Toshikazu Kubo's research while affiliated with Kyoto Prefectural University of Medicine and other places

Objectives This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity. Design Retrospective observational study of a nationwide database. Setting The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint. Participants This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018. Main outcome measure The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis. Results The median time to surgery was 9 months (IQR 4–22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p<0.001, respectively), in early stage ONFH with no or mild joint destruction (stages II and III, p<0.001), and with joint preserving surgery (p<0.001). The proportion without surgery was 75.8% at 3 months, 59.6% at 6 months, 48.2% at 9 months, 40.5% at 1 year, 22.2% at 2 years and 8.3% at 5 years. Conclusion ONFH has been considered to be an intractable disease that often requires surgical treatment, but the fact that surgery was performed in more than half of the patients within 9 months from diagnosis suggests severe disease with a significant clinical impact. Trial registration number Chiba University ID1049.

Unlabelled: There seems to be a lack of consistency of maintenance/community-based rehabilitation through long-term care insurance. We aimed to clarify whether consistent rehabilitation can be performed through long-term care insurance by questionnaires. Materials and methods: This study was a cross-sectional study in a nationwide survey among rehabilitation staff and care recipients who completed disease-specific rehabilitation and required maintenance/community-based rehabilitation through long-term care insurance. Consistency of rehabilitation was compared using Fisher's exact tests. The concordance of the rehabilitation evaluation and treatment conducted under medical and long-term care insurance was assessed using the κ coefficient. Results: Six hundred questionnaires from care recipients and staff were analyzed. Of the rehabilitation staff, 264 (44%) obtained rehabilitation plans from medical institutions. There was a significant difference between the responses of "referral from the same medical corporation" and "obtaining the rehabilitation plan" by Fisher's exact test (odds ratio: 3.242; P<0.001). Most rehabilitation treatments under medical insurance comprised walking or training with parallel rods/canes [498 patients (83%)], and 454 patients (76%) received stretching and range-of-motion training for the limbs and spine for long-term care insurance. Muscle strength evaluation was the most frequently conducted under medical and long-term care insurance [383 (73%) and 487 (83%), respectively]. The concordance of the evaluation and treatment content, except for disease-specific evaluation, was low (κ coefficient≤0.6). Conclusions: The rate of provision of rehabilitation plans was low, and evaluation and treatment content under medical and long-term care insurance was inconsistent. Our results draw attention to the need for consistent rehabilitation plans between disease-specific and maintenance/community-based rehabilitation.

Purpose: Since the enactment of the long-term care insurance (LTCI) act in 2000, the number of LTCI users has increased annually. However, evidence regarding what is being carried out as rehabilitation treatment under LTCI is lacking. In this study, a scoping review was performed to bridge this knowledge gap. Methods: Articles related to rehabilitation in connection with LTCI published between April 2000 and November 2020 were searched for in PubMed, CINAHL, CENTRAL (Cochrane Central Register of Controlled Trials), Ichushi Web Ver.5, and CiNii and randomized controlled trials (RCTs) of rehabilitation provided under LTCI were examined. Results: Of the 15,572 publications identified, 15 RCTs, including rehabilitation treatment by physiatrists and therapists, met the eligibility criteria of our review and were included. The rehabilitation trials in the 15 RCTs varied and included balance training, exercise therapy, cognitive tasks, and activities such as singing and dancing. The results allowed us to focus on three categories: fall prevention, dementia, and theory and tools interventions related to occupational therapy practice. Conclusion: The focal points of attention in the rehabilitation treatment of LTCI were identified. However, the physical function, quality of life, and activities of daily living (ADL) of those who "need support" vary from person to person. Therefore, the consolidation of evidence on rehabilitation treatment of LTCI must be continued.

