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BackgroundRecently, it has been reported that older adults with type 2 diabetes mellitus (T2DM) have lower skeletal muscle mass than healthy individuals. Although skeletal muscle mass in older adults with diabetes is occasionally reported, similar reports on young to middle-aged adults are limited. ObjectiveThis study aims to assess the prevalence of skeletal muscle loss in young to middle-aged adults with diabetes, examine the relationship between skeletal muscle loss and physical function in these patients, and examine whether there are differences in these characteristics between men and women. MethodsThis cross-sectional, observational study included patients younger than 65 years with T2DM who were admitted to our hospital between 2014 and 2022 for educational admission for glycemic control and requested rehabilitation by the Department of Metabolic Medicine. The control group consisted of patients who received rehabilitation during their hospitalization at our hospital and did not have diabetes. The main parameters included skeletal muscle mass, muscle strength, physical function, and activities of daily living. ResultsThe prevalence of skeletal muscle mass loss in this study was 18.2% (10/55) in men and 7.7% (4/52) in women. The skeletal muscle mass index (SMI) was 7.7 (SD 0.8) and 8.4 (SD 0.5) for men in the T2DM and control groups, respectively, and 7.0 (SD 0.9) and 6.8 (SD 0.7) for women in the T2DM and control groups, respectively. Therefore, compared with the nondiabetes group, a significant difference was observed in men but not in women (men: P

An aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event associated with a high mortality and morbidity rate. Though numerous medications are used to prevent cerebral vasospasm and vasospasm-related cerebral infarction after aSAH, no effective pharmacological treatment has been established. Clazosentan, a highly selective endothelin receptor type A antagonist, was approved for use in Japan in April 2022 based on results of two pivotal randomized, placebo-controlled phase 3 studies (JapicCTI-163369, JapicCTI-163368). These studies indicated that clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling and clipping. Clazosentan is thus expected to become a “game changer” for improving the neurological prognosis after aSAH. However, other reports indicate that even when clazosentan or nimodipine are administered for prophylaxis against delayed neurological decline, patients treated with increased colloid administration or hypertonic saline (3% sodium chloride) load exhibit poor functional outcome and higher mortality, suggesting that extra fluid and sodium derived from prophylactic colloid administration contribute to negative outcomes after aSAH. Pharmacological treatments such as clazosentan in addition to perioperative management involving delivery of less water and sodium might be crucial for achieving better outcomes than conventional therapy. Based on a literature review, we present here the future perspectives regarding clazosentan and the necessity for modifying management of the water-electrolyte balance by focusing on endothelin-1 and blood–brain barrier disruption.

Abstract Human movements are adjusted by motor adaptation in order to maintain their accuracy. There are two systems in motor adaptation, referred to as explicit or implicit adaptation. It has been suggested that the implicit adaptation is based on the prediction error and has been used in a number of motor adaptation studies. This study aimed to examine the effect of visual memory on prediction error in implicit visuomotor adaptation by comparing visually- and memory-guided reaching tasks. The visually-guided task is thought to be implicit learning based on prediction error, whereas the memory-guided task requires more cognitive processes. We observed the adaptation to visuomotor rotation feedback that is gradually rotated. We found that the adaptation and retention rates were higher in the visually-guided task than in the memory-guided task. Furthermore, the delta-band power obtained by electroencephalography (EEG) in the visually-guided task was increased immediately following the visual feedback, which indicates that the prediction error was larger in the visually-guided task. Our results show that the visuomotor adaptation is enhanced in the visually-guided task because the prediction error, which contributes update of the internal model, was more reliable than in the memory-guided task. Therefore, we suggest that the processing of the prediction error is affected by the task-type, which in turn affects the rate of the visuomotor adaptation.

Abstract Muscle atrophy due to fragility fractures or frailty worsens not only activity of daily living and healthy life expectancy, but decreases life expectancy. Although several therapeutic agents for muscle atrophy have been investigated, none is yet in clinical use. Here we report that bezafibrate, a drug used to treat hyperlipidemia, can reduce immobilization-induced muscle atrophy in mice. Specifically, we used a drug repositioning approach to screen 144 drugs already utilized clinically for their ability to inhibit serum starvation-induced elevation of Atrogin-1, a factor related to muscle atrophy, in myotubes in vitro. Two candidates were selected, and here we demonstrate that one of them, bezafibrate, significantly reduced muscle atrophy in an in vivo model of muscle atrophy induced by leg immobilization. In gastrocnemius muscle, immobilization reduced muscle weight by an average of ~ 17.2%, and bezafibrate treatment prevented ~ 40.5% of that atrophy. In vitro, bezafibrate significantly inhibited expression of the inflammatory cytokine Tnfa in lipopolysaccharide-stimulated RAW264.7 cells, a murine macrophage line. Finally, we show that expression of Tnfa and IL-1b is induced in gastrocnemius muscle in the leg immobilization model, an activity significantly antagonized by bezafibrate administration in vivo. We conclude that bezafibrate could serve as a therapeutic agent for immobilization-induced muscle atrophy.

Abstract Osteosarcoma is rare but is the most common bone tumor. Diagnostic tools such as magnetic resonance imaging development of chemotherapeutic agents have increased the survival rate in osteosarcoma patients, although 5-year survival has plateaued at 70%. Thus, development of new treatment approaches is needed. Here, we report that IL-17, a proinflammatory cytokine, increases osteosarcoma mortality in a mouse model with AX osteosarcoma cells. AX cell transplantation into wild-type mice resulted in 100% mortality due to ectopic ossification and multi-organ metastasis. However, AX cell transplantation into IL-17-deficient mice significantly prolonged survival relative to controls. CD4-positive cells adjacent to osteosarcoma cells express IL-17, while osteosarcoma cells express the IL-17 receptor IL-17RA. Although AX cells can undergo osteoblast differentiation, as can patient osteosarcoma cells, IL-17 significantly inhibited that differentiation, indicating that IL-17 maintains AX cells in the undifferentiated state seen in malignant tumors. By contrast, IL-17RA-deficient mice transplanted with AX cells showed survival comparable to wild-type mice transplanted with AX cells. Biopsy specimens collected from osteosarcoma patients showed higher expression of IL-17RA compared to IL-17. These findings suggest that IL-17 is essential to maintain osteosarcoma cells in an undifferentiated state and could be a therapeutic target for suppressing tumorigenesis.

Abstract Lumbar spinal stenosis (LSS) is a degenerative disease characterized by intermittent claudication and numbness in the lower extremities. These symptoms are caused by the compression of nerve tissue in the lumbar spinal canal. Ligamentum flavum (LF) hypertrophy and spinal epidural lipomatosis in the spinal canal are known to contribute to stenosis of the spinal canal: however, detailed mechanisms underlying LSS are still not fully understood. Here, we show that surgically harvested LFs from LSS patients exhibited significantly increased thickness when transthyretin (TTR), the protein responsible for amyloidosis, was deposited in LFs, compared to those without TTR deposition. Multiple regression analysis, which considered age and BMI, revealed a significant association between LF hypertrophy and TTR deposition in LFs. Moreover, TTR deposition in LF was also significantly correlated with epidural fat (EF) thickness based on multiple regression analyses. Mesenchymal cell differentiation into adipocytes was significantly stimulated by TTR in vitro. These results suggest that TTR deposition in LFs is significantly associated with increased LF hypertrophy and EF thickness, and that TTR promotes adipogenesis of mesenchymal cells. Therapeutic agents to prevent TTR deposition in tissues are currently available or under development, and targeting TTR could be a potential therapeutic approach to inhibit LSS development and progression.

Background: Superior migration of the humeral head is common in large and massive rotator cuff tears (RCTs). Humeral heads migrate superiorly according to an increase in the RCT size; however, the relevance of the remaining cuff has not been elucidated. This study investigated the relation between superior migration of the humeral head and the remaining rotator cuff, especially the teres minor (TM) and subscapularis (SSC), in RCTs involving tears and atrophy of the infraspinatus (ISP). Methods: Plain anteroposterior radiographic and magnetic resonance imaging examinations were performed on 1345 patients between January 2013 and March 2018. A total of 188 shoulders with tears of the supraspinatus and ISP with atrophic ISP were evaluated. Gradings of superior migration of the humeral head and osteoarthritic change were evaluated using the acromiohumeral interval, Oizumi classification, and Hamada classification on plain anteroposterior radiographs. The cross-sectional area of the remaining rotator cuff muscles was evaluated using oblique sagittal magnetic resonance imaging. The TM was classified as hypertrophic (H) and normal and atrophic (NA). The SSC was classified as nonatrophic (N) and atrophic (A). All shoulders were classified as groups A (H-N), B (NA-N), C (H-A), and D (NA-A). Age- and sex-matched patients with no cuff tears were also enrolled (control). Results: The acromiohumeral intervals of the control group and groups A-D were 11.4 ± 2.4, 9.5 ± 3.8, 7.8 ± 4.1, 7.2 ± 4.0, and 5.4 ± 3.5 mm (84, 74, 64, 21, and 29 shoulders, respectively), with significant differences between groups A and D (P

Introduction: Exercise tolerance, an important factor affecting life prognosis and rehospitalization in patients with chronic heart failure, is a major outcome of cardiac rehabilitation. Heart failure with preserved ejection fraction (HFpEF) from reduced diastolic capacity has recently increased among patients with chronic heart failure. This study evaluated and clarified the factors indicating exercise tolerance in patients with HFpEF from various perspectives, including cardiac and skeletal muscle functions. Material and Methods: The subjects were 31 patients with HFpEF who underwent cardiac rehabilitation. Exercise tolerance was assessed using a 6-minute walking test. Physical function, physical activity, body composition test, baseline characteristics, blood data, and echocardiography results were extracted from medical records to identify the indicators of exercise tolerance. Results: Gait speed was significantly different in exercise tolerance for HFpEF patients (β=0.75, p

Abstract The purpose of the current study was to clarify the effect of eccentricity on visual motion prediction using a time‐to‐contact (TTC) task. TTC indicates the predictive ability to accurately estimate the time‐to‐contact of a moving object based on visual motion perception. We also measured motion reaction time (motion RT) as an indicator of the speed of visual motion perception. The TTC task was to press a button when the moving target would arrive at the stationary goal. In the occluded condition, the target dot was occluded 500 ms before the time to contact. The motion RT task was to press a button as soon as the target moved. The visual targets were randomly presented at five different eccentricities (4°, 6°, 8°, 10°, 12°) and moved on a circular trajectory at a constant tangent velocity (8°/s) to keep the eccentricity constant. Our results showed that TTC in the occluded condition showed an earlier response as the eccentricity increased. Furthermore, the motion RT became longer as the eccentricity increased. Therefore, it is most likely that a slower speed perception in peripheral vision delays the perceived speed of motion onset and leads to an earlier response in the TTC task.

Abstract Currently, implants are utilized clinically for bone transplant procedures. However, if infectious osteomyelitis occurs at implant sites, removal of bacteria can be challenging. Moreover, altered blood flow at peri-implant infectious sites can create an anaerobic environment, making it more difficult to treat infection with antibiotics. Thus, it would be beneficial if implants could be modified to exhibit antibacterial activity, even in anaerobic conditions. Here, we show antibacterial activity of silver ions coated on titanium rods, even against the anaerobic bacteria Porphyromonas gingivalis (P. gingivalis), both in vitro and in vivo. Specifically, we implanted silver-coated or control uncoated titanium rods along with P. gingivalis in mouse femoral bone BM cavities and observed significantly inhibited P. gingivalis infection with silver-coated compared with non-coated rods, based on in vivo bio-imaging. Osteonecrosis by infectious osteomyelitis and elevation of the inflammatory factors C-reactive protein and IL-6 promoted by P. gingivalis s were also significantly reduced in the presence of silver-coated rods. Overall, our study indicates that silver ion coating of an implant represents a therapeutic option to prevent associated infection, even in anaerobic conditions or against anaerobic bacteria.

Introduction: Although patients with diffuse idiopathic skeletal hyperostosis (DISH) do not have low bone density, it is a risk factor for spine fractures associated with DISH. We investigated the characteristics and bone metabolism markers of patients with DISH having low bone density to assess whether osteoporosis medication is necessary to prevent fractures. Methods: A cross-sectional study was conducted between April 1, 2008, and March 31, 2019. The 86 patients included were divided into two groups according to their T-scores―one group had low bone density and DISH, and the other group did not. Group A (T-score−1) and B (T-score>−1) data were adjusted for confounding factors and compared for differences in age, body weight, maximum number of vertebral bodies with bony bridges between adjacent vertebrae (max VB), and previous history (hypertension, malignant tumors, diabetes mellitus, cardiac diseases, chronic renal failure, and spinal fractures). In Group A, multiple linear regression was used to investigate relationships among max VB, femur bone mineral density (BMD), total type I procollagen N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Results: Group A had 36, and Group B had 50 male patients with DISH. Patients in Group B were heavier than those in Group A. The mean femur BMD in Group A was age-appropriate, and that in Group B was higher than the age-appropriate femur BMD. The mean values of P1NP and TRACP-5b were within the normal range. Max VB was positively correlated with total P1NP in Group A. Total P1NP was significantly and positively correlated with TRACP-5b. Conclusions: The DISH group with a T-score of −1 was age-appropriate. The group with a T-score of >−1 had higher BMD because of their higher body weight. The group with a T-score of −1 had good bone metabolism and did not require aggressive osteoporosis treatment.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Abstract Background and purpose An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na+/K+-ATPase (ATP1α3). Methods Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet. Results Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p

Study Design Cross-sectional study. Purpose To examine whether the number of continuous vertebral bone bridges and bone mineral density (BMD) influence the fracture risk in diffuse idiopathic skeletal hyperostosis (DISH) patients. Overview of Literature Bone bridges connecting through the intervertebral body in DISH create long lever arms that can increase the risk of fractures from minor trauma. DISH patients have a BMD that is higher than or comparable to those of age-matched healthy subjects. Methods We examined the computed tomography scans from the thoracic vertebra to the sacrum used to diagnose DISH in 140 patients (98 men and 42 women; average age, 78.6 years). We compared patients who did (n=52) and did not have (n=88) fractures at the continuous vertebral bodies fused by bone bridges. The relationship between the vertebral fractures and the maximum number of vertebrae that are bony cross-linked with contiguous adjacent vertebrae (max VB) from the thoracic vertebra to the sacrum or from the lumbar vertebra to the sacrum and proximal femur BMD were analyzed using a logistic regression model. Results We found that after adjusting for the confounding factors, higher max VB, both from the thoracic vertebrae to the sacrum and the lumbar vertebrae to the sacrum, was associated with a higher risk of vertebral fractures. This difference was statistically significant. The risk was higher when only the lumbar vertebrae to the sacrum was considered (thoracic vertebrae to the sacrum: odds ratio, 1.21; p

Abstract Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

Abstract The smooth pursuit system has the ability to perform predictive feedforward control of eye movements. This study attempted to examine how stimulus and behavioral histories of past trials affect the control of predictive pursuit of target motion with randomized velocities. We used sequential ramp stimuli where the rightward velocity was fixed at 16 deg/s while the leftward velocity was either fixed (predictable) at one of seven velocities (4, 8, 12, 16, 20, 24, or 28 deg/s) or randomized (unpredictable). As a result, predictive pursuit responses were observed not only in the predictable condition but also in the unpredictable condition. Linear mixed-effects (LME) models showed that both stimulus and behavioral histories of the previous two or three trials influenced the predictive pursuit responses in the unpredictable condition. Intriguingly, the goodness of fit of the LME model was improved when both historical effects were fitted simultaneously rather than when each type of historical data was fitted alone. Our results suggest that predictive pursuit systems allow us to track randomized target motion using weighted averaging of the information of target velocity (stimulus) and motor output (behavior) in past time sequences.

Abstract Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.

Abstract Background Mechanical overload applied on the articular cartilage may play an important role in the pathogenesis of osteoarthritis. However, the mechanism of chondrocyte mechanotransduction is not fully understood. The purpose of this study was to assess the effects of compressive mechanical stress on interleukin-1 receptor (IL-1R) and matrix-degrading enzyme expression by three-dimensional (3D) cultured ATDC5 cells. In addition, the implications of transient receptor potential vanilloid 4 (TRPV4) channel regulation in promoting effects of compressive mechanical loading were elucidated. Methods ATDC5 cells were cultured in alginate beads with the growth medium containing insulin-transferrin-selenium and BMP-2 for 6 days. The cultured cell pellet was seeded in collagen scaffolds to produce 3D-cultured constructs. Cyclic compressive loading was applied on the 3D-cultured constructs at 0.5 Hz for 3 h. The mRNA expressions of a disintegrin and metalloproteinases with thrombospondin motifs 4 (ADAMTS4) and IL-1R were determined with or without compressive loading, and effects of TRPV4 agonist/antagonist on mRNA expressions were examined. Immunoreactivities of reactive oxygen species (ROS), TRPV4 and IL-1R were assessed in 3D-cultured ATDC5 cells. Results In 3D-cultured ATDC5 cells, ROS was induced by cyclic compressive loading stress. The mRNA expression levels of ADAMTS4 and IL-1R were increased by cyclic compressive loading, which was mostly prevented by pyrollidine dithiocarbamate. Small amounts of IL-1β upregulated ADAMTS4 and IL-1R mRNA expressions only when combined with compressive loading. TRPV4 agonist suppressed ADAMTS4 and IL-1R mRNA levels induced by the compressive loading, whereas TRPV4 antagonist enhanced these levels. Immunoreactivities to TRPV4 and IL-1R significantly increased in constructs with cyclic compressive loading. Conclusion Cyclic compressive loading induced mRNA expressions of ADAMTS4 and IL-1R through reactive oxygen species. TRPV4 regulated these mRNA expressions, but excessive compressive loading may impair TRPV4 regulation. These findings suggested that TRPV4 regulates the expression level of IL-1R and subsequent IL-1 signaling induced by cyclic compressive loading and participates in cartilage homeostasis.

Abstract Pain is an undesirable sensory experience that can induce depression and limit individuals’ activities of daily living, in turn negatively impacting the labor force. Affected people frequently feel pain during activity; however, pain is subjective and difficult to judge objectively, particularly during activity. Here, we developed a system to objectively judge pain levels in walking subjects by recording their quantitative electroencephalography (qEEG) and analyzing data by machine learning. To do so, we enrolled 23 patients who had undergone total hip replacement for pain, and recorded their qEEG during a five-minute walk via a wearable device with a single electrode placed over the Fp1 region, based on the 10–20 Electrode Placement System, before and three months after surgery. We also assessed subject hip pain using a numerical rating scale. Brain wave amplitude differed significantly among subjects with different levels of hip pain at frequencies ranging from 1 to 35 Hz. qEEG data were also analyzed by a support vector machine using the Radial Basis Functional Kernel, a function used in machine learning. That approach showed that an individual’s hip pain during walking can be recognized and subdivided into pain quartiles with 79.6% recognition Accuracy. Overall, we have devised an objective and non-invasive tool to monitor an individual’s pain during walking.

Introduction: When spinal fracture occurred in ankylosing spinal disorder (ASD) patients, it is important to evaluate not only the long lever arm but also bone density and bone quality for the determination of treatment strategies. This case-controlled study examined bone mineral density (BMD), bone metabolism markers, and pentosidine levels in patients with ASD. Methods: Subjects with bridging of minimum four contiguous vertebral bodies were classified into ASD group and the rest into non-ASD group. The former was further divided into two subgroups based on the presence/absence of sacroiliac joint ankylosis (SJA). We compared BMD, bone metabolism markers, and pentosidine levels in these groups. Results: The BMD T and Z scores of the femur proximal extremity were lower in the ASD with SJA group than those in the ASD without SJA group. When groups were matched for age, weight, and eGFR, compared with the non-ASD group, the ASD with SJA group had lower BMD of the lumbar spine and femur proximal extremity and the ASD without SJA group had significantly higher BMDs of the lumbar spine and femur proximal extremity. After matching, the ASD without SJA group showed a significantly higher pentosidine level than the non-ASD group. Conclusions: Patients with SJA have low femur proximal extremity BMD, whereas those with ASD without SJA have a higher BMD of the femur proximal extremity with high pentosidine level. Investigating the presence or absence of SJA is important for the determination of treatment strategies in fractured ASD patients.

Background: Although mechanical thrombectomy is a standard endovascular therapy for patients with acute ischemic stroke (AIS), the incidence of and risk factors for contrast-induced nephropathy (CIN) following mechanical thrombectomy are infrequently reported. Objectives: The aim of this study was to investigate the incidence and risk factors for CIN following mechanical thrombectomy for AIS, and whether the incidence of CIN is related to a poor prognosis. Methods: We examined consecutive patients who underwent a mechanical thrombectomy in the period from January 2014 to March 2018. The patients’ clinical backgrounds, treatments, and clinical prognoses were analyzed. CIN was defined as an increase in the serum creatinine level of ≥44.2 μmol/L (0.5 mg/dL) or 25% above baseline within 72 h after exposure to the contrast medium. Results: In total, 80 patients (46 men and 34 women aged 74.5 ± 11.5 years) who met our inclusion criteria were analyzed. CIN occurred in 8.8% (7/80) of the patients following mechanical thrombectomy. Although no patients needed permanent dialysis, 1 required temporary dialysis. The median amount of contrast medium was 109 mL. A comparison between the groups with and without CIN showed a significant difference in white blood cell (WBC) count at the time of admission (11.6 ± 2.7 × 103/μL and 8.1 ± 2.7 × 103/μL; p < 0.01) and the cut-off value was 9.70 × 103/μL. In multivariate analysis, contrast volume/estimated glomerular filtration rate by creatinine and WBC count were significantly associated with the incidence of CIN, with odds ratios of 1.64 (95% CI 1.02–2.65; p = 0.04) and 1.61 (95% CI 1.15–2.25; p < 0.01), respectively. Conclusions: This study found that CIN occurred in 8.8% of patients with AIS following mechanical thrombectomy. High WBC count was associated with an increased risk of CIN and may be helpful for predicting CIN.

ABSTRACT We investigated the role of hematopoietically expressed homeobox protein (Hhex) in osteoclast development. Trimethylation of lysine 27 of histone H3 at the cis‐regulatory element of Hhex was maintained and that of lysine 4 was reduced during receptor activator of nuclear factor κB ligand (RANKL)‐induced osteoclastogenesis, which was associated with a reduction of Hhex expression. Overexpression of Hhex in bone marrow–derived macrophages inhibited, whereas Hhex suppression promoted, RANKL‐induced osteoclastogenesis in vitro. Conditional deletion of Hhex in osteoclast‐lineage cells promoted osteoclastogenesis and reduced cancellous bone volume in mice, confirming the negative regulatory role of Hhex in osteoclast differentiation. Expression of cyclin‐dependent kinase inhibitors such as Cdkn2a and Cdkn1b in osteoclast precursors was negatively regulated by Hhex, and Hhex deletion increased the ratio of cells at the G1 phase of the cell cycle. In conclusion, Hhex is an inhibitor of osteoclast differentiation that is regulated in an epigenetic manner and regulates the cell cycle of osteoclast precursors and the skeletal homeostasis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background and Purpose: Little attention has been paid to the pathogenesis of in-hospital stroke, despite poor outcomes and a longer time from stroke onset to treatment. We studied the pathophysiology and biomarkers for detecting patients who progress to in-hospital ischemic stroke (IHS). Methods: Seventy-nine patients with IHS were sequentially recruited in the period 2011–2017. Their characteristics, care, and outcomes were compared with 933 patients who had an out-of-hospital ischemic stroke (OHS) using a prospectively collected database of the Tokushima University Stroke Registry. Results: Active cancer and coronary artery disease were more prevalent in patients with IHS than in those with OHS (53.2 and 27.8% vs. 2.0 and 10.9%, respectively; p < 0.001), the median onset-to-evaluation time was longer (300 vs. 240 min; p = 0.015), and the undetermined etiology was significantly higher (36.7 vs. 2.4%; p < 0.001). Although there was no significant difference in stroke severity at onset between the groups, patients with IHS had higher modified Rankin Scale (mRS) scores (3–6) at discharge (67.1 vs. 50.3%; p = 0.004) and rates of death during hospitalization (16.5 vs. 2.9%; p < 0.001). D-dimer (5.8 vs. 0.8 µg/mL; p < 0.001) and fibrinogen (532 vs. 430 mg/dL; p = 0.014) plasma levels at the time of onset were significantly higher in patients with IHS after propensity score matching. Multivariate logistic regression analysis revealed that active cancer (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.26–4.20), prestroke mRS scores 3–5 (OR 6.78; 95% CI 3.96–11.61), female sex (OR 1.57; 95% CI 1.19–2.08), and age ≥75 years (OR 2.36; 95% CI 1.80–3.08) were associated with poor outcomes. Conclusions: Patients with IHS had poorer outcomes than those with OHS because of a higher prevalence of active cancer and functional dependence before stroke onset. Elevated plasma levels of D-dimer and fibrinogen, especially with active cancer, can help identify patients who are at a higher risk of progression to IHS.

Abstract The purpose of this study was to determine whether smooth pursuit eye movements affect visual motion prediction using a time‐to‐contact task where observers anticipate the exact instant that a partially occluded target would coincide with a stationary object. Moreover, we attempted to clarify the influence of second‐order motion on visual motion prediction during smooth pursuit. One target object moved to another stationary object (6 deg apart) at constant velocity of 3, 4, and 5 deg/s, and then the two objects disappeared 500 ms after the onset of target motion. The observers estimated the moment the moving object would overlap the stationary object and pressed a button. For the pursuit condition, both a Gaussian window and a random dots texture moved in the same direction at the same speed for the first‐order motion, whereas a Gaussian window moved over a static background composed of random dots texture for the second‐order motion. The results showed that the constant error of the time‐to‐contact shifted to a later response for the pursuit condition compared to the fixation condition, regardless of the object velocity. In addition, during smooth pursuit, the constant error for the second‐order motion shifted to an earlier response compared to the first‐order motion when the object velocity was 3 deg/s, whereas no significant difference was found at 4 and 5 deg/s. Therefore, our results suggest that visual motion prediction using a time‐to‐contact task is affected by both eye movements and motion configuration such as second‐order motion.

Bisphosphonates and the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab are effective anti-resorptive drugs commonly prescribed for osteoporosis. Both drugs may, however, have intolerable side effects; so, it is critical to examine their residual efficacy such as maintenance of bone mass following cessation. Therefore, we compared the changes in bone histology following discontinuation of the aminobisphosphonate risedronate and anti-RANKL antibody in ovariectomized (OVX) mice. Twelve-week-old female C57BL/6 N mice were OVX or sham operated. Four weeks after surgery, mice were treated with vehicle, a single injection of anti-RANKL antibody (5 mg/kg), or risedronate (5 μg/kg/day, s.c.) for 4 weeks (the treatment period), followed by vehicle treatment for an additional 4 weeks (discontinuation period). The lumbar spine and proximal tibia were evaluated by micro-computed tomography. In addition, the lumbar spine, proximal tibia, and the femoral shaft were examined by bone histomorphometry. After 4 weeks of discontinuation, OVX mice initially treated with the anti-RANKL antibody exhibited a trend of bone loss associated with increased turnover in both trabecular and cortical bones, although the difference was not significant. By contrast, OVX mice treated with risedronate exhibited maintained or even increased bone mass and suppressed bone turnover. Patients discontinuing denosumab should be carefully monitored for recurrent osteoporosis symptoms, and a replacement drug should be considered.

Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Low bone mass and/or pre-existing bone fragility fractures serve as diagnostic criteria in deciding when to start medication for osteoporosis. Although osteoporosis is a metabolic disorder, metabolic markers to predict reduced bone mass are unknown. Here, we show serum metabolomics profiles of women grouped as pre-menopausal with normal bone mineral density (BMD) (normal estrogen and normal BMD; NN), post-menopausal with normal BMD (low estrogen and normal BMD; LN) or post-menopausal with low BMD (low estrogen and low BMD; LL) using comprehensive metabolomics analysis. To do so, we enrolled healthy volunteer and osteoporosis patient female subjects, surveyed them with a questionnaire, measured their BMD, and then undertook a comprehensive metabolomics analysis of sera of the three groups named above. We identified 24 metabolites whose levels differed significantly between NN/LN and NN/LL groups, as well as 18 or 10 metabolites whose levels differed significantly between NN/LN and LN/LL, or LN/LL and NN/LN groups, respectively. Our data shows metabolomics changes represent useful markers to predict estrogen deficiency and/or bone loss. Keywords: Metabolomics, Metabolite, Women, Estradiol, Estrogen, Menopause, Bone mineral density

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 Background Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. Methods Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed. Results During 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERβ, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1β and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERβ and decreased the level of interleukin-1β and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERβ. Conclusions Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.

Abstract Control of phosphate metabolism is crucial to regulate aging in mammals. Klotho is a well-known anti-aging factor that regulates phosphate metabolism: mice mutant or deficient in Klotho exhibit phenotypes resembling human aging. Here we show that ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is required for Klotho expression under phosphate overload conditions. Loss-of-function Enpp1 ttw/ttw mice under phosphate overload conditions exhibited phenotypes resembling human aging and Klotho mutants, such as short life span, arteriosclerosis and osteoporosis, with elevated serum 1,25(OH)2D3 levels. Enpp1 ttw/ttw mice also exhibited significantly reduced renal Klotho expression under phosphate overload conditions, and aging phenotypes in these mice were rescued by Klotho overexpression, a low vitamin D diet or vitamin D receptor knockout. These findings indicate that Enpp1 plays a crucial role in regulating aging via Klotho expression under phosphate overload conditions.

Abstract Hip fracture is the most severe bone fragility fracture among osteoporotic injuries. Family history is a known risk factor for fracture and now included among criteria for osteoporosis diagnosis and treatment; however, genetic factors underlying family history favoring fracture remain to be elucidated. Here we demonstrate that a missense SNP in the ALDH2 gene, rs671 (ALDH2*2), is significantly associated with hip fracture (odds ratio = 2.48, 95% confidence interval: 1.20–5.10, p = 0.021). The rs671 SNP was also significantly associated with osteoporosis development (odds ratio = 2.04, 95% confidence interval: 1.07–3.88, p = 0.040). For analysis we enrolled 92 hip fracture patients plus 48 control subjects without bone fragility fractures with higher than −2.5 SD bone mineral density. We also recruited 156 osteoporosis patients diagnosed as below −2.5 SD in terms of bone mineral density but without hip fracture. Association of rs671 with hip fracture and osteoporosis was significant even after adjustment for age and body mass index. Our results provide new insight into the pathogenesis of hip fracture.

A large number of psychophysical and neurophysiological studies have demonstrated that smooth pursuit eye movements are tightly related to visual motion perception. This could be due to the fact that visual motion sensitive cortical areas such as meddle temporal (MT), medial superior temporal (MST) areas are involved in motion perception as well as pursuit initiation. Although the directional-discrimination and perceived target velocity tasks are used to evaluate visual motion perception, it is still uncertain whether the speed of visual motion perception, which is determined by visuomotor reaction time (RT) to a small target, is related to pursuit initiation. Therefore, we attempted to determine the relationship between pursuit latency/acceleration and the visual motion RT which was measured to the visual motion stimuli that moved leftward or rightward. The participants were instructed to fixate on a stationary target and press one of the buttons corresponding to the direction of target motion as soon as possible once the target starts to move. We applied five different visual motion stimuli including first- and second-order motion for smooth pursuit and visual motion RT tasks. It is well known that second-order motion induces lower retinal image motion, which elicits weaker responses in MT and MST compared to first-order motion stimuli. Our results showed that pursuit initiation including latency and initial eye acceleration were suppressed by second-order motion. In addition, second-order motion caused a delay in visual motion RT. The better performances in both pursuit initiation and visual motion RT were observed for first-order motion, whereas second-order (theta motion) induced remarkable deficits in both variables. Furthermore, significant Pearson's correlation and within-subjects correlation coefficients were obtained between visual motion RT and pursuit latency/acceleration. Our findings support the suggestion that there is a common neuronal pathway involved in both pursuit initiation and the speed of visual motion perception.

A multipotent cell population co-expressing a basic-helix-loop-helix transcription factor scleraxis (Scx) and SRY-box 9 (Sox9) has been shown to contribute to the establishment of entheses (tendon attachment sites) during mouse embryonic development. The present study aimed to investigate the involvement of Scx+/Sox9+ cells in the postnatal formation of fibrocartilaginous entheses and in the healing process after injury, using ScxGFP transgenic mice. We demonstrate that Scx+/Sox9+ cells are localized in layers at the insertion site during the postnatal formation of fibrocartilaginous entheses of supraspinatus tendon until postnatal 3 weeks. Further, these cells were rarely seen at postnatal 6 weeks, when mature fibrocartilaginous entheses were formed. Furthermore, we investigated the involvement of Scx+/Sox9+ cells in the healing process after supraspinatus tendon enthesis injury, comparing the responses of 20- and 3-week-old mice. In the healing process of 20-week-old mice with disorganized fibrovascular tissue in response to injury, a small number of Scx+/Sox9+ cells transiently appeared from 1 week after injury, but they were rarely seen at 4 weeks after injury. Meanwhile, in 3-week-old mice, a thin layer of fibrocartilaginous tissue with calcification was formed at healing enthesis at 4 weeks after injury. From 1 to 2 weeks after injury, more Scx+/Sox9+ cells, widely distributed at the injured site, were seen compared with the 20-week-old mice. At 4 weeks after injury, these cells were located near the surface of the recreated fibrocartilaginous layer. This spatiotemporal localization pattern of Scx+/Sox9+ cells at the injured enthesis in our 3-week-old mouse model was similar to that in postnatal fibrocartilaginous enthesis formation. These findings indicate that Scx+/Sox9+ cells may have a role as entheseal progenitor-like cells during postnatal maturation of fibrocartilaginous entheses and healing after injury in a manner similar to that seen in embryonic development.

The purpose of this study is to obtain better physical understandings of the theoretical thresholds of the insonation acoustic pressure amplitudes for medical diagnostic ultrasound applications. For this purpose, a physical model in terms of non-linear resonance of single bubble volumetric oscillations has been developed, to reproduce the threshold insonation acoustic pressure amplitudes that are numerical solutions of Gilmore's equation. It is confirmed, under the condition of the adiabatic state change of the in-bubble gas with a maximum temperature of 5000 K, the present model well-reproduces the influences of the insonation center frequency, the liquid viscosity and surface tension in a range of 0.5 to 16 MHz, 0.0 to 8.0 mPa･s, and 30 to 70 mN/s, respectively, on the threshold insonation acoustic pressure amplitudes. Based on this model, a dimensionless physical index of the insonation acoustic pressure amplitude with a threshold value and a set of fundamental dimensionless parameters constituting that index are defined.

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.

Introduction: As an essential factor affecting life prognosis and rehospitalization in patients with chronic heart failure, exercise tolerance is a significant outcome of cardiac rehabilitation. Heart failure with preserved ejection fraction (HFpEF) from reduced diastolic capacity has recently increased among patients with chronic heart failure. This study evaluates the factors indicating exercise tolerance in patients with HFpEF from various perspectives, including cardiac and skeletal muscle functions. Materials and Methods: The subjects were 31 patients with HFpEF who underwent cardiac rehabilitation. The exercise tolerance was assessed using a 6-min walking test. Physical function, physical activity, body composition test, baseline characteristics, blood data, and echocardiography results were extracted from medical records to identify the indicators of exercise tolerance. Results: Gait speed significantly differed in exercise tolerance for HFpEF patients (ß=0.75, P<0.01). Unlike heart failure with reduced ejection fraction (HFrEF), HFpEF was not significantly different in brain natriuretic peptide levels and cardiac function. Conclusion: Gait speed indicates exercise tolerance in HFpEF patients; however, its pathological course differs from heart failure with reduced ejection fraction, suggesting that it is poorly related to brain natriuretic peptide, a biomarker for heart failure and cardiac function. [ABSTRACT FROM AUTHOR]