity of ASB20123 was limited to bone- and cartilage-specific changes, and these changes were triggered by an excessive growth accelerating effect. Furthermore, our data suggested that the thickness of the epiphyseal plate and BMD could be reliable biomarkers to predict bone toxicity.

ASB20123: A novel C-type natriuretic peptide derivative for treatment of growth failure and dwarfism.

C-type natriuretic peptide (CNP) and its receptor natriuretic peptide receptor B (NPR-B) are physiological potent positive regulators of endochondral bone growth; therefore, the CNP/NPR-B signaling pathway is one of the most promising therapeutic targets for treating growth failure and dwarfism. In this article, we summarized the pharmacological properties of a novel CNP analog peptide ASB20123 as a therapeutic agent for short stature. ASB20123, one of the CNP/ghrelin chimeric peptides, is composed of CNP(1-22) and human ghrelin(12-28, E17D). Compared to CNP(1-22), ASB20123 showed similar agonist activity for NPR-B and improved biokinetics with a longer plasma half-life in rats. In addition, the distribution of ASB20123 to the cartilage was higher than that of CNP(1-22) after single subcutaneous (sc) injection to mice. These results suggested that the C-terminal part of ghrelin, which has clusters of basic amino acid residues and a BX7B motif, might contribute to the retention of ASB20123 in the extracellular matrix of the growth plate. Multiple sc doses of ASB20123 potently stimulated skeletal growth in rats in a dose-dependent manner, and sc infusion was more effective than bolus injection at the same dose. Our data indicated that high plasma levels of ASB20123 would not necessarily be required for bone growth acceleration. Thus, pharmaceutical formulation approaches for sustained-release dosage forms to allow chronic exposure to ASB20123 might be suitable to ensure drug effectiveness and safety.