Trial design: How body position affects unilateral spatial neglect (USN) is unclear. This cluster randomized trial aimed to examine the effects of different positions (supine, sitting, and standing) on USN in stroke patients. Methods: Twenty stroke patients (hemorrhage [n = 11], infarction [n = 9]) who were right-handed, had left hemiplegia due to right hemisphere damage that occurred within the last 2 years, and were in a state of arousal with a Glasgow Coma Scale score of 15 were included in the study. Table-top pen-and-pencil tests for USN (Bells Test, Line Bisection, Scene Copy, and Star Cancellation) were randomly conducted in the supine, sitting, and standing positions. Results: The mean values in each test were significantly smaller in the supine position than were those in the sitting position (P = .015, .047, .015, and <.001), and those in the standing position were significantly smaller than those in the sitting position (P = .007, <.001, =.006, and < .001). The results of the 4 tests in the standing position were similar to those in the supine position. Conclusions: Body position affects USN in stroke patients and that the standing and supine positions improve USN better than the sitting position. Some possible mechanisms are: muscle contractions in the lower limbs and the trunk could have affected results in the standing position, and reduction in gravitational stimulation in the supine position could have played a role.

While cartilage can be produced from induced pluripotent stem cells (iPSCs), challenges such as long culture periods and compromised tissue purity continue to prevail. The present study aimed to determine whether cartilaginous tissue could be produced from iPSCs under hypoxia and, if so, to evaluate its effects on cellular metabolism and purity of the produced tissue. Human iPSCs (hiPSCs) were cultured for cartilage differentiation in monolayers under normoxia or hypoxia (5% O2), and chondrocyte differentiation was evaluated using reverse transcription‑quantitative PCR and fluorescence‑activated cell sorting. Subsequently, cartilage differentiation of hiPSCs was conducted in 3D culture under normoxia or hypoxia (5% O2), and the formed cartilage‑like tissues were evaluated on days 28 and 56 using histological analyses. Hypoxia suppressed the expression levels of the immature mesodermal markers brachyury (T) and forkhead box protein F1; however, it promoted the expression of the chondrogenic markers Acan and CD44. The number of sex‑determining region Y‑box 9‑positive cells and the percentages of safranin O‑positive and type 2 collagen‑positive tissues increased under hypoxic conditions. Moreover, upon hypoxia‑inducible factor (HIF)‑1α staining, nuclei of tissues cultured under hypoxia stained more deeply compared with those of tissues cultured under normoxia. Overall, these findings indicated that hypoxia not only enhanced cartilage matrix production, but also improved tissue purity by promoting the expression of HIF‑1α gene. Potentially, pure cartilage‑like tissues could be produced rapidly and conveniently using this method.

Introduction Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. Methods We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in-silico analyses. Results The Japanese GWAS identified four significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 (OR = 1.99, P-value = 1.1 × 10−9), TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10−8) and MYO16 (OR = 3.91, P-value = 4.9 × 10−10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. Conclusions We identified three novel susceptibility loci for S-ONFH in SLE.

The aim of the study was to evaluate the outcomes of arthroscopic repair using the all-inside inter-leaf vertical suture arthroscopic technique for sports-related horizontal meniscal tears. The inter-leaf vertical suture procedure was performed to repair sports-related horizontal tears in the middle and posterior segments of the medial (11 cases) and lateral (2 cases) menisci in 13 patients (mean age: 30 ± 14 years). Pre- and post-operative Barrett criteria, Lysholm scores, and patient ability to resume sports were assessed. Magnetic resonance imaging (MRI) grades and signal intensity changes near the joint capsule were evaluated in the 9 cases among which pre- and post-operative MRI images were available. All Barrett criteria items were negative following surgery; Lysholm scores increased from 70.2 ± 13.1 before surgery to 98.9 ± 2.64 after surgery (P < .01). All patients were able to resume their sport. Preoperative MRI grade of tears was 3 for all patients; postoperative MRI grades were 1 in 3 cases, 2 in 4 cases, and 3 in 2 cases (P < .05). Importantly, MRI signal intensity at the repaired menisci near the joint capsule was reduced in 8 of these 9 cases postoperatively. The inter-leaf vertical suture procedure is associated with good outcomes for horizontal tears in the middle and posterior segments of the medial and lateral menisci. The procedure is useful and convenient.

Background While cartilage can be formed from induced pluripotent stem cells (iPSCs), challenges such as long culture periods and compromised tissue purity remain. We aimed to determine whether cartilaginous tissue can be produced from iPSCs under hypoxia and to evaluate the effects on the cellular metabolism and purity of the tissue.Methods Human iPSCs (hiPSCs) were cultured for cartilage differentiation in monolayers under normoxia or hypoxia (5% O 2 ). We evaluated chondrocyte differentiation by real-time reverse transcription-polymerase chain reaction and fluorescence-activated cell sorting. Then, hiPSCs were cultured for cartilage differentiation in 3D culture under normoxia or hypoxia (5% O 2 ). We evaluated cartilage-like tissues on days 28 and 56 through histological analyses.ResultsHypoxia suppressed the expression of immature mesodermal markers T ( Brachyury ) and Forkhead box protein F1 ( FOXF1) and promoted the expression of the chondrogenic markers aggrecan and CD44 . Sex determining region Y- box (SOX) 9-positive cells were increased by culture under hypoxia. Percentages of safranin O-positive and type 2 collagen-positive tissues were increased under hypoxia. Moreover, upon hypoxia-inducible factor (HIF)-1α staining, the nuclear dyeability in tissues cultured under hypoxia was greater than that under normoxia.Conclusions Hypoxia not only led to enhanced cartilage matrix production but also improved cell purity by promoting the expression of HIF-1α . By applying this method, highly pure cartilaginous-like tissues may be produced more rapidly and conveniently.

Intervertebral discs are important for maintaining mobility and offer support to the body trunk. If these discs lose their biomechanical features, lower back pain can occur. We previously reported that hepatocyte growth factor (HGF) promotes cell proliferation and suppresses apoptosis, inflammation, and matrix degradation in nucleus pulposus (NP) cells. In the present study, we investigated the molecular mechanisms of how HGF promotes the proliferation of NP cells in hypoxic conditions. Hypoxic stimulation promoted modest cell proliferation, which was further upregulated by HGF. Expression of hypoxia inducible factor (HIF‐1α) protein, which contributes to the maintenance of homeostasis in NP cells, was also upregulated in hypoxia‐treated cells groups; HGF further increased HIF‐1α expression in NP cells. Additionally, knockdown of HIF‐1α expression significantly reduced the proliferation of NP cells. A MAPK inhibitor inhibited the expression of HIF‐1α and pERK, as well as and cell proliferation in a dose‐dependent manner. Similarly, inhibiting the PI3K/Akt and STAT3 pathways also decreased the expression HIF‐1α and cell proliferation. These results show that under hypoxic conditions, HGF promotes NP cell proliferation via HIF‐1α, and MAPK, PI3K/Akt, and STAT3 mediated signaling is involved in this pathway. The control of these signaling pathways may be a target for potential therapeutic strategies for the treatment of disc degeneration in hypoxic conditions. This article is protected by copyright. All rights reserved.

Purpose In total knee arthroplasty (TKA), various landmarks are generally used to ensure correct osteotomy. In this study, we examined whether the tibialis anterior tendon (TAT) or the extensor hallucis longus tendon (EHLT) could be used as a landmark of the center of the ankle joint in patients with knee osteoarthrosis (OA), using magnetic resonance imaging (MRI). Methods The subjects were 61 patients with OA in 79 knees (males: 8 with 9 knees and females: 53 with 70 knees). With the ankle joint secured in the intermediate position, MRI from the knee joint to the ankle joint was performed in the same foot position. We prepared individual lines connecting the center of the ankle joint with the TAT or EHLT to measure the angle difference (ΔA) from Akagi’s line in the knee joint. We analyzed whether the ΔA might be affected by deformity of the knee joint or foot region, and tibial torsion. Results At the ankle joint level, the ΔA of EHLT was the smallest, with an average of 1.6 ± 3.4°. The ΔA for the femorotibial angle, hallux valgus angle, and varus–valgus angle showed no correlations with deformity of the knee joint and foot region, or tibial torsion. Conclusions MRI findings showed that EHLT would be useful as a landmark of the ankle joint center in extramedullary tibial osteotomy in TKA for medial knee OA. It was also clarified that the landmark would not be affected by severe deformity of the knee joint, deformity of the foot region, or external torsion of the tibia.