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Background/Objectives: Abnormalities in cerebrospinal fluid (CSF) dynamics cause diverse conditions, such as hydrocephalus, but the underlying mechanism is still unknown. Methods to study CSF dynamics in small animals have not been established due to the lack of an evaluation system. Therefore, the purpose of this research study is to establish the time-spatial labeling inversion pulse (Time-SLIP) MRI technique for the evaluation of CSF dynamics in mice. Methods: We performed the Time-SLIP technique on 10 wild-type mice and 20 Tiptoe-walking Yoshimura (TWY) mice, a mouse model of ossification of the posterior longitudinal ligament (OPLL). We defined the stir distance as the distance of CSF stirring and calculated the mean ± standard deviation. The intraclass correlation coefficient of intraobserver reliability was also calculated. Furthermore, in TWY mice, the correlation coefficient between stir distance and canal stenosis ratio (CSR) was calculated. Results: The stir distance was significantly lower in TWY mice at 12 weeks and 17 weeks of age (1.20 ± 0.16, 1.21 ± 0.06, and 1.21 ± 0.15 mm at 12 weeks and 1.32 ± 0.21, 1.28 ± 0.23, and 1.38 ± 0.31 mm at 17 weeks for examiners A, B, and C). The intrarater reliability of the three examiners was excellent (>0.90) and there was a strongly negative correlation between stir distance and CSR in TWY mice (>−0.80). Conclusions: In this study, we established the Time-SLIP technique in experimental mice. This technique allows for a better understanding of CSF dynamics in small laboratory animals. [ABSTRACT FROM AUTHOR]

Romidepsin is an important therapeutic option for patients with peripheral T-cell lymphoma (PTCL). However, the timing of romidepsin administration remains controversial. The objective of this study was to characterize the safety and efficacy of romidepsin as consolidation therapy after gemcitabine, dexamethasone, and cisplatin (GDP) therapy (GDPR). This study of patients treated between March 2019 and March 2021 was registered with the Japan Registry of Clinical Trials (registration number: jRCT0000000519). If complete response, partial response, or stable disease was confirmed after 2–4 GDP cycles, romidepsin was administered every 4 weeks for 1 year. Seven patients with relapsed/refractory (R/R) PTCL (T-follicular helper phenotype [n = 1] and angioimmunoblastic T-cell lymphoma [n = 6]) were included in this prospective study (PTCL-GDPR). After a median follow-up of 34 months of patients in PTCL-GDPR, the 2-year overall survival rate was 71%, and the overall response rate after treatment was 57%. Common adverse events in patients with PTCL-GDPR included hematological toxicities such as neutropenia, which improved with supportive treatment. There were no treatment-related mortalities. GDPR might be safe and effective in elderly transplant-ineligible patients with R/R PTCL; however, further investigation is required. [ABSTRACT FROM AUTHOR]

Background/Objectives: An important aspect of the pathophysiology of frailty seems to be the dysregulation of inflammatory pathways and the coagulation system. However, an objective assessment of the impact of frailty on the recovery from surgery is not fully studied. This study sought to assess how frailty affects the recovery of adult spinal deformity (ASD) surgery using blood biomarkers. Methods: 153 consecutive ASD patients (age 64 ± 10 yr, 93% female) who had corrective spine surgery in a single institution and reached 2y f/u were included. The subjects were stratified by frailty using the modified frailty index-11 (robust [R] group or prefrail and frail [F] group). Results of commonly employed laboratory tests at baseline, 1, 3, 7, and 14 post-operative days (POD) were compared. Further comparison was performed in propensity-score matched-39 paired patients between the groups by age, curve type, and baseline alignment. A correlation between HRQOLs, major complications, and biomarkers was performed. Results: Among the propensity-score matched groups, CRP was significantly elevated in the F group at POD1,3(POD1; 5.3 ± 3.1 vs. 7.9 ± 4.7 p = 0.02, POD3; 6.6 ± 4.6 vs. 8.9 ± 5.2 p = 0.02). Transaminase was also elevated in the F group at POD3(ASD: 36 ± 15 vs. 51 ± 58 U/L, p = 0.03, ALT: 32 ± 16 vs. 47 ± 55 U/L, p = 0.04). Interestingly, moderate correlation was observed between transaminase at POD1 and 2 y SRS22 (AST; function r = −0.37, mental health r = −0.39, satisfaction −0.28, total r = −0.40, ALT; function r = −0.37, satisfaction −0.34, total r = −0.39). Conclusions: Frailty affected the serum CRP and transaminase differently following ASD surgery. Transaminase at early POD was correlated with 2 y HRQOLs. These findings support the hypothesis that there is a specific physiological basis to the frailty that is characterized in part by increased inflammation and that these physiological differences persist. [ABSTRACT FROM AUTHOR]

Featured Application: Prediction of orthopedic implant stability, particularly pedicle screws, as an index comparable to insertion torque. To prevent pedicle screw implant failure, a diagnostic technique that allows surgeons to evaluate implant stability easily, quickly, and quantitatively in clinical orthopedic situations is required. This study aimed to predict the insertion torque equivalent to laboratory-level evaluation accuracy. This serves as an index of the implant stability of pedicle screws placed in cadaveric bone, which relies on laser resonance frequency analyses (L-RFA) when irradiating with two types of lasers. The machine learning analysis was optimized using a dataset with artificial bone as teaching data. In this analysis, many explanatory variables extracted from the laser-induced vibration spectra obtained during an analysis/RFA evaluation were predicted by selecting important variables using the least absolute shrinkage and selection operator and performing a non-linear approximation using support vector regression. It was found that combining both artificial and cadaveric bone data with the bone densities as teaching data dramatically improved the determination coefficient from R2 = −0.144 to R2 = 0.858 as the prediction accuracy and reduced the influence of differences between artificial and cadaveric bones. This technology will contribute to the development of preventive diagnostic technologies that can be used during surgery, which is necessary in order to further advance treatment technologies. [ABSTRACT FROM AUTHOR]

The features of non-neoplastic lesions are often similar to those of intramedullary tumors, and a differential diagnosis is challenging to obtain in some cases. A surgical biopsy, which is performed on highly invasive tumors, should be avoided in cases of non-neoplastic lesions. Therefore, an accurate diagnosis is important prior to treatment. We evaluated 43 patients suspected of having spinal cord tumors and, finally, were diagnosed with non-neoplastic intramedullary lesions via magnetic resonance imaging. The patients commonly presented with myelitis. The patients with non-neoplastic neurological diseases had a significantly shorter symptom duration than those with intramedullary astrocytomas. The proportion of patients with non-neoplastic neurological diseases who presented with lesions at the cervical spinal level and focal lesions on axial imaging but without a spinal cord enlargement was significantly higher than that of patients with intramedullary astrocytomas. The current study aimed to distinguish spinal cord tumors from non-neoplastic intramedullary lesions based on their distinct features. [ABSTRACT FROM AUTHOR]

Epidermal wearable sweat biomarker sensing technologies are likely affected by sweat rate because of the dilution effect and limited measurement methods. However, there is a dearth of reports on the local sweat rate (LSR) monitored in real-time during exercise. This explorative study investigated the feasibility of real-time LSR monitoring and clarified LSR kinetics on the forehead and upper arm during constant-load exercise using a perspiration meter with an airflow compensation system. This observational cross-sectional study included 18 recreationally trained males (mean age, 20.6 ± 0.8 years). LSR on the forehead and upper arm (mg/cm2/min) were measured during a constant-load exercise test at 25% of their pre-evaluated peak power until exhaustion. The LSR kinetics had two inflection points, with a gradual decrease in the incremental slope for each section. After the second flexion point, the LSR slope slightly decreased and was maintained until exhaustion. However, the degree of change varied among the participants. Although the ratio of forehead LSR to upper arm LSR tended to decrease gradually over time, there was little change in this ratio after a second flexion point of LSR in both. These findings suggest possible differences in LSR control between the forehead and upper arm during constant-load exercise to prolonged exhaustion. [ABSTRACT FROM AUTHOR]

We aimed to investigate the risk factors of spontaneous osseous fusion (SOF) of the atlantoaxial joint after closed reduction under general anesthesia followed by halo fixation (remodeling therapy) for chronic atlantoaxial rotatory fixation, and to elucidate the recovery mechanism of the rotatory range of motion (ROM) after halo removal. Twelve patients who underwent remodeling therapy were retrospectively reviewed. Five patients with SOF were categorized as the fusion group and seven patients without SOF as the non-fusion group. Three dimensional CT was used to detect direct osseous contact (DOC) of facet joints before and during halo fixation, while dynamic CT at neutral and maximally rotated head positions was performed to measure rotatory ROM after halo removal. The duration from onset to initial visit was significantly longer (3.2 vs. 5.7 months, p = 0.04), incidence of DOC during halo fixation was higher (0/7 [0%] vs. 4/5 [80%], p = 0.004), and segmental rotatory ROM of Occiput/C1 (Oc/C1) at final follow-up was larger (9.8 vs. 20.1 degrees, p = 0.003) in the fusion group. Long duration from the onset to the initial visit might induce irreversible damage to the articular surface of the affected facet, which was confirmed as DOC during halo fixation and resulted in SOF. Long duration from the onset to the initial visit and DOC during halo fixation could be used to suggest the risk for SOF. Nonetheless, rotatory ROM of Oc/C1 increased to compensate for SOF. [ABSTRACT FROM AUTHOR]

Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo. [ABSTRACT FROM AUTHOR]

Evaluation of the initial stability of implants is essential to reduce the number of implant failures of pedicle screws after orthopedic surgeries. Laser resonance frequency analysis (L-RFA) has been recently proposed as a viable diagnostic scheme in this regard. In a previous study, L-RFA was used to demonstrate the diagnosis of implant stability of monoaxial screws with a fixed head. However, polyaxial screws with movable heads are also frequently used in practice. In this paper, we clarify the characteristics of the laser-induced vibrational spectra of polyaxial screws which are required for making L-RFA diagnoses of implant stability. In addition, a novel analysis scheme of a vibrational spectrum using L-RFA based on machine learning is demonstrated and proposed. The proposed machine learning-based diagnosis method demonstrates a highly accurate prediction of implant stability (peak torque) for polyaxial pedicle screws. This achievement will contribute an important analytical method for implant stability diagnosis using L-RFA for implants with moving parts and shapes used in various clinical situations. [ABSTRACT FROM AUTHOR]

The increasing number of patients with osteoporosis and sarcopenia is a global concern among countries with progressively aging societies. The high medical costs of treating those patients suggest that prevention rather than treatment is preferable. We enrolled 729 subjects who attended both the second and third surveys of the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. Blood samples were collected from subjects at the second survey, and then a comprehensive metabolomic analysis was performed. It was found that 35 had newly developed osteoporosis at the third survey performed four years later, and 39 were newly diagnosed with sarcopenia at the third survey. In the second survey, we found that serum Gly levels were significantly higher even after adjustment for age, sex, and BMI in subjects with newly developed osteoporosis relative to those who remained osteoporosis-negative during the four-year follow-up. We also show that serum taurine levels were significantly lower at the second survey, even after adjustment for age, sex, and BMI in subjects with newly developed sarcopenia during the four-year follow-up compared with those not diagnosed with sarcopenia at the second or third surveys. Though our sample size and odds ratios were small, increased Gly and decreased taurine levels were found to be predictive of new development of osteoporosis and sarcopenia, respectively, within four years. [ABSTRACT FROM AUTHOR]

Prolonged computer work and smartphone use can cause stiffness of the neck and shoulder muscles, including the trapezius muscle. Hence, muscle hardness quantification is clinically beneficial. The present study aimed to examine the reliability of trapezius muscle hardness measurement using a portable muscle hardness meter and ultrasound strain elastography. Overall, 20 healthy young men participated in this study. Prior to measurement, the participant's subjective symptoms, particularly shoulder muscle stiffness, were rated using an 11-point verbal scale. Furthermore, hardness of the right and left upper trapezius muscles was assessed. In the strain elastography assessment, muscle hardness was evaluated using strain ratio. Results showed that, in quantifying upper trapezius muscle hardness, both portable muscle hardness meter and strain elastography had an excellent intra-tester reliability (>0.9). However, the correlation coefficients between muscle hardness values assessed using a muscle hardness meter and those evaluated with strain elastography did not significantly differ, and the scores for subjective shoulder stiffness did not correspond to muscle hardness values. Therefore, the hardness of the trapezius muscle does not directly reflect the subjective shoulder stiffness. Future studies should thoroughly examine the location of the shoulder stiffness, and check whether it is accompanied by local pain or tenderness. [ABSTRACT FROM AUTHOR]

Bacterial infection of biomaterials is a serious problem in the field of medical devices. It is urgently necessary to develop new biomaterials with bactericidal activity. Antimicrobial peptides and proteins (AMPs), alternative antibacterial agents, are expected to overcome the bacterial resistance. The aim of this study was to develop a new intelligent material in bone tissue engineering based on protamine-loaded hydroxyapatite (protamine/HAp) that uses AMPs rather than antibiotics. It was found that the adsorption of protamine to HAp followed the Langmuir adsorption model and was due to electrostatic and/or hydrophobic interactions. In vitro bacterial adhesion and growth on protamine/HAp was inhibited in a protamine dose-dependent manner. Adherent bacteria exhibited an aberrant morphology for high dosages of protamine/HAp, resulting in the formation of large aggregates and disintegration of the membrane. The released protamine from protamine/HAp also prevented the growth of planktonic bacteria in vitro. However, a high dosage of protamine from powders at loading concentrations over 1000 μg·mL−1 induced a cytotoxic effect in vitro, although those exhibited no apparent cytotoxicity in vivo. These data revealed that protamine/HAp (less than 1000 μg·mL−1) had both antimicrobial activity and biocompatibility and can be applied for bone substitutes in orthopedic fields. [ABSTRACT FROM AUTHOR]

Bacterial adhesion to the calcium phosphate surface is a serious problem in surgery. To prevent bacterial infection, the development of calcium-phosphate cements (CPCs) with bactericidal properties is indispensable. The aim of this study was to fabricate antibacterial CPCs and evaluate their biological properties. Silver-containing tricalcium phosphate (Ag-TCP) microspheres consisting of α/β-TCP phases were synthesized by an ultrasonic spray-pyrolysis technique. The powders prepared were mixed with the setting liquid to fabricate the CPCs. The resulting cements consisting of β-TCP and hydroxyapatite had a porous structure and wash-out resistance. Additionally, silver and calcium ions could be released into the culture medium from Ag-TCP cements for a long time accompanied by the dissolution of TCP. These data showed the bioresorbability of the Ag-TCP cement. In vitro antibacterial evaluation demonstrated that both released and immobilized silver suppressed the growth of bacteria and prevented bacterial adhesion to the surface of CPCs. Furthermore, histological evaluation by implantation of Ag-TCP cements into rabbit tibiae exhibited abundant bone apposition on the cement without inflammatory responses. These results showed that Ag-TCP cement has a good antibacterial property and good biocompatibility. The present Ag-TCP cements are promising for bone tissue engineering and may be used as antibacterial biomaterials. [ABSTRACT FROM AUTHOR]

Background: The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. We examined the efficacy of a small interfering RNA (siRNA) to TNIK and a small-molecule TNIK inhibitor, NCB-0846, for synovial sarcoma. Methods: The expression of TNIK was determined in 20 clinical samples of synovial sarcoma. The efficacy of NCB-0846 was evaluated in four synovial sarcoma cell lines and a mouse xenograft model. Results: We found that synovial sarcoma cell lines with Wnt activation were highly dependent upon the expression of TNIK for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including MYC, and oral administration of NCB-846 induced regression of xenografts established by inoculation of synovial sarcoma cells. Discussion: It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma. [ABSTRACT FROM AUTHOR]

Although several genetic and environmental factors have been identified as risk factors of adolescent idiopathic scoliosis (AIS), the influence of dietary intake has not been elucidated. We evaluated the association between AIS and dietary habits among female students. Junior high school girls aged 12 to 15 years in the Tokyo metropolitan area who underwent a second school screening for scoliosis were recruited. AIS was diagnosed by orthopedic surgeons specializing in scoliosis, using standing whole spine radiography. Students with a Cobb angle of ≥15° were classified into the AIS group, and others were considered healthy controls. Dietary assessment was performed using a validated diet history questionnaire. Dietary intakes were categorized into quintiles based on distribution, and crude and multivariable odds ratios and 95% confidence intervals for AIS for each quintile category of dietary variable were calculated, with the lowest quintile category used as a reference. In total, 2431 subjects were included in the analysis, and 47.8% of them were diagnosed with AIS. None of the selected nutrients or food groups was significantly associated with AIS. In conclusion, dietary habits may not be associated with AIS. [ABSTRACT FROM AUTHOR]

In bone regeneration, there are some important cellular biological processes, such as mineralization, cell organization, and differentiation. In particular, vascularization into regenerative tissues is a key step for the survival of cells and tissues. In this study, to fabricate biomimetic-engineered bone, including vascular networks, we focused on connective tissue growth factor (CTGF), a multifunctional protein which could regulate the extracellular matrix remodeling. By combination with CTGF and hydroxyapatite (HAp) ceramics (2D) or apatite-fiber scaffold (AFS, 3D), we have fabricated bioactive materials. The CTGF-loaded HAp ceramics could enhance the cellular attachment through interaction with integrin and promote actin cytoskeletal reorganization. CTGF-loaded HAp also enhanced the differentiation of osteoblasts by integrin-mediated activation of the signaling pathway. Under co-culture conditions, both osteoblasts and endothelial cells in the CTGF-loaded AFS were stimulated by CTGF, and each cell could penetrate the central region of the scaffold in vitro and in vivo. Direct cell-cell interaction would also improve the functionality of cells in bone formation. These results suggest that coupling between effective optimized scaffold and CTGF with multifunction could provide better mimicking natural bone by stimulation of angiogenesis. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) was first identified as a potent mitogen for mature hepatocytes, and has also gained attention as a strong neurotrophic factor in the central nervous system. We found that during the acute phase of spinal cord injury (SCI) in rats, c-Met, the specific receptor for HGF, increases sharply, while the endogenous HGF up-regulation is relatively weak. Introducing exogenous HGF into the spinal cord by injecting an HGF-expressing viral vector significantly increased the neuron and oligodendrocyte survival, angiogenesis, and axonal regeneration, to reduce the area of damage and to promote functional recovery in rats after SCI. Other recent studies in rodents have shown that exogenously administered HGF during the acute phase of SCI reduces astrocyte activation to decrease glial scar formation, and exerts anti-inflammatory effects to reduce leukocyte infiltration. We also reported that the intrathecal infusion of recombinant human HGF (intrathecal rhHGF) improves neurological hand function after cervical contusive SCI in the common marmoset, a non-human primate. Based on these collective results, we conducted a phase I/II clinical trial of intrathecal rhHGF for patients with acute cervical SCI who showed a modified Frankel grade of A/B1/B2 72 h after injury onset, from June 2014 to May 2018. [ABSTRACT FROM AUTHOR]

Although the external knee adduction moment (KAM) during gait was shown to be a quantitative parameter of medial knee osteoarthritis (OA), it requires expensive equipment and a dedicated large space to measure. Therefore, it becomes a major reason to limit KAM measurement in a clinical environment. The purpose of this study was to estimate KAM using a single inertial measurement unit (IMU) during gait in patients with knee OA. A total of 22 medial knee OA patients (44 knee joints) performed conventional gait analysis using three-dimensional (3D) motion capture system. At the same time, we attached commercial IMUs to six body segments (sternum, pelvis, both thighs, and both shanks), and IMU signals during gait were recorded synchronized with the motion capture system. The peak-to-peak difference of acceleration in the lateral/medial axis immediately after heel contact was defined as the thrust acceleration (TA). We hypothesized that TA would represent the lateral thrust of the knee during the stance phase and correlate with the first peak of KAM. The relationship between the peak KAM and TA of pelvis (R = 0.52, p < 0.001), shanks (R = 0.57, p < 0.001) and thighs (R = 0.49, p = 0.001) showed a significant correlation. The root mean square error (RMSE) of linear regression models of pelvis, shanks, and thighs to estimate KAM were 0.082, 0.079, and 0.084 Nm/(kg·m), respectively. Our newly established parameter TA showed a moderate correlation with conventional KAM. The current study confirmed our hypothesis that a single IMU would predict conventional KAM during gait. Since KAM is known as an indicator for prognosis and severity of knee OA, this new parameter has the potential to become an accessible predictor for medial knee OA instead of KAM